Natalie L. Rasgon

All Publications

• The researcher's guide to selecting biomarkers in mental health studies. BioEssays : news and reviews in molecular, cellular and developmental biology Verhoeven, J. E., Wolkowitz, O. M., Barr Satz, I., Conklin, Q., Lamers, F., Lavebratt, C., Lin, J., Lindqvist, D., Mayer, S. E., Melas, P. A., Milaneschi, Y., Picard, M., Rampersaud, R., Rasgon, N., Ridout, K., Söderberg Veibäck, G., Trumpff, C., Tyrka, A. R., Watson, K., Wu, G. W., Yang, R., Zannas, A. S., Han, L. K., Månsson, K. N. 2024: e2300246

  Abstract

  Clinical mental health researchers may understandably struggle with how to incorporate biological assessments in clinical research. The options are numerous and are described in a vast and complex body of literature. Here we provide guidelines to assist mental health researchers seeking to include biological measures in their studies. Apart from a focus on behavioral outcomes as measured via interviews or questionnaires, we advocate for a focus on biological pathways in clinical trials and epidemiological studies that may help clarify pathophysiology and mechanisms of action, delineate biological subgroups of participants, mediate treatment effects, and inform personalized treatment strategies. With this paper we aim to bridge the gap between clinical and biological mental health research by (1) discussing the clinical relevance, measurement reliability, and feasibility of relevant peripheral biomarkers; (2) addressing five types of biological tissues, namely blood, saliva, urine, stool and hair; and (3) providing information on how to control sources of measurement variability.

  View details for DOI 10.1002/bies.202300246

  View details for PubMedID 39258367

• Insulin Receptor Substrate in Bipolar 1 and 2 Disorder Kim, B., Watson, K., Rasgon, N. ELSEVIER SCIENCE INC. 2024: S139

  View details for Web of Science ID 001282811900322

• Insulin Receptor Substrate 1 (IRS1) Isolated From Neuronally Derived Exosomes is Associated With Mood State in Bipolar Disorder Robakis, T., Watson, K., Eitan, E., Myoraku, A., Abbasi, F., Biernacka, J. M., Frye, M. A., Rasgon, N. ELSEVIER SCIENCE INC. 2024: S141

  View details for Web of Science ID 001282811900327

• Proteomic profiles of cytokines and chemokines in moderate to severe depression: Implications for comorbidities and biomarker discovery. Brain, behavior, & immunity - health Watson, K. T., Keller, J., Spiro, C. M., Satz, I. B., Goncalves, S. V., Pankow, H., Kosti, I., Lehallier, B., Sequeira, A., Bunney, W. E., Rasgon, N. L., Schatzberg, A. F. 2024; 36: 100731

  Abstract

  Objective: This study assessed the proteomic profiles of cytokines and chemokines in individuals with moderate to severe depression, with or without comorbid medical disorders, compared to healthy controls. Two proteomic multiplex platforms were employed for this purpose.Metods: An immunofluorescent multiplex platform and an aptamer-based method were used to evaluate 32 protein analytes from 153 individuals with moderate to severe major depressive disorder (MDD) and healthy controls (HCs). The study focused on determining the level of agreement between the two platforms and evaluating the ability of individual analytes and principal components (PCs) to differentiate between the MDD and HC groups. Additionally, the study investigated the relationship between PCs consisting of chemokines and cytokines and comorbid inflammatory and cardiometabolic diseases.Findings: Analysis revealed a small or moderate correlation between 47% of the analytes measured by the two platforms. Two proteomic profiles were identified that differentiated individuals with moderate to severe MDD from HCs. High eotaxin, age, BMI, IP-10, or IL-10 characterized profile 1. This profile was associated with several cardiometabolic risk factors, including hypertension, hyperlipidemia, and type 2 diabetes. Profile 2 is characterized by higher age, BMI, interleukins, and a strong negative loading for eotaxin. This profile was associated with inflammation but not cardiometabolic risk factors.Conclusion: This study provides further evidence that proteomic profiles can be used to identify potential biomarkers and pathways associated with MDD and comorbidities. Our findings suggest that MDD is associated with distinct profiles of proteins that are also associated with cardiometabolic risk factors, inflammation, and obesity. In particular, the chemokines eotaxin and IP-10 appear to play a role in the relationship between MDD and cardiometabolic risk factors. These findings suggest that a focus on the interplay between MDD and comorbidities may be useful in identifying potential targets for intervention and improving overall health outcomes.

  View details for DOI 10.1016/j.bbih.2024.100731

  View details for PubMedID 38435722

• Toward a Precision Treatment Approach for Metabolic Depression: Integrating Epidemiology, Neuroscience, and Psychiatry. Biological psychiatry global open science Watson, K., Akil, H., Rasgon, N. 2023; 3 (4): 623-631

  Abstract

  Background: Individuals with comorbid major depressive disorder and type 2 diabetes represent an important subgroup of patients for whom conventional treatment may be insufficient. A precision treatment approach that addresses insulin resistance with an outcome of a positive response to antidepressants may prove beneficial.Methods: This study utilized an emulated target trial on a large dataset from the Optum Clinformatics Data Mart Database. We evaluated the effect of adjuvant pioglitazone, an insulin-sensitizing drug, on antidepressant response among 4696 people with type 2 diabetes, comparing it with DPP4 (dipeptidyl peptidase-4) inhibitors (non-insulin-sensitizing). An additional analysis involving 6518 participants was conducted to assess the efficacy of pioglitazone versus sulfonylureas.Results: The instrumental variable analysis indicated that the initiation of an antidepressant with pioglitazone was superior to DPP4 inhibitors in terms of antidepressant response, with fewer treatment shifts and/or additions of new antidepressant or antipsychotic over a 1-year period. This result was consistent when pioglitazone was compared with sulfonylureas in a supplemental analysis.Conclusions: Our findings suggest that pioglitazone may be more effective than DPP4 inhibitors or sulfonylureas in enhancing antidepressant response among people with comorbid major depressive disorder and type 2 diabetes. This provides a strong case for the use of pioglitazone in patients with these conditions, emphasizing the potential of precision medicine strategies. The results should be interpreted with caution due to inherent limitations associated with observational data.

  View details for DOI 10.1016/j.bpsgos.2023.08.008

  View details for PubMedID 37881556

• Longitudinal Digital Mood Charting in Bipolar Disorder: Experiences with ChronoRecord Over 20 Years. Pharmacopsychiatry Bauer, M., Glenn, T., Alda, M., Grof, P., Bauer, R., Ebner-Priemer, U. W., Ehrlich, S., Pfennig, A., Pilhatsch, M., Rasgon, N., Whybrow, P. C. 2023; 56 (5): 182-187

  Abstract

  INTRODUCTION: Longitudinal study is an essential methodology for understanding disease trajectories, treatment effects, symptom changes, and long-term outcomes of affective disorders. Daily self-charting of mood and other illness-related variables is a commonly recommended intervention. With the widespread acceptance of home computers in the early 2000s, automated tools were developed for patient mood charting, such as ChronoRecord, a software validated by patients with bipolar disorder. The purpose of this study was to summarize the daily mood, sleep, and medication data collected with ChronoRecord, and highlight some of the key research findings. Lessons learned from implementing a computerized tool for patient self-reporting are also discussed.METHODS: After a brief training session, ChronoRecord software for daily mood charting was installed on a home computer and used by 609 patients with affective disorders.RESULTS: The mean age of the patients was 40.3±11.8 years, a mean age of onset was 22±11.2 years, and 71.4% were female. Patients were euthymic for 70.8% of days, 15.1% had mild depression, 6.6% had severe depression, 6.6% had hypomania, and 0.8% had mania. Among all mood groups, 22.4% took 1-2 medications, 37.2% took 3-4 medications, 25.7 took 5-6 medications, 11.6% took 7-8 medications, and 3.1% took >8 medications.CONCLUSION: The daily mood charting tool is a useful tool for increasing patient involvement in their care, providing detailed patient data to the physician, and increasing understanding of the course of illness. Longitudinal data from patient mood charting was helpful in both clinical and research settings.

  View details for DOI 10.1055/a-2156-5667

  View details for PubMedID 37678394

• Prevalence and outcomes of rapid cycling bipolar disorder: Mixed method systematic meta-review. Journal of psychiatric research Miola, A., Fountoulakis, K. N., Baldessarini, R. J., Veldic, M., Solmi, M., Rasgon, N., Ozerdem, A., Perugi, G., Frye, M. A., Preti, A. 2023; 164: 404-415

  Abstract

  Rapid-cycling in bipolar disorder (RC-BD) is associated with greater illness morbidity and inferior treatment response but many aspects remain unclear, prompting this systematic review of its definitions, prevalence, and clinical characteristics. We searched multiple literature databases through April 2022 for systematic reviews or meta-analyses on RC-BD and extracted associated definitions, prevalence, risk-factors, and clinical outcomes. We assessed study quality (NIH Quality Assessment Tool) and levels of evidence (Oxford criteria). Of 146 identified reviews, 22 fulfilling selection criteria were included, yielding 30 studies involving 13,698 BD patients, of whom 3777 (27.6% [CI: 26.8-28.3]) were considered RC-BD, as defined in 14 reports by≥4 recurrences/year within the past 12 months or in any year, without considering responsiveness to treatment. Random-effects meta-analytically pooled one-year prevalence was 22.3% [CI: 14.4-32.9] in 12 reports and lifetime prevalence was 35.5% [27.6-44.3] in 18 heterogenous reports. Meta-regression indicated greater lifetime prevalence of RC-BD among women than men (p=0.003). Association of RC-BD with suicide attempts, and unsatisfactory response to mood-stabilizers was supported by strong evidence (Level 1); associations with childhood maltreatment, mixed-features, female sex, and type-II BD had moderate evidence (Level 2). Other factors: genetic predisposition, metabolic disturbances or hypothyroidism, antidepressant exposure, predominant depressive polarity (Level 3), along with greater illness duration and immune-inflammatory dysfunction (Level 4) require further study. RC-BD was consistently recognized as having high prevalence (22.3%-35.5% of BD cases) and inferior treatment response. Identified associated factors can inform clinical practice. Long-term illness-course, metabolic factors, and optimal treatment require further investigation.

  View details for DOI 10.1016/j.jpsychires.2023.06.021

  View details for PubMedID 37429185

• Exploratory study of ultraviolet B (UVB) radiation and age of onset of bipolar disorder. International journal of bipolar disorders Bauer, M., Glenn, T., Achtyes, E. D., Alda, M., Agaoglu, E., Altinbas, K., Andreassen, O. A., Angelopoulos, E., Ardau, R., Aydin, M., Ayhan, Y., Baethge, C., Bauer, R., Baune, B. T., Balaban, C., Becerra-Palars, C., Behere, A. P., Behere, P. B., Belete, H., Belete, T., Belizario, G. O., Bellivier, F., Belmaker, R. H., Benedetti, F., Berk, M., Bersudsky, Y., Bicakci, S., Birabwa-Oketcho, H., Bjella, T. D., Brady, C., Cabrera, J., Cappucciati, M., Castro, A. M., Chen, W., Cheung, E. Y., Chiesa, S., Crowe, M., Cuomo, A., Dallaspezia, S., Del Zompo, M., Desai, P., Dodd, S., Etain, B., Fagiolini, A., Fellendorf, F. T., Ferensztajn-Rochowiak, E., Fiedorowicz, J. G., Fountoulakis, K. N., Frye, M. A., Geoffroy, P. A., Gitlin, M. J., Gonzalez-Pinto, A., Gottlieb, J. F., Grof, P., Haarman, B. C., Harima, H., Hasse-Sousa, M., Henry, C., Hoffding, L., Houenou, J., Imbesi, M., Isometsa, E. T., Ivkovic, M., Janno, S., Johnsen, S., Kapczinski, F., Karakatsoulis, G. N., Kardell, M., Kessing, L. V., Kim, S. J., Konig, B., Kot, T. L., Koval, M., Kunz, M., Lafer, B., Landen, M., Larsen, E. R., Lenger, M., Licht, R. W., Lopez-Jaramillo, C., MacKenzie, A., Madsen, H. O., Madsen, S. A., Mahadevan, J., Mahardika, A., Manchia, M., Marsh, W., Martinez-Cengotitabengoa, M., Martini, J., Martiny, K., Mashima, Y., McLoughlin, D. M., Meesters, Y., Melle, I., Meza-Urzua, F., Mikolas, P., Mok, Y. M., Monteith, S., Moorthy, M., Morken, G., Mosca, E., Mozzhegorov, A. A., Munoz, R., Mythri, S. V., Nacef, F., Nadella, R. K., Nakanotani, T., Nielsen, R. E., O'Donovan, C., Omrani, A., Osher, Y., Ouali, U., Pantovic-Stefanovic, M., Pariwatcharakul, P., Petite, J., Petzold, J., Pfennig, A., Ruiz, Y. P., Pinna, M., Pompili, M., Porter, R. J., Quiroz, D., Rabelo-da-Ponte, F. D., Ramesar, R., Rasgon, N., Ratta-Apha, W., Ratzenhofer, M., Redahan, M., Reddy, M. S., Reif, A., Reininghaus, E. Z., Richards, J. G., Ritter, P., Rybakowski, J. K., Sathyaputri, L., Scippa, A. M., Simhandl, C., Smith, D., Smith, J., Stackhouse, P. W., Stein, D. J., Stilwell, K., Strejilevich, S., Su, K., Subramaniam, M., Sulaiman, A. H., Suominen, K., Tanra, A. J., Tatebayashi, Y., Teh, W. L., Tondo, L., Torrent, C., Tuinstra, D., Uchida, T., Vaaler, A. E., Vieta, E., Viswanath, B., Yoldi-Negrete, M., Yalcinkaya, O. K., Young, A. H., Zgueb, Y., Whybrow, P. C. 2023; 11 (1): 22

  Abstract

  BACKGROUND: Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about>40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample.METHODS: Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P≤0.001.RESULTS: The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6years. Of the onset locations, 34.0% had at least 1month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66years younger.CONCLUSION: UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

  View details for DOI 10.1186/s40345-023-00303-w

  View details for PubMedID 37347392

• The role of ketogenic therapy in developmental disorders. Journal of psychiatric research Taoulost, S., Rasgon, N., Ferretti, C. J., Hollander, E. 2023; 161: 307-309

  View details for DOI 10.1016/j.jpsychires.2023.03.025

  View details for PubMedID 36989905

• Carnitine octanoyltransferase is important for the assimilation of exogenous acetyl-L-carnitine into acetyl-CoA in mammalian cells. The Journal of biological chemistry Hsu, J., Fatuzzo, N., Weng, N., Michno, W., Dong, W., Kienle, M., Dai, Y., Pasca, A., Abu-Remaileh, M., Rasgon, N., Bigio, B., Nasca, C., Khosla, C. 2022: 102848

  Abstract

  In eukaryotes carnitine is best known for its ability to shuttle esterified fatty acids across mitochondrial membranes for β-oxidation. It also returns to the cytoplasm, in the form of acetyl-L-carnitine (LAC), some of the resulting acetyl groups for post-translational protein modification and lipid biosynthesis. While dietary LAC supplementation has been clinically investigated, its effects on cellular metabolism are not well understood. To explain how exogenous LAC influences mammalian cell metabolism, we synthesized isotope-labeled forms of LAC and its analogs. In cultures of glucose-limited U87MG glioma cells, exogenous LAC contributed more robustly to intracellular acetyl-CoA pools than did β-hydroxybutyrate, the predominant circulating ketone body in mammals. The fact that most LAC-derived acetyl-CoA is cytosolic is evident from strong labeling of fatty acids in U87MG cells by exogenous 13C2-acetyl-L-carnitine. We found that the addition of d3-acetyl-L-carnitine increases the supply of acetyl-CoA for cytosolic post-translational modifications due to its strong kinetic isotope effect on acetyl-CoA carboxylase, the first committed step in fatty acid biosynthesis. Surprisingly, whereas cytosolic carnitine acetyltransferase (CRAT) is believed to catalyze acetyl group transfer from LAC to Coenzyme A, CRAT-/- U87MG cells were unimpaired in their ability to assimilate exogenous LAC into acetyl-CoA. We identified carnitine octanoyltransferase (CROT) as the key enzyme in this process, implicating a role for peroxisomes in efficient LAC utilization. Our work has opened the door to further biochemical investigations of a new pathway for supplying acetyl-CoA to certain glucose-starved cells.

  View details for DOI 10.1016/j.jbc.2022.102848

  View details for PubMedID 36587768

• Insulin Resistance and Accelerated Cognitive Aging Lin, K., Abbasi, F., Robakis, T., Myoraku, A., Satz, I., Rasgon, N. SPRINGERNATURE. 2022: 73-74

  View details for Web of Science ID 000929613800177

• Endophenotypic correlates of cognitive function in reproductive-age individuals with polycystic ovary syndrome. F&S reports Huddleston, H. G., Casaletto, K. B., Jaswa, E. G., Rasgon, N. L., Maki, P. P., Cedars, M. I., Pasch, L. 2022; 3 (4): 372-379

  Abstract

  Objective: To characterize cognitive performance in relation to hormonal and metabolic factors in women with polycystic ovary syndrome (PCOS).Design: Cross-sectional study.Setting: Tertiary university center.Patients: A total of 48 individuals, aged 21-46 years, with PCOS according to the Rotterdam criteria.Interventions: Complete history and physical examinations, endovaginal ultrasounds, dermatologic assessments, neuropsychological assessments, and metabolic and hormonal serum tests.Main Outcome Measures: Sample-based z-scores on a comprehensive cognitive test battery.Results: Subjects were defined as having an androgenic (n = 31) or a nonandrogenic (n = 17) PCOS phenotype. Compared with their nonandrogenized counterparts, subjects with hyperandrogenism demonstrated lower relative performance on the tests of executive function (beta-coefficient for the executive function composite z-score, -0.44; 95% confidence interval, -0.79 to -0.09), despite similar performance on the tests of memory, verbal reasoning, and perceptual reasoning. These differences were independent of age, years of education, and obesity. In an exploratory analysis in which subjects were stratified by the presence of insulin resistance (IR), subjects with PCOS with both IR and hyperandrogenism showed the lowest performance on a composite score of executive function, followed by those with hyperandrogenism alone.Conclusions: In this small study, subjects with hyperandrogenic PCOS demonstrated lower performance on the tests of executive function than subjects with nonandrogenic PCOS. Additional research is needed to confirm these findings in larger cohorts and investigate the role of modifiable factors, including IR, on cognitive outcomes.

  View details for DOI 10.1016/j.xfre.2022.08.008

  View details for PubMedID 36568925

• Insulin Resistance and Accelerated Cognitive Aging Lin, K., Abbasi, F., Robakis, T., Myoraku, A., Satz, I., Rasgon, N. SPRINGERNATURE. 2022: 73-74

  View details for Web of Science ID 000897934700176

• Insulin resistance and accelerated cognitive aging. Psychoneuroendocrinology Abbasi, F., Robakis, T. K., Myoraku, A., Watson, K. T., Wroolie, T., Rasgon, N. L. 2022; 147: 105944

  Abstract

  Insulin resistance may be an early sign of metabolic dysfunction with the potential to lead to neuropsychiatric sequelae in the long term. In order to identify whether insulin resistance in otherwise healthy young and middle-aged adults is associated with preclinical signs of neuropsychiatric impairment, we recruited 126 overweight but nondiabetic, nondepressed individuals who completed an insulin suppression test for direct measurement of insulin resistance as well as a battery of cognitive and neuropsychiatric measures. Insulin resistance was associated with weaker performance on a fine motor task (Purdue Pegboard) as well as increases in subclinical symptoms of depression. We submit that insulin resistance in early to mid-adulthood may be an important predictor of long-term risk for metabolic, psychiatric, and neurobehavioral dysfunction.

  View details for DOI 10.1016/j.psyneuen.2022.105944

  View details for PubMedID 36272362

• Association between polarity of first episode and solar insolation in bipolar I disorder. Journal of psychosomatic research Bauer, M., Glenn, T., Achtyes, E. D., Alda, M., Agaoglu, E., Altinbas, K., Andreassen, O. A., Angelopoulos, E., Ardau, R., Aydin, M., Ayhan, Y., Baethge, C., Bauer, R., Baune, B. T., Balaban, C., Becerra-Palars, C., Behere, A. P., Behere, P. B., Belete, H., Belete, T., Belizario, G. O., Bellivier, F., Belmaker, R. H., Benedetti, F., Berk, M., Bersudsky, Y., Bicakci, S., Birabwa-Oketcho, H., Bjella, T. D., Brady, C., Cabrera, J., Cappucciati, M., Castro, A. M., Chen, W., Cheung, E. Y., Chiesa, S., Crowe, M., Cuomo, A., Dallaspezia, S., Del Zompo, M., Desai, P., Dodd, S., Etain, B., Fagiolini, A., Fellendorf, F. T., Ferensztajn-Rochowiak, E., Fiedorowicz, J. G., Fountoulakis, K. N., Frye, M. A., Geoffroy, P. A., Gonzalez-Pinto, A., Gottlieb, J. F., Grof, P., Haarman, B. C., Harima, H., Hasse-Sousa, M., Henry, C., Hoffding, L., Houenou, J., Imbesi, M., Isometsa, E. T., Ivkovic, M., Janno, S., Johnsen, S., Kapczinski, F., Karakatsoulis, G. N., Kardell, M., Kessing, L. V., Kim, S. J., Konig, B., Kot, T. L., Koval, M., Kunz, M., Lafer, B., Landen, M., Larsen, E. R., Lenger, M., Lewitzka, U., Licht, R. W., Lopez-Jaramillo, C., MacKenzie, A., Madsen, H. O., Madsen, S. A., Mahadevan, J., Mahardika, A., Manchia, M., Marsh, W., Martinez-Cengotitabengoa, M., Martiny, K., Mashima, Y., McLoughlin, D. M., Meesters, Y., Melle, I., Meza-Urzua, F., Mok, Y. M., Monteith, S., Moorthy, M., Morken, G., Mosca, E., Mozzhegorov, A. A., Munoz, R., Mythri, S. V., Nacef, F., Nadella, R. K., Nakanotani, T., Nielsen, R. E., O'Donovan, C., Omrani, A., Osher, Y., Ouali, U., Pantovic-Stefanovic, M., Pariwatcharakul, P., Petite, J., Pfennig, A., Ruiz, Y. P., Pinna, M., Pompili, M., Porter, R., Quiroz, D., Rabelo-da-Ponte, F. D., Ramesar, R., Rasgon, N., Ratta-Apha, W., Ratzenhofer, M., Redahan, M., Reddy, M. S., Reif, A., Reininghaus, E. Z., Richards, J. G., Ritter, P., Rybakowski, J. K., Sathyaputri, L., Scippa, A. M., Simhandl, C., Smith, D., Smith, J., Stackhouse, P. W., Stein, D. J., Stilwell, K., Strejilevich, S., Su, K., Subramaniam, M., Sulaiman, A. H., Suominen, K., Tanra, A. J., Tatebayashi, Y., Teh, W. L., Tondo, L., Torrent, C., Tuinstra, D., Uchida, T., Vaaler, A. E., Vieta, E., Viswanath, B., Yoldi-Negrete, M., Yalcinkaya, O. K., Young, A. H., Zgueb, Y., Whybrow, P. C. 2022; 160: 110982

  Abstract

  OBJECTIVE: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth.METHODS: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer.RESULTS: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001).CONCLUSION: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted.

  View details for DOI 10.1016/j.jpsychores.2022.110982

  View details for PubMedID 35932492

• Family history of diabetes moderates metabolic depression endophenotypes in overweight/obese adults. Journal of psychiatric research Ong, S. L., Abbasi, F., Watson, K., Robakis, T., Myoraku, A., Rasgon, N. 2022; 151: 583-589

  Abstract

  Insulin resistance (IR) is linked to depressive disorders, and there is growing evidence that targeting IR may be beneficial in treating them. We examine the association between depressive symptoms and a direct measure of IR, and whether family history of type 2 diabetes (FHx-T2DM) or major depressive disorder (FHx-MDD) moderate this relationship.Cross-sectional data were collected from 96 primarily overweight/obese adults ages 25-50 without diabetes or clinical depression. Multiple regression and correlation analyses were used to assess the association between depressive symptoms and a direct measure of IR (steady-state plasma glucose) as well as moderating effects of FHx-T2DM or FHx-MDD.In the total sample, elevated depressive symptoms were positively associated with IR (p = 0.005). IR was associated with depressive symptoms in subjects with FHx-T2DM (p = 0.002) or FHx-MDD (p = 0.009) whereas BMI was associated with depressive symptoms in subjects without FHx-T2DM (p = 0.049) or FHx-MDD (p = 0.029). The odds of being in the top tertile of IR increased with elevated depressive symptoms alone (OR, 4.22; 95%CI, 1.15 to 17.33), presence of FHx-T2DM alone (OR, 3.42; 95%CI, 1.26 to 10.00), and presence of both FHx-T2DM and elevated depressive symptoms (OR, 10.08; 95%CI, 1.94 to 96.96).Our findings indicate that depressive symptoms are positively associated with a direct measure of IR in overweight/obese individuals without diabetes or clinical depression. This association is moderated by FHx-T2DM. Early identification of groups vulnerable to IR related to depressive symptomatology may be useful for determining personalized interventions that have the potential to reduce morbidity in later years.

  View details for DOI 10.1016/j.jpsychires.2022.05.018

  View details for PubMedID 35636036

• Maternal attachment insecurity, maltreatment history, and depressive symptoms are associated with broad DNA methylation signatures in infants. Molecular psychiatry Robakis, T. K., Roth, M. C., King, L. S., Humphreys, K. L., Ho, M., Zhang, X., Chen, Y., Li, T., Rasgon, N. L., Watson, K. T., Urban, A. E., Gotlib, I. H. 2022

  Abstract

  The early environment, including maternal characteristics, provides many cues to young organisms that shape their long-term physical and mental health. Identifying the earliest molecular events that precede observable developmental outcomes could help identify children in need of support prior to the onset of physical and mental health difficulties. In this study, we examined whether mothers' attachment insecurity, maltreatment history, and depressive symptoms were associated with alterations in DNA methylation patterns in their infants, and whether these correlates in the infant epigenome were associated with socioemotional and behavioral functioning in toddlerhood. We recruited 156 women oversampled for histories of depression, who completed psychiatric interviews and depression screening during pregnancy, then provided follow-up behavioral data on their children at 18 months. Buccal cell DNA was obtained from 32 of their infants for a large-scale analysis of methylation patterns across 5 × 106 individual CpG dinucleotides, using clustering-based significance criteria to control for multiple comparisons. We found that tens of thousands of individual infant CpGs were alternatively methylated in association with maternal attachment insecurity, maltreatment in childhood, and antenatal and postpartum depressive symptoms, including genes implicated in developmental patterning, cell-cell communication, hormonal regulation, immune function/inflammatory response, and neurotransmission. Density of DNA methylation at selected genes from the result set was also significantly associated with toddler socioemotional and behavioral problems. This is the first report to identify novel regions of the human infant genome at which DNA methylation patterns are associated longitudinally both with maternal characteristics and with offspring socioemotional and behavioral problems in toddlerhood.

  View details for DOI 10.1038/s41380-022-01592-w

  View details for PubMedID 35577912

• Lower functional hippocampal connectivity in healthy adults is jointly associated with higher levels of leptin and insulin resistance. European psychiatry : the journal of the Association of European Psychiatrists Haas, S. S., Myoraku, A., Watson, K., Robakis, T., Frangou, S., Abbasi, F., Rasgon, N. 2022: 1-23

  View details for DOI 10.1192/j.eurpsy.2022.21

  View details for PubMedID 35492025

• Molecular Endophenotypes of Depression: From Computational Approaches to Exosome Biology Bigio, B., Dobbin, J., Mathe, A., Rasgon, N., Nasca, C., McEwen, B. ELSEVIER SCIENCE INC. 2022: S28-S29

  View details for Web of Science ID 000789022200072

• From exosomes to in-vivo Molecular Signatures of Aberrant Brain Mitochondrial Metabolism: Mapping the Signaling From Early Life Stress to Trajectories of Main CNS Diseases Bigio, B., Barnhill, O., Dobbin, J., de Angelis, P., Kautz, M., Lee, F., Murrough, J., Rasgon, N., Nasca, C. ELSEVIER SCIENCE INC. 2022: S28

  View details for Web of Science ID 000789022200070

• Using Computational Approaches for Predictive Models of Antidepressant Response: Integrating Biological Networks With Clinical Outcomes Bigio, B., Barnhill, O., de Angelis, P., Dobbin, J., Watson, K., Rasgon, N., Nasca, C. ELSEVIER SCIENCE INC. 2022: S193

  View details for Web of Science ID 000789022200471

• A novel peripheral biomarker for depression and antidepressant response. Molecular psychiatry Targum, S. D., Schappi, J., Koutsouris, A., Bhaumik, R., Rapaport, M. H., Rasgon, N., Rasenick, M. M. 1800

  Abstract

  In contrast to healthy controls, the heterotrimeric G protein, Gsalpha (Gsalpha) is ensconced predominantly in lipid rafts in subjects with major depressive disorder (MDD) resulting in impaired stimulation of adenylyl cyclase. In this small proof-of-concept study, we examined the hypothesis that translocation of Gsalpha from lipid rafts toward a more facile activation of adenylyl cyclase is a biomarker for clinical response to antidepressants. There were 49 subjects with MDD (HamD17 score ≥15) and 59 healthy controls at the screen visit. The AlphaScreen (PerkinElmer) assay measured both basal activity and prostaglandin E1 (PGE1) stimulation of Gsalpha-adenylyl cyclase to assess the extent of coupling of Gsalpha with adenylyl cyclase. At screen, platelet samples obtained from MDD subjects revealed significantly lower PGE1 activation of adenylyl cyclase activity than controls (p=0.02). Subsequently, 19 consenting MDD subjects completed a 6-week open label antidepressant treatment trial. The 11 antidepressant responders (HamD17 improvement ≥50% from screen) revealed significant increase in PGE1-stimulated adenylyl cyclase compared to non-responders (p=0.05) with an effect size of 0.83 for the PGE1/Gsalpha lipid-raft biomarker. PGE1 stimulation increased by ≥30% from screen assessment in eight responders (72.7%) and two non-responders (25.0%) [Fisher exact=0.07] with a positive predictive value for response of 80.0%. In this small, pilot study, increased PGE1 stimulated adenylyl cyclase was associated with antidepressant response in MDD subjects. These data suggest that a simple, high-throughput-capable assay for depression and antidepressant response can be developed. Future studies are needed to evaluate the utility of this biomarker for the treatment of MDD.

  View details for DOI 10.1038/s41380-021-01399-1

  View details for PubMedID 34969978

• Relevance of Sex Specific Metabolic Phenotypes in Diagnosis and Treatment of Mood Disorders and PTSD PSYCHIATRIC ANNALS Henry, S. S., Ross, R. A., Rasgon, N. 2022; 52 (1): 20-25

  View details for DOI 10.3928/00485713-20211221-01

  View details for Web of Science ID 000747391600005

• Shared genetic influences on depression and menopause symptoms. Psychological medicine Meijsen, J. J., Shen, H., Vemuri, M., Rasgon, N. L., Koenen, K. C., Duncan, L. E. 2021: 1-11

  Abstract

  BACKGROUND: Women experience major depression and post-traumatic stress disorder (PTSD) approximately twice as often as men. Estrogen is thought to contribute to sex differences in these disorders, and reduced estrogen is also known to be a key driver of menopause symptoms such as hot flashes. Moreover, estrogen is used to treat menopause symptoms. In order to test for potential shared genetic influences between menopause symptoms and psychiatric disorders, we conducted a genome-wide association study (GWAS) of estrogen medication use (as a proxy for menopause symptoms) in the UK Biobank.METHODS: The analysis included 232 993 women aged 39-71 in the UK Biobank. The outcome variable for genetic analyses was estrogen medication use, excluding women using hormonal contraceptives. Trans-ancestry GWAS meta-analyses were conducted along with genetic correlation analyses on the European ancestry GWAS results. Hormone usage was also tested for association with depression and PTSD.RESULTS: GWAS of estrogen medication use (compared to non-use) identified a locus in the TACR3 gene, which was previously linked to hot flashes in menopause [top rs77322567, odds ratio (OR) = 0.78, p = 7.7 * 10-15]. Genetic correlation analyses revealed shared genetic influences on menopause symptoms and depression (rg = 0.231, s.e.= 0.055, p = 2.8 * 10-5). Non-genetic analyses revealed higher psychiatric symptoms scores among women using estrogen medications.CONCLUSIONS: These results suggest that menopause symptoms have a complex genetic etiology which is partially shared with genetic influences on depression. Moreover, the TACR3 gene identified here has direct clinical relevance; antagonists for the neurokinin 3 receptor (coded for by TACR3) are effective treatments for hot flashes.

  View details for DOI 10.1017/S0033291721004037

  View details for PubMedID 34865661

• Brain Imaging Correlates of Metabolic Function in Adults Who are Overweight/Obese Myoraku, A., Haas, S., Watson, K., Robakis, T., Frangou, S., Abbasi, F., Schatzberg, A., Rasgon, N. SPRINGERNATURE. 2021: 82-83

  View details for Web of Science ID 000725511400170

• Target Trial Emulation: Evaluating a Treatment for Metabolic Depression Lin, K., Spiro, C., Carta, K., Myoraku, A., Rasgon, N. SPRINGERNATURE. 2021: 240

  View details for Web of Science ID 000725511401036

• Incident Major Depressive Disorder Predicted by Three Measures of Insulin Resistance: A Dutch Cohort Study. The American journal of psychiatry Watson, K. T., Simard, J. F., Henderson, V. W., Nutkiewicz, L., Lamers, F., Nasca, C., Rasgon, N., Penninx, B. W. 2021: appiajp202120101479

  Abstract

  OBJECTIVE: Major depressive disorder is the leading cause of disability worldwide. Yet, there remain significant challenges in predicting new cases of major depression and devising strategies to prevent the disorder. An important first step in this process is identifying risk factors for the incidence of major depression. There is accumulating biological evidence linking insulin resistance, another highly prevalent condition, and depressive disorders. The objectives of this study were to examine whether three surrogate measures of insulin resistance (high triglyceride-HDL [high-density lipoprotein] ratio; prediabetes, as indicated by fasting plasma glucose level; and high central adiposity, as measured by waist circumference) at the time of study enrollment were associated with an increased rate of incident major depressive disorder over a 9-year follow-up period and to assess whether the new onset of these surrogate measures during the first 2 years after study enrollment was predictive of incident major depressive disorder during the subsequent follow-up period.METHODS: The Netherlands Study of Depression and Anxiety (NESDA) is a multisite longitudinal study of the course and consequences of depressive and anxiety disorders in adults. The study population comprised 601 NESDA participants (18-65 years old) without a lifetime history of depression or anxiety disorders. The study's outcome was incident major depressive disorder, defined using DSM-IV criteria. Exposure measures included triglyceride-HDL ratio, fasting plasma glucose level, and waist circumference.RESULTS: Fourteen percent of the sample developed major depressive disorder during follow-up. Cox proportional hazards models indicated that higher triglyceride-HDL ratio was positively associated with an increased risk for incident major depression (hazard ratio=1.89, 95% CI=1.15, 3.11), as were higher fasting plasma glucose levels (hazard ratio=1.37, 95% CI=1.05, 1.77) and higher waist circumference (hazard ratio=1.11 95% CI=1.01, 1.21). The development of prediabetes in the 2-year period after study enrollment was positively associated with incident major depressive disorder (hazard ratio=2.66, 95% CI=1.13, 6.27). The development of high triglyceride-HDL ratio and high central adiposity (cut-point ≥100 cm) in the same period was not associated with incident major depression.CONCLUSIONS: Three surrogate measures of insulin resistance positively predicted incident major depressive disorder in a 9-year follow-up period among adults with no history of depression or anxiety disorder. In addition, the development of prediabetes between enrollment and the 2-year study visit was positively associated with incident major depressive disorder. These findings may have utility for evaluating the risk for the development of major depression among patients with insulin resistance or metabolic pathology.

  View details for DOI 10.1176/appi.ajp.2021.20101479

  View details for PubMedID 34551583

• Variations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder. International journal of bipolar disorders Bauer, M., Glenn, T., Achtyes, E. D., Alda, M., Agaoglu, E., Altinbas, K., Andreassen, O. A., Angelopoulos, E., Ardau, R., Vares, E. A., Aydin, M., Ayhan, Y., Baethge, C., Bauer, R., Baune, B. T., Balaban, C., Becerra-Palars, C., Behere, A. P., Behere, P. B., Belete, H., Belete, T., Belizario, G. O., Bellivier, F., Belmaker, R. H., Benedetti, F., Berk, M., Bersudsky, Y., Bicakci, S., Birabwa-Oketcho, H., Bjella, T. D., Brady, C., Cabrera, J., Cappucciati, M., Castro, A. M., Chen, W., Cheung, E. Y., Chiesa, S., Crowe, M., Cuomo, A., Dallaspezia, S., Del Zompo, M., Desai, P., Dodd, S., Donix, M., Etain, B., Fagiolini, A., Fellendorf, F. T., Ferensztajn-Rochowiak, E., Fiedorowicz, J. G., Fountoulakis, K. N., Frye, M. A., Geoffroy, P. A., Gonzalez-Pinto, A., Gottlieb, J. F., Grof, P., Haarman, B. C., Harima, H., Hasse-Sousa, M., Henry, C., Hoffding, L., Houenou, J., Imbesi, M., Isometsa, E. T., Ivkovic, M., Janno, S., Johnsen, S., Kapczinski, F., Karakatsoulis, G. N., Kardell, M., Kessing, L. V., Kim, S. J., Konig, B., Kot, T. L., Koval, M., Kunz, M., Lafer, B., Landen, M., Larsen, E. R., Lenger, M., Lewitzka, U., Licht, R. W., Lopez-Jaramillo, C., MacKenzie, A., Madsen, H. O., Madsen, S. A., Mahadevan, J., Mahardika, A., Manchia, M., Marsh, W., Martinez-Cengotitabengoa, M., Martiny, K., Mashima, Y., McLoughlin, D. M., Meesters, Y., Melle, I., Meza-Urzua, F., Ming, M. Y., Monteith, S., Moorthy, M., Morken, G., Mosca, E., Mozzhegorov, A. A., Munoz, R., Mythri, S. V., Nacef, F., Nadella, R. K., Nakanotani, T., Nielsen, R. E., O'Donovan, C., Omrani, A., Osher, Y., Ouali, U., Pantovic-Stefanovic, M., Pariwatcharakul, P., Petite, J., Pfennig, A., Ruiz, Y. P., Pilhatsch, M., Pinna, M., Pompili, M., Porter, R., Quiroz, D., Rabelo-da-Ponte, F. D., Ramesar, R., Rasgon, N., Ratta-Apha, W., Ratzenhofer, M., Redahan, M., Reddy, M. S., Reif, A., Reininghaus, E. Z., Richards, J. G., Ritter, P., Rybakowski, J. K., Sathyaputri, L., Scippa, A. M., Simhandl, C., Severus, E., Smith, D., Smith, J., Stackhouse, P. W., Stein, D. J., Stilwell, K., Strejilevich, S., Su, K., Subramaniam, M., Sulaiman, A. H., Suominen, K., Tanra, A. J., Tatebayashi, Y., Teh, W. L., Tondo, L., Torrent, C., Tuinstra, D., Uchida, T., Vaaler, A. E., Veeh, J., Vieta, E., Viswanath, B., Yoldi-Negrete, M., Yalcinkaya, O. K., Young, A. H., Zgueb, Y., Whybrow, P. C. 2021; 9 (1): 26

  Abstract

  BACKGROUND: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries.METHODS: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun's electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries).RESULTS: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p<0.01.CONCLUSION: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.

  View details for DOI 10.1186/s40345-021-00231-7

  View details for PubMedID 34467430

• Hippocampal Volume Reduction is Associated with Direct Measure of Insulin Resistance in Adults. Neuroscience research Frangou, S., Abbasi, F., Watson, K., Haas, S. S., Antoniades, M., Modabbernia, A., Myoraku, A., Robakis, T., Rasgon, N. 2021

  Abstract

  Hippocampal integrity Is highly susceptible to metabolic dysfunction, yet its mechanisms are not well defined. We studied 126 healthy individuals aged 23-61 years. Insulin resistance (IR) was quantified by measuring steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Body mass index (BMI), adiposity, fasting insulin, glucose, leptin as well as structural neuroimaing with automatic hippocampal subfields segmentation were performed. Data analysis using unsupervised machine learning (k-means clustering) identified two subgroups reflecting a pattern of more pronounced hippocampal volume reduction being concurrently associated with greater adiposity and insulin resistance; the hippocampal volume reductions were uniform across subfields. Individuals in the most deviant subgroup were predominantly women (79 versus 42%) with higher BMI [27.9 (2.5) versus 30.5 (4.6) kg/m2], IR (SSPG concentration, [156 (61) versus 123 (70) mg/dL] and leptinemia [21.7 (17.0) versus 44.5 (30.4) g/L]. The use of person-based modeling in healthy individuals suggests that adiposity, insulin resistance and compromised structural hippocampal integrity behave as a composite phenotype; female sex emerged as risk factor for this phenotype.

  View details for DOI 10.1016/j.neures.2021.07.006

  View details for PubMedID 34352294

• Shared Genetic Effects may Partially Explain Higher Depression and PTSD Prevalence Among Women Using Hormone Therapy (HT) Duncan, L., Meijsen, J., Shen, H., Vemuri, M., Rasgon, N., Koenen, K. ELSEVIER SCIENCE INC. 2021: S101-S102

  View details for Web of Science ID 000645683800242

• Depression Symptoms and Insulin Resistance in Individuals With Family History of Type 2 Diabetes Mellitus and Major Depressive Disorder Ong, S., Abbasi, F., Watson, K., Myoraku, A., Rasgon, N. ELSEVIER SCIENCE INC. 2021: S232

  View details for Web of Science ID 000645683800556

• Multidimensional predictors of antidepressant responses: Integrating mitochondrial, genetic, metabolic and environmental factors with clinical outcomes. Neurobiology of stress Nasca, C., Barnhill, O., DeAngelis, P., Watson, K., Lin, J., Beasley, J., Young, S. P., Myoraku, A., Dobbin, J., Bigio, B., McEwen, B., Rasgon, N. 2021; 15: 100407

  Abstract

  Major depressive disorder (MDD) is a primary psychiatric illness worldwide; there is a dearth of new mechanistic models for the development of better therapeutic strategies. Although we continue to discover individual biological factors, a major challenge is the identification of integrated, multidimensional traits underlying the complex heterogeneity of depression and treatment outcomes. Here, we set out to ascertain the emergence of the novel mitochondrial mediator of epigenetic function acetyl-L-carnitine (LAC) in relation to previously described individual predictors of antidepressant responses to the insulin-sensitizing agent pioglitazone. Herein, we report that i) subjects with MDD and shorter leukocyte telomere length (LTL) show decreased levels of LAC, increased BMI, and a history of specific types of childhood trauma; and that ii) these multidimensional factors spanning mitochondrial metabolism, cellular aging, metabolic function, and childhood trauma provide more detailed signatures to predict longitudinal changes in depression severity in response to pioglitazone than individual factors. The findings of multidimensional signatures involved in the pathophysiology of depression and their role in predicting treatment outcomes provide a starting point for the development of a mechanistic framework linking biological networks and environmental factors to clinical outcomes in pursuit of personalized medicine strategies to effectively treat MDD.

  View details for DOI 10.1016/j.ynstr.2021.100407

  View details for PubMedID 34815985

  View details for PubMedCentralID PMC8592929

• Association between Adherence with an Atypical Antipsychotic and with Other Psychiatric Drugs in Patients with Bipolar Disorder. Pharmacopsychiatry Bauer, M., Glenn, T., Alda, M., Grof, P., Monteith, S., Rasgon, N., Severus, E., Whybrow, P. C. 2020

  Abstract

  BACKGROUND: Using U.S. pharmacy and medical claims, medication adherence patterns of patients with serious mental illness suggest that adherence to atypical antipsychotics may be related to adherence to other prescription drugs. This study investigated whether adherence to an atypical antipsychotic was related to adherence to other prescribed psychiatric drugs using self-reported data from patients with bipolar disorder.METHODS: Daily self-reported medication data were available from 123 patients with a diagnosis of bipolar disorder receiving treatment as usual who took at least 1 atypical antipsychotic over a 12-week period. Patients took a mean of 4.0±1.7 psychiatric drugs including the antipsychotic. The adherence rate for the atypical antipsychotic was compared to that for other psychiatric drugs to determine if the adherence rate for the atypical antipsychotic differed from that of the other psychiatric drug by at least ±10%.RESULTS: Of the 123 patients, 58 (47.2%) had an adherence rate for the atypical antipsychotic that differed from the adherence rate for at least 1 other psychiatric drug by at least±10%, and 65 (52.8%) patients had no difference in adherence rates. The patients with a difference took a larger total number of psychiatric drugs (p<0.001), had a larger daily pill burden (p=0.020) and a lower adherence rate with the atypical antipsychotic (p=0.007), and were more likely to take an antianxiety drug (p<0.001).CONCLUSION: Adherence with an atypical antipsychotic was not useful for estimating adherence to other psychiatric drugs in about half of the patients with bipolar disorder.

  View details for DOI 10.1055/a-1257-0813

  View details for PubMedID 33202423

• Effects of LDL Cholesterol and Statin Use on Verbal Learning and Memory in Older Adults at Genetic Risk for Alzheimer's Disease. Journal of Alzheimer's disease : JAD Wroolie, T., Roat-Shumway, S., Watson, K., Reiman, E., Rasgon, N. 2020

  Abstract

  BACKGROUND: The apolipoprotein epsilon 4 (APOE4) allele is a well-established genetic risk factor for Alzheimer's disease (AD). However, there are mixed findings as to how the APOE4 allele modifies the effects of both higher low-density lipoprotein cholesterol (LDL) and statin use on cognitive functioning.OBJECTIVE: This study sought to examine the effects of LDL levels and statin use on verbal learning and memory, as modified by the presence of the APOE4 allele, in a sample of cognitively unimpaired, older adults at risk for AD.METHODS: Neuropsychological, LDL, statin use, and APOE4 data were extracted from an ongoing longitudinal study at the Banner Alzheimer's Institute in Arizona. Participants were cognitively unimpaired based on Mini-Mental State Examination scores within a normal range, aged 47-75, with a family history of probable AD in at least one first-degree relative.RESULTS: In the whole sample, higher LDL was associated with worse immediate verbal memory in APOE4 non-carriers, but did not have an effect on immediate verbal memory in APOE4 carriers. In APOE4 non-carriers, statin use was associated with better verbal learning, but did not have an effect on verbal learning in APOE4 carriers. Among women, higher LDL in APOE4 carriers was associated with worse verbal learning than in APOE4 non-carriers, and statin use in APOE4 non-carriers was associated with better verbal learning and immediate and delayed verbal memory but worse performances on these tasks in APOE4 carriers.CONCLUSION: LDL and statin use may have differential effects on verbal learning and/or memory depending on genetic risk for AD. Women appear to be particularly vulnerable to statin use depending on their APOE4 status.

  View details for DOI 10.3233/JAD-191090

  View details for PubMedID 32390619

• Epigenetic signatures of attachment insecurity and childhood adversity provide evidence for role transition in the pathogenesis of perinatal depression. Translational psychiatry Robakis, T. K., Zhang, S., Rasgon, N. L., Li, T., Wang, T., Roth, M. C., Humphreys, K. L., Gotlib, I. H., Ho, M., Khechaduri, A., Watson, K., Roat-Shumway, S., Budhan, V. V., Davis, K. N., Crowe, S. D., Ellie Williams, K., Urban, A. E. 2020; 10 (1): 48

  Abstract

  Early life adversity and insecure attachment style are known risk factors for perinatal depression. The biological pathways linking these experiences, however, have not yet been elucidated. We hypothesized that overlap in patterns of DNA methylation in association with each of these phenomena could identify genes and pathways of importance. Specifically, we wished to distinguish between allostatic-load and role-transition hypotheses of perinatal depression. We conducted a large-scale analysis of methylation patterns across 5*106 individual CG dinucleotides in 54 women participating in a longitudinal prospective study of perinatal depression, using clustering-based criteria for significance to control for multiple comparisons. We identified 1580 regions in which methylation density was associated with childhood adversity, 3 in which methylation density was associated with insecure attachment style, and 6 in which methylation density was associated with perinatal depression. Shorter telomeres were observed in association with childhood trauma but not with perinatal depression or attachment insecurity. A detailed analysis of methylation density in the oxytocin receptor gene revealed similar patterns of DNA methylation in association with perinatal depression and with insecure attachment style, while childhood trauma was associated with a distinct methylation pattern in this gene. Clinically, attachment style was strongly associated with depression only in pregnancy and the early postpartum, whereas the association of childhood adversity with depression was time-invariant. We concluded that the broad DNA methylation signature and reduced telomere length associated with childhood adversity could indicate increased allostatic load across multiple body systems, whereas perinatal depression and attachment insecurity may be narrower phenotypes with more limited DNA methylation signatures outside the CNS, and no apparent association with telomere length or, by extension, allostatic load. In contrast, the finding of matching DNA methylation patterns within the oxytocin receptor gene for perinatal depression and attachment insecurity is consistent with the theory that the perinatal period is a time of activation of existing attachment schemas for the purpose of structuring the mother-child relationship, and that such activation may occur in part through specific patterns of methylation of the oxytocin receptor gene.

  View details for DOI 10.1038/s41398-020-0703-3

  View details for PubMedID 32066670

• Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin. Journal of psychiatric research Mansur, R. B., Delgado-Peraza, F. n., Subramaniapillai, M. n., Lee, Y. n., Iacobucci, M. n., Nasri, F. n., Rodrigues, N. n., Rosenblat, J. D., Brietzke, E. n., Cosgrove, V. E., Kramer, N. E., Suppes, T. n., Raison, C. L., Fagiolini, A. n., Rasgon, N. n., Chawla, S. n., Nogueras-Ortiz, C. n., Kapogiannis, D. n., McIntyre, R. S. 2020; 133: 82–92

  Abstract

  Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3β, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.

  View details for DOI 10.1016/j.jpsychires.2020.12.007

  View details for PubMedID 33316649

• Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance. Molecular psychiatry Nasca, C. n., Dobbin, J. n., Bigio, B. n., Watson, K. n., de Angelis, P. n., Kautz, M. n., Cochran, A. n., Mathé, A. A., Kocsis, J. H., Lee, F. S., Murrough, J. W., McEwen, B. S., Rasgon, N. n. 2020

  Abstract

  Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies, impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in vivo molecular mechanisms of brain IR until recently has proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared with age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM+ exosomes in subjects with MDD as compared with age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM+ exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM+ exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM+ exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.

  View details for DOI 10.1038/s41380-020-0804-7

  View details for PubMedID 32536688

• Association of Insulin Resistance With Depression Severity and Remission Status: Defining a Metabolic Endophenotype of Depression. JAMA psychiatry Watson, K. T., Simard, J. F., Henderson, V. W., Nutkiewicz, L. n., Lamers, F. n., Rasgon, N. n., Penninx, B. n. 2020

  View details for DOI 10.1001/jamapsychiatry.2020.3669

  View details for PubMedID 33263725

• Development and Validation of the Muslims' Perceptions and Attitudes to Mental Health (M-PAMH) Scale with a Sample of American Muslim Women JOURNAL OF MUSLIM MENTAL HEALTH Awaad, R., Fisher, A. J., Ali, S., Rasgon, N. 2019; 13 (2): 119–35

  View details for DOI 10.3998/jmmh.10381607.0013.205

  View details for Web of Science ID 000526417600006

• Insulin Resistance and Structural Change in the Anterior Cingulate Cortex in Youth With Depression and Obesity Hagan, K., Fischer, A., Nrusimha, A., Nimarko, A., Gorelik, A., Bohon, C., Rasgon, N., Singh, M. NATURE PUBLISHING GROUP. 2019: 143–44

  View details for Web of Science ID 000509665600281

• The Effects of Statins on Cognition in Older Women at Genetic Risk for Alzheimer's Disease Wroolie, T., Roat-Shumway, S., Watson, K., Rasgon, N. NATURE PUBLISHING GROUP. 2019: 386

  View details for Web of Science ID 000509665600702

• REWARD PROCESSING IN DEPRESSED AND OBESE CHILDREN Angal, S., Fischer, A. S., Bohon, C., Nimarko, A. F., Rolle, C. E., Lu, Y., Pan, T., Kuramkote, S. R., Rasgon, N. L., Singh, M. K. ELSEVIER SCIENCE INC. 2019: S274

  View details for DOI 10.1016/j.jaac.2019.08.402

  View details for Web of Science ID 000518857302223

• Trajectories of adherence to mood stabilizers in patients with bipolar disorder. International journal of bipolar disorders Bauer, M., Glenn, T., Alda, M., Bauer, R., Grof, P., Marsh, W., Monteith, S., Munoz, R., Rasgon, N., Sagduyu, K., Whybrow, P. C. 2019; 7 (1): 19

  Abstract

  BACKGROUND: Nonadherence with mood stabilizers is a major problem that negatively impacts the course of bipolar disorder. Medication adherence is a complex individual behavior, and adherence rates often change over time. This study asked if distinct classes of adherence trajectories with mood stabilizers over time could be found, and if so, which patient characteristics were associated with the classes.METHODS: This analysis was based on 12weeks of daily self-reported data from 273 patients with bipolar 1 or II disorder using ChronoRecord computer software. All patients were taking at least one mood stabilizer. The latent class mixed model was used to detect trajectories of adherence based on 12 weekly calculated adherence datapoints per patient.RESULTS: Two distinct trajectory classes were found: an adherent class (210 patients; 77%) and a less adherent class (63 patients; 23%). The characteristics associated with the less adherent class were: more time not euthymic (p<0.001) and female gender (p=0.016). No other demographic associations were found.CONCLUSION: In a sample of motivated patients who complete daily mood charting, about one quarter were in the less adherent class. Even patients who actively participate in their care, such as by daily mood charting, may be nonadherent. Demographic characteristics may not be useful in assessing individual adherence. Future research on longitudinal adherence patterns in bipolar disorder is needed.

  View details for DOI 10.1186/s40345-019-0154-z

  View details for PubMedID 31482209

• The Relation Between Tanner Stage and Age is Moderated by Trauma in Youth With Depression and Obesity Ridout, S., Ridout, K., Nimarko, A., Packer, M., Tang, W., Rah, E., Fonseca, C., Lu, Y., Angal, S., Rasgon, N., Singh, M. ELSEVIER SCIENCE INC. 2019: S315–S316

  View details for DOI 10.1016/j.biopsych.2019.03.801

  View details for Web of Science ID 000472661000773

• Nucleus Accumbens Volume Predicts Allostatic Load and is Moderated by Sex and Treatment Modality in Youth With Depression and Obesity Ridout, K., Nimarko, A., Packer, M., Tang, W., Rah, E., Fonseca, C., Lu, Y., Angal, S., Rasgon, N., Singh, M. ELSEVIER SCIENCE INC. 2019: S262

  View details for DOI 10.1016/j.biopsych.2019.03.663

  View details for Web of Science ID 000472661000639

• Childhood trauma and insulin resistance in patients suffering from depressive disorders EXPERIMENTAL NEUROLOGY Nasca, C., Watson-Lin, K., Bigio, B., Robakis, T. K., Myoraku, A., Wroolie, T. E., McEwen, B. S., Rasgon, N. 2019; 315: 15–20

  View details for DOI 10.1016/j.expneurol.2019.01.005

  View details for Web of Science ID 000462102100003

• Depression precedes, but does not follow, gestational diabetes ACTA PSYCHIATRICA SCANDINAVICA Clark, C. E., Rasgon, N. L., Reed, D. E., Robakis, T. K. 2019; 139 (4): 311–21

  View details for DOI 10.1111/acps.12998

  View details for Web of Science ID 000461872400003

• Association between solar insolation and a history of suicide attempts in bipolar I disorder. Journal of psychiatric research Bauer, M., Glenn, T., Alda, M., Andreassen, O. A., Angelopoulos, E., Ardau, R., Ayhan, Y., Baethge, C., Bauer, R., Baune, B. T., Becerra-Palars, C., Bellivier, F., Belmaker, R. H., Berk, M., Bersudsky, Y., Bicakci, S., Birabwa-Oketcho, H., Bjella, T. D., Cabrera, J., Wo Cheung, E. Y., Del Zompo, M., Dodd, S., Donix, M., Etain, B., Fagiolini, A., Fountoulakis, K. N., Frye, M. A., Gonzalez-Pinto, A., Gottlieb, J. F., Grof, P., Harima, H., Henry, C., Isometsa, E. T., Janno, S., Kapczinski, F., Kardell, M., Khaldi, S., Kliwicki, S., Konig, B., Kot, T. L., Krogh, R., Kunz, M., Lafer, B., Landen, M., Larsen, E. R., Lewitzka, U., Licht, R. W., Lopez-Jaramillo, C., MacQueen, G., Manchia, M., Marsh, W., Martinez-Cengotitabengoa, M., Melle, I., Meza-Urzua, F., Ming, M. Y., Monteith, S., Morken, G., Mosca, E., Mozzhegorov, A. A., Munoz, R., Mythri, S. V., Nacef, F., Nadella, R. K., Nery, F. G., Nielsen, R. E., O'Donovan, C., Omrani, A., Osher, Y., Sorensen, H. O., Ouali, U., Ruiz, Y. P., Pilhatsch, M., Pinna, M., da Ponte, F. D., Quiroz, D., Ramesar, R., Rasgon, N., Reddy, M. S., Reif, A., Ritter, P., Rybakowski, J. K., Sagduyu, K., Raghuraman, B. S., Scippa, A. M., Severus, E., Simhandl, C., Stackhouse, P. W., Stein, D. J., Strejilevich, S., Subramaniam, M., Sulaiman, A. H., Suominen, K., Tagata, H., Tatebayashi, Y., Tondo, L., Torrent, C., Vaaler, A. E., Vares, E., Veeh, J., Vieta, E., Viswanath, B., Yoldi-Negrete, M., Zetin, M., Zgueb, Y., Whybrow, P. C. 2019; 113: 1–9

  Abstract

  In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p < 0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.

  View details for DOI 10.1016/j.jpsychires.2019.03.001

  View details for PubMedID 30878786

• Management of perinatal depression with non-drug interventions. BMJ (Clinical research ed.) Johansen, S. L., Robakis, T. K., Williams, K. E., Rasgon, N. L. 2019; 364: l322

  Abstract

  Perinatal depression is a common disorder that has been associated with serious risks to mother and child. Recently, screening for depression in pregnant and postpartum women has increased, as has the development of new psychotherapy and non-drug treatment modalities. Matching patients to treatments can be challenging, and although research into personalized treatment of major depression in the general population has increased, no published guidelines focus on personalized treatment approaches to perinatal depression. In particular, guidelines on non-drug treatments are lacking. This review summarizes the evidence on personalized non-drug treatment of perinatal depression, how to incorporate patients' preferences, novel treatments under investigation, and the potential role of biomarkers in matching patients to treatment. The review provides recommendations for future research in personalized care of perinatal depression.

  View details for PubMedID 30803997

• Management of perinatal depression with non-drug interventions BMJ-BRITISH MEDICAL JOURNAL Johansen, S. L., Robakis, T. K., Williams, K., Rasgon, N. L. 2019; 364

  View details for DOI 10.1136/bmj.l322

  View details for Web of Science ID 000460389500001

• Brain and behavioral correlates of insulin resistance in youth with depression and obesity HORMONES AND BEHAVIOR Singh, M. K., Leslie, S. M., Packer, M., Zaiko, Y. V., Phillips, O. R., Weisman, E. F., Wall, D. M., Jo, B., Rasgon, N. 2019; 108: 73–83

  View details for DOI 10.1016/j.yhbeh.2018.03.009

  View details for Web of Science ID 000460189100008

• Childhood trauma and insulin resistance in patients suffering from depressive disorders. Experimental neurology Nasca, C., Watson, K., Bigio, B., Robakis, T., Myoraku, A., Wroolie, T., McEwen, B. S., Rasgon, N. 2019

  Abstract

  OBJECTIVE: Insulin resistance (IR) is a metabolic dysfunction often co-morbid with major depressive disorder (MDD). The paths to development of MDD remain largely unspecified, highlighting a need for identification of risk factors. Here, we tested whether specific subscales of childhood trauma as well as family history of type-2 diabetes (Fam-Hx-Dm2) contribute to the development of metabolic dysfunction and severity of depressive symptoms.RESEARCH DESIGN AND METHODS: We used a sample of 45 adults suffering from MDD that was well-characterized for insulin resistance and sensitivity as assessed by measures of fasting plasma glucose (FPG) plasma insulin (FPI) levels, body mass index (BMI), weight, homeostasis model assessment of insulin sensitivity (HOMA), Matsuda index as well as both glucose and insulin responses to oral glucose challenges. Severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HDRS-21). Physical, sexual and emotional abuse as well as physical and emotional neglect were assessed with the Childhood Trauma Questionnaire. First- or second-degree relatives with type-2 diabetes defined fam-Hx-DM2.RESULTS: Individuals reporting higher rates of emotional abuse were more likely to have greater IR as showed by elevated FPI levels and HOMA. No association was found with any of the other subscales of childhood trauma (e.g., physical abuse). Similarly, Fam-Hx-DM2 was associated with greater degree of IR as shown by elevated FPI, HOMA, but also FPG, weigh and BMI.. Moreover, we report a relationship and interaction between Fam-Hx-DM2 and emotional abuse on severity of depressive symptoms. Specifically, emotional abuse and Fam-HX-DM2 predicted severity of depressive symptoms at HDRS-21. Also, severity of depressive symptoms was greater with higher reported rates of emotional abuse but only in patients with negative Fam-Hx-Dm2. Individuals reporting higher emotional abuse and negative Fam-Hx-Dm2 also showed higher FPG levels. Conversely, individuals reporting higher emotional abuse and positive Fam-Hx-Dm2 showed higher FPI levels. This data suggest that Fam-Hx-Dm2 may define two different metabolic endophenotypes.CONCLUSIONS: Our findings suggest that Fam-HX-DM2 and emotional abuse represent separate risk factors for developing metabolic dysfunction (i.e.: IR) in patients suffering from MDD, and that the effects of emotional abuse on psychiatric illness may depend upon the personal characteristics, including Fam-Hx-DM2.

  View details for PubMedID 30639184

• Early life adversity blunts responses to pioglitazone in depressed, overweight adults EUROPEAN PSYCHIATRY Robakis, T. K., Watson-Lin, K., Wroolie, T. E., Myoraku, A., Nasca, C., Bigio, B., McEwen, B., Rasgon, N. L. 2019; 55: 4–9

  View details for DOI 10.1016/j.eurpsy.2018.09.009

  View details for Web of Science ID 000453747200002

• Multidimensional Predictors of Susceptibility and Resilience to Social Defeat Stress. Biological psychiatry Nasca, C. n., Menard, C. n., Hodes, G. n., Bigio, B. n., Pena, C. n., Lorsch, Z. n., Zelli, D. n., Ferris, A. n., Kana, V. n., Purushothaman, I. n., Dobbin, J. n., Nassim, M. n., DeAngelis, P. n., Merad, M. n., Rasgon, N. n., Meaney, M. n., Nestler, E. J., McEwen, B. S., Russo, S. J. 2019; 86 (6): 483–91

  Abstract

  Previous studies identified several separate risk factors for stress-induced disorders. However, an integrative model of susceptibility versus resilience to stress including measures from brain-body domains is likely to yield a range of multiple phenotypic information to promote successful adaptation to stress.We used computational and molecular approaches to test whether 1) integrative brain-body behavioral, immunological, and structural domains characterized and predicted susceptibility or resilience to social defeat stress (SDS) in mice and 2) administration of acetyl-L-carnitine promoted resilience at the SDS paradigm.Our findings identified multidimensional brain-body predictors of susceptibility versus resilience to SDS. The copresence of anxiety, decreased hippocampal volume, and elevated systemic interleukin-6 characterized a susceptible phenotype that developed behavioral and neurobiological deficits after exposure to SDS. The susceptible phenotype showed social withdrawal and impaired transcriptomic-wide changes in the ventral dentate gyrus after SDS. At the individual level, a computational approach predicted whether a given animal developed SDS-induced social withdrawal, or remained resilient, based on the integrative in vivo measures of anxiety and immune system function. Finally, we provide initial evidence that administration of acetyl-L-carnitine promoted behavioral resilience at the SDS paradigm.The current findings of multidimensional brain-body predictors of susceptibility versus resilience to stress provide a starting point for in vivo models of mechanisms predisposing apparently healthy individuals to develop the neurobiological and behavioral deficits resulting from stress exposure. This framework can lead to novel therapeutic strategies to promote resilience in susceptible phenotypes.

  View details for DOI 10.1016/j.biopsych.2019.06.030

  View details for PubMedID 31466563

• Hormonal Contraceptives and Mood: Review of the Literature and Implications for Future Research. Current psychiatry reports Robakis, T. n., Williams, K. E., Nutkiewicz, L. n., Rasgon, N. L. 2019; 21 (7): 57

  Abstract

  We examine recent studies that investigate the effects of hormonal contraception on mood in different populations of women, including women in the general population and women with diagnosed psychiatric and gynecologic disorders. We address the mechanisms of several types of hormonal contraceptives and assess how these may affect mood and gynecologic disorders.The effects of hormonal contraceptives seem to be most relevant in selected subsets of women, as they may promote improved mental health in particular psychiatric disorders such as PMDD. Currently, there is no consistent evidence for negative effects of most hormonal contraceptives in the general population. Even though some studies reveal that certain individuals appear susceptible to negative mood effects from some forms of hormonal contraceptives, more research is needed to better identify these susceptible individuals.

  View details for DOI 10.1007/s11920-019-1034-z

  View details for PubMedID 31172309

• Effort-based decision-making is affected by overweight/obesity in major depressive disorder. Journal of affective disorders Mansur, R. B., Subramaniapillai, M. n., Zuckerman, H. n., Park, C. n., Iacobucci, M. n., Lee, Y. n., Tuineag, M. n., Hawco, C. n., Frey, B. N., Rasgon, N. n., Brietzke, E. n., McIntyre, R. S. 2019; 256: 221–27

  Abstract

  Anhedonia and abnormalities in reward behavior are core features of major depressive disorder (MDD). Convergent evidence indicates that overweight/obesity (OW), a highly prevalent condition in MDD, is independently associated with reward disturbances. We therefore aimed to investigate the moderating effect of OW on the willingness to expend efforts for reward in individuals with MDD and healthy controls (HC).Forty-one adults (HC n = 20, MDD n = 21) completed the Effort Expenditure for Rewards Task (EEfRT), clinical and cognitive measures. Anthropometric parameters were assessed in all participants, and an additional evaluation of laboratorial parameters were conducted solely on those with MDD. Individuals with MDD were all on vortioxetine monotherapy (10-20 mg/day).Interactions between reward magnitude, group and OW were observed (χ2 = 9.192, p = 0.010); the OW-MDD group chose the hard task significantly less than normal weight (NW)-HC (p = 0.033) and OW-HC (p = 0.034), whereas there were no differences between NW-MDD and HCs. Within individuals with MDD, the proportion of hard task choices was more strongly correlated with body mass index (BMI) (r = -0.456, p = 0.043) and insulin resistance (HOMA2-IR) (r = -0.467, p = 0.038), than with depressive symptoms (r = 0.290, p = 0.214).OW significantly moderated the association between MDD and willingness to make efforts for rewards. These findings offer novel evidence on the potential role of metabolic factors on the basis of anhedonia, and for the heuristic models proposing a pathophysiological connection between mood and metabolic disorders.

  View details for DOI 10.1016/j.jad.2019.06.002

  View details for PubMedID 31181378

• Neural correlates of liraglutide effects in persons at risk for Alzheimer's disease BEHAVIOURAL BRAIN RESEARCH Watson, K. T., Wroolie, T. E., Tong, G., Foland-Ross, L. C., Frangou, S., Singh, M., McIntyre, R. S., Roat-Shumway, S., Myoraku, A., Reiss, A. L., Rasgon, N. L. 2019; 356: 271–78

  View details for DOI 10.1016/j.bbr.2018.08.006

  View details for Web of Science ID 000449894800031

• An emerging epigenetic framework of systemic and central mechanisms underlying stress-related disorders NEUROPSYCHOPHARMACOLOGY Nasca, C., Rasgon, N., McEwen, B. 2019; 44 (1): 235–36

  View details for DOI 10.1038/s41386-018-0227-1

  View details for Web of Science ID 000450178000038

• Neural and Endocrine Correlates of Early Life Abuse in Youth With Depression and Obesity. Frontiers in psychiatry Sun, K. L., Watson, K. T., Angal, S., Bakkila, B. F., Gorelik, A. J., Leslie, S. M., Rasgon, N. L., Singh, M. K. 2018; 9: 721

  Abstract

  Depression and insulin resistance are becoming increasingly prevalent in younger populations. The origin and consequence of insulin resistance in depressed youth may, in part, be rooted in exposure to environmental stressors, such as early life abuse, that may lead to aberrant brain motivational networks mediating maladaptive food-seeking behaviors and insipient insulin resistance. In this paper, we aimed to investigate the impact of early life abuse on the development of insulin resistance in depressed and overweight youth aged 9 to 17 years. We hypothesized that youth with the greatest burden of early life abuse would have the highest levels of insulin resistance and corresponding aberrant reward network connectivities. To test this hypothesis, we evaluated sixty-nine depressed and overweight youth aged 9 to 17, using multimodal assessments of early life abuse, food-seeking behavior, and insulin resistance. Based on results of the Childhood Trauma Questionnaire (CTQ), we separated our study participants into two groups: 35 youth who reported high levels of the sum of emotional, physical, or sexual abuse and 34 youth who reported insignificant or no levels of any abuse. Results of an oral glucose tolerance test (OGTT) and resting state functional connectivity (RSFC), using the amygdala, insula, and nucleus accumbens (NAcc) as seed-based reward network regions of interest, were analyzed for group differences between high abuse and low abuse groups. High abuse youth exhibited differences from low abuse youth in amygdala-precuneus, NAcc-paracingulate gyrus, and NAcc-prefrontal cortex connectivities, that correlated with levels of abuse experienced. The more different their connectivity from of that of low abuse youth, the higher were their fasting glucose and glucose at OGTT endpoint. Importantly, level of abuse moderated the relation between reward network connectivity and OGTT glucose response. In contrast, low abuse youth showed hyperinsulinemia and more insulin resistance than high abuse youth, and their higher OGTT insulin areas under the curve correlated with more negative insula-precuneus connectivity. Our findings suggest distinct neural and endocrine profiles of youth with depression and obesity based on their histories of early life abuse.

  View details for DOI 10.3389/fpsyt.2018.00721

  View details for PubMedID 30622489

  View details for PubMedCentralID PMC6308296

• Neural and Endocrine Correlates of Early Life Abuse in Youth With Depression and Obesity FRONTIERS IN PSYCHIATRY Sun, K. L., Watson, K. T., Angal, S., Bakkila, B. F., Gorelik, A. J., Leslie, S. M., Rasgon, N. L., Singh, M. K. 2018; 9

  View details for DOI 10.3389/fpsyt.2018.00721

  View details for Web of Science ID 000454082600001

• Depression Precedes, But Does Not Follow, Gestational Diabetes. Acta psychiatrica Scandinavica Clark, C. E., Rasgon, N. L., Reed, D. E., Robakis, T. K. 2018

  Abstract

  OBJECTIVES: To determine whether past history of depression is associated with increased rates of gestational diabetes, and whether history of gestational diabetes is associated with increased rates of postpartum depression.RESEARCH DESIGN: Data for this case-control study consisted of deidentified chart records for 1,439 women who received pregnancy care at a large university hospital between 1998 and 2017.RESULTS: A history of depression prior to pregnancy was associated with gestational diabetes requiring insulin, although not with subtler degrees of gestational hyperglycemia. Diabetes in pregnancy was not associated with an increased risk of postpartum depression. Trauma history was associated with both impaired glucose tolerance in pregnancy and postpartum depression.CONCLUSIONS: Past episodes of depression increase risk for the most severe form of gestational diabetes; however gestational diabetes does not contribute significantly to risk for postpartum depression. This suggests a unidirectional association, unlike the bidirectional association of diabetes with depression among the general population. History of trauma increases risk for both gestational hyperglycemia and postpartum depression, suggesting important health effects of trauma that may differ measurably from those associated with depression. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30561785

• Expression of dopamine signaling genes in the post-mortem brain of individuals with mental illnesses is moderated by body mass index and mediated by insulin signaling genes JOURNAL OF PSYCHIATRIC RESEARCH Mansur, R. B., Fries, G. R., Subramaniapillai, M., Frangou, S., De Felice, F. G., Rasgon, N., McEwen, B., Brietzke, E., McIntyre, R. S. 2018; 107: 128–35

  View details for DOI 10.1016/j.jpsychires.2018.10.020

  View details for Web of Science ID 000451490800018

• Early life adversity blunts responses to pioglitazone in depressed, overweight adults. European psychiatry : the journal of the Association of European Psychiatrists Robakis, T. K., Watson-Lin, K., Wroolie, T. E., Myoraku, A., Nasca, C., Bigio, B., McEwen, B., Rasgon, N. L. 2018; 55: 4–9

  Abstract

  PURPOSE: Early life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression.PURPOSE: Early life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression.FINDINGS: We found that early life adversity significantly impaired the metabolic response to pioglitazone. Effects on depressive symptoms did not reach significance, but nonetheless suggested that pioglitazone could mitigate the depressant effects of childhood adversity, only among those insulin resistant at baseline.CONCLUSIONS: We conclude that a history of early life adversity may impair the body's ability to respond to insulin sensitizing pharmacotherapy, and furthermore that its contribution to resistant depression may function in part via the generation of an insulin resistant phenotype.

  View details for PubMedID 30384111

• Expression of dopamine signaling genes in the post-mortem brain of individuals with mental illnesses is moderated by body mass index and mediated by insulin signaling genes. Journal of psychiatric research Mansur, R. B., Fries, G. R., Subramaniapillai, M., Frangou, S., De Felice, F. G., Rasgon, N., McEwen, B., Brietzke, E., McIntyre, R. S. 2018; 107: 128–35

  Abstract

  Preclinical studies implicate insulin signaling as a modulator of dopamine transmission, but human data is currently limited. We hypothesize that changes in the expression of insulin receptor-related genes in the post-mortem brain tissue of patients with mood and psychotic disorders mediate the expression of dopamine regulation-related genes. From a database containing microarray data from the post-mortem dorsolateral prefrontal cortex (dlPFC) (healthy controls [HC]: n = 209; patients: n = 321) and hippocampus (HC: n = 180; patients: n = 196), we conducted a hypothesis-driven analysis through the a priori selection of 12 dopamine- and 3 insulin-related genes. Mediation and moderated mediation models, accounting for the role of body mass index (BMI), were used. In the dlPFC, expressions of insulin receptor- and dopamine regulation-related genes were moderated by BMI, with significantly lower expression in high BMI patients. In the hippocampus, there were significantly lower expressions of these genes, which were not moderated by BMI. Illnesses by BMI effects on expression of dopamine genes were fully mediated by expression of insulin receptor gene (INSR). Analysis of conditional indirect effects showed interactions between INSR and BMI, indicating significantly stronger indirect effects at higher BMI values. In the hippocampus we observed that expression of insulin receptor substrate 1 and 2 fully mediated the effects of illnesses on expression of dopamine genes. In conclusion, differential expression of dopamine-related genes was related to altered expression of insulin signaling genes. BMI had region-specific effects, supporting the hypothesis that metabolic systems are critical mediators of dopaminergic function.

  View details for PubMedID 30391805

• Cognitive effects of mifepristone in overweight, euthymic adults with depressive disorders JOURNAL OF AFFECTIVE DISORDERS Roat-Shumway, S., Wroolie, T. E., Watson, K., Schatzberg, A. F., Rasgon, N. L. 2018; 239: 242–46

  View details for DOI 10.1016/j.jad.2018.07.014

  View details for Web of Science ID 000441280500032

• An emerging epigenetic framework of systemic and central mechanisms underlying stress-related disorders. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Nasca, C., Rasgon, N., McEwen, B. 2018

  View details for PubMedID 30294001

• INSULIN RESPONSE MEDIATES THE EFFECT OF FAMILY HISTORY OF DEPRESSION ON CONSUMMATORY PLEASURE IN YOUTH WITH DEPRESSION AND OBESITY Sun, K. L., Watson, K. T., Packer, M., Wall, D. M., Staver, A. C., Leslie, S. M., Bahl, N. E., Nimarko, A. F., Rasgon, N. L., Singh, M. K. ELSEVIER SCIENCE INC. 2018: S241–S242

  View details for DOI 10.1016/j.jaac.2018.09.340

  View details for Web of Science ID 000544087501403

• Acetyl-L-carnitine deficiency in patients with major depressive disorder PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Nasca, C., Bigio, B., Lee, F. S., Young, S. P., Kautz, M. M., Albright, A., Beasley, J., Millington, D. S., Mathe, A. A., Kocsis, J. H., Murrough, J. W., McEwen, B. S., Rasgon, N. 2018; 115 (34): 8627–32

  Abstract

  The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The endogenously produced molecule acetyl-l-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.

  View details for PubMedID 30061399

• Neural correlates of liraglutide effects in persons at risk for Alzheimer's Disease. Behavioural brain research Watson, K. T., Wroolie, T. E., Tong, G., Foland-Ross, L. C., Frangou, S., Singh, M., McIntyre, R., Roat-Shumway, S., Myoraku, A., Reiss, A. L., Rasgon, N. L. 2018

  Abstract

  Insulin resistance (IR) is a metabolic state preceding development of type 2 diabetes (DM2), cardiovascular disease, and neurodegenerative disorders, including Alzheimer's Disease (AD). Liraglutide, a glucagon-like peptide-1 (GLP) agonist, is an insulin-sensitizing agent with neuroprotective properties, as shown in animal studies. The purpose of this double-blinded, placebo-controlled study was to examine the neural effects of administration of liraglutide in cognitively normal late middle-aged individuals with subjective cognitive complaints (half of subjects had family history of AD). Seed-based resting state connectivity using functional magnetic resonance imaging (fMRI) conducted before and after 12 weeks of liraglutide treatment or placebo. Neuropsychological testing was conducted before and after treatment to determine whether there were any potential behavioral correlates to neural changes.RESULTS: At baseline (time point 1), higher fasting plasma glucose (FPG) was associated with decreased connectivity between bilateral hippocampal and anterior medial frontal structures. At time point 2, we observed significant improvement in intrinsic connectivity within the default mode network (DMN) in the active group relative to placebo. There were no detectable cognitive differences between study groups after this duration of treatment. To our knowledge, this is the first placebo-controlled study to report neural effects of liraglutide in a middle-aged population with subjective cognitive complaints. Larger and longer duration studies are warranted to determine whether liraglutide has neuroprotective benefit for individuals at risk for AD.

  View details for PubMedID 30099030

• Cognitive effects of mifepristone in overweight, euthymic adults with depressive disorders. Journal of affective disorders Roat-Shumway, S., Wroolie, T. E., Watson, K., Schatzberg, A. F., Rasgon, N. L. 2018; 239: 242–46

  Abstract

  BACKGROUND: Previous studies have shown that individuals with mood disorders have a higher prevalence of both hypercortisolemia and insulin resistance. Insulin resistance is posited to contribute to the cognitive deficits observed in individuals who have depression. However, the mechanistic relationship between cortisol and insulin within the central nervous system remains to be further elucidated. This study aimed to evaluate the effects of the antiglucocorticoid agent, mifepristone, on metabolic function and cognitive performance in individuals receiving treatment for depressive disorders who were euthymic at baseline.METHODS: Participants were administered a 600 mg/day dose of mifepristone for 28 days. Oral glucose tolerance tests (OGTTs) and cognitive assessments measuring verbal memory and executive functioning were administered at baseline and after 28 days of treatment.RESULTS: Improvements in attention and verbal learning were associated with reduction of fasting plasma glucose (FPG) in response to mifepristone treatment.LIMITATIONS: Limitations include the open-label design of this study and a small sample size.CONCLUSIONS: The findings from this study suggest that improvement in fasting plasma glucose levels, upon administration of mifepristone, is associated with the improvement in early input of verbal information. Further studies are warranted in order to better evaluate the use of mifepristone or other antiglucocorticoid agents in treatment of mood disorders characterized by metabolic dysfunction.

  View details for PubMedID 30025313

• Insulin resistance, an unmasked culprit in depressive disorders: Promises for interventions NEUROPHARMACOLOGY Watson, K., Nasca, C., Aasly, L., McEwen, B., Rasgon, N. 2018; 136: 327–34

  View details for DOI 10.1016/j.neuropharm.2017.11.038

  View details for Web of Science ID 000440121600019

• Regularity of self-reported daily dosage of mood stabilizers and antipsychotics in patients with bipolar disorder INTERNATIONAL JOURNAL OF BIPOLAR DISORDERS Pilhatsch, M., Glenn, T., Rasgon, N., Alda, M., Sagduyu, K., Grof, P., Munoz, R., Marsh, W., Monteith, S., Severus, E., Bauer, R., Ritter, P., Whybrow, P. C., Bauer, M. 2018; 6: 10

  Abstract

  Polypharmacy is often prescribed for bipolar disorder, yet medication non-adherence remains a serious problem. This study investigated the regularity in the daily dosage taken of mood stabilizers and second generation antipsychotics.Daily self-reported data on medications taken and mood were available from 241 patients with a diagnosis of bipolar disorder who received treatment as usual. Patients who took the same mood stabilizer or second generation antipsychotic for ≥ 100 days were included. Approximate entropy was used to determine serial regularity in daily dosage taken. Generalized estimating equations were used to estimate if demographic or clinical variables were associated with regularity.There were 422 analysis periods available from the 241 patients. Patients took drugs on 84.4% of days. Considerable irregularity was found, mostly due to single-day omissions and dosage changes. Drug holidays (missing 3 or more consecutive days) were found in 35.8% of the analysis periods. Irregularity was associated with an increasing total number of psychotropic drugs taken (p = 0.009), the pill burden (p = 0.026), and the percent of days depressed (p = 0.049).Despite low missing percent of days, daily drug dosage may be irregular primarily due to single day omissions and dosage changes. Drug holidays are common. Physicians should expect to see partial adherence in clinical practice, especially with complex drug regimens. Daily dosage irregularity may impact the continuity of drug action, contribute to individual variation in treatment response, and needs further study.

  View details for DOI 10.1186/s40345-018-0118-8

  View details for Web of Science ID 000431244400001

  View details for PubMedID 29713845

• Allostatic Load Predictors of Treatment Response in Patients With Unremitted Depression Rasgon, N., Watson, K., Singh, M., Wroolie, T., Myoraku, A., Roat-Shumway, S. ELSEVIER SCIENCE INC. 2018: S36–S37

  View details for Web of Science ID 000432466300089

• Role of the Epigenetic Agent Acetyl-L-Carnitine as Gating Biomarker in Depression and Influences of Childhood Trauma Nasca, C., Bigio, B., Lee, F., Zelli, D., Young, S., Lau, T., Issler, O., Menard, C., Murrough, J., Kocsis, J., Russo, S., Nestler, E., Rasgon, N., McEwen, B. ELSEVIER SCIENCE INC. 2018: S35–S36

  View details for Web of Science ID 000432466300087

• Multivariate Associations Among Behavioral, Clinical, and Multimodal Imaging Phenotypes in Patients With Psychosis JAMA PSYCHIATRY Moser, D. A., Doucet, G. E., Lee, W., Rasgon, A., Krinsky, H., Leibu, E., Ing, A., Schumann, G., Rasgon, N., Frangou, S. 2018; 75 (4): 386–95

  Abstract

  Alterations in multiple neuroimaging phenotypes have been reported in psychotic disorders. However, neuroimaging measures can be influenced by factors that are not directly related to psychosis and may confound the interpretation of case-control differences. Therefore, a detailed characterization of the contribution of these factors to neuroimaging phenotypes in psychosis is warranted.To quantify the association between neuroimaging measures and behavioral, health, and demographic variables in psychosis using an integrated multivariate approach.This imaging study was conducted at a university research hospital from June 26, 2014, to March 9, 2017. High-resolution multimodal magnetic resonance imaging data were obtained from 100 patients with schizophrenia, 40 patients with bipolar disorder, and 50 healthy volunteers; computed were cortical thickness, subcortical volumes, white matter fractional anisotropy, task-related brain activation (during working memory and emotional recognition), and resting-state functional connectivity. Ascertained in all participants were nonimaging measures pertaining to clinical features, cognition, substance use, psychological trauma, physical activity, and body mass index. The association between imaging and nonimaging measures was modeled using sparse canonical correlation analysis with robust reliability testing.Multivariate patterns of the association between nonimaging and neuroimaging measures in patients with psychosis and healthy volunteers.The analyses were performed in 92 patients with schizophrenia (23 female [25.0%]; mean [SD] age, 27.0 [7.6] years), 37 patients with bipolar disorder (12 female [32.4%]; mean [SD] age, 27.5 [8.1] years), and 48 healthy volunteers (20 female [41.7%]; mean [SD] age, 29.8 [8.5] years). The imaging and nonimaging data sets showed significant covariation (r = 0.63, P < .001), which was independent of diagnosis. Among the nonimaging variables examined, age (r = -0.53), IQ (r = 0.36), and body mass index (r = -0.25) were associated with multiple imaging phenotypes; cannabis use (r = 0.23) and other substance use (r = 0.33) were associated with subcortical volumes, and alcohol use was associated with white matter integrity (r = -0.15). Within the multivariate models, positive symptoms retained associations with the global neuroimaging (r = -0.13), the cortical thickness (r = -0.22), and the task-related activation variates (r = -0.18); negative symptoms were mostly associated with measures of subcortical volume (r = 0.23), and depression/anxiety was associated with measures of white matter integrity (r = 0.12).Multivariate analyses provide a more accurate characterization of the association between brain alterations and psychosis because they enable the modeling of other key factors that influence neuroimaging phenotypes.

  View details for PubMedID 29516092

  View details for PubMedCentralID PMC5875357

• Brain and behavioral correlates of insulin resistance in youth with depression and obesity. Hormones and behavior Singh, M. K., Leslie, S. M., Packer, M. M., Zaiko, Y. V., Phillips, O. R., Weisman, E., Wall, D., Jo, B., Rasgon, N. L. 2018

  Abstract

  Depression, together with insulin resistance, is increasingly prevalent among youth. These conditions have traditionally been compartmentalized, but recent evidence suggests that a shared brain motivational network underlies their co-occurrence. We posit that, in the context of depressive symptoms, insulin resistance is associated with aberrant structure and functional connectivity in the Anterior Cingulate Cortex (ACC) and hippocampus. This motivational neural circuit underlies dysfunctional behavioral responses and increased sensitivity to rewarding aspects of ingesting high calorie food that lead to disinhibition of eating even when satiated. To investigate this shared mechanism, we evaluated a sample of forty-two depressed and overweight (BMI > 85th%) youth aged 9 to 17. Using ACC and hippocampus structural and seed-based regions of interest, we investigated associations between insulin resistance, depression, structure (ACC thickness, and ACC and hippocampal area), and resting-state functional connectivity (RSFC). We predicted that aberrant associations among these neural and behavioral characteristics would be stronger in insulin resistant compared to insulin sensitive youth. We found that youth with greater insulin resistance had higher levels of anhedonia and more food seeking behaviors, reduced hippocampal and ACC volumes, and greater levels of ACC and hippocampal dysconnectivity to fronto-limbic reward networks at rest. For youth with high levels of insulin resistance, thinner ACC and smaller hippocampal volumes were associated with more severe depressive symptoms, whereas the opposite was true for youth with low levels of insulin resistance. The ACC-hippocampal motivational network that subserves depression and insulin resistance separately, may represent a critical neural interaction that link these syndromes together.

  View details for PubMedID 29596854

• Elevated Body Mass Index is Associated with Increased Integration and Reduced Cohesion of Sensory-Driven and Internally Guided Resting-State Functional Brain Networks CEREBRAL CORTEX Doucet, G. E., Rasgon, N., McEwen, B. S., Micali, N., Frangou, S. 2018; 28 (3): 988–97

  Abstract

  Elevated body mass index (BMI) is associated with increased multi-morbidity and mortality. The investigation of the relationship between BMI and brain organization has the potential to provide new insights relevant to clinical and policy strategies for weight control. Here, we quantified the association between increasing BMI and the functional organization of resting-state brain networks in a sample of 496 healthy individuals that were studied as part of the Human Connectome Project. We demonstrated that higher BMI was associated with changes in the functional connectivity of the default-mode network (DMN), central executive network (CEN), sensorimotor network (SMN), visual network (VN), and their constituent modules. In siblings discordant for obesity, we showed that person-specific factors contributing to obesity are linked to reduced cohesiveness of the sensory networks (SMN and VN). We conclude that higher BMI is associated with widespread alterations in brain networks that balance sensory-driven (SMN, VN) and internally guided (DMN, CEN) states which may augment sensory-driven behavior leading to overeating and subsequent weight gain. Our results provide a neurobiological context for understanding the association between BMI and brain functional organization while accounting for familial and person-specific influences.

  View details for PubMedID 28119342

• An epigenetic biomarker for depression and trait of childhood trauma with sex-specific effects Nasca, C., Bigio, B., Young, S., Cochran, A., Beasley, J., Millington, D., Kocsis, J., Murrough, J., Lee, F., McEwen, B., Rasgon, N. ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER. 2018: S316

  View details for Web of Science ID 000461256104061

• Determinants of cognitive function in individuals with type 2 diabetes mellitus: A meta-analysis ANNALS OF CLINICAL PSYCHIATRY Mansur, R. B., Lee, Y., Zhou, A. J., Carmona, N. E., Cha, D. S., Rosenblat, J. D., Bruins, R., Kakar, R., Rasgon, N. L., Lovshin, J. A., Wroolie, T. E., Sim, K., Brietzke, E., Gerstein, H. C., Rong, C., McIntyre, R. S. 2018; 30 (1): 38–50

  Abstract

  Type 2 diabetes mellitus (T2DM) is associated with deficits across multiple cognitive domains; however, the determinants of cognitive impairment in T2DM are not well characterized. We aimed to evaluate body mass index (BMI), glycemic control, and T2DM duration as moderators of cognitive dysfunction in T2DM.We conducted a meta-analytic review of the literature reporting data on BMI, hemoglobin A1c (HbA1c), T2DM duration, and validated measures of processing speed (ie, Digit Symbol Substitution Test, Trail Making Test [TMT]-A), verbal learning and memory (ie, Rey Auditory Verbal Learning Test), and working memory/executive function (ie, TMT-B) among individuals with vs without T2DM.Individuals with T2DM demonstrated deficits across multiple cognitive domains (k = 40; n = 4,252 T2DM; n = 22,322 non-T2DM; effect sizes 0.21 to 0.35). Illness duration and BMI did not significantly moderate measures of cognition; however, higher HbA1c levels were significantly associated with deficits in measures of processing speed (R2 values 0.41 to 0.73, P < .01) and working memory/executive function (R2 = 0.62, P < .001).Adults with T2DM exhibited significant deficits across multiple domains of cognitive function. Additionally, we identified an association between poorer glycemic control and cognitive dysfunction. A clinical translation of our findings relates to the reduction in morbidity by improving glycemic control.

  View details for Web of Science ID 000438453600007

  View details for PubMedID 29373617

• Solar insolation in springtime influences age of onset of bipolar I disorder ACTA PSYCHIATRICA SCANDINAVICA Bauer, M., Glenn, T., Alda, M., Aleksandrovich, M. A., Andreassen, O. A., Angelopoulos, E., Ardau, R., Ayhan, Y., Baethge, C., Bharathram, S. R., Bauer, R., Baune, B. T., Becerra-Palars, C., Bellivier, F., Belmaker, R. H., Berk, M., Bersudsky, Y., Bicakci, S., Birabwa-Oketcho, H., Bjella, T. D., Bossini, L., Cabrera, J., Cheung, E. W., Del Zompo, M., Dodd, S., Donix, M., Etain, B., Fagiolini, A., Fountoulakis, K. N., Frye, M. A., Gonzalez-Pinto, A., Gottlieb, J. F., Grof, P., Harima, H., Henry, C., Isometsae, E. T., Janno, S., Kapczinski, F., Kardell, M., Khaldi, S., Kliwicki, S., Koenig, B., Kot, T. L., Krogh, R., Kunz, M., Lafer, B., Landen, M., Larsen, E. R., Lewitzka, U., Licht, R. W., Lopez-Jaramillo, C., MacQueen, G., Manchia, M., Marsh, W., Martinez-Cengotitabengoa, M., Melle, I., Meza-Urzua, F., Yee Ming, M., Monteith, S., Morken, G., Mosca, E., Munoz, R., Mythri, S. V., Nacef, F., Nadella, R. K., Nery, F. G., Nielsen, R. E., O'Donovan, C., Omrani, A., Osher, Y., Ostermark Sorensen, H., Ouali, U., Pica Ruiz, Y., Pilhatsch, M., Pinna, M., da Ponte, F. R., Quiroz, D., Ramesar, R., Rasgon, N., Reddy, M. S., Reif, A., Ritter, P., Rybakowski, J. K., Sagduyu, K., Scippa, A. M., Severus, E., Simhandl, C., Stein, D. J., Strejilevich, S., Subramaniam, M., Sulaiman, A. H., Suominen, K., Tagata, H., Tatebayashi, Y., Tondo, L., Torrent, C., Vaaler, A. E., Veeh, J., Vieta, E., Viswanath, B., Yoldi-Negrete, M., Zetin, M., Zgueb, Y., Whybrow, P. C. 2017; 136 (6): 571–82

  Abstract

  To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder.Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density.There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001).A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

  View details for DOI 10.1111/acps.12772

  View details for Web of Science ID 000414594900005

  View details for PubMedID 28722128

• Roles of Inflammation and Depression in the Development of Gestational Diabetes. Current behavioral neuroscience reports Robakis, T. K., Aasly, L., Williams, K. E., Clark, C., Rasgon, N. 2017; 4 (4): 369-383

  Abstract

  Inflammation, the body's response to harmful external agents, has long been found to be associated with depressive symptoms. The relationship between inflammation and depression is well established in the general population of people with depression, but is less so among perinatal women. Depression in the perinatal period is a common disorder, however available data do not indicate that there is a specific inflammatory picture associated with perinatal depression. We suggest that perinatal depression may be a heterogeneous construct, and that inflammation may be relevant to it in the context of other inflammatory morbidities of pregnancy. In this review we explore the available support for the hypothesis that inflammation associated with depression can represent a precipitating insult for the development of gestational diabetes, a known inflammatory morbidity of pregnancy.

  View details for DOI 10.1007/s40473-017-0131-8

  View details for PubMedID 30693175

  View details for PubMedCentralID PMC6348007

• Lifetime eating disorder comorbidity associated with delayed depressive recovery in bipolar disorder. International journal of bipolar disorders Balzafiore, D. R., Rasgon, N. L., Yuen, L. D., Shah, S., Kim, H., Goffin, K. C., Miller, S., Wang, P. W., Ketter, T. A. 2017; 5 (1): 25-?

  Abstract

  Although eating disorders (EDs) are common in bipolar disorder (BD), little is known regarding their longitudinal consequences. We assessed prevalence, clinical correlates, and longitudinal depressive severity in BD patients with vs. without EDs.Outpatients referred to Stanford University BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) affective disorders evaluation, and while receiving naturalistic treatment for up to 2 years, were monitored with the STEP-BD clinical monitoring form. Patients with vs. without lifetime EDs were compared with respect to prevalence, demographic and unfavorable illness characteristics/current mood symptoms and psychotropic use, and longitudinal depressive severity.Among 503 BD outpatients, 76 (15.1%) had lifetime EDs, which were associated with female gender, and higher rates of lifetime comorbid anxiety, alcohol/substance use, and personality disorders, childhood BD onset, episode accumulation (≥10 prior mood episodes), prior suicide attempt, current syndromal/subsyndromal depression, sadness, anxiety, and antidepressant use, and earlier BD onset age, and greater current overall BD severity. Among currently depressed patients, 29 with compared to 124 without lifetime EDs had significantly delayed depressive recovery. In contrast, among currently recovered (euthymic ≥8 weeks) patients, 10 with compared to 95 without lifetime EDs had only non-significantly hastened depressive recurrence.Primarily Caucasian, insured, suburban, American specialty clinic-referred sample limits generalizability. Small number of recovered patients with EDs limited statistical power to detect relationships between EDs and depressive recurrence.Further studies are warranted to explore the degree to which EDs impact longitudinal depressive illness burden in BD.

  View details for DOI 10.1186/s40345-017-0094-4

  View details for PubMedID 28480483

• Insulin resistance, an unmasked culprit in depressive disorders: Promises for interventions. Neuropharmacology Watson, K., Nasca, C., Aasly, L., McEwen, B., Rasgon, N. 2017

  Abstract

  Depressive disorders constitute a set of debilitating diseases with psychological, societal, economic and humanitarian consequences for millions of people worldwide. Scientists are beginning to understand the reciprocal communication between the brain and the rest of the body in the etiology of these diseases. In particular, scientists have noted a connection between depressive disorders, which are primarily seen as brain-based, and, insulin resistance (IR), a modifiable metabolic inflammatory state that is typically seen as peripheral. We highlight evidence showing how treating IR, with drugs or behavioral interventions, may ameliorate or possibly prevent, depressive disorders and their long-term consequences at various stages of the life course.

  View details for PubMedID 29180223

• Association of Fasting Insulin Levels and Depression Severity With Resting-State Functional Connectivity in Depressed Adolescents Leslie, S., Weisman, E., Staver, A., Wall, D., Andrade, A., Zaiko, Y., Onopa, A., Packer, M., Phillips, O., Rasgon, N., Singh, M. NATURE PUBLISHING GROUP. 2017: S381

  View details for Web of Science ID 000416846302137

• Treatment with a GLP-1R agonist over four weeks promotes weight loss-moderated changes in frontal-striatal brain structures in individuals with mood disorders EUROPEAN NEUROPSYCHOPHARMACOLOGY Mansur, R. B., Zugman, A., Ahmed, J., Cha, D. S., Subramaniapillai, M., Lee, Y., Lovshin, J., Lee, J. G., Lee, J., Drobinin, V., Newport, J., Brietzke, E., Reininghaus, E. Z., Sim, K., Vinberg, M., Rasgon, N., Hajek, T., McIntyre, R. S. 2017; 27 (11): 1153–62

  Abstract

  Cognitive deficits are a core feature across psychiatric disorders. Emerging evidence indicates that metabolic pathways are highly relevant for the substrates and phenomenology of the cognitive domain. Herein, we aimed to determine the effects of liraglutide, a GLP-1R agonist, on brain structural/volumetric parameters in adults with a mood disorder. This is the secondary analysis of a 4-week, pilot, proof-of-concept, open-label study. Participants (N=19) exhibiting impairments in executive function with either major depressive disorder (MDD) or bipolar disorder (BD) were recruited. Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy. Structural magnetic resonance imaging (MRI) scanning was obtained at baseline and endpoint. Results showed that at endpoint there was significant weight loss (mean: 3.15%; p<0.001). Changes in frontal and striatal volumes were significantly correlated with changes in body mass index (BMI), indicating the weight loss was associated with volume increase in most regions (e.g. r=-0.561, p=0.042 in the left superior frontal area). After adjusting for intracranial volume, age, gender, and BMI, we observed significant changes from baseline to endpoint in multiple regions (e.g. RR: 1.011, p=0.049 in the left rostral middle frontal area). Changes in regional volumes were associated with improvement in executive function (e.g. r=0.698, p=0.003 for the right superior frontal area). Adjunctive liraglutide results in clinically significant weight loss, with corresponding improvement in cognitive function; changes in cognitive function were partially moderated by changes in brain morphometry, underscoring the interrelationship between weight and brain structure/function.

  View details for PubMedID 28867303

• Attachment Insecurity and DNA Methylation in Risk for Postpartum Depression Robakis, T., On, B., Budhan, V., Crowe, S., Williams, K., Rasgon, N., Urban, A. ELSEVIER SCIENCE INC. 2017: S298

  View details for DOI 10.1016/j.biopsych.2017.02.803

  View details for Web of Science ID 000400348700733

• Insulin resistance and telomere length in treatment of depressive disorders Rasgon, N., McEwen, B., Lin, K. W. ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER. 2017: S61–S62

  View details for DOI 10.1016/j.eurpsy.2017.01.052

  View details for Web of Science ID 000404952200188

• Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: A pilot, open-label study JOURNAL OF AFFECTIVE DISORDERS Mansur, R. B., Ahmed, J., Cha, D. S., Woldeyohannes, H. O., Subramaniapillai, M., Lovshin, J., Lee, J. G., Lee, J., Brietzke, E., Reininghaus, E. Z., Sim, K., Vinberg, M., Rasgon, N., Hajek, T., McIntyre, R. S. 2017; 207: 114-120

  Abstract

  There is a paucity of treatments that are capable of reliably and robustly improving cognitive function in adults with mood disorders. Glucagon-like peptide-1 is synthesized centrally and its receptors are abundantly expressed in neural circuits subserving cognitive function. We aimed to determine the effects of liraglutide, a GLP-1 receptor (GLP-1R) agonist, on objective measures of cognition in adults with a depressive or bipolar disorder.In this 4-week, pilot, open-label, domain-based study (e.g. cognition), we recruited 19 individuals with major depressive disorder (MDD) or bipolar disorder (BD) and an impairment in executive function, defined as a below-average performance in the Trail Making Test-B (TMTB). Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy.Participants had significant increases from baseline to week 4 in the TMTB standard score (age and education corrected) (Cohen's d=0.64, p=0.009) and in a composite Z-score comprising multiple cognitive tests (i.e. Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Stroop test) (Cohen's d=0.77, p<0.001). Neither changes in mood rating scales nor metabolic parameters were associated with changes in cognitive performance (all p>0.05); however baseline insulin resistance (IR) and body mass index (BMI) moderated the changes in the composite Z-score (p=0.021 and p=0.046, respectively), indicating larger responses in individuals with higher IR and BMI at baseline. There was a significant increase in lipase (p<0.001), but individual values were above the upper limit of normality.Small sample size, open-label design, lack of a placebo group.Liraglutide was safe and well tolerated by a sample of non-diabetic individuals with mood disorders and had beneficial effects on objective measures of cognitive function. Larger studies with controlled trial designs are necessary to confirm and expand the results described herein.

  View details for DOI 10.1016/j.jad.2016.09.056

  View details for Web of Science ID 000389088600017

• Roles of Inflammation and Depression in the Development of Gestational Diabetes Current Behavioral Neuroscience Reports Robakis, T. K., Aasly, L., Williams, K. E., Clark, C., Rasgon, N. L. 2017; 4 (4)

  View details for DOI 10.1007/s40473-017-0131-8

• Histopathology and Florbetaben PET in Patients Incorrectly Diagnosed with Alzheimer's Disease. Journal of Alzheimer's disease : JAD Sabbagh, M. N., Schäuble, B., Anand, K., Richards, D., Murayama, S., Akatsu, H., Takao, M., Rowe, C. C., Masters, C. L., Barthel, H., Gertz, H., Peters, O., Rasgon, N., Jovalekic, A., Sabri, O., Schulz-Schaeffer, W. J., Seibyl, J. 2017; 56 (2): 441-446

  Abstract

  Of 57 individuals diagnosed with Alzheimer's disease (AD) in a phase III study, 13 (23%) had amyloid-β (Aβ) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aβ pathology.

  View details for DOI 10.3233/JAD-160821

  View details for PubMedID 27983552

• Insulin resistance-a missing link no more MOLECULAR PSYCHIATRY Rasgon, N. L., McEwen, B. S. 2016; 21 (12): 1648–52

  View details for PubMedID 27698431

• Intrinsic Brain Connectivity in Youth With Depression at High Risk for Insulin Insensitivity Singh, M., Leslie, S., Foland-Ross, L., Weisman, E., Bhattacharjee, K., Onopa, A., Soudi, L., Staver, A., Bohon, C., Rasgon, N. NATURE PUBLISHING GROUP. 2016: S185–S186

  View details for Web of Science ID 000440365600330

• Postpartum Psychosis: Madness, Mania, and Melancholia in Motherhood AMERICAN JOURNAL OF PSYCHIATRY Bergink, V., Rasgon, N., Wisner, K. L. 2016; 173 (12): 1179–88

  Abstract

  Psychosis or mania after childbirth is a psychiatric emergency with risk for suicide and infanticide.The authors reviewed the epidemiologic and genetic research and physiological postpartum triggers (endocrine, immunological, circadian) of psychosis. They also summarized all systematic reviews and synthesized the sparse clinical studies to provide diagnostic recommendations, treatment options, and strategies for prevention.The incidence of first-lifetime onset postpartum psychosis/mania from population-based register studies of psychiatric admissions varies from 0.25 to 0.6 per 1,000 births. After an incipient episode, 20%-50% of women have isolated postpartum psychosis. The remaining women have episodes outside the perinatal period, usually within the bipolar spectrum. Presumably, the mechanism of onset is related to physiological changes after birth (e.g., hormonal, immunological, circadian), which precipitate disease in genetically vulnerable women. Some women have treatable causes and comorbidities, such as autoimmune thyroiditis or infections. N-methyl-d-aspartate-encephalitis or inborn errors of metabolism may present after birth with psychosis. Fewer than 30 publications have focused on the treatment of postpartum psychosis. The largest study (N=64) provided evidence that lithium is highly efficacious for both acute and maintenance treatment. Another report (N=34) described successful ECT treatment. Inpatient care is usually required to ensure safety, complete the diagnostic evaluation, and initiate treatment. The relapse risk after a subsequent pregnancy for women with isolated postpartum psychoses is 31% (95% CI=22-42). Strategies for prevention of postpartum psychosis include lithium prophylaxis immediately postpartum and proactive safety monitoring.Postpartum psychosis offers an intriguing model to explore etiologic contributions to the neurobiology of affective psychosis.

  View details for PubMedID 27609245

• More Time for Science and Less Time for Administration? NEUROPSYCHOPHARMACOLOGY Nemeroff, C. B., Rasgon, N. 2016; 41 (11): 2625–26

  View details for PubMedID 27277117

  View details for PubMedCentralID PMC5026746

• Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: A pilot, open-label study. Journal of affective disorders Mansur, R. B., Ahmed, J., Cha, D. S., Woldeyohannes, H. O., Subramaniapillai, M., Lovshin, J., Lee, J. G., Lee, J., Brietzke, E., Reininghaus, E. Z., Sim, K., Vinberg, M., Rasgon, N., Hajek, T., McIntyre, R. S. 2016; 207: 114-120

  Abstract

  There is a paucity of treatments that are capable of reliably and robustly improving cognitive function in adults with mood disorders. Glucagon-like peptide-1 is synthesized centrally and its receptors are abundantly expressed in neural circuits subserving cognitive function. We aimed to determine the effects of liraglutide, a GLP-1 receptor (GLP-1R) agonist, on objective measures of cognition in adults with a depressive or bipolar disorder.In this 4-week, pilot, open-label, domain-based study (e.g. cognition), we recruited 19 individuals with major depressive disorder (MDD) or bipolar disorder (BD) and an impairment in executive function, defined as a below-average performance in the Trail Making Test-B (TMTB). Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy.Participants had significant increases from baseline to week 4 in the TMTB standard score (age and education corrected) (Cohen's d=0.64, p=0.009) and in a composite Z-score comprising multiple cognitive tests (i.e. Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Stroop test) (Cohen's d=0.77, p<0.001). Neither changes in mood rating scales nor metabolic parameters were associated with changes in cognitive performance (all p>0.05); however baseline insulin resistance (IR) and body mass index (BMI) moderated the changes in the composite Z-score (p=0.021 and p=0.046, respectively), indicating larger responses in individuals with higher IR and BMI at baseline. There was a significant increase in lipase (p<0.001), but individual values were above the upper limit of normality.Small sample size, open-label design, lack of a placebo group.Liraglutide was safe and well tolerated by a sample of non-diabetic individuals with mood disorders and had beneficial effects on objective measures of cognitive function. Larger studies with controlled trial designs are necessary to confirm and expand the results described herein.

  View details for DOI 10.1016/j.jad.2016.09.056

  View details for PubMedID 27721184

• Puberty-specific presentations of bipolar bisorder Holtzman, J. N., Miller, S., Hooshmand, F., Wang, P. W., Chang, K. D., Goffin, K. C., Hill, S. J., Ketter, T. A., Rasgon, N. L. WILEY-BLACKWELL. 2016: 42-+

  View details for Web of Science ID 000379941500088

• Gender by onset age interaction may characterize distinct phenotypic subgroups in bipolar patients JOURNAL OF PSYCHIATRIC RESEARCH Holtzman, J. N., Miller, S., Hooshmand, F., Wang, P. W., Chang, K. D., Goffin, K. C., Hill, S. J., Ketter, T. A., Rasgon, N. L. 2016; 76: 128-135

  Abstract

  Although bipolar disorder (BD) is a common recurrent condition with highly heterogeneous illness course, data are limited regarding clinical implications of interactions between gender and onset age. We assessed relationships between onset age and demographic/illness characteristics among BD patients stratified by gender.Demographic and unfavorable illness characteristics, descriptive traits, and clinical correlates were compared in 502 patients from Stanford University BD Clinic patients enrolled in the Systematic Treatment Enhancement Program for BD between 2000 and 2011, stratified by gender, across pre-, peri-, and post-pubertal (<12, 13-16, and >17 years, respectively) onset-age subgroups.Among 502 BD patients, 58.2% were female, of whom 21.9% had pre-pubertal, 30.7% peri-pubertal, and 47.4% post-pubertal onset. Between genders, although demographics, descriptive characteristics, and most clinical correlates were statistically similar, there were distinctive onset-age related patterns of unfavorable illness characteristics. Among females, rates of 6/8 primary unfavorable illness characteristics were significantly higher in pre-pubertal and peri-pubertal compared to post-pubertal onset patients. However, among males, rates of only 3/8 unfavorable illness characteristics were significantly higher in only pre-pubertal versus post-pubertal onset patients, and none between peri-pubertal versus post-pubertal onset patients.Caucasian, insured, suburban, American specialty clinic-referred sample limits generalizability, onset age based on retrospective recall.We describe different phenotypic presentations across age at illness onset groups according to gender. Among females and males, peri-pubertal and post-pubertal onset age groups were more different and more similar, respectively. Further investigation is warranted to assess implications of gender-by-onset-age interactions to more accurately delineate distinctive BD phenotypes.

  View details for DOI 10.1016/j.jpsychires.2016.02.009

  View details for PubMedID 26926801

• Maternal attachment insecurity is a potent predictor of depressive symptoms in the early postnatal period JOURNAL OF AFFECTIVE DISORDERS Robakis, T. K., Williams, K. E., Crowe, S., Lin, K. W., Gannon, J., Rasgon, N. L. 2016; 190: 623-631

  View details for DOI 10.1016/j.jad.2015.09.067

  View details for Web of Science ID 000366463000086

  View details for PubMedCentralID PMC4897028

• Maternal attachment insecurity is a potent predictor of depressive symptoms in the early postnatal period. Journal of affective disorders Robakis, T. K., Williams, K. E., Crowe, S., Lin, K. W., Gannon, J., Rasgon, N. L. 2016; 190: 623-631

  View details for DOI 10.1016/j.jad.2015.09.067

  View details for PubMedID 26583352

  View details for PubMedCentralID PMC4897028

• Telomere length as a predictor of response to Pioglitazone in patients with unremitted depression: a preliminary study TRANSLATIONAL PSYCHIATRY Rasgon, N., Lin, K. W., Lin, J., Epel, E., Blackburn, E. 2016; 6

  Abstract

  We studied peripheral leukocyte telomere length (LTL) as a predictor of antidepressant response to PPAR-γ agonist in patients with unremitted depression. In addition we examined correlation between LTL and the insulin resistance (IR) status in these subjects. Forty-two medically stable men and women ages 23-71 with non-remitted depression participated in double-blind placebo-controlled add-on of Pioglitazone to treatment-as-usual. Oral glucose tolerance tests were administered at baseline and at 12 weeks. Diagnostic evaluation of psychiatric disorders was performed at baseline and mood severity was followed weekly throughout the duration of the trial. At baseline, no differences in LTL were detected by depression severity, duration or chronicity. LTL was also not significantly different between insulin-resistant and insulin-sensitive subjects at baseline. Subjects with longer telomeres exhibited greater declines in depression severity in the active arm, but not in a placebo arm, P=0.005, r=-0.63, 95% confidence interval (95% CI)=(-0.84,-0.21). In addition, LTL predicted improvement in insulin sensitivity in the group overall and did not differ between intervention arms, P=0.036, r=-0.44, 95% CI=(-0.74,0.02) for the active arm, and P=0.026, r=-0.50, 95% CI=(-0.78,-0.03) for the placebo arm. LTL may emerge as a viable predictor of antidepressant response. An association between insulin sensitization and LTL regardless of the baseline IR status points to potential role of LTL as a non-specific moderator of metabolic improvement in these patients.

  View details for DOI 10.1038/tp.2015.187

  View details for Web of Science ID 000368549500009

• Diagnosing binge eating disorder in a primary care setting POSTGRADUATE MEDICINE Montano, C., Rasgon, N. L., Herman, B. K. 2016; 128 (1): 115–23

  Abstract

  Binge eating disorder (BED), now recognized as a distinct eating disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, is the most prevalent eating disorder. Although nearly half of individuals with BED are obese, BED also occurs in nonobese individuals. Despite the relatively high percentage of weight loss treatment-seeking individuals meeting BED criteria, primary care physicians may not be familiar with or have ever diagnosed BED. Many providers may also have difficulty distinguishing BED as a contributory factor in obesity. This review differentiates BED from other causes of obesity by describing how obese individuals with BED differ from obese individuals without BED and from nonobese individuals with BED in areas including psychopathology, behavior, genetics, physiology, quality of life and productivity. The ways in which health-care providers can identify individuals who may have BED are also highlighted so the proper course of treatment is pursued. Overall, obese individuals with BED demonstrate a number of key characteristics that differentiate them from obese individuals without eating disorders, including increased impulsivity in response to food stimuli with loss of control over eating, resulting in the consumption of more calories. They also experience significant guilt and other negative emotions following a meal. In addition, individuals with BED patients have more psychiatric comorbidity, display more psychopathology, exhibit longer binge durations, consume more meals as snacks during the day and have less dietary restraint compared with individuals with BED who are not obese. However, the differences between individuals with BED who are obese versus not obese are not as prominent. Taken together, the evidence appears to support the conclusion that BED is a unique and treatable neurobehavioral disorder associated with distinct behavioral and psychological profiles and distinct medical and functional outcomes, and that it is not merely a subtype of obesity.

  View details for PubMedID 26592916

• Telomere length as a predictor of response to Pioglitazone in patients with unremitted depression: a preliminary study. Translational psychiatry Rasgon, N., Lin, K. W., Lin, J., Epel, E., Blackburn, E. 2016; 6

  Abstract

  We studied peripheral leukocyte telomere length (LTL) as a predictor of antidepressant response to PPAR-γ agonist in patients with unremitted depression. In addition we examined correlation between LTL and the insulin resistance (IR) status in these subjects. Forty-two medically stable men and women ages 23-71 with non-remitted depression participated in double-blind placebo-controlled add-on of Pioglitazone to treatment-as-usual. Oral glucose tolerance tests were administered at baseline and at 12 weeks. Diagnostic evaluation of psychiatric disorders was performed at baseline and mood severity was followed weekly throughout the duration of the trial. At baseline, no differences in LTL were detected by depression severity, duration or chronicity. LTL was also not significantly different between insulin-resistant and insulin-sensitive subjects at baseline. Subjects with longer telomeres exhibited greater declines in depression severity in the active arm, but not in a placebo arm, P=0.005, r=-0.63, 95% confidence interval (95% CI)=(-0.84,-0.21). In addition, LTL predicted improvement in insulin sensitivity in the group overall and did not differ between intervention arms, P=0.036, r=-0.44, 95% CI=(-0.74,0.02) for the active arm, and P=0.026, r=-0.50, 95% CI=(-0.78,-0.03) for the placebo arm. LTL may emerge as a viable predictor of antidepressant response. An association between insulin sensitization and LTL regardless of the baseline IR status points to potential role of LTL as a non-specific moderator of metabolic improvement in these patients.

  View details for DOI 10.1038/tp.2015.187

  View details for PubMedID 26731446

• Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response PSYCHIATRY RESEARCH Lin, K. W., Wroolie, T. E., Robakis, T., Rasgon, N. L. 2015; 230 (3): 846-852

  Abstract

  Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPARγ-agonist pioglitazone. Patients (N=37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction.

  View details for DOI 10.1016/j.psychres.2015.10.013

  View details for Web of Science ID 000367860900016

• Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response. Psychiatry research Lin, K. W., Wroolie, T. E., Robakis, T., Rasgon, N. L. 2015; 230 (3): 846-52

  Abstract

  Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPARγ-agonist pioglitazone. Patients (N=37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction.

  View details for DOI 10.1016/j.psychres.2015.10.013

  View details for PubMedID 26602230

• Common use of dietary supplements for bipolar disorder: a naturalistic, self-reported study. International journal of bipolar disorders Bauer, M., Glenn, T., Conell, J., Rasgon, N., Marsh, W., Sagduyu, K., Munoz, R., Lewitzka, U., Bauer, R., Pilhatsch, M., Monteith, S., Whybrow, P. C. 2015; 3 (1): 29-?

  Abstract

  Dietary supplements are taken by about half of Americans. Knowledge of dietary supplement use is important because they may interact with prescription drugs or other supplements, cause adverse reactions including psychiatric symptoms, or contain inherently toxic ingredients or contaminants. This study explores the use of dietary supplements by patients with bipolar disorder in the US.Data were obtained from an ongoing, naturalistic study of patients with bipolar disorder who received pharmacological treatment as usual. The patients self-reported their daily mood, sleep, and medications taken, including all drugs prescribed for bipolar disorder or that the patient felt impacted their mood. These included other prescribed drugs, over-the-counter drugs and dietary supplements. Drugs that received premarketing approval from the FDA were not included as dietary supplements. Patient demographics and daily medication use were characterized.Data were available from 348 patients in the US who returned a mean 249.5 days of data. In addition to prescribed psychiatric drugs, 101 of the 348 patients (29 %) used a dietary supplement for at least 7 days and 69 (20 %) used a supplement long term (for at least 50 % of days). Of the 101 supplement users, 72 (71.3 %) took one supplement daily. The 101 patients tried over 40 different supplements, and the long-term users took 19 different supplements. The most commonly taken supplements for both groups were fish oil, B vitamins, melatonin, and multivitamins. Patients using supplements were more likely to be white (p < 0.001), older (p = 0.009), and ill for more years (p = 0.025).Many patients with bipolar disorder use dietary supplements in addition to prescribed drugs. Physicians should obtain detailed information about all dietary supplements taken by patients with bipolar disorder.

  View details for DOI 10.1186/s40345-015-0029-x

  View details for PubMedID 26033382

  View details for PubMedCentralID PMC4451053

• Telomere Length as a Predictor of Response to Pioglitazone in Patients with Unremitted Depression: A Preliminary Study Rasgon, N., Lin, K., Lin, J., Epel, E., Jones, M., Roat-Shumway, S., Blackburn, E. NATURE PUBLISHING GROUP. 2015: S160–S161

  View details for Web of Science ID 000366597700293

• Cognitive Effects of Hormone Therapy Continuation or Discontinuation in a Sample of Women at Risk for Alzheimer Disease. American journal of geriatric psychiatry Wroolie, T. E., Kenna, H. A., Williams, K. E., Rasgon, N. L. 2015; 23 (11): 1117-1126

  Abstract

  Use of estrogen-based hormone therapy (HT) as a protection from cognitive decline and Alzheimer disease (AD) is controversial, although cumulative data support HT use when initiated close to menopause onset with estrogen formulations containing 17β-estradiol preferable to conjugated equine estrogen formulations. Little is known regarding specific populations of women who may derive benefit from HT.Women with heightened risk for AD (aged 49-69), all of whom were taking HT for at least 1 year and most of whom initiated HT close to menopause onset, underwent cognitive assessment followed by randomization to continue or discontinue HT. Assessments were repeated at 2 years after randomization.Women who continued HT performed better on cognitive domains composed of measures of verbal memory and combined attention, working memory, and processing speed measures. Women who used 17β-estradiol versus conjugated equine estrogen, whether randomized to continue or discontinue HT, showed better verbal memory performance at the 2-year follow-up assessment. An interaction was also found with HT randomization and family history of AD in a first-degree relative. All female offspring of patients with AD declined in verbal memory; however, women who continued HT declined less than women who discontinued HT. Women without a first-degree relative with AD showed verbal memory improvement (likely because of practice effects) with continuance and declined with discontinuance of HT.Continuation of HT use appears to protect cognition in women with heightened risk for AD when initiated close to menopause onset.

  View details for DOI 10.1016/j.jagp.2015.05.009

  View details for PubMedID 26209223

  View details for PubMedCentralID PMC4654994

• Childhood-compared to adolescent-onset bipolar disorder has more statistically significant clinical correlates JOURNAL OF AFFECTIVE DISORDERS Holtzman, J. N., Miller, S., Hooshmand, F., Wang, P. W., Chang, K. D., Hill, S. J., Rasgon, N. L., Ketter, T. A. 2015; 179: 114-120

  Abstract

  The strengths and limitations of considering childhood-and adolescent-onset bipolar disorder (BD) separately versus together remain to be established. We assessed this issue.BD patients referred to the Stanford Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation. Patients with childhood- and adolescent-onset were compared to those with adult-onset for 7 unfavorable bipolar illness characteristics with replicated associations with early-onset patients.Among 502 BD outpatients, those with childhood- (<13 years, N=110) and adolescent- (13-18 years, N=218) onset had significantly higher rates for 4/7 unfavorable illness characteristics, including lifetime comorbid anxiety disorder, at least ten lifetime mood episodes, lifetime alcohol use disorder, and prior suicide attempt, than those with adult-onset (>18 years, N=174). Childhood- but not adolescent-onset BD patients also had significantly higher rates of first-degree relative with mood disorder, lifetime substance use disorder, and rapid cycling in the prior year. Patients with pooled childhood/adolescent - compared to adult-onset had significantly higher rates for 5/7 of these unfavorable illness characteristics, while patients with childhood- compared to adolescent-onset had significantly higher rates for 4/7 of these unfavorable illness characteristics.Caucasian, insured, suburban, low substance abuse, American specialty clinic-referred sample limits generalizability. Onset age is based on retrospective recall.Childhood- compared to adolescent-onset BD was more robustly related to unfavorable bipolar illness characteristics, so pooling these groups attenuated such relationships. Further study is warranted to determine the extent to which adolescent-onset BD represents an intermediate phenotype between childhood- and adult-onset BD.

  View details for DOI 10.1016/j.jad.2015.03.019

  View details for PubMedID 25863906

• Prevalence and socio-demographic and clinical correlates of eating disorder comorbidity in bipolar disorder patients Balzafiore, D., Kim, H., Goffin, K., Rasgon, N., Ketter, T. WILEY-BLACKWELL. 2015: 114–15

  View details for Web of Science ID 000355338100321

• Influence of light exposure during early life on the age of onset of bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Bauer, M., Glenn, T., Alda, M., Andreassen, O. A., Angelopoulos, E., Ardau, R., Baethge, C., Bauer, R., Baune, B. T., Bellivier, F., Belmaker, R. H., Berk, M., Bjella, T. D., Bossini, L., Bersudsky, Y., Cheung, E. Y., Conell, J., Del Zompo, M., Dodd, S., Etain, B., Fagiolini, A., Frye, M. A., Fountoulakis, K. N., Garneau-Fournier, J., Gonzalez-Pinto, A., Gottlieb, J. F., Harima, H., Hassel, S., Henry, C., Iacovides, A., Isometsa, E. T., Kapczinski, F., Kliwicki, S., Koenig, B., Krogh, R., Kunz, M., Lafer, B., Larsen, E. R., Lewitzka, U., Lopez-Jaramillo, C., MacQueen, G., Manchia, M., Marsh, W., Martinez-Cengotitabengo, M., Melle, I., Monteith, S., Morken, G., Munoz, R., Nery, F. G., O'Donovan, C., Osher, Y., Pfennig, A., Quiroz, D., Ramesar, R., Rasgon, N., Reif, A., Ritter, P., Rybakowski, J. K., Sagduyu, K., Miranda-Scippa, A., Severus, E., Simhandl, C., Stein, D. J., Strejilevich, S., Sulaiman, A. H., Suominen, K., Tagata, H., Tatebayashi, Y., Torrent, C., Vieta, E., Viswanath, B., Wanchoo, M. J., Zetin, M., Whybrow, P. C. 2015; 64: 1-8

  Abstract

  Environmental conditions early in life may imprint the circadian system and influence response to environmental signals later in life. We previously determined that a large springtime increase in solar insolation at the onset location was associated with a younger age of onset of bipolar disorder, especially with a family history of mood disorders. This study investigated whether the hours of daylight at the birth location affected this association.Data collected previously at 36 collection sites from 23 countries were available for 3896 patients with bipolar I disorder, born between latitudes of 1.4 N and 70.7 N, and 1.2 S and 41.3 S. Hours of daylight variables for the birth location were added to a base model to assess the relation between the age of onset and solar insolation.More hours of daylight at the birth location during early life was associated with an older age of onset, suggesting reduced vulnerability to the future circadian challenge of the springtime increase in solar insolation at the onset location. Addition of the minimum of the average monthly hours of daylight during the first 3 months of life improved the base model, with a significant positive relationship to age of onset. Coefficients for all other variables remained stable, significant and consistent with the base model.Light exposure during early life may have important consequences for those who are susceptible to bipolar disorder, especially at latitudes with little natural light in winter. This study indirectly supports the concept that early life exposure to light may affect the long term adaptability to respond to a circadian challenge later in life.

  View details for DOI 10.1016/j.jpsychires.2015.03.013

  View details for Web of Science ID 000354342000001

  View details for PubMedID 25862378

• Lamotrigine and GABAA receptor modulators interact with menstrual cycle phase and oral contraceptives to regulate mood in women with bipolar disorder. Journal of affective disorders Robakis, T. K., Holtzman, J., Stemmle, P. G., Reynolds-May, M. F., Kenna, H. A., Rasgon, N. L. 2015; 175: 108-115

  Abstract

  To examine the occurrence of menstrually-entrained mood cycling in women with treated bipolar disorder as compared to healthy controls, and to explore whether there is a specific effect of lamotrigine in dampening menstrually-entrained cyclicity of mood.Observational comparison study of daily self-ratings of mood, sleep, and insomnia obtained over a mean of four menstrual cycles in 42 women with bipolar disorder taking lamotrigine as part of their treatment, 30 women with bipolar disorder receiving mood stabilizing regimens without lamotrigine, and 13 healthy controls, all with physiological menstrual cycles. Additional exploratory analysis of interactions between psychopharmacological regimen and hormonal contraceptive use in the group of women with bipolar disorder, with the addition of 19 women with bipolar disorder who were using hormonal contraceptives.Women treated for bipolar disorder manifested lower average mood, longer average nightly sleep duration, and greater fluctuations in mood and sleep across menstrual cycle phases than healthy controls. Women with bipolar disorder who were taking lamotrigine had less fluctuation in mood both within and across menstrual cycle phases, and were more similar to the control group than to women with bipolar disorder who were not taking lamotrigine in this respect. In addition, medications with GABA-A receptor modulating effects were found to result in improved mood ratings when combined with hormonal contraceptives.Menstrually-entrained mood fluctuation is present in women treated for bipolar disorder to a greater degree than in healthy controls. Lamotrigine may be of use in mitigating this fluctuation. GABA-A receptor modulators in general may act synergistically with hormonal contraceptives to enhance mood in women with bipolar disorder; this hypothesis merits further study.

  View details for DOI 10.1016/j.jad.2014.12.040

  View details for PubMedID 25601310

  View details for PubMedCentralID PMC4352404

• Optimistic outlook regarding maternity protects against depressive symptoms postpartum ARCHIVES OF WOMENS MENTAL HEALTH Robakis, T. K., Williams, K. E., Crowe, S., Kenna, H., Gannon, J., Rasgon, N. L. 2015; 18 (2): 197-208

  Abstract

  The transition to motherhood is a time of elevated risk for clinical depression. Dispositional optimism may be protective against depressive symptoms; however, the arrival of a newborn presents numerous challenges that may be at odds with initially positive expectations, and which may contribute to depressed mood. We have explored the relative contributions of antenatal and postnatal optimism regarding maternity to depressive symptoms in the postnatal period. Ninety-eight pregnant women underwent clinician interview in the third trimester to record psychiatric history, antenatal depressive symptoms, and administer a novel measure of optimism towards maternity. Measures of depressive symptoms, attitudes to maternity, and mother-to-infant bonding were obtained from 97 study completers at monthly intervals through 3 months postpartum. We found a positive effect of antenatal optimism, and a negative effect of postnatal disconfirmation of expectations, on depressive mood postnatally. Postnatal disconfirmation, but not antenatal optimism, was associated with more negative attitudes toward maternity postnatally. Antenatal optimism, but not postnatal disconfirmation, was associated with reduced scores on a mother-to-infant bonding measure. The relationships between antenatal optimism, postnatal disconfirmation of expectations, and postnatal depression held true among primigravidas and multigravidas, as well as among women with prior histories of mood disorders, although antenatal optimism tended to be lower among women with mental health histories. We conclude that cautious antenatal optimism, rather than immoderate optimism or frank pessimism, is the approach that is most protective against postnatal depressive symptoms, and that this is true irrespective of either mood disorder history or parity. Factors predisposing to negative cognitive assessments and impaired mother-to-infant bonding may be substantially different than those associated with depressive symptoms, a finding that merits further study.

  View details for DOI 10.1007/s00737-014-0446-3

  View details for Web of Science ID 000351476400006

  View details for PubMedID 25088532

• Brain Derived Neurotrophic Factor and Biomarkers of Insulin Resistance in Women with BD Rasgon, N. ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER. 2015

  View details for DOI 10.1016/S0924-9338(15)30070-5

  View details for Web of Science ID 000361116600071

• Association between insulin resistance and cognition in patients with depressive disorders: Exploratory analyses into age-specific effects JOURNAL OF PSYCHIATRIC RESEARCH Wroolie, T. E., Kenna, H. A., Singh, M. K., Rasgon, N. L. 2015; 60: 65-72

  Abstract

  The current preliminary cross sectional study sought to examine the effects of insulin resistance (IR) and body mass index (BMI) on cognitive performance in adult patients with a history depression, currently not in an acute Major Depressive Episode (MDD). As an exploratory post hoc investigation, special consideration was given to adults <45 years and ≥45 years old. Subjects included men and women ages 19-71 (N = 39) with a history of a non-psychotic, non-melancholic MDD. All subjects underwent an insulin suppression test to determine Steady-State Plasma Glucose (SSPG), a battery of neuropsychological tests, and measurement of BMI. Multiple linear regressions were conducted to determine whether there were differential effects of direct (SSPG) and indirect (BMI) measures on cognition in the whole sample and within dichotomized age groups (<45 and ≥45 years). Preliminary results showed that in the sample as a whole, SSPG was not associated with worse performance on any cognitive variables, while higher BMI was associated with worse dominant hand fine motor skills. Within age groups, differential effects on cognition were found in relation to SSPG and BMI. Higher SSPG was associated with worse cognitive flexibility in the group <45 years, whereas higher BMI was associated with worse estimate of global intelligence in the group ≥45 years. The potential negative impact of IR in younger adults with depression raises concerns regarding the long-term impact on cognition and risk for Alzheimer's disease in undiagnosed younger adults with IR and depression. These negative consequences may not be seen with indirect measures of IR in younger adult populations. Overweight and obesity in older adults with a history of depression appear to have further negative impacts on cognition similar to deficits seen in patients with diabetes.Clinical Trial NCT01106313.

  View details for DOI 10.1016/j.jpsychires.2014.10.001

  View details for Web of Science ID 000347268500008

• Association between insulin resistance and cognition in patients with depressive disorders: exploratory analyses into age-specific effects. Journal of psychiatric research Wroolie, T. E., Kenna, H. A., Singh, M. K., Rasgon, N. L. 2015; 60: 65-72

  Abstract

  The current preliminary cross sectional study sought to examine the effects of insulin resistance (IR) and body mass index (BMI) on cognitive performance in adult patients with a history depression, currently not in an acute Major Depressive Episode (MDD). As an exploratory post hoc investigation, special consideration was given to adults <45 years and ≥45 years old. Subjects included men and women ages 19-71 (N = 39) with a history of a non-psychotic, non-melancholic MDD. All subjects underwent an insulin suppression test to determine Steady-State Plasma Glucose (SSPG), a battery of neuropsychological tests, and measurement of BMI. Multiple linear regressions were conducted to determine whether there were differential effects of direct (SSPG) and indirect (BMI) measures on cognition in the whole sample and within dichotomized age groups (<45 and ≥45 years). Preliminary results showed that in the sample as a whole, SSPG was not associated with worse performance on any cognitive variables, while higher BMI was associated with worse dominant hand fine motor skills. Within age groups, differential effects on cognition were found in relation to SSPG and BMI. Higher SSPG was associated with worse cognitive flexibility in the group <45 years, whereas higher BMI was associated with worse estimate of global intelligence in the group ≥45 years. The potential negative impact of IR in younger adults with depression raises concerns regarding the long-term impact on cognition and risk for Alzheimer's disease in undiagnosed younger adults with IR and depression. These negative consequences may not be seen with indirect measures of IR in younger adult populations. Overweight and obesity in older adults with a history of depression appear to have further negative impacts on cognition similar to deficits seen in patients with diabetes.Clinical Trial NCT01106313.

  View details for DOI 10.1016/j.jpsychires.2014.10.001

  View details for PubMedID 25455511

• Influence of birth cohort on age of onset cluster analysis in bipolar I disorder. European psychiatry Bauer, M., Glenn, T., Alda, M., Andreassen, O. A., Angelopoulos, E., Ardau, R., Baethge, C., Bauer, R., Bellivier, F., Belmaker, R. H., Berk, M., Bjella, T. D., Bossini, L., Bersudsky, Y., Cheung, E. Y., CONELL, J., Del Zompo, M., Dodd, S., Etain, B., Fagiolini, A., Frye, M. A., Fountoulakis, K. N., Garneau-Fournier, J., Gonzalez-Pinto, A., Harima, H., Hassel, S., Henry, C., Iacovides, A., Isometsä, E. T., Kapczinski, F., Kliwicki, S., König, B., Krogh, R., Kunz, M., Lafer, B., Larsen, E. R., Lewitzka, U., Lopez-Jaramillo, C., MacQueen, G., Manchia, M., Marsh, W., Martinez-Cengotitabengoa, M., Melle, I., Monteith, S., Morken, G., MUNOZ, R., Nery, F. G., O'Donovan, C., Osher, Y., Pfennig, A., Quiroz, D., Ramesar, R., Rasgon, N., Reif, A., Ritter, P., Rybakowski, J. K., Sagduyu, K., Scippa, A. M., Severus, E., Simhandl, C., Stein, D. J., Strejilevich, S., Hatim Sulaiman, A., Suominen, K., Tagata, H., TATEBAYASHI, Y., Torrent, C., Vieta, E., Viswanath, B., Wanchoo, M. J., ZETIN, M., Whybrow, P. C. 2015; 30 (1): 99-105

  Abstract

  Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

  View details for DOI 10.1016/j.eurpsy.2014.10.005

  View details for PubMedID 25498240

• fMRI Activation During Executive Function Predicts Response to Cognitive Behavioral Therapy in Older, Depressed Adults AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Thompson, D. G., Kesler, S. R., Sudheimer, K., Mehta, K. M., Thompson, L. W., Marquett, R. M., Holland, J. M., Reiser, R., Rasgon, N., Schatzberg, A., O'Hara, R. M. 2015; 23 (1): 13-22

  Abstract

  To test our hypothesis that pre-treatment executive function and brain regional activation during executive function would discriminate between responders and non-responders to cognitive behavioral therapy (CBT) in elderly depressed outpatients.Clinical cohort study.University-affiliated hospital.Sixty outpatients (age 59 years and older) completed 12 weeks of CBT between July 2010 and December 2011. Forty-four completed fMRI procedures.The main outcome consisted of a conversion from a clinical diagnosis (Mini-International Neuropsychiatric Interview) of depression to no clinical diagnosis of depression or a significant improvement in diagnostic criteria. Brain activation measured by functional magnetic resonance imaging during the Wisconsin Card Sorting task (WCST) was the primary predictor variable.67% of patients had a positive response to CBT. Decreased activation in the left inferior frontal triangle and right superior frontal gyrus as well as increased activity in the right middle frontal gyrus and left superior frontal gyrus predicted a positive response to CBT. Demographic and neurocognitive measures of WCST performance were not significant predictors of a positive CBT outcome, whereas the measure of WCST-induced activity in the prefrontal cortex was a significant predictor.These data are among the first to suggest that measures of prefrontal brain activation during executive functioning predict response to CBT in older adults. Further exploration of the specific underlying processes that these prefrontal cortical regions are engaging that contributes to better CBT outcomes is warranted in larger, randomized studies.

  View details for DOI 10.1016/j.jagp.2014.02.001

  View details for Web of Science ID 000346204400003

  View details for PubMedID 24656506

• Influence of birth cohort on age of onset cluster analysis in bipolar I disorder. European psychiatry Bauer, M., Glenn, T., Alda, M., Andreassen, O. A., Angelopoulos, E., Ardau, R., Baethge, C., Bauer, R., Bellivier, F., Belmaker, R. H., Berk, M., Bjella, T. D., Bossini, L., Bersudsky, Y., Cheung, E. Y., CONELL, J., Del Zompo, M., Dodd, S., Etain, B., Fagiolini, A., Frye, M. A., Fountoulakis, K. N., Garneau-Fournier, J., Gonzalez-Pinto, A., Harima, H., Hassel, S., Henry, C., Iacovides, A., Isometsä, E. T., Kapczinski, F., Kliwicki, S., König, B., Krogh, R., Kunz, M., Lafer, B., Larsen, E. R., Lewitzka, U., Lopez-Jaramillo, C., MacQueen, G., Manchia, M., Marsh, W., Martinez-Cengotitabengoa, M., Melle, I., Monteith, S., Morken, G., MUNOZ, R., Nery, F. G., O'Donovan, C., Osher, Y., Pfennig, A., Quiroz, D., Ramesar, R., Rasgon, N., Reif, A., Ritter, P., Rybakowski, J. K., Sagduyu, K., Scippa, A. M., Severus, E., Simhandl, C., Stein, D. J., Strejilevich, S., Hatim Sulaiman, A., Suominen, K., Tagata, H., TATEBAYASHI, Y., Torrent, C., Vieta, E., Viswanath, B., Wanchoo, M. J., ZETIN, M., Whybrow, P. C. 2015; 30 (1): 99-105

  Abstract

  Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

  View details for DOI 10.1016/j.eurpsy.2014.10.005

  View details for PubMedID 25498240

• Association Between Direct and Indirect Measures of Insulin Resistance and Cognition in Euthymic Adults with Histories of Major Depressive Disorder Wroolie, T., Kenna, H., Singh, M., Rasgon, N. NATURE PUBLISHING GROUP. 2014: S282

  View details for Web of Science ID 000345905000465

• Relationship between sunlight and the age of onset of bipolar disorder: An international multisite study. Journal of affective disorders Bauer, M., Glenn, T., Alda, M., Andreassen, O. A., Angelopoulos, E., Ardau, R., Baethge, C., Bauer, R., Bellivier, F., Belmaker, R. H., Berk, M., Bjella, T. D., Bossini, L., Bersudsky, Y., Cheung, E. Y., Conell, J., Zompo, M. D., Dodd, S., Etain, B., Fagiolini, A., Frye, M. A., Fountoulakis, K. N., Garneau-Fournier, J., González-Pinto, A., Harima, H., Hassel, S., Henry, C., Iacovides, A., Isometsä, E. T., Kapczinski, F., Kliwicki, S., König, B., Krogh, R., Kunz, M., Lafer, B., Larsen, E. R., Lewitzka, U., Lopez-Jaramillo, C., MacQueen, G., Manchia, M., Marsh, W., Martinez-Cengotitabengoa, M., Melle, I., Monteith, S., Morken, G., Munoz, R., Nery, F. G., O'Donovan, C., Osher, Y., Pfennig, A., Quiroz, D., Ramesar, R., Rasgon, N., Reif, A., Ritter, P., Rybakowski, J. K., Sagduyu, K., Scippa, A. M., Severus, E., Simhandl, C., Stein, D. J., Strejilevich, S., Hatim Sulaiman, A., Suominen, K., Tagata, H., Tatebayashi, Y., Torrent, C., Vieta, E., Viswanath, B., Wanchoo, M. J., Zetin, M., Whybrow, P. C. 2014; 167: 104-111

  Abstract

  The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode.Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations.There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduced by half if there was no family history. The maximum monthly increase in solar insolation occurred in springtime. The effect was one-third smaller for initial episodes of mania than depression. The largest maximum monthly increase in solar insolation occurred in northern latitudes such as Oslo, Norway, and warm and dry areas such as Los Angeles, California.Recall bias for onset and family history data.A large springtime increase in sunlight may have an important influence on the onset of bipolar disorder, especially in those with a family history of mood disorders.

  View details for DOI 10.1016/j.jad.2014.05.032

  View details for PubMedID 24953482

• Insulin resistance and medial prefrontal gyrus metabolism in women receiving hormone therapy PSYCHIATRY RESEARCH-NEUROIMAGING Rasgon, N. L., Kenna, H. A., Wroolie, T. E., Williams, K. E., DeMuth, B. N., Silverman, D. H. 2014; 223 (1): 28-36

  Abstract

  Insulin resistance (IR) is a putative risk factor for cognitive decline and dementia, and has been shown to impede neuronal glucose metabolism in animal models. This post hoc study focused on metabolic changes in the medial prefrontal region, a brain region exhibiting decline years before documented cognitive changes, relative to high or low IR status in a cohort of postmenopausal women at risk for dementia who were randomized to continue or discontinue existing stable hormone therapy (HT) for 2 years. Subjects were dichotomized into high and low IR groups based on the homeostatic model assessment of insulin resistance, which was within clinically normal limits for the group as a whole at both baseline and 2-year follow-up. Results showed that high and low IR groups showed significant differences in metabolic decline of the medial prefrontal gyrus, regardless of HT randomization group. However, HT randomization was predictive of metabolic decline only in women with low HOMA (homeostatic assessment of insulin resistance). Performance in working memory was consistent with observed metabolic changes. These results suggest IR may be an independent moderator of regional metabolic changes, while protective metabolic effects of HT are most apparent in those at low-end range of IR. If replicated in future studies, these findings will help to better understand the interaction between putative risk and protective factors, and further delineate cohort postmenopausal women who may benefit from HT.

  View details for DOI 10.1016/j.pscychresns.2014.04.004

  View details for Web of Science ID 000338596500005

• Insulin resistance and medial prefrontal gyrus metabolism in women receiving hormone therapy. Psychiatry research Rasgon, N. L., Kenna, H. A., Wroolie, T. E., Williams, K. E., DeMuth, B. N., Silverman, D. H. 2014; 223 (1): 28-36

  Abstract

  Insulin resistance (IR) is a putative risk factor for cognitive decline and dementia, and has been shown to impede neuronal glucose metabolism in animal models. This post hoc study focused on metabolic changes in the medial prefrontal region, a brain region exhibiting decline years before documented cognitive changes, relative to high or low IR status in a cohort of postmenopausal women at risk for dementia who were randomized to continue or discontinue existing stable hormone therapy (HT) for 2 years. Subjects were dichotomized into high and low IR groups based on the homeostatic model assessment of insulin resistance, which was within clinically normal limits for the group as a whole at both baseline and 2-year follow-up. Results showed that high and low IR groups showed significant differences in metabolic decline of the medial prefrontal gyrus, regardless of HT randomization group. However, HT randomization was predictive of metabolic decline only in women with low HOMA (homeostatic assessment of insulin resistance). Performance in working memory was consistent with observed metabolic changes. These results suggest IR may be an independent moderator of regional metabolic changes, while protective metabolic effects of HT are most apparent in those at low-end range of IR. If replicated in future studies, these findings will help to better understand the interaction between putative risk and protective factors, and further delineate cohort postmenopausal women who may benefit from HT.

  View details for DOI 10.1016/j.pscychresns.2014.04.004

  View details for PubMedID 24819305

• Relationship Between Leukocyte Telomere Length, Telomerase Activity, and Hippocampal Volume in Early Aging JAMA NEUROLOGY Jacobs, E. G., Epel, E. S., Lin, J., Blackburn, E. H., Rasgon, N. L. 2014; 71 (7): 921–23

  View details for PubMedID 25023551

  View details for PubMedCentralID PMC5287208

• Blood levels of brain derived neurotrophic factor in women with bipolar disorder and healthy control women. Journal of affective disorders Kenna, H. A., Reynolds-May, M., Stepanenko, A., Ketter, T. A., Hallmayer, J., Rasgon, N. L. 2014; 156: 214-218

  Abstract

  Brain-derived neurotrophic factor (BDNF) protein has been implicated in the pathophysiology of mood disorders, with early data suggesting that blood levels may vary by severity of mood symptoms. BDNF polymorphism, val66met, has also been implicated in mood disorders.Euthymic women with bipolar disorder (BD) (n=47) and healthy control women (n=26), ages 18-45, were clinically rated using the Montgomery-Asberg Depression Rating Scale (MADRS) and sampled for plasma BDNF concentration, with a subset undergoing genetic analysis for the val66met.BD and control groups did not differ on any demographic variables, nor in plasma BDNF levels or val66met polymorphism. Plasma BDNF concentration did not differ by val66met or BD subtype, nor was it correlated with age or illness duration. Within women with BD, lower plasma BDNF concentrations were significantly associated with higher MADRS scores, even after controlling for psychotropic medication use and illness duration.The sample was relatively small and exclusive to women, with further research needed to investigate the links between BDNF markers and mood symptom severity in both men and women.The study provides a gender-specific investigation of plasma BDNF levels and mood, and the results add further evidence of a significant interplay between BDNF markers and psychiatric symptomatology. Further, this association did not appear to be confounded by use of psychotropic medication. Studies with larger samples of both genders are needed to further delineate this relationship.

  View details for DOI 10.1016/j.jad.2013.01.054

  View details for PubMedID 24398043

• Neuroendocrine and metabolic contributions to sex-specific presentations of bipolar disorder Rasgon, N. WILEY-BLACKWELL. 2014: 34

  View details for Web of Science ID 000332169400049

• Evaluation of reproductive function in women treated for bipolar disorder compared to healthy controls. Bipolar disorders Reynolds-May, M. F., Kenna, H. A., Marsh, W., Stemmle, P. G., Wang, P., Ketter, T. A., Rasgon, N. L. 2014; 16 (1): 37-47

  Abstract

  The purpose of the present study was to investigate the reproductive function of women with bipolar disorder (BD) compared to healthy controls.Women diagnosed with BD and healthy controls with no psychiatric history, aged 18-45 years, were recruited from a university clinic and surrounding community. Participants completed a baseline reproductive health questionnaire, serum hormone assessment, and ovulation tracking for three consecutive cycles using urine luteinizing hormone (LH)-detecting strips with a confirmatory luteal-phase serum progesterone.Women with BD (n = 103) did not differ from controls (n = 36) in demographics, rates of menstrual abnormalities (MAs), or number of ovulation-positive cycles. Of the women with BD, 17% reported a current MA and 39% reported a past MA. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone levels were higher in controls (p = 0.052 and 0.004, respectively), but there were no other differences in biochemical levels. Medication type, dose, or duration was not associated with MA or biochemical markers, although those currently taking an atypical antipsychotic agent indicated a greater rate of current or past MA (80% versus 55%, p = 0.013). In women with BD, 22% reported a period of amenorrhea associated with exercising or stress, versus 8% of controls (p = 0.064). Self-reported rates of bulimia and anorexia nervosa were 10% and 5%, respectively.Rates of MA and biochemical levels did not significantly differ between women with BD and controls. Current atypical antipsychotic agent use was associated with a higher rate of current or past MA and should be further investigated. The incidence of stress-induced amenorrhea should be further investigated in this population, as should the comorbid incidence of eating disorders.

  View details for DOI 10.1111/bdi.12149

  View details for PubMedID 24262071

• Women with bipolar disorder: a lifetime challenge from diagnosis to treatment BIPOLAR DISORDERS Ozerdem, A., Rasgon, N. 2014; 16 (1): 1–4

  View details for DOI 10.1111/bdi.12161

  View details for Web of Science ID 000331202700001

  View details for PubMedID 24467468

• Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia. PloS one Rasgon, N. L., Geist, C. L., Kenna, H. A., Wroolie, T. E., Williams, K. E., Silverman, D. H. 2014; 9 (3)

  Abstract

  The objective of this study was to examine the effects of estrogen-based hormone therapy (HT) on regional cerebral metabolism in postmenopausal women (mean age = 58, SD = 5) at risk for development of dementia. The prospective clinical trial design included pre- and post-intervention neuroimaging of women randomized to continue (HT+) or discontinue (HT-) therapy following an average of 10 years of use. The primary outcome measure was change in brain metabolism during the subsequent two years, as assessed with fluorodeoxyglucose-18 positron emission tomography (FDG-PET). Longitudinal FDG-PET data were available for 45 study completers. Results showed that women randomized to continue HT experienced relative preservation of frontal and parietal cortical metabolism, compared with women randomized to discontinue HT. Women who discontinued 17-β estradiol (17βE)-based HT, as well as women who continued conjugated equine estrogen (CEE)-based HT, exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical (PCC) area. Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins (with either 17βE or CEE). Together, these findings suggest that among postmenopausal subjects at risk for developing dementia, regional cerebral cortical metabolism is relatively preserved for at least two years in women randomized to continue HT, compared with women randomized to discontinue HT. In addition, continuing unopposed 17βE therapy is associated specifically with preservation of metabolism in PCC, known to undergo the most significant decline in the earliest stages of Alzheimer's disease.ClinicalTrials.gov NCT00097058.

  View details for DOI 10.1371/journal.pone.0089095

  View details for PubMedID 24622517

  View details for PubMedCentralID PMC3951184

• Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia. PloS one Rasgon, N. L., Geist, C. L., Kenna, H. A., Wroolie, T. E., Williams, K. E., Silverman, D. H. 2014; 9 (3)

  View details for DOI 10.1371/journal.pone.0089095

  View details for PubMedID 24622517

• High Rates of Comorbid Depressive and Anxiety Disorders Among Women with Premutation of the FMR1 Gene AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Kenna, H. A., Tartter, M., Hall, S. S., Lightbody, A. A., Quynh Nguyen, Q., de los Angeles, C. P., Reiss, A. L., Rasgon, N. L. 2013; 162 (8): 872-878

  Abstract

  Phenotypic variations are emerging from investigations of carriers of the fragile X mental retardation 1 (FMR1) premutation gene (55 to 200 CGG repeats). Initial studies suggest elevated psychiatric and reproductive system dysfunction, but have largely used self-reports for assessment of psychiatric history. The present study used diagnostic psychiatric interviews and assessed reproductive and menstrual history in women with FMR1 premutation. History of psychiatric diagnoses and data on reproductive functioning were collected in 46 women with FMR1 premutation who were mothers of at least one child with the fragile X full mutation. Results showed a significantly earlier age of menopause (mean age = 45.6 years) relative to the national average age of menopause (mean age = 51 years) and a high rate (76%) of lifetime depressive or anxiety history, with 43% of the overall sample reporting a comorbid history of both diagnoses. Compared to those free of psychiatric history, significantly longer premutation length was observed among women with psychiatric history after adjusting for age, with comorbid women having the highest number of CGG repeats (mean = 95.8) compared to women free of psychiatric history (mean = 79.9). Psychiatric history did not appear significantly related to reproductive system dysfunction, though results may have been obscured by the high rates of psychiatric dysfunction in the sample. These data add to the growing evidence base that women with the FMR1 premutation have an increased risk of psychiatric illness and risk for early menopause. Future investigations may benefit from inclusion of biochemical reproductive markers and longitudinal assessment of psychiatric and reproductive functioning. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32196

  View details for Web of Science ID 000326506700010

• Differential Effects of Estrogen Hormone Therapy on CA1 Hippocampal Subfield Volume Change over a 2-Year Observation Period in Postmenopausal Women at Risk for Alzheimer's Disease: Conjugated Equine Estrogen Versus Estradiol Kenna, H., Sheau, K., Wroolie, T., Kelley, R. G., Williams, K., Reiss, A., Rasgon, N. NATURE PUBLISHING GROUP. 2013: S137

  View details for Web of Science ID 000209477100255

• High rates of comorbid depressive and anxiety disorders among women with premutation of the FMR1 gene. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Kenna, H. A., Tartter, M., Hall, S. S., Lightbody, A. A., Nguyen, Q., de los Angeles, C. P., Reiss, A. L., Rasgon, N. L. 2013; 162 (8): 872-878

  Abstract

  Phenotypic variations are emerging from investigations of carriers of the fragile X mental retardation 1 (FMR1) premutation gene (55 to 200 CGG repeats). Initial studies suggest elevated psychiatric and reproductive system dysfunction, but have largely used self-reports for assessment of psychiatric history. The present study used diagnostic psychiatric interviews and assessed reproductive and menstrual history in women with FMR1 premutation. History of psychiatric diagnoses and data on reproductive functioning were collected in 46 women with FMR1 premutation who were mothers of at least one child with the fragile X full mutation. Results showed a significantly earlier age of menopause (mean age = 45.6 years) relative to the national average age of menopause (mean age = 51 years) and a high rate (76%) of lifetime depressive or anxiety history, with 43% of the overall sample reporting a comorbid history of both diagnoses. Compared to those free of psychiatric history, significantly longer premutation length was observed among women with psychiatric history after adjusting for age, with comorbid women having the highest number of CGG repeats (mean = 95.8) compared to women free of psychiatric history (mean = 79.9). Psychiatric history did not appear significantly related to reproductive system dysfunction, though results may have been obscured by the high rates of psychiatric dysfunction in the sample. These data add to the growing evidence base that women with the FMR1 premutation have an increased risk of psychiatric illness and risk for early menopause. Future investigations may benefit from inclusion of biochemical reproductive markers and longitudinal assessment of psychiatric and reproductive functioning. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32196

  View details for PubMedID 24003006

• DIFFERENTIAL EFFECTS OF HORMONE THERAPY TYPE AND USE ON COGNITION IN WOMEN AT RISK FOR DEMENTIA Wroolie, T. E., Kenna, H., Williams, K., Rasgon, N. OXFORD UNIV PRESS INC. 2013: 164

  View details for Web of Science ID 000327442102279

• Metabolic and immunological correlates of bipolar disorder Rasgon, N. WILEY-BLACKWELL. 2013: 24

  View details for Web of Science ID 000319826800045

• A double challenge: pregnancy and post-partum in bipolar disorder Frey, B. N., Ozerdem, A., Geerling, B., Akdeniz, F., Stevens, A., Sharma, V., Marsh, W., Rasgon, N., Frye, M. A. WILEY-BLACKWELL. 2013: 156

  View details for Web of Science ID 000319826800363

• Fasting plasma insulin and the default mode network in women at risk for Alzheimer's disease NEUROBIOLOGY OF AGING Kenna, H., Hoeft, F., Kelley, R., Wroolie, T., Demuth, B., Reiss, A., Rasgon, N. 2013; 34 (3): 641-649

  Abstract

  Brain imaging studies in Alzheimer's disease research have demonstrated structural and functional perturbations in the hippocampus and default mode network (DMN). Additional evidence suggests risk for pathological brain aging in association with insulin resistance (IR). This study piloted investigation of associations of IR with DMN-hippocampal functional connectivity among postmenopausal women at risk for Alzheimer's disease. Twenty middle-aged women underwent resting state functional magnetic resonance imaging. Subjects were dichotomized relative to fasting plasma insulin levels (i.e., > 8 μIU/mL [n = 10] and < 8 μIU/mL [n = 10]), and functional connectivity analysis contrasted their respective blood oxygen level-dependent signal correlation between DMN and hippocampal regions. Higher-insulin women had significantly reduced positive associations between the medial prefrontal cortex and bilateral parahippocampal regions extending to the right hippocampus, and conversely, between the left and right hippocampus and medial prefrontal cortex. Neuropsychological data (all within normal ranges) also showed significant differences with respect to executive functioning and global intelligence. The results provide further evidence of deleterious effects of IR on the hippocampus and cognition. Further imaging studies of the IR-related perturbations in DMN-hippocampal functional connectivity are needed.

  View details for DOI 10.1016/j.neurobiolaging.2012.06.006

  View details for Web of Science ID 000313117900001

  View details for PubMedID 22770543

• Accelerated Cell Aging in Female APOE-epsilon 4 Carriers: Implications for Hormone Therapy Use PLOS ONE Jacobs, E. G., Kroenke, C., Lin, J., Epel, E. S., Kenna, H. A., Blackburn, E. H., Rasgon, N. L. 2013; 8 (2)

  Abstract

  Apolipoprotein-ε4 (APOE-ε4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-ε4 status impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N = 63, Mean age = 57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study. Half of the participants (N = 32) remained on their HT regimen and half (N = 31) went off HT for approximately two years (Mean  = 1.93 years). Participants included 24 APOE-ε4 carriers and 39 non-carrier controls. Leukocyte TL was measured at baseline and the end of year 2 using quantitative polymerase chain reaction. Logistic regression analysis indicated that the odds of an APOE-ε4 carrier exhibiting telomere shortening (versus maintenance/growth) over the 2-year study were more than 6 (OR  = 6.26, 95% CI  = 1.02, 38.49) times higher than a non-carrier, adjusting for established risk factors and potential confounds. Despite the high-functioning, healthy mid-life status of study participants, APOE-ε4 carriers had marked telomere attrition during the 2-year study window, the equivalent of approximately one decade of additional aging compared to non-carriers. Further analyses revealed a modulatory effect of hormone therapy on the association between APOE status and telomere attrition. APOE-ε4 carriers who went off their HT regimen exhibited TL shortening, as predicted for the at-risk population. APOE-ε4 carriers who remained on HT, however, did not exhibit comparable signs of cell aging. The opposite pattern was found in non-carriers. The results suggest that hormone use might buffer against accelerated cell aging in mid-life women at risk for dementia. Importantly, for non-carrier women there was no evidence that HT conferred protective effects on telomere dynamics.

  View details for DOI 10.1371/journal.pone.0054713

  View details for Web of Science ID 000315970300020

  View details for PubMedID 23418430

  View details for PubMedCentralID PMC3572118

• Enhanced Ziprasidone Combination Therapy Effectiveness in Obese Compared to Nonobese Patients With Bipolar Disorder JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Miller, S., Ittasakul, P., Wang, P. W., Hill, S. J., Childers, M. E., Rasgon, N., Ketter, T. A. 2012; 32 (6): 814-819

  Abstract

  To assess longer-term ziprasidone effectiveness in obese and non-obese patients with bipolar disorder (BD).Outpatients assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation and monitored with the Systematic Treatment Enhancement Program for BD Clinical Monitoring Form received open ziprasidone.Eighty-two patients (39 patients with BD I, 39 patients with BD II, and 4 patients with BD not otherwise specified; mean age, 41.1 years; females, 78.0%; obese, 48.8%) received ziprasidone combined with an average of 3.6 (in 74.4% at least 3) other prescription psychotropics and 1.2 prescription nonpsychotropics. Mean (median) ziprasidone final dose and duration were 134.3 (150) mg/d and 489 (199.5) days, respectively. Ziprasidone yielded in obese compared to nonobese patients less discontinuation (42.5% vs 71.4%, P = 0.01), albeit with a higher rate of addition of subsequent psychotropic medication (62.5% vs 35.7%, P = 0.03). Moreover, obese compared to nonobese patients had a higher rate of shift to final-visit euthymia (27.5% vs 0.0%, P = 0.0002), and more weight loss (-20.7 lbs vs -0.6 lbs, P = 0.001), and obese (but not nonobese) patients had significant improvements in mean Clinical Global Impression-Severity of Illness (decreased 0.6 points; P = 0.03) and Global Assessment of Functioning (increased 3.3 points, P = 0.01) scores. Weight change correlated significantly with Global Assessment of Functioning change (P = 0.047) but not with Clinical Global Impression-Severity of Illness change. Limitations are small sample size and open-label, uncontrolled, observational design.Controlled and additional observational studies seem warranted to confirm our preliminary findings suggesting ziprasidone may be more effective in obese compared to nonobese patients with BD already receiving combination pharmacotherapy.

  View details for DOI 10.1097/JCP.0b013e318270dea9

  View details for Web of Science ID 000310923500014

  View details for PubMedID 23131875

• Review of Different Approaches in the Evaluation of Alzheimer's Patients including Amyloid Brain PET Scan 4th International Symposium on Targeted Radiotherapy and Dosimetry (ISTARD) in Conjunction with the 25th Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) Akram, S. M., Vasanawala, M., Zeineh, M., Rasgon, N., Goris, M. L. SPRINGER. 2012: S549–S549

  View details for Web of Science ID 000309726603208

• Impact of sunlight on the age of onset of bipolar disorder BIPOLAR DISORDERS Bauer, M., Glenn, T., Alda, M., Andreassen, O. A., Ardau, R., Bellivier, F., Berk, M., Bjella, T. D., Bossini, L., Del Zompo, M., Dodd, S., Fagiolini, A., Frye, M. A., Gonzalez-Pinto, A., Henry, C., Kapczinski, F., Kliwicki, S., Koenig, B., Kunz, M., Lafer, B., Lopez-Jaramillo, C., Manchia, M., Marsh, W., Martinez-Cengotitabengoa, M., Melle, I., Morken, G., Munoz, R., Nery, F. G., O'Donovan, C., Pfennig, A., Quiroz, D., Rasgon, N., Reif, A., Rybakowski, J., Sagduyu, K., Simhandl, C., Torrent, C., Vieta, E., Zetin, M., Whybrow, P. C. 2012; 14 (6): 654-663

  Abstract

  Although bipolar disorder has high heritability, the onset occurs during several decades of life, suggesting that social and environmental factors may have considerable influence on disease onset. This study examined the association between the age of onset and sunlight at the location of onset.Data were obtained from 2414 patients with a diagnosis of bipolar I disorder, according to DSM-IV criteria. Data were collected at 24 sites in 13 countries spanning latitudes 6.3 to 63.4 degrees from the equator, including data from both hemispheres. The age of onset and location of onset were obtained retrospectively, from patient records and/or direct interviews. Solar insolation data, or the amount of electromagnetic energy striking the surface of the earth, were obtained from the NASA Surface Meteorology and Solar Energy (SSE) database for each location of onset.The larger the maximum monthly increase in solar insolation at the location of onset, the younger the age of onset (coefficient= -4.724, 95% CI: -8.124 to -1.323, p=0.006), controlling for each country's median age. The maximum monthly increase in solar insolation occurred in springtime. No relationships were found between the age of onset and latitude, yearly total solar insolation, and the maximum monthly decrease in solar insolation. The largest maximum monthly increases in solar insolation occurred in diverse environments, including Norway, arid areas in California, and Chile.The large maximum monthly increase in sunlight in springtime may have an important influence on the onset of bipolar disorder.

  View details for DOI 10.1111/j.1399-5618.2012.01025.x

  View details for Web of Science ID 000308286800008

  View details for PubMedID 22612720

  View details for PubMedCentralID PMC3525652

• Women are more vulnerable for thyroid function abnormality in bipolar disorder Ozerdem, A., Tunca, Z., Cimrin, D., Hidiroglu, C., Ergor, G., Rasgon, N. WILEY-BLACKWELL. 2012: 23

  View details for Web of Science ID 000301531000030

• Brain derived neurotrophic factor in women with bipolar disorder compared to controls Rasgon, N. L., Reynolds-May, M. F., Kenna, H. A., Marsh, W., Stemmle, P. G., Wang, P., Ketter, T. A. WILEY-BLACKWELL. 2012: 24

  View details for Web of Science ID 000301531000033

• Enhanced zipirasidone combination therapy effectiveness in obese compared to nonobese patients with bipolar disorder J Clin Psychopharmacol Rasgon, N. 2012; Dec
• Insulin resistance and hippocampal volume in women at risk for Alzheimer's disease NEUROBIOLOGY OF AGING Rasgon, N. L., Kenna, H. A., Wroolie, T. E., Kelley, R., Silverman, D., Brooks, J., Williams, K. E., Powers, B. N., Hallmayer, J., Reiss, A. 2011; 32 (11): 1942-1948

  Abstract

  Insulin resistance (IR) is the main pathological condition underlying vascular disorders, such as diabetes and cardiovascular disease, which are well established risk factors for cognitive decline and Alzheimer disease (AD). Hippocampal atrophy has been associated with cognitive decline, but little is known about the influence of IR on hippocampus integrity in non-diabetic, cognitively intact individuals. Herein, 50 women ages 50-65, current users of hormone therapy, underwent magnetic resonance imaging, cognitive testing, and homeostatic assessment of insulin resistance (HOMA-IR), as part of a longitudinal study examining brain structure and function in postmenopausal women at risk for AD. Results demonstrated a significant negative relationship between HOMA-IR and right and total hippocampal volume, overall cognitive performance, and selective tests of verbal and non-verbal memory. The main effect of HOMA-IR on brain structure and cognition was not altered by the presence of APOE-ε4 allele or by reproductive history, such as duration of endogenous and exogenous estrogen exposure. These results suggest that IR in middle-aged individuals at risk for AD may be biomarker for dementia risk.

  View details for DOI 10.1016/j.neurobiolaging.2009.12.005

  View details for Web of Science ID 000295220700003

  View details for PubMedID 20031276

  View details for PubMedCentralID PMC2891925

• Cortisol Outcomes among Caucasian and Latina/Hispanic Women Caring for a Family Member with Dementia: A Preliminary Examination of Psychosocial Predictors and Effects of a Psychoeducational Intervention STRESS AND HEALTH Holland, J. M., Thompson, L. W., Cucciare, M. A., Tsuda, A., Okamura, H., Spiegel, D., Rasgon, N. L., Gallagher-Thompson, D. 2011; 27 (4): 334-346

  View details for DOI 10.1002/smi.1375

  View details for Web of Science ID 000295876000007

• Differences in Verbal Memory Performance in Postmenopausal Women Receiving Hormone Therapy: 17 beta-Estradiol Versus Conjugated Equine Estrogens AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Wroolie, T. E., Kenna, H. A., Williams, K. E., Powers, B. N., Holcomb, M., Khaylis, A., Rasgon, N. L. 2011; 19 (9): 792-802

  Abstract

  Much controversy exists and many questions remain unanswered about the effects of hormone therapy (HT) on cognition in postmenopausal women. There is growing evidence suggesting that HT compounds containing conjugated equine estrogen (CEE) have negative effects on cognition whereas 17β-estradiol (17β-E) either has positive or neutral effects. The present study sought to further examine this issue in a sample of postmenopausal women with risk factors for Alzheimer's disease (AD).Cross-sectional neuropsychological evaluation.Academic research clinic.68 healthy postmenopausal women (aged 49-68) receiving either 17β-E or CEE for at least one year with increased risk for AD.Neuropsychological test battery of the cognitive domains of attention/working memory/processing speed, verbal memory, visual memory, and executive functioning.Multivariate analyses of variance (MANOVA) showed significantly better verbal memory performance in women receiving 17β-E compared to women receiving CEE regardless of age, IQ, years of education, risk factors for AD (including APOE-ε4 carriership), duration of endogenous and exogenous estrogen exposure, concurrent progesterone use, or natural versus surgical menopause status.Verbal memory performance was better in postmenopausal women receiving 17β-E compared to CEE in a sample population of women with risk factors for AD. Genetic risk for AD as well as other confounds did not affect this finding. The results suggest a differential effect of HT type on verbal memory, with 17β-E being a preferential compound. Further evaluation of HT types, regimens and duration of use on cognitive performance in postmenopausal women in a controlled longitudinal design is warranted.

  View details for DOI 10.1097/JGP.0b013e3181ff678a

  View details for Web of Science ID 000294415800006

  View details for PubMedID 21873835

  View details for PubMedCentralID PMC3164805

• Open adjunctive ziprasidone associated with weight loss in obese and overweight bipolar disorder patients JOURNAL OF PSYCHIATRIC RESEARCH Wang, P. W., Hill, S. J., Childers, M. E., Chandler, R. A., Rasgon, N. L., Ketter, T. A. 2011; 45 (8): 1128-1132

  Abstract

  To assess effectiveness and tolerability of open adjunctive ziprasidone for weight loss in obese/overweight patients with bipolar disorders (BD) in diverse mood states, taking weight gain-implicated psychotropic medications.22 obese and three overweight BD patients (20 female; 10 BD-I, 14 BD-II, 1 BD-NOS) with mean ± SD baseline body mass index (BMI) of 31.8 ± 2.5 kg/m2 received ZIP (mean final dose 190 ± 92 mg/day) for mean of 79.2 ± 23.2 days. Weight was assessed at six weekly and three biweekly visits. Subjects entered the study in diverse mood states. At baseline, 21 were taking second-generation antipsychotics, 7 lithium, and 1 valproate, which could be reduced/discontinued at investigators' discretion.Weight and BMI decreased from baseline to endpoint by 4.5 ± 3.4 kg and 1.6 ± 1.2 kg/m2, respectively, at weekly rates of 0.37 kg and 0.13 kg/m2, respectively (all p < 0.00001). 48% of patients had at least 5% weight loss. Obesity rate decreased from 88% to 35% (p < 0.0001). Waist circumference decreased 1.6 inches (p = 0.0001). Overall, mood did not change. Patients with at least moderate baseline mood symptoms experienced significant mood improvement, despite 72% patients decreasing/discontinuing weight gain-implicated psychotropic medications. Seven patients discontinued ZIP early: 3 for weight loss inefficacy, and 1 each for viral gastroenteritis, loss of consciousness, pneumonia with hypomania, and lost to follow up.Open adjunctive ziprasidone may be effective for weight loss in obese/overweight BD patients taking weight gain-implicated psychotropic medications. These preliminary data should be considered with caution due to the open uncontrolled design, small sample size, and brief duration.

  View details for DOI 10.1016/j.jpsychires.2011.01.019

  View details for Web of Science ID 000293938900019

  View details for PubMedID 21371718

• Decreasing the minimum length criterion for an episode of hypomania: evaluation using self-reported data from patients with bipolar disorder EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE Bauer, M., Glenn, T., Rasgon, N., Marsh, W., Sagduyu, K., Grof, P., Alda, M., Murray, G., Munoz, R., Quiroz, D., Bauer, R., Jabs, B., Whybrow, P. C. 2011; 261 (5): 341-347

  Abstract

  Brief hypomania lasting less than 4 days may impair functioning and help to detect bipolarity. This study analyzed brief hypomania that occurred in patients with bipolar disorder who were diagnosed according to the DSM-IV criteria. Daily self-reported mood ratings were obtained from 393 patients (247 bipolar I and 146 bipolar II) for 6 months (75,284 days of data, mean 191.6 days). Episodes of hypomania were calculated using a 4, 3, 2, and single day length criterion. Brief hypomania occurred frequently. With a decrease in the minimum criterion from 4 days to 2 days, there were almost twice as many patients with an episode of hypomania (102 vs. 190), and more than twice as many episodes (305 vs. 863). Single days of hypomania were experienced by 271 (69%) of the sample. With a 2-day episode length, 33% of all hypomania remained outside of an episode. There was no significant difference in the percent of hypomanic days outside of an episode between patients with bipolar I and II disorders. There were no significant differences in the demographic characteristics of patients who met the 4-day minimum as compared with those who only experienced episodes of hypomania using a shortened length criterion. Decreasing the minimum length criterion for an episode of hypomania will cause a large increase in the number of patients who experience an episode and in the aggregate number of episodes, but will not distinguish subgroups within a sample who meet the DSM-IV criteria for bipolar disorder. Frequency may be an important dimensional aspect of brief hypomania. Clinicians should regularly probe for brief hypomania.

  View details for DOI 10.1007/s00406-010-0187-x

  View details for Web of Science ID 000293471900004

  View details for PubMedID 21267744

  View details for PubMedCentralID PMC3149120

• Gender-specific lipid profiles in patients with bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Vemuri, M., Kenna, H. A., Wang, P. W., Ketter, T. A., Rasgon, N. L. 2011; 45 (8): 1036-1041

  Abstract

  High rates of dyslipidemia and insulin resistance (IR) are reported in patients with bipolar disorder (BD). We assessed gender effects upon rates of dyslipidemia/IR in outpatients with BD.Data from 491 outpatients (ages 18-88) seen in the Stanford Bipolar Disorders clinic between 2000 and 2007 were evaluated. Patients were followed longitudinally and received naturalistic treatment. BD patients (n = 234; 61% female; 42% Type I, 47% Type II, 11% NOS) with a mean age of 40.3 ± 14.0 years, mean BMI 26.8 ± 6.4, and 81% Caucasian, who had one of four lipid measures (total cholesterol, LDL, HDL, TG) at clinicians' discretion, a psychiatry clinic visit within 2 months of laboratory, and were not medicated for dyslipidemia were included. IR was imputed from TG/HDL ratio.Women, compared with men, had significantly lower mean triglycerides (105.58 ± 64.12 vs. 137.99 ± 105.14, p = 0.009), higher mean HDL cholesterol (60.17 ± 17.56 vs. 46.07 ± 11.91 mg/dl, p < 0.001), lower mean LDL cholesterol (109.84 ± 33.47 vs. 123.79 ± 35.96 mg/dl, p = 0.004), and lower TG/HDL ratio (1.98 ± 1.73 vs. 3.59 ± 3.14 p < 0.001). Compared to men, women had a significantly lower prevalence of abnormal total cholesterol, LDL, TG, HDL, and TG/HDL ratio. No significant differences were found between men and women with regard to age, BMI, ethnicity, educational attainment, smoking habits, bipolar illness type, illness severity or duration, or weight-liable medication exposure.In outpatients with BD, women had more favorable lipid profiles than men despite similar demographic variables. This sample of primarily Caucasian and educated patients, receiving vigilant clinical monitoring, may represent a relatively healthy psychiatric population demonstrating gender differences similar to those in the general population.

  View details for DOI 10.1016/j.jpsychires.2011.02.002

  View details for Web of Science ID 000293938900006

  View details for PubMedID 21377167

• Differences in regional brain metabolism associated with specific formulations of hormone therapy in postmenopausal women at risk for AD PSYCHONEUROENDOCRINOLOGY Silverman, D. H., Geist, C. L., Kenna, H. A., Williams, K., Wroolie, T., Powers, B., Brooks, J., Rasgon, N. L. 2011; 36 (4): 502-513

  Abstract

  Differential cerebral metabolic effects of various hormone therapy formulations, and their associations with cognitive status, remain to be established. The principal aim of the current study was to assess relationships between regional cerebral metabolism and estrogen-based hormone therapies. Postmenopausal women (n=53) at elevated risk for Alzheimer's disease (AD) were on estrogen-containing hormone therapy for at least one year prior to enrollment in a prospective, randomized clinical trial. Subjects underwent an FDG-PET scan, along with neuropsychological, medical, and demographic assessments at time of enrollment, to be repeated one year following randomization to hormone therapy continuation versus discontinuation, and results from analyses of the baseline assessments are reported here. Across all subjects, years of endogenous estrogen exposure correlated most closely with metabolism in right superior frontal gyrus (p<0.0005). Women taking 17β-estradiol (E) performed three standard deviations higher in verbal memory than women taking conjugated equine estrogen (CEE), and their verbal memory performance positively correlated with metabolism in Wernicke's (p=0.003) and auditory association (p=0.002) areas. Women taking progesterone-plus-estrogen had lower metabolism than women taking unopposed estrogen within the mesial and inferior lateral temporal regions (p<0.0005) and the inferior frontal cortex, contralateral to Broca's area (p<0.0005). In conclusion, particular areas of relatively preserved metabolism were seen in women with more years of endogenous estrogen exposure, as well as in women taking estradiol-based formulations or estrogen therapies unopposed by progesterone, together suggesting regionally specific neuroprotective estrogenic effects.

  View details for DOI 10.1016/j.psyneuen.2010.08.002

  View details for Web of Science ID 000288922300008

  View details for PubMedID 20810219

  View details for PubMedCentralID PMC3021636

• Altered Default-Mode Network Functional Connectivity in Insulin Resistant Women at Risk for Alzheimer's Disease Kenna, H., Hoeft, F., Kelley, R., Reiss, A., Rasgon, N. ELSEVIER SCIENCE INC. 2011: 67S

  View details for Web of Science ID 000290641800217

• Mood disorders in oocyte donor candidates: brief report and implications for future research HUMAN REPRODUCTION Williams, K. E., Stemmle, P. G., Westphal, L. M., Rasgon, N. L. 2011; 26 (4): 847-852

  Abstract

  BACKGROUND IVF, using donor oocytes, has become increasingly common. The donation procedure carries psychiatric risks, including depression, anxiety and rarely, psychosis, and this risk increases when there is a past history of psychiatric illness. We report on the psychiatric status, at intake assessment, of a group of candidate oocyte donors. METHODS The authors reviewed clinical records of 63 women continuously presenting to a University medical center for psychiatric evaluation as part of the screening process for oocyte donation. A board certified psychiatrist administered a structured clinical interview to candidate donors, and self-report measures were obtained from 28 women. RESULTS There was a significant discrepancy between psychiatric history of depression and current mood status, as measured by both clinical interview and psychometric self-report data. Nearly one-quarter of candidate donors (22%) reported a history of major depressive disorder; however, all candidate donors denied current mood disturbance on clinical interview, and mean Beck depression inventory and profile of mood states scores were lower than expected compared with psychometric norms (P < 0.0005), epidemiological data and the recurrent nature of depressive disorders. CONCLUSIONS Candidate donors may minimize psychiatric symptoms. Given the potential for ovarian stimulation protocols to induce or exacerbate mood symptoms, and the moderate heritability of mood disorders, careful evaluation of candidate donor affective disorder history is recommended. This evaluation should focus on sensitivity to mood destabilization during times of hormonal change. Measures that examine whether a candidate donor may have a tendency to present herself in an overly favorable manner, and/or a tendency to minimize symptoms, are recommended.

  View details for DOI 10.1093/humrep/deq394

  View details for PubMedID 21242150

• Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline Workshop on Window of Opportunity Lin, J., Kroenke, C. H., Epel, E., Kenna, H. A., Wolkowitz, O. M., Blackburn, E., Rasgon, N. L. ELSEVIER SCIENCE BV. 2011: 224–231

  Abstract

  Longer duration of reproductive years of life and thus greater exposure to endogenous estrogen may be associated with a lower risk of age-related diseases in women. The present study examined the relationship between estimated endogenous estrogen exposure and telomere length (TL) and telomerase activity, two biomarkers of cellular aging, in a sample of postmenopausal women at risk for cognitive decline. Telomere length was measured using a quantitative PCR method and telomerase activity by TRAP (Telomere-Repeats Amplification Protocol) assay in peripheral blood mononuclear cells (PBMCs). Study subjects were 53 postmenopausal women (35 with natural and 18 with surgical menopause) receiving hormone therapy (HT) for at least one year or longer. Length of reproductive years of life, computed as the difference between age at menopause and age at menarche, was used as a proxy of duration of exposure to endogenous estrogen. Length of time on HT was the measure used for duration of exogenous estrogen exposure. We found that longer endogenous estrogen exposure was associated with greater TL (standardized β=0.06, Wald χ(2)=3.7, p=0.04) and with lower telomerase activity (standardized β=-0.09, Wald χ(2)=5.0, p=0.03). Length of reproductive years was also inversely associated with the combination of short TL and high telomerase (OR=0.78, 95% CI: 0.63, 0.97, p=0.02). Length of HT use was not associated with TL or telomerase activity in this study. The results suggest that the endogenous estrogens may be associated with deceleration of cellular aging. This is the first study to examine associations between endogenous estrogens, telomere length and telomerase activity.

  View details for DOI 10.1016/j.brainres.2010.10.033

  View details for Web of Science ID 000288844300022

  View details for PubMedID 20965155

  View details for PubMedCentralID PMC3057451

• Timing Matters: Menopause and Brain Effects of Ovarian Steroids Introduction BRAIN RESEARCH Rasgon, N. L., Henderson, V. W., Brinton, R., Milner, T. A. 2011; 1379: 1

  View details for DOI 10.1016/j.brainres.2011.02.019

  View details for Web of Science ID 000288844300001

• Association between median family income and self-reported mood symptoms in bipolar disorder COMPREHENSIVE PSYCHIATRY Bauer, M., Glenn, T., Rasgon, N., Marsh, W., Sagduyu, K., Munoz, R., Schmid, R., Haack, S., Whybrow, P. C. 2011; 52 (1): 17-25

  Abstract

  There is broad consensus from epidemiologic research that lower socioeconomic status is related to poorer health. This study investigated the relation between median family income and self-reported mood symptoms in patients with bipolar disorder who reside in the United States.Two hundred eighty-four patients with bipolar disorder provided daily self-reported mood ratings for 6 months (50,054 days of data). Regardless of income, all patients were treated by a psychiatrist, took psychotropic medications, and participated in computerized self-monitoring throughout the study. Median family income was obtained from US census tract data. The association between income and mood was analyzed using income as both a continuous and categorical variable. Demographic characteristics were compared by income group. Education level was included in the analysis a priori.Both the continuous and categorical approaches found a positive association between income and euthymia, a negative association between income and manic/hypomanic symptoms including those due to mixed states, and no association between income and depressive symptoms. Patients in the lower-income group spent 12.4% fewer days euthymic than those in the upper-income group and 9.7% fewer days euthymic than those in the middle-income group. Patients in the lower-income group spent 7.1% more days with manic/hypomanic symptoms than those in the upper-income group. There was no association between education and income.Median family income is associated with mood symptoms in patients with bipolar disorder. Inclusion of income as a measure of socioeconomic status is recommended for future studies of outcome in bipolar disorder.

  View details for DOI 10.1016/j.comppsych.2010.04.005

  View details for Web of Science ID 000286410100003

  View details for PubMedID 21220061

• Association between age of onset and mood in bipolar disorder: Comparison of subgroups identified by cluster analysis and clinical observation JOURNAL OF PSYCHIATRIC RESEARCH Bauer, M., Glenn, T., Rasgon, N., Marsh, W., Sagduyu, K., Munoz, R., Lewitzka, U., Schmid, R., Whybrow, P. C. 2010; 44 (16): 1170-1175

  Abstract

  This study compared subgroups identified by cluster analysis and clinical observation by evaluating the association between the age of onset of bipolar disorder and self-reported daily mood ratings.Two hundred and seventy patients with bipolar disorder provided daily self-reported mood ratings for about 6 months returning 55,188 days of data. The age of onset subgroups were determined both using previously defined cutoff values based upon clinical observation (≤12 years, 13-19 years, 20-29 years, >29 years), and model-based cluster analysis. Demographic characteristics were compared in the age of onset subgroups. Univariate general linear models with age of onset subgroups and other demographic variables as fixed factors and covariates were used to analyze the percent of days depressed, euthymic and hypomanic/manic.Using the predetermined subgroups, demographic differences were found between the four subgroups in the diagnosis of bipolar I/II, years of illness, age and use of lamotrigine. Post-hoc pairwise comparison found that patients with an age of onset less ≤ 12 years spent more days hypomanic/manic: 16.4 percent versus 8.0 for patients with an age of onset between 13 and 19 years (p=0.006) and 8.2 percent for patients with an age of onset between 20 and 29 years (p = 0.031). The majority of the additional days of hypomania/mania occurred outside of an episode. Model-based cluster analysis found a mixture of 2 distributions of onset with peaks at age 15.1 years (SD = 4.7) and 27.5 years (SD = 10.2). Analysis of these two subgroups detected no significant differences in demographic characteristics or mood ratings.Age of onset subgroups arising from clinical observation may be more useful than those determined by cluster analysis.

  View details for DOI 10.1016/j.jpsychires.2010.04.009

  View details for Web of Science ID 000285952000008

  View details for PubMedID 20451218

• Metabolic dysfunction in women with bipolar disorder: the potential influence of family history of type 2 diabetes mellitus BIPOLAR DISORDERS Rasgon, N. L., Kenna, H. A., Reynolds-May, M. F., Stemmle, P. G., Vemuri, M., Marsh, W., Wang, P., Ketter, T. A. 2010; 12 (5): 504-513

  Abstract

  Overweight/obesity, insulin resistance (IR), and other types of metabolic dysfunction are common in patients with bipolar disorder (BD); however, the pathophysiological underpinnings of metabolic dysfunction in BD are not fully understood. Family history of type 2 diabetes mellitus (FamHxDM2), which has been shown to have deleterious effects on metabolic function in the general population, may play a role in the metabolic dysfunction observed in BD.Using multivariate analysis of variance, the effects of BD illness and/or FamHxDM2 were examined relative to metabolic biomarkers in 103 women with BD and 36 healthy, age-matched control women.As a group, women with BD had higher levels of fasting plasma insulin (FPI) and fasting plasma glucose (FPG), higher homeostatic assessment of IR (HOMA-IR) scores, body mass index (BMI), waist circumference (WC), and hip circumference (HC) compared to control women. FamHxDM2 was associated with significantly worse metabolic biomarkers among women with BD but not among healthy control women. Among women with BD, there was a significant main effect of FamHxDM2 on FPI, HOMA-IR, BMI, WC, and HC, even after controlling for type of BD illness, duration of medication exposure, and depression severity. Metabolic biomarkers were not influenced by use of weight-liable psychotropic medication (WLM), even after controlling for type of BD illness, duration of medication exposure, and depression severity.Women with BD have overall worse metabolic biomarkers than age-matched control women. The use of WLM, duration of medication use, type of BD illness, and depression severity did not appear to be associated with more pronounced metabolic dysfunction. FamHxDM2 may represent a risk factor for the development of IR in women with BD. Further, focused studies of the endocrine profiles of families of BD patients are needed.

  View details for DOI 10.1111/j.1399-5618.2010.00839.x

  View details for Web of Science ID 000280987800005

  View details for PubMedID 20712751

  View details for PubMedCentralID PMC2941396

• Neuroendocrinology of BD in women Rasgon, N. WILEY-BLACKWELL PUBLISHING, INC. 2010: 63

  View details for Web of Science ID 000275344600227

• Neuroactive steroids after estrogen exposure in depressed postmenopausal women treated with sertraline and asymptomatic postmenopausal women ARCHIVES OF WOMENS MENTAL HEALTH Morgan, M. L., Rapkin, A. J., Biggio, G., Serra, M., Pisu, M. G., Rasgon, N. 2010; 13 (1): 91-98

  Abstract

  Neuroactive steroids (NAS) allopregnanolone (ALLO), Allotetrahydrodeoxycorticosterone (THDOC) and dehydroepiandrosterone (DHEA) are important in the regulation of mood and behavior. Knowledge about these steroids in postmenopausal depression and the effect of estrogen on NAS is lacking. We elected to determine if there were differences in NAS between postmenopausal depressed women and age matched controls. We also investigated the effect of estradiol on NAS in post menopausal depressed women receiving a selective serotonin reuptake inhibitor (SSRI), and in non-depressed postmenopausal controls. As part of a previously published double blind study on estrogen acceleration of antidepressant action, post menopausal women with major depression receiving sertraline and healthy non depressed controls were randomized to transdermal estrogen patch 0.1 mg or placebo. NAS were measured at baseline and after 10 weeks of treatment. Depressed subjects were treated with sertraline 50 mg/day to 100 mg/day for 9 weeks. At the baseline and after treatment ALLO and DHEA were significantly lower in depressed women compared to controls. Although all depressed subjects experienced a positive clinical response, estrogen administration was not associated with changes in NAS in either the depressed or the asymptomatic postmenopausal women. The lower ALLO and DHEA in postmenopausal depressed women suggests that symptoms of depression may be influenced by the synthesis or fluctuation of these NAS. Estradiol exposure did not alter ALLO, DHEA, or THDOC, implying these NAS are unlikely to play a role in any mood changes in post menopausal women given estrogen therapy.

  View details for DOI 10.1007/s00737-009-0106-1

  View details for Web of Science ID 000275747200020

  View details for PubMedID 19728035

  View details for PubMedCentralID PMC2815799

• Brain volume abnormalities and neurocognitive deficits in diabetes mellitus: Points of pathophysiological commonality with mood disorders? ADVANCES IN THERAPY McIntyre, R. S., Kenna, H. A., Nguyen, H. T., Law, C. W., Sultan, F., Woldeyohannes, H. O., Alsuwaidan, M. T., Soczynska, J. K., Adams, A. K., Cheng, J. S., Lourenco, M., Kennedy, S. H., Rasgon, N. L. 2010; 27 (2): 63-80

  Abstract

  It is hypothesized that diabetes mellitus (DM) and mood disorders share points of pathophysiological commonality in the central nervous system.A PubMed search of all English-language articles published between 1966 and March 2009 was performed with the following search terms: depression, mood disorders, hippocampus, amygdala, central nervous system, brain, neuroimaging, volumetric, morphometric, and neurocognitive deficits, cross-referenced with DM. Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. The primary author was principally responsible for adjudicating the merit of articles that were included.Volumetric studies indicate that individuals with Type 1/2 DM exhibit regional abnormalities in both cortical and subcortical (e.g., hippocampus, amygdala) brain structures. The pattern of neurocognitive deficits documented in individuals with Type 1 DM overlap with Type 2 populations, with suggestions of discrete abnormalities unique to each phenotype. The pattern of volumetric and neurocognitive deficits in diabetic populations are highly similar to that reported in populations of individuals with major depressive disorder.The prevailing models of disease pathophysiology in DM and major depressive disorder are distinct. Notwithstanding, the common abnormalities observed in disparate effector systems (e.g., insulin resistance, immunoinflammatory activation) as well as brain volume and neurocognitive performance provide the nexus for hypothesizing that both conditions are subserved by overlapping pathophysiology. This conception provides a novel framework for disease modeling and treatment development in mood disorder.

  View details for DOI 10.1007/s12325-010-0011-z

  View details for Web of Science ID 000277095200001

  View details for PubMedID 20390390

• Regional cerebral glucose metabolism and anxiety symptoms in bipolar depression: Effects of levothyroxine PSYCHIATRY RESEARCH-NEUROIMAGING Bauer, M., Berman, S. M., Schlagenhauf, F., Voytek, B., Rasgon, N., Mandelkern, M. A., Whybrow, P. C., London, E. D. 2010; 181 (1): 71-76

  Abstract

  We examined the relationships between regional brain activity and anxiety in bipolar depressed patients receiving adjunctive treatment with levothyroxine. Regional brain activity was assessed with positron emission tomography and [18F]fluorodeoxyglucose in 10 euthyroid, depressed bipolar women before and after 7 weeks of adjunctive therapy with levothyroxine. The primary biological measures were relative (to global) regional radioactivity as a surrogate index of glucose metabolism in pre-selected brain regions. Relationships were assessed between regional brain activity and anxiety symptoms while controlling for depression severity. At baseline, Trait Anxiety Inventory measures covaried positively with relative brain activity bilaterally in the dorsal anterior cingulate, superior temporal gyri, parahippocampal gyri, amygdala, hippocampus, ventral striatum, and right insula; state anxiety showed a similar pattern. After treatment anxiety was improved significantly. Change in trait anxiety covaried positively with changes in relative activity in right amygdala and hippocampus. Change in state anxiety covaried positively with changes in relative activity in the hippocampus bilaterally and left thalamus, and negatively with changes in left middle frontal gyrus and right dorsal anterior cingulate. Results indicate that comorbid anxiety symptoms have specific regional cerebral metabolic correlates in bipolar depression and cannot only be explained exclusively by the depressive state of the patients.

  View details for DOI 10.1016/j.pscychresns.2009.07.001

  View details for Web of Science ID 000274423000011

  View details for PubMedID 19962861

• Rosiglitazone Add-On in Treatment of Depressed Patients with Insulin Resistance: a Pilot Study THESCIENTIFICWORLDJOURNAL Rasgon, N. L., Kenna, H. A., Williams, K. E., Powers, B., Wroolie, T., Schatzberg, A. F. 2010; 10: 321-328

  Abstract

  A number of cross-sectional studies have suggested an association between insulin resistance (IR) and affective disorders. However, limited data exist on potential changes in IR in a prospective treatment of depression. The present pilot study tested the hypothesis that improvement of IR with the addition of an insulin-sensitizing agent would improve mood in nondiabetic patients with unipolar or bipolar depression, who had surrogate blood markers suggestive of IR. Surrogate IR-criteria blood markers were fasting plasma glucose >100 mg/dl or triglyceride (TG) to high density lipoprotein (HDL) ratio >3.0. Open-label rosiglitazone, titrated to a dose of 8 mg/day, was administered for 12 weeks to 12 patients with depressive disorder receiving treatment as usual (TAU). Eight patients who completed the 12-week study exhibited significant declines in both depression severity by the Hamilton Depression Rating Scale and the Clinical Global Impression scale, with moderate effect sizes noted. Modest improvement in Matsuda Index scores was also noted at 12 weeks, yet declines in depression severity scores were not associated with improvements in the endocrine markers (Matsuda Index, TG/HDL ratio, and body mass index). These results suggest the potential novel use for an insulin-sensitizing agent in the treatment of depressive disorders. Larger placebo-controlled studies are warranted.

  View details for DOI 10.1100/tsw.2010.32

  View details for Web of Science ID 000274935000007

  View details for PubMedID 20191245

• Management of Bipolar Disorders in Women HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Zappert, L. N., Rasgon, N. L., Ketter, T. A. 2010: 425–51

  View details for Web of Science ID 000294220800012

• Epidemiology of Mental Disorders in Older Women PUBLIC HEALTH PERSPECTIVE OF WOMEN'S MENTAL HEALTH Kenna, H. A., Ghezel, T., Rasgon, N. L., Levin, B. L., Becker, M. A. 2010: 65–80

  View details for DOI 10.1007/978-1-4419-1526-9_4

  View details for Web of Science ID 000276045200004

• Genetic overlap between polycystic ovary syndrome and bipolar disorder: The endophenotype hypothesis MEDICAL HYPOTHESES Jiang, B., Kenna, H. A., Rasgon, N. L. 2009; 73 (6): 996-1004

  Abstract

  Polycystic Ovary Syndrome (PCOS) is a polygenic disorder caused by the interaction of susceptible genomic polymorphisms with environmental factors. PCOS, characterized by hyperandrogenism and menstrual abnormalities, has a higher prevalence in women with Bipolar Disorder (BD). Theories explaining this high prevalence have included the effect of PCOS itself or the effect of drugs such as Valproate, which may cause PCOS either directly or indirectly. Incidentally, metabolic abnormalities are observed in both bipolar and PCOS patients. Endophenotypes such as insulin resistance, obesity, and hyperglycemia are common among BD and PCOS patients, suggesting some degree of pathophysiological overlap. Since both BD and PCOS are complex polygenetic diseases, the endophenotype overlap may be the result of common genetic markers. This paper postulates that shared clinical endophenotypes between PCOS and BD indicate common pathophysiological platforms and will review these for the potential of genetic overlap between the two disorders.

  View details for DOI 10.1016/j.mehy.2008.12.056

  View details for Web of Science ID 000272923000032

  View details for PubMedID 19556071

• Brain Glucose Metabolism in Hypothyroidism: A Positron Emission Tomography Study before and after Thyroid Hormone Replacement Therapy JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Bauer, M., Silverman, D. H., Schlagenhauf, F., London, E. D., Geist, C. L., Van Herle, K., Rasgon, N., Martinez, D., Miller, K., Van Herle, A., Berman, S. M., Phelps, M. E., Whybrow, P. C. 2009; 94 (8): 2922-2929

  Abstract

  Hypothyroidism is frequently associated with subtle behavioral and psychiatric symptoms. The consequences of inadequate thyroid hormone availability to brain metabolism are poorly understood.This study assessed the relationships between neuropsychiatric symptoms and changes in relative regional cerebral glucose metabolism in hypothyroid patients undergoing thyroid hormone replacement therapy. DESIGN, SETTING, AND OUTCOME MEASURE: Relative regional cerebral glucose metabolism was compared in 13 previously untreated hypothyroid patients and 10 healthy control participants. Effects of thyroid hormone replacement therapy (levothyroxine, 3 months) were assessed using neuropsychiatric measures and positron emission tomography with [(18)F]fluorodeoxyglucose.Before treatment, hypothyroid patients exhibited lower regional activity than control subjects in the bilateral amygdala, hippocampus, and perigenual anterior cingulate cortex (ACC), left subgenual ACC, and right posterior cingulate cortex. Severity of depressive symptoms covaried negatively with pretreatment activity in the bilateral middle frontal gyrus and right subgenual and dorsal ACC. Thyroid hormone replacement therapy abolished pretreatment group differences in regional activity, robustly increased activity in the ventral ACC, and significantly reduced both clinician-rated and self-rated behavioral and psychiatric symptoms. Increased activity within the ventral ACC was associated with reduced somatic complaints, whereas increased activity within the dorsal ACC was associated with reduced depressive symptoms.Reduction of the behavioral complaints during thyroid hormone therapy is associated with a restoration of metabolic activity in brain areas that are integral to the regulation of affect and cognition. The findings suggest that thyroid hormone modulates regional glucose metabolism and psychiatric symptoms in the mature brain.

  View details for DOI 10.1210/jc.2008-2235

  View details for Web of Science ID 000268687700036

  View details for PubMedID 19435829

• Comparison of sleep/wake parameters for self-monitoring bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Bauer, M., Glenn, T., Grof, P., Rasgon, N., Alda, M., Marsh, W., Sagduyu, K., Schmid, R., Adli, M., Whybrow, P. C. 2009; 116 (3): 170-175

  Abstract

  Psychosocial interventions may teach patients with bipolar disorder to successfully detect warning signs of relapse. These interventions often include ongoing self-monitoring of sleep. We previously reported that a change in sleep duration (sleep plus bedrest) of >3 h may indicate that a mood change is imminent. This analysis further investigated whether sleep duration, sleep onset or sleep offset was the most useful sleep/wake parameter to monitor for an oncoming mood change.101 adult outpatients receiving treatment as usual recorded mood, sleep and medications every day on a home computer for a mean of 265+/-103 days. A daily time series of mood, sleep duration (sleep plus bedrest), sleep onset and sleep offset was constructed for each patient. After applying an ARIMA (0,1,1) filter, a cross correlation function was used to analyze the temporal relationship between the residuals for lags of +/-7 days.Less frequent significant correlations were found between a change in either sleep onset or sleep offset and mood, than between sleep duration and mood. Patients with a significant correlation between sleep duration and mood included 86% of those with a significant correlation between sleep onset or sleep offset and mood. Mean sleep duration when euthymic was long (> or =8 h in 89% of patients, > or =9 h in 51% of patients).Self-reported data, naturalistic study, and computer access required.Self-monitoring of sleep duration is recommended for patients with bipolar disorder. Better understanding of the long sleep duration of euthymic patients is required.

  View details for DOI 10.1016/j.jad.2008.11.014

  View details for Web of Science ID 000268074400003

  View details for PubMedID 19118904

• Frequency of subsyndromal symptoms and employment status in patients with bipolar disorder SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY Bauer, M., Glenn, T., Grof, P., Rasgon, N. L., Marsh, W., Sagduyu, K., Alda, M., Lewitzka, U., Sasse, J., Kozuch-Krolik, E., Whybrow, P. C. 2009; 44 (7): 515-522

  Abstract

  This study investigated the frequency of episodes and subsyndromal symptoms based on employment status in patients with bipolar disorder.Patients with bipolar disorder (n = 281) provided daily self-reported mood ratings for 5 months, returning 46,292 days of data. Data were analyzed using three employment status groups: disabled (n = 75), full-time employee or full-time student (n = 135), and other (n = 71). Demographic characteristics were compared by employment status. A univariate general linear model with employment status and other demographic variables as fixed factors and covariates was used to analyze the percent of days in episodes and percent of days with subsyndromal symptoms.While there was no significant difference in the percent of days in episodes among the employment groups, disabled patients suffered subsyndromal symptoms of depression twice as frequently as those in the full-time group. Disabled patients spent 15% more days either in episodes or with subsyndromal symptoms than those in the full-time group, equivalent to about 45 extra sick days a year.Frequent subsyndromal symptoms, especially depressive, may preclude full-time responsibilities outside the home and contribute to disability in bipolar disorder. Additional treatments to reduce the frequency of subsyndromal symptoms are needed.

  View details for DOI 10.1007/s00127-008-0464-4

  View details for Web of Science ID 000266824500001

  View details for PubMedID 19011720

• A 54-year-old Man with History of PTSD PSYCHIATRIC ANNALS Tan, V. O., Rasgon, N. L. 2009; 39 (7): 699-+

  View details for DOI 10.3928/00485713-20090625-02

  View details for Web of Science ID 000267916100004

• Relationship among latitude, climate, season and self-reported mood in bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Bauer, M., Glenn, T., Grof, P., Rasgon, N. L., Marsh, W., Sagduyu, K., Alda, M., Murray, G., Quiroz, D., Malliaris, Y., Sasse, J., Pilhatsch, M., Whybrow, P. C. 2009; 116 (1-2): 152-157

  Abstract

  Many researchers have analyzed seasonal variation in hospital admissions for bipolar disorder with inconsistent results. We investigated if a seasonal pattern was present in daily self-reported daily mood ratings from patients living in five climate zones in the northern and southern hemispheres. We also investigated the influence of latitude and seasonal climate variables on mood.360 patients who were receiving treatment as usual recorded mood daily (59,422 total days of data). Both the percentage of days depressed and hypomanic/manic, and the episodes of depression and mania were determined. The observations were provided by patients from different geographic locations in North and South America, Europe and Australia. These data were analyzed for seasonality by climate zone using both a sinusoidal regression and the Gini index. Additionally, the influence of latitude and climate variables on mood was estimated using generalized linear models for each season and month.No seasonality was found in any climate zone by either method. In spite of vastly different weather, neither latitude nor climate variables were associated with mood by season or month.Daily self-reported mood ratings of most patients with bipolar disorder did not show a seasonal pattern. Neither climate nor latitude has a primary influence on the daily mood changes of most patients receiving medication for bipolar disorder.

  View details for DOI 10.1016/j.jad.2008.11.013

  View details for Web of Science ID 000267247000026

  View details for PubMedID 19091424

• Employment status and subsyndromal symptoms in bipolar disorder 8th International Conference on Bipolar Disorder Glenn, T., Bauer, M., Grof, P., Rasgon, N. L., Marsh, W., Sagduyu, K., Alda, M., Lewitzka, U., Sasse, J., Kozuch-Krolik, E., Whybrow, P. C. WILEY-BLACKWELL. 2009: 43–43

  View details for Web of Science ID 000268963500115

• Latitude, climate, season and self-reported mood in bipolar disorder 8th International Conference on Bipolar Disorder Bauer, M., Glenn, T., Grof, P., Rasgon, N. L., Marsh, W., Sagduyu, K., Alda, M., Murray, G., Quiroz, D., Malliaris, Y., Sasse, J., Whybrow, P. C. WILEY-BLACKWELL. 2009: 19–19

  View details for Web of Science ID 000268963500049

• Increased depressive symptoms in menopausal age women with bipolar disorder: Age and gender comparison JOURNAL OF PSYCHIATRIC RESEARCH Marsh, W. K., Ketter, T. A., Rasgon, N. L. 2009; 43 (8): 798-802

  Abstract

  Emerging data suggest the menopausal transition may be a time of increased risk for depression. This study examines the course of bipolar disorder focusing on depressive symptoms in menopausal transition age women, compared to similar-aged men as well as younger adult women and men.Outpatients with bipolar disorder were assessed with the systematic treatment enhancement program for bipolar disorder (STEP-BD) affective disorders evaluation and longitudinally monitored during naturalistic treatment with the STEP-BD clinical monitoring form. Clinical status (syndromal/subsyndromal depressive symptoms, syndromal/subsyndromal elevation or mixed symptoms, and euthymia) was compared between menopausal transition age women (n=47) and pooled similar-aged men (n=30) 45-55 years old, younger women (n=48) and men (n=39) 30-40 years old.Subjects included 164 bipolar disorder patients (67 type I, 82 type II, and 15 not otherwise specified), 34% were rapid cycling and 58% women. Bipolar II disorder/bipolar NOS was more common in women. Monitoring averaged 30+/-22 months, with an average of 0.9+/-0.5 clinic visits/month. Menopausal age women had a significantly greater proportion of visits with depressive symptoms (p<0.05), significantly fewer euthymic visits (p<0.05) and no difference in proportion of visits with elevated/mixed symptoms compared to pooled comparison group.Menopausal transition age women with bipolar disorder experience a greater proportion of clinic visits with depressive symptoms compared to similarly aged men, and younger women and men with bipolar disorder. Further systematic assessment on the influence of the menopausal transition and reproductive hormones upon mood is needed to better inform clinical practice in treating women with bipolar disorder.

  View details for DOI 10.1016/j.jpsychires.2008.11.003

  View details for Web of Science ID 000266177600008

  View details for PubMedID 19155021

• Verbal memory performance of postmenopausal women on estradiol therapy is positively correlated with regional brain metabolism in receptive language and auditory association areas Geist, C., Silverman, D., Kenna, H., Rasgon, N. SOC NUCLEAR MEDICINE INC. 2009

  View details for Web of Science ID 000444145700367

• Cognitive effects of memantine in postmenopausal women at risk of dementia: a pilot study ACTA NEUROLOGICA SCANDINAVICA Wroolie, T. E., Kenna, H. A., Williams, K. E., Powers, B. N., Holcomb, M., Lazzeroni, L., Rasgon, N. L. 2009; 119 (3): 172-179

  Abstract

  To determine the effects of memantine on cognition in a normal population of postmenopausal women with putative risk factors for Alzheimer's disease (AD) using a built-in control for the genetic risk factor for AD (apoE-epsilon4 status).A prospective, open-label, 6-month pilot medication trial with memantine and follow-up after discontinuance conducted at the Center for Neuroscience in Women's Health, Stanford University School of Medicine. Neuropsychological data were collected on 22 community-dwelling postmenopausal women (11 apoE-epsilon4 carriers and 11 apoE-epsilon4 non-carriers) with at least one putative risk factor for AD.ApoE-epsilon4 status was not a significant predictor of change in neuropsychological performance. Changes associated with memantine treatment for entire sample included significant declines in some variables associated with verbal learning and memory that improved upon medication withdrawal. A positive medication effect was noted with executive functions and possibly category fluency. Trend-level improvements were seen in motor dexterity of the non-dominant hand and maintained even after drug discontinuance.Treatment with memantine appeared to have differential effects on cognitive performance in a population of women with putative risk factors for AD. ApoE-epsilon4 carrier status did not account for observed changes in cognition.

  View details for DOI 10.1111/j.1600-0404.2008.01084.x

  View details for Web of Science ID 000262949100005

  View details for PubMedID 18705678

• Metabolic syndrome and major depressive disorder: Co-occurrence and pathophysiologic overlap CURRENT DIABETES REPORTS McIntyre, R. S., Rasgon, N. L., Kemp, D. E., Nguyen, H. T., Law, C. W., Taylor, V. H., Woldeyohannes, H. O., Alsuwaidan, M. T., Soczynska, J. K., Kim, B., Lourenco, M. T., Kahn, L. S., Goldstein, B. I. 2009; 9 (1): 51-59

  Abstract

  The metabolic syndrome and its components are associated with depressive symptomatology. This article discusses the rate of co-occurrence and the points of pathophysiologic commonality between the metabolic syndrome and major depressive disorder.

  View details for DOI 10.1007/s11892-009-0010-0

  View details for Web of Science ID 000263478200007

  View details for PubMedID 19192425

• Thalamo-Basal Ganglia Connectivity in Postmenopausal Women Receiving Estrogen Therapy NEUROCHEMICAL RESEARCH Kenna, H. A., Rasgon, N. L., Geist, C., Small, G., Silverman, D. 2009; 34 (2): 234-237

  Abstract

  Cumulative data on the effects of estrogen therapy (ET) on brain function in postmenopausal women suggests that ET influences cerebral metabolism and may protect against age-related declines in various domains of cognitive function. The beneficial cognitive effects of ET may relate to its modulation of the thalamic-striatum cholinergic and dopaminergic systems, as the activity of both neurotransmitter systems in the thalamus appears to be positively influenced by estrogen. In the current study, we attempted to evaluated regional cerebral brain metabolism utilizing [18F]-fluorodeoxyglucose positron emission tomography in 11 healthy recently-postmenopausal women on ET (ET+) in comparison to 11 recently-postmenopausal and ET-naïve women (ET-) in order to assess the effects of ET on cholinergic and dopaminergic system regulation. Results showed thalamo-basal ganglia connectivity among ET+ women but not among ET- women. The presence of connectivity in the thalamo-striatal pathway in recently postmenopausal women suggests estrogen effects in preserving integrity of the cholinergic and dopaminergic systems. The results also suggest that ET initiated at or near the menopausal transition may modulate brain aging by mediating complex sensory-motor functions.

  View details for DOI 10.1007/s11064-008-9756-z

  View details for Web of Science ID 000262811300005

  View details for PubMedID 18535904

• Postmenopausal hormone therapy in a prospective randomized trial of termination versus long-term continuation results in greater regional brain metabolism. Silverman, D. S., Geist, C. L., Kenna, H. A., Rasgon, N. L. AMER ASSOC CANCER RESEARCH. 2009: 326S

  View details for Web of Science ID 000262583201410

• Reproductive and Metabolic Abnormalities Associated with Bipolar Disorder and Its Treatment HARVARD REVIEW OF PSYCHIATRY Kenna, H. A., Jiang, B., Rasgon, N. L. 2009; 17 (2): 138-146

  Abstract

  Women with mood disorders, especially bipolar disorder (BD), have been shown to have high rates of reproductive and metabolic dysfunction. The available data on the functional, anatomic, and clinical neuroendocrine abnormalities in women with BD suggest a two-tiered relationship with mood pathology. First, many of the medications commonly used in the treatment of BD can have deleterious effects on blood levels of reproductive hormones and consequently on the hypothalamic-pituitary-gonadal (HPG) axis and reproductive function. Studies that have specifically addressed the association between psychotropic medications and menstrual abnormalities, polycystic ovary syndrome, and overall reproductive endocrine function in women with BD have found high rates of HPG irregularities in women with BD. Second, there is evidence of reproductive dysfunction in women with BD prior to treatment. In addition, many of the psychotropic medications used in the treatment of BD are associated with weight gain, insulin resistance, and dyslipidemia. These metabolic side effects further compound the neuroendocrine system dysregulation in women with BD. Current understanding of the reproductive and metabolic function in women with BD points to vulnerability, which in turn increases the risk of later-life cardiovascular disease and diabetes, among other morbidities, for women with BD.

  View details for DOI 10.1080/10673220902899722

  View details for Web of Science ID 000265294600006

  View details for PubMedID 19373621

• Insulin Resistance in Bipolar Women: Effects of Mood-Stabilizing Drugs METABOLIC EFFECTS OF PSYCHOTROPIC DRUGS Vemuri, M., Stemmle, P., Jiang, B., Morenkova, A., Rasgon, N., Thakore, J., Leonard, B. E. 2009; 26: 12–24

  View details for DOI 10.1159/000189772

  View details for Web of Science ID 000332260600003

• Insulin resistance and hyperlipidemia in women with bipolar disorder. Journal of psychiatric research Stemmle, P. G., Kenna, H. A., Wang, P. W., Hill, S. J., Ketter, T. A., Rasgon, N. L. 2009; 43 (3): 341-343

  View details for DOI 10.1016/j.jpsychires.2008.04.003

  View details for PubMedID 18490029

• Relationship between adjunctive medications for anxiety and time spent ill in patients with bipolar disorder INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE Bauer, M., Glenn, T., Grof, P., Rasgon, N. L., Marsh, W., Sagduyu, K., Alda, M., Lewitzka, U., Schmid, R., Whybrow, P. C. 2009; 13 (1): 70-77

  Abstract

  Objective. Many patients with bipolar disorder take adjunctive medications for anxiety. Using naturalistic data, we investigated the relationship between the use of adjunctive anxiolytics and the time spent in episodes or with subsyndromal mood symptoms. Methods. This was a post-hoc analysis of 310 patients with bipolar disorder who previously recorded mood and medications daily for 5 months using ChronoRecord software. One hundred patients were taking adjunctive anxiolytics for at least 50% of days; 210 were not. Of the 100 patients, 73 were taking a benzodiazepine. All patients taking anxiolytics were also receiving treatments for bipolar disorder. Results. Patients with bipolar disorder who were taking adjunctive medications for anxiety spent more time ill. Comparing patients who were taking or not taking anxiolytics, the mean days spent either in any episode or with subsyndromal symptoms was 45.6 vs. 29.6%, respectively (P<0.001), the mean days in any episode was 17.1 vs. 9.2%, respectively (P=0.016), and the mean days with subsyndromal depression was 26.4 vs. 16.2%, respectively (P=0.004). Conclusion. While this methodology cannot determine causality, these findings highlight the need for controlled studies of the long-term impact of adjunctive medications for anxiety on mood symptoms in patients being treated for bipolar disorder.

  View details for DOI 10.1080/13651500802450514

  View details for Web of Science ID 000263445900011

• Cerebral metabolic patterns in untreated postmenopausal women with major depressive disorder PSYCHIATRY RESEARCH-NEUROIMAGING Rasgon, N. L., Kenna, H. A., Geist, C., Small, G., Silverman, D. 2008; 164 (1): 77-80

  Abstract

  Cerebral metabolic rates were assessed using [(18)F]-fluorodeoxyglucose positron emission tomography in six naturally postmenopausal women with untreated unipolar depression and 11 matched controls. All subjects were hormone therapy-naive and medication-free. Findings include hypermetabolism in the middle frontal gyrus and Broca regions, and hypometabolism in the pons among depressed compared with non-depressed women.

  View details for DOI 10.1016/j.psychresns.2007.12.006

  View details for Web of Science ID 000261023800007

  View details for PubMedID 18707852

• Changes in self-reported sleep duration predict mood changes in bipolar disorder PSYCHOLOGICAL MEDICINE Bauer, M., Glenn, T., Whybrow, P. C., Grof, P., Rasgon, N., Alda, M., Marsh, W., Sagduyu, K., Schmid, R., Adli, M. 2008; 38 (7): 1069-1071

  View details for DOI 10.1017/S0033291708003280

  View details for Web of Science ID 000257506100018

  View details for PubMedID 18377675

• Self-reporting software for bipolar disorder: Validation of ChronoRecord by patients with mania PSYCHIATRY RESEARCH Bauer, M., Wilson, T., Neuhaus, K., Sasse, J., Pfennig, A., Lewitzka, U., Grof, P., Glenn, T., Rasgon, N., Bschor, T., Whybrow, P. C. 2008; 159 (3): 359-366

  Abstract

  With the widespread recognition of the value of active patient participation in their care, ChronoRecord software was developed to automate daily self-reporting by patients with bipolar disorder. A prior study demonstrated concurrent validity between self-ratings on ChronoRecord and clinician ratings on the Hamilton Depression Rating Scale (HAMD), but validity with the Young Mania Rating Scale (YMRS) could not be shown due to a lack of data when the outpatients were manic (Bauer et al., Bipolar Disorders 6, 67-74, 2004). This study expanded upon the prior validation study to include inpatients with mania. Self-reported mood ratings on ChronoRecord and clinician ratings on the YMRS were obtained on the same day from 27 inpatients (57 ratings); these data were also combined with the ratings from the 80 outpatients (total 107 patients, 340 ratings). Using Pearson correlation, the self-reported ratings on ChronoRecord were significantly correlated with the YMRS. The accuracy of ChronoRecord to discriminate hypomania and mania was high, as described by the area under the receiver operating characteristic curve. Post-hoc analysis of the level of agreement between ChronoRecord and YMRS ratings was excellent or good in all cases using the kappa statistic. These data demonstrate concurrent validity between ChronoRecord and YMRS.

  View details for DOI 10.1016/j.psychres.2007.04.013

  View details for Web of Science ID 000256743800011

  View details for PubMedID 18423616

• Regional cerebral metabolism and neuropsychological performance among healthy postmenopausal users of estrogen therapy 63rd Annual Convention of the Society-of-Biological-Psychiatry Rasgon, N., Kenna, H., Geist, C., Powers, B., Wroolie, T., Williams, K. E., Silverman, D. ELSEVIER SCIENCE INC. 2008: 16S–16S

  View details for Web of Science ID 000254163700050

• Insulin resistance and hyperlipidemia in women with bipolar disorder Rasgon, N. L., Stemmle, P. G., Kenna, H. A., Wong, P. W., Hill, S. J., Ketter, T. A. ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER. 2008: S235–S235

  View details for Web of Science ID 000254987801089

• Increased frequency of depressive episodes during the menopausal transition in women with bipolar disorder: Preliminary report JOURNAL OF PSYCHIATRIC RESEARCH Marsh, W. K., Templeton, A., Ketter, T. A., Rasgon, N. L. 2008; 42 (3): 247-251

  Abstract

  Data are emerging in bipolar disorder regarding mood across phases of the female reproductive life, yet information about mood during the menopausal transition remains limited. The menopausal transition in women without mood disorders is associated with an increase in depression. This study assesses mood course during the menopausal transition in women with bipolar disorder.We monitored mood episodes in 47 women with bipolar disorder ages 45-55 for 17.0+/-14.0 months with systematic treatment enhancement program for bipolar disorder (STEP-BD) standardized evaluations. Charts were additionally reviewed for menstrual status and menstrual history, as well as mood episode type, duration, frequency and history.During the menopausal transition 68% of women with bipolar disorder experienced at least one depressive episode. Depression (but not mood elevation) episode frequency significantly increased during the menopausal transition compared to reported frequency during patients' reproductive years. History of pre-menstrual and or post-partum mood instability did not predict perimenopausal mood episodes.Women with bipolar disorder experience a high frequency of depressive episodes during perimenopausal years and this frequency appears greater than during prior reproductive years. Prospective controlled studies are needed to better understand the course of mood episodes and to enhance the effectiveness of managing bipolar disorder during the menopausal transition.

  View details for DOI 10.1016/j.jpsychires.2006.12.006

  View details for Web of Science ID 000253397900010

  View details for PubMedID 17266987

• Children of persons with Alzheimer disease - What does the future hold? ALZHEIMER DISEASE & ASSOCIATED DISORDERS Jarvik, L., LaRue, A., Blacker, D., Gatz, M., Kawas, C., McArdle, J. J., Morris, J. C., Mortimer, J. A., Ringman, J. M., Ercoli, L., Freimer, N., Gokhman, I., Manly, J. J., Plassman, B. L., Rasgon, N., Roberts, J. S., Sunderland, T., Swan, G. E., Wolf, P. A., Zonderman, A. B. 2008; 22 (1): 6-20

  Abstract

  Children of persons with Alzheimer disease (AD), as a group, face an increased risk of developing AD. Many of them, throughout their adult lives, seek input on how to reduce their chances of one day suffering their parent's fate. We examine the state of knowledge with respect to risk and protective factors for AD and recommend a research agenda with special emphasis on AD offspring.

  View details for Web of Science ID 000253700000003

  View details for PubMedID 18317242

  View details for PubMedCentralID PMC3377487

• The electronic assessment of the longitudinal course of bipolar disorder with ChronoRecord (R) software NERVENHEILKUNDE Bauer, M., Kozuch, E., Glenn, T., Grof, P., Gutzmann, C., Kiermeir, J., Neuhaus, K., Rasgon, N., Ricken, R., Sasse, J., Schmid, R., Whybrow, P. C. 2008; 27 (3): 165-?

  View details for Web of Science ID 000254302700006

• A case of olanzapine-induced gestational diabetes mellitus in the absence of weight gain JOURNAL OF CLINICAL PSYCHIATRY Vemuri, M. P., Rasgon, N. L. 2007; 68 (12): 1989-1989

  View details for Web of Science ID 000252045900026

  View details for PubMedID 18162037

• Mood disorders and fertility in women: a critical review of the literature and implications for future research HUMAN REPRODUCTION UPDATE Williams, K. E., Marsh, W. K., Rasgon, N. L. 2007; 13 (6): 607-616

  Abstract

  A medline literature review of fertility and mood disorder articles published since 1980 was performed in order to critically review the literature regarding a relationship between mood disorders, fertility and infertility treatment. Previous studies suggests that mood disorders, both in the bipolar and unipolar spectrum, may be associated with decreased fertility rates. Most studies report that women seeking treatment for infertility have an increased rate of depressive symptoms and possibly major depression (none showed evaluated mood elevations). Many, but not all, studies found that depressive symptoms may decrease the success rate of fertility treatment. Treatments for infertility may independently influence mood through their effects on estrogen and progesterone, which have been shown to influence mood through their actions on serotonin. Studies are limited in scope and confounding variables are many, limiting the strength of the results. In conclusion, a range of existing studies suggests that fertility and mood disorders are related in a complex way. Future studies should use clinical interviews and standardized and validated measures to confirm the diagnosis of mood disorders and control for the variables of medication treatment, desire for children, frequency of sexual intercourse, age, FSH levels, menstrual cycle regularity in assessing an interrelationship between mood disorders and fertility.

  View details for DOI 10.1093/humupd/dmm019

  View details for Web of Science ID 000250679900009

  View details for PubMedID 17895237

• Self-reported data from patients with bipolar disorder: Frequency of brief depression JOURNAL OF AFFECTIVE DISORDERS Bauer, M., Glenn, T., Grof, P., Pfennig, A., Rasgon, N. L., Marsh, W., Munoz, R. A., Sagduyu, K., Alda, M., Quiroz, D., Sasse, J., Whybrow, P. C. 2007; 101 (1-3): 227-233

  Abstract

  Patients with bipolar disorder often report depressive symptoms that do not meet the DSM-IV criteria for an episode. Using daily self-reported mood ratings, we studied how changing the length requirement to that typical of recurrent brief depression (2-4 days) would impact the number of depressed episodes.203 patients (135 bipolar I and 68 bipolar II by DSM-IV criteria) recorded mood daily using ChronoRecord software on a home computer (30,348 total days; mean 150 days). Episodes of depression and days of depression outside of episodes were determined. Symptom intensity (mild versus moderate or severe) was investigated within and outside of depressive episodes.Decreasing the minimum duration criterion for an episode of depression to 2 days increased the number of patients with a depressed episode two and a half times (52 to 131), and quadrupled both the number of depressed episodes per patient (0.62 to 2.88) and the number of depressed episodes for all patients (125 to 584). With a 2-day episode length, 34% of days of depression remained outside an episode. The ratio of days with severe symptoms within episodes remained consistent (about 25%) in spite of decreasing the episode length to 2 days. Considering only days with severe symptoms, about 25% remained outside of episodes even with a 2-day length. None of the results distinguished bipolar I from bipolar II disorder.Self-reported data, computer access required, relatively short study length, no control group.Brief depressive episodes and single days of depression outside of episodes occur frequently in both bipolar I and bipolar II disorder. Moderate or severe symptoms occur during brief episodes at a ratio similar to that for episodes that meet the DSM-IV criteria.

  View details for DOI 10.1016/j.jad.2006.11.021

  View details for Web of Science ID 000247860000024

  View details for PubMedID 17224186

• Self-reported depression and minimum length of depression episodes in bipolar disorder 7th International Conference on Bipolar Disorder Bauer, M., Grof, P., Glenn, T., Rasgon, N. L., Sasse, J., Whybrow, P. C. WILEY-BLACKWELL. 2007: 19–19

  View details for Web of Science ID 000253284000051

• Approximate entropy of self-reported mood prior to episodes in patients with bipolar disorder 7th International Conference on Bipolar Disorder Glenn, T., Whybrow, P. C., Rasgon, N. L., Grof, P., Alda, M., Baethge, C., Bauer, M. WILEY-BLACKWELL. 2007: 45–45

  View details for Web of Science ID 000253284000125

• Verbal memory retrieval deficits associated with untreated hypothyroidism JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES Miller, K. J., Parsons, T. D., Whybrow, P. C., Van Herle, K., Rasgon, N., Van Herle, A., Martinez, D., Silverman, D. H., Bauer, M. 2007; 19 (2): 132-136

  Abstract

  The effects of inadequate thyroid hormone availability to the brain on adult cognitive function are poorly understood. This study assessed the effects of hypothyroidism on cognitive function using a standard neuropsychological battery in 14 patients suffering from untreated hypothyroidism and complaining of subjective cognitive difficulties in comparison with 10 age-matched healthy comparison subjects. Significant differences between groups were limited to verbal memory retrieval as measured by the California Verbal Learning Test (CVLT). On short delay free recall, long delay free recall, and long delay cued recall, significant differences remained between groups despite the limited statistical power of this study. There were no significant results found between groups on attentional or nonverbal tasks. Results suggest that hypothyroid-related memory deficits are not attributable to an attentional deficit but rather to specific retrieval deficits.

  View details for Web of Science ID 000245666300004

  View details for PubMedID 17431058

• Functional brain imaging studies in estrogen depleted postmenopausal women with major depressive disorder Rasgon, N. ELSEVIER SCIENCE INC. 2007: 15S

  View details for Web of Science ID 000245698100041

• Estrogen and response to sertraline in postmenopausal women with major depressive disorder: A pilot study JOURNAL OF PSYCHIATRIC RESEARCH Rasgon, N. L., Dunkin, J., Fairbanks, L., Altshuler, L. L., Troung, C., Elman, S., Wroolie, T. E., Brunhuber, M. V., Rapkin, A. 2007; 41 (3-4): 338-343

  Abstract

  Pilot study examining the effects of estrogen therapy (ET) on antidepressant response in postmenopausal women with major depressive disorder (MDD).Twenty-two subjects received sertraline at 50mg/day for one week, with an increase to 100mg/day at week 2 for a 10-week trial. Transdermal estrogen or placebo patches 0.1mg were randomly administered concurrent with the initiation of sertraline treatment. The 21 item Hamilton Depression Rating Scale (HDRS-21) was administered to all patients at baseline and weekly thereafter.Both groups showed a similar significant reduction in HDRS-21 scores by the end of the study. There was no significant difference between the two treatment groups at the end of the 10-week trial, but the women receiving sertraline with ET showed significantly greater early improvement (weeks 2-4) compared to the women receiving sertraline with placebo.Sertraline is an effective antidepressant for postmenopausal women with MDD. ET does not alter the response rate to antidepressant therapy however ET may play a role in accelerating the antidepressant response.

  View details for DOI 10.1016/j.jpsychires.2006.03.009

  View details for Web of Science ID 000243214000019

  View details for PubMedID 16697413

• Hypothalamic-pituitary-end organ function in women with bipolar depression 61st Annual Convention of the Society-of-Biological-Psychiatry Rasgon, N. L., Kenna, H. A., Wong, M., Whybrow, P. C., Bauer, M. PERGAMON-ELSEVIER SCIENCE LTD. 2007: 279–86

  Abstract

  Disturbance of each of the three hypothalamic-pituitary-end organ systems [hypothalamic-pituitary-thyroid (HPT), -adrenal (HPA), and -gonadal (HPG)] has been reported in depressive disorders. Little is known about potential reciprocal interaction among the three HP-end organ systems in patients with depressive disorders. The present pilot study examined selective HPA and HPG hormones in a detailed time series in women with bipolar disorder (depressed type) before and after treatment with levothyroxine (L-T4), and in matched control subjects. Six medically stable, euthyroid, premenopausal women with bipolar depression, and 5 age-matched controls underwent overnight blood sampling from 2100 to 0900 h for measurement of adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), and estradiol every 15 min. Bipolar patients underwent a second overnight blood sampling procedure following 7-weeks of open-label add-on treatment with L-T4. Results revealed lower baseline cortisol parameters in bipolar patients in comparison to control subjects, while ACTH, LH, and estradiol parameters were similar. Thyroid hormones (TSH, free and total T4) were not correlated with any of the HPA or HPG hormones. ACTH and cortisol levels were correlated in control subjects, but not in bipolar patients. After L-T4 treatment, thyroid hormones increased significantly and depression scores significantly declined. No significant changes in HPA or HPG hormones parameters were observed, although the small sample size may have limited results. Upon visual inspection, ACTH and cortisol appeared to decrease after L-T4 treatment, while estradiol appeared to increase. These pilot data suggest lower levels of cortisol in women with bipolar depression, unlike previously published studies that reported higher cortisol in patients with depression. The data also suggest reciprocal changes in the HPA and HPG axes upon pharmacological modulation of the HPT system, although whether this change was due to the L-T4 treatment or the improvement of depression is unknown. The results are preliminary, and require replication in larger samples.

  View details for DOI 10.1016/j.psyneuen.2006.12.014

  View details for Web of Science ID 000245741300007

  View details for PubMedID 17317022

• Valproate and neuroendocrine changes in relation to women treated for epilepsy and bipolar disorder: A review CURRENT MEDICINAL CHEMISTRY Reynolds, M. F., Sisk, E. C., Rasgon, N. L. 2007; 14 (26): 2799-2812

  Abstract

  Valproic acid (2-n-propylpentanoic acid, VPA) is well-established as a mood-stabilizer for bipolar disorder, in addition to its application as a treatment in neurological disorders such as epilepsy, migraine headaches, and chronic neuropathic pain. Its mechanisms of actions in any of the disorders have not yet been fully elucidated but currently include GABA-ergic inhibitory effects, the suppression of NMDA-mediated excitatory neurotransmission, and possibly effects on monoamines and cerebral glucose metabolism. Given the rising use of VPA by women of reproductive age for various conditions it is increasingly important to understand how VPA affects reproductive and metabolic function in women, yet a number of key issues regarding VPA use in women of reproductive age remain unclear. These include the question of whether VPA use is associated with the development of polycystic ovary syndrome (PCOS)-like features (such as elevated androgen concentrations and/or chronic anovulation). The metabolic effects of VPA use, particularly on insulin sensitivity and weight gain, are also important to understand. Lastly, questions of VPA use during pregnancy and lactation require continued attention. This article reviews the current understanding of VPA's mechanisms of action, effects on the reproductive and metabolic system, and teratogenic qualities, highlighting important future areas of study.

  View details for Web of Science ID 000253578100007

  View details for PubMedID 18045126

• Self-reported data from patients with bipolar disorder: Impact on minimum episode length for hypomania JOURNAL OF AFFECTIVE DISORDERS Bauer, M., Grof, P., Rasgon, N. L., Marsh, W., Munoz, R. A., Sagduyu, K., Alda, M., Quiroz, D., Glenn, T., Baethge, C., Whybrow, P. C. 2006; 96 (1-2): 101-105

  Abstract

  Some investigators have suggested decreasing the minimum hypomania episode length criterion from 4 days, as in the DSM-IV, to 2 days. Using daily self-reported mood ratings, we studied the impact of changing the length requirement on the number of hypomanic episodes in patients with bipolar disorder.203 patients (135 bipolar I and 68 bipolar II by DSM-IV criteria) recorded mood daily using ChronoRecord software (30,348 total days, mean 150 days). Episodes of hypomania and days of hypomania outside of episodes were determined.Decreasing the minimum duration criterion for an episode of hypomania from 4 to 2 days doubled the mean percent of days in a hypomanic episode for each patient (4% to 8%), doubled the number of patients with a hypomanic episode (44 to 96) and increased the number of hypomanic episodes for all patients about three-fold (129 to 404). With a minimum episode length of 4 days, bipolar I patients were more likely to report hypomania outside episodes than bipolar II patients (p=0.010), but with a length of 2 or 3 days there was no significant difference in the distribution of hypomania outside of episodes by diagnosis. With a 2-day length, about one-third (36%) of hypomania remained outside of an episode.Self-reported data, computer access, relatively short length, fewer bipolar II than bipolar I patients.As the minimum length for an episode of hypomania decreases, there was a large increase in both the number of episodes and number of patients with episodes. One-day hypomania outside of episodes occurs frequently in both bipolar I and bipolar II disorder.

  View details for DOI 10.1016/j.jad.2006.05.006

  View details for Web of Science ID 000241930900013

  View details for PubMedID 16782206

• Approximate entropy of self-reported mood prior to episodes in bipolar disorder BIPOLAR DISORDERS Glenn, T., Whybrow, P. C., Rasgon, N., Grof, P., Alda, M., Baethge, C., Bauer, M. 2006; 8 (5): 424-429

  Abstract

  Approximate entropy (ApEn) measures regularity in time series data, while traditional linear statistics measure variability. Using self-reported mood data from patients with bipolar disorder, this preliminary study addressed whether ApEn could distinguish (i) the 60 days prior to the start of a manic or depressed episode from the 60 days prior to a month of euthymia, and (ii) the 60 days prior to a manic episode from the 60 days prior to a depressed episode.Self-reported mood data from 49 outpatients with bipolar disorder receiving standard treatment were analysed. The data contained 27 episodes (12 manic and 15 depressed), and 43 periods of 1 month of euthymia. For the 60 days prior to episode or euthymia, the ApEn, linear statistics and the correlation between linear and non-linear measures were calculated.ApEn was significantly greater in the 60 days prior to a manic or depressive episode than the 60 days prior to a month of euthymia. The onset of an episode was associated with greater irregularity in mood. Variability was also significantly larger and correlated with ApEn. ApEn was significantly greater in the 60 days prior to a manic episode than in the 60 days prior to a depressed episode, whereas measures of variability were not significantly different. Mood in the 60 days prior to mania was more irregular than prior to depression.Non-linear measures may complement traditional linear measures in the analysis of longitudinal data in bipolar disorder. A larger study is indicated.

  View details for Web of Science ID 000241241300003

  View details for PubMedID 17042880

• Mood and neuropsychological changes in women with midlife depression treated with escitalopram JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Wroolie, T. E., Williams, K. E., Keller, J., Zappert, L. N., Shelton, S. D., Kenna, H. A., Reynolds, M. F., Rasgon, N. L. 2006; 26 (4): 361-366

  Abstract

  This study assessed mood and neuropsychological function in a population of middle-aged women with major depressive disorder treated with escitalopram.Psychometric data measuring severity of depression were collected from 19 women and neuropsychological data were collected from 17 women aged between 45 and 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depression in a study in the Behavioral Neuroendocrinology Program at the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine. All women were treated with escitalopram in an open-label design. Mean age was 55.94 years and mean number of years of education was 16.36 years. Diagnosis of major depressive disorder was assessed with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and mood was evaluated with the 21-item Hamilton Depression Rating Scale (HAM-D) at baseline and at weekly follow-ups for 12 weeks. Cognition was assessed at baseline and 3 months after treatment using a neuropsychological test battery, which included an abbreviated measure of Full Scale Intelligence Quotient, measures of attention and processing speed, verbal and nonverbal memory, executive functioning, and verbal fluency. Self-report data were collected on current menopause status and current hormone therapy use in the postmenopausal women. Paired sample t tests were used to analyze the change in total HAM-D scores and neuropsychological variables.Statistically significant improvements were found in total HAM-D score, Wechsler Memory Scale III Logical Memory 1st Recall, I, and II scores, Wechsler Memory Scale III Visual Reproduction I scores, and Trail Making Test Part B scores. There was a statistically significant decrease in Controlled Oral Word Association Test FAS scores.Treatment of depression with escitalopram in a population of middle-aged women was shown to improve mood and cognitive efficiency in complex attention, short- and long-term recall of contextual information, short-term recall of visual information, and cognitive flexibility; however, it was shown to worsen phonemic fluency.

  View details for DOI 10.1097/01.jcp.0000227699.26375.f8

  View details for Web of Science ID 000239551200003

  View details for PubMedID 16855452

• Metabolic syndrome with atypical antipsychotics: State of the art Rasgon, N. L. BLACKWELL PUBLISHING. 2006: 7

  View details for Web of Science ID 000239186300018

• Reproductive and metabolic markers in women with bipolar disorder Rasgon, N. L. BLACKWELL PUBLISHING. 2006: 21

  View details for Web of Science ID 000239186300046

• Improving symptom monitoring - using technology to explore the course of bipolar disorder 2nd Biennial Conference of the International-Society-for-Bipolar-Disorders Glenn, T., Bauer, M., Grof, P., Rasgon, N., Whybrow, P. C. WILEY-BLACKWELL. 2006: 13–13

  View details for Web of Science ID 000239186300028

• Memory improvement with treatment of hypothyroidism INTERNATIONAL JOURNAL OF NEUROSCIENCE Miller, K. J., Parsons, T. D., Whybrow, P. C., Van Herle, K., Rasgon, N., Van Herle, A., Martinez, D., Silverman, D. H., Bauer, M. 2006; 116 (8): 895-906

  Abstract

  The consequences of inadequate thyroid hormone availability to the brain and treatment effects of levothyroxine on cognitive function are still poorly understood. This study prospectively assessed the effects of thyroid replacement therapy on cognitive function in patients suffering from biochemical evidenced, untreated hypothyroidism. Significant effects between the untreated hypothyroid group and control group were limited to verbal memory retrieval. When assessing the effects of 3-month treatment, results revealed that the treated hypothyroid group had significant increased verbal memory retrieval. Results suggest that specific memory retrieval deficits associated with hypothyroidism can resolve after replacement therapy with levothyroxine.

  View details for DOI 10.1080/00207450600550154

  View details for Web of Science ID 000239385300002

  View details for PubMedID 16861154

• Bipolar disorders in women: Clinical and metabolic considerations Rasgon, N. L. CAMBRIDGE UNIV PRESS. 2006: S92

  View details for Web of Science ID 000239495500368

• Do antidepressants influence mood patterns? A naturalistic study in bipolar disorder EUROPEAN PSYCHIATRY Bauer, M., Rasgon, N., Grof, P., Glenn, T., Lapp, M., Marsh, W., MUNOZ, R., Suwalska, A., Baethge, C., Bschor, T., Alda, M., Whybrow, P. C. 2006; 21 (4): 262-269

  Abstract

  This prospective, longitudinal study compared the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. One hundred and eighty-two patients with bipolar disorder self-reported mood and psychiatric medications for 4 months using a computerized system (ChronoRecord) and returned 22,626 days of data. One hundred and four patients took antidepressants, 78 did not. Of the antidepressants taken, 95% were selective serotonin or norepinephrine reuptake inhibitors, or second-generation antidepressants. Of the patients taking an antidepressant, 91.3% were concurrently taking a mood stabilizer. The use of antidepressants did not influence the daily rate of switching from depression to mania or the rate of rapid cycling, independent of diagnosis of bipolar I or II. The primary difference in mood pattern was the time spent normal or depressed. Patients taking antidepressants frequently remained in a subsyndromal depression. In this naturalistic study using self-reported data, patients with bipolar disorder who were taking antidepressants--overwhelmingly not tricyclics and with a concurrent mood stabilizer--did not experience an increase in the rate of switches to mania or rapid cycling compared to those not taking antidepressants. Antidepressants had little impact on the mood patterns of bipolar patients taking mood stabilizers.

  View details for DOI 10.1016/j.eurpsy.2006.04.009

  View details for Web of Science ID 000239032900009

  View details for PubMedID 16782312

• REPRODUCTIVE HEALTH AND BIPOLAR DISORDER CNS SPECTRUMS Ketter, T. A., Suppes, T., Morrell, M. J., Rasgon, N., Cohen, L. S., Viguera, A. C. 2006; 11 (5): 1–16

  View details for Web of Science ID 000207075400001

• Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal interaction in women with bipolar depression 61st Annual Convention of the Society-of-Biological-Psychiatry Kenna, H. A., Rasgon, N. L., Wong, M. L., Bauer, M. ELSEVIER SCIENCE INC. 2006: 157S–157S

  View details for Web of Science ID 000236767301088

• Temporal relation between sleep and mood in patients with bipolar disorder BIPOLAR DISORDERS Bauer, M., Grof, P., Rasgon, N., Bschor, T., Glenn, T., Whybrow, P. C. 2006; 8 (2): 160-167

  Abstract

  Early recognition of the prodromal symptoms of bipolar disorder, combined with a patient action plan, may help to prevent relapses. Sleep disturbances are frequent warning signs of both mania and depression. This study used cross correlation analysis to characterize the relationship between mood, sleep and bedrest in longitudinal data.Self-reported mood, sleep and bedrest (mean 169 +/- 59 days of data per patient) from 59 outpatients with bipolar disorder receiving standard treatment were analyzed. The cross correlation function was used to determine the latency between the changes in sleep and/or bedrest and mood for time shifts of between -7 and 7 days.For sleep and/or bedrest, a significant inverse correlation was found with the change in mood, most commonly with a time latency of one day. Sleep plus bedrest had the strongest relationship with a change in mood, with a significant correlation in 24 of 59 patients (41%) for the night before or night of a mood change. The patients with a significant cross-correlation between mood and sleep plus bedrest reported about two thirds of all large sleep changes of >3 h and three fourths of all large mood changes (>20 on 100-unit scale). Patients with a significant cross correlation were more likely to take benzodiazepines.In most patients with a significant cross correlation between sleep and/or bedrest and mood, the mood change occurred on the day following the change in sleep and/or bedrest. Sleep changes from a previous pattern, especially those of more than 3 h, may indicate that a large mood change is imminent.

  View details for Web of Science ID 000236022400007

  View details for PubMedID 16542186

• Cannon-Spoor et al.'s assessment AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Rasgon, N., Jarvik, L. 2006; 14 (3): 293-293

  View details for Web of Science ID 000235620900013

  View details for PubMedID 16505136

• Estrogen replacement and cognition in postmenopausal women: Effects of years since menopause on response to treatment. Drug Development Research Dunkin J, Rasgon N, Zeller M, Wagner-Steh K, David S, Altshuler L, Rapkin A 2006; 66: 150-159
• Mood Charting and Technology: New Approach to Monitoring Patients with Mood Disorders CURRENT PSYCHIATRY REVIEWS Bauer, M., Grof, P., Rasgon, N., Glenn, T., Alda, M., Priebe, S., Ricken, R., Whybrow, P. C. 2006; 2 (4): 423–29

  View details for DOI 10.2174/157340006778699747

  View details for Web of Science ID 000213208400001

• Do antidepressants influence mood patterns? A naturalistic study in bipolar disorder. European Psychiatry Bauer M, Rasgon N, Grof P, Glenn T, Marsh W, Munoz R, Suwalska A, Lapp M, Bschor T, Alda M, Whybrow P 2006; 21: 262-269
• Hepatic encephalopathy: A neurochemical, neuroanatomical, and neuropsychological study JOURNAL OF APPLIED CLINICAL MEDICAL PHYSICS Binesh, N., Huda, A., Thomas, M. A., Wyckoff, N., Bugbee, M., Han, S., Rasgon, N., Davanzo, P., Sayre, J., Guze, B., Martin, P., Fawzy, F. 2006; 7 (1): 86-96

  Abstract

  Hepatic encephalopathy (HE) is normally diagnosed by neuropsychological (NP) tests, which are not very specific and do not reveal the underlying pathology. Magnetic resonance imaging (MRI) and spectroscopy (MRS) of the brain offer alternative and possibly more specific markers for HE. These methods were applied in conjunction with NP testing in order to determine their usefulness in the identification of HE and to understand the pathogenesis of HE more clearly. MR imaging and spectroscopy examinations, in addition to a battery of 15 NP tests, were administered to investigate 31 patients awaiting liver transplantation and 23 healthy controls. MR image intensities from the globus pallidus region were calculated and normalized to those of the thalamus. Absolute concentrations and ratios with respect to creatine (Cr) of several metabolites were computed from MR spectra. The MR data were correlated with the results of NP tests. The patients showed impairment in NP tests of attention and visuospatial and verbal fluency. In T1-weighted MRI, the relative intensity of the globus pallidus with respect to that of the thalamus region was significantly elevated in patients and correlated(negatively) with three NP tests (Hooper, FAS, and Trails B). The absolute concentrations of myo-inositol (mI) and choline (Ch) were significantly reduced in three brain regions. In addition, the absolute concentrations of glutamine (Gln) and combined glutamate and glutamine (Glx) were increased in all three locations, with Gln increase being significant in all areas while that of Glx only in the occipital white matter. In summary, this study partially confirms a hypothesized mechanism of HE pathogenesis, an increased synthesis of glutamine by brain glutamate in astrocytes due to excessive blood ammonia, followed by a compensatory loss of myo-inositol to maintain astrocyte volume homeostasis. It also indicates that the hyperintensity observed in globus pallidus could be used as complementary to the NP test scores in evaluating the mental health of HE patients.

  View details for Web of Science ID 000247342900009

  View details for PubMedID 16518320

• Changes in regional brain metabolism and insulin resistance in postmenopausal women. Journal of Nuclear Medicine Rasgon NL, Geist CL, Phelps ME, Silverman DHS 2006; 47 (S1): 300P
• Middle-aged children of Alzheimer parents, a pilot study: Stable neurocognitive performance at 20-year follow-up Workshop on Children of Alzheimer Parent Jarvik, L. F., La Rue, A., Gokhman, I., Harrison, T., Holt, L., Steh, B., Harker, J., Larson, S., Yaralian, P., Matsuyama, S., Rasgon, N., Geschwind, D., Freimer, N., Jimenez, E., Schaeffer, J. SAGE PUBLICATIONS INC. 2005: 187–91

  Abstract

  The objective of this pilot study on a convenience sample of 25 offspring of Alzheimer patients (mean age 61.5 +/- 8.8 years; range, 50-82) was the early detection of neurocognitive decline. This preliminary report appears to be the first one dealing with 20-year follow-up of neurocognitive data of Alzheimer's disease (AD) children. Digit symbol (Wechsler Adult Intelligence Scale) was the only of 11 neurocognitive measures with a significant decline. And that decline between first and last testing (mean = 19.98 +/- 0.30 years) was on raw scores, not scaled scores. Neither parents' age at onset of AD nor autopsy confirmation or offspring APOE-e4 status influenced neurocognitive results. More robust data than currently available are needed to confirm the findings of this first pilot study and to determine both the trajectory of neurocognitive decline in AD and the risks of developing AD faced by children whose parent had the disease.

  View details for DOI 10.1177/0891988705281862

  View details for Web of Science ID 000233433100002

  View details for PubMedID 16306237

• Depression-insulin resistance link Rasgon, N. L., Reynolds, M. F., Zappert, L. N., Kenna, H. A. NATURE PUBLISHING GROUP. 2005: S233

  View details for Web of Science ID 000233442100603

• Insulin resistance in depressive disorders and Alzheimer's disease: revisiting the missing link hypothesis. Neurobiology of aging Rasgon, N. L., Kenna, H. A. 2005; 26: 103-107

  Abstract

  Several lines of evidence suggest an association between depressive disorders and Alzheimer's disease (AD). We previously suggested central nervous system (CNS) effects of insulin resistance (IR) to be an important link between depressive disorders and AD. Although the exact mechanism of central IR is not known, it is thought that central IR results in inadequate glucose metabolism in the brain. According to our hypothesis, inadequate glucose utilization resulting from IR underlies neuronal changes in crucial brain regions (i.e. limbic system) observed among patients with depressive disorders, the same brain regions affected in AD. Further, in patients with undetected and/or untreated IR, such changes in glucose utilization, if unresolved, may lead to neurodegeneration. Our studies have demonstrated a high prevalence of IR in patients with depressive disorders, and reciprocally, a high prevalence of depression in patients with the primary IR disorder polycystic ovary syndrome (PCOS), and we believe these populations have significantly increased risk of cognitive decline. Herein, we review the IR link in depressive disorders and AD and describe the results of our studies and others in support of this hypothesis.

  View details for PubMedID 16225963

• Longitudinal evaluation of reproductive function in women treated for bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Rasgon, N. L., Reynolds, M. F., Elman, S., Saad, M., Frye, M. A., Bauer, M., Altshuler, L. L. 2005; 89 (1-3): 217-225

  Abstract

  We assessed reproductive endocrine and metabolic markers in women treated for bipolar disorder over a 2-year time period, controlling for valproate use.Twenty-five women ages 18-45 with bipolar disorder underwent longitudinal evaluations. Subjects completed a reproductive health questionnaire and endocrinological exam at baseline. Total and free testosterone, progesterone, LH, FSH, fasting insulin and glucose, and other hormones were measured across the menstrual cycle at baseline and at 2-year follow-up.Ten subjects were currently receiving valproate as a mood stabilizing agent; of the remaining subjects, six received lithium and five received atypical antipsychotics. Of all subjects, 41.7% reported current oligomenorrhea, while 40% reported oligomenorrhea before starting medication. Rates of oligomenorrhea and clinical hyperandrogenism did not differ by medication use. Eighty percent of women had a high homeostatic model assessment of insulin resistance (HOMA-IR) at baseline; all other measures were normal. Over time, all subjects exhibited a significant decrease in luteal phase progesterone and increase in free testosterone concentrations. Valproate use was associated with an increase over time in total testosterone. Baseline values and changes in BMI were similar across groups.Limitations include small sample size and the absence of a control group.We confirm our previous observations of high rates of menstrual abnormalities, hyperandrogenemia and insulin resistance in women with bipolar disorder. These results tentatively support the role of valproate in hyperandrogenemia; however, rates of oligomenorrhea and clinical hyperandrogenism did not differ between medication groups.

  View details for DOI 10.1016/j.jad.2005.08.002

  View details for Web of Science ID 000234355500025

  View details for PubMedID 16171873

• Use of polypharmacy and self-reported mood in outpatients with bipolar disorder INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE Adli, M., Whybrow, P. C., Grof, P., Rasgon, N., Gyulai, L., Baethge, C., Glenn, T., Bauer, M. 2005; 9 (4): 251-256

  Abstract

  Objective. As polypharmacy is routinely used for the treatment of bipolar disorder, the relation between the daily number of psychotropic medications and self-reported mood was investigated. Method. Eighty patients (35 men and 45 women) with a diagnosis of bipolar disorder I or II, recruited from academic centres, entered their mood, sleep, and psychotropic medications for 3 months into ChronoRecord software. A total of 8662 days of data was received (mean 114.7 days/per patient). Results. Seventy-nine patients took a mean of 3.8 medications daily (SD 1.7; range 1-9); one took none. Of these patients, 73 (92.4%) took mood stabilizers, 47 (58.8%) took antidepressants, 31 (38.8%) took antipsychotics, 34 (42.5%) took benzodiazepines and 17 (21.1%) took thyroid hormones. Patients reporting normal mood more frequently took fewer medications; the Pearson correlation coefficient between the number of medications and the percent of days normal was -0.481 (P < 0.001). Grouping by number of medications, ANOVA analysis showed those taking fewer medications reported normal mood more frequently (P<0.001). Conclusion. Combination treatment regimens are routinely prescribed for bipolar disorder. Patients reporting normal mood more frequently took a fewer number of daily medications. Studies are needed to better identify those patients who would benefit from polypharmacy and to optimise the combinations of medications for patients with refractory disorder.

  View details for DOI 10.1080/13651500510029200

  View details for Web of Science ID 000232801200005

• Insulin resistance in depressive disorders and Alzheimer's disease: Revisiting the missing link hypothesis SPARK Workshop 2004 Rasgon, N. L., Kenna, H. A. ELSEVIER SCIENCE INC. 2005: S103–S107

  View details for Web of Science ID 000234123400023

• Metabolic and endocrine disturbances in psychiatric disorders: a multidisciplinary approach to appropriate atypical antipsychotic utilization. CNS spectrums Masand, P. S., Culpepper, L., Henderson, D., Lee, S., Littrell, K., Newcomer, J. W., Rasgon, N. 2005; 10 (10): 14 1-15

  Abstract

  Patients with psychiatric disorders have an increased rate of cardiovascular morbidity and mortality compared with the general population. Metabolic issues such as weight gain, dyslipidemia, diabetes mellitus, diabetic ketoacidosis,and pancreatitis have been reported with the use of antipsychotic agents. Although atypical antipsychotics have not been linked directly to the development of metabolic syndrome, these medications have been shown to increase risk factors that can lead to metabolic and endocrine disturbances. Therefore, clinicians should provide ongoing monitoring for patients who are being treated for psychiatric disorders with these agents. According to the 2004 Consensus Report on Antipsychotics, screening measures should include baseline and follow-up monitoring of personal/family histories, weight (body mass index), waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile.

  View details for PubMedID 16404802

• Metabolic and Endocrine Disturbances in Psychiatric Disorders A Multidisciplinary Approach to Appropriate Atypical Antipsychotic Utilization CNS SPECTRUMS Masand, P. S., Culpepper, L., Henderson, D., Lee, S., Littrell, K., Newcomer, J. W., Rasgon, N. 2005; 10 (10): 1–15

  View details for Web of Science ID 000207075600001

• Estrogen replacement and cognition in postmenopausal women: Effect of years since menopause on response to treatment 32nd Annual Meeting of the International-Neuropsychological-Society Dunkin, J., Rasgon, N., Zeller, M., Wagner-Steh, K., David, S., Altshuler, L., Rapkin, A. WILEY-LISS. 2005: 150–59

  View details for DOI 10.1002/ddr.20054

  View details for Web of Science ID 000235910300010

• Vitamin E for the treatment of dysmenorrhea BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY Rasgon, N. L., Yarygin, K. N. 2005; 112 (8): 1164-1164

  View details for DOI 10.1111/j.1471-0528.2005.00741.x

  View details for Web of Science ID 000230578600030

  View details for PubMedID 16045539

• Endogenous and exogenous hormone exposure and risk of cognitive impairment in Swedish twins: a preliminary study PSYCHONEUROENDOCRINOLOGY Rasgon, N. L., Magnusson, C., Johansson, A. L., Pedersen, N. L., Elman, S., Gatz, M. 2005; 30 (6): 558-567

  Abstract

  To analyze the risk of cognitive impairment among female Swedish Twins with regard to endogenous and exogenous hormone exposure.A cross-sectional analysis of data from the HARMONY Study, a population-based cohort study of cognitive impairment in the Swedish Twin Registry.Information regarding age at menarche and menopause, parity, and length and type of hormone therapy (HT) was collected via a telephone interview from 6604 women, aged 65-84. Cognitive impairment was assessed with the TELE, a brief telephone cognitive screen.Length of reproductive period was inversely associated with risk of cognitive impairment (p<0.01). The OR was 1.15 (CI 95% 0.96-1.36) for women with reproductive periods <35 years and 0.82 (CI 95% 0.66-1.00) for women with reproductive periods >39 years. Age at menopause was inversely associated with risk of cognitive impairment. Use of HT was associated with average 40% decline in the risk of cognitive impairment, independent of type and timing of treatment.Our results suggest that both increased length of reproductive period and HT are associated with reduced risk of cognitive impairment.

  View details for DOI 10.1016/j.psyneuen.2005.01.004

  View details for Web of Science ID 000228502700005

  View details for PubMedID 15808925

• Perimenopausal mental disorders: Epidemiology and phenomenology CNS SPECTRUMS Rasgon, N., Shelton, S., Halbreich, U. 2005; 10 (6): 471-478

  Abstract

  Perimenopause, the interval of irregular menstrual activity which directly precedes menopause, is characterized by widely fluctuating hormone levels amidst a large-scale decline in circulating estrogen. This phase in a woman's life is typically accompanied by physical discomforts including vasomotor symptoms, such as headaches, insomnia, and hot flushes, as well as genital atrophy. Not surprisingly, studies suggest a significant increase in mood lability for women during this time. While some evidence points toward an exacerbation of bipolar mood symptoms and an increase in schizophrenic psychosis during perimenopause, the majority of research conducted on perimenopausal mental disorders has focused on unipolar depression. Studies vary widely in methodology, definitions of menopausal status, and degrees of depression among subjects; however, the majority of findings indicate an increased susceptibility to depression during the perimenopausal transition. This greater susceptibility may be due to neuroendocrine effects of declining estrogen levels, the subjective experience of somatic symptoms resulting from this hormonal decline, and/or the more frequent occurrence of "exit" or "loss" events for women during this stage of life. At this time, more research is needed to address questions of prevalence, risk, and etiology for depression and other major mental disorders as related to the physiological and psychosocial changes associated with perimenopause.

  View details for Web of Science ID 000230160000012

  View details for PubMedID 15908901

• Temporal relation between sleep and mood in patients with bipolar disorder 6th International Conference on Bipolar Disorder Bauer, M., Grof, P., Rasgon, N., Bschor, T., Glenn, T., Whybrow, P. C. WILEY-BLACKWELL. 2005: 31–32

  View details for Web of Science ID 000229369500049

• Clinical course of bipolar disorder during pregnancy in women receiving minimal or no prescription psychotropic medication 6th International Conference on Bipolar Disorder Marsh, W. K., Zappert, L. N., Williams, E. K., Templeton, A. J., Reynolds, M. F., Keller, T. A., Rasgon, N. L. WILEY-BLACKWELL. 2005: 75–76

  View details for Web of Science ID 000229369500180

• Validation study of chrono record self-reporting software by inpatients with mania 6th International Conference on Bipolar Disorder Bauer, M., Neuhaus, K., Sasse, J., Schlosser, T., Bschor, T., Rasgon, N., Grof, P., Gyulai, L., Glenn, T., Whybrow, P. C. WILEY-BLACKWELL. 2005: 32–32

  View details for Web of Science ID 000229369500050

• Effects of gender on mood in the clinical course of bipolar disorder 6th International Conference on Bipolar Disorder Zappert, L. N., Glenn, T. G., Bauer, M., Elman, S., Frye, M., Altshuler, L., Gitlin, M., Marsh, W. K., Reynolds, M. F., Shelton, S. D., Kenna, H., Templeton, A. J., Rasgon, N. L. WILEY-BLACKWELL. 2005: 115–115

  View details for Web of Science ID 000229369500305

• Prospective longitudinal study of women treated for bipolar disorder 6th International Conference on Bipolar Disorder Reynolds, M. F., Rasgon, N. L., Elman, S., Saad, M., Frye, M. A., Bauer, M., Altshuler, L. L. WILEY-BLACKWELL. 2005: 90–90

  View details for Web of Science ID 000229369500229

• Reproductive function and risk for PCOS in women treated for bipolar disorder BIPOLAR DISORDERS Rasgon, N. L., Altshuler, L. L., Fairbanks, L., Elman, S., Bitran, J., Labarca, R., Saad, M., Kupka, R., Nolen, W. A., Frye, M. A., Suppes, T., McElroy, S. L., Keck, P. E., Leverich, G., Grunze, H., Walden, J., Post, R., Mintz, J. 2005; 7 (3): 246-259

  Abstract

  This study examined the reproductive function and prevalence of polycystic ovary syndrome (PCOS) in women with bipolar disorder taking antimanic medications.Women aged 18-45 treated for bipolar disorder and not taking steroid contraceptives were recruited to complete questionnaires about their menstrual cycle and to provide blood samples for measurement of a range of reproductive endocrine and metabolic hormone levels. Eighty women participated in completing the questionnaires and 72 of them provided blood samples.Fifty-two of the 80 women (65%) reported current menstrual abnormalities, 40 of which (50%) reported one or more menstrual abnormalities that preceded the diagnosis of bipolar disorder. Fifteen women (38%) reported developing menstrual abnormalities since treatment for bipolar disorder, 14 of which developed abnormalities since treatment with valproate (p = 0.04). Of the 15 patients reporting menstrual abnormalities since starting medication, 12 (80%) reported changes in menstrual flow (heavy or prolonged bleeding) and five (33%) reported changes in cycle frequency. No significant differences were observed between women receiving or not receiving valproate in mean levels of free or total serum testosterone levels. This was true for the total sample and for the sub-group without preexisting menstrual problems. However, within the valproate group, duration of use was significantly correlated with free testosterone levels (r = 0.33, p = 0.02). Three of the 50 women (6%) taking VPA, and 0% of the 22 taking other antimanic medications, met criteria for PCOS (p = 0.20). Other reproductive and metabolic values outside the normal range across treatment groups included elevated 17 alpha-OH progesterone levels, luteinizing hormone: follicle-stimulating hormone ratios, homeostatic model assessment (HOMA) values, and low estrogen and dehydroepiandrosterone sulfate (DHEAS) levels. Preexisting menstrual abnormalities predicted higher levels of 17 alpha-OH progesterone, free testosterone, and estrone as well as development of new menstrual abnormalities. Body mass index (BMI) was significantly positively correlated with free testosterone levels and insulin resistance (HOMA) across all subjects, regardless of medication used.Rates of menstrual disturbances are high in women with bipolar disorder and, in many cases, precede the diagnosis and treatment for the disorder. Treatment with valproate additionally contributes significantly to the development of menstrual abnormalities and an increase in testosterone levels over time. A number of bipolar women, regardless of type of medication treatment received, have reproductive and metabolic hormonal abnormalities, yet the etiology of such abnormalities requires further study. Women with preexisting menstrual abnormalities may represent a group at risk for development of reproductive dysfunction while being treated for bipolar disorder.

  View details for Web of Science ID 000229081100004

  View details for PubMedID 15898962

• Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression 40th Annual Meeting of the American-College-of-Neuropsychopharmacology Bauer, M., London, E. D., Rasgon, N., Berman, S. M., Frye, M. A., Altshuler, L. L., Mandelkern, M. A., Bramen, J., Voytek, B., Woods, R., Mazziotta, J. C., Whybrow, P. C. NATURE PUBLISHING GROUP. 2005: 456–69

  Abstract

  Supplementation of standard treatment with high-dose levothyroxine (L-T(4)) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T(4) treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [(18)F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T(4) (mean dose 320 microg/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T(4) treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T(4) treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T(4) improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T(4) may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders.

  View details for DOI 10.1038/sj.mp.4001647

  View details for Web of Science ID 000228692300008

  View details for PubMedID 15724143

• Reproduction events modify the effects of estrogen replacement therapy on cognition in healthy postmenopausal women 32nd Annual Meeting of the International-Neuropsychological-Society Dunkin, J., Rasgon, N., Wagner-Steh, K., David, S., Altshuler, L., Rapkin, A. PERGAMON-ELSEVIER SCIENCE LTD. 2005: 284–96

  Abstract

  The question of whether estrogen replacement therapy (ERT) is beneficial to cognitive functioning in postmenopausal women has become controversial in the past several years. Early studies suggested that ERT improved cognitive functioning and decreased the risk of Alzheimer's disease, but recent studies have failed to find any benefit. However, studies have varied in terms of the age of participants, the estrogen preparation used, whether progesterone is administered concurrently, and the study design. The present study used a randomized, placebo-controlled design and a transdermal estrogen preparation composed of 17-beta estradiol. A neuropsychological battery was administered at baseline and after completion of the 10-week trial, and test scores were grouped into four composite scores using psychometric techniques. Baseline to follow-up change was analyzed using multiple regression techniques. Results indicate that while little overall beneficial effect of estrogen was found, years since menopause was significantly related to change in executive functioning in the estrogen but not the placebo group, such that more recently postmenopausal women demonstrated greater positive change than older women. Body mass index, a gross estimate of circulating estrogen, was significantly positively related to change in attentional and psychomotor processes regardless of treatment group, and to a weaker extent, verbal memory, but only in the estrogen-treated group. These results suggest that reproductive events and levels of endogenous estrogen are related to the clinical response to ERT, but larger studies with longer follow-up periods are needed to determine the strength of these effects.

  View details for Web of Science ID 000225229200006

  View details for PubMedID 15511602

• Adding another spectral dimension to H-1 magnetic resonance spectroscopy of hepatic encephalopathy JOURNAL OF MAGNETIC RESONANCE IMAGING Binesh, N., Huda, A., Bugbee, M., Gupta, R., Rasgon, N., Kumar, A., Green, M., Han, S., Thomas, M. A. 2005; 21 (4): 398-405

  Abstract

  To evaluate a localized two-dimensional correlated magnetic resonance spectroscopic (L-COSY) technique in patients with hepatic encephalopathy (HE) and healthy subjects, and to correlate the cerebral metabolite changes with neuropsychological (NP) test scores.Eighteen minimal hepatic encephalopathy (MHE) patients and 21 healthy controls have been investigated. A GE 1.5-T magnetic resonance (MR) scanner was used in combination with a body MR coil for transmission and a 3-inch surface coil for reception. A 27-mL voxel was localized by three slice-selective radio frequency (RF) pulses (90 degrees-180 degrees-90 degrees) in the anterior cingulate region. The total duration of each two-dimensional L-COSY spectrum was approximately 25 minutes. The NP battery included a total of 15 tests, which were grouped into six domains.MR spectroscopic results showed a statistically significant decrease in myo-inositol (mI) and choline (Ch) and an increase in glutamate/glutamine (Glx) in patients when compared to healthy controls. There was also an increase in taurine (Tau) in patients. The NP results indicated a significant correlation between motor function assessed by NP tests and mI ratios recorded using two-dimensional L-COSY.The study demonstrated the feasibility of evaluating the two-dimensional L-COSY sequence in a clinical environment. The results showed additional cerebral metabolites that can be measured with the technique in comparison to one-dimensional study.

  View details for DOI 10.1002/jmri.20291

  View details for Web of Science ID 000228029900012

  View details for PubMedID 15779041

• Estrogen use and brain metabolic change in postmenopausal women NEUROBIOLOGY OF AGING Rasgon, N. L., Silverman, D., Siddarth, P., Miller, K., Ercoli, L. M., Elman, S., Lavretsky, H., Huang, S. C., Phelps, M. E., Small, G. W. 2005; 26 (2): 229-235

  Abstract

  We used positron emission tomography to evaluate cerebral glucose metabolic change in postmenopausal women in a naturalistic observational study.Women estrogen users (n = 11) and non-users (n = 9) were studied at baseline and 2 years later. Analyses focused on glucose metabolism in regions previously reported to decline in older persons at risk for Alzheimer's disease (AD) (posterior cingulate and lateral temporal cortex).Region of interest (ROI) analysis at baseline showed no regional differences between women estrogen users and non users. ROI follow-up analysis revealed that women non-users declined significantly in the posterior cingulate cortex (P= 0.04). Statistical parametric mapping (SPM) analysis confirmed a significant decrease in metabolism of the posterior cingulate cortex among non-users at 2-year follow-up (P = 0.004). In contrast, women estrogen users did not exhibit significant metabolic change in the posterior cingulate.Estrogen use may preserve regional cerebral metabolism and protect against metabolic decline in postmenopausal women, especially in posterior cingulate cortex, the region of the brain found to decline in the earliest stages of AD.

  View details for DOI 10.1016/j.neurobiolaging.2004.03.003

  View details for Web of Science ID 000226178800007

  View details for PubMedID 15582750

• Mood changes related to antidepressants: a longitudinal study of patients with bipolar disorder in a naturalistic setting PSYCHIATRY RESEARCH Bauer, M., Rasgon, N., Grof, P., Altshuler, L., Gyulai, L., Lapp, M., Glenn, T., Whybrow, P. C. 2005; 133 (1): 73-80

  Abstract

  This prospective, longitudinal study investigated the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. Eighty patients with bipolar disorder self-reported mood and psychiatric medications daily for 3 months using a computerized system (ChronoRecord) and returned 8662 days of data. Of the total group of 80 patients, 47 took antidepressants; 33 did not. Patients taking antidepressants reported depression twice as frequently (29% of days vs. 13.8% of days). In both groups, two-thirds of all mood changes over a 1-, 2- and 3-day period were small, between -5 and 5 on a 100-point scale. No statistically significant difference was found in the frequency of large mood changes (>10 on a 100-point scale) or in switches between depression and mania (0.7% if not taking antidepressants vs. 0.9% if taking), independent of diagnosis of bipolar I or II. Eighty-nine percent of patients taking antidepressants were also taking mood stabilizers. In this naturalistic setting, no significant difference between the rate of switches to mania or rapid cycling was found between those taking and not taking antidepressants, regardless of diagnosis. The primary difference in pattern between the groups was the time spent in depressed or normal mood, with minor daily mood variations.

  View details for DOI 10.1016/j.psychres.2004.08.006

  View details for Web of Science ID 000227611400008

  View details for PubMedID 15698679

• Does the use of an automated tool for self-reporting mood by patients with bipolar disorder bias the collected data? MedGenMed : Medscape general medicine Bauer, M., Rasgon, N., Grof, P., Gyulai, L., Glenn, T., Whybrow, P. C. 2005; 7 (3): 21-?

  Abstract

  Automating data collection from patients can improve data quality, enhance compliance, and decrease costs in longitudinal studies. About half of all households in industrialized countries now have a home computer.While we previously validated the ChronoRecord software for self-reporting mood on a home computer with patients who have bipolar disorder, this study further investigates whether this technology created a bias in the collected data.During the validation study, 80 of 96 (83%) patients returned 8662 days of data (mean, 114.7 +/- 32.3 SD days). The patients' demographics were compared with those of similar longitudinal studies in which patients used paper-based data collection tools. In addition, because demographic characteristics may influence attitudes toward technology, observer-rated scores on the Hamilton Depression Rating Scale and Young Mania Rating Scale were used to group patients by severity of illness, and the self-reported mood ratings were analyzed for evidence of bias from the patients' gender, ethnicity, diagnosis, age, disability status, or years of education. Analysis was performed using the 2-way analysis of variance and general linear model.The patients' demographic characteristics were very similar to those of patients with bipolar disorder who participated in comparable longitudinal studies using paper-based tools. After grouping the patients by severity of illness, none of the demographic variables had a significant effect on the patients' self-reported mood using the automated tool.The use of a computer does not seem to bias sample data. As with studies using paper-based self-reporting, results from studies of patients using ChronoRecord software on a home computer to report mood can be generalized.

  View details for PubMedID 16369247

• Sex-specific self-reported mood changes by patients with bipolar disorder 155th Annual Meeting of the American-Psychiatric-Association Rasgon, N., Bauer, M., Grof, P., Gyulai, L., Elman, S., Glenn, T., Whybrow, P. C. PERGAMON-ELSEVIER SCIENCE LTD. 2005: 77–83

  Abstract

  While the prevalence of bipolar disorder I is similar between men and women, the clinical course may differ. This study investigated if there are differences in the clinical presentation of bipolar disorder between the sexes.Mood patterns were documented using ChronoRecord software for self-reporting. Patients entered mood, medications, sleep, life events and menstrual data daily acquired over the period of three months. 8662 Days of data were received from 80 patients: 3483 days from 35 men and 5179 days from 45 women.The distribution of the time spent in mood categories differed between men and women (P<0.001). Men were depressed 17.0% of the time, euthymic 74.0% of the time and manic 5.6% of the time. Women were depressed 28.3% of the time, euthymic 64.2% of the time and manic 7.5% of the time. Over 80% of all reported symptoms for both sexes were mild. Women exhibited large mood fluctuations (greater than 10 in either direction on a 100-unit scale) more frequently than men. Most of the reproductive aged women (55%) reported significant mood changes across the menstrual cycle.The clinical course of bipolar disorder differed between the sexes. Women reported depression and large fluctuations in mood more frequently than men. Women also experienced mood changes across the menstrual cycle.

  View details for DOI 10.1016/j.jpsychires.2004.05.006

  View details for Web of Science ID 000227033700008

  View details for PubMedID 15504425

• Gender Differences in Bipolar Disorder Bipolar Case Review Quarterly Templeton A, Rasgon N 2005; 1: 3-6
• Use of polypharmacy and self-report mood in outpatients with bipolar disorder. International Journal of Psychiatry in Clinical Practice. Adli M, Whybrow PC, Grof P, Rasgon N, Gyulai L, Baethge C, Glenn T, Bauer M 2005; 9 (4): 251-256
• Bone mineral density during maintenance treatment with supraphysiological doses of levothyroxine in affective disorders: a longitudinal study JOURNAL OF AFFECTIVE DISORDERS Bauer, M., Fairbanks, L., Berghofer, A., HIERHOLZER, J., Bschor, T., Baethge, C., Rasgon, N., Sasse, J., Whybrow, P. C. 2004; 83 (2-3): 183-190

  Abstract

  This prospective study was designed to determine whether patients with prophylaxis-resistant affective disorders, receiving adjunctive maintenance therapy with supraphysiological doses of levothyroxine (L-T4), show evidence of accelerated bone loss compared to the reference population database.In 21 patients, bone mineral density (BMD) of the spine (lumbar vertebrae L1-L4) and femur (femoral neck, trochanter, and Ward's triangle) was measured by dual energy X-ray absorptiometry (DXA). BMD measurement was performed first after patients had been on thyroid-stimulating hormone (TSH)-suppressive therapy with L-T4 (mean dose=411 mcg/d) for an average of 16.4 months and again after 33.6 months of L-T4 (mean dose=416 mcg/d) therapy.There was no statistically significant difference between the actual percentage decline in bone mineral density and the expected percentage decline in any of the measured bone regions. In a stepwise linear regression analysis, age was identified as a predictor of percentage change in BMD. After controlling for age, the only other variable that showed a consistent trend was the dose of L-T4, with higher doses being positively correlated with the percentage decline of BMD.Relatively small sample size, no bone density assessment prior to treatment with L-T4, no patient control group with mood disorders who did not receive L-T4 treatment, and bone density follow-up intervals were variable.This study did not demonstrate evidence that long-term treatment of affectively ill patients with supraphysiological doses of L-T4 significantly accelerates loss of bone mineral density compared to the age-matched reference population. However, the decline of BMD in one individual patient underscores that caution is indicated and that regular assessment of BMD during longer-term supraphysiological thyroid hormone treatment is needed.

  View details for DOI 10.1016/j.jad.2004.08.011

  View details for Web of Science ID 000225822100011

  View details for PubMedID 15555712

• Children of Alzheimer patients: More data needed JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES Jarvik, L. F., Harrison, T. R., Holt, L., Jimenez, E., Larson, S. W., LaRue, A., Matsuyama, S. S., Rasgon, N., Schaeffer, J., Steh, B., Yaralian, P. 2004; 59 (10): 1076-1077

  View details for Web of Science ID 000224907700014

  View details for PubMedID 15528781

• Alzheimer offspring 20-years later - No significant cognitive decline? Jarvik, L., Matsuyama, S., Rasgon, N., Jimenez, E., La Rue, A., Holt, L., Larson, S., Steh, B., Schaeffer, J., Harrison, T., Yaralian, P. GERONTOLOGICAL SOCIETY AMER. 2004: 259–60

  View details for Web of Science ID 000225458801061

• Lamotrigine therapy in treatment-resistant menstrually-related rapid cycling bipolar disorder: a case report BIPOLAR DISORDERS Becker, O. V., Rasgon, N. L., Marsh, W. K., Glenn, T., Ketter, T. A. 2004; 6 (5): 435-439

  Abstract

  To evaluate lamotrigine in a woman with a 30-year history of treatment-resistant menstrually-entrained rapid cycling bipolar II disorder with follicular phase depressive and luteal phase mood elevation symptoms.Lamotrigine was started at 5 mg/day and gradually increased up to 300 mg/day, while venlafaxine was tapered gradually and discontinued, and divalproex sodium 500 mg/day and levothyroxine 175 mcgm/day were continued. Daily self-reported mood ratings were obtained from the patient, using ChronoRecord software.As lamotrigine was increased gradually, mood cycle amplitude attenuated. There was notable decrease in the severity and duration of depressive symptoms specifically during the follicular phase of the menstrual cycle. At the time of submission of this paper, the subject had remained euthymic for a total of 12 months.This case suggests the potential utility of lamotrigine in treatment-resistant menstrually-related rapid cycling bipolar disorder, and raises the possibility that lamotrigine might be able to treat pathological entrainment of mood with the menstrual cycle. Both of these issues merit systematic assessment.

  View details for Web of Science ID 000223996200013

  View details for PubMedID 15383138

• The impact of depression and fluoxetine treatment on obstetrical outcome. Archives of women's mental health Suri, R., Altshuler, L., Hendrick, V., Rasgon, N., Lee, E., Mintz, J. 2004; 7 (3): 193-200

  Abstract

  This study prospectively followed women over the course of pregnancy to assess the impact of depression and/or antidepressant treatment on obstetrical outcome.Sixty-four outpatient women with an Axis I diagnosis of major depressive disorder or no psychiatric history were followed in each trimester of pregnancy with administration of the CES-D. A subset of the women with depression received treatment with fluoxetine during pregnancy. Subjects with a CES-D score greater than 16 at any time point were further assessed for the presence of an active major or minor depressive episode. Primary outcome variables included infant gestational age, birth weight, Apgar score, and admission to the neonatal intensive care unit.Analyzable data were available for 62 women. No significant differences were found in outcome variables between those women with exposure to medication and/or prenatal depressed mood and those women without a history of depression.In contrast to other studies, our study did not demonstrate an adverse effect of fluoxetine exposure per se on obstetrical outcome. In addition, we did not find a significant impact of depression during pregnancy on obstetrical outcome.

  View details for PubMedID 15241665

• The relationship between polycystic ovary syndrome and antiepileptic drugs - A review of the evidence JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Rasgon, N. 2004; 24 (3): 322-334

  Abstract

  Polycystic ovary syndrome (PCOS) is a serious endocrine disorder characterized by ovulatory dysfunction and hyperandrogenism that is thought to have a higher prevalence in women with epilepsy and perhaps bipolar disorder. Various theories have been offered to explain this higher prevalence of PCOS and other reproductive disorders in these patient populations, including the effects of the disease itself and of antiepileptic drugs, especially valproate, which may directly cause PCOS or indirectly lead to the disorder by causing weight gain that triggers insulin resistance, increased testosterone levels, and other reproductive abnormalities. A prospective, longitudinal study with larger cohorts in newly diagnosed women with epilepsy or bipolar disorder is needed to definitively characterize the relationship between antiepileptic drugs and PCOS. Until data from such a study are available, physicians need to be aware that there is a possibility of developing symptoms of PCOS in women of reproductive age who are treated with antiepileptic drugs. Despite this concern, the choice of antiepileptic drug for women with epilepsy or bipolar disorder should be based on the most effective agent for controlling neurologic symptoms.

  View details for DOI 10.1097/01.jcp.0000125745.60149.c6

  View details for Web of Science ID 000221548500012

  View details for PubMedID 15118487

• Special considerations in treating bipolar disorder in women BIPOLAR DISORDERS Burt, V. K., Rasgon, N. 2004; 6 (1): 2-13

  Abstract

  There are obvious gaps in research surrounding issues specific to women who suffer from bipolar disorder, including gender differences and their implications for management, the impact of the reproductive cycle, and evidence based treatment guidelines for pregnancy and the postpartum period. Gender differences have not been reported for the prevalence of bipolar disorder; however, women are more likely to experience rapid cycling, mixed mania, and antidepressant-induced manias. This may affect response to treatment, which has been found, in some cases, to differ in men and women. In addition, side effects in response to treatments may well differ in men and women, especially with regard to lithium and valproate prescription. The course of bipolar disorder in women may be influenced by the menstrual cycle, pregnancy, the postpartum period, and menopause, although many issues require further clarification. Treatment of bipolar disorder during pregnancy and the postmenopausal period requires careful consideration, as does treatment during the childbearing years, as some mood stabilizers influence the metabolism of oral contraceptives. This review article has attempted to evaluate existing literature regarding women with bipolar disorder in a comprehensive and critical way, and to consolidate into a single source the gender-specific aspects of the disorder that may have treatment implications for women.

  View details for Web of Science ID 000188809800001

  View details for PubMedID 14996136

• The association between insulin resistance, depression, and dementia - Response JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES Rasgon, N., Jarvik, L. 2004; 59 (2): 191–92

  View details for Web of Science ID 000189331200020

• Using technology to improve longitudinal studies: self-reporting with ChronoRecord in bipolar disorder 16th Annual Meeting of the International-Group-for-the-Study-of-Lithium-Treated-Patients (IGSLI) Bauer, M., Grof, P., Gyulai, L., Rasgon, N., Glenn, T., Whybrow, P. C. WILEY-BLACKWELL PUBLISHING, INC. 2004: 67–74

  Abstract

  Longitudinal studies are an optimal approach to investigating the highly variable course and outcome associated with bipolar disorder, but are expensive and often have missing data. This study validates patient self-reported mood ratings using a home computer-based system (ChronoRecord) with clinician mood ratings on the Hamilton Depression Rating scale (HAMD) and Young Mania Rating scale (YMRS), and investigates the patient acceptance of the technology.After brief training, outpatients with bipolar disorder were given the software version of an established paper based self-reporting form (ChronoSheet) to install on a home computer. Every day for 3 months, patients entered mood, medications, sleep, life events, and menstrual data. Weight was entered weekly.Eighty of 96 (83%) patients returned 8662 days of data. The mean days of data returned was 114.7 +/- 32.3 SD The mean percentage of days missing for mood data was 6.1% +/- 9.3 SD, equivalent to missing 7.3 day of the 114.7 days. Self-reported ratings were strongly correlated with clinician HAMD ratings (-0.683, p < 0.001).This study demonstrates concurrent validity between ChronoRecord and HAMD. Patients with bipolar disorder showed high acceptance of a computer-based system for self-reporting of daily data. Automation of data collection can reduce missing data and eliminate errors associated with data entry. This technology also enables on-going feedback for both patient and researcher during a long-term study.

  View details for Web of Science ID 000188809800008

  View details for PubMedID 14996143

• Insulin resistance, affective disorders, and Alzheimer's disease: Review and hypothesis JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES Rasgon, N., Jarvik, L. 2004; 59 (2): 178-183

  Abstract

  Affective disorders (ad) and Alzheimer's disease (AD) have been associated for almost a century, and various neurophysiologic factors have been implicated as common biologic markers. Yet, links between ad and AD still await elucidation. We propose that insulin resistance (IR) is one of the missing links between ad and AD. IR with hyperinsulinemia and subsequent impairment of glucose metabolism especially in ad patients may promote neurodegeneration and facilitate the onset of AD. According to our hypothesis, IR may persist even into ad remission in some patients. Persistent regional hypometabolism and vascular changes resulting from long-standing IR may lead to currently irreversible structural changes. Evidence in support of the hypothesis is reviewed and clinical implications suggested.

  View details for Web of Science ID 000189331200014

  View details for PubMedID 14999034

• Using software to improve longitudinal studies: self-reporting with chronorecord in bipolar disorder Trendelenburg, M., Sasse, J., Schlosser, I., Whybrow, P. C., Grof, P., Gyulai, L., Rasgon, N. L., Glenn, T., Bschor, T., Bauer, M. WILEY-BLACKWELL. 2004: 39–40

  View details for Web of Science ID 000224297100105

• The electronic assessment of the longitudinal course of bipolar disorder: The ChronoRecord software 1st International Charite Conference on Psychiatric Research: Challenges and Goals Whybrow, P. C., Grof, P., Gyulai, L., Rasgon, N., Glenn, T., Bauer, M. GEORG THIEME VERLAG KG. 2003: S244–S249

  Abstract

  Longitudinal studies are the optimal approach when investigating the highly variable course of bipolar disorder, but such studies are expensive, prone to reporting errors and to missing data. Automation of data collection may reduce such errors and improve data quality. The ChronoRecord, validated software that patients can install on a home computer to report mood, medications, sleep, life events, weight and menstrual data, has been designed to achieve such automation. In the trial of the ChronoRecord reported here, 80 of 96 (83 %) patients with bipolar disorder showed high acceptance of this computer-based system for self-report, entering daily recordings for a period of 3-months. This new technology, in addition to providing an accurate longitudinal record for research purposes, also facilitates on-going patient feedback and accurate study monitoring.

  View details for Web of Science ID 000188081200016

  View details for PubMedID 14677086

• Thyroid, brain and mood modulation in affective disorder: Insights from molecular research and functional brain imaging 1st International Charite Conference on Psychiatric Research: Challenges and Goals Bauer, M., London, E. D., Silverman, D. H., Rasgon, N., Kirchheiner, J., Whybrow, P. C. GEORG THIEME VERLAG KG. 2003: S215–S221

  Abstract

  The efficacy resulting from adjunctive use of supraphysiological doses of levothyroxine has emerged as a promising approach to therapy and prophylaxis for refractory mood disorders. Most patients with mood disorders who receive treatment with supraphysiological doses of levothyroxine have normal peripheral thyroid hormone levels, and also respond differently to the hormone and tolerate it better than healthy individuals and patients with primary thyroid diseases. Progress in molecular and functional brain imaging techniques has provided a new understanding of these phenomena, illuminating the relationship between thyroid function, mood modulation and behavior. Thyroid hormones are widely distributed in the brain and have a multitude of effects on the central nervous system. Notably many of the limbic system structures where thyroid hormone receptors are prevalent have been implicated in the pathogenesis of mood disorders. The influence of the thyroid system on neurotransmitters (particularly serotonin and norepinephrine), which putatively play a major role in the regulation of mood and behavior, may contribute to the mechanisms of mood modulation. Recent functional brain imaging studies using positron emission tomography (PET) with [ (18)F]-fluorodeoxyglucose demonstrated that thyroid hormone treatment with levothyroxine affects regional brain metabolism in patients with hypothyroidism and bipolar disorder. Theses studies confirm that thyroid hormones are active in modulating metabolic function in the mature adult brain, and provide intriging neuroanatomic clues that may guide future research.

  View details for Web of Science ID 000188081200012

  View details for PubMedID 14677082

• Emergent oscillations in mathematical model of the human menstrual cycle CNS SPECTRUMS Rasgon, N. L., Pumphrey, L., Prolo, P., Elman, S., Negrao, A. B., Licinio, J., Garfinkel, A. 2003; 8 (11): 805-814

  Abstract

  The aim of this study was to develop a mathematical model of the hypothalamo-pituitary-gonadal axis that would reflect available data in humans.A model of hormonal relationships at the early follicular and midluteal phases of the human menstrual cycle is proposed.Two distinct temporal patterns of oscillatory behavior have been demonstrated for both pituitary and gonadal steroids in the early follicular phase: first, rapid oscillations in gonadotropin releasing hormone, follicle stimulating hormone and luteinizing hormone (Q approximate to 1 hour) that were an immediate consequence of the programmed equations. Second, there were slower, undulating, emergent rhythms in luteinizing hormone and follicle stimulating hormone, and also in estrogen, having oscillatory periods of 2-12 hours. There was also a longer-period (Q2-3 days) emergent rhythm in progesterone. In the mid-luteal phase, estrogen and progesterone rhythms were correlated, and all hormones showed an approximately 6-hour periodicity.To our knowledge, the oscillatory behavior of peripheral sex steroids in the follicular phase has not been previously noted.

  View details for Web of Science ID 000187284300003

  View details for PubMedID 14702003

• Children of Alzheimer patients: A 20-year prospective study Jarvik, L., Harrison, T., Freimer, N., Holt, L., Larson, S., Matsuyama, S., Rasgon, N., Schaeffer, J., Yaralian, P. GERONTOLOGICAL SOCIETY AMER. 2003: 303

  View details for Web of Science ID 000186078100836

• Depression in women with polycystic ovary syndrome: clinical and biochemical correlates JOURNAL OF AFFECTIVE DISORDERS Rasgon, N. L., Rao, R. C., Hwang, S., Altshuler, L. L., Elman, S., Zuckerbrow-Miller, J., KORENMAN, S. G. 2003; 74 (3): 299-304

  Abstract

  We assessed the prevalence of mood disturbance among women with prospectively documented polycystic ovary syndrome (PCOS).Thirty-two women with PCOS completed the Center for Epidemiological Studies-Depression Rating Scale (CES-D). Clinical and biochemical characteristics were assessed.Sixteen women had CES-D scores indicative of depression. Depression was associated with greater insulin resistance (P=0.02) and higher body mass index (P=0.05). Women receiving oral contraceptives for the treatment of PCOS were less depressed than patients not receiving treatment (P=0.03).Possible selection bias, use of a screening tool alone without further diagnostic evaluation of depression, small samples size and lack of direct comparison with an age matched control group, should be considered in interpretation of these results.Findings suggest a high prevalence of depression among women with PCOS, and an association between depression and PCOS markers.

  View details for DOI 10.1016/S0165-0327(02)00117-9

  View details for Web of Science ID 000183025700012

  View details for PubMedID 12738050

• Menstrual cycle related mood changes in women with bipolar disorder BIPOLAR DISORDERS Rasgon, N., Bauer, M., Glenn, T., Elman, S., Whybrow, P. C. 2003; 5 (1): 48-52

  Abstract

  A relationship between affective symptoms and menstrual cycle in women with bipolar disorder (BPD) has been suggested. This study investigates the influence of the menstrual cycle on mood in women with BPD who are taking medication, but not selected for menstrual abnormalities.Data from women with BPD (n = 17) consecutively enrolled into a ChronoRecord validation study were included in the current analysis. All women received medication for BPD, in addition, 35% received oral contraceptives (OC). Participants entered mood, menstrual data, psychiatric medications, and life events daily for a 3-month period using a computerized version (ChronoRecord) of an established paper based form for self-reporting (ChronoSheet).The majority of women treated for BPD (65%) reported significant mood changes across the menstrual cycle. Long menstrual cycle was present in 59% of subjects, including those taking OC.Women with BPD taking medication report a high rate of long menstrual cycles, and significant mood changes in relation to menstrual cycle phase.

  View details for Web of Science ID 000180967300008

  View details for PubMedID 12656938

• UCLA/VA follow-up study of Alzheimer families Harrison, T. R., Freimer, N. B., Holt, L., Larson, S. W., Matsuyama, S. S., Rasgon, N., Schaeffer, J., Yaralian, P. S., Jarvik, L. F. SPRINGER PUBLISHING CO. 2003: 305

  View details for Web of Science ID 000222209400697

• Insulin resistance may link affective disorders and Alzheimer's disease: A missing link hypothesis Rasgon, N., Jarvik, L. SPRINGER PUBLISHING CO. 2003: 153

  View details for Web of Science ID 000222209400373

• The clinical nature and formal diagnosis of premenstrual, postpartum, and perimenopausal affective disorders. Current psychiatry reports Rapkin, A. J., Mikacich, J. A., Moatakef-Imani, B., Rasgon, N. 2002; 4 (6): 419-428

  Abstract

  Various mood and anxiety disorders are more prevalent in reproductive-aged women, and appear to be linked to hormonal and reproductive events. Premenstrual affective disorders consist of premenstrual syndrome, premenstrual dysphoric disorder, and premenstrual exacerbation of mood or anxiety disorders. Postpartum affective disorders can range from postpartum "blues" to postpartum depression with or without psychosis, and also include anxiety disorders, such as panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder. In perimenopausal women, the vulnerability to mood and anxiety disorders is increased. All of these disorders share risk factors, and have etiologic features in common, such as exposure to the rise and fall of ovarian sex steroids. The following is a review of these syndromes and their etiology, diagnosis, and treatment.

  View details for PubMedID 12441021

• Mood symptoms and cognitive performance in women estrogen users and nonusers and men JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Miller, K. J., Conney, J. C., Rasgon, N. L., Fairbanks, L. A., Small, G. W. 2002; 50 (11): 1826-1830

  Abstract

  Previous studies have suggested sex differences in mood and cognition and that estrogen effects may partially explain such differences. In this study, we explore sex differences for a range of mood symptoms and for neuropsychological performance in men and postmenopausal women and assess the potential influence of estrogen on these measures.Cross-sectional study of men and women examining mood, neuropsychological test data, and estrogen replacement therapy (ERT) use.Outpatient study at an urban teaching hospital with subjects recruited from the community.All subjects (N = 96) were between the ages of 57 and 75 and included 31 women using ERT, 16 non-ERT users, and 49 men. Subjects did not have major depression and were nondemented.The three groups were compared according to profile of mood states and neuropsychological performance, and statistical analyses were controlled for socioeconomic status, age, and education level.Female ERT users were less depressed and less angry and performed better on measures of verbal fluency and working memory than the other subject groups.Postmenopausal estrogen use is associated with better mood and cognitive performance on tasks of fluency and working memory. These results suggest that estrogen should be examined as a potentially critical variable influencing late-life sex differences in mood and cognition.

  View details for Web of Science ID 000178971500010

  View details for PubMedID 12410901

• Common treatment of polycystic ovarian syndrome and major depressive disorder: case report and review. Current drug targets. Immune, endocrine and metabolic disorders Rasgon, N. L., Carter, M. S., Elman, S., Bauer, M., Love, M., KORENMAN, S. G. 2002; 2 (1): 97-102

  Abstract

  We present the case of a young woman with treatment-resistant major depression, who presented to the Mood Disorders Clinic with a Hamilton Psychiatric Rating Scale for Depression (HAM-D-21) score of 28, after a year-long treatment with Effexor-XR. The patient also had untreated Polycystic Ovarian Syndrome (PCOS). The resolution of her depressive symptoms resulted from the treatment for PCOS with metformin and spironolactone. The patient remained euthymic 5 months after discontinuation of the antidepressant while continuing therapy for PCOS. We briefly overview of the pertinent literature of the pathophysiology of PCOS and affective disorders, highlighting an overlap in phenotypical presentations between these two disorders. Dysregulation of the hypothalamo-pituitary axis and various end organ systems are implicated in both PCOS and affective disorders. As such, several clinical and biochemical markers are common to both disorders, namely insulin resistance, obesity, and hyperandrogenism. In addition, these metabolic abnormalities are interrelated, causing women with PCOS or affective disorders to get caught in a "vicious cycle" of hormonal dysregulation. The case report presented here illustrates how treatment of symptoms such as insulin resistance and hyperandrogenism can lead to remission of major depressive disorder and PCOS. We suggest that through treatment of underlying metabolic defects, both the mood of the patient and the metabolic condition of PCOS can be assisted.

  View details for PubMedID 12477299

• Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women Closed Roundtable Symposium on Womens Issues in Antidepressant Therapy Rasgon, N. L., Altshuler, L. L., Fairbanks, L. A., Dunkin, J. J., Davtyan, C., Elman, S., Rapkin, A. J. PHYSICIANS POSTGRADUATE PRESS. 2002: 45–48

  Abstract

  Increased vulnerability to mood disorders has been reported during perimenopause. Fluctuating estrogen levels accompany the perimenopausal transition. Thus, estrogen replacement therapy (ERT) has been proposed as a potentially effective treatment for mood disorders occurring during perimenopause.We examined the efficacy of ERT in the treatment of depression in 16 perimenopausal women with DSM-IV-defined major depressive disorder who were participating in the Mood Disorders Research Program at the Department of Psychiatry of the University of California, Los Angeles. Ten antidepressant- and ERT-naive women received ERT alone. Six women who were nonresponders or partial responders to an antidepressant received ERT in addition to existing treatment with fluoxetine. The Hamilton Rating Scale for Depression (HAM-D) was administered to all patients at baseline and weekly thereafter during the 8-week open-protocol trial. Partial response was operationalized as a final HAM-D score < or = 50% of the baseline score. Remission was defined as a final HAM-D score < or = 7.All patients exhibited clinical improvement as measured by HAM-D scores after the first week of treatment. Of the 10 perimenopausal depressed women receiving ERT alone, 6 remitted, 3 partially responded to treatment, and 1 did not respond by the end of the trial. Of the 6 women receiving antidepressant treatment with ERT, 1 patient remitted and 5 had a partial response by the end of the trial.This small study suggests that for some antidepressant-naive perimenopausal women with clinical depression, ERT may have antidepressant efficacy. In depressed women who have minimal response to a selective serotonin reuptake inhibitor, ERT may augment response. Further controlled trials are needed.

  View details for Web of Science ID 000175324600006

  View details for PubMedID 11995778

• Estrogen-replacement therapy for depression AMERICAN JOURNAL OF PSYCHIATRY Rasgon, N. L., Altshuler, L. L., Fairbanks, L. 2001; 158 (10): 1738-1738

  View details for Web of Science ID 000171374500040

  View details for PubMedID 11579020

• Affective disorders and Alzheimer disease: A missing-link hypothesis AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Rasgon, N., Jarvik, G. P., Jarvik, L. 2001; 9 (4): 444-445

  View details for Web of Science ID 000171698200015

  View details for PubMedID 11739073

• Neuroactive steroid-serotonergic interaction: responses to an intravenous L-tryptophan challenge in women with premenstrual syndrome EUROPEAN JOURNAL OF ENDOCRINOLOGY Rasgon, N., Serra, M., Biggio, G., Pisu, M. G., Fairbanks, L., Tanavoli, S., Rapkin, A. 2001; 145 (1): 25-33

  Abstract

  To evaluate the circulating concentrations of the neuroactive steroids in response to an i.v. L-tryptophan (L-TP) challenge across the menstrual cycle in women with premenstrual syndrome (PMS) and in controls.An i.v. L-TP challenge was administered eight times during 1 month to five women with prospectively documented PMS and five age- and body mass-matched controls. Progesterone, allopregnanolone pregnenolone and 3alpha-5alpha-tetrahydrocorticosterone were assessed 15 and 0 min before, and at 30, 60 and 90 min after the challenge, across the menstrual cycle.In response to L-TP challenge, only allopregnanolone concentrations were significantly increased across the cycle and this increase was of a greater magnitude in women with PMS. Pregnenolone and 3alpha-5alpha-tetrahydrocorticosterone concentrations were not affected in women with PMS or controls after L-TP challenge.The data provide evidence for possible interaction between the serotonergic system and the neuroactive steroid, allopregnanolone. Women with PMS demonstrated a more significant increase in allopregnanolone concentrations in response to L-TP challenge, which could be due to an initial low basal serotonergic tone in the luteal phase in the PMS group.

  View details for Web of Science ID 000169787700004

  View details for PubMedID 11415849

• Estrogen use and brain metabolic change in older adults. A preliminary report PSYCHIATRY RESEARCH-NEUROIMAGING Rasgon, N. L., Small, G. W., Siddarth, P., Miller, K., Ercoli, L. M., Bookheimer, S. Y., Lavretsky, H., Huang, S. C., Barrio, J. R., Phelps, M. E. 2001; 107 (1): 11-18

  Abstract

  Because estrogen may influence brain blood flow and metabolism in older adults, we used positron emission tomography to evaluate cerebral glucose metabolic change in post-menopausal women and men. Women estrogen users (n=4), women non-users (n=8) and men (n=10) were scanned at baseline and two years later. Analyses focused on glucose metabolism in lateral temporal, inferior parietal and posterior cingulate brain regions, previously reported to decline in non-demented older persons. No metabolic differences in cerebral regions of interest were found among groups at baseline. At follow-up, women estrogen users showed significantly increased glucose metabolism in the lateral temporal region, whereas women non-users and men exhibited no significant metabolic change in this region. These findings suggest that estrogen use may protect against regional cerebral metabolic decline in postmenopausal women.

  View details for Web of Science ID 000170736000002

  View details for PubMedID 11472860

• Menstrual cycle-related brain metabolite changes using H-1 magnetic resonance spectroscopy in premenopausal women: a pilot study PSYCHIATRY RESEARCH-NEUROIMAGING Rasgon, N. L., Thomas, M. A., Guze, B. H., Fairbanks, L. A., Yue, K., Curran, J. G., Rapkin, A. J. 2001; 106 (1): 47-57

  Abstract

  Proton magnetic resonance spectroscopy (1H-MRS) was used to assess neurochemical brain changes across the menstrual cycle in five women with premenstrual dysphoric disorder (PMDD) and six control subjects. Women with PMDD and control subjects were scanned on days 8 and 26 within one menstrual cycle (i.e. at times of complete absence and height of PMDD symptoms, respectively). The point resolved spectroscopic sequence (PRESS) was used to localize a voxel of 8 ml in the medial frontal gray matter and in the occipito-parietal white matter. The ratio of N-acetyl-aspartate to creatine in the region of the medial prefrontal cortex and the cingulate gyrus declined significantly from the follicular to the luteal phase in both groups of subjects. The menstrual phase-dependent significant increase in the ratio of choline to creatine was observed in the parietal white matter. The myo-inositol/creatine ratio exhibited a trend toward higher levels in the PMDD patients in the luteal phase of the menstrual cycle. Differences between PMDD and control subjects were not statistically significant. Menstrual cycle phase-dependent changes in ovarian hormonal concentrations may influence the neurochemistry of brain activity in premenopausal women.

  View details for Web of Science ID 000167495300005

  View details for PubMedID 11231099

• Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Small, G. W., Ercoli, L. M., Silverman, D. H., Huang, S. C., Komo, S., Bookheimer, S. Y., Lavretsky, H., Miller, K., Siddarth, P., Rasgon, N. L., Mazziotta, J. C., Saxena, S., Wu, H. M., Mega, M. S., Cummings, J. L., Saunders, A. M., Pericak-Vance, M. A., Roses, A. D., Barrio, J. R., Phelps, M. E. 2000; 97 (11): 6037-6042

  Abstract

  The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments.

  View details for Web of Science ID 000087318700066

  View details for PubMedID 10811879

• Medication status and polycystic ovary syndrome in women with bipolar disorder: A preliminary report 39th Congress of the International-Society-of-Psychoneuroendocrinology Rasgon, N. L., Altshuler, L. L., Gudeman, D., Burt, V. K., Tanavoli, S., Hendrick, V., Korenman, S. PHYSICIANS POSTGRADUATE PRESS. 2000: 173–78

  Abstract

  In patients with epilepsy, polycystic ovary (PCO) syndrome has been reported to be associated with the use of the anticonvulsant divalproex sodium. Whether PCO syndrome is associated with divalproex use in patients with bipolar disorder has not previously been explored.Twenty-two female outpatients with a DSM-IV diagnosis of bipolar disorder who were between the ages of 18 and 45 years (inclusive) and who were taking lithium and/or divalproex (10, divalproex monotherapy; 10, lithium monotherapy; 2, divalproex/lithium combination therapy) were evaluated. Patients completed questionnaires about their medical, psychiatric, and reproductive health histories, and body mass indices were calculated. In the early follicular phase of their menstrual cycle, women were examined for hirsutism, given a pelvic ultrasound, and/or assessed for changes in laboratory values such as serum levels of testosterone, free testosterone, estradiol, estrone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, luteinizing hormone, follicle-stimulating hormone, and 17-OH progesterone.All 10 patients on lithium monotherapy, 6 of 10 patients on divalproex monotherapy, and both of the patients on divalproex/lithium combination therapy reported some type of menstrual dysfunction, which, in 4 cases, had preceded the diagnosis of bipolar disorder. Hirsutism was not common in any group, but obesity was prominent in all groups. Ovarian ultrasound revealed an increased number of ovarian follicles in 1 patient taking lithium and in none of the patients taking divalproex. Hormonal screening did not indicate PCO-like changes in any patient.In this pilot study of bipolar patients, PCO-like changes were not seen in women receiving divalproex or lithium. However, independent of therapeutic agent used, the bipolar women in this study reported high rates of menstrual disturbances, suggesting that the hypothalamic-pituitary-gonadal axis may be compromised in some women with bipolar disorder.

  View details for Web of Science ID 000086531000005

  View details for PubMedID 10817101

• Efficacy and response time to sertraline versus fluoxetine in the treatment of unipolar major depressive disorder 153rd Annual Meeting of the American-Psychiatric-Association Suri, R. A., Altshuler, L. L., Rasgon, N. L., Calcagno, J. L., Frye, M. A., Gitlin, M. J., Hwang, S., Zuckerbrow-Miller, J. PHYSICIANS POSTGRADUATE PRESS. 2000: 942–46

  Abstract

  Few studies have compared the treatment efficacy of the 2 selective serotonin reuptake inhibitors sertraline and fluoxetine.A randomized, single-blind, parallel-group study of 10 weeks' duration comparing the efficacy of sertraline, 50 mg/day; sertraline, 100 mg/day; and fluoxetine, 20 mg/day, was conducted in 44 psychiatric outpatients with DSM-IV unipolar major depressive disorder. Antidepressant dosages were doubled at 6 weeks for subjects who had not achieved remission. Primary outcome measurements included the 21-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impressions-Improvement scale (CGI-I), with scores of < or = 7 on the HAM-D and < or = 2 on the CGI-I representing a positive treatment response, i.e., remission.At 4 weeks, significant differences in rate of positive treatment response were noted, with 0% for sertraline, 50 mg; 46% for sertraline, 100 mg; and 31% for fluoxetine, 20 mg (p = .023). At 6 weeks, positive treatment response rates were 21%, 43%, and 31% for subjects taking 50 mg of sertraline, those taking 100 mg of sertraline, and those taking 20 mg of fluoxetine, respectively, with treatment groups no longer differing significantly from each other. In subjects for whom antidepressant dose was doubled at week 6, response rates at week 10 (4 weeks on increased dose) were 40% for sertraline, 100 mg; 43% for sertraline, 200 mg; and 55% for fluoxetine, 40 mg.Subjects taking sertraline, 100 mg, and fluoxetine, 20 mg, demonstrated an earlier treatment response compared with subjects taking sertraline, 50 mg. For patients without a positive response at 6 weeks, an increased antidepressant dose resulted in remission for a substantial proportion of patients when assessed 4 weeks later.

  View details for Web of Science ID 000166534300009

  View details for PubMedID 11206600

• Neuroendocrine response to an intravenous L-tryptophan challenge in women with premenstrual syndrome 46th Annual Meeting of the Society-for-Gynecologic-Investigation Rasgon, N., McGuire, M., Tanavoli, S., Fairbanks, L., Rapkin, A. ELSEVIER SCIENCE INC. 2000: 144–49

  Abstract

  To evaluate the neuroendocrine responses to an intravenous L-tryptophan challenge across the menstrual cycle in women with premenstrual syndrome (PMS) and controls.Controlled clinical study.The Clinical Research Center of an academic research environment.Women with PMS and healthy volunteers.An intravenous L-tryptophan challenge was administered two times a week during 1 month to five subjects with prospectively documented PMS and five age- and body mass-matched controls.Whole-blood serotonin, cortisol, and prolactin levels were assessed at the baseline and at 30, 50, 60, 70, 80, and 90 minutes after the challenge.Whole-blood serotonin response to the L-tryptophan challenge was blunted in the luteal phase of the menstrual cycle in subjects with PMS compared with controls. Cortisol levels differed between groups and cycle phases only at the baseline, with higher baseline cortisol levels during the luteal phase in women with PMS, whereas baseline and postchallenge prolactin levels did not differ between groups.The present results support previously reported findings of alterations in tryptophan handling in women with PMS. The elevated baseline luteal phase cortisol concentrations in subjects with PMS warrants further investigation.

  View details for Web of Science ID 000084537500028

  View details for PubMedID 10632430

• Toward optimal health: the experts respond to depression. Interview by Jodi Godfrey Meisler. Journal of women's health & gender-based medicine Rasgon, N., Nonacs, R. 1999; 8 (9): 1141-1146

  View details for PubMedID 10595326

• Depressive symptoms in the perimenopause: Prevalence, assessment, and guidelines for treatment HARVARD REVIEW OF PSYCHIATRY Burt, V. K., Altshuler, L. L., Rasgon, N. 1998; 6 (3): 121-132

  Abstract

  This review describes the biological changes occurring in perimenopause and analyzes epidemiological studies that shed light on the relationship between perimenopause and mood. The role of estrogen as a treatment for depressive symptoms is also examined. We found that a positive association may exist between depressive symptoms and the perimenopause, and that a prior history of depression may be associated with such symptoms. In most of the studies reviewed, the use of estrogen in replacement doses appears to improve depressive symptoms in perimenopausal patients who do not have major depression. We suggest an approach to the treatment of middle-aged women presenting with such symptoms. No careful study of the incidence of DSM-IV major depression associated with perimenopause has been done, and the efficacy of estrogen as a primary or adjunctive treatment for the disorder during perimenopause is unclear.

  View details for Web of Science ID 000075739200001

  View details for PubMedID 10372280

• AGENESIS OF CORPUS-CALLOSUM AND DEMENTIA OF THE ALZHEIMERS TYPE - A REVIEW AND CASE-REPORT CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE Rasgon, N., Ananth, J., MENA, I., KROUT, B., Boone, K. 1994; 39 (7): 429-432

  Abstract

  This paper describes a previously sufficiently functioning 57 year old man who presented with a recent onset of frontal behaviour. Partial agenesis of corpus callosum was an incidental finding on a computerized tomography scan. The EEG was within normal limits and neuropsychological testing did not reveal any interhemispheric disconnection. A SPECT-Scan revealed bilateral hypoperfusion, consistent with Alzheimer's dementia. Normal functioning up to 50 years of age and a later manifestation of Alzheimer's disease along with agenesis of carpus callosum is of clinical interest as such an association has not been published.

  View details for Web of Science ID A1994QG20200007

  View details for PubMedID 7987785

• [Alpha-tocopherol induced activation of the endogenous opioid system]. Biulleten' eksperimental'noi biologii i meditsiny Kryzhanovskii, G. N., LUZINA, N. L., IARYGIN, K. N. 1989; 108 (11): 566-567

  Abstract

  In an attempt to clarify the nature of analgesic effect of alpha-tocopherol, the influence of alpha-tocopherol on the levels of endogenic opioids was studied in the experiments in vitro. Main changes of the level of adenohypophyseal (tissue) beta-endorphins and in the incubation media were evaluated as well as the involvement of the endogenous opioid system in the analgesic effect of alpha-tocopherol.

  View details for PubMedID 2534474

• [The inhibition stage of lipid peroxidation during stress]. Biulleten' eksperimental'noi biologii i meditsiny Guliaeva, N. V., LUZINA, N. L., Levshina, I. P., Kryzhanovskii, G. N. 1988; 106 (12): 660-663

  Abstract

  Stress is shown to induce at first the generalized inhibition of lipid peroxidation (LPO), and then the activation of LPO. In brain and blood serum of rats subjected to continuous footshock as well as to restraint stress LPO products decreased and superoxide scavenging activity increased during the initial period of stress, after 1 hour of footshock LPO indices nearly reached normal values, and after 2 hours of footshock the accumulation of LPO products and decrease of superoxide scavenging activity were seen. LPO inhibition was accompanied by accumulation of easy oxidizable brain phospholipids and by depletion of brain cholesterol, during LPO activation brain cholesterol content and cholesterol-phospholipid ratio increased. The content of LPO products--fluorescent Schiff bases in blood plasma of women suffering from algomenorrhea at first decreased (O-12 h) and then dramatically increased (12-24 h) after a onset of pain at the beginning of menstruation. The data suggest that the stage of LPO inhibition precedes its activation during stress.

  View details for PubMedID 3207869

• [Endogenous opioid system in the realization of the analgesic effect of alpha-tocopherol in reference to algomenorrhea]. Biulleten' eksperimental'noi biologii i meditsiny Kryzhanovskii, G. N., BAKULEVA, L. P., LUZINA, N. L., Vinogradov, V. A., IARYGIN, K. N. 1988; 105 (2): 148-150

  Abstract

  Beta-endorphin-like immunoreactivity was studied in 7 patients with algomenorrhea during pain attack and 15 minutes after alpha-tocopherol administration with a therapeutic aim (till the analgetic effect was reached). There was an increase in beta-endorphin-like immunoreactivity after alpha-tocopherol administration. Naloxone administration to 9 patients with algomenorrhea of various etiology resumed the pain. The effect of alpha-tocopherol application for pain relief depended on the pathogenesis of algomenorrhea. At the same time naloxone administration failed to resume the pain in patients, in whom alpha-tocopherol had a strong analgetic effect. It is assumed that the endogenous opioid system participates in alpha-tocopherol effect on pain relief in patients with algomenorrhea.

  View details for PubMedID 2964879

• [Use of an antioxidant, alpha-tocopherol acetate, in the complex treatment of algomenorrhea]. Akusherstvo i ginekologii?a LUZINA, N. L., Vakuleva, L. P. 1987: 67-69

  View details for PubMedID 3618955

• [Body reactivity characteristics of chronic salpingo-oophoritis patients at the health resort stage of rehabilitation]. Akusherstvo i ginekologii?a LUZINA, N. L., Zelinskii, A. A., Kryzhanovskii, G. N. 1986: 69-71

  View details for PubMedID 2949664