Jennifer Keller

All Publications

• 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

• Corticotropin-releasing factor 1 receptor haplotype and cognitive features of major depression. Translational psychiatry Davis, E. G., Keller, J. n., Hallmayer, J. n., Pankow, H. R., Murphy, G. M., Gotlib, I. H., Schatzberg, A. F. 2018; 8 (1): 5

  Abstract

  Corticotropin-releasing factor signaling through CRF receptor type 1 (CRF1) has been shown to contribute to learning and memory function. A haplotype of alleles T-A-T in a set of common polymorphisms in the gene encoding for CRF1(CRHR1) has been associated with both depression vulnerability and alterations in cognitive functioning. The present study investigated the relations between the TAT haplotype and specific symptoms of depression, self-reported ruminative behaviors, and neuropsychological performance on a learning and memory task. Participants were adults with major depression with and without psychotic features (N = 406). Associations were examined between TAT haplotype and endorsement of depression symptoms from diagnostic interviews, scores on the rumination response scale (RRS), and verbal memory performance on the California Verbal Learning Test-II (CVLT-II). All analyses included depression subtype, age, and sex as covariates; CVLT-II analyses also included evening cortisol levels. Across the entire sample, carriers of more copies of the TAT haplotype reported greater endorsement of the symptom describing difficulty concentrating and making decisions. In separate subsamples, TAT homozygotes had higher rumination scores on the RRS, both brooding and reflection subscales, and more TAT copies were associated with poorer CVLT-II performance in both total learning and free recall trials. These data demonstrate that the CRHR1 TAT haplotype is associated with cognitive features of depression including difficulty with decision-making, higher rumination, and poorer learning and memory. It will be important in future research to identify the specific molecular mechanisms for CRF1signaling that contribute to depression-related cognitive dysfunction.

  View details for PubMedID 29317606

  View details for PubMedCentralID PMC5802461

• A 6-Week School Curriculum Improves Boys' Attitudes and Behaviors Related to Gender-Based Violence in Kenya JOURNAL OF INTERPERSONAL VIOLENCE Keller, J., Mboya, B. O., Sinclair, J., Githua, O. W., Mulinge, M., Bergholz, L., Paiva, L., Golden, N. H., Kapphahn, C. 2017; 32 (4): 535-557

  Abstract

  This study investigated the effects of a gender-based violence (GBV) educational curriculum on improving male attitudes toward women and increasing the likelihood of intervention if witnessing GBV, among adolescent boys in Nairobi, Kenya. In total, 1,543 adolescents participated in this comparison intervention study: 1,250 boys received six 2-hr sessions of the "Your Moment of Truth" (YMOT) intervention, and 293 boys comprised the standard of care (SOC) group. Data on attitudes toward women were collected anonymously at baseline and 9 months after intervention. At follow-up, boys were also asked whether they encountered situations involving GBV and whether they successfully intervened. Compared with baseline, YMOT participants had significantly higher positive attitudes toward women at follow-up, whereas scores for SOC participants declined. At follow-up, the percentage of boys who witnessed GBV was similar for the two groups, except for physical threats, where the intervention group reported witnessing more episodes. The percentage of boys in the intervention group who successfully intervened when witnessing violence was 78% for verbal harassment, 75% for physical threat, and 74% for physical or sexual assault. The percentage of boys in the SOC group who successfully intervened was 38% for verbal harassment, 33% for physical threat, and 26% for physical or sexual assault. Results from the logistic regression demonstrate that more positive attitudes toward women predicted whether boys in the intervention group would intervene successfully when witnessing violence. This standardized 6-week GBV training program is highly effective in improving attitudes toward women and increasing the likelihood of successful intervention when witnessing GBV.

  View details for DOI 10.1177/0886260515586367

  View details for Web of Science ID 000398894000004

• Trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and paralimbic reward pathways. Journal of psychiatric research Keller, J., Young, C. B., Kelley, E., Prater, K., Levitin, D. J., Menon, V. 2013; 47 (10): 1319-1328

  Abstract

  Anhedonia is the inability to experience pleasure from normally pleasant stimuli. Although anhedonia is a prominent feature of many psychiatric disorders, trait anhedonia is also observed dimensionally in healthy individuals. Currently, the neurobiological basis of anhedonia is poorly understood because it has been mainly investigated in patients with psychiatric disorders. Thus, previous studies have not been able to adequately disentangle the neural correlates of anhedonia from other clinical symptoms. In this study, trait anhedonia was assessed in well-characterized healthy participants with no history of Axis I psychiatric illness. Functional magnetic resonance imaging with musical stimuli was used to examine brain responses and effective connectivity in relation to individual differences in anhedonia. We found that trait anhedonia was negatively correlated with pleasantness ratings of music stimuli and with activation of key brain structures involved in reward processing, including nucleus accumbens (NAc), basal forebrain and hypothalamus which are linked by the medial forebrain bundle to the ventral tegmental area (VTA). Brain regions important for processing salient emotional stimuli, including anterior insula and orbitofrontal cortex were also negatively correlated with trait anhedonia. Furthermore, effective connectivity between NAc, VTA and paralimbic areas, that regulate emotional reactivity to hedonic stimuli, was negatively correlated with trait anhedonia. Our results indicate that trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and related limbic and paralimbic systems involved in reward processing. Critically, this association can be detected even in individuals without psychiatric illness. Our findings have important implications both for understanding the neurobiological basis of anhedonia and for the treatment of anhedonia in psychiatric disorders.

  View details for DOI 10.1016/j.jpsychires.2013.05.015

  View details for PubMedID 23791396

• Hippocampal and amygdalar volumes in psychotic and nonpsychotic unipolar depression AMERICAN JOURNAL OF PSYCHIATRY Keller, J., Shen, L., Gomez, R. G., Garrett, A., Solvason, H. B., Reiss, A., Schatzberg, A. F. 2008; 165 (7): 872-880

  Abstract

  The limbic system is thought to underlie dysfunctional affective and cognitive processes in individuals with depression. Neuroanatomical studies of subjects with depression have often examined hippocampal and amygdalar structures, since they are two key structures of the limbic system. Research has often but not always found reduced hippocampal volume in patients with major depression. The purpose of the present study was to examine differences in hippocampal and amygdalar volumes in patients with depression subtypes relative to healthy comparison subjects.Participants were 1) patients with major depression with psychosis, 2) patients with major depression without psychosis, and 3) healthy comparison subjects. To examine hippocampal and amygdalar volumes, all participants underwent structural magnetic resonance imaging (MRI). The authors further examined the effects of clinical and chronicity data on these two brain structures.After age, gender, and total brain volume were controlled, depressed patients with psychosis had a significantly smaller mean amygdala volume relative to depressed patients without psychosis and healthy comparison subjects. There were no differences between depressed patients without psychosis and healthy comparison subjects. Correlational analyses suggested that age of depression onset was strongly associated with amygdala volume. No group differences in hippocampal volume were found.There were no differences between depressed patients and healthy comparison subjects in hippocampal volume. However, psychotic but not nonpsychotic depression was associated with reduced amygdala volume. Reduced amygdala volume was not associated with severity of depression or severity of psychosis but was associated with age at onset of depression. Smaller amygdala volume may be a risk factor for later development of psychotic depression. In addition, chronicity of depression and depression subtype might be two important factors associated with hippocampal and amygdalar volumes in depression.

  View details for DOI 10.1176/appi.ajp.2008.07081257

  View details for Web of Science ID 000257320100016

  View details for PubMedID 18450931

  View details for PubMedCentralID PMC3733673

• Cortisol circadian rhythm alterations in psychotic major depression BIOLOGICAL PSYCHIATRY Keller, J., Flores, B., Gomez, R. G., Solvason, H. B., Kenna, H., Williams, G. H., Schatzberg, A. F. 2006; 60 (3): 275-281

  Abstract

  Increased hypothalamic-pituitary-adrenal axis activity is well described in psychotic depression with an emphasis on 24-hour, urinary free cortisol levels or dexamethasone suppression tests. There are limited data on cortisol levels during specific times of the day.Patients with depression with (PMD) and without (NPMD) psychosis and healthy control subjects were studied using rating scales of depression and psychosis and measures of HPA activity, including overnight cortisol and adrenocorticotropin levels. We used analysis of variance to determine group differences and regression analyses to assess contributions of specific measures to cortisol levels.PMDs had higher cortisol during the evening hours than did NPMDs or control subjects, who did not differ from one another. Regression analyses suggest that depression and the combination of depressive and psychotic symptoms were important contributors to variance in evening cortisol.PMD is associated with increased cortisol levels during the quiescent hours. Enhanced cortisol activity, particularly a higher nadir, was related to depression severity and the interaction of depressive and psychotic symptoms. This increase suggests a defect in the action of the circadian timing system and HPA axis, creating a hormonal milieu similarly seen in early Cushing's syndrome and potentially an (im)balance of mineralocorticoid and glucocorticoid receptor activity.

  View details for DOI 10.1016/j.biopsych.2005.10.014

  View details for Web of Science ID 000239543800009

  View details for PubMedID 16458262

• Magnesium-ibogaine therapy in veterans with traumatic brain injuries. Nature medicine Cherian, K. N., Keynan, J. N., Anker, L., Faerman, A., Brown, R. E., Shamma, A., Keynan, O., Coetzee, J. P., Batail, J., Phillips, A., Bassano, N. J., Sahlem, G. L., Inzunza, J., Millar, T., Dickinson, J., Rolle, C. E., Keller, J., Adamson, M., Kratter, I. H., Williams, N. R. 2024

  Abstract

  Traumatic brain injury (TBI) is a leading cause of disability. Sequelae can include functional impairments and psychiatric syndromes such as post-traumatic stress disorder (PTSD), depression and anxiety. Special Operations Forces (SOF) veterans (SOVs) may be at an elevated risk for these complications, leading some to seek underexplored treatment alternatives such as the oneirogen ibogaine, a plant-derived compound known to interact with multiple neurotransmitter systems that has been studied primarily as a treatment for substance use disorders. Ibogaine has been associated with instances of fatal cardiac arrhythmia, but coadministration of magnesium may mitigate this concern. In the present study, we report a prospective observational study of the Magnesium-Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), provided together with complementary treatment modalities, in 30 male SOVs with predominantly mild TBI. We assessed changes in the World Health Organization Disability Assessment Schedule from baseline to immediately (primary outcome) and 1month (secondary outcome) after treatment. Additional secondary outcomes included changes in PTSD (Clinician-Administered PTSD Scale for DSM-5), depression (Montgomery-Asberg Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale). MISTIC resulted in significant improvements in functioning both immediately (Pcorrected<0.001, Cohen's d=0.74) and 1month (Pcorrected< 0.001, d=2.20) after treatment and in PTSD (Pcorrected<0.001, d=2.54), depression (Pcorrected<0.001, d=2.80) and anxiety (Pcorrected<0.001, d=2.13) at 1month after treatment. There were no unexpected or serious adverse events. Controlled clinical trials to assess safety and efficacy are needed to validate these initial open-label findings. ClinicalTrials.gov registration: NCT04313712 .

  View details for DOI 10.1038/s41591-023-02705-w

  View details for PubMedID 38182784

• In Their Own Words: Sexual Assault Resistance Strategies Among Kenyan Adolescent Girls Following Participation in an Empowerment Self-Defense Program. Violence against women Edwards, K. M., Omondi, B., Wambui, R. A., Darragh-Ford, E., Apollo, R., Devisheim, H. H., Langat, N., Kaede, B., Ntinyari, W., Keller, J. 2023: 10778012231153360

  Abstract

  The purpose of this study was to examine, via testimonial data, resistance strategies used to thwart a sexual assault among slum-dwelling Kenyan adolescent girls (N=678) following their participation in an empowerment self-defense program (IMpower). A subset of girls from the larger trials participated. The majority (58.2%) of perpetrators were strangers; there were no differences in resistance strategies used between strangers versus known perpetrators (83.8% used verbal strategies, 33.2% used resistance strategies, 16.7% ran away, and 7.9% used distraction). Associations between resistance strategies and perpetrator tactics, number of assailants, location of the assault, and the presence of a bystander were also examined.

  View details for DOI 10.1177/10778012231153360

  View details for PubMedID 36710565

• Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. The American journal of psychiatry Cole, E. J., Phillips, A. L., Bentzley, B. S., Stimpson, K. H., Nejad, R., Barmak, F., Veerapal, C., Khan, N., Cherian, K., Felber, E., Brown, R., Choi, E., King, S., Pankow, H., Bishop, J. H., Azeez, A., Coetzee, J., Rapier, R., Odenwald, N., Carreon, D., Hawkins, J., Chang, M., Keller, J., Raj, K., DeBattista, C., Jo, B., Espil, F. M., Schatzberg, A. F., Sudheimer, K. D., Williams, N. R. 2021: appiajp202120101429

  Abstract

  OBJECTIVE: Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of 90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression.METHODS: Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Asberg Depression Rating Scale (MADRS) 4 weeks after treatment.RESULTS: At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group.CONCLUSIONS: SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT's durability and to compare it with other treatments.

  View details for DOI 10.1176/appi.ajp.2021.20101429

  View details for PubMedID 34711062

• Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. The American journal of psychiatry Cole, E. J., Stimpson, K. H., Bentzley, B. S., Gulser, M. n., Cherian, K. n., Tischler, C. n., Nejad, R. n., Pankow, H. n., Choi, E. n., Aaron, H. n., Espil, F. M., Pannu, J. n., Xiao, X. n., Duvio, D. n., Solvason, H. B., Hawkins, J. n., Guerra, A. n., Jo, B. n., Raj, K. S., Phillips, A. L., Barmak, F. n., Bishop, J. H., Coetzee, J. P., DeBattista, C. n., Keller, J. n., Schatzberg, A. F., Sudheimer, K. D., Williams, N. R. 2020: appiajp201919070720

  Abstract

  New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for treatment-resistant depression.Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT.One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score <11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects.SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.

  View details for DOI 10.1176/appi.ajp.2019.19070720

  View details for PubMedID 32252538

• HPA axis in psychotic major depression and schizophrenia spectrum disorders: Cortisol, clinical symptomatology, and cognition. Schizophrenia research Cherian, K., Schatzberg, A. F., Keller, J. 2019

  Abstract

  The Hypothalamic Pituitary Adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance, and a potential role of HPA axis genetic variation in cognition. In schizophrenia differential HPA activity has been found, including higher rates of non-suppression to dexamethasone challenge and higher salivary cortisol levels, which have been a premonitory risk factor for conversion to psychosis in adolescents at risk for developing schizophrenia. The present study investigated the simultaneous roles HPA axis activity and clinical symptomatology play in poor cognitive performance. Patients with major depression with psychosis (PMD) or schizophrenia spectrum disorder (SCZ) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, and overnight hourly blood sampling for cortisol. Cognitive performance did not differ between the clinical groups, though they both performed more poorly than the HC's across a variety of cognitive domains. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher evening cortisol levels than did SCZ and HCs. Cortisol and clinical symptoms, as well as age, sex, and antipsychotic use predicted cognitive performance. Diathesis stress models and their links to symptomatology, cognition, and HPA function are discussed.

  View details for DOI 10.1016/j.schres.2019.07.003

  View details for PubMedID 31307859

• Diagnostic differences in verbal learning strategies and verbal memory in patients with mood disorders and psychotic disorders. Psychiatry research Gill, S. K., Gomez, R. G., Keller, J., Schatzberg, A. F. 2018; 269: 733–39

  Abstract

  A better understanding of verbal learning strategies can offer insight to the difference in verbal memory performance and learning between patients with schizophrenia and schizoaffective disorders, non-psychotic major depression, and psychotic major depression. To date, a comparison of the use of verbal learning strategies and verbal memory performance amongst these specific diagnostic groups has not been investigated. This study examined differences in verbal learning and memory between psychotic major depression (n = 31), nonpsychotic major depression (n = 30), and schizophrenia spectrum disorders (n = 17) disorders. Verbal learning and memory were assessed through the use of the California Verbal Learning Test-II (CVLT-II). Correlations and multiple regression analyses were conducted to analyze differences in verbal learning and memory amongst these groups. There were no significant differences in the use of Semantic Clustering. Diagnostic differences were observed in the use of Serial and Subjective Clustering. The psychotic major depression group utilized Serial Clustering strategy significantly less than the nonpsychotic major depression group. Learning strategies significantly predicted learning and recall. These findings lend support to the hypothesis that learning strategies predict verbal memory performance across diagnostic groups. The present study contains useful information on diagnostic differences in verbal learning and memory, and a framework by which treatment could be tailored to enhance learning specific to these diagnostic groups.

  View details for PubMedID 30273898

• High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. Brain : a journal of neurology Williams, N. R., Sudheimer, K. D., Bentzley, B. S., Pannu, J. n., Stimpson, K. H., Duvio, D. n., Cherian, K. n., Hawkins, J. n., Scherrer, K. H., Vyssoki, B. n., DeSouza, D. n., Raj, K. S., Keller, J. n., Schatzberg, A. F. 2018

  View details for PubMedID 29415152

• Increased Intra-Limbic Functional Connectivity to Insula, Thalamus, Caudate, Putamen, and Cingulate Cortex in Patients With Major Depression Sudheimer, K., Keller, J., Tennakoon, L., Gomez, R., Garrett, A., Schatzberg, A. NATURE PUBLISHING GROUP. 2017: S172–S173

  View details for Web of Science ID 000416846301094

• Resting-state connectivity biomarkers define neurophysiological subtypes of depression NATURE MEDICINE Drysdale, A. T., Grosenick, L., Downar, J., Dunlop, K., Mansouri, F., Meng, Y., Fetcho, R. N., Zebley, B., Oathes, D. J., Etkin, A., Schatzberg, A. F., Sudheimer, K., Keller, J., Mayberg, H. S., Gunning, F. M., Alexopoulos, G. S., Fox, M. D., Pascual-Leone, A., Voss, H. U., Casey, B. J., Dubin, M. J., Liston, C. 2017; 23 (1): 28-38

  Abstract

  Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82-93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.

  View details for DOI 10.1038/nm.4246

  View details for Web of Science ID 000391646800011

  View details for PubMedID 27918562

• Decreased hypothalamic functional connectivity with subgenual cortex in psychotic major depression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Sudheimer, K., Keller, J., Gomez, R., Tennakoon, L., Reiss, A., Garrett, A., Kenna, H., O'Hara, R., Schatzberg, A. F. 2015; 40 (4): 849-860

  Abstract

  Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the hypothalamic pituitary adrenal (HPA) axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting-state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized that this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation. Resting-state functional magnetic resonance imaging (fMRI) scans were collected to observe low-frequency resting-state functional connectivity patterns of the hypothalamus in 39 healthy participants, 39 patients with major depression, and 22 patients with major depression with psychotic symptoms. Hourly overnight measures of cortisol secretion and multiple measures of psychiatric symptom severity were also collected on all. Strong hypothalamic functional connectivity with the subgenual cortex was observed in healthy participants. This connectivity was significantly reduced in patients with psychotic major depression. Increased cortisol secretion during the circadian nadir and reduced connectivity were both associated with symptom severity. Reduced connectivity and high cortisol secretion during the circadian nadir are both useful for explaining a significant amount of variance in symptom severity that occurs between healthy participants and depressed patients. However, only cortisol secretion was useful for explaining the severity of symptoms within the depressed groups. This study suggests that the communication between the hypothalamus and the subgenual cortex is disrupted in patients with major depression with psychotic features. It also suggests that these disruptions are associated with increased symptom severity and may be a cause or a consequence of cortisol dysregulation.

  View details for DOI 10.1038/npp.2014.259

  View details for PubMedID 25292261

  View details for PubMedCentralID PMC4330499

• Plasma oxytocin concentrations are lower in depressed vs. healthy control women and are independent of cortisol. Journal of psychiatric research Yuen, K. W., Garner, J. P., Carson, D. S., Keller, J., Lembke, A., Hyde, S. A., Kenna, H. A., Tennakoon, L., Schatzberg, A. F., Parker, K. J. 2014; 51: 30-36

  Abstract

  The neuropeptide oxytocin (OT) promotes social behavior and attenuates stress responsivity in mammals. Recent clinical evidence suggests OT concentrations may be dysregulated in major depression. This study extends previous research by testing whether: 1) OT concentrations vary systematically in depressive disorders with and without hypercortisolemia, 2) gender differences in OT concentrations are observed in depressed vs. healthy control participants, and 3) OT concentrations are predictive of clinical phenotypes. Plasma OT concentrations of psychotic major depressive (PMD; n = 14: 10 female, 4 male), non-psychotic major depressive (NPMD; n = 17: 12 female, 5 male), and non-depressed, healthy control (n = 19: 11 female, 8 male) participants were assayed at 2000, 2400, 0400, and 0800 h. Plasma cortisol concentrations were quantified at 2300 h, and clinical phenotypes were determined. As expected, PMD participants, compared to NPMD and healthy control participants, showed higher plasma cortisol concentrations. Although both depressed groups showed similar OT concentrations, a significant interaction effect between group and gender was observed. Specifically, depressed females exhibited lower mean OT concentrations than depressed males. Further, depressed vs. healthy control female participants exhibited lower mean OT concentrations, whereas depressed vs. healthy control male participants showed a trend in the opposite direction. OT concentrations were also predictive of desirability, drug dependence, and compulsivity scores as measured by the Million Clinical Multiaxial Inventory-III. All findings were independent of cortisol. These data suggest that OT signaling may provide a mechanism by which to better understand female-biased risk to develop depressive disorders and that plasma OT concentrations may be a useful biomarker of certain clinical phenotypes.

  View details for DOI 10.1016/j.jpsychires.2013.12.012

  View details for PubMedID 24405552

• Insular cortex abnormalities in psychotic major depression: relationship to gender and psychotic symptoms. Neuroscience research Cohen, J. D., Nichols, T., Keller, J., Gomez, R. G., Schatzberg, A. F., Reiss, A. L. 2013; 75 (4): 331-339

  Abstract

  Recent data suggests that psychotic major depression (PMD) may be a discrete disorder distinguishable from nonpsychotic major depression (NPMD), and that patients with PMD may be more similar to individuals with schizophrenia than individuals with NPMD. The insula is a brain region in which morphometric changes have been associated with psychotic symptom severity in schizophrenia and affective psychosis. It was hypothesized that insular volumes would be reduced in PMD compared to NPMD and controls, and insular volumes would correlate with psychosis but not depression severity. Insular gray matter volumes were measured in PMD and NPMD patients and matched healthy controls using magnetic resonance images and manual morphometry. Clinical measures of illness severity were obtained to determine their relationship with insular volume. Posterior insular volumes were significantly reduced in PMD compared to HC. There were also significant group-by-gender interactions for total, anterior and posterior insular volumes. Using Pearson product-moment correlations, anterior insular volumes did not correlate with depression severity. Left anterior insular volume was significantly correlated with total and positive symptom psychosis severity in the PMD group. Atypical insular morphometry may be related to the inability to distinguish between internally and externally generated sensory inputs characteristic of psychosis.

  View details for DOI 10.1016/j.neures.2013.02.005

  View details for PubMedID 23471015

  View details for PubMedCentralID PMC3662543

• Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression. Psychiatry research Kelley, R., Garrett, A., Cohen, J., Gomez, R., Lembke, A., Keller, J., Reiss, A. L., Schatzberg, A. 2013; 211 (2): 119-126

  Abstract

  Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either "man-made" or "not man-made." For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits.

  View details for DOI 10.1016/j.pscychresns.2012.06.008

  View details for PubMedID 23149036

  View details for PubMedCentralID PMC3645926

• Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression PSYCHIATRY RESEARCH-NEUROIMAGING Kelley, R., Garrett, A., Cohen, J., Gomez, R., Lembke, A., Keller, J., Reiss, A. L., Schatzberg, A. 2013; 211 (2): 119-126

  Abstract

  Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either "man-made" or "not man-made." For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits.

  View details for DOI 10.1016/j.pscychresns.2012.06.008

  View details for Web of Science ID 000316828400004

  View details for PubMedID 23149036

  View details for PubMedCentralID PMC3645926

• The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary-adrenal activity in humans with psychotic major depression PSYCHONEUROENDOCRINOLOGY Lembke, A., Gomez, R., Tenakoon, L., Keller, J., Cohen, G., Williams, G. H., Kraemer, F. B., Schatzberg, A. F. 2013; 38 (1): 115-121

  Abstract

  Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs).Fourteen PMDs, 16 NPMDs, and 19 HCs were admitted to the Stanford University Hospital General Clinical Research Center. Serum cortisol levels were sampled at baseline and every hour from 18:00 to 23:00h, when greatest MR activity is expected, on two consecutive nights. On the second afternoon at 16:00h all subjects were given 0.5mg fludrocortisone. Mean cortisol levels pre- and post-fludrocortisone and percent change in cortisol levels were computed.There were no significant group differences for cortisol at baseline: F(2,47)=.19, p=.83. There were significant group differences for post-fludrocortisone cortisol: F(2,47)=5.13, p=.01, which were significantly higher in PMDs compared to HCs (p=.007), but not compared to NPMDs (p=.18). There were no differences between NPMD's and HC's (p=.61). Also, PMDs had a lower percent change from baseline in cortisol levels at 2200h than NPMDs (p=.01) or HCs (p=.009).Individuals with psychotic major depression compared to healthy control subjects have diminished feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in response to the mineralocorticoid receptor agonist fludrocortisone. To our knowledge, this is the first study to examine HPA axis response to MR stimulation in major depression (with and without psychosis), and only the third study to demonstrate that exogenously administered fludrocortisone can down-regulate the HPA axis in humans.

  View details for DOI 10.1016/j.psyneuen.2012.05.006

  View details for Web of Science ID 000313761000011

  View details for PubMedID 22727477

  View details for PubMedCentralID PMC3633490

• The relationships of positive and negative symptoms with neuropsychological functioning and their ability to predict verbal memory in psychotic major depression PSYCHIATRY RESEARCH Che, A. M., Gomez, R. G., Keller, J., Lembke, A., Tennakoon, L., Cohen, G. H., Schatzberg, A. F. 2012; 198 (1): 34-38

  Abstract

  Neuropsychological functioning, in relation to positive and negative symptoms in psychotic major depression (PMD), has not been as thoroughly studied as it has been in schizophrenia. Thus, the current study investigated the associations between positive and negative symptoms with cognitive functioning, with an emphasis on verbal memory in PMD. Attention, working memory, and the executive functioning domains were analyzed among 49 PMD participants. Positive symptoms did not correlate significantly with any measures of verbal memory but did correlate with one measure of attention, working memory, and executive functioning. Negative symptoms correlated significantly with two California Verbal Learning Test-II (CVLT-II) measures of verbal memory and three measures of executive function. Hierarchical regressions were conducted to determine if negative symptoms could predict verbal memory performance after controlling for depression. Of the two verbal memory measures, negative symptoms significantly explained additional variance for CVLT Recognition, but not for CVLT Trials 1-5 total score. Our results provide some evidence that, consistent with the schizophrenia literature, negative symptoms contributed more to verbal memory deficits in PMD than positive symptoms, regardless of depression severity.

  View details for DOI 10.1016/j.psychres.2011.12.001

  View details for Web of Science ID 000313848200007

  View details for PubMedID 22410589

• Aberrant Brain Activation During a Working Memory Task in Psychotic Major Depression AMERICAN JOURNAL OF PSYCHIATRY Garrett, A., Kelly, R., Gomez, R., Keller, J., Schatzberg, A. F., Reiss, A. L. 2011; 168 (2): 173-182

  Abstract

  The authors sought to better understand the neural circuitry associated with working memory deficits in psychotic major depression by examining brain function during an N-back task.Study subjects were 16 patients with psychotic major depression, 15 patients with nonpsychotic major depression, and 19 healthy comparison subjects. Functional MRI data were collected while participants responded to letter stimuli that were repeated from the previous trial (1-back) or the one before that (2-back).Relative to the healthy comparison group, both the psychotic and nonpsychotic major depression groups had significantly greater activation in the right parahippocampal gyrus during the 2-back task, and the psychotic major depression group showed this overactivation during the 1-back task as well. The nonpsychotic major depression group showed significantly lower activation than other groups in the right dorsolateral prefrontal cortex and greater activation than the healthy comparison group in the superior occipital cortex. The psychotic major depression group was unique in showing greater activation than both other groups in the right temporoparietal junction, a cluster that also demonstrated connectivity with activation in the left prefrontal cortex.The psychotic major depression group showed aberrant parahippocampal activation at a lower demand level than observed in nonpsychotic major depression. While the nonpsychotic major depression group showed abnormalities in frontal executive regions, the psychotic major depression group showed abnormalities in temporoparietal regions associated with orienting to unexpected stimuli. Considering the functional connectivity of this cluster with left dorsolateral prefrontal cortex regions, these findings may reflect neural compensation for sensory gating deficits in psychotic major depression.

  View details for DOI 10.1176/appi.ajp.2010.09121718

  View details for Web of Science ID 000286972800011

  View details for PubMedID 21078708

• Preliminary evidence that plasma oxytocin levels are elevated in major depression PSYCHIATRY RESEARCH Parker, K. J., Kenna, H. A., Zeitzer, J. M., Keller, J., Blasey, C. M., Amico, J. A., Schatzberg, A. F. 2010; 178 (2): 359-362

  Abstract

  It is well established that the neuropeptide oxytocin (OT) is involved in regulating social behavior, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis physiology in mammals. Because individuals with major depression often exhibit functional irregularities in these measures, we test in this pilot study whether depressed subjects (n=11) exhibit dysregulated OT biology compared to healthy control subjects (n=19). Subjects were hospitalized overnight and blood samples were collected hourly between 1800 and 0900h. Plasma levels of OT, the closely related neuropeptide argine-vasopressin (AVP), and cortisol were quantified. Results indicated that depressed subjects exhibit increased OT levels compared to healthy control subjects, and this difference is most apparent during the nocturnal peak. No depression-related differences in AVP or cortisol levels were discerned. This depression-related elevation in plasma OT levels is consistent with reports of increased hypothalamic OT-expressing neurons and OT mRNA in depressed patients. This present finding is likewise consistent with the hypothesis that dysregulated OT biology may be a biomarker of the emotional distress and impaired social relationships which characterize major depression. Additional research is required to elucidate the role of OT in the pathophysiology of this psychiatric disorder.

  View details for DOI 10.1016/j.psychres.2009.09.017

  View details for Web of Science ID 000279988900025

  View details for PubMedID 20494448

  View details for PubMedCentralID PMC2902664

• Semantic processing of emotional words in depression and schizophrenia INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY Klumpp, H., Keller, J., Miller, G. A., Casas, B. R., Best, J. L., Deldin, P. J. 2010; 75 (2): 211-215

  Abstract

  Major depressive disorder is associated with dysfunction in brain regions involved in language and emotion processing. Despite evidence of emotion processing biases in depression, neurophysiological evidence of language dysfunction for emotional words in depression has been inconsistent. This series of three studies evaluated whether depressed individuals exhibited abnormal semantic processing of emotionally-valenced words. During the passive viewing of sentences with mood congruent and incongruent sentence endings, the N400 component of the event-related brain potential was measured in patients with depression, dysthymia, or schizophrenia and in healthy controls. In each study, results revealed normal semantic processing in depression. That is, N400 was similar for both mood-incongruent (positive and neutral) endings and mood-congruent (negative) endings. In contrast, the small sample of individuals with schizophrenia exhibited a significantly exaggerated N400 for negative word endings compared to the depressed and healthy control groups. These data suggest anomalies in semantic network interactions with emotion processing in schizophrenia.

  View details for DOI 10.1016/j.ijpsycho.2009.12.004

  View details for Web of Science ID 000275700800016

  View details for PubMedID 20006969

• CURRENT ISSUES IN THE CLASSIFICATION OF PSYCHOTIC MAJOR DEPRESSION Conference on Deconstructing Psychosis Keller, J., Schatzberg, A. F., Maj, M. AMER PSYCHIATRIC PRESS, INC. 2010: 29–44

  View details for Web of Science ID 000294244000004

• Effects of major depression diagnosis and cortisol levels on indices of neurocognitive function PSYCHONEUROENDOCRINOLOGY Gomez, R. G., Posener, J. A., Keller, J., DeBattista, C., Solvason, B., Schatzberg, A. F. 2009; 34 (7): 1012-1018

  Abstract

  Although many studies have examined separately the effects of depression and cortisol on cognition, no study has examined their relative or potentially additive effects. Our study simultaneously investigated the contributions of clinical status [major depression (MD) versus psychiatrically healthy controls (HC)] and cortisol on a hippocampal/mediotemporal mediated verbal memory task (Paragraph Recall) and a prefrontal cortex/cingulate mediated executive functioning task (Stroop). Thirty-seven unmedicated nondelusional MDs and 18 HCs underwent psychiatric ratings, hourly assessments of cortisol activity over 24 h, and neuropsychological assessments. Hierarchical multiple regressions indicated a significant effect of cortisol but not of diagnosis on verbal memory. Greater cortisol levels were related to poorer memory performance independent of group. In contrast, a significant interaction between cortisol and diagnosis was found for a color-word index of response inhibition. This interaction suggests that the detrimental effect of elevated cortisol level on this type of executive functioning exists only in the healthy control group but not in MDs. On an Interference score, another measure of response inhibition, cortisol had a significant independent effect, but neither the effects of diagnosis and the interaction attained full significance. Our study suggests that cortisol has an independent effect on verbal memory. Also, our study produced evidence of an interaction between diagnosis and cortisol on response inhibition.

  View details for DOI 10.1016/j.psyneuen.2009.01.017

  View details for Web of Science ID 000267471900008

  View details for PubMedID 19261389

• Impact of clinician gender on examination anxiety among female veterans with sexual trauma: A pilot study JOURNAL OF WOMENS HEALTH Lee, T. T., Westrup, D. A., Ruzek, J. I., Keller, J., Weitlauf, J. C. 2007; 16 (9): 1291-1299

  Abstract

  The sequelae of sexual trauma, including symptoms or diagnosis of posttraumatic stress disorder (PTSD), may impact women's anxiety and avoidance of preventive healthcare measures such as breast, pelvic, and rectal examinations. As sexual trauma is unfortunately a common occurrence among female patients, particularly veterans, understanding how it influences examination-related distress may improve provision of care to this population. We explored the impact of clinician gender and examination type (breast, pelvic, rectal, and dental) on anticipated examination-related anxiety among women veterans with a history of sexual trauma.We present a cross-sectional pilot study that examines anticipated examination-related distress among 31 female veterans with a history of sexual trauma. Sexual trauma history was verified by chart review. Self-report instruments assessed patient demographics and patients' anticipated anxiety during breast, pelvic, rectal, and dental examinations (stratified by gender of clinician). The PTSD Checklist-Civilian Version (PCL-C) assessed symptom severity.The women reported significantly more anticipated anxiety during breast, pelvic, and rectal examinations, (p < 0.05) when clinician gender was male. Severity of PTSD symptoms was generally unrelated to anticipated examination-related anxiety.Anticipated anxiety was found to be a function of both examination type and clinician gender but not of PTSD symptom severity. These findings emphasize the importance of screening for sexual trauma and the careful consideration of female veterans' unique needs during sensitive medical procedures.

  View details for DOI 10.1089/jwh.2006.0208

  View details for Web of Science ID 000251174900006

  View details for PubMedID 18001185

• Current issues in the classification of psychotic major depression Conference on Deconstructing Psychosis Keller, J., Schatzberg, A. F., Maj, M. OXFORD UNIV PRESS. 2007: 877–85

  Abstract

  Depression is one of the most common mental disorders worldwide. There are a number of depression subtypes, and there has been much debate about how to most accurately capture and organize the features and subtypes of major depression. We review the current state of categorizing unipolar major depression with psychotic features (psychotic major depression, PMD), including clinical, biological, and treatment aspects of the disorder. We then propose some improvements to the current unipolar major depression categorization system. Finally, we identify important issues in need of further research to help elucidate the subtype of unipolar PMD.

  View details for DOI 10.1093/schbul/sbm065

  View details for Web of Science ID 000248178800009

  View details for PubMedID 17548842

  View details for PubMedCentralID PMC2632329

• Empirically assessing participant perceptions of the research experience in a randomized clinical trial: The Women's Self-Defense Project as a case example JOURNAL OF EMPIRICAL RESEARCH ON HUMAN RESEARCH ETHICS Weitlauf, J. C., Ruzek, J. I., Westrup, D. A., Lee, T., Keller, J. 2007; 2 (2): 11-23

  Abstract

  A growing body of empirical literature has systematically documented the reactions to research participation among participants in traumafocused research. To date, the available data has generally presented an optimistic picture regarding participants' ability to tolerate and even find benefit from their participation. However, this literature has been largely limited to cross-sectional designs. No extant literature has yet examined the perceptions of participants with psychiatric illness who are participating in randomized clinical trials (RCTs) designed to evaluate the efficacy or effectiveness of novel trauma treatments. The authors posit that negative experiences of, or poor reactions to, the research experience in the context of a trauma-focused RCT may elevate the risk of participation. Indeed, negative reactions may threaten to undermine the potential therapeutic gains of participants and promoting early drop out from the trial. Empirically assessing reactions to research participation at the pilot-study phase of a clinical trial can both provide investigators and IRB members alike with empirical evidence of some likely risks of participation. In turn, this information can be used to help shape the design and recruitment methodology of the full-scale trial. Using data from the pilot study of the Women's Self-Defense Project as a case illustration, we provide readers with concrete suggestions for empirically assessing participants' perceptions of risk involved in their participation in behaviorally oriented clinical trials.

  View details for DOI 10.1525/JERHRE.2007.2.2.11

  View details for PubMedID 19385792

• Dissociable intrinsic connectivity networks for salience processing and executive control JOURNAL OF NEUROSCIENCE Seeley, W. W., Menon, V., Schatzberg, A. F., Keller, J., Glover, G. H., Kenna, H., Reiss, A. L., Greicius, M. D. 2007; 27 (9): 2349-2356

  Abstract

  Variations in neural circuitry, inherited or acquired, may underlie important individual differences in thought, feeling, and action patterns. Here, we used task-free connectivity analyses to isolate and characterize two distinct networks typically coactivated during functional MRI tasks. We identified a "salience network," anchored by dorsal anterior cingulate (dACC) and orbital frontoinsular cortices with robust connectivity to subcortical and limbic structures, and an "executive-control network" that links dorsolateral frontal and parietal neocortices. These intrinsic connectivity networks showed dissociable correlations with functions measured outside the scanner. Prescan anxiety ratings correlated with intrinsic functional connectivity of the dACC node of the salience network, but with no region in the executive-control network, whereas executive task performance correlated with lateral parietal nodes of the executive-control network, but with no region in the salience network. Our findings suggest that task-free analysis of intrinsic connectivity networks may help elucidate the neural architectures that support fundamental aspects of human behavior.

  View details for DOI 10.1523/JNEUROSCI.5587-06.2007

  View details for Web of Science ID 000244758500023

  View details for PubMedID 17329432

  View details for PubMedCentralID PMC2680293

• Reply: Clinical and biological effects of mifepristone treatment for psychotic treatment - Reply to Carroll and Rubin NEUROPSYCHOPHARMACOLOGY Keller, J., Schatzberg, A. F. 2006; 31 (12): 2795-2797

  View details for DOI 10.1038/sj.npp.1301171

  View details for Web of Science ID 000242046800025

• The neuropsychological profile of psychotic major depression and its relation to cortisol BIOLOGICAL PSYCHIATRY Gomez, R. G., Fleming, S. H., Keller, J., Flores, B., Kenna, H., DeBattista, C., Solvason, B., Schatzberg, A. F. 2006; 60 (5): 472-478

  Abstract

  Our study described the neuropsychological profile of psychotic major depression (PMD) compared to nonpsychotic major depression (NPMD) patients and psychiatrically healthy controls (HC). We predicted that higher cortisol levels would be associated with greater cognitive deficits.Twenty-nine PMDs, 24 NPMDs, and 26 HCs were recruited at Stanford University Medical Center. Psychiatric ratings, cortisol levels from 1800-0900 hours, and neuropsychological test data were obtained.PMDs had more severe cognitive impairments compared with NPMDs and HCs with the exception of simple verbal attention. PMDs had elevated mean cortisol levels from 1800 to 0100 hours which were significantly correlated with poorer verbal memory and psychomotor speed performance. Cortisol slopes from 1800 to 0100 hours were also significantly correlated with verbal memory and working memory.While PMDs' ability to attend passively to information appears intact, they have more difficulty processing, manipulating, and encoding new information. Elevated cortisol levels, as seen in PMD patients, are associated with poorer cognitive performance especially related to verbal memory for lists of words and working memory.

  View details for DOI 10.1016/j.biopsych.2005.11.010

  View details for Web of Science ID 000240506000007

  View details for PubMedID 16483550

• 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

• Clinical and biological effects of mifepristone treatment for psychotic depression NEUROPSYCHOPHARMACOLOGY Flores, B. H., Kenna, H., Keller, J., Solvason, H. B., Schatzberg, A. F. 2006; 31 (3): 628-636

  Abstract

  Psychotic major depression (PMD) is found to be a relatively common psychiatric condition that affects up to nearly 20% of patients with major depression. Previous studies by our group have shown rapid reversal of psychotic symptoms in some PMD patients treated with mifepristone, in addition to restoring a more normal afternoon cortisol release. The rationale for treating patients with PMD with a glucocorticosteroid receptor antagonist is further discussed. In total, 30 patients with PMD were treated with either 600 mg/day mifepristone or placebo for 8 days in a randomized double-blind manner. The Hamilton Depression Rating Scale (HDRS) and the Brief Psychiatric Rating Scale (BPRS) were administered at baseline and again after 8 days of treatment. Cortisol and ACTH were measured hourly from 1800 to 0900 at baseline and after 8 days of treatment. Significantly, more patients in the mifepristone group (seven of 15) showed a 50% or greater decline on the BPRS positive symptom subscale, an index of psychotic symptoms, as compared to the placebo group (two of 15). Patients who received mifepristone had lower HDRS and BPRS scores at study completion compared to those who received placebo, but these differences were not statistically significant. In addition, mifepristone significantly elevated cortisol and ACTH levels and steepened ascending slopes from 1800 to 0100 and from 0100 to 0900 as compared to placebo. Clinical and biological effects of mifepristone were comparable among males and females. Age was found to significantly and positively correlate with changes in cortisol and ACTH. These results suggest that short-term use of mifepristone may be effective in the treatment of PMD and may re-regulate the HPA axis. Additional blinded studies are warranted.

  View details for DOI 10.1038/sj.npp.1300884

  View details for Web of Science ID 000236141600015

  View details for PubMedID 16160710

• Detecting psychotic major depression using psychiatric rating scales JOURNAL OF PSYCHIATRIC RESEARCH Keller, J., Gomez, R. G., Kenna, H. A., Poesner, J., Debattista, C., Flores, B., Schatzberg, A. F. 2006; 40 (1): 22-29

  Abstract

  The aim of this study was to assess whether individual or clusters of psychiatric symptoms can differentiate patients with psychotic major depression (PMD) from those with nonpsychotic depression (NPMD).Data were pooled from two studies investigating patients with moderate depression. A total of 129 subjects were studied. Patients in Sample 1 were unmedicated, while the majority of the patients in Sample 2 were taking psychotropic medications. Baseline rating scales were obtained for all subjects, including the Hamilton depression rating scale and the brief psychiatric rating scale (BPRS). We used discriminant function analyses, logistic regression, and ROC analyses to determine the patterns in symptoms that differentiated the groups.Psychotic patients were adequately differentiated by the unusual thought content (UTC) item of the BPRS. Even mild UTC endorsement was an indicator of PMD. Furthermore, results suggest that the positive symptom subscale of the BPRS was even better at differentiating PMD from NMPD patients. Sensitivity and specificity for this scale were 84% and 99%, respectively.Psychotic major depression is often undiagnosed and poorly treated. One reason for this trend is the failure of physicians to inquire in a more detailed manner about positive symptoms in patients with primary mood symptoms. Although physicians are not likely to have the time to conduct an entire BPRS during an evaluation, our results suggest that a few key symptoms, if assessed directly, may aid the psychiatrist to more effectively diagnose and subsequently treat their depressed patients.

  View details for DOI 10.1016/j.jpsychires.2005.07.003

  View details for Web of Science ID 000235466200002

  View details for PubMedID 16165160

• Normal N400 in mood disorders BIOLOGICAL PSYCHOLOGY Deldin, P., Keller, J., Casas, B. R., Best, J., Gergen, J., MILLER, G. A. 2006; 71 (1): 74-79

  Abstract

  Individuals diagnosed with major depression have been characterized as having a variety of cognitive problems based on a number of behavioral and psychophysiological measures, but it is not clear whether there is a consistent language processing abnormality in depression. Three studies sought to determine whether diverse mood disordered samples show abnormal semantic processing, as indexed by a failure to show increased N400 event-related brain potential amplitudes to passively viewed incongruent, relative to congruent sentence endings. Individuals with major depression (N = 50) or dysthymia (N = 14) had N400 amplitudes similar to those of controls (N = 41) in this sentence processing paradigm. These results are consistent with a small behavioral literature suggesting intact semantic processing in depression and further indicate that abnormal controlled processing in some tasks does not simply reflect a generalized deficit.

  View details for DOI 10.1016/j.biopsycho.2005.02.005

  View details for Web of Science ID 000234530500009

  View details for PubMedID 15885876

• I Got My Life Back! Making a Case for Self Defense Training for Older Women with PTSD. Clinical Gerontologist Westrup D, Weitlauf J, Keller J 2005; 28 (3): 113-118
• Cognitive bias and emotion in neuropsychological models of depression COGNITION & EMOTION Deldin, P. J., Keller, J., Gergen, J. A., MILLER, G. A. 2001; 15 (6): 787-802

  View details for Web of Science ID 000171618800005

• Cognitive bias and emotion in neuropsychological models of depression Cognition & Emotion Deldin, P., Keller, J., Gergen, J.A., Miller, G.A. 2001; 15 (6): 787-802
• Right-posterior face processing anomaly in depression JOURNAL OF ABNORMAL PSYCHOLOGY Deldin, P. J., Keller, J., Gergen, J. A., MILLER, G. A. 2000; 109 (1): 116-121

  Abstract

  Evidence of a right-posterior brain anomaly was found in a study of 19 individuals with major depression and 15 controls. Participants performed a recognition-memory task involving positive, neutral, and negative face and word stimuli. Scalp brain wave topography suggested a region-specific anomaly in the depressed group. Individuals with major depression demonstrated a reduction in the N200 component of the event-related brain potential to faces and not words. Furthermore, results indicate that the regional anomaly is specific to positive facial stimuli. Findings are interpreted in light of a model of regional brain specialization in emotion and psychopathology.

  View details for Web of Science ID 000085841400013

  View details for PubMedID 10740942

• Neuropsychological differentiation of depression and anxiety JOURNAL OF ABNORMAL PSYCHOLOGY Keller, J., Nitschke, J. B., Bhargava, T., Deldin, P. J., Gergen, J. A., Miller, G. A., Heller, W. 2000; 109 (1): 3-10

  Abstract

  The high comorbidity of depression and anxiety is well established empirically but not well understood conceptually, in terms of either psychological or biological mechanisms. A neuropsychological model of regional brain activity in emotion provides contrasting hypotheses for depression and anxiety, with depression associated with a relative decrease and anxiety with a relative increase in right-posterior activity. These hypotheses received support in a comparison of individuals diagnosed with depression and community controls, and also in a separate study of nonpatients administered a measure of perceptual asymmetry. Hierarchical regressions revealed that depression and anxiety were uniquely and jointly associated with perceptual asymmetry. In light of consistent empirical support for the model, implications for conceptualizations of the comorbidity of depression and anxiety are discussed.

  View details for Web of Science ID 000085841400001

  View details for PubMedID 10740930

• Psychology and neuroscience: Making peace Current Directions in Psychological Science Miller, G., Keller, Jennifer 2000; 9 (6): 212-215
• Converging evidence for a cognitive anomaly in early psychopathology PSYCHOPHYSIOLOGY Fernandes, L. O., Keller, J., Giese-Davis, J. E., Hicks, B. D., Klein, D. N., MILLER, G. A. 1999; 36 (4): 511-521

  Abstract

  Subcomponents of the N200 component of the event-related brain potential believed to be differentially sensitive to involuntary and voluntary cognitive processes were examined. Nonpatients (N = 131) identified initially by the Chapman and Depue research scales and classified later on the basis of diagnostic symptom clusters and family psychiatric history provided converging evidence for an intact mismatch negativity subcomponent. In contrast, the N2b subcomponent distinguished several groups of subjects. Results suggested abnormal voluntary cognitive processing, perhaps reflecting compensatory efforts in subjects at risk for or manifesting psychopathology, particularly those showing negative symptoms.

  View details for Web of Science ID 000081470300011

  View details for PubMedID 10432801