- Psychosomatic Medicine
- Consultation Liaison Psychiatry
Associate Professor - University Medical Line, Psychiatry and Behavioral Sciences - Medical Psychiatry
Member, Wu Tsai Neurosciences Institute
Honors & Awards
NIH Research Project Grant (R01), National Institute of Mental Health (2020-2024)
Visiting Professorship Award, Academy of Consultation Liaison Psychiatry (2019)
Dlin/Fischer Clinical Research Award, Academy of Consultation Liaison Psychiatry (2018)
Inventor Award, University of Iowa (2018)
NSF I-Corp Award, National Science Foundation (2016-2017)
Inventor Award, University of Iowa (2016)
Startup Launched Award, University of Iowa (2016)
NIH Mentored Patient-Oriented Research Career Development Award (K23), National Institute of Mental Health (2015-2019)
UI Venture Gap Funding Award, University of Iowa Research Foundation (2015-2017)
Helen Johnson Scholar in Informatics, University of Iowa (2014-2016)
William Webb Fellowship Award, Academy of Psychosomatic Medicine (2008-2009)
Research Colloquium for Junior Investigators, American Psychiatric Association (2008, 2009, 2010)
Departmental Small Grant Award, Mayo Clinic Department of Psychiatry and Psychology (2008)
Howard P. Rome Resident Academic Writing Award, Mayo Clinic Department of Psychiatry and Psychology (2008)
Howard P. Rome Resident Grand Rounds Award, Mayo Clinic Department of Psychiatry and Psychology (2008)
Resident Fellowship Award, Academy of Occupational and Organization Psychiatry (2007)
Scholarship Award, Noguchi Medical Institute (2004-2005)
Boards, Advisory Committees, Professional Organizations
Distinguished Fellow, American Psychiatric Association (2018 - Present)
Fellow, Academy of Consultation Liaison Psychiatry (2013 - Present)
Research Committee, Academy of Consultation Liaison Psychiatry (2011 - Present)
Research Committee, American Delirium Society (2019 - Present)
Editorial Board, Psychiatry and Clinical Neurosciences (2018 - Present)
Editorial Board, PLOS One (2018 - Present)
Fellowship: Mayo Clinic - Rochester (2009) MN
Residency: Mayo Clinic - Rochester (2008) MN
Board Certification: American Board of Psychiatry and Neurology, Psychosomatic Medicine (2011)
Board Certification: American Board of Psychiatry and Neurology, Psychiatry (2009)
Internship: US Naval Hospital Okinawa (2003) Japan
Medical Education: University of Yamanashi (2002) Japan
DNA methylation in the TNF-alpha gene decreases along with aging among delirium inpatients.
Neurobiology of aging
2021; 105: 310-317
It has been suggested that aging and inflammation play key roles in the development of delirium. In the present study, we investigated the differences of the DNAm patterns in the TNF gene between patients with delirium and without. The data and samples derived from previous and ongoing cohort studies were analyzed. DNAm levels of the TNF gene were analyzed using the Illumina EPIC array genome-wide method and pyrosequencing method. Correlations between age and DNAm levels of each CpG were calculated. Several CpG in the TNF gene in blood showed negative correlation between their DNAm and age in delirium cases both with the EPIC array and by the pyrosequencing method. However, there was no CpG that had significant correlation between their DNAm and age regardless of delirium status among buccal samples. On the other hand, among peripheral blood mononuclear cells samples, it was found that several CpG showed negative correlation between their DNAm and age in delirium cases. The evidence of DNAm change in the TNF gene among delirious subjects was demonstrated.
View details for DOI 10.1016/j.neurobiolaging.2021.05.005
View details for PubMedID 34192631
New Cutoff Scores for Delirium Screening Tools to Predict Patient Mortality.
Journal of the American Geriatrics Society
2021; 69 (1): 140-147
Detecting delirium is important to identify patients with a high risk of poor outcomes. Although many different kinds of screening instruments for delirium exist, there is no solid consensus about which methods are the most effective. In addition, it is important to find the most useful tools in predicting outcomes such as mortality.Retrospective cohort study.University of Iowa Hospitals and Clinics.A total of 1,125 adult inpatients (mean age = 67.7; median age = 69).Post hoc analyses were performed based on existing data from the Confusion Assessment Method for Intensive Care Unit (CAM-ICU), Delirium Rating Scale-Revised-98 (DRS), and the Delirium Observation Screening Scale (DOSS). Correlation among these scales and relationships between 365-day mortality and each scale were evaluated.A positive result on the CAM-ICU ("CAM-ICU positive") was associated with higher DRS and DOSS scores. A DRS score = 9/10 was the best cutoff to detect CAM-ICU positive, and DOSS = 2/3 was the best cutoff to detect CAM-ICU positive. CAM-ICU positive was associated with high 365-day mortality. DRS score = 9/10 and DOSS score = 0/1 were found to differentiate mortality risk the most significantly. Higher DRS and DOSS scores significantly coincided with a decrease in a patient's survival rate at 365 days.The best DRS and DOSS cutoff scores to differentiate 365-day mortality risk were lower than those commonly used to detect delirium in the literature. New cutoff scores for the DRS and DOSS might be useful in differentiating risk of mortality among hospital patients.
View details for DOI 10.1111/jgs.16815
View details for PubMedID 32905636
Bispectral EEG (BSEEG) quantifying neuro-inflammation in mice induced by systemic inflammation: A potential mouse model of delirium.
Journal of psychiatric research
2021; 133: 205-211
Most of the animal studies using inflammation-induced cognitive change have relied on behavioral testing without objective and biologically solid methods to quantify the severity of cognitive disturbances. We have developed a bispectral EEG (BSEEG) method using a novel algorithm in clinical study. This method effectively differentiates between patients with and without delirium, and predict long-term mortality. In the present study, we aimed to apply our bispectral EEG (BSEEG) method, which can detect patients with delirium, to a mouse model of delirium with systemic inflammation induced by lipopolysaccharides (LPS) injection. We recorded EEG after LPS injection using wildtype early adulthood mice (2~3-month-old) and aged mice (18-19-month-old). Animal EEG recordings were converted for power spectral density to calculate BSEEG score using the similar BSEEG algorithm previously developed for our human study. The BSEEG score was relatively stable and slightly high during the day. Alternatively, the BSEEG score was erratic and low in average during the night. LPS injection increased the BSEEG score dose-dependently and diminished the diurnal changes. The mean BSEEG score increased much more in the aged mice group as dosage increased. Our results suggest that BSEEG method can objectively "quantify" level of neuro-Inflammation induced by systemic inflammation (LPS), and that this BSEEG method can be useful as a model of delirium in mice.
View details for DOI 10.1016/j.jpsychires.2020.12.036
View details for PubMedID 33360427
Topological data analysis (TDA) enhances bispectral EEG (BSEEG) algorithm for detection of delirium.
2021; 11 (1): 304
Current methods for screening and detecting delirium are not practical in clinical settings. We previously showed that a simplified EEG with bispectral electroencephalography (BSEEG) algorithm can detect delirium in elderly inpatients. In this study, we performed a post-hoc BSEEG data analysis using larger sample size and performed topological data analysis to improve the BSEEG method. Data from 274 subjects included in the previous study were analyzed as a 1st cohort. Subjects were enrolled at the University of Iowa Hospitals and Clinics (UIHC) between January 30, 2016, and October 30, 2017. A second cohort with 265 subjects was recruited between January 16, 2019, and August 19, 2019. The BSEEG score was calculated as a power ratio between low frequency to high frequency using our newly developed algorithm. Additionally, Topological data analysis (TDA) score was calculated by applying TDA to our EEG data. The BSEEG score and TDA score were compared between those patients with delirium and without delirium. Among the 274 subjects from the first cohort, 102 were categorized as delirious. Among the 206 subjects from the second cohort, 42 were categorized as delirious. The areas under the curve (AUCs) based on BSEEG score were 0.72 (1st cohort, Fp1-A1), 0.76 (1st cohort, Fp2-A2), and 0.67 (2nd cohort). AUCs from TDA were much higher at 0.82 (1st cohort, Fp1-A1), 0.84 (1st cohort, Fp2-A2), and 0.78 (2nd cohort). When sensitivity was set to be 0.80, the TDA drastically improved specificity to 0.66 (1st cohort, Fp1-A1), 0.72 (1st cohort, Fp2-A2), and 0.62 (2nd cohort), compared to 0.48 (1st cohort, Fp1-A1), 0.54 (1st cohort, Fp2-A2), and 0.46 (2nd cohort) with BSEEG. BSEEG has the potential to detect delirium, and TDA is helpful to improve the performance.
View details for DOI 10.1038/s41598-020-79391-y
View details for PubMedID 33431928
View details for PubMedCentralID PMC7801387
Mortality prediction by bispectral electroencephalography among 502 patients: its role in dementia.
2021; 3 (2): fcab037
Complications of delirium and dementia increase mortality; however, it is difficult to diagnose delirium accurately, especially among dementia patients. The bispectral electroencephalography score can detect delirium and predict mortality in elderly patients. We aimed to develop an efficient and reliable bispectral electroencephalography device for high-throughput screening. We also hypothesized that bispectral electroencephalography score can predict mortality among dementia patients. A prospective cohort study was conducted between January 2016 and December 2018 to measure bispectral electroencephalography from elderly patients and correlate with outcomes. A total of 502 elderly (55 years old or older) patients with and without dementia were enrolled. For a replication of the utility of bispectral electroencephalography, mortalities between bispectral electroencephalography-positive and bispectral electroencephalography-negative group were compared. In addition, patients with and without dementia status were added to examine the utility of bispectral electroencephalography among dementia patients. The mortality within 180 days in the bispectral electroencephalography-positive group was higher than that of the bispectral electroencephalography-negative group in both the replication and the total cohorts. Mortality of those in the bispectral electroencephalography-positive group showed a dose-dependent increase in both cohorts. When the dementia patients showed bispectral electroencephalography positive, their mortality was significantly higher than those with dementia but who were bispectral electroencephalography-negative. Mortality within 30 days in the bispectral electroencephalography-positive group was significantly higher than that of the bispectral electroencephalography-negative group. The utility of the bispectral electroencephalography to predict mortality among large sample of 502 elderly patients was shown. The bispectral electroencephalography score can predict mortality among elderly patients in general, and even among dementia patients, as soon as 30 days.
View details for DOI 10.1093/braincomms/fcab037
View details for PubMedID 34136808
View details for PubMedCentralID PMC8204260
The relationship between DNA methylation in neurotrophic genes and age as evidenced from three independent cohorts: differences by delirium status.
Neurobiology of aging
2020; 94: 227-235
We previously reported the association between DNA methylation (DNAm) of pro-inflammatory cytokine genes and age. In addition, neurotrophic factors are known to be associated with age and neurocognitive disorders. Therefore, we hypothesized that DNAm of neurotrophic genes change with age, especially in delirium patients. DNAm was analyzed using the Illumina HumanMethylation450 or HumanMethylationEPIC BeadChip Kit in 3 independent cohorts: blood from 383 Grady Trauma Project subjects, brain from 21 neurosurgery patients, and blood from 87 inpatients with and without delirium. Both blood and brain samples showed that most of the DNAm of neurotrophic genes were positively correlated with age. Furthermore, DNAm of neurotrophic genes was more positively correlated with age in delirium cases than in non-delirium controls. These findings support our hypothesis that the neurotrophic genes may be epigenetically modulated with age, and this process may be contributing to the pathophysiology of delirium.
View details for DOI 10.1016/j.neurobiolaging.2020.06.003
View details for PubMedID 32650186
View details for PubMedCentralID PMC7444651
Bispectral EEG (BSEEG) to assess arousal after electro-convulsive therapy (ECT).
2020; 285: 112811
Postictal confusion is encountered among most patients following electro-convulsive therapy (ECT). This study aimed to test the capabilities of a point-of-care electroencephalography (EEG) method to quantitatively measure and monitor postictal confusion immediately following ECT. We evaluated whether a two-channel frontal EEG device may provide a purely quantitative measure of the postictal state that could aid in the continuous, clinical monitoring of patients following ECT.50 patients receiving ECT at the University of Iowa Hospitals and Clinics were recruited for this study. Subsequently, we obtained 5 min of frontal bispectral EEG (BSEEG) recording from a hand-held EEG device at baseline and 10-20 min following ECT. We performed power spectral density analysis to yield a "BSEEG" score and to capture the difference between patients at baseline and after ECT.The BSEEG score was demonstrated to be a significant indicator of postictal confusion compared to baseline. For 5 patients, we also obtained continuous EEG recordings following ECT to determine the time course required for a patient's BSEEG score to return to baseline. In this subset of patients, it took between 2 and 3 h in duration for the BSEEG score to return to the baseline range.In this pilot study, we showed that BSEEG score was able to distinguish between baseline condition and postictal confusion in patients treated with ECT, and assess the duration for recovery from postictal confusion following ECT. BSEEG may provide a more sensitive measure of arousal in patients following ECT compared to traditional survey-based methods.
View details for DOI 10.1016/j.psychres.2020.112811
View details for PubMedID 32032823
View details for PubMedCentralID PMC7605101
Epigenetics of neuroinflammation: Immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients.
Journal of psychiatric research
2020; 129: 61-65
Previously our study has shown that the DNA methylation (DNAm) levels at CpG sites in the pro-inflammatory cytokine gene, TNF-alpha, decrease along with aging, suggesting the potential role of DNAm in aging and heightened inflammatory process leading to increased risk for delirium. However, DNAm differences between delirium cases and non-delirium controls have not been investigated directly. Therefore, we examined genome-wide DNAm differences in blood between patients with delirium and controls to identify useful epigenetic biomarkers for delirium. Data from a total of 87 subjects (43 delirium cases) were analyzed by a genome-wide DNAm case-control association study. A genome-wide significant CpG site near the gene of LDLRAD4 was identified (p = 5.07E-8). In addition, over-representation analysis showed several significant pathways with a false discovery rate adjusted p-value < 0.05. The top pathway with a Gene Ontology term was immune response, and the second top pathway with a Kyoto Encyclopedia of Genes and Genomes term was cholinergic synapse. Significant DNAm differences related to immune/inflammatory response were shown both at gene and pathway levels between patients with delirium and non-delirium controls. This finding indicates that DNAm status in blood has the potential to be used as epigenetic biomarkers for delirium.
View details for DOI 10.1016/j.jpsychires.2020.06.005
View details for PubMedID 32590150
View details for PubMedCentralID PMC7486988
Genome-wide DNA methylation investigation of glucocorticoid exposure within buccal samples.
Psychiatry and clinical neurosciences
2019; 73 (6): 323-330
Glucocorticoids play a major role in regulating the stress response, and an imbalance of glucocorticoids has been implicated in stress-related disorders. Within mouse models, CpGs across the genome have been shown to be differentially methylated in response to glucocorticoid treatment, and using the Infinium 27K array, it was shown that humans given synthetic glucocorticoids had DNA methylation (DNAm) changes in blood. However, further investigation of the extent to which glucocorticoids affect DNAm across a larger proportion of the genome is needed.Buccal samples were collected before and after synthetic glucocorticoid treatment in the context of a dental procedure. This included 30 tooth extraction surgery patients who received 10 mg of dexamethasone. Genome-wide DNAm was assessed with the Infinium HumanMethylationEPIC array.Five CpGs showed genome-wide significant DNAm changes that were >10%. These differentially methylated CpGs were in or nearest the following genes: ZNF438, KLHDC10, miR-544 or CRABP1, DPH5, and WDFY2. Using previously published datasets of human blood gene expression changes following dexamethasone exposure, a significant proportion of genes with false-discovery-rate-adjusted significant CpGs were also differentially expressed. A pathway analysis of the genes with false-discovery-rate-adjusted significant CpGs revealed significant enrichment of olfactory transduction, pentose and glucuronate interconversions, ascorbate and aldarate metabolism, and steroid hormone biosynthesis pathways.High-dose synthetic glucocorticoid administration in the setting of a dental procedure was significantly associated with DNAm changes within buccal samples. These findings are consistent with prior findings of an influence of glucocorticoids on DNAm in humans.
View details for DOI 10.1111/pcn.12835
View details for PubMedID 30821055
View details for PubMedCentralID PMC6561812
Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals.
2019; 9 (1): 47
Differential DNA methylation in the brain is associated with many psychiatric diseases, but access to brain tissues is essentially limited to postmortem samples. The use of surrogate tissues has become common in identifying methylation changes associated with psychiatric disease. In this study, we determined the extent to which peripheral tissues can be used as surrogates for DNA methylation in the brain. Blood, saliva, buccal, and live brain tissue samples from 27 patients with medically intractable epilepsy undergoing brain resection were collected (age range 5-61 years). Genome-wide methylation was assessed with the Infinium HumanMethylation450 (n = 12) and HumanMethylationEPIC BeadChip arrays (n = 21). For the EPIC methylation data averaged for each CpG across subjects, the saliva-brain correlation (r = 0.90) was higher than that for blood-brain (r = 0.86) and buccal-brain (r = 0.85) comparisons. However, within individual CpGs, blood had the highest proportion of CpGs correlated to brain at nominally significant levels (20.8%), as compared to buccal tissue (17.4%) and saliva (15.1%). For each CpG and each gene, levels of brain-peripheral tissue correlation varied widely. This indicates that to determine the most useful surrogate tissue for representing brain DNA methylation, the patterns specific to the genomic region of interest must be considered. To assist in that objective, we have developed a website, IMAGE-CpG, that allows researchers to interrogate DNA methylation levels and degree of cross-tissue correlation in user-defined locations across the genome.
View details for DOI 10.1038/s41398-019-0376-y
View details for PubMedID 30705257
View details for PubMedCentralID PMC6355837
Identification of Patients With High Mortality Risk and Prediction of Outcomes in Delirium by Bispectral EEG.
The Journal of clinical psychiatry
2019; 80 (5)
Delirium is common and dangerous, yet underdetected and undertreated. Current screening questionnaires are subjective and ineffectively implemented in busy hospital workflows. Electroencephalography (EEG) can objectively detect the diffuse slowing characteristic of delirium, but it is not suitable for high-throughput screening due to size, cost, and the expertise required for lead placement and interpretation. This study hypothesized that an efficient and reliable point-of-care EEG device for high-throughput screening could be developed.This prospective study, which measured bispectral EEG (BSEEG) from elderly inpatients to assess their outcomes, was conducted at the University of Iowa Hospitals and Clinics from January 2016 to October 2017. A BSEEG score was defined based on the distribution of 2,938 EEG recordings from the 428 subjects who were assessed for delirium; primary outcomes measured were hospital length of stay, discharge disposition, and mortality.A total of 274 patients had BSEEG score data available for analysis. Delirium and BSEEG score had a significant association (P < .001). Higher BSEEG scores were significantly correlated with length of stay (P < .001 unadjusted, P = .001 adjusted for age, sex, and Charlson Comorbidity Index [CCI] score) as well as with discharge not to home (P < .01). Hazard ratio for survival controlling for age, sex, CCI score, and delirium status was 1.35 (95% CI,1.04 to 1.76; P = .025).In BSEEG, an efficient and reliable device that provides an objective measurement of delirium status was developed. The BSEEG score is significantly associated with pertinent clinical outcomes of mortality, hospital length of stay, and discharge disposition. The BSEEG score better predicts mortality than does clinical delirium status. This study identified a previously unrecognized subpopulation of patients without clinical features of delirium who are at increased mortality risk.
View details for DOI 10.4088/JCP.19m12749
View details for PubMedID 31483958
View details for PubMedCentralID PMC7181374
Delirium detection by a novel bispectral electroencephalography device in general hospital
PSYCHIATRY AND CLINICAL NEUROSCIENCES
2018; 72 (12): 856–63
Delirium is common and dangerous among elderly inpatients; yet, it is underdiagnosed and thus undertreated. This study aimed to test the diagnostic characteristics of a noninvasive point-of-care device with two-channel (bispectral) electroencephalography (EEG) for the screening of delirium in the hospital.Patients admitted to the University of Iowa Hospitals and Clinics were assessed for the presence of delirium with a clinical assessment, the Confusion Assessment Method for Intensive Care Unit and Delirium Rating Scale. Subsequently, we obtained a 10-min bispectral EEG (BSEEG) recording from a hand-held electroencephalogram device during hospitalization. We performed power spectral density analysis to differentiate between those patients with and without delirium.Initially 45 subjects were used as a test dataset to establish a cut-off. The BSEEG index was determined to be a significant indicator of delirium, with sensitivity 80% and specificity 87.7%. An additional independent validation dataset with 24 patients confirmed the validity of the approach, with a sensitivity of 83.3% and specificity of 83.3%.In this pilot study, the BSEEG method was able to distinguish delirious patients from non-delirious patients. Our data showed the feasibility of this technology for mass screening of delirium in the hospital.
View details for PubMedID 30246448
Epigenetics of Delirium and Aging: Potential Role of DNA Methylation Change on Cytokine Genes in Glia and Blood Along With Aging.
Frontiers in aging neuroscience
2018; 10: 311
Background: Delirium in elderly patients is common and dangerous. Major risk factors include aging and exogenous insults, such as infection or surgery. In animal models, aging enhances pro-inflammatory cytokine release from microglia in response to exogenous insults. The epigenetic mechanism DNA methylation (DNAm) regulates gene expression and changes with age. Older individuals may have methylation changes that influence the increased cytokine upon insult, but the degree to which aging affects DNAm of cytokine genes is not fully understood. Methods: The relationship between DNAm and aging of pro-inflammatory cytokine genes (TNF-alpha, IL1-beta, IL-6) was investigated using methylation array data in two cohorts. Brain and blood samples were collected from a neurosurgery cohort (NSG) of 21 subjects who underwent brain resection. A second cohort, the Grady Trauma Project (GTP), included blood samples from 265 subjects. Results: In the NSG cohort, a significant negative correlation between age and DNAm in brain was found at a CpG in IL-6. With the GTP dataset, significant negative correlations between age and DNAm were seen at most of the CpGs in TNF-alpha. Also, TNF-Alpha expression increases with age. These GTP DNAm correlations were also nominally significant in NSG blood samples. In neuronal negative NSG brain tissue, a similar negative trend was observed. Conclusions: With aging, a decrease in DNAm of cytokines gene CpGs in glia and blood was seen. As this can affect their expression, additional research is needed to fully elucidate the role of DNAm in aging and how it may influence the pathogenesis of delirium.
View details for DOI 10.3389/fnagi.2018.00311
View details for PubMedID 30405391
View details for PubMedCentralID PMC6206747
- Integrated Inpatient Medical and Psychiatric Care: Experiences of 5 Institutions. Annals of internal medicine 2018; 168 (11): 815-817
New developments in the genetics of bipolar disorder.
Current psychiatry reports
2014; 16 (11): 493
The last several years have been breakthrough ones in bipolar disorder (BPD) genetics, as the field has identified robust risk variants for the first time. Leading the way have been genome-wide association studies (GWAS) that have assessed common genetic markers across very large groups of patients and controls. These have resulted in findings in genes including ANK3, CACNA1C, SYNE1, ODZ4, and TRANK1. Additional studies have begun to examine the biology of these genes and how risk variants influence aspects of brain and behavior that underlie BPD. For example, carriers of the CACNA1C risk variant have been found to exhibit hippocampal and anterior cingulate dysfunction during episodic memory recall. This work has shed additional light on the relationship of bipolar susceptibility variants to other disorders, particularly schizophrenia. Even larger BPD GWAS are expected with samples now amassed of 21,035 cases and 28,758 controls. Studies have examined the pharmacogenomics of BPD with studies of lithium response, yielding high profile results that remain to be confirmed. The next frontier in the field is the identification of rare bipolar susceptibility variants through large-scale DNA sequencing. While only a couple of papers have been published to date, many studies are underway. The Bipolar Sequencing Consortium has been formed to bring together all of the groups working in this area, and to perform meta-analyses of the data generated. The consortium, with 13 member groups, now has exome data on ~3,500 cases and ~5,000 controls, and on ~162 families. The focus will likely shift within several years from exome data to whole genome data as costs of obtaining such data continue to drop. Gene-mapping studies are now providing clear results that provide insights into the pathophysiology of the disorder. Sequencing studies should extend this process further. Findings could eventually set the stage for rational therapeutic development.
View details for DOI 10.1007/s11920-014-0493-5
View details for PubMedID 25194313
State dependent gene-environment interaction: Serotonin transporter gene-child abuse interaction associated with suicide attempt history among depressed psychiatric inpatients
JOURNAL OF AFFECTIVE DISORDERS
2013; 147 (1-3): 373-378
The serotonin transporter gene polymorphism (5HTTLPR) and child abuse history have been associated with an increased suicide risk for general population, but such association is not clear among psychiatric depressed inpatients.A chart review identified 422 depressed inpatients genotyped for 5HTTLPR. Child abuse and suicide attempt history were recorded. The relationship between 5HTTLPR, child abuse, and suicide attempts were analyzed.There was a significant relationship between 5HTTLPR and history of suicide attempt (the long/long versus the short carriers, 47.9% versus 31.8%, p=0.0015). There was also a significant main effect from child abuse history (abused versus not abused, 45.1% versus 28.6%, p=0.0001). The likelihood ratio test showed a significant result for the l/l genotype group with child abuse history (odds ratio 4.11, χ2 = 23.5, p<0.0001). No significant result was obtained from other groups.This is a retrospective study based on chart review. Replication with more standardized research setting for measurements of child abuse history and suicide attempt history is needed. The rs25531 variant among a long allele (long-A and long-G) of 5HTTLPR was not genotyped.In addition to the direct effect from 5HTTLPR and child abuse history, an interaction between the 5HTTLPR gene and child abuse history influenced psychiatric profiles of depressed inpatients. Contrary to the widely recognized "reactivity" associated with the short allele, our patients with the l/l genotype and child abuse history showed significantly severer psychiatric pathology than short carriers with child abuse history.
View details for DOI 10.1016/j.jad.2012.11.043
View details for Web of Science ID 000316790400053
View details for PubMedID 23261136
The integrated model of serotonin transporter gene variation (5HTTLPR) and the glial cell transporter in stress vulnerability and depression.
2012; 78 (3): 410-4
The serotonin transporter gene (SLC6A4) promoter polymorphism (5HTTLPR) has been associated with individual stress responses such that individuals with childhood abuse history have higher rates of depression in later life if they are homozygous short (s/s) of the gene. It is hypothesized that these findings could be explained by an integrated model of a role of the glial cell transporter and a functional difference of 5HTTLPR in the capacity of absorbing serotonin from the synapse. A hypothetical integrated model of the SLC6A4 function and the role of glial cells are put forward to explain accumulating results of recent investigations exploring the relationship between the gene and the diverse mental activities including depression and stress response. A model based on SLC6A4 variation is proposed to explain individual differences in stress vulnerability/resilience. The role of the glial cell transporter surrounding the synapse is integrated in the model to understand the modulation of the neurotransmission. It is hypothesized that a synapse with less serotonin transporter contributes to unstable processing in neurotransmission as compared to a synapse with more serotonin transporter. As such, based on functional differences of 5HTTLPR in the expression of the serotonin transporter, it is asserted that individuals with the s/s genotype process neurotransmission differently and in a reactive way. This integrated model of 5HTTLPR and glial cells suggests that the efficacy of serotonin reuptake in the synapse may play a crucial role in variability of neurotransmission, which can lead to differences in the stress response and the pathophysiology of depression.
View details for DOI 10.1016/j.mehy.2011.10.043
View details for PubMedID 22236459
Relationship between FKBP5 polymorphisms and depression symptoms among kidney transplant recipients.
Depression and anxiety
2011; 28 (12): 1111-8
Several polymorphisms in FK506 Binding Protein gene (FKBP5) and a history of child abuse have been shown to be associated with an increased risk for posttraumatic stress disorder (PTSD). It has also been demonstrated that the same polymorphisms of FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. However, there are only limited numbers of studies replicating the polymorphisms as vulnerability factors for the development of mental illnesses, such as PTSD and depression after stressful life event, especially with a specific incidence, such as kidney transplant surgery.A retrospective analysis was conducted using the electronic medical records of 131 adult kidney transplant recipients. Depression severity after kidney transplantation was measured by PHQ-9, and stored blood was genotyped for variants in the Serotonin Transporter (SLC6A4), Brain-Derived Neurotrophic Factor, Catecholamine-O-Methyltransferase, Corticotropin-Releasing Hormone Receptor, and FKBP5 genes. Spearman correlations were used to test for association between genetic variants and depression severity.The rare alleles at three out of four SNPs in FKBP5 (rs1360780, rs9296158, and rs9470080) were associated with increased PHQ-9 scores (P<.05), whereas the last FKBP5 SNP (rs3800373) showed a trend of association (P<.10). All four FKBP5 SNPs are in strong linkage disequilibrium. Although in a subgroup of Caucasian non-Hispanic subjects the association was not statistically significant, the direction of association was consistent with that observed in the entire sample as well as in previous studies. Polymorphisms in genes other than FKBP5 were not associated with PHQ-9 scores.Polymorphisms in FKBP5 may be associated with higher depression scores in kidney transplant recipients.
View details for DOI 10.1002/da.20879
View details for PubMedID 22134958
A new interaction between SLC6A4 variation and child abuse is associated with resting heart rate.
Depression and anxiety
2011; 28 (3): 227-33
The short form of the indel promoter polymorphism (5HTTLPR) of the serotonin transporter gene (SLC6A4) and a history of child abuse have been reported to be associated with an increased risk for the development of depression. A child abuse history has also been associated with more rapid heart rate reactions.A retrospective chart review identified 282 patients with major depression who had been hospitalized and genotyped for the 5HTTLPR polymorphism. A subgroup of 185 females of European ancestry was also identified and analyzed. While hospitalized, heart rate was measured. Child abuse history was documented during the diagnostic evaluation. Analyses of the relationship between 5HTTLPR genotype, history of child abuse, and admission heart rate were conducted.No main effect on heart rate from the 5HTTLPR genotype or a child abuse history was demonstrated for the entire sample or the subgroup of female patients. However, a genotype-by-abuse interaction was associated with resting heart rate on admission to the hospital (P<.05). Depressed patients, who were homozygous for the long allele and who had been abused, had a heart rate on hospital admission, which was statistically higher than patients with the same genotype but who had not been abused. These findings were consistent both for the 282 patients (7.2 bpm higher) as well as for the subgroup of 185 female patients of European ancestry (9.6 bpm higher).A 5HTTLPR genotype interaction of elevated heart rate with a history of child abuse was demonstrated in depressed psychiatric inpatients.
View details for DOI 10.1002/da.20779
View details for PubMedID 21394855
Sexual abuse and lifetime diagnosis of psychiatric disorders: systematic review and meta-analysis.
Mayo Clinic proceedings
2010; 85 (7): 618-29
To systematically assess the evidence for an association between sexual abuse and a lifetime diagnosis of psychiatric disorders.We performed a comprehensive search (from January 1980-December 2008, all age groups, any language, any population) of 9 databases: MEDLINE, EMBASE, CINAHL, Current Contents, PsycINFO, ACP Journal Club, CCTR, CDSR, and DARE. Controlled vocabulary supplemented with keywords was used to define the concept areas of sexual abuse and psychiatric disorders and was limited to epidemiological studies. Six independent reviewers extracted descriptive, quality, and outcome data from eligible longitudinal studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled across studies by using the random-effects model. The I(2) statistic was used to assess heterogeneity.The search yielded 37 eligible studies, 17 case-control and 20 cohort, with 3,162,318 participants. There was a statistically significant association between sexual abuse and a lifetime diagnosis of anxiety disorder (OR, 3.09; 95% CI, 2.43-3.94), depression (OR, 2.66; 95% CI, 2.14-3.30), eating disorders (OR, 2.72; 95% CI, 2.04-3.63), posttraumatic stress disorder (OR, 2.34; 95% CI, 1.59-3.43), sleep disorders (OR, 16.17; 95% CI, 2.06-126.76), and suicide attempts (OR, 4.14; 95% CI, 2.98-5.76). Associations persisted regardless of the victim's sex or the age at which abuse occurred. There was no statistically significant association between sexual abuse and a diagnosis of schizophrenia or somatoform disorders. No longitudinal studies that assessed bipolar disorder or obsessive-compulsive disorder were found. Associations between sexual abuse and depression, eating disorders, and posttraumatic stress disorder were strengthened by a history of rape.A history of sexual abuse is associated with an increased risk of a lifetime diagnosis of multiple psychiatric disorders.
View details for DOI 10.4065/mcp.2009.0583
View details for PubMedID 20458101
View details for PubMedCentralID PMC2894717
Mortality among patients with sepsis associated with a bispectral electroencephalography (BSEEG) score.
2021; 11 (1): 14211
We have previously developed a bispectral electroencephalography (BSEEG) device, which was shown to be effective in detecting delirium and predicting patient outcomes. In this study we aimed to apply the BSEEG approach for a sepsis. This was a retrospective cohort study conducted at a single center. Sepsis-positive cases were identified based on retrospective chart review. EEG raw data and calculated BSEEG scores were obtained in the previous studies. The relationship between BSEEG scores and sepsis was analyzed, as well as the relationship among sepsis, BSEEG score, and mortality. Data were analyzed from 628 patients. The BSEEG score from the first encounter (1st BSEEG) showed a significant difference between patients with and without sepsis (p=0.0062), although AUC was very small indicating that it isnot suitable for detection purpose. Sepsis patients with high BSEEG scores showed the highest mortality, and non-sepsis patients with low BSEEG scores showed the lowest mortality. Mortality of non-sepsis patients with high BSEEG scores was as bad as that of sepsis patients with low BSEEG scores. Even adjusting for age, gender, comorbidity, and sepsis status, BSEEG remained a significant predictor of mortality (p=0.008). These data are demonstrating its usefulness as a potential tool for identification of patients at high risk and management of sepsis.
View details for DOI 10.1038/s41598-021-93588-9
View details for PubMedID 34244577
Increased mortality in patients with standard EEG findings of 'diffuse slowing'.
Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists
2021; 33 (2): 93-100
We aimed to confirm the association between slow brain wave activity typically described as "diffuse slowing" on standard electroencephalogram (EEG) and patient outcomes, including mortality.This retrospective study was conducted with patient chart data from March 2015 to March 2017 at a tertiary care academic hospital in the midwestern United States. In total, 1,069 participants age ≥55 years on an inpatient floor or ICU received a standard 24-hour EEG. The primary outcome was all-cause mortality at 30, 90, 180, and 365 days. Secondary outcomes were time to discharge, and discharge to home.Having diffuse slowing on standard EEG was significantly associated with 30-, 90-, 180-, and 365-day mortality compared with patients who had normal EEG findings, after controlling for age, sex, and Charlson Comorbidity Index score. When controlling for these factors, patients with diffuse slowing had a significantly longer time to discharge and were significantly less likely to discharge to home. Our findings showed that a standard EEG finding of diffuse slowing for inpatients age ≥55 years is associated with poor outcomes, including greater mortality.This study suggested that the finding of diffuse slowing on EEG may be an important clinical marker for predicting mortality in geriatric inpatients.
View details for DOI 10.12788/acp.0018
View details for PubMedID 33878283
Stress increases blood beta-hydroxybutyrate levels and prefrontal cortex NLRP3 activity jointly in a rodent model.
2021; 41 (2): 159-167
This study aimed to assess the response of endogenous beta-hydroxybutyrate to psychological stress, and its association with nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing 3 (NLRP3) inflammasome, and stress-induced behavior.Male C57BL/6J mice were subjected to 1-hour restraint stress to examine changes in the endogenous beta-hydroxybutyrate and active NLRP3 levels in the prefrontal cortex. Subsequently, we created a depression model applying 10-day social defeat stress to the male C57BL/6J mice.One-hour restraint stress rapidly increased beta-hydroxybutyrate levels in the blood. The active NLRP3 levels in the prefrontal cortex also increased significantly. A correlation was found between the increased beta-hydroxybutyrate levels in the blood and the active NLRP3 levels in the prefrontal cortex. The mice exposed to social defeat stress exhibited depression- and anxiety-like behavioral changes in the open field, social interaction, and forced swim tests. There was a correlation between these behavioral changes and endogenous beta-hydroxybutyrate levels. Among the social defeat model mice, those with high beta-hydroxybutyrate levels tended to have more depression- and anxiety-like behavior.The increased blood beta-hydroxybutyrate levels due to psychological stress correlate with the active NLRP3 levels in the prefrontal cortex, suggesting that the increased beta-hydroxybutyrate levels due to stress may reflect a reaction to brain inflammation. In addition, mice with higher blood beta-hydroxybutyrate levels tend to exhibit increased depression- and anxiety-like behaviors; thus, an increase in blood beta-hydroxybutyrate levels due to stress may indicate stress vulnerability.
View details for DOI 10.1002/npr2.12164
View details for PubMedID 33609086
Beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, attenuates anxiety-related behavior in a rodent post-traumatic stress disorder model.
2020; 10 (1): 21629
Accumulating evidence suggests that elevated inflammation contributes to the pathophysiology of post-traumatic stress disorder (PTSD) and that anti-inflammatory drugs might be a new treatment strategy for PTSD. It has been reported that beta-hydroxybutyrate (BHB), one of the main ketone bodies produced, can have an anti-inflammatory and antidepressant effect. Here, we investigated the potential anti-anxiety and anti-inflammatory effects of BHB using a rodent PTSD model, induced by single prolonged stress (SPS). Male, Sprague-Dawley rats were employed in this study. Repeated administration of BHB attenuated SPS-induced anxiety-related behaviors evaluated by the elevated plus maze test. SPS increased the serum levels of TNF-α and IL-1β. In contrast, BHB administration partially attenuated the increase of serum TNF-α. These findings demonstrate that BHB exerts its anxiolytic effects, possibly by inhibiting systemic TNF-α. Hence, BHB may be a novel therapeutic candidate for the treatment of PTSD.
View details for DOI 10.1038/s41598-020-78410-2
View details for PubMedID 33303808
View details for PubMedCentralID PMC7728809
Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.
2020; 11 (1): 5965
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.
View details for DOI 10.1038/s41467-020-19615-x
View details for PubMedID 33235198
View details for PubMedCentralID PMC7686485
Effect of interaction between a specific subtype of child abuse and the FKBP5 rs1360780 SNP on DNA methylation among patients with bipolar disorder.
Journal of affective disorders
2020; 272: 417-422
Child abuse is a risk factor for mood disorders, and linked to decreased DNA methylation (DNAm) of FKBP5 intron 7 through interactions with the single nucleotide polymorphism (SNP) rs1360780. However, no study has investigated which specific subtypes of child abuse are related to decreased DNAm of FKBP5 intron 7 in mood disorders. We therefore aimed to examine the relationship among various subtypes of child abuse, rs1360780, and the DNAm level of FKBP5 intron 7.A total of 190 subjects (87 patients with major depressive disorder [MDD], 61 patients with bipolar disorder [BD], and 42 healthy controls) participated. The Child Abuse and Trauma Scale (CATS) was used to evaluate child abuse. Whole blood was processed for genotyping, and pyrosequencing was conducted to assess the DNAm level of FKBP5 intron 7. A multiple regression analysis was used to analyze the DNAm level as a dependent variable, and the CATS subtypes and rs1360780 were used as independent variables.Emotional abuse/neglect, one of the specific subtypes of child abuse, was related to lower DNAm of FKBP5 intron 7 interacting with rs1360780 in the BD patients. There were no significant results in the MDD patients or the controls.Since the study was limited to Japanese individuals, particularly those with MDD and BD, the findings are not generalizable. Furthermore, as child abuse was measured retrospectively, there may be recall bias.This finding indicates that a specific subtype of child abuse may play an important role in the development of BD.
View details for DOI 10.1016/j.jad.2020.03.120
View details for PubMedID 32553385
Symptoms of anxiety and depression and use of anxiolytic-hypnotics and antidepressants in current and former smokers with and without COPD - A cross sectional analysis of the COPDGene cohort.
Journal of psychosomatic research
2019; 118: 18-26
To compare the frequency of anxiety/depressive symptoms and use of anxiolytic-hypnotics/antidepressants in smokers with and without COPD and to identify characteristics associated with having unmedicated symptoms.Cross-sectional analysis of ambulatory, current/former smokers ≥10 pack years enrolled in the COPDGene study. We measured anxiety/depressive symptoms using the Hospital Anxiety and Depression Scale (subscales ≥8), recorded anxiolytic-hypnotic/antidepressant use, and defined unmedicated symptoms as elevated anxiety/depressive symptoms and not on medications. Regression analysis identified characteristics associated with having unmedicated symptoms.Of 5331 current/former smokers (45% with and 55% without COPD), 1332 (25.0%) had anxiety/depressive symptoms. Anxiety symptoms were similar in frequency in smokers with and without COPD (19.7% overall), while depressive symptoms were most frequent in severe-very severe COPD at 20.7% (13.1% overall). In the entire cohort, 1135 (21.2%) were on medications. Anxiolytic-hypnotic use was highest in severe-very severe COPD (range 7.6%-12.0%), while antidepressant use showed no significant variation in smokers with and without COPD (range 14.7%-17.1%). Overall, 881 (66% of those with symptoms) had unmedicated symptoms, which was associated with African American race (adjusted OR 2.95, 95% CI 2.25-3.87), male gender (adjusted OR 1.93, 95% CI 1.57-2.36), no health insurance (adjusted OR 2.38, 95% CI 1.30-4.35), severe-very severe COPD (adjusted OR 1.48, 95% CI 1.04-2.11), and higher respiratory symptoms/exacerbation history (adjusted OR 2.21, 95% CI 1.62-3.02).Significant unmet mental health care needs exist in current and former smokers with and without COPD. One in five have unmedicated symptoms, identified by key demographic and clinical characteristics.National Institutes of Health and The COPD Foundation.
View details for DOI 10.1016/j.jpsychores.2019.01.002
View details for PubMedID 30782350
View details for PubMedCentralID PMC6383809
Pharmacokinetic-Pharmacodynamic interaction associated with venlafaxine-XR remission in patients with major depressive disorder with history of citalopram / escitalopram treatment failure.
Journal of affective disorders
2019; 246: 62-68
The purpose of this study was to identify specific pharmacokinetic (PK) and pharmacodynamics (PD) factors that affect the likelihood of treatment remission with a serotonin norepinephrine reuptake inhibitor (SNRI) in depressed patients whose initial selective serotonin reuptake inhibitor (SSRI) failed.Multiple logistic regression modeling of PK and PD variation hypothesized to contribute to SNRI (i.e. duloxetine or venlafaxine) treatment remission in prior SSRI (i.e. citalopram or escitalopram) failure was conducted on 139 subjects from the Pharmacogenomics Research Network (PGRN) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies. Depressive symptoms were assessed with the Quick Inventory of Depressive Symptomatology Clinician-rated (QIDS-C16).Venlafaxine-XR remission was associated with a significant interaction between CYP2D6 ultra-rapid metabolizer (URM) phenotype and SLC6A4 5-HTTLPR L/L genotype. A similar significant interaction effect was observed between CYP2D6 URM and SLC6A2 G1287A GA genotype. Stratifying by transporter genotypes, venlafaxine-XR remission was associated with CYP2D6 URM in patients with SLC6A4 L/L (p = 0.001) and SLC6A2 G1287A GA genotypes.The primary limitation of this post hoc study was small sample size.Our results suggest that CYP2D6 ultra-rapid metabolizer status contributes to venlafaxine-XR treatment remission in MDD patients; in particular, there is a PK-PD interaction with treatment remission associated with CYP2D6 URM phenotype and SLC6A4 5-HTTLPR L/L or SLC6A2 G1287A G/A genotype, respectively. These preliminary data are encouraging and support larger pharmacogenomics studies differentiating treatment response to mechanistically different antidepressants in addition to further PK-PD interactive analyses.
View details for DOI 10.1016/j.jad.2018.12.021
View details for PubMedID 30578947
View details for PubMedCentralID PMC6501809
- The point-of-care EEG for delirium detection in the emergency department. The American journal of emergency medicine 2019; 37 (5): 995-996
GWAS and systems biology analysis of depressive symptoms among smokers from the COPDGene cohort.
Journal of affective disorders
2019; 243: 16-22
Large sample GWAS is needed to identify genetic factors associated with depression. This study used genome-wide genotypic and phenotypic data from the COPDGene study to identify genetic risk factors for depression.Data were from 9716 COPDGene subjects with ≥10 pack-year history. Depression was defined as antidepressant use and/or a HADS depression subscale score ≥8. Non-Hispanic White (6576) and African-American (3140) subsets were analyzed. A GWAS pipeline identified SNPs associated with depression in each group. Network analysis software analyzed gene interactions through common biological pathways, genetic interactions, and tissue-specific gene expression.The mean age was 59.4 years (SD 9.0) with 46.5% female subjects. Depression was in 24.7% of the NHW group (1622) and 12.5% of the AA group (391). No SNPs had genome-wide significance. One of the top SNPs, rs12036147 (p = 1.28 × 10-6), is near CHRM3. Another SNP was near MDGA2 (rs17118176, p = 3.52 × 10-6). Top genes formed networks for synaptic transmission with a statistically significant level of more co-expression in brain than other tissues, particularly in the basal ganglia (p = 1.00 × 10-4).Limitations included a depression definition based on antidepressant use and a limited HADS score subgroup, which could increase false negatives in depressed patients not on antidepressants. Antidepressants used for smoking cessation in non-depressed patients could lead to false positives.Systems biology analysis identified statistically significant pathways whereby multiple genes influence depression. The gene set pathway analysis and COPDGene data can help investigate depression in future studies.
View details for DOI 10.1016/j.jad.2018.09.003
View details for PubMedID 30219690
View details for PubMedCentralID PMC6186181
Relationship of genetic variation in the serotonin transporter gene (SLC6A4) and congenital and acquired cardiovascular diseases.
Genetic testing and molecular biomarkers
2015; 19 (3): 115-23
Recent reports have suggested an association between variation in the serotonin transporter and primary pulmonary hypertension and myocardial infarction. We set out to determine whether these associations were present in a population of patients who underwent SLC6A4 genotyping and to explore whether genetic variation in the serotonin transporter might be also associated with other cardiovascular functional and structural abnormalities. Included were 3473 patients who were genotyped for the SLC6A4 5HTTLPR polymorphism and a subset for rs25531 (n=816) and STin2 (n=819). An association was observed between 5HTTLPR and primary pulmonary hypertension (p=0.0130), anomalies of the cerebrovascular system (p<0.0001), and other anomalies of great veins (p=0.0359). The combined 5HTTLPR and rs25531 genotype was associated with tachycardia (p=0.0123). There was an association of the STin2 genotype with abnormal electrocardiogram (ECG) (p=0.0366) and abnormal cardiac study (0.0311). Overall, these results represent a step toward the understanding of the impact of SLC6A4 variation on cardiovascular pathology.
View details for DOI 10.1089/gtmb.2014.0250
View details for PubMedID 25671637
CYP2C19 variation, not citalopram dose nor serum level, is associated with QTc prolongation.
Journal of psychopharmacology (Oxford, England)
2014; 28 (12): 1143-8
Recently, a FDA Safety Communication warned of a dose-dependent risk for QTc prolongation with citalopram, which is metabolized by CYP2C19 of the cytochrome P450 system. We investigate associations between citalopram and escitalopram dose, serum concentration, CYP2C19 phenotype, and QTc. We undertook a retrospective chart review of citalopram or escitalopram patients with the inclusion criteria of consistent medication dose, CYP2C19 phenotype (extensive metabolizers [EM], intermediate metabolizers [IM], poor metabolizers [PM]), and QTc interval on ECG. We further identified 42 citalopram users with citalopram serum concentration measurements and ECG. Regression and one-way ANOVA were used to examine the relationship between citalopram dose, citalopram serum concentration, CYP2C19 phenotype, and QTc interval. Of 75 citalopram patients, the EM group had significantly shorter QTc intervals than a combined IM+PM group (427.1±23.6 ms vs. 440.1±26.6 ms, one-tailed t-test, p=0.029). In the 80 escitalopram cohort, there was no significant difference in QTc between phenotype groups. There was no statistical correlation between citalopram (p=0.62) or escitalopram (p=0.30) dose and QTc. QTc was not associated with citalopram serum level (p=0.45). In contrast to the FDA warning, this study found no association between citalopram/escitalopram dose and QTc. However, PM of the drug tended to have longer QTc intervals. Our findings suggest cytochrome P450 genotyping in select patients may be helpful to guide medication optimization while limiting harmful effects.
View details for DOI 10.1177/0269881114543720
View details for PubMedID 25122046
Treatment outcomes of depression: the pharmacogenomic research network antidepressant medication pharmacogenomic study.
Journal of clinical psychopharmacology
2014; 34 (3): 313-7
The effectiveness of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD) is controversial.The clinical outcomes of subjects with nonpsychotic MDD were reported and compared with the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study outcomes to provide guidance on the effectiveness of SSRIs.Subjects were treated with citalopram/escitalopram for up to 8 weeks. Depression was measured using the Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) and the 17-item Hamilton Depression Rating Scale.The group of subjects with at least 1 follow-up visit had a remission (QIDS-C16 ≤ 5) rate of 45.8% as well as a response (50% reduction in QIDS-C16) rate of 64.8%, and 79.9% achieved an improvement of 5 points or higher in QIDS-C16 score. The Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study subjects were more likely to achieve a response than STAR*D study subjects. After adjustment for demographic factors, the response rates were not significantly different. When reporting the adverse effect burden, 60.5% of the subjects reported no impairment, 31.7% reported a minimal-to-mild impairment, and 7.8% reported a moderate-to-severe burden at the 4-week visit.Patients contemplating initiating an SSRI to treat their MDD can anticipate a high probability of symptom improvement (79.9%) with a low probability that their symptoms will become worse. Patients with lower baseline severity have a higher probability of achieving remission. The Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study replicates many findings of the first phase of the STAR*D study after controlling for the differences between the studies.
View details for DOI 10.1097/JCP.0000000000000099
View details for PubMedID 24743713
View details for PubMedCentralID PMC3992481
Biological pathways, candidate genes, and molecular markers associated with quality-of-life domains: an update.
Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation
2014; 23 (7): 1997-2013
There is compelling evidence of a genetic foundation of patient-reported quality of life (QOL). Given the rapid development of substantial scientific advances in this area of research, the current paper updates and extends reviews published in 2010.The objective was to provide an updated overview of the biological pathways, candidate genes, and molecular markers involved in fatigue, pain, negative (depressed mood) and positive (well-being/happiness) emotional functioning, social functioning, and overall QOL.We followed a purposeful search algorithm of existing literature to capture empirical papers investigating the relationship between biological pathways and molecular markers and the identified QOL domains.Multiple major pathways are involved in each QOL domain. The inflammatory pathway has the strongest evidence as a controlling mechanism underlying fatigue. Inflammation and neurotransmission are key processes involved in pain perception, and the catechol-O-methyltransferase (COMT) gene is associated with multiple sorts of pain. The neurotransmitter and neuroplasticity theories have the strongest evidence for their relationship with depression. Oxytocin-related genes and genes involved in the serotonergic and dopaminergic pathways play a role in social functioning. Inflammatory pathways, via cytokines, also play an important role in overall QOL.Whereas the current findings need future experiments and replication efforts, they will provide researchers supportive background information when embarking on studies relating candidate genes and/or molecular markers to QOL domains. The ultimate goal of this area of research is to enhance patients' QOL.
View details for DOI 10.1007/s11136-014-0656-1
View details for PubMedID 24604075
View details for PubMedCentralID PMC4199387
Does 5HTTLPR long allele prevent hospitalization? Test of Hardy-Weinberg equilibrium.
2014; 24 (1): 34-6
Many studies suggest an association of the serotonin transporter gene polymorphism (5HTTLPR) long allele with better antidepressant treatment response than the short allele. However, there is controversy over these findings. We hypothesized that if the long allele is associated with a better outcome, we would find fewer inpatients with the long allele compared with the short allele. Chart review identified 925 depressed inpatients and 201 outpatients genotyped for 5HTTLPR. The sample was primarily White (>90%). We tested potential departures from Hardy-Weinberg equilibrium for each sample. We analyzed three independent sets of inpatient samples separately and combined, a White subgroup of 791 patients of the total 925 inpatients, and 201 outpatients. There was no departure from Hardy-Weinberg equilibrium with any of these samples. We also compared 5HTTLPR genotype prevalence between 925 inpatients and 201 outpatients, which showed no statistically significant difference.
View details for DOI 10.1097/YPG.0000000000000024
View details for PubMedID 24300662
HTR2A gene-child abuse interaction and association with a history of suicide attempt among Caucasian depressed psychiatric inpatients
JOURNAL OF AFFECTIVE DISORDERS
2013; 150 (3): 1200-1203
The serotonin transporter gene polymorphism (5HTTLPR) has been associated with vulnerability for depression after exposure to stressful life event as well as with difference in treatment response to SSRI. Although the A/A genotype of the serotonin receptor SNP (rs7997012) was associated with better citalopram response than the G/G in the STAR⁎D sample, the effects of this SNP in the moderation of child abuse history on the characteristics of mental illnesses are not well understood. We examined if there are similar gene-environment interaction with the SNP.Retrospective chart review of 250 Caucasian depressed psychiatric inpatients, who had genotype for rs7997012. Subjects with each genotype were subcategorized into 2 groups with/without history of child abuse. The history of suicide attempts of each group was compared.A trend for an interaction was found between the HTR2A genotype and child abuse history influencing the prevalence of suicide attempts. Although each genotype did not show significant difference in the risk of suicide attempt when there was no abuse history, the A carriers (A/A+A/G) showed significantly higher rate of suicide attempt compared to the G/G when there is a history of child abuse (48.4% versus 22.7% respectively, p=0.0050). The likelihood ratio test from the logistic model showed a trend for an interaction between the A/A genotype and abuse history (Odds Ratio 2.10, χ(2)=2.49, p=0.11).Retrospective study design and small sample size with borderline significance.Our findings showed a potential interaction between the HTR2A gene and stressful life events.
View details for DOI 10.1016/j.jad.2013.05.028
View details for Web of Science ID 000324038000073
View details for PubMedID 23759279
Biological pathways and genetic mechanisms involved in social functioning.
Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation
2013; 22 (6): 1189-200
To describe the major findings in the literature regarding associations between biological and genetic factors and social functioning, paying special attention to: (1) heritability studies on social functioning and related concepts; (2) hypothesized biological pathways and genetic variants that could be involved in social functioning, and (3) the implications of these results for quality-of-life research.A search of Web of Science and PubMed databases was conducted using combinations of the following keywords: genetics, twins, heritability, social functioning, social adjustment, social interaction, and social dysfunction.Variability in the definitions and measures of social functioning was extensive. Moderate to high heritability was reported for social functioning and related concepts, including prosocial behavior, loneliness, and extraversion. Disorders characterized by impairments in social functioning also show substantial heritability. Genetic variants hypothesized to be involved in social functioning are related to the network of brain structures and processes that are known to affect social cognition and behavior.Better knowledge and understanding about the impact of genetic factors on social functioning is needed to help us to attain a more comprehensive view of health-related quality-of-life (HRQOL) and will ultimately enhance our ability to identify those patients who are vulnerable to poor social functioning.
View details for DOI 10.1007/s11136-012-0277-5
View details for PubMedID 23054492
"Diminished" association between the serotonin transporter linked polymorphism (5HTTLPR) and body mass index in a large psychiatric sample.
Journal of affective disorders
2013; 151 (1): 397-400
The role of the promoter polymorphism (5HTTLPR) of the serotonin transporter gene (SLC6A4) in psychiatric illnesses has been studied extensively. Serotonergic function also regulates many central nervous system, including appetite and feeding behaviors. The 5HTTLPR short allele was found to be associated with increased body mass index and obesity risk among the general population. No data is available to support generalizability of such association among psychiatric population.We examined the relationship between BMI and the 5HTTLPR genotype in a large sample of 1831 psychiatric patients at Mayo Clinic, Rochester, Minnesota, using a retrospective chart review.Average BMI among groups with the short/short (28.29 ± 7.27 kg/m(2)), the short/long (28.07 ± 6.45 kg/m(2)) and the long/long (28.15 ± 7.51 kg/m(2)) genotypes of 5HTTLPR were not statistically different. This negative association persisted even with the sub-analysis of the Caucasians. However, we observed an increased rate of obesity among our psychiatric patient sample compared to the general population of Minnesota (36.6% versus 27.6%, p=0.0001 for males, 30.3% versus 24.4%, p=0.0001 for females). Also, sub-analysis showed female inpatients to have a significantly higher average BMI than outpatients (28.64 ± 8.08 kg/m(2) versus 27.13 ± 6.92 kg/m(2), p=0.026). This confirmed a significant association between mental health disorder and BMI.Retrospective study design with limited control for potential confounders.In this large sample of psychiatric patients we found no significant association between 5HTTLPR genotype and BMI, which is different from the case with general population reported in the literature.
View details for DOI 10.1016/j.jad.2013.06.021
View details for PubMedID 23838390
Testing a Diathesis-Stress Model: Potential Genetic Risk Factors for Development of Distress in Context of Acute Leukemia Diagnosis and Transplant
2012; 53 (5): 456-462
Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals and may be implicated in the etiology of mood-related phenotypes, specifically in the context of stressful life events. We hypothesized that this single-nucleotide polymorphism will predict the development of psychological distress among patients diagnosed with acute leukemia and preparing for hematopoietic stem cell transplant (HSCT). We also explored the relationship of other genetic factors to psychological distress, including 5HTTLPR and STin2, FKBP5, and the CRHR1 TAT haplotype.In a retrospective cohort design, 107 adult acute leukemia survivors preparing for HSCT at a major medical center completed a pre-HSCT psychological evaluation and volunteered to donate blood to the HSCT Cell and Serum Research Repository for future research studies.There was evidence of a potential association between BDNF (Val66Met) and psychological distress. More specifically, rs6265 was related to both personal mental health history (P = 0.09, 0.06 adjusted) and diagnosis of depression/adjustment disorder at time of pre-transplant evaluation (P = 0.11, 0.09 adjusted). Other genetic factors were unrelated to distress.The BDNF Val66Met polymorphism may contribute to development of depressive symptomatology in patients undergoing stressful life events, such as diagnosis of acute leukemia and preparation for HSCT. The SNPs in BDNF might be applicable in identifying patients at risk for developing psychological distress and depression in the context of coping with stressful medical conditions. Polymorphism in other genes (FKBP5, CRHR1, and 5HTT) did not show any significant relationships. Replication studies are needed with larger samples of people undergoing similar significant life stressors.
View details for DOI 10.1016/j.psym.2012.01.004
View details for Web of Science ID 000309030000007
View details for PubMedID 22652301
State Dependent Gene-Environment Interaction: Serotonin Transporter Gene-Child Abuse Interaction Associated with Suicide Attempt among Large Sample of Depressed Psychiatric Inpatients
ELSEVIER SCIENCE INC. 2012: 157S
View details for Web of Science ID 000302466000494
Investigation of serotonin transporter gene (SLC6A4) by child abuse history interaction with body mass index and diabetes mellitus of White female depressed psychiatric inpatients.
2012; 22 (3): 109-14
The serotonin transporter gene promoter polymorphism (5HTTLPR) and child abuse have been associated with an increased risk for depression. We previously reported the long/long (l/l) genotype of 5HTTLPR being associated with higher heart rate among patients with a history of child abuse compared with those without a history of child abuse, whereas the short allele carriers did not have heart rate differences dependent on child abuse history. This time, we extended our investigation to other outcomes with body mass index (BMI), and diabetes mellitus (DM) diagnosis.A retrospective chart review identified 185 White female depressed inpatients who were genotyped for 5HTTLPR. Child abuse history, BMI, and DM diagnosis were recorded. The relationship between 5HTTLPR, child abuse, and BMI, as well as a prevalence of DM were analyzed.Among the l/l genotype group, patients with a history of child abuse had a higher prevalence of DM (14.3 vs. 0%, P=0.06), and higher BMI (32.3 vs. 27.3 kg/m, P=0.03) compared with those without. Patients with the short allele (s/s or s/l) had fewer differences on the basis of abuse history.A potential interaction between 5HTTLPR and child abuse influenced metabolic profiles of White female depressed inpatients. In contrast with the widely recognized 'reactivity' associated with the short allele of 5HTTLPR, our White female depressed psychiatric inpatients with the l/l genotype showed relatively greater clinical pathology in metabolic profiles if they have a history of child abuse than inpatients with at least one short allele who had a history of child abuse.
View details for DOI 10.1097/YPG.0b013e32834f3542
View details for PubMedID 22311265
- Continuous un-SERT-ainty of 5-HTTLPR. Pharmacogenomics 2011; 12 (7): 935-8
- Post-pump chorea--choreiform movements developing after pulmonary thromboendarterectomy for chronic pulmonary hypertension presenting as "functional" movement disorder. Psychosomatics 2011; 52 (5): 459-62
Serotonin transporter gene promotor polymorphism (5-HTTLPR) associations with number of psychotropic medication trials in a tertiary care outpatient psychiatric consultation practice.
2010; 52 (2): 147-53
The authors tested the hypothesis that the short allele of 5-HTTLPR is associated with number of psychotropic medication trials as a measure of treatment-resistance or intolerance in psychosomatic medicine (PM) outpatients.Review of Mayo Clinic PM outpatient 2008 records identified 44 (20.6%) who had 5-HTTLPR genotype tests. A univariate analysis screened for factors that could account for number of medication trials. Logistic regression then determined degree of association between 5-HTTLPR genotype category and number of pharmacological trials.Univariate analysis revealed significant differences across the ordinal genotype spectrum long/long, short/long, short/short in mean number of overall psychotropic medication trials (8.9, 14.8, 18.0, P = 0.002), mean number of antidepressant trials (4.3, 7.2, 8.1, P = 0.018), mean number of mood stabilizer trials (0.8, 1.9, 2.3, P = 0.008), percent living alone (7%, 25%, 50%, P = 0.020), reported family history of depression (93%, 65%, 40%, P = 0.006), and reported family history of chemical dependency treatment (50%, 35%, 10%, P = 0.050). There were trends for differences in consultation reason for unexplained symptoms (14%, 25%, 50%, P = 0.063), and diagnoses of somatoform disorder (7%, 30%, 40%, P = 0.060), and generalized anxiety disorder (43%, 65%, 80%, P = 0.064). After controlling for other differences, presence of the short allele remained associated with number of psychotropic medication trials (OR 4.779, 95% CI 2.263-6.771, P = 0.004), and number of antidepressant trials (OR 1.591, 95% CI 1.072-2.762, P = 0.019).5-HTTLPR testing may identify PM outpatients at higher relative risk for pharmacotherapy treatment non-response or intolerance who may benefit from alternative or augmentative medication recommendations or non-pharmacological interventions.
View details for DOI 10.1016/j.psym.2010.12.013
View details for PubMedID 21397107
Which patient will feel down, which will be happy? The need to study the genetic disposition of emotional states.
Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation
2010; 19 (10): 1429-37
In quality-of-life (QL) research, the genetic susceptibility of negative and positive emotions is frequently ignored, taken for granted, or treated as noise. The objectives are to describe: (1) the major findings of studies addressing the heritable and environmental causes of variation in negative and positive emotional states and (2) the major biological pathways of and genetic variants involved in these emotional states.Literature overview.The heritability estimates for anxiety and depression are 30-40%. Related traits as neuroticism and loneliness are also highly heritable. The hypothalamo-pituitary-adrenal axis is the 'final common pathway' for most depressive symptoms. The many findings of investigated genes are promising but not definitive. Heritability estimates of positive emotional states range between 40 and 50%. Life satisfaction and mental health share common genetic factors with optimism and self-esteem. The prefrontal cortex is a candidate brain area for positive emotional states. Biological and genetic research into positive emotional states is scarce.Genetically informative studies may provide insights into a wide variety of complex questions that traditional QL studies cannot deliver. This insight in turn will help us to design more effective supportive programs that could moderate the outcomes of genetically based predispositions.
View details for DOI 10.1007/s11136-010-9652-2
View details for PubMedID 20419396
View details for PubMedCentralID PMC2977055
Biological pathways and genetic variables involved in pain.
Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation
2010; 19 (10): 1407-17
This paper summarizes current knowledge of pain-related and analgesic-related pathways as well as genetic variations involved in pain perception and management.The pain group of the GENEQOL Consortium was given the task of summarizing the current status of research on genetic variations in pain and analgesic efficacy. This review is neither exhaustive nor comprehensive; we focus primarily on single-nucleotide polymorphisms.Two categories of potential genetic pain-perception pathways were identified: neurotransmission modulators and mechanisms that affect inflammation. Four categories were identified for analgesic efficacy: genes related to receptor interaction, modulation of opioid effects, metabolism, and transport. Various genetic variations involved in these pathways are proposed as candidate genetic markers for pain perception and for individual sensitivity to analgesics.Candidate gene association studies have been used to provide evidence for the genetic modulation of pain perception and response to analgesics. However, the nature and range of genetic modulation of pain is not well addressed due to the limited number of patients and the limited number of genes and genetic variants investigated in studies to date. Moreover, personalized analgesic treatments will require a more complete understanding of the effects of genetic variants and gene-gene interactions in response to analgesics.
View details for DOI 10.1007/s11136-010-9738-x
View details for PubMedID 20842532
Scientific imperatives, clinical implications, and theoretical underpinnings for the investigation of the relationship between genetic variables and patient-reported quality-of-life outcomes.
Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation
2010; 19 (10): 1395-403
There is emerging evidence for a genetic basis of patient-reported quality-of-life (QOL) outcomes that can ultimately be incorporated into clinical research and practice. Objectives are (1) to provide arguments for the timeliness of investigating the genetic basis of QOL given the scientific advances in genetics and patient-reported QOL research; (2) to describe the clinical implications of such investigations; (3) to present a theoretical foundation for investigating the genetic underpinnings of QOL; and (4) to describe a series of papers resulting from the GENEQOL Consortium that was established to move this work forward.Discussion of scientific advances based on relevant literature.In genetics, technological advances allow for increases in speed and efficiency and decreases in costs in exploring the genetic underpinnings of disease processes, drug metabolism, treatment response, and survival. In patient-based research, advances yield empirically based and stringent approaches to measurement that are scientifically robust. Insights into the genetic basis of QOL will ultimately allow early identification of patients susceptible to QOL deficits and to target care. The Wilson and Cleary model for patient-reported outcomes was refined by incorporating the genetic underpinnings of QOL.This series of papers provides a path for QOL and genetics researchers to work together to move this field forward and to unravel the intricate interplay of the genetic underpinnings of patient-reported QOL outcomes. The ultimate result will be a greater understanding of the process relating disease, patient, and doctor that will have the potential to lead to improved survival, QOL, and health services delivery.
View details for DOI 10.1007/s11136-010-9759-5
View details for PubMedID 20945161
View details for PubMedCentralID PMC2977054
I'm so tired: biological and genetic mechanisms of cancer-related fatigue.
Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation
2010; 19 (10): 1419-27
The goal of this paper is to discuss cancer-related fatigue (CRF) and address issues related to the investigation into potential biological and genetic causal mechanisms. The objectives are to: (1) describe CRF as a component of quality of life (QOL); (2) address measurement issues that have slowed progress toward an understanding of mechanisms underlying this symptom; (3) review biological pathways and genetic approaches that have promise for the exploration of causal mechanisms of CRF; and (4) offer directions for future research.Review, synthesis, and interpretation of the literature.Until recently, CRF and QOL have been understood primarily as subjective patient-reported experiences. With increased understanding of human genetics, theories and research are being expanded to incorporate biological and genetic understandings of these subjective experiences. Proposed biological and genetic mechanisms of CRF that have been examined include cytokine dysregulation, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, five hydroxy tryptophan (5-HT) neurotransmitter dysregulation, circadian rhythm disruption, alterations in adenosine triphosphate (ATP) and muscle metabolism, and vagal afferent activation. Approaches to the study of genetic mechanisms have also been addressed including candidate genes, genome-wide scanning, and gene expression. Based on the review and synthesis of the literature, directions for future research are proposed.Understanding the biological and genetic basis of CRF has the potential to contribute to a more complete understanding of the genetic determinants of QOL.
View details for DOI 10.1007/s11136-010-9757-7
View details for PubMedID 20953908
View details for PubMedCentralID PMC3031957
Pharmacogenomic testing in a tertiary care outpatient psychosomatic medicine practice.
2009; 52 (2): 141-6
Pharmacogenomic testing (PGT) has applicability in psychosomatic medicine (PM) practice where medical comorbidity and polypharmacy present particularly difficult challenges of drug-drug and drug-disease interactions. No guidelines currently exist for cost-effective use of PGT in PM practice.The authors tested the hypothesis that naturalistically observed PGT ordering patterns and clinical data on test utility derived from a PM practice where PGT is readily available may inform the development of clinical guidelines for cost-effective use of PGT.Two sets of data were collected from an outpatient PM practice staffed by seven PM-certified psychiatrists. Psychiatrists were surveyed regarding their indications for ordering PGT. Medical records of patients seen in the PM practice during 2008 were reviewed. Patients who had PGT were compared with two sets of case controls who were not tested, one matched by demographics, the other by ordering psychiatrist. Psychiatrists' ordering indications were compared with clinical data derived from the case-control analyses.Psychiatrists listed treatment-resistance as the most common reason for PGT, ahead of intolerance to previous medications. Tested patients differed from controls on measures of both clinical severity and treatment-resistance, including higher self-reported anxiety and depression levels, greater likelihood of family history of mood or anxiety disorders, and larger numbers of prior antidepressant, mood stabilizer, and antipsychotic medication trials.Ordering guidelines that emphasize markers of clinical severity and early indicators of treatment-resistance may provide a useful rationale for PGT in outpatient PM practice. Prospective investigations of this proposition are warranted.
View details for DOI 10.1016/j.psym.2010.12.023
View details for PubMedID 21397106
The establishment of the GENEQOL consortium to investigate the genetic disposition of patient-reported quality-of-life outcomes.
Twin research and human genetics : the official journal of the International Society for Twin Studies
2009; 12 (3): 301-11
To our knowledge, no comprehensive, interdisciplinary initiatives have been taken to examine the role of genetic variants on patient-reported quality-of-life outcomes. The overall objective of this paper is to describe the establishment of an international and interdisciplinary consortium, the GENEQOL Consortium, which intends to investigate the genetic disposition of patient-reported quality-of-life outcomes. We have identified five primary patient-reported quality-of-life outcomes as initial targets: negative psychological affect, positive psychological affect, self-rated physical health, pain, and fatigue. The first tangible objective of the GENEQOL Consortium is to develop a list of potential biological pathways, genes and genetic variants involved in these quality-of-life outcomes, by reviewing current genetic knowledge. The second objective is to design a research agenda to investigate and validate those genes and genetic variants of patient-reported quality-of-life outcomes, by creating large datasets. During its first meeting, the Consortium has discussed draft summary documents addressing these questions for each patient-reported quality-of-life outcome. A summary of the primary pathways and robust findings of the genetic variants involved is presented here. The research agenda outlines possible research objectives and approaches to examine these and new quality-of-life domains. Intriguing questions arising from this endeavor are discussed. Insight into the genetic versus environmental components of patient-reported quality-of-life outcomes will ultimately allow us to explore new pathways for improving patient care. If we can identify patients who are susceptible to poor quality of life, we will be able to better target specific clinical interventions to enhance their quality of life and treatment outcomes.
View details for DOI 10.1375/twin.12.3.301
View details for PubMedID 19456223
View details for PubMedCentralID PMC2824176