Neuroimaging alterations and relapse in early-stage psychosis.

BACKGROUND: Recent reports have indicated that symptom exacerbation after a period of improvement, referred to as relapse, in early-stage psychosis could result in brain changes and poor disease outcomes. We hypothesized that substantial neuroimaging alterations may exist among patients who experience relapse in early-stage psychosis. METHODS: We studied patients with psychosis within 2 years after the first psychotic event and healthy controls. We divided patients into 2 groups, namely those who did not experience relapse between disease onset and the magnetic resonance imaging (MRI) scan (no-relapse group) and those who did experience relapse between these 2 timings (relapse group). We analyzed 3003 functional connectivity estimates between 78 regions of interest (ROIs) derived from resting-state functional MRI data by adjusting for demographic and clinical confounding factors. RESULTS: We studied 85 patients, incuding 54 in the relapse group and 31 in the no-relapse group, along with 94 healthy controls. We observed significant differences in 47 functional connectivity estimates between the relapse and control groups after multiple comparison corrections, whereas no differences were found between the no-relapse and control groups. Most of these pathological signatures (64%) involved the thalamus. The Jonckheere-Terpstra test indicated that all 47 functional connectivity changes had a significant cross-group progression from controls to patients in the no-relapse group to patients in the relapse group. LIMITATIONS: Longitudinal studies are needed to further validate the involvement and pathological importance of the thalamus in relapse. CONCLUSION: We observed pathological differences in neuronal connectivity associated with relapse in early-stage psychosis, which are more specifically associated with the thalamus. Our study implies the importance of considering neurobiological mechanisms associated with relapse in the trajectory of psychotic disorders.

Prevalence and correlates of lifetime suicide attempt in obsessive-compulsive disorder with major depression.

BACKGROUND: Little is known about specific obsessive-compulsive clinical features associated with lifetime history of suicide attempt in individuals with obsessive-compulsive disorder (OCD) and major depression. METHODS: The study sample included 515 adults with OCD and a history of major depression. In exploratory analyses, we compared the distributions of demographic characteristics and clinical features in those with and without a history of attempted suicide and used logistic regression to evaluate the association between specific obsessive-compulsive clinical features and lifetime suicide attempt. RESULTS: Sixty-four (12%) of the participants reported a lifetime history of suicide attempt. Those who had attempted suicide were more likely to report having experienced violent or horrific images (52% vs. 30%; p < 0.001). The odds of lifetime suicide attempt were more than twice as great in participants with versus without violent or horrific images (O.R. = 2.46, 95%, CI = 1.45-4.19; p < 0.001), even after adjustment for other risk correlates of attempted suicide, including alcohol dependence, post-traumatic stress disorder, parental conflict, excessive physical discipline, and number of episodes of depression. The association between violent or horrific images and attempted suicide was especially strong in men, 18-29 year olds, those with post-traumatic stress disorder, and those with particular childhood adversities. CONCLUSIONS: Violent or horrific images are strongly associated with lifetime suicide attempts in OCD-affected individuals with a history of major depression. Prospective clinical and epidemiological studies are needed to elucidate the basis of this relationship.

Longitudinal changes in brain metabolites in healthy controls and patients with first episode psychosis: a 7-Tesla MRS study.

Seven Tesla magnetic resonance spectroscopy (7T MRS) offers a precise measurement of metabolic levels in the human brain via a non-invasive approach. Studying longitudinal changes in brain metabolites could help evaluate the characteristics of disease over time. This approach may also shed light on how the age of study participants and duration of illness may influence these metabolites. This study used 7T MRS to investigate longitudinal patterns of brain metabolites in young adulthood in both healthy controls and patients. A four-year longitudinal cohort with 38 patients with first episode psychosis (onset within 2 years) and 48 healthy controls was used to examine 10 brain metabolites in 5 brain regions associated with the pathophysiology of psychosis in a comprehensive manner. Both patients and controls were found to have significant longitudinal reductions in glutamate in the anterior cingulate cortex (ACC). Only patients were found to have a significant decrease over time in γ-aminobutyric acid, N-acetyl aspartate, myo-inositol, total choline, and total creatine in the ACC. Together we highlight the ACC with dynamic changes in several metabolites in early-stage psychosis, in contrast to the other 4 brain regions that also are known to play roles in psychosis. Meanwhile, glutathione was uniquely found to have a near zero annual percentage change in both patients and controls in all 5 brain regions during a four-year follow-up in young adulthood. Given that a reduction of the glutathione in the ACC has been reported as a feature of treatment-refractory psychosis, this observation further supports the potential of glutathione as a biomarker for this subset of patients with psychosis.

Psychiatric comorbidity in the Baltimore ECA follow-up study: the matrix approach.

BACKGROUND: Psychiatric comorbidity is defined as the joint occurrence of two or more mental or substance use disorders. Widespread psychiatric comorbidity has been reported in treatment and population-based studies. The aim of this study was to measure the extent and impact of psychiatric comorbidity in a cohort of the Baltimore Epidemiologic Catchment Area study. METHODS: We examined the comorbidity burden of 16 mental disorders in a cohort of 847 participants using both established and novel analytical approaches The Comorbidity to Diagnosis Inflation Ratio (CDIR), is a statistical instrument that quantifies impact of pairwise comorbid associations, both on the whole sample, as well as on each specific disorder. RESULTS: Most anxiety disorders had substantial co-occurrence with each other, as well as with Major Depressive Disorder (MDD). In addition, mood disorders had a high degree of comorbidity with Alcohol Dependence (AD). The CDIR for the whole sample was 1.32, indicating a ratio of 132 comorbidities per 100 diagnoses. The conditions with high sample prevalence were relatively less comorbid than the low prevalence conditions. Obsessive Compulsive Disorder had a comorbidity burden that was 89% greater than the overall sample. CONCLUSION: Anxiety disorders are highly interrelated, as well as highly comorbid with depression. The comorbidity phenomenon is linked to the differential prevalence of the analyzed conditions. Comorbidity frequency (most prevalent comorbid condition) appears mutually exclusive to comorbidity burden (most widely interrelated condition). While AD and MDD were the most frequently diagnosed disorders; low prevalence conditions as OCD and GAD were the most widely interrelated.

Brain regions associated with olfactory dysfunction in first episode psychosis patients.

OBJECTIVES: Olfactory dysfunction is reproducibly reported in psychotic disorders, particularly in association with negative symptoms. The superior frontal gyrus (SFG) has been frequently studied in patients with psychotic disorders, in particular with their associations with negative symptoms. The relationship between olfactory functions and brain structure has been studied in healthy controls (HCs). Nevertheless, the studies with patients with psychotic disorders are limited. Here we report the olfactory-brain relationship in a first episode psychosis (FEP) cohort through both hypothesis-driven (centred on the SFG) and data-driven approaches. METHODS: Using data from 88 HCs and 76 FEP patients, we evaluated the correlation between olfactory functions and structural/resting-state functional magnetic resonance imaging (MRI) data. RESULTS: We found a significant correlation between the left SFG volume and odour discrimination in FEP patients, but not in HCs. We also observed a significant correlation between rs-fMRI connectivity involving the left SFG and odour discrimination in FEP patients, but not in HCs. The data-driven approach didn't observe any significant correlations, possibly due to insufficient statistical power. CONCLUSION: The left SFG may be a promising brain region in the context of olfactory dysfunction and negative symptoms in FEP.

Sex-specific involvement of the Notch-JAG pathway in social recognition.

Under the hypothesis that olfactory neural epithelium gene expression profiles may be useful to look for disease-relevant neuronal signatures, we examined microarray gene expression in olfactory neuronal cells and underscored Notch-JAG pathway molecules in association with schizophrenia (SZ). The microarray profiling study underscored JAG1 as the most promising candidate. Combined with further validation with real-time PCR, downregulation of NOTCH1 was statistically significant. Accordingly, we reverse-translated the significant finding from a surrogate tissue for neurons, and studied the behavioral profile of Notch1+/- mice. We found a specific impairment in social novelty recognition, whereas other behaviors, such as sociability, novel object recognition and olfaction of social odors, were normal. This social novelty recognition deficit was male-specific and was rescued by rapamycin treatment. Based on the results from the animal model, we next tested whether patients with psychosis might have male-specific alterations in social cognition in association with the expression of NOTCH1 or JAG1. In our first episode psychosis cohort, we observed a specific correlation between the expression of JAG1 and a face processing measure only in male patients. The expression of JAG1 was not correlated with any other cognitive and symptomatic scales in all subjects. Together, although we acknowledge the pioneering and exploratory nature, the present work that combines both human and animal studies in a reciprocal manner suggests a novel role for the Notch-JAG pathway in a behavioral dimension(s) related to social cognition in psychotic disorders in a male-specific manner.

A multimodal study of a first episode psychosis cohort: potential markers of antipsychotic treatment resistance.

Treatment resistant (TR) psychosis is considered to be a significant cause of disability and functional impairment. Numerous efforts have been made to identify the clinical predictors of TR. However, the exploration of molecular and biological markers is still at an early stage. To understand the TR condition and identify potential molecular and biological markers, we analyzed demographic information, clinical data, structural brain imaging data, and molecular brain imaging data in 7 Tesla magnetic resonance spectroscopy from a first episode psychosis cohort that includes 136 patients. Age, gender, race, smoking status, duration of illness, and antipsychotic dosages were controlled in the analyses. We found that TR patients had a younger age at onset, more hospitalizations, more severe negative symptoms, a reduction in the volumes of the hippocampus (HP) and superior frontal gyrus (SFG), and a reduction in glutathione (GSH) levels in the anterior cingulate cortex (ACC), when compared to non-TR patients. The combination of multiple markers provided a better classification between TR and non-TR patients compared to any individual marker. Our study shows that ACC-GSH, HP and SFG volumes, and age at onset, could potentially be biomarkers for TR diagnosis, while hospitalization and negative symptoms could be used to evaluate the progression of the disease. Multimodal cohorts are essential in obtaining a comprehensive understanding of brain disorders.

An investigation of COVID-19 related worry in a United States population sample.

BACKGROUND: Although general anxiety has increased markedly since the onset of the COVID-19 pandemic, little has been reported about the demographic distribution of COVID-19 related worry, its relationship with psychological features, and its association with depression symptoms in the United States (US). METHODS: 2117 participants, selected to represent the age, gender, and race/ethnic distributions of the US population, completed an online survey. Analysis of variance and correlation analyses were used to assess relationships between the COVID-19 related worry score and demographic characteristics, past psychiatric diagnoses, personality dimensions, and current psychological symptoms. Logistic regression was used to evaluate the association between the COVID-19 worry score and depression symptoms. RESULTS: The COVID-19 worry score was markedly higher in younger (18-49 year-olds) than older participants, and moderately higher in men, those who were married or cohabiting, with post-college education, and/or living in large urban areas. The COVID-19 worry score also was markedly higher in those who reported having been diagnosed with a psychiatric disorder. The COVID-19 worry score correlated with neuroticism, current psychological symptoms, and COVID-19 risk and COVID-19 behavior scores. The COVID-19 worry score was associated with current depression symptoms (OR = 1.10, 95% CI = 1.09-1.11; p < 0.001) in univariable models and remained significant after adjustment for other correlates of depression, including COVID-19 risk. CONCLUSIONS: In this US sample, the COVID-19 worry score was inversely related to age, strongly related to psychological symptoms, and independently associated with depression symptoms. These findings have implications for the community mental health response to the COVID-19 pandemic in the US.

Face processing of social cognition in patients with first episode psychosis: Its deficits and association with the right subcallosal anterior cingulate cortex.

The clinical importance of social cognition is well acknowledged in patients with psychosis, in particular those with first episode psychosis (FEP). Nevertheless, its brain substrates and circuitries remain elusive, lacking precise analysis between multimodal brain characteristics and behavioral sub-dimensions within social cognition. In the present study, we examined face processing of social cognition in 71 FEP patients and 77 healthy controls (HCs). We looked for a possible correlation between face processing and multimodal MRI characteristics such as resting-state functional connectivity (rsFC) and brain volume. We observed worse recognition accuracy, longer recognition response time, and longer memory response time in FEP patients when compared with HCs. Of these, memory response time was selectively correlated with specific rsFCs, which included the right subcallosal sub-region of BA24 in the ACC (scACC), only in FEP patients. The volume of this region was also correlated with memory response time in FEP patients. The scACC is functionally and structurally important in FEP-associated abnormalities of face processing measures in social cognition.

Neural correlates of doubt in decision-making.

The experience of doubt, the lack of confidence in one's perceptions, internal states, memory and attention, can be due to the variability in occurrence of a phenomenon or can be driven by the internal experience of uncertainty based on subjective evaluation of the environment. Although the experience of some doubt is adaptive in normal cognitive functioning, excessive doubt can significantly impair decision-making and in extreme cases give rise to psychopathology. Although neuroimaging studies have provided some insight into the network of brain areas that is engaged when decision-making involves uncertainty, it remains unclear if dysfunction in these areas also gives rise to the experience and pathological expression of doubt. This study examined the neural correlates of doubt using neuroimaging during the performance of a forced-choice perceptual decision-making task under varying levels of uncertainty in participants who reported either low or high doubt. Participants reporting high doubt exhibited increased activation in the bilateral inferior parietal lobule (IPL) during perceptual decision-making which was not observed in participants who reported low doubt. Furthermore, activity in the IPL in high doubt participants was associated with clinical measures of doubt and showed functional connectivity differences between the high and low doubt groups. The findings of the current study suggest a key role of the IPL and provide a network of brain regions that may play a role in the experience and expression of doubt.

Long-term physical health outcomes of obsessive-compulsive personality disorder traits.

BACKGROUND: Obsessive-compulsive personality disorder (OCPD) is characterized by pervasive and persistent traits including preoccupation with orderliness, perfectionism, and control. Relatively little is known about the potential relationship between OCPD traits and physical health. METHODS: We investigated the association between OCPD traits and several self-reported medical conditions in 249 individuals followed prospectively from 1981 until 2004/2005 as part of the Epidemiological Catchment Area. RESULTS: The OCPD trait score was inversely related to hypertension in males, in models unadjusted (OR = 0.66; 95% CI, 0.45-0.90) and adjusted (OR = 0.70; 95% CI, 0.47-0.95) for sociodemographic variables. Perfectionism was inversely related to hypertension in the unadjusted models for men (OR = 0.34; 95% CI, 0.12-0.89). Indecisiveness was positively associated with heart conditions in adjusted models for women (OR = 3.46; 95% CI, 1.11-10.52). CONCLUSION: OCPD traits are associated with cardiovascular health in both sexes. Further studies are needed to understand the specificity of these relationships, as well as to determine the underlying mechanism.

Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants.

Obsessive-compulsive disorder (OCD) affects 1-2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk. In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants. In case-control analyses (n = 1,263/11,580), the most significant single-gene result was observed in SLITRK5 (odds ratio (OR) = 8.8, 95% confidence interval 3.4-22.5, P = 2.3 × 10-6). Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant (OR = 1.33, P = 0.01). In an analysis of trios, we observed an excess of de novo missense predicted damaging variants relative to controls (OR = 1.22, P = 0.02), alongside an excess of de novo LoF mutations in LoF-intolerant genes (OR = 2.55, P = 7.33 × 10-3). These data support a contribution of rare coding variants to OCD genetic risk.

Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

BACKGROUND: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. OBJECTIVE: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. METHODS: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta-analyses, incorporating data from previously published literature. RESULTS: Rates of obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta-analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First-degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. CONCLUSIONS: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Peripartum complications associated with obsessive compulsive disorder exacerbation during pregnancy.

Prior research has shown that onset or exacerbation of OCD is associated with menstruation, pregnancy, and the post-partum period. However, the underlying cause is unclear. The goal of this study was to assess whether pregnancy and birth complications were associated with OCD symptoms exacerbation, among women with established OCD. Two-hundred and five (n=205) women with OCD retrospectively reported information on their physical and mental health during their first pregnancy. Over a third of the sample (34%) reported an exacerbation in their OCD symptoms. History of pregnancy and birth complications in the first pregnancy were similar between women who did and did not experience symptom exacerbation, with the exception of gestational diabetes, which was significantly more common among women who experienced exacerbation (7% vs 1%, p=0.03). In a multivariable logistic regression model, gestational diabetes remained significantly associated with exacerbation of OCD symptoms (OR=8.44 [95% CI 1.37-77.27]; p=0.03), even after adjusting for maternal age, OCD severity and treatment, premenstrual OCD symptom increase, stress during pregnancy, and major depression or anxiety disorder diagnosis during pregnancy. We discuss potential explanations for this link. These findings should be treated as hypothesis-generating and need to be replicated in a larger, prospective study.

Specialty knowledge and competency standards for pharmacotherapy for adult obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) affects approximately one person in 40 and causes substantial suffering. Evidence-based treatments can benefit many; however, optimal treatment can be difficult to access. Diagnosis is frequently delayed, and pharmacological and psychotherapeutic interventions often fail to follow evidence-based guidelines. To ameliorate this distressing situation, the International OCD Accreditation Task Force of the Canadian Institute for Obsessive-Compulsive Disorders has developed knowledge and competency standards for specialized treatments for OCD through the lifespan. These are foundational to evidence-based practice and will form the basis for upcoming ATF development of certification/accreditation programs. Here, we present specialty standards for the pharmacological treatment of adult OCD. We emphasize the importance of integrating pharmacotherapy with clear diagnosis, appreciation of complicating factors, and evidence-based cognitive behavioral therapy. Clear evidence exists to inform first- and second-line pharmacological treatments. In disease refractory to these initial efforts, multiple strategies have been investigated, but the evidence is more equivocal. These standards summarize this limited evidence to give the specialist practitioner a solid basis on which to make difficult decisions in complex cases. It is hoped that further research will lead to development of a clear, multi-step treatment algorithm to support each step in clinical decision-making.

Contamination-related behaviors, obsessions, and compulsions during the COVID-19 pandemic in a United States population sample.

BACKGROUND: Contamination-prevention behaviors such as mask wearing and physical distancing are crucial to reduce coronavirus transmission during the COVID-19 pandemic. We hypothesized that engagement in these behaviors could provoke obsessions and phobias in vulnerable individuals in the community. METHODS: A total of 2117 participants, systematically selected to represent the age, gender, and race distributions of the US population, completed an online survey that assessed demographic characteristics, clinical features, COVID-19 risks, and COVID-19 contamination-prevention behaviors. Logistic regression was used to estimate the magnitude of the relationships between the COVID-19 behavior score and clinically significant contamination obsessions, contamination compulsions, and pre-COVID-19 to current change in obsessive-compulsive symptom scores. RESULTS: The COVID-19 behavior score was significantly associated with contamination obsessions (odds ratio (OR) = 1.15, 95% CI = 1.12-1.16; p < 0.001) and contamination phobias (OR = 1.14, 95% CI = 1.12-1.16; p < 0.001). The COVID-19 behavior score also was associated with pre-pandemic to current increase in the overall obsessive-compulsive symptom score (OR = 1.16, 95% CI = 1.09-1.23; p < 0.001), as well as increase in obsessive-compulsive symptom score excluding washing items (OR = 1.13, 95% CI = 1.07-1.19; p < 0.001). The magnitude of these relationships did not appreciably change, after adjustment for other variables associated with the outcomes. Moreover, the relationship was significant in those with or without OCD, and in individuals with different levels of doubt and COVID-19 risk. CONCLUSIONS: Contamination safety measures are critical for reducing the spread of COVID-19 in the community. However, they may be related to the development of contamination-related symptoms and OCD in vulnerable individuals, complicating the diagnosis and treatment of mental disorders during this period.

Genome-wide association study of pediatric obsessive-compulsive traits: shared genetic risk between traits and disorder.

Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10-8). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p's < 0.01). OC traits were highly, but not significantly, genetically correlated with OCD (rg = 0.71, p = 0.062). We report the first validated genome-wide significant variant for OC traits in PTPRD, downstream of the most significant locus in a previous OCD GWAS. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the feasibility and power of using trait-based approaches in community samples for genetic discovery.

De novo variation in bipolar disorder.

Bipolar disorder (BD) is a common, highly heritable disorder that affects 1-2% of the world's population. To date, most genetic studies of BD have focused on common gene variation, and while robustly associated loci have been identified, a substantial proportion of the heritability remains missing and could be partially attributable to rare variation. In this study, we apply a de novo paradigm in BD to identify newly arisen variants that have yet to undergo natural selection and may represent highly pathogenic variants. We performed whole genome sequencing of 97 trios of Ashkenazi Jewish descent, selecting "simplex" families with no family history of BD and an early age of onset. We found a total of 6882 de novo variants (an average of 70.9 ± 12.9 S.D. variants per trio), including 107 variants within protein-coding genes. We combined our exonic variations with the results of 79 previously published BD trios, identifying 20 loss-of-function (LoF) and 77 missense damaging de novo variants in BD. These variants showed significant enrichment for constrained genes and for genes located to the postsynaptic density (PSD) (all Bonferroni corrected p < 0.05). Pathway analyses showed enrichment in several pathways, including "Phosphoinositides (PI) and their downstream targets" (Bonferroni p = 4.2 × 10-6), a pathway prominently featured in lithium's hypothesized mechanism of action. In addition, while we found overall evidence for transmission of common variant polygenic risk of BD in our full sample (pTDT p = 2.21 × 10-4), specific trios with LoF variants showed no evidence of polygenic transmission. In sum, our findings support the de novo paradigm as a contributor to the genetic architecture of BD and provide evidence that constrained genes, as well as genes within the PSD and PI pathway harbor rare variation associated with BD.

The serotonin transporter gene polymorphism (SLC6A4) and risk for psychiatric morbidity and comorbidity in the Baltimore ECA follow-up study.

BACKGROUND: The human serotonin transporter (SERT) gene polymorphism (5HTTLPR) has been associated with multiple psychiatric disorders, including major depression, anxiety disorders, and substance use disorders. This study investigated the association between 5HTTLPR and psychiatric morbidity and comorbidity in a psychiatrist-examined population sample. METHODS: 628 participants, mean age 48.3 years old, were assessed by psychiatrists using the Schedules for Clinical Assessment in Neuropsychiatry. Associations between 5HTTLPR and the prevalence, comorbidity, and time-to-diagnoses for 16 psychiatric conditions were evaluated, using several analytical approaches. RESULTS: The SERT S allele was significantly associated with an increased lifetime prevalence of panic disorder. There was a "protective" association between SERT gene S allele carrier status and the risk of obsessive-compulsive disorder (OCD) in time-to-event analysis. Carriers of the S allele had a significant increased risk of two specific comorbid disorder pairs: major depressive disorder (MDD) and social phobia, and MDD and agoraphobia. Overall, there was no increased risk of receiving an initial or an additional diagnosis for a mental disorder in the SERT S allele carriers CONCLUSIONS: The findings suggest that the S allele carrier status is associated with an increased prevalence of panic disorder in a community sample. There was an increased risk for comorbidity in a more homogeneous subgroup of cases with MDD and social phobia, as well as or agoraphobia. Our findings suggest a specific effect of the SERT promoter gene polymorphism on a subgroup of individuals identifiable by their comorbidity.