The authors sought to identify clinical predictors of new-onset suicidal behavior in children of parents with a history of mood disorder and suicidal behavior.
In a prospective study of offspring of parents with mood disorders, 365 offspring (average age, 20 years) of 203 parents were followed for up to 6 years. Offspring with incident suicide attempts or emergency referrals for suicidal ideation or behavior (“incident events”) were compared with offspring without such events on demographic and clinical characteristics. Multivariate analyses were conducted to examine predictors of incident events and predictors of time to incident event.
Offspring of probands who had made suicide attempts, compared with offspring of parents with mood disorders who had not made attempts, had a higher rate of incident suicide attempts (4.1% versus 0.6%, relative risk=6.5) as well as overall suicidal events (8.3% versus 1.9%, relative risk=4.4). Mood disorder and self-reported impulsive aggression in offspring and a history of sexual abuse and self-reported depression in parents predicted earlier time to, and greater hazard of, an incident suicidal event.
In offspring of parents with mood disorders, precursors of early-onset suicidal behavior include mood disorder and impulsive aggression as well as parental history of suicide attempt, sexual abuse, and self-reported depression. These results suggest that efforts to prevent the familial transmission of early-onset suicidal behavior by targeting these domains could reduce the morbidity of suicidal behavior in high-risk youths.
To evaluate the link between antidepressants and suicidal behavior and ideation (suicidality) in youth, adverse events from pediatric clinical trials were classified in order to identify suicidal events. The authors describe the Columbia Classification Algorithm for Suicide Assessment (C-CASA), a standardized suicidal rating system that provided data for the pediatric suicidal risk analysis of antide-pressants conducted by the Food and Drug Administration (FDA).
Adverse events (N=427) from 25 pediatric antidepressant clinical trials were systematically identified by pharmaceutical companies. Randomly assigned adverse events were evaluated by three of nine independent expert suicidologists using the Columbia classification algorithm. Reliability of the C-CASA ratings and agreement with pharmaceutical company classification were estimated.
Twenty-six new, possibly suicidal events (behavior and ideation) that were not originally identified by pharmaceutical companies were identified in the C-CASA, and 12 events originally labeled as suicidal by pharmaceutical companies were eliminated, which resulted in a total of 38 discrepant ratings. For the specific label of “suicide attempt,” a relatively low level of agreement was observed between the C-CASA and pharmaceutical company ratings, with the C-CASA reporting a 50% reduction in ratings. Thus, although the C-CASA resulted in the identification of more suicidal events overall, fewer events were classified as suicide attempts. Additionally, the C-CASA ratings were highly reliable (intraclass correlation coefficient [ICC]=0.89).
Utilizing a methodical, anchored approach to categorizing suicidality provides an accurate and comprehensive identification of suicidal events. The FDA’s audit of the C-CASA demonstrated excellent transportability of this approach. The Columbia algorithm was used to classify suicidal adverse events in the recent FDA adult antidepressant safety analyses and has also been mandated to be applied to all anticonvulsant trials and other centrally acting agents and nonpsychotropic drugs.
Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts.
The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort.
Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety.
The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.
Cross-sectional studies have demonstrated high rates of comorbidity among substance use disorders. However, few studies have examined the developmental course of incident comorbidity, and how it changes from adolescence to adulthood. Patterns of comorbidity among substance use disorders provides insight into the effect of shared versus specific etiological influences on measures of substance abuse and dependence.
We evaluated the pattern of correlations among nicotine, alcohol, and marijuana abuse and dependence symptom counts as well as their underlying genetic and environmental influences in a community-representative twin sample (N=3762). Symptoms were assessed at ages 11, 14, 17, 20, 24, and 29. A single common factor was used to model the correlations among symptom counts at each age. Age-related changes in the influence of this general factor were examined by testing for differences in the mean factor loading across time.
Mean levels of abuse/dependence symptoms increased throughout adolescence, peaked around age20, and declined from age 24 to 29. The influence of the general factor was highest at ages 14 and 17, but decreased from age 17 to 24. Genetic influences of the general factor declined considerably with age, along with an increase in non-shared environmental influences.
Adolescent substance abuse/dependence is largely a function of shared etiology. As individuals age, symptoms are increasingly influenced by substance-specific etiological factors. Heritability analyses showed that the generalized risk is primarily influenced by genetic factors in adolescence, but non-shared environmental influences increase in importance as substance dependence becomes more specialized in adulthood.
In schizophrenia, alterations within the prefrontal cortical GABA system appear to be most prominent in neurons that contain parvalbumin or somatostatin but not calretinin. The transcription factors Lhx6 and Sox6 play critical roles in the specification, migration, and maturation of parvalbumin and somatostatin neurons, but not calretinin neurons, and continue to be strongly expressed in this cell type-specific manner in the prefrontal cortex of adult humans. The authors investigated whether Lhx6 and/or Sox6 mRNA levels are deficient in schizophrenia, which may contribute to cell type-specific disturbances in cortical parvalbumin and somatostatin neurons.
The authors used quantitative PCR and in situ hybridization with film and grain counting analyses to quantify mRNA levels in postmortem samples of pre-frontal cortex area 9 of 42 schizophrenia subjects and 42 comparison subjects who had no psychiatric diagnoses in life, as well as antipsychotic-exposed monkeys.
In schizophrenia subjects, the authors observed lower mRNA levels for Lhx6, parvalbumin, somatostatin, and glutamate decarboxylase (GAD67; the principal enzyme in GABA synthesis), but not Sox6 or calretinin. Cluster analysis revealed that a subset of schizophrenia subjects consistently showed the most severe deficits in the affected transcripts. Grain counting analyses revealed that some neurons that normally express Lhx6 were not detectable in schizophrenia subjects. Finally, lower Lhx6 mRNA levels were not attributable to psychotropic medications or illness chronicity.
These data suggest that in a subset of individuals with schizophrenia, Lhx6 deficits may contribute to a failure of some cortical parvalbumin and somatostatin neurons to successfully migrate or develop a detectable GABA-ergic phenotype.
It has been suggested that there is a mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with antidepressant response, and poorer outcomes among NSAID-treated patients were reported in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. To attempt to confirm this association in an independent population-based treatment cohort and explore potential confounding variables, the authors examined use of NSAIDs and related medications among 1,528 outpatients in a New England health care system.
Treatment outcomes were classified using a validated machine learning tool applied to electronic medical records. Logistic regression was used to examine the association between medication exposure and treatment outcomes, adjusted for potential confounding variables. To further elucidate confounding and treatment specificity of the observed effects, data from the STAR*D study were reanalyzed.
NSAID exposure was associated with a greater likelihood of depression classified as treatment resistant compared with depression classified as responsive to selective serotonin reuptake inhibitors (odds ratio=1.55, 95% CI=1.21–2.00). This association was apparent in the NSAIDs-only group but not in those using other agents with NSAID-like mechanisms (cyclooxygenase-2 inhibitors and salicylates). Inclusion of age, sex, ethnicity, and measures of comorbidity and health care utilization in regression models indicated confounding; association with outcome was no longer significant in fully adjusted models. Reanalysis of STAR*D results likewise identified an association in NSAIDs but not NSAID-like drugs, with more modest effects persisting after adjustment for potential confounding variables.
These results support an association between NSAID use and poorer antidepressant outcomes in major depressive disorder but indicate that some of the observed effect may be a result of confounding.
Whether sex differences exist in clinical risk factors associated with suicidal behavior is unknown. The authors postulated that among men with a major depressive episode, aggression, hostility, and history of substance misuse increase risk for future suicidal behavior, while depressive symptoms, childhood history of abuse, fewer reasons for living, and borderline personality disorder do so in depressed women.
Patients with DSM-III-R major depression or bipolar disorder seeking treatment for a major depressive episode (N=314) were followed for 2 years. Putative predictors were tested with Cox proportional hazards regression analysis.
During follow-up, 16.6% of the patients attempted or committed suicide. Family history of suicidal acts, past drug use, cigarette smoking, borderline personality disorder, and early parental separation each more than tripled the risk of future suicidal acts in men. For women, the risk for future suicidal acts was sixfold greater for prior suicide attempters; each past attempt increased future risk threefold. Suicidal ideation, lethality of past attempts, hostility, subjective depressive symptoms, fewer reasons for living, comorbid borderline personality disorder, and cigarette smoking also increased the risk of future suicidal acts for women.
These findings suggest that the importance of risk factors for suicidal acts differs in depressed men and women. This knowledge may improve suicide risk evaluation and guide future research on suicide assessment and prevention.
A major barrier to developing treatments for negative symptoms has been measurement concerns with existing assessment tools. Fulfilling the top recommendation of the National Institute of Mental Health’s Consensus Development Conference on Negative Symptoms, the Clinical Assessment Interview for Negative Symptoms (CAINS) was developed using an iterative, empirical approach, and includes items assessing motivation, pleasure, and emotion expression. The authors employed multiple analytic techniques to develop the CAINS and here provide final development and validation results.
The CAINS structure, interrater agreement, test-retest reliability, and convergent and discriminant validity were assessed in a large and diverse sample of 162 outpatients with schizophrenia or schizoaffective disorder recruited from four sites.
Three items with poor psychometric properties were removed, resulting in a 13-item CAINS. The CAINS factor structure was replicated, demonstrating two modestly correlated scales: expression (four items) and motivation/pleasure (nine items). The scales demonstrated good internal consistency, test-retest stability, and interrater agreement. Strong convergent validity was demonstrated by linkages with other negative symptom measures, self-report scales of sociality, pleasure, and motivation, and coded facial expressions. Discriminant validity was shown by independence from depression, medication side effects, and cognition. Notably, the CAINS scales were related to real-world vocational, independent living, and social/familial functioning.
The CAINS is an empirically developed and evaluated measure of negative symptoms. Findings indicate that the CAINS is brief yet comprehensive and employable across a wide range of research and clinical contexts.
Although attention-deficit/hyperactivity disorder (ADHD) in adults is associated with significant morbidity and dysfunction and afflicts both sexes, relatively few imaging studies have examined females and none have had sufficient power to adequately examine sex differences. We sought to examine sex differences in neural functioning of ADHD adults during performance on a verbal working memory task.
Participants were 44 adults with ADHD matched on age, sex, and estimated IQ to 49 controls. Accuracy and reaction time on an n-back task were measures of working memory performance. The blood-oxygenation-level dependent functional magnetic resonance imaging response was used as a measure of neural activity.
A group by sex ANOVA showed no between-group differences in either reaction time or percent correct for the working memory task. For imaging data, with both sexes combined, ADHD adults showed less activity than controls in prefrontal regions. However, sex-by-group analyses revealed an interaction, such that male ADHD adults showed significantly less activity lateralized to right frontal, temporal and subcortical regions, as well as left occipital and cerebellar regions relative to male controls, whereas female ADHD adults showed no differences from female controls. Exploratory correlation analyses revealed negative associations between working memory related activation and number of hyperactive symptoms for males and number of inattentive symptoms for females.
Male but not female adults with ADHD showed significantly altered patterns of neural activity during performance on a verbal working memory task. Males and females showed different associations between neural activity and ADHD symptoms.
ADHD; fMRI; sex differences; working memory; cerebellum; frontal cortex
This study assesses the two-year outcomes, costs, and financial sustainability of a medical care management intervention for community mental health settings.
A total of 407 psychiatric outpatients with serious mental illnesses were randomized to usual care or to a medical care manager, who provided care coordination and education. Two-year follow-up chart reviews and interviews assessed quality and outcomes of care, and costs from both the health system and managerial perspective.
Subjects in the intervention group had sustained improvements in quality of primary care preventive services (p<0.001), quality of cardiometabolic care (p<0.001), and mental health-related quality of life (p<0.001). From a health system perspective, by year 2, the program showed a $932 reduction in total costs (95% CI (−1973, 102) with a 92.3% probability that the program was associated with lower costs than usual care. From the community mental health center perspective, the program would break even (i.e., revenues would cover setup costs) if 58% or more of clients had Medicaid or another form of insurance. Given that only 40.5% of clients in the study had Medicaid, the program was not sustainable after grant funding ended.
The positive long-term outcomes and favorable cost profile provided evidence of the potential value of this model. However, the discrepancy between health system and managerial cost perspectives limited the program’s financial sustainability. With anticipated insurance expansions under health reform, there is likely to be a stronger business case for safety net organizations considering implementing these and other evidence-based interventions.
Poor quality of health care contributes to impaired health and excess mortality in individuals with severe mental disorders. This study tests a population-based medical care management intervention to improve primary medical care in community mental health settings.
A total of 407 subjects with severe mental illnesses at an urban community mental health center were randomized to either care management or usual care. For individuals in the intervention group, care managers provided communication and advocacy with medical providers, health education for patients, and support in overcoming system-level fragmentation and barriers to primary medical care.
At 12-month follow-up, the intervention group received an average of 58.7% of recommended preventive services, compared to 21.8% in the usual care group (p<0.001). They received a significantly higher proportion of evidence-based services for cardiometabolic conditions (34.9% vs. 27.7%, p=0.03), and were more likely to have a primary care provider (71.2% vs. 51.9%, p=0.003). On the SF-36, the intervention group showed significant improvement on the Mental Component Summary score (8.0% improvement in intervention versus 1.1% decline in the control group, p=0.008) with a nonsigificant improvement on the Physical Component Summary score. Among subjects with available laboratory data, Framingham Cardiovascular Risk Scores were significantly lower (better) for intervention (6.9%) than control (9.8%) subjects (p=0.02).
Medical care management was associated with significant improvements in quality and outcomes of primary care. The findings suggest that care management is a promising approach for improving medical care for patients treated in community mental health settings.
Clinicaltrials.gov identifier NCT00183313
We conducted a multi-site, randomized controlled trial examining the strategy of switching from olanzapine, quetiapine, or risperidone to aripiprazole to ameliorate metabolic risk factors for cardiovascular disease.
Patients with schizophrenia or schizoaffective disorder with BMI ≥ 27 and non-HDL cholesterol (non-HDL-C) ≥ 130 mg/dl on a stable dosage of olanzapine, quetiapine, or risperidone were randomly assigned to stay on the current medication (n=106) or switch to aripiprazole (n=109) for 24 weeks. All participants were enrolled in a behaviorally oriented diet and exercise program. Raters were blinded to treatment assignment. The primary and key secondary outcomes were non-HDL-C change and efficacy failure, respectively.
The pre-specified primary analysis included 89 switchers and 98 stayers who had at least one post-baseline non-HDL-C measurement. The least squares mean estimates of non-HDL-C decreased more for the switch than the stay groups (−20.2 vs. −10.8 mg/dl). Switching was associated with larger reductions in weight (2.9 kg) and a net reduction of serum triglycerides of 32.7 mg/dl. Twenty-two (20.6%) switchers and 18 (17.0%) stayers experienced protocol-defined efficacy failure. Forty-seven (43.9%) switchers and 26 (24.5%) stayers discontinued the assigned antipsychotic before 24 weeks.
Switching to aripiprazole led to improvement of non-HDL-C and other metabolic parameters. Rates of efficacy failure were similar between groups, but switching to aripiprazole was associated with a higher rate of treatment discontinuation. In the context of close clinical monitoring, switching from an antipsychotic with high metabolic risk to one with lower risk to improve metabolic parameters is an effective strategy.
Neuroimaging studies have revealed functional abnormalities in the
anterior cingulate cortex in posttraumatic stress disorder (PTSD). The goal
of the current research was to determine whether hyperresponsivity of the
dorsal anterior cingulate in PTSD is an acquired characteristic or familial
Using a case-control twin design, we studied combat-exposed veterans
with PTSD (n=12) and their identical combat-unexposed co-twins
(n=12), as well as combat-exposed veterans without PTSD
(n=14) and their identical combat-unexposed co-twins (n=14).
Participants underwent functional magnetic resonance imaging during
completion of the Multi-Source Interference Task, which reliably activates
the dorsal anterior cingulate.
Combat veterans with PTSD and their co-twins had significantly
greater activation in the dorsal anterior cingulate and tended to have
larger response time difference scores, as compared to non-PTSD veterans and
their co-twins. Dorsal anterior cingulate activation in the exposed twins
was positively correlated with their PTSD symptom severity. Dorsal anterior
cingulate activation in the unexposed twins was positively
correlated with their combat-exposed co-twins’ PTSD symptom
severity, but not with depression or alcohol use severity in the
Hyperresponsivity in the dorsal anterior cingulate appears to be a
familial risk factor for the development of PTSD following psychological
magnetic resonance imaging; limbic system; stress disorders; post-traumatic; twins; monozygotic; gyrus cinguli; Multi-Source Interference Task
Schizotypal personality traits are associated with schizophrenia spectrum disorders. Individuals with schizophrenia spectrum disorders demonstrate increased dopamine transmission in the striatum. We sought to determine if individual differences in normal variation in schizotypal traits correlate with dopamine transmission in the striatum and extra-striatal brain regions.
63 healthy individuals with no history of psychiatric illness completed the Schizotypal Personality Questionnaire and underwent positron emission tomography (PET) imaging with [18F]fallypride at baseline and after administration of oral (0.43 mg/kg) d-amphetamine. Dopamine release, quantified by subtracting each subject’s d-amphetamine scan from their baseline scan, was correlated with Schizotypal Personality Questionnaire total and factor scores using region-of-interest and voxel-wise analyses.
Dopamine release in the striatum positively correlated with overall schizotypal traits. The association was especially robust in the associative sub-division of the striatum. Voxel-wise analyses identified additional correlations between dopamine release and schizotypal traits in the left middle frontal gyrus and left supramarginal gyrus. Exploratory analyses of Schizotypal Personality Questionnaire factor scores revealed correlations between dopamine release and disorganized schizotypal traits in the striatum, thalamus, medial prefrontal cortex, temporal lobe, insula, and inferior frontal cortex.
The association between dopamine signaling and psychosis phenotypes extends to individual differences in normal variation in schizotypal traits and involves dopamine transmission in both striatal and extra-striatal brain regions. D-amphetamine induced dopamine release may be a useful endophenotype for investigating the genetic basis of schizophrenia spectrum disorders.
Despite increasing awareness of the many important roles played by brain-derived neurotrophic factor (BDNF) activation of TrkB, a fuller understanding of this system and the use of potential TrkB-acting therapeutic agents has been limited by the lack of any identified small-molecule TrkB agonists that fully mimic the actions of BDNF at brain TrkB receptors in vivo. However, 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intra-peritoneal administration. The authors combined pharmacological, biochemical, and behavioral approaches in a preclinical study examining the role of 7,8-DHF in modulating emotional memory in mice.
The authors first examined the ability of systemic 7,8-DHF to activate TrkB receptors in the amygdala. They then examined the effects of systemic 7,8-DHF on acquisition and extinction of conditioned fear, using specific and well-characterized BDNF-dependent learning paradigms in several models using naive mice and mice with prior traumatic stress exposure.
Amygdala TrkB receptors, which have previously been shown to be required for emotional learning, were activated by systemic 7,8-DHF (at 5 mg/kg i.p.). 7,8-DHF enhanced both the acquisition of fear and its extinction. It also appeared to rescue an extinction deficit in mice with a history of immobilization stress.
These data suggest that 7,8-DHF may be an excellent agent for use in understanding the effects of TrkB activation in learning and memory paradigms and may be attractive for use in reversing learning and extinction deficits associated with psychopathology.
Bipolar disorder is associated with high risk for suicidal acts. Observational studies suggest a protective effect of lithium against suicidal behavior. However, testing this effect in randomized clinical trials is logistically and ethically challenging. The authors tested the hypothesis that lithium offers bipolar patients with a history of suicide attempt greater protection against suicidal behavior compared to valproate.
Patients with bipolar disorder and past suicide attempts (N=98) were randomly assigned to treatment with lithium or valproate, plus adjunctive medications as indicated, in a double-blind 2.5-year trial. An intent-to-treat analysis was performed using the log-rank test for survival data. Two models were fitted: time to suicide attempt and time to suicide event (attempt or hospitalization or change in medication in response to suicide plans).
There were 45 suicide events in 35 participants, including 18 suicide attempts made by 14 participants, six from the lithium group and eight from the valproate group. There were no suicides. Intent-to-treat analysis using the log-rank test showed no differences between treatment groups in time to suicide attempt or to suicide event. Post hoc power calculations revealed that the modest sample size, reflective of challenges in recruitment, only permits detection of a relative risk of 5 or greater.
Despite the high frequency of suicide events during the study, this randomized controlled trial detected no difference between lithium and valproate in time to suicide attempt or suicide event in a sample of suicide attempters with bipolar disorder. However, smaller clinically significant differences between the two drugs were not ruled out.
The authors examined treatment utilization and outcomes over 2 years among patients admitted to emergency departments with early-phase primary or substance-induced psychosis. The main hypothesis was that patients with substance-induced psychosis would have a more benign course of illness than those with primary psychosis.
Using a prospective naturalistic cohort study design, the authors compared 217 patients with early-phase primary psychosis plus substance use and 134 patients with early-phase substance-induced psychosis who presented to psychiatric emergency departments at hospitals in Upper Manhattan. Assessments at baseline and at 6, 12, 18, and 24 months included psychiatric diagnoses, service use, and institutional outcomes using the Psychiatric Research Interview for Substance and Mental Disorders; psychiatric symptoms using the Positive and Negative Syndrome Scale; social, vocational, and family functioning using the World Health Organization Psychiatric Disability Assessment Schedule; and life satisfaction using the Quality of Life Interview. Longitudinal analyses were conducted using generalized estimating equations.
Participants with primary psychosis were more likely to receive antipsychotic and mood-stabilizing medications, undergo hospitalizations, and have out-patient psychiatric visits; those with substance-induced psychosis were more likely to receive addiction treatments. Only a minority of each group received minimally adequate treatments. Both groups improved significantly over time on substance dependence, psychotic symptoms, homelessness, and psychosocial outcomes, and few group-by-time interactions emerged.
Patients presenting to Upper Manhattan emergency departments with either early-phase primary psychosis or substance-induced psychosis improved steadily over 2 years despite minimal use of mental health and substance abuse services.
The course of alcohol disorders in women is often described as “telescoped” compared to that in men, with a later age at initiation of alcohol use but shorter times from use to dependence and treatment. This study examined evidence for such a telescoping effect in the general population and tested birth cohort effects for gender differences.
Data from two U.S. national surveys conducted 10 years apart (1991–1992 and 2001–2002) using the same diagnostic instrument (the Alcohol Use Disorder and Associated Disabilities Interview Schedule–IV) were used to analyze five birth cohorts. Age at initiation of alcohol use, time from first use to dependence, and time from dependence to first treatment were analyzed. Interaction terms (cohort by gender; cohort by gender by time) were tested in Cox proportional hazards models.
Little evidence was found for a telescoping effect in women. For alcohol use and dependence, cohort and gender interacted, which suggests that gender differences are diminished in more recent cohorts. A three-way interaction of cohort, gender, and time was significant for time from first use to dependence, suggesting that men have a shorter time to dependence, especially in younger cohorts.
A telescoping effect is not evident in the general population. Gender differences in the overall hazard of alcohol use and dependence are decreasing in more recent cohorts, while gender differences in time from first use to dependence are increasing. These findings challenge the commonly held notion of a gender-specific course of alcohol disorders and suggest the need for a greater clinical focus on problem drinking in women and further research on accelerated time to dependence in men.
Many studies have shown that 5-HTTLPR genotype interacts with exposure to stress in conferring risk for psychopathology. However, the specific neural mechanisms through which this gene-by-environment interaction confers risk remain largely unknown, and no study to date has directly examined the modulatory effects of the 5-HTTLPR on corticolimbic circuit responses during exposure to acute stress.
An acute laboratory stressor was administered to 51 healthy women during BOLD fMRI scanning. In this task, electric shocks of uncertain intensity were threatened and unpredictably delivered to the wrist after a long anticipatory cue period of unpredictable duration.
Relative to those carrying the L allele, SS homozygotes showed enhanced activation during threat anticipation in a network of regions including amygdala, hippocampus, anterior insula, thalamus, pulvinar, caudate, precuneus, anterior cingulate cortex, and medial prefrontal cortex. SS homozygotes also displayed enhanced positive coupling between medial prefrontal cortex activation and anxiety experience, whereas individuals carrying the L allele displayed enhanced negative coupling between insula activation and perceived success at regulating anxiety.
The present findings suggest that, when exposed to stress, SS homozygotes may preferentially engage neural systems which enhance fear and arousal, modulate attention toward threat, and perseverate on emotional salience of the threat. This may be one mechanism underlying risk for psychopathology conferred by the S allele upon exposure to life stressors.