American Journal of Psychiatry Articles

Genome-Wide Linkage and Follow-Up Association Study of Postpartum Mood Symptoms [Articles]

Mon, 02 Nov 2009 10:01:53 PST

OBJECTIVE: Family studies have suggested that postpartum mood symptoms might have a partly genetic etiology. The authors used a genome-wide linkage analysis to search for chromosomal regions that harbor genetic variants conferring susceptibility for such symptoms. The authors then fine-mapped their best linkage regions, assessing single nucleotide polymorphisms (SNPs) for genetic association with postpartum symptoms. METHOD: Subjects were ascertained from two studies: the NIMH Genetics Initiative Bipolar Disorder project and the Genetics of Recurrent Early-Onset Depression. Subjects included women with a history of pregnancy, any mood disorder, and information about postpartum symptoms. In the linkage study, 1,210 women met criteria (23% with postpartum symptoms), and 417 microsatellite markers were analyzed in multipoint allele sharing analyses. For the association study, 759 women met criteria (25% with postpartum symptoms), and 16,916 SNPs in the regions of the best linkage peaks were assessed for association with postpartum symptoms. RESULTS: The maximum linkage peak for postpartum symptoms occurred on chromosome 1q21.3-q32.1, with a chromosome-wide significant likelihood ratio Z score (Z_LR) of 2.93 (permutation p=0.02). This was a significant increase over the baseline Z_LR of 0.32 observed at this locus among all women with a mood disorder (permutation p=0.004). Suggestive linkage was also found on 9p24.3-p22.3 (Z_LR=2.91). In the fine-mapping study, the strongest implicated gene was HMCN1 (nominal p=0.00017), containing four estrogen receptor binding sites, although this was not region-wide significant. CONCLUSIONS: This is the first study to examine the genetic etiology of postpartum mood symptoms using genome-wide data. The results suggest that genetic variations on chromosomes 1q21.3-q32.1 and 9p24.3-p22.3 may increase susceptibility to postpartum mood symptoms.

Anxiety and Outcome in Bipolar Disorder [Articles]

Mon, 02 Nov 2009 10:01:53 PST

OBJECTIVE: Important differences exist between bipolar disorder with and without comorbid anxiety, but little is known about the long-term prognostic significance of coexisting anxiety in bipolar disorder. The authors sought to identify the anxiety features most predictive of subsequent affective morbidity and to evaluate the persistence of the prognostic relationship. METHOD: Probands with bipolar I or II disorder from the National Institute of Mental Health Collaborative Depression Study were followed prospectively for a mean of 17.4 years (SD=8.4) and were characterized according to various manifestations of anxiety present at baseline. A series of general linear model analyses examined the relationship between these measures and the proportion of follow-up weeks in episodes of major depression and in episodes of mania or hypomania. RESULTS: Patients whose episode at intake included a depressive phase spent nearly three times as many weeks in depressive episodes than did those whose intake episode was purely manic. Psychic and somatic anxiety ratings, but not the presence of panic attacks or of any lifetime anxiety disorder, added to the predictive model. Combined ratings of psychic and somatic anxiety were associated in a stepwise fashion with a greater proportion of weeks in depressive episodes, and this relationship persisted over the follow-up period. CONCLUSIONS: The presence of higher levels of anxiety during bipolar mood episodes appears to mark an illness of substantially greater long-term depressive morbidity.

Enhancing Multiyear Guideline Concordance for Bipolar Disorder Through Collaborative Care [Articles]

Bauer, M. S., Biswas, K., Kilbourne, A. M. — Mon, 02 Nov 2009 10:01:53 PST

OBJECTIVE: Implementation of evidence-based care for serious mental illnesses such as bipolar disorder has been suboptimal. Improving and sustaining concordance with clinical practice guidelines has been a cornerstone of efforts to enhance evidence-based care and improve outcomes. For bipolar disorder, however, there has been only one regional controlled trial reporting guideline concordance, and no data are available for time periods longer than 1 year. In a multiregion effectiveness trial in veterans with bipolar disorder, the authors assessed the effects of a collaborative care model for this disorder on guideline concordance in care over a 3-year period. METHOD: A total of 306 participants with bipolar disorder were randomly assigned at hospital discharge to 3 years of follow-up treatment with a collaborative care model or to usual care. The collaborative care model included provider support through simplified practice guidelines, patient skills management enhancement through group psychoeducation, and facilitated access and continuity via nurse care management. Concordance with guideline-recommended antimanic pharmacotherapy was assessed at baseline and prospectively over six 6-month epochs. Group differences were assessed with generalized estimating equations that controlled for relevant covariates. RESULTS: The collaborative care model achieved significantly higher rates of guideline-concordant antimanic treatment than usual care over the entire follow-up period. Baseline guideline concordance, but not patient age or bipolar type, was associated with higher concordance. CONCLUSIONS: Multicomponent collaborative care models, which include not only provider support for guideline implementation but also patient self-management skill enhancement and facilitated treatment access and continuity, can improve guideline concordance over the long term, even in severely impaired patients.

Association of Pre-Onset Cannabis, Alcohol, and Tobacco Use With Age at Onset of Prodrome and Age at Onset of Psychosis in First-Episode Patients [Articles]

Mon, 02 Nov 2009 10:01:53 PST

OBJECTIVE: Several reports suggest that cannabis use is associated with an earlier age at onset of psychosis, although not all studies have operationalized cannabis use as occurring prior to onset of symptoms. This study addressed whether pre-onset cannabis use, alcohol use, and tobacco use are associated with an earlier age at onset of prodromal and psychotic symptoms. Effects of the progression of frequency of use were examined through time-dependent covariates in survival analyses. METHOD: First-episode patients (N=109) hospitalized in three public-sector inpatient psychiatric units underwent in-depth cross-sectional retrospective assessments. Prior substance use and ages at onset of prodromal and psychotic symptoms were determined by standardized methods, and analyses were conducted using Cox regression modeling. RESULTS: Whereas classifying participants according to maximum frequency of use prior to onset (none, ever, weekly, or daily) revealed no significant effects of cannabis or tobacco use on risk of onset, analysis of change in frequency of use prior to onset indicated that progression to daily cannabis and tobacco use was associated with an increased risk of onset of psychotic symptoms. Similar or even stronger effects were observed when onset of illness or prodromal symptoms was the outcome. A gender-by-daily-cannabis-use interaction was observed; progression to daily use resulted in a much larger increased relative risk of onset of psychosis in females than in males. CONCLUSIONS: Pre-onset cannabis use may hasten the onset of psychotic as well as prodromal symptoms. Age at onset is a key prognostic factor in schizophrenia, and discovering modifiable predictors of age at onset is crucial.

The Influence of Neighborhood Environment on Treatment Continuity and Rehospitalization in Dually Diagnosed Patients Discharged From Acute Inpatient Care [Articles]

Stahler, G. J., Mennis, J., Cotlar, R., Baron, D. A. — Mon, 02 Nov 2009 10:01:53 PST

OBJECTIVE: Environmental contingencies inherent in neighborhoods and communities have been shown to affect individual behavior. The authors analyzed neighborhood and individual factors predicting initial outpatient treatment attendance and rehospitalization within 1 year among patients who were dually diagnosed with at least one mental disorder and a substance use disorder and discharged from an acute psychiatric inpatient care unit. METHOD: Stepwise-forward logistic regression modeling and a geographic information system were utilized to assess data extracted from the medical records of 380 patients who, upon hospital admission, had one or more mental health disorders and a positive urine drug screen for prototypical illicit drugs. Geographic data on patients’ neighborhood environment were obtained from public sources. Outcome variables were whether a patient attended the first outpatient treatment appointment within 30 days of hospital discharge and whether a patient was readmitted to the inpatient unit within 1 year of discharge. Predictor variables were features relating to individual-level patient characteristics and features associated with neighborhood environment. RESULTS: Factors that decreased the likelihood of attending the initial outpatient treatment were returning home following hospitalization (versus returning to an institutional setting), residing in an area with a high vacant housing rate, residing in an area far from an Alcoholics Anonymous meeting location, having the chief complaint of bizarre behavior (i.e., grossly inappropriate behavior), and having a urine drug screen positive for heroin. The likelihood of being rehospitalized within 1 year was greater for Hispanic patients, patients who had at least one prior hospital admission, and patients who lived in close proximity to a Narcotics Anonymous meeting location. Patients living in areas with higher educational attainment had a reduced likelihood of rehospitalization. CONCLUSIONS: A more explicit focus on the neighborhood and community context represents an important area in psychiatry, in terms of both research and clinical practice, which can potentially enhance long-term care and treatment planning for psychiatric patients. Future research is needed to better understand the influence of the neighborhood environment to help predict important clinical outcomes.

Randomized, Double-Blind, Placebo-Controlled Trial of Vigabatrin for the Treatment of Cocaine Dependence in Mexican Parolees [Articles]

Mon, 02 Nov 2009 10:01:53 PST

OBJECTIVE: Cocaine dependence is associated with severe medical, psychiatric, and social morbidity, but no pharmacotherapy is approved for its treatment in the United States. The atypical antiepileptic vigabatrin (-vinyl gamma-aminobutyric acid [GABA]) has shown promise in animal studies and open-label trials. The purpose of the present study was to assess the efficacy of vigabatrin for short-term cocaine abstinence in cocaine-dependent individuals. METHOD: Participants were treatment seeking parolees who were actively using cocaine and had a history of cocaine dependence. Subjects were randomly assigned to a fixed titration of vigabatrin (N=50) or placebo (N=53) in a 9-week double-blind trial and 4-week follow-up assessment. Cocaine use was determined by directly observed urine toxicology testing twice weekly. The primary endpoint was full abstinence for the last 3 weeks of the trial. RESULTS: Full end-of-trial abstinence was achieved in 14 vigabatrin-treated subjects (28.0%) versus four subjects in the placebo arm (7.5%). Twelve subjects in the vigabatrin group and two subjects in the placebo group maintained abstinence through the follow-up period. The retention rate was 62.0% in the vigabatrin arm versus 41.5% in the placebo arm. Among subjects who reported prestudy alcohol use, vigabatrin, relative to placebo, was associated with superior self-reported full end-of-trial abstinence from alcohol (43.5% versus 6.3%). There were no differences between the two groups in drug craving, depressed mood, anxiety, or Clinical Global Impression scores, and no group differences in adverse effects emerged. CONCLUSIONS: This first randomized, double-blind, placebo-controlled trial supports the safety and efficacy of short-term vigabatrin treatment of cocaine dependence.

Randomized, Single-Blind, Controlled Trial of a Specialist Behavior Therapy Team for Challenging Behavior in Adults With Intellectual Disabilities [Articles]

Mon, 02 Nov 2009 10:01:53 PST

OBJECTIVE: Community-based specialist behavior therapy teams may be helpful in managing challenging behavior, but evidence of their effectiveness is limited. This study was designed to examine the effectiveness and costs associated with treatment by a specialist behavior therapy team. METHOD: This was a parallel-group, randomized, single-blind controlled trial carried out in an intellectual disabilities service in England. Participants were 63 male and female service users with mild to severe intellectual disability who presented with challenging behavior. The interventions were standard treatment plus applied behavioral analysis (N=32) and standard treatment only (N=31). The primary outcome measure was challenging behavior, as measured by total and subscale scores on the Aberrant Behavior Checklist 3 and 6 months after randomization. Secondary outcome measures were psychiatric comorbidity assessed at 3 and 6 months using the Psychiatric Assessment Schedule for Adults With a Developmental Disability Checklist (PAS-ADD) and total costs recorded at 6 months. Multilevel modeling was used to compare square root transformations of Aberrant Behavior Checklist scores. RESULTS: Significant differences were found in the transformed total scores on the Aberrant Behavior Checklist (difference=–0.89, 95% CI=–1.74 to –0.04) and transformed lethargy and hyperactivity subscale scores (common intervention effect=–0.56, 95% CI=–0.97 to –0.15). Standard care participants fared worse on the PAS-ADD comorbid organic disorder subscale. There was a clear trend for lower overall costs of the intervention. CONCLUSIONS: Use of a specialist behavior therapy team in addition to standard treatment appears to be more effective in improving challenging behavior and may have financial advantages over standard treatment.

An fMRI Study of the Effects of Psychostimulants on Default-Mode Processing During Stroop Task Performance in Youths With ADHD [Articles]

Mon, 02 Nov 2009 10:01:54 PST

OBJECTIVE: The authors examined the effect of psychostimulants on brain activity in children and adolescents with ADHD performing the Stroop Color and Word Test. METHOD: The authors acquired 52 functional MRI scans in 16 youths with ADHD who were known responders to stimulant medication and 20 healthy comparison youths. Participants with ADHD were scanned on and off medication in a counterbalanced design, and comparison subjects were scanned once without medication. RESULTS: Stimulant medication significantly improved suppression of default-mode activity in the ventral anterior cingulate cortex in the ADHD group. When off medication, youths with ADHD were unable to suppress default-mode activity to the same degree as comparison subjects, whereas when on medication, they suppressed this activity to comparison group levels. Greater activation of the lateral prefrontal cortex when off medication predicted a greater reduction in ADHD symptoms when on medication. Granger causality analyses demonstrated that activity in the lateral prefrontal and ventral anterior cingulate cortices mutually influenced one another but that the influence of the ventral anterior cingulate cortex on the lateral prefrontal cortex was significantly reduced in youths with ADHD off medication relative to comparison subjects and increased significantly to normal levels when ADHD youths were on medication. CONCLUSIONS: Psychostimulants in youths with ADHD improved suppression of default-mode activity in the ventral anterior cingulate and posterior cingulate cortices, components of a circuit in which activity has been shown to correlate with the degree of mind-wandering during attentional tasks. Stimulants seem to improve symptoms in youths with ADHD by normalizing activity within this circuit and improving its functional interactions with the lateral prefrontal cortex.

Familial Aggregation of Suicide Explained by Cluster B Traits: A Three-Group Family Study of Suicide Controlling for Major Depressive Disorder [Articles]

McGirr, A., Alda, M., Seguin, M., Cabot, S., Lesage, A., Turecki, G. — Thu, 01 Oct 2009 10:01:37 PDT

OBJECTIVE: There is substantial evidence suggesting that suicide aggregates in families. However, the extent of overlap between the liability to suicide and psychiatric disorders, particularly major depressive disorder, remains an important issue. Similarly, factors that account for the familial transmission of suicidal behavior remain unclear. Thus, through direct and blind assessment of first-degree relatives, the authors conducted a family study of suicide by examining three proband groups: probands who committed suicide in the context of major depressive disorder, living depressed probands with no history of suicidal behavior, and psychiatrically normal community comparison probands. METHOD: Participants were 718 first-degree relatives from 120 families: 296 relatives of 51 depressed probands who committed suicide, 185 relatives of 34 nonsuicidal depressed probands, and 237 relatives of 35 community comparison subjects. Psychopathology, suicidal behavior, and behavioral measures were assessed via interviews. RESULTS: The relatives of probands who committed suicide had higher levels of suicidal behavior (10.8%) than the relatives of nonsuicidal depressed probands (6.5%) and community comparison probands (3.4%). Testing cluster B traits as intermediate phenotypes of suicide showed that the relatives of depressed probands who committed suicide had elevated levels of cluster B traits; familial predisposition to suicide was associated with increased levels of cluster B traits; cluster B traits demonstrated familial aggregation and were associated with suicide attempts among relatives; and cluster B traits mediated, at least in part, the relationship between familial predisposition and suicide attempts among relatives. Analyses were repeated for severity of attempts, where cluster B traits also met criteria for endophenotypes of suicide. CONCLUSIONS: Familial transmission of suicide and major depression, while partially overlapping, are distinct. Cluster B traits and impulsive-aggressive behavior represent intermediate phenotypes of suicide.

Suicide Attempts, Gender, and Sexual Abuse: Data From the 2000 British Psychiatric Morbidity Survey [Articles]

Thu, 01 Oct 2009 10:01:37 PDT

OBJECTIVE: The purpose of this study was to utilize data from the 2000 British National Survey of Psychiatric Morbidity, a randomized cross-sectional survey of the British population that included questions relating to the phenomena of suicidality and sexual abuse, to test the hypothesis that suicide attempts in women are significantly associated with a history of sexual abuse. METHOD: Participants were male and female volunteers, ages 16 to 74 years old (N=8,580), interviewed in the 2000 British National Survey of Psychiatric Morbidity. RESULTS: Sexual abuse was strongly associated with a history of suicide attempts as well as of suicidal intent and was more common in women. The population attributable risk fraction was considerably greater in female respondents (28%) than in male respondents (7%), which is consistent with more prevalent exposure to sexual abuse among women. The effect of sexual abuse on suicidal attempts and suicidal intent was reduced by controlling for affective symptoms, suggesting that the effect of the former was likely to be mediated by affective changes. CONCLUSIONS: Sexual abuse is a significant antecedent of suicidal behavior, particularly among women. In identifying suicidal behavior, it is important to consider the possibility of sexual abuse, since it implies a need for focused treatment.

The Treatment for Adolescents With Depression Study (TADS): Outcomes Over 1 Year of Naturalistic Follow-Up [Articles]

Treatment for Adolescents With Depression Study (TADS) Team — Thu, 01 Oct 2009 10:01:37 PDT

OBJECTIVE: The Treatment for Adolescents With Depression Study (TADS) evaluates the effectiveness of fluoxetine, cognitive-behavioral therapy (CBT), and their combination in adolescents with major depressive disorder. The authors report effectiveness outcomes across a 1-year naturalistic follow-up period. METHOD: The randomized, controlled trial was conducted in 13 academic and community sites in the United States. Stages I, II, and III consisted of 12, 6, and 18 weeks of acute, consolidation, and continuation treatment, respectively. Following discontinuation of TADS treatments at the end of stage III, stage IV consisted of 1 year of naturalistic follow-up. The participants were 327 subjects between the ages of 12 and 17 with a primary DSM-IV diagnosis of major depressive disorder. No TADS treatment was provided during the follow-up period; treatment was available in the community. The primary dependent measures, rated by an independent evaluator blind to treatment status, were the total score on the Children’s Depression Rating Scale—Revised and the rate of response, defined as a rating of much or very much improved on the Clinical Global Impressions improvement measure. RESULTS: Sixty-six percent of the eligible subjects participated in at least one stage IV assessment. The benefits seen at the end of active treatment (week 36) persisted during follow-up on all measures of depression and suicidality. CONCLUSIONS: In contrast to earlier reports on short-term treatments, in which worsening after treatment is the rule, the longer treatment in the TADS was associated with persistent benefits over 1 year of naturalistic follow-up.

A Developmental Twin Study of Church Attendance and Alcohol and Nicotine Consumption: A Model for Analyzing the Changing Impact of Genes and Environment [Articles]

Kendler, K. S., Myers, J. — Thu, 01 Oct 2009 10:01:37 PDT

OBJECTIVE: Church attendance is one of the most consistent predictors of alcohol and nicotine consumption. The authors sought to clarify changes in the role of genetic and environmental factors in influencing church attendance and the interrelationship between church attendance and alcohol and nicotine use from early adolescence into adulthood. METHOD: The authors used data from two interview waves 6 years apart of 1,796 male twins from a population-based register, in which respondents were asked about current and past church attendance and psychoactive drug use. Structural twin models were fitted and tested using the Mx software program. RESULTS: As twins developed from childhood through adulthood, the influence of shared environmental factors on church attendance declined dramatically while genetic factors increased. In early and late adolescence, the negative correlations between church attendance and alcohol and nicotine consumption resulted largely from shared environmental factors. In adulthood, the inverse relationship between church attendance and substance use became stronger and arose largely from genetic factors. CONCLUSIONS: As individuals mature, they increasingly shape their own social environment in large part as a result of their genetically influenced temperament. When individuals are younger and living at home, frequent church attendance reflects a range of familial and social-environmental influences that reduce levels of substance use. In adulthood, by contrast, high levels of church attendance largely index genetically influenced temperamental factors that are protective against substance use. Using genetically informative designs such as twin studies, it is possible to show that the causes of the relationship between social risk factors and substance use can change dramatically over development.

Prevalence and Heritability of Compulsive Hoarding: A Twin Study [Articles]

Thu, 01 Oct 2009 10:01:37 PDT

OBJECTIVE: Compulsive hoarding is a serious health problem for the sufferers, their families, and the community at large. It appears to be highly prevalent and to run in families. However, this familiality could be due to genetic or environmental factors. This study examined the prevalence and heritability of compulsive hoarding in a large sample of twins. METHOD: A total of 5,022 twins completed a validated measure of compulsive hoarding. The prevalence of severe hoarding was determined using empirically derived cutoffs. Genetic and environmental influences on compulsive hoarding were estimated using liability threshold models, and maximum-likelihood univariate model-fitting analyses were employed to decompose the variance in the liability to compulsive hoarding into additive genetic and shared and nonshared environmental factors (female twins only; N=4,355). RESULTS: A total of 2.3% of twins met criteria for caseness, with significantly higher rates observed for male (4.1%) than for female (2.1%) twins. Model-fitting analyses in female twins showed that genetic factors accounted for approximately 50% of the variance in compulsive hoarding, with nonshared environmental factors and measurement error accounting for the other half. CONCLUSIONS: Compulsive hoarding is highly prevalent and heritable, at least in women, with nonshared environmental factors also likely to play an important role.

The Epidemiology of At-Risk and Binge Drinking Among Middle-Aged and Elderly Community Adults: National Survey on Drug Use and Health [Articles]

Blazer, D. G., Wu, L.-T. — Thu, 01 Oct 2009 10:01:37 PDT

OBJECTIVE: The purpose of this article was to estimate the prevalence, distribution, and correlates of at-risk alcohol use (especially binge drinking) among middle-aged and elderly persons in the United States and to compare at-risk alcohol use between women and men. METHOD: Secondary analysis of the 2005 and 2006 National Survey on Drug Use and Health was conducted for 10,953 respondents aged 50 years and older. Among respondents, 6,717 were 50 to 64 years of age and 4,236 were ≥65 years. Social and demographic variables, alcohol use (including at-risk use), binge drinking, serious psychological distress, and self-rated health were assessed. RESULTS: Overall, 66% of male respondents and 55% of female respondents reported alcohol use during the past year. At-risk alcohol use and binge drinking were more frequent among respondents 50 to 64 years of age relative to respondents aged 65 years or older. In the ≥65 years old age group, 13% of men and 8% of women reported at-risk alcohol use, and more than 14% of men and 3% of women reported binge drinking. Among male subjects, binge drinking compared with no alcohol use was associated with higher income and being separated, divorced, or widowed, while being employed and nonmedical use of prescription drugs were associated with binge drinking compared with no alcohol use among women. For all respondents, binge drinking relative to no alcohol use was associated with the use of tobacco and illicit drugs. Among women who reported using alcohol, being African American and less educated were associated with binge drinking, but race/ethnicity and educational level were not associated with binge drinking in men who reported using alcohol. CONCLUSIONS: At-risk and binge drinking are frequently reported by middle-aged and elderly adults nationwide and are therefore of public health concern. Clinicians working with middle-aged and older adults should screen for binge drinking and coexisting use of other substances.

Lower Level of Endogenous Dopamine in Patients With Cocaine Dependence: Findings From PET Imaging of D2/D3 Receptors Following Acute Dopamine Depletion [Articles]

Thu, 01 Oct 2009 10:01:37 PDT

OBJECTIVE: Previous positron emission tomography (PET) imaging studies have demonstrated that cocaine dependence is associated with a decrease in dopamine type 2 and 3 (D₂/D₃) receptor binding in cocaine-dependent individuals relative to healthy comparison subjects. However, given the nature of PET imaging, it is possible that the measured decrease in radiotracer binding results from an increase in baseline dopamine levels. The purpose of this study was to measure D₂/D₃ receptors following acute dopamine depletion in cocaine-dependent volunteers relative to healthy comparison subjects. METHOD: Cocaine-dependent volunteers (N=15) and healthy matched comparison subjects (N=15) were scanned using PET, with the dopamine receptor radiotracer [¹¹C]raclopride, at baseline and again following acute depletion of endogenous dopamine via alpha-methyl-para-tyrosine (AMPT) administration. Changes in radiotracer binding were measured in the subdivisions of the striatum (caudate, putamen, and ventral striatum) in addition to the striatum as a whole. RESULTS: Findings revealed that cocaine-dependent volunteers exhibited lower levels of endogenous dopamine relative to comparison subjects, which was measured as an increase in [¹¹C]raclopride binding following AMPT administration. The increase in [¹¹C]raclopride binding in the striatum was 11.1% (SD=4.4%) in healthy comparison subjects and 5.7% (SD=5.9%) in cocaine-dependent volunteers. Similar differences were seen in the subdivisions of the striatum. CONCLUSIONS: The decrease in striatal D₂/D₃receptors associated with cocaine dependence cannot be attributed to higher levels of endogenous dopamine.

Effect of Acute Antidepressant Administration on Negative Affective Bias in Depressed Patients [Articles]

Thu, 01 Oct 2009 10:01:37 PDT

OBJECTIVE: Acute administration of an antidepressant increases positive affective processing in healthy volunteers, an effect that may be relevant to the therapeutic actions of these medications. The authors investigated whether this effect is apparent in depressed patients early in treatment, prior to changes in mood and symptoms. METHOD: In a double-blind, placebo-controlled, between-groups randomized design, the authors examined the effect of a single 4-mg dose of the norepinephrine reuptake inhibitor reboxetine on emotional processing. Thirty-three depressed patients were recruited through primary care clinics and the community and matched to 31 healthy comparison subjects. Three hours after dosing, participants were given a battery of emotional processing tasks comprising facial expression recognition, emotional categorization, and memory. Ratings of mood, anxiety, and side effects were also obtained before and after treatment. RESULTS: Depressed patients who received placebo showed reduced recognition of positive facial expressions, decreased speed in responding to positive self-relevant personality adjectives, and reduced memory for this positive information compared to healthy volunteers receiving placebo. However, this effect was reversed in patients who received a single dose of reboxetine, despite the absence of changes in subjective ratings of mood or anxiety. CONCLUSIONS: Antidepressant drug administration modulates emotional processing in depressed patients very early in treatment, before changes occur in mood and symptoms. This effect may ameliorate the negative biases in information processing that characterize mood and anxiety disorders. It also suggests a mechanism of action compatible with cognitive theories of depression.

Sudden Death and Use of Stimulant Medications in Youths [Articles]

Tue, 01 Sep 2009 10:01:41 PDT

OBJECTIVE: The authors sought to determine whether a significant association exists between the use of stimulants and the rare event of sudden unexplained death in children and adolescents. METHOD: A matched case-control design was performed. Mortality data from 1985–1996 state vital statistics were used to identify 564 cases of sudden death occurring at ages 7 through 19 years across the United States along with a matched group of 564 young people who died as passengers in motor vehicle traffic accidents. The primary exposure measure was the presence of amphetamine, dextroamphetamine, methamphetamine, or methylphenidate according to informant reports or as noted in medical examiner records, toxicology results, or death certificates. RESULTS: In 10 (1.8%) of the sudden unexplained deaths it was determined that the youths were taking stimulants, specifically methylphenidate; in contrast, use of stimulants was found in only two subjects in the motor vehicle accident comparison group (0.4%), with only one involving methylphenidate use. A significant association of stimulant use with sudden unexplained death emerged from the primary analysis, which was based on exact conditional logistic regression (odds ratio=7.4, 95% CI=1.4 to 74.9). A comprehensive series of sensitivity analyses yielded qualitatively similar findings. CONCLUSIONS: This case-control study provides support for an association between the use of stimulants and sudden unexplained death among children and adolescents. Although sudden unexplained death is a rare event, this finding should be considered in the context of other data about the risk and benefit of stimulants in medical treatment.

Long-Term Benefits of Short-Term Quality Improvement Interventions for Depressed Youths in Primary Care [Articles]

Tue, 01 Sep 2009 10:01:41 PDT

OBJECTIVE: Quality improvement programs for depressed youths in primary care settings have been shown to improve 6-month clinical outcomes, but longer-term outcomes are unknown. The authors examined 6-, 12-, and 18-month outcomes of a primary care quality improvement intervention. METHOD: Primary care patients 13–21 years of age with current depressive symptoms were randomly assigned to a 6-month quality improvement intervention (N=211) or to treatment as usual enhanced with provider training (N=207). The quality improvement intervention featured expert leader teams to oversee implementation of the intervention; clinical care managers trained in cognitive-behavioral therapy for depression to support patient evaluation and treatment; and support for patient and provider choice of treatments. RESULTS: The quality improvement intervention, relative to enhanced treatment as usual, lowered the likelihood of severe depression (Center for Epidemiological Studies Depression Scale score ≥24) at 6 months; a similar trend at 18 months was not statistically significant. Path analyses revealed a significant indirect intervention effect on long-term depression due to the initial intervention improvement at 6 months. CONCLUSIONS: In this randomized effectiveness trial of a primary care quality improvement intervention for depressed youths, the main effect of the intervention on outcomes was to decrease the likelihood of severe depression at the 6-month outcome assessment. These early intervention-related improvements conferred additional long-term protection through a favorable shift in illness course through 12 and 18 months.

A Molecular Signature of Depression in the Amygdala [Articles]

Tue, 01 Sep 2009 10:01:42 PDT

OBJECTIVE: Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Recent gene array attempts to identify the molecular underpinnings of the illness in human postmortem subjects have not yielded a consensus. The authors hypothesized that controlling several sources of clinical and technical variability and supporting their analysis with array results from a parallel study in the unpredictable chronic mild stress (UCMS) rodent model of depression would facilitate identification of the molecular pathology of major depression. METHOD: Large-scale gene expression was monitored in postmortem tissue from the anterior cingulate cortex and amygdala in paired male subjects with familial major depression and matched control subjects without major depression (N=14–16 pairs). Area dissections and analytical approaches were optimized. Results from the major depression group were compared with those from the UCMS study and confirmed by quantitative polymerase chain reaction and Western blot. Gene coexpression network analysis was performed on transcripts with conserved major depression-UCMS effects. RESULTS: Significant and bidirectional predictions of altered gene expression were identified in amygdala between major depression and the UCMS model of depression. These effects were detected at the group level and also identified a subgroup of depressed subjects with a more homogeneous molecular pathology. This phylogenetically conserved "molecular signature" of major depression was reversed by antidepressants in mice, identified two distinct oligodendrocyte and neuronal phenotypes, and participated in highly cohesive and interactive gene coexpression networks. CONCLUSIONS: These studies demonstrate that the biological liability to major depression is reflected in a persistent molecular pathology that affects the amygdala, and support the hypothesis of maladaptive changes in this brain region as a putative primary pathology in major depression.

Evidence for an Interaction Between Familial Liability and Prenatal Exposure to Infection in the Causation of Schizophrenia [Articles]

Clarke, M. C., Tanskanen, A., Huttunen, M., Whittaker, J. C., Cannon, M. — Tue, 01 Sep 2009 10:01:42 PDT

OBJECTIVE: The authors sought to determine whether prenatal exposure to infection and a positive family history of psychotic disorders interact synergistically to increase the risk of later developing schizophrenia. METHOD: The authors linked two national registers, the Medical Birth Register and the Finnish Population Register, to identify all women in Helsinki who received hospital treatment during pregnancy for an upper urinary tract infection (N=9,596) between 1947 and 1990. The Finnish Hospital Discharge Register was used to ascertain psychiatric outcomes in adulthood of offspring exposed to infection prenatally. Family history of psychotic disorders was determined by linking the Hospital Discharge Register and the Population Register. The authors used an additive statistical interaction model to calculate the amount of biological synergism between positive family history and prenatal exposure to infection. RESULTS: Prenatal exposure to infection did not significantly increase the risk of schizophrenia. However, the effect of prenatal exposure to pyelonephritis was five times greater in those who had a family history of psychosis compared to those who did not. The synergy analysis suggested that an estimated 38%–46% of the offspring who developed schizophrenia and had both prenatal exposure to infection and a positive family history of psychotic disorders did so as a result of the synergistic action of both risk factors. CONCLUSIONS: These findings support a mechanism of gene-environment interaction in the causation of schizophrenia.

Association of Substance Use Disorders With Childhood Trauma but not African Genetic Heritage in an African American Cohort [Articles]

Tue, 01 Sep 2009 10:01:42 PDT

OBJECTIVE: Genetic variation influences differential vulnerability to addiction within populations. However, it remains unclear whether differences in frequencies of vulnerability alleles contribute to disparities between populations and to what extent ancestry correlates with differential exposure to environmental risk factors, including poverty and trauma. METHOD: The authors used 186 ancestry-informative markers to measure African ancestry in 407 addicts and 457 comparison subjects self-identified as African Americans. The reference group was 1,051 individuals from the Human Genome Diversity Cell Line Panel, which includes 51 diverse populations representing most worldwide genetic diversity. RESULTS: African Americans varied in degrees of African, European, Middle Eastern, and Central Asian genetic heritage. The overall level of African ancestry was actually smaller among cocaine, opiate, and alcohol addicts (proportion=0.76–0.78) than nonaddicted African American comparison subjects (proportion=0.81). African ancestry was associated with living in impoverished neighborhoods, a factor previously associated with risk. There was no association between African ancestry and exposure to childhood abuse or neglect, a factor that strongly predicted all types of addictions. CONCLUSIONS: These results suggest that African genetic heritage does not increase the likelihood of genetic risk for addictions. They highlight the complex interrelation between genetic ancestry and social, economic, and environmental conditions and the strong relation of those factors to addiction. Studies of epidemiological samples characterized for genetic ancestry and social, psychological, demographic, economic, cultural, and historical factors are needed to better disentangle the effects of genetic and environmental factors underlying interpopulation differences in vulnerability to addiction and other health disparities.

Childhood Motor Coordination and Adult Schizophrenia Spectrum Disorders [Articles]

Tue, 01 Sep 2009 10:01:42 PDT

OBJECTIVE: The authors examined whether motor coordination difficulties assessed in childhood predict later adult schizophrenia spectrum outcomes. METHOD: A standardized childhood neurological examination was administered to a sample of 265 Danish children in 1972, when participants were 10–13 years old. Adult diagnostic information was available for 244 members of the sample. Participants fell into three groups: children whose mothers or fathers had a psychiatric hospital diagnosis of schizophrenia (N=94); children who had at least one parent with a psychiatric record of hospitalization for a nonpsychotic disorder (N=84); and children with no parental records of psychiatric hospitalization (N=66). Psychiatric outcomes of the offspring were assessed through psychiatric interviews in 1992 when participants were 31–33 years of age, as well as through a scan of national psychiatric registers completed in May 2007. RESULTS: Children who later developed a schizophrenia spectrum disorder (N=32) displayed significantly higher scores on a scale of coordination deficits compared with those who did not develop a mental illness in this category (N=133). CONCLUSIONS: Results from this study provide further support for the neurodevelopmental hypothesis of schizophrenia and underscore the potential role of cerebellar and/or basal ganglia abnormalities in the etiology and pathophysiology of schizophrenia.

Adult Outcomes of Youth Irritability: A 20-Year Prospective Community-Based Study [Articles]

Stringaris, A., Cohen, P., Pine, D. S., Leibenluft, E. — Tue, 01 Sep 2009 10:01:42 PDT

OBJECTIVE: Irritability is a widely occurring DSM-IV symptom in youths. However, little is known about the relationship between irritability in early life and its outcomes in mid-adulthood. This study examines the extent to which youth irritability is related to adult psychiatric outcomes by testing the hypothesis that it predicts depressive and generalized anxiety disorders. METHOD: The authors conducted a longitudinal community-based study of 631 participants whose parents were interviewed when participants were in early adolescence (mean age=13.8 years [SD=2.6]) and who were themselves interviewed 20 years later (mean age=33.2 years [SD=2.9]). Parent-reported irritability in adolescence was used to predict self-reported psychopathology, assessed by standardized diagnostic interview at 20-year follow-up. RESULTS: Cross-sectionally, irritability in adolescence was widely associated with other psychiatric disorders. After adjustment for baseline emotional and behavioral disorders, irritability in adolescence predicted major depressive disorder (odds ratio=1.33, 95% confidence interval [CI]=1.00–1.78]), generalized anxiety disorder (odds ratio=1.72, 95% CI=1.04–2.87), and dysthymia (odds ratio=1.81, 95% CI=1.06–3.12) at 20-year follow-up. Youth irritability did not predict bipolar disorder or axis II disorders at follow-up. CONCLUSIONS: Youth irritability as reported by parents is a specific predictor of self-reported depressive and anxiety disorders 20 years later. The role of irritability in developmental psychiatry, and in the pathophysiology of mood and anxiety disorders specifically, should receive further study.

The Cognitive Cost of Anticholinergic Burden: Decreased Response to Cognitive Training in Schizophrenia [Articles]

Tue, 01 Sep 2009 10:01:42 PDT

OBJECTIVE: Schizophrenia is treated with medications that raise serum anticholinergic activity and are known to adversely affect cognition. The authors examined the relationship between serum anticholinergic activity and baseline cognitive performance and response to computerized cognitive training in outpatients with schizophrenia. METHOD: Fifty-five patients were randomly assigned to either computerized cognitive training or a computer games control condition. A neurocognitive battery based on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was performed at baseline and after the intervention. Serum anticholinergic activity, measured at study entry by radioreceptor assay, was available for 49 patients. RESULTS: Serum anticholinergic activity showed a significant negative correlation with baseline performance in verbal working memory and verbal learning and memory, accounting for 7% of the variance in these measures, independent of age, IQ, or symptom severity. Patients in the cognitive training condition (N=25) showed a significant gain in global cognition compared to those in the control condition, but this improvement was negatively correlated with anticholinergic burden. Serum anticholinergic activity uniquely accounted for 20% of the variance in global cognition change, independent of age, IQ, or symptom severity. CONCLUSIONS: Serum anticholinergic activity in schizophrenia patients shows a significant association with impaired performance in MATRICS-based measures of verbal working memory and verbal learning and memory and is significantly associated with a lowered response to an intensive course of computerized cognitive training. These findings underscore the cognitive cost of medications that carry a high anticholinergic burden. The findings also have implications for the design and evaluation of cognitive treatments for schizophrenia.

Short-Term Psychodynamic Psychotherapy and Cognitive-Behavioral Therapy in Generalized Anxiety Disorder: A Randomized, Controlled Trial [Articles]

Mon, 03 Aug 2009 10:01:40 PDT

OBJECTIVE: While several studies have shown that cognitive-behavioral therapy (CBT) is an efficacious treatment for generalized anxiety disorder, few studies have addressed the outcome of short-term psychodynamic psychotherapy, even though this treatment is widely used. The aim of this study was to compare short-term psychodynamic psychotherapy and CBT with regard to treatment outcome in generalized anxiety disorder. METHOD: Patients with generalized anxiety disorder according to DSM-IV were randomly assigned to receive either CBT (N=29) or short-term psychodynamic psychotherapy (N=28). Treatments were carried out according to treatment manuals and included up to 30 weekly sessions. The primary outcome measure was the Hamilton Anxiety Rating Scale, which was applied by trained raters blind to the treatment conditions. Assessments were carried out at the completion of treatment and 6 months afterward. RESULTS: Both CBT and short-term psychodynamic psychotherapy yielded significant, large, and stable improvements with regard to symptoms of anxiety and depression. No significant differences in outcome were found between treatments in regard to the primary outcome measure. These results were corroborated by two self-report measures of anxiety. In measures of trait anxiety, worry, and depression, however, CBT was found to be superior. CONCLUSIONS: The results suggest that CBT and short-term psychodynamic psychotherapy are beneficial for patients with generalized anxiety disorder. In future research, large-scale multicenter studies should examine more subtle differences between treatments, including differences in the patients who benefit most from each form of therapy.

Reducing Suicidal Ideation and Depression in Older Primary Care Patients: 24-Month Outcomes of the PROSPECT Study [Articles]

Mon, 03 Aug 2009 10:01:40 PDT

OBJECTIVE: The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) evaluated the impact of a care management intervention on suicidal ideation and depression in older primary care patients. This is the first report of outcomes over a 2-year period. METHOD: Study participants were patients 60 years of age or older (N=599) with major or minor depression selected after screening 9,072 randomly identified patients of 20 primary care practices randomly assigned to provide either the PROSPECT intervention or usual care. The intervention consisted of services of 15 trained care managers, who offered algorithm-based recommendations to physicians and helped patients with treatment adherence over 24 months. RESULTS: Compared with patients receiving usual care, those receiving the intervention had a higher likelihood of receiving antidepressants and/or psychotherapy (84.9%–89% versus 49%–62%) and had a 2.2 times greater decline in suicidal ideation over 24 months. Treatment response occurred earlier on average in the intervention group and increased from months 18 to 24, while no appreciable increase in treatment response occurred in the usual care group during the same period. Among patients with major depression, a greater number achieved remission in the intervention group than in the usual-care group at 4 months (26.6% versus 15.2%), 8 months (36% versus 22.5%), and 24 months (45.4% versus 31.5%). Patients with minor depression had favorable outcomes regardless of treatment assignment. CONCLUSIONS: Sustained collaborative care maintains high utilization of depression treatment, reduces suicidal ideation, and improves the outcomes of major depression over 2 years.

Relationship Between Cingulo-Insular Functional Connectivity and Autistic Traits in Neurotypical Adults [Articles]

Mon, 03 Aug 2009 10:01:40 PDT

OBJECTIVE: The Social Responsiveness Scale—Adult Version (SRS-A) measures autistic traits that are continuously distributed in the general population. Based on increased recognition of the dimensional nature of autistic traits, the authors examined the neural correlates of these traits in neurotypical individuals using the SRS-A and established a novel approach to assessing the neural basis of autistic characteristics, attempting to directly relate SRS-A scores to patterns of functional connectivity observed in the pregenual anterior cingulate cortex, a region commonly implicated in social cognition. METHOD: Resting state functional magnetic resonance imaging scans were collected for 25 neurotypical adults. All participants provided SRS-A ratings completed by an informant who had observed them in natural social settings. Whole brain-corrected connectivity analyses were then conducted using SRS-A scores as a covariate of interest. RESULTS: Across participants, a significant negative relationship between SRS-A scores and the functional connectivity of the pregenual anterior cingulate cortex with the anterior portion of the mid-insula was found. Specifically, low levels of autistic traits were observed when a substantial portion of the anterior mid-insula showed positive connectivity with the pregenual anterior cingulate cortex. In contrast, elevated levels of autistic traits were associated with negative connectivity between these two regions. CONCLUSIONS: Resting state functional connectivity of the pregenual anterior cingulate cortex-insula social network was related to autistic traits in neurotypical adults. Application of this approach in samples with autism spectrum disorders is needed to confirm whether this circuit is dimensionally related to the severity of autistic traits in clinical populations.

Differentiating Early-Onset Persistent Versus Childhood-Limited Conduct Problem Youth [Articles]

Barker, E. D., Maughan, B. — Mon, 03 Aug 2009 10:01:40 PDT

OBJECTIVE: Among young children who demonstrate high levels of conduct problems, less than 50% will continue to exhibit these problems into adolescence. Such developmental heterogeneity presents a serious challenge for intervention and diagnostic screening in early childhood. The purpose of the present study was to inform diagnostic screening and preventive intervention efforts by identifying youths whose conduct problems persist. The authors examined 1) the extent to which early-onset persistent versus childhood-limited trajectories can be identified from repeated assessments of childhood and early-adolescent conduct problems and 2) how prenatal and early postnatal risks differentiate these two groups. METHOD: To identify heterogeneity in early-onset conduct problems, the authors used data from a large longitudinal population-based cohort of children followed from the prenatal period to age 13. Predictive risk factors examined were prenatal and postnatal measures of maternal distress (anxiety, depression), emotional and practical support, and family and child characteristics (from birth to 4 years of age). RESULTS: Findings revealed a distinction between early-onset persistent versus childhood-limited conduct problems in youths. Robust predictors of the early-onset persistent trajectory were maternal anxiety during pregnancy (32 weeks gestation), partner cruelty to the mother (from age 0 to 4 years), harsh parenting, and higher levels of child undercontrolled temperament. Sex differences in these risks were not identified. CONCLUSIONS: Interventions aiming to reduce childhood conduct problems should address prenatal risks in mothers and early postnatal risks in both mothers and their young children.

Effects of Catechol-O-Methyltransferase on Normal Variation in the Cognitive Function of Children [Articles]

Barnett, J. H., Heron, J., Goldman, D., Jones, P. B., Xu, K. — Mon, 03 Aug 2009 10:01:40 PDT

OBJECTIVE: Genetic variants that contribute to the risk of psychiatric disorders may also affect normal variation in psychological function. Indeed, the behavioral effects of many genetic variants may be better understood as process-specific rather than disease-specific. A functional valine-to-methionine (Val¹⁵⁸Met) polymorphism in the catechol-O-methyltransferase (COMT) gene has been associated with cognitive function and brain metabolic activity accompanying such tasks. Not all studies are consistent, and less is known about the effect of this polymorphism during development. The authors tested the hypothesis that a more informative COMT haplotype predicts normal cognitive development in a large population-based cohort of children enrolled in the Avon Longitudinal Study of Parents and Children. METHOD: Effects on verbal and performance IQ as well as verbal inhibition were assessed at age 8, and effects on working memory were assessed at age 10. From the five COMT single nucleotide polymorphisms (SNPs) genotyped, the effect of a functional three-SNP haplotype consisting of Val¹⁵⁸Met and two synonymous SNPs (rs6269 and rs4818), which together exert a major influence on the level of COMT expression and enzyme activity, was evaluated. RESULTS: This three-SNP haplotype predicted both verbal inhibition and working memory, and there was a genotype-by-sex interaction on verbal IQ. The effect of COMT genotype (diplotype) on cognition was curvilinear, which is consistent with the "inverted U" model of dopamine effect on frontal cortical efficiency. In addition, the SNP rs2075507 (previously rs2097603) was independently associated with verbal inhibition, while rs165599 showed no main cognitive effects. However, rs165599 showed a genotype-by-sex interaction with working memory. CONCLUSIONS: Genetic variation at several loci in the COMT gene affects normal cognitive function in children.

Neuroanatomic Alterations and Social and Communication Deficits in Monozygotic Twins Discordant for Autism Disorder [Articles]

Mon, 03 Aug 2009 10:01:40 PDT

OBJECTIVE: Investigating neuroanatomic differences in monozygotic twins who are discordant for autism can help unravel the relative contributions of genetics and environment to this pervasive developmental disorder. The authors used magnetic resonance imaging (MRI) to investigate several brain regions of interest in monozygotic twins who varied in degree of phenotypic discordance for narrowly defined autism. METHOD: The subjects were 14 pairs of monozygotic twins between the ages of 5 and 14 years old and 14 singleton age- and gender-matched typically developing comparison subjects. The monozygotic twin group was a cohort of children with narrowly defined autistic deficits and their co-twins who presented with varying levels of autistic deficits. High-resolution MRIs were acquired and volumetric/area measurements obtained for the frontal lobe, amygdala, and hippocampus and subregions of the prefrontal cortex, corpus callosum, and cerebellar vermis. RESULTS: No neurovolumetric/area differences were found between twin pairs. Relative to typically developing comparison subjects, dorsolateral prefrontal cortex volumes and anterior areas of the corpus callosum were significantly altered in autistic twins, and volumes of the posterior vermis were altered in both autistic twins and co-twins. Intraclass correlation analysis of brain volumes between children with autism and their co-twins indicated that the degree of within-pair neuroanatomic concordance varied with brain region. In the group of subjects with narrowly defined autism only, dorsolateral prefrontal cortex, amygdala, and posterior vermis volumes were significantly associated with the severity of autism based on scores from the Autism Diagnostic Observation Schedule—Generic. CONCLUSIONS: These findings support previous research demonstrating alterations in the prefrontal cortex, corpus callosum, and posterior vermis in children with autism and further suggest that alterations are associated with the severity of the autism phenotype. Continued research involving twins who are concordant and discordant for autism is essential to disentangle the genetic and environmental contributions to autism.

Serotonin Transporter Gene (SLC6A4) Promoter Polymorphisms and the Susceptibility to Posttraumatic Stress Disorder in the General Population [Articles]

Mon, 03 Aug 2009 10:01:40 PDT

OBJECTIVE: There has been debate whether polymorphisms within the serotonin transporter-linked polymorphic region (5-HTTLPR) moderate susceptibility to posttraumatic stress disorder (PTSD). The authors investigated 5-HTTLPR genotypes and their interaction with the number of traumatic events in the prediction of PTSD in a general population sample. METHOD: Analyses were based on data from 3,045 subjects who participated in the Study of Health in Pomerania. All participants were assessed with the PTSD module of the Structured Clinical Interview for DSM–IV. The short (S)/long (L) polymorphism of 5-HTTLPR (rs4795541) and the A-G polymorphism (rs25531) were genotyped. RESULTS: Among the participants, 1,663 had been exposed to at least one traumatic event, and 67 (4.0%) developed PTSD. Among those who had experienced less than three traumatic events, the lifetime prevalence of PTSD was 2.6%, 3.5%, and 4.3% for those with zero, one, and two L_A alleles, respectively, but the lifetime prevalence was 0%, 7.3%, and 19.6%, respectively, among those with three or more traumatic experiences. This finding suggests that there is an additive excess risk for frequent trauma in the L_A/L_A genotype, which was confirmed by the relative excess risk due to interaction (RERI). In allelic analysis, RERI was 3.3. Thus, the odds ratio for PTSD in L_A allele carriers exposed to three or more traumas was 3.3 times higher as a result of the interaction between PTSD and the L_A allele. CONCLUSIONS: An additive gene-environment interaction with the high expression L_A allele of 5-HTTLPR and frequent trauma in PTSD was found. The attributable proportion indicated that more than 60% of all L_A allele carriers who were exposed to three or more traumas developed PTSD as a result of an interaction between genotype and exposure.