Robert Keers

Gender differences in antidepressant drug response.

Epidemiological studies suggest there are considerable differences in the prevalence and presentation of depression in men and women. Women are more than twice as likely to be diagnosed with depression and may also report more atypical and anxiety symptoms than men. Men and women also differ in the metabolism and distribution of antidepressants and the presence of oestrogen in women of childbearing age may interfere with the mechanism of action of a number of antidepressants. These differences have led many researchers to question whether antidepressants are equally effective and tolerated in men and women. While some reports suggest that selective serotonin re-uptake inhibitors (SSRIs) are more effective and result in fewer adverse drug reactions in women than tricyclic antidepressants (TCAs), gender differences in antidepressant response remains a controversial topic. The potential effects of antidepressant exposure in utero and in breast milk further complicate treatment options for antenatal and postnatal depression. While some research suggests the SSRI paroxetine is teratogenic, further carefully designed naturalistic studies are required to fully evaluate these effects. Finally, response to antidepressants and the occurrence of adverse drug reactions is marked by inter-individual variability which may be in part due to genetic differences. Future studies should therefore consider genotypes of the mother, foetus and infant in antidepressant response.

Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project

There is substantial inter-individual variation in response to antidepressants, and genetic variation may, in part, explain these differences. For example, there is evidence to suggest that variation in the serotonin transporter gene (SLC6A4) predicts response to selective serotonin reuptake inhibitors (SSRIs). Environmental factors such as the occurrence of stressful life events before treatment may also be important. One prior report suggests that both factors interact in predicting response to antidepressants. GENDEP, a prospective part-randomized pharmacogenomics trial, collected longitudinal data on the outcome of 811 patients with major depression undergoing treatment with either an SSRI (escitalopram) or a tricyclic antidepressant (nortriptyline). Life events experienced over 6 months preceding treatment were measured using a List of Threatening Experiences Questionnaire, and several polymorphisms in the serotonin transporter gene (SLC6A4) have been genotyped including the serotonin transporter-linked polymorphic region (5-HTTLPR). Stressful life events were shown to predict a significantly better response to escitalopram but had no effect on response to nortriptyline. Variation in the 5-HTTLPR and another polymorphism in the gene, STin4, significantly modified these effects. Gene–environment interactions including life events may therefore be important not only in the aetiology of depression, but also in predicting response to antidepressant medication.

Stressful life events and the brain-derived neurotrophic factor gene in bipolar disorder

BACKGROUND Gene-environment interactions may contribute to the high heritability of bipolar affective disorder. The aim of the present study was to examine the interplay between the BDNF Val(66)Met polymorphism and stressful life events (SLEs) in bipolar disorder. METHOD A total of 1085 participants were recruited, including 487 bipolar I cases and 598 psychiatrically healthy controls. All participants completed the List of Threatening Life Events Questionnaire; bipolar subjects reported the events that occurred 6 months leading up to their worst manic episode and 6 months prior to their worst depressive episode, controls recorded events experienced 6 months before interview. The sample was genotyped for the BDNF Val(66)Met polymorphism (rs6265). RESULTS Both Met carrier BDNF genotype and SLEs were significantly associated with the worst depressive episode of bipolar disorder. For the worst depressive episodes the effects of SLEs were also significantly moderated by BDNF genotype (gene x environment interaction). LIMITATIONS The use of a self report questionnaire to measure stressful life events may increase recall inaccuracies, therefore caution should be taken when interpreting these results. DISCUSSION The findings of this study highlight the importance of the interplay between genes and the environment in bipolar disorder.

Association of Violence With Emergence of Persecutory Delusions in Untreated Schizophrenia

OBJECTIVE Psychosis is considered an important risk factor for violence, but studies show inconsistent results. The mechanism through which psychotic disorders influence violence also remains uncertain. The authors investigated whether psychosis increased the risk of violent behavior among released prisoners and whether treatment reduced this risk. They also explored whether active symptoms of psychosis at the time of violent behavior explained associations between untreated psychosis and violence. METHOD The U.K. Prisoner Cohort Study is a prospective longitudinal study of prisoners followed up in the community after release. Adult male and female offenders serving sentences of 2 or more years for a sexual or violent offense were classified into four groups: no psychosis (N=742), schizophrenia (N=94), delusional disorder (N=29), and drug-induced psychosis (N=102). Symptoms of psychosis, including hallucinations, thought insertion, strange experiences, and delusions of persecution, were measured before and after release. Information on violence between release and follow-up was collected through self-report and police records. RESULTS Schizophrenia was associated with violence but only in the absence of treatment (odds ratio=3.76, 95% CI=1.39-10.19). Untreated schizophrenia was associated with the emergence of persecutory delusions at follow-up (odds ratio=3.52, 95% CI=1.18-10.52), which were associated with violence (odds ratio=3.68, 95% CI=2.44-5.55). The mediating effects of persecutory delusions were confirmed in mediation analyses (β=0.02, 95% CI=0.01-0.04). CONCLUSIONS The results indicate that the emergence of persecutory delusions in untreated schizophrenia explains violent behavior. Maintaining psychiatric treatment after release can substantially reduce violent recidivism among prisoners with schizophrenia. Better screening and treatment of prisoners is therefore essential to prevent violence.

Gene-Environment Interaction in Major Depression and Antidepressant Treatment Response

Response to antidepressants is interindividually variable. It has been suggested that this variability is a direct consequence of etiological heterogeneity. Therefore, the same genes, environments, and gene–environment interactions implicated in different etiological pathways to depression may also predict response to treatment. This article reviews the evidence relevant to this hypothesis by first outlining the roles of genes, environments, and gene–environment interplay in the etiology of depression, and then considering the same factors in treatment response. Environmental exposures, such as childhood maltreatment, are potent predictors of both depression and treatment response. Although alone genetic factors have failed to consistently predict either phenotype, several polymorphisms have been shown to moderate the effects of environmental adversity on the development of depression and treatment response. These findings suggest that the dissection of etiological pathways to depression may provide the key to understanding and predicting response to antidepressants.

Clinical Predictors of Response to Cognitive-Behavioral Therapy in Pediatric Anxiety Disorders: The Genes for Treatment (GxT) Study

Objective The Genes for Treatment study is an international, multisite collaboration exploring the role of genetic, demographic, and clinical predictors in response to cognitive-behavioral therapy (CBT) in pediatric anxiety disorders. The current article, the first from the study, examined demographic and clinical predictors of response to CBT. We hypothesized that the child’s gender, type of anxiety disorder, initial severity and comorbidity, and parents’ psychopathology would significantly predict outcome. Method A sample of 1,519 children 5 to 18 years of age with a primary anxiety diagnosis received CBT across 11 sites. Outcome was defined as response (change in diagnostic severity) and remission (absence of the primary diagnosis) at each time point (posttreatment, 3-, 6-, and/or 12-month follow-up) and analyzed using linear and logistic mixed models. Separate analyses were conducted using data from posttreatment and follow-up assessments to explore the relative importance of predictors at these time points. Results Individuals with social anxiety disorder (SoAD) had significantly poorer outcomes (poorer response and lower rates of remission) than those with generalized anxiety disorder (GAD). Although individuals with specific phobia (SP) also had poorer outcomes than those with GAD at posttreatment, these differences were not maintained at follow-up. Both comorbid mood and externalizing disorders significantly predicted poorer outcomes at posttreatment and follow-up, whereas self-reported parental psychopathology had little effect on posttreatment outcomes but significantly predicted response (although not remission) at follow-up. Conclusion SoAD, nonanxiety comorbidity, and parental psychopathology were associated with poorer outcomes after CBT. The results highlight the need for enhanced treatments for children at risk for poorer outcomes.

Gang membership, violence, and psychiatric morbidity.

OBJECTIVE Gang members engage in many high-risk activities associated with psychiatric morbidity, particularly violence-related ones. The authors investigated associations between gang membership, violent behavior, psychiatric morbidity, and use of mental health services. METHOD The authors conducted a cross-sectional survey of 4,664 men 18-34 years of age in Great Britain using random location sampling. The survey oversampled men from areas with high levels of violence and gang activities. Participants completed questionnaires covering gang membership, violence, use of mental health services, and psychiatric diagnoses measured using standardized screening instruments. RESULTS Violent men and gang members had higher prevalences of mental disorders and use of psychiatric services than nonviolent men, but a lower prevalence of depression. Violent ruminative thinking, violent victimization, and fear of further victimization accounted for the high levels of psychosis and anxiety disorders in gang members, and with service use in gang members and other violent men. Associations with antisocial personality disorder, substance misuse, and suicide attempts were explained by factors other than violence. CONCLUSIONS Gang members show inordinately high levels of psychiatric morbidity, placing a heavy burden on mental health services. Traumatization and fear of further violence, exceptionally prevalent in gang members, are associated with service use. Gang membership should be routinely assessed in individuals presenting to health care services in areas with high levels of violence and gang activity. Health care professionals may have an important role in promoting desistence from gang activity.

Pharmacogenetics of antidepressant response

There is substantial interindividual variation in response to antidepressants. Family and twin studies suggest that genetic variation may, at least in part, explain these differences. Pharmacogenetic research attempts to identify the genetic variants associated with antidepressant response to both understand the mechanism of action of pharmacotherapies and to predict outcome. Genes implicated in the pharmacokinetics or pharmacodyamics of antidepressants have been shown to predict response; however, the failure of some findings to replicate has been disappointing. More recent hypothesis-free approaches have identified novel candidates for antidepressant response. However, results have been considerably modest and suggest that treatment outcome is determined by multiple genetic variants of small effect. The small effect sizes of genetic variants and heterogeneity between studies have significantly hindered attempts to find robust genetic predictors of response to antidepressants. To allow the direct comparison of findings, future pharmacogenetic studies should employ standardized methodology and consider using intermediate phenotypes of response, such as neurogenesis, that may more closely reflect the mechanism of action of antidepressants.

Variation in GNB3 predicts response and adverse reactions to antidepressants

There is substantial inter-individual variation in response and adverse reactions to antidepressants, and genetic variation may, in part, explain these differences. GNB3 encodes the β3 subunit of the G protein complex, which is involved in the downstream signalling cascade following monoamine receptor activation. A functional polymorphism in this gene (C825T) has been associated with response to antidepressants. Several lines of evidence suggest that GNB3 moderates improvement in the neurovegetative symptoms of depression (such as sleep and appetite) and related adverse reactions independently of change in core mood symptoms. We here report analysis of data from GENDEP, a part-randomized pharmacogenomic trial, on the outcome of 811 subjects with major depression undergoing treatment with either escitalopram or nortriptyline in which the C825T SNP and three further SNPs in GNB3 were genotyped. The TT genotype was significantly associated with a superior response to nortriptyline and these effects were specific to improvements in neurovegetative symptoms. In addition, the same genotype predicted fewer incidents of treatment-emergent insomnia and greater weight gain on the same drug. Our results are consistent with previous associations with GNB3 and emphasize the importance of signalling genes in antidepressant response.

Reduced Anxiety and Depression-Like Behaviours in the Circadian Period Mutant Mouse Afterhours

Background Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours. Methodology Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder. Principal Findings Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009). Conclusions Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans.