Bruce R. Lawford

Cannabinoid receptor 1 (CNR1) gene: Impact on antidepressant treatment response and emotion processing in Major Depression.

The endocannabinoid system has been implicated in the pathogenesis of depression and anxiety, the mediation of antidepressant drug effects in animal models and the neurobiology of emotion processing in healthy volunteers. Therefore, the impact of cannabinoid receptor 1 gene (CNR1) variants rs1049353 and rs12720071 on antidepressant treatment response was evaluated in 256 Caucasian patients with Major Depression. A subsample of 33 depressed patients was additionally scanned by fMRI under visual presentation of emotional faces. The CNR1 rs1049353 G allele conferred an increased risk of antidepressant treatment resistance, particularly in female patients with high comorbid anxiety. CNR1 rs1049353 G allele carriers also demonstrated weaker bilateral amygdala, putamen and pallidum activity as well as left lateralized caudate and thalamus activity in response to masked happy faces. This analysis provides preliminary support for a role of CNR1 gene variation in depression and anxiety, potentially mediated by subcortical hypo-responsiveness to social reward stimuli.

Brain-derived neurotrophic factor (BDNF) gene: no major impact on antidepressant treatment response

The brain-derived neurotrophic factor (BDNF) has been suggested to play a pivotal role in the aetiology of affective disorders. In order to further clarify the impact of BDNF gene variation on major depression as well as antidepressant treatment response, association of three BDNF polymorphisms [rs7103411, Val66Met (rs6265) and rs7124442] with major depression and antidepressant treatment response was investigated in an overall sample of 268 German patients with major depression and 424 healthy controls. False discovery rate (FDR) was applied to control for multiple testing. Additionally, ten markers in BDNF were tested for association with citalopram outcome in the STAR*D sample. While BDNF was not associated with major depression as a categorical diagnosis, the BDNF rs7124442 TT genotype was significantly related to worse treatment outcome over 6 wk in major depression (p = 0.01) particularly in anxious depression (p = 0.003) in the German sample. However, BDNF rs7103411 and rs6265 similarly predicted worse treatment response over 6 wk in clinical subtypes of depression such as melancholic depression only (rs7103411: TT < CC, p = 0.003; rs6265: GG < AA, p = 0.001). All SNPs had main effects on antidepressant treatment response in ANOVA models when the remaining SNPs were considered as covariates. The STAR*D analyses did not yield significant results at any of the ten BDNF markers. Our results do not support an association between genetic variation in BDNF and antidepressant treatment response or remission. Post-hoc analyses provide some preliminary support for a potential minor role of genetic variation in BDNF and antidepressant treatment outcome in the context of melancholic depression.

Smoking and schizophrenia: Is symptom profile related to smoking and which antipsychotic medication is of benefit in reducing cigarette use?

Objective: Smoking rate is disproportionately high among patients with schizophrenia, resulting in significant morbidity and mortality. However, cigarette smoking has been reported to have beneficial effects on negative symptoms, extrapyramidal symptoms, cognitive functioning and mood symptoms. Therefore, smoking cessation may worsen disability in schizophrenia. The association between smoking and these key clinical parameters was examined. Additionally, severity of smoking across four different antipsychotic treatment groups was explored. Method: One hundred and forty-six patients with schizophrenia were assessed for smoking using expired carbon monoxide and smoking history. They were administered the Positive and Negative Symptom Scale, The Extrapyramidal Symptom Rating Scale, the Barnes Akathisia Rating Scale, Reitans Trail-making Test (A and B) and General Health Questionnaire-28. Results: There was no difference in the chlorpromazine equivalent dose of any of the medications studied. Atypical agents were associated with significantly lower levels of smoking when compared with typical medications. There was no difference in smoking severity between the individual atypical medications examined. Similarly, there were no significant differences between smoking and non-smoking groups with regard to Positive and Negative Symptom Scale, Extrapyramidal Symptom Rating Scale, Trail-making Test and General Health Questionnaire-28. However, there was a significant difference between these groups with the smoking group demonstrating less akathisia. Conclusions: Smoking is not associated with positive, negative cognitive and mood symptoms in schizophrenia. Smoking is associated with lower levels of antipsychotic induced akathisia. Clinicians should not be discouraged from helping patients stop smoking for fear of worsening symptoms. However, akathisia may emerge upon cessation of smoking. Switching patients from typical to atypical antipsychotics may assist patients with schizophrenia to give up smoking.

The C/C genotype of the C957T polymorphism of the dopamine D2 receptor is associated with schizophrenia

The T allele of the human dopamine D2 receptor (DRD2) gene C957T polymorphism is associated with reduced mRNA translation and stability. This results in decreased dopamine induced DRD2 upregulation and decreased in vivo D2 dopamine binding. Conversely, the C allele of the C957T polymorphism is not associated with such changes in mRNA leading to increased DRD2 expression. PET and postmortem binding studies show that schizophrenia is often associated with increased DRD2 availability. We report that on the basis of comparing the frequencies of the C/C and T/T genotypes of 153 patients with schizophrenia and 148 controls that schizophrenia is associated with the C/C genotype. The C957T shows a population attributable risk for schizophrenia of 24% and an attributable risk in those with schizophrenia of 42%. Increased expression of D2 receptors associated with the C allele is likely to be important in the underlying pathophysiology of at least some forms of schizophrenia. Enhanced understanding of schizophrenia afforded by this finding may lead to advances in treatment and prevention.

The DRD2 gene 957C>T polymorphism is associated with Posttraumatic Stress Disorder in war veterans

Background: Variations in genes related to the dopaminergic pathway have been implicated in neuropsychiatric disorders such as schizophrenia, substance misuse, Alzheimers disease and Post Traumatic Stress Disorder (PTSD). A single nucleotide polymorphism (SNP) (957C>T) and a deletion polymorphism (‐141delC) in the DRD2 gene and a SNP (Taq1A) in a gene directly downstream of DRD2 have all been implicated in dopamine functioning in the brain. Methods: To test the importance of these three polymorphisms in PTSD susceptibility, a genetic screen was performed in 127 war veterans diagnosed with PTSD and 228 control individuals without a history of PTSD. Results: No significant association was found between PTSD and the Taq1A or ‐141delC polymorphisms. However, a significant association was observed with PTSD and the 957C>T polymorphism. PTSD individuals were more likely to carry the C allele compared to the controls (P=0.021). Conclusions: Our findings suggest that the 957C>T polymorphism in the DRD2 gene is one of the genetic factors for susceptibility to PTSD. Depression Anxiety, 2009.

GABAA receptor β3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population

GABAergic systems have been implicated in the pathogenesis of anxiety, depression and insomnia. These symptoms are part of the core and comorbid psychiatric disturbances in post-traumatic stress disorder (PTSD). In a sample of Caucasian male PTSD patients, dinucleotide repeat polymorphisms of the GABA(A) receptor beta 3 subunit gene were compared to scores on the General Health Questionnaire-28 (GHQ). As the major allele at this gene locus (GABRB3) was G1, the alleles were divided into G1 and non-G1 groups. On the total score of the GHQ, which comprises the somatic symptoms, anxiety/insomnia, social dysfunction and depression subscales, patients with the G1 non-G1 genotype had a significantly higher score when compared to either the G1G1 genotype (alpha=0.01) or the non-G1 non-G1 genotype (alpha=0.05). No significant difference was found between the G1G1 and non-G1 non-G1 genotypes. When the G1 non-G1 heterozygotes were compared to the combined G1G1 and non-G1 non-G1 homozygotes, a significantly higher total GHQ score was found in the heterozygotes (P=0.002). These observations suggest a heterosis effect. Further analysis of GHQ subscale scores showed that heterozygotes compared to the combined homozygotes had higher scores on the somatic symptoms (P=0.006), anxiety/insomnia (P=0.003), social dysfunction (P=0.054) and depression (P=0.004) subscales. In conclusion, the present study indicates that in a population of PTSD patients, heterozygosity of the GABRB3 major (G1) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity.

Interaction Between DRD2 C957T Polymorphism and An Acute Psychosocial Stressor on Reward-Related Behavioral Impulsivity

The dopamine D2 receptor (DRD2) C957T polymorphism CC genotype is associated with decreased striatal binding of DRD2 and executive function and working memory impairments in healthy adults. We investigated the relationships between C957T and acute stress with behavioral phenotypes of impulsivity in 72 young adults randomly allocated to either an acute psychosocial stress or relaxation induction condition. Homozygotes for 957C showed increased reward responsiveness after stress induction. They were also quicker when making immediate choices on the delay discounting task when stressed, compared with homozygotes who were not stressed. No effects were found for response inhibition, a dimension of impulsivity not related to extrinsic rewards. These data suggest that C957T is associated with a reward-related impulsivity endophenotype in response to acute psychosocial stress. Future studies should examine whether the greater sensitivity of 957C homozygotes to the effects of stress is mediated through dopamine release.

Progress towards understanding the genetics of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a complex syndrome that occurs following exposure to a potentially life threatening traumatic event. This review summarises the literature on the genetics of PTSD including gene-environment interactions (GxE), epigenetics and genetics of treatment response. Numerous genes have been shown to be associated with PTSD using candidate gene approaches. Genome-wide association studies have been limited due to the large sample size required to reach statistical power. Studies have shown that GxE interactions are important for PTSD susceptibility. Epigenetics plays an important role in PTSD susceptibility and some of the most promising studies show stress and child abuse trigger epigenetic changes. Much of the molecular genetics of PTSD remains to be elucidated. However, it is clear that identifying genetic markers and environmental triggers has the potential to advance early PTSD diagnosis and therapeutic interventions and ultimately ease the personal and financial burden of this debilitating disorder.

A polymorphism in the dysbindin gene (DTNBP1) associated with multiple psychiatric disorders including schizophrenia

BackgroundA number of studies have found associations between dysbindin (DTNBP1) polymorphisms and schizophrenia. Recently we identified a DTNBP1 SNP (rs9370822) that is strongly associated with schizophrenia. Individuals diagnosed with schizophrenia were nearly three times as likely to carry the CC genotype compared to the AA genotype.MethodsTo investigate the importance of this SNP in the function of DTNBP1, a number of psychiatric conditions including addictive behaviours and anxiety disorders were analysed for association with rs9370822.ResultsThe DTNBP1 polymorphism was significantly associated with post-traumatic stress disorder (PTSD) as well as nicotine and opiate dependence but not alcohol dependence. Individuals suffering PTSD were more than three times as likely to carry the CC genotype compared to the AA genotype. Individuals with nicotine or opiate dependence were more than twice as likely to carry the CC genotype compared to the AA genotype.ConclusionsThis study provides further support for the importance of DTNBP1 in psychiatric conditions and suggests that there is a common underlying molecular defect involving DTNBP1 that contributes to the development of several anxiety and addictive disorders that are generally recognised as separate clinical conditions. These disorders may actually be different expressions of a single metabolic pathway perturbation. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.

Dopamine D3 receptor gene variation: impact on electroconvulsive therapy response and ventral striatum responsiveness in depression

Dysfunction of dopamine D₃ receptors, particularly in the mesocorticolimbic system, has been linked to the pathogenesis of major depression. Preclinical data show enhanced D₃ receptor binding in the striatum upon antidepressant medication and electroconvulsive therapy (ECT). Thus, the potential impact of dopamine D₃ receptor gene (DRD3) variation on ECT outcome in treatment-resistant major depression was evaluated by applying a combined molecular and imaging genetic approach. Altogether, 10 representative variants covering 95.4% of DRD3 gene variation were investigated for association with response to ECT in a sample of 104 (71 female, 33 male) Caucasian patients with pharmacorefractory major depression. Additionally, ventral striatum responsiveness to happy faces was assessed in two independent samples of depressed patients (total N=54) by means of functional magnetic resonance imaging at 3 T. Significant association of DRD3 rs3732790, rs3773679 and rs9817063 variants with response (uncorrected p=0.02-0.03) and remission (uncorrected p=0.01) after ECT was discerned. Logistic regression analyses revealed association of rs3732790 (uncorrected p=0.009; corrected p=0.045) and rs3773679 (uncorrected p=0.009; corrected p=0.045) with remission when applying a recessive model of inheritance. The rs3732790T allele conferring a more favourable treatment response was furthermore found to be associated with stronger striatal responsiveness to happy facial expressions (sample 1: cluster-corrected p=0.002; sample 2: p=0.023). In summary, the present study suggests some impact of DRD3 gene variation on ECT response, potentially mediated by alteration of striatal engagement during the processing of emotionally rewarding stimuli.