Cerisse Gunasinghe

Association of DISC1 and TSNAX genes and affective disorders in the depression case-control (DeCC) and bipolar affective case-control (BACCS) studies.

The gene known as Disrupted-in-Schizophrenia-1, DISC1, was originally discovered in a large family, in which it also co-segregated with bipolar affective disorder (BD) and with major depressive disorder (MDD). The TSNAX (Translin-associated factor X) gene, located immediately upstream of DISC1, has also been suggested as a candidate gene in relation to psychiatric illness, as one transcript resulting from intergenic splicing encodes a novel TSNAX–DISC1 fusion protein. We explored the TSNAX–DISC1 gene region for an association with BD and MDD in a sample of 1984 patients (1469 MDD, 515 BD) and 1376 ethnically matched controls. Eight single nucleotide polymorphisms (SNPs) within the TSNAX–DISC1 region (rs766288, rs3738401, rs2492367, rs6675281, rs12133766, rs1000731, rs7546310 and rs821597) were investigated using the SNPlex Genotyping System. We found a significant allelic and genotypic association of the TSNAX–DISC1 gene region with BD, whereas a haplotypic association was found for both BD and MDD. Therefore, our results suggest an association between the TSNAX–DISC1 region and both forms of affective disorders, and support the hypothesis that a portion of the genotypic overlap between schizophrenia and affective disorders is attributable to this gene.

Depression Case Control (DeCC) Study fails to support involvement of the muscarinic acetylcholine receptor M2 (CHRM2) gene in recurrent major depressive disorder

It has been suggested that alteration in the muscarinic-cholinergic system is involved in modulation of mood. Three studies have reported linkage on chromosome 7 with major depressive disorder (MDD) in or close to a region containing the muscarinic receptor CHRM2 gene. A haplotype of SNPs located in CHRM2 (rs1824024-rs2061174-rs324650) has been significantly associated with MDD in a previous study. We report the first study investigating this gene in a large, adequately powered, clinical depression case-control sample (n = 1420 cases, 1624 controls). Our data fail to support association with the CHRM2 polymorphisms previously implicated in the genetic aetiology of depression. It is possible our failure to replicate may be a consequence of differences in definition of the MDD phenotype and/or ethnic differences.

Body weight as a predictor of antidepressant efficacy in the GENDEP project

BACKGROUND Being overweight or obese may be associated with poor response to antidepressants. The present report explores the moderation of antidepressant response by body weight to establish the specificity to antidepressant mode of action, type of depressive symptoms and gender. METHODS Height and weight were measured in 797 men and women with major depression treated with escitalopram or nortriptyline for twelve weeks as part of the Genome Based Therapeutic Drugs for Depression (GENDEP) project. Body mass index (BMI) and obesity (BMI>30) were tested as predictors of change in depressive symptoms using mixed linear models. RESULTS Higher BMI and obesity predicted poor response to nortriptyline but did not significantly influence response to escitalopram. The moderation of response by body weight was due to differential improvement in neurovegetative symptoms, including sleep and appetite. The relationship between body weight and change in neurovegetative symptoms was moderated by gender with obese men responding less to nortriptyline and obese women having poorer response to both antidepressants. LIMITATIONS As no placebo arm was included, the specificity of findings to antidepressants is relative. Lack of specific measures precluded accounting for differences in body fat distribution. CONCLUSIONS Body weight should be considered in the assessment of depression as it may inform the selection of antidepressant treatment.

CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP

In vitro work shows CYP2C19 and CYP2D6 contribute to the metabolism of escitalopram to its primary metabolite, N-desmethylescitalopram. We report the effect of CYP2C19 and CYP2D6 genotypes on steady state morning concentrations of escitalopram and N-desmethylescitalopram and the ratio of this metabolite to the parent drug in 196 adult patients with depression in GENDEP, a clinical pharmacogenomic trial. Subjects who had one CYP2D6 allele associated with intermediate metabolizer phenotype and one associated with poor metabolizer (i.e. IM/PM genotypic category) had a higher mean logarithm escitalopram concentration than CYP2D6 extensive metabolizers (EMs) (p = 0.004). Older age was also associated with higher concentrations of escitalopram. Covarying for CYP2D6 and age, we found those homozygous for the CYP2C19*17 allele associated with ultrarapid metabolizer (UM) phenotype had a significantly lower mean escitalopram concentration (2-fold, p = 0.0001) and a higher mean metabolic ratio (p = 0.0003) than EMs, while those homozygous for alleles conferring the PM phenotype had a higher mean escitalopram concentration than EMs (1.55-fold, p = 0.008). There was a significant overall association between CYP2C19 genotypic category and escitalopram concentration (p = 0.0003; p = 0.0012 Bonferroni corrected). In conclusion, we have demonstrated an association between CYP2C19 genotype, including the CYP2C19*17 allele, and steady state escitalopram concentration.

Suicidal ideation during treatment of depression with escitalopram and nortriptyline in Genome-Based Therapeutic Drugs for Depression (GENDEP): a clinical trial

BackgroundSuicidal thoughts and behaviours during antidepressant treatment, especially during the first weeks of treatment, have prompted warnings by regulatory bodies. The aim of the present study is to investigate the course and predictors of emergence and worsening of suicidal ideation during tricyclic antidepressant and serotonin reuptake inhibitor treatment.MethodsIn a multicentre part-randomised open-label study, 811 adult patients with moderate to severe unipolar depression were allocated to flexible dosage of escitalopram or nortriptyline for 12 weeks. The suicidality items of three standard measures were integrated in a suicidal ideation score. Increases in this score were classified as treatment emergent suicidal ideation (TESI) or treatment worsening suicidal ideation (TWOSI) according to the absence or presence of suicidal ideation at baseline.ResultsSuicidal ideation decreased during antidepressant treatment. Rates of TESI and TWOSI peaked in the fifth week. Severity of depression predicted TESI and TWOSI. In men, nortriptyline was associated with a 9.8-fold and 2.4-fold increase in TESI and TWOSI compared to escitalopram, respectively. Retirement and history of suicide attempts predicted TWOSI.ConclusionIncreases in suicidal ideation were associated with depression severity and decreased during antidepressant treatment. In men, treatment with escitalopram is associated with lower risk of suicidal ideation compared to nortriptyline. Clinicians should remain alert to suicidal ideation beyond the initial weeks of antidepressant treatment.Trial registrationEudraCT (No.2004-001723-38) and ISRCTN (No. 03693000).

Adverse life event reporting and worst illness episodes in unipolar and bipolar affective disorders measuring environmental risk for genetic research

BACKGROUND Studies exploring gene-environment interplay in affective disorders now include very large numbers of participants. Methods for evaluating the role of adversity in such studies need to be developed that do not rely on lengthy and labour-intensive interviews. In the present study, a brief questionnaire method for measuring 11 adverse events reported before interview and before their worst illness episodes by bipolar, unipolar and healthy control participants, participating in genetic association studies, was evaluated. METHOD Five hundred and twelve bipolar disorder (BD) participants, 1447 participants with recurrent unipolar depression (UPD) and 1346 psychiatrically healthy control participants underwent the researcher-administered version of the List of Threatening Experiences Questionnaire (LTE-Q) for the 6 months before their worst affective episodes for UPD and BD participants, and for the 6 months before interview for the UPD participants and controls. RESULTS UPD and BD cases were significantly more likely to report at least one event, as well as more events in the 6 months before interview and before their worst illness episodes, than healthy controls. Both manic and depressive episodes were significantly associated with adverse events in the BD cases. Depressed mood at the time of interview influenced event reporting in UPD and control participants but not the BD cases. Age was negatively correlated with the number of events reported by controls. CONCLUSIONS The researcher-administered LTE-Q provides a measure of case-control differences for adversity that is applicable in large genetic association studies. Confounding factors for event reporting include present mood and age.

OPCRIT+: an electronic system for psychiatric diagnosis and data collection in clinical and research settings

Background The increasingly large sample size requirements of modern adult mental health research suggests the need for a data collection and diagnostic application that can be used across a broad range of clinical and research populations. Aims To develop a data collection and diagnostic application that can be used across a broad range of clinical and research settings. Method We expanded and redeveloped the OPCRIT system into a broadly applicable diagnostic and data-collection package and carried out an interrater reliability study of this new tool. Results OPCRIT+ performed well in an interrater reliability study with relatively inexperienced clinicians, giving a combined, weighted kappa of 0.70 for diagnostic reliability. Conclusions OPCRIT+ showed good overall interrater reliability scores for diagnoses. It is now incorporated in the electronic patient record of the Maudsley and associated hospitals. OPCRIT+ can be downloaded free of charge at http://sgdp.iop.kcl.ac.uk/opcritplus.

The Bipolar Association case-control study (BACCS) and meta-analysis: no association with the 5,10-Methylenetetrahydrofolate reductase gene and bipolar disorder

Bipolar disorder (BD) is a complex genetic disease for which the underlying pathophysiology has yet to be fully explained. 5,10‐Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in folate‐mediated one‐carbon metabolism and folate deficiency can be associated with psychiatric symptoms. A single base variant in MTHFR gene (C677T) results in the production of a mildly dysfunctional thermolabile enzyme and has recently been implicated in BD. We conducted an association study of this polymorphism in 897 patients with bipolar I or bipolar II disorder, and 1,687 healthy control subjects. We found no evidence for genotypic or allelic association in this sample. We also performed a meta‐analysis of our own, and all published data, and report no evidence for association. Our findings suggest that the MTHFR C677T polymorphism is not involved in the genetic etiology of clinically significant BD.

Personality and the bipolar spectrum: normative and classification data for the Eysenck Personality Questionnaire-Revised

BACKGROUND Personality traits dispose individuals toward particular affective states and may therefore have an important role in the etiology of affective disorders in particular. Despite being one of the most widely used and well-researched personality instruments, few studies have studied bipolar spectrum disorders using the revised Eysenck Personality Questionnaire (EPQ-R) (Eysenck HJ, Eysenck SBG. The Eysenck Personality Questionnaire-Revised. Sevenoaks: UK; Hodder & Stoughton, 1992). METHODS The EPQ-R was administered to 50 bipolar patients, 50 unipolar patients, and 50 controls matched on age and sex. Participants in clinical groups were euthymic, and participants in the control groups were screened for symptoms of depression. RESULTS The EPQ-R scores were most effective at discriminating unipolar patients from controls, such that unipolar patients were higher on neuroticism and lower on extraversion. Bipolar patients showed a similar personality profile to, but were not clearly distinguished from, unipolar patients. CONCLUSIONS This research provides preliminary normative data for the EPQ-R that complement previous theoretical and empirical work in this area and suggests the usefulness of this tool in a clinical setting.

A follow-up case-control association study of tractable (druggable) genes in recurrent major depression

The High‐Throughput Disease‐specific target Identification Program (HiTDIP) aimed to study case–control association samples for 18 common diseases. Here we present the results of a follow‐up case–control association study of HiTDIP in major depressive disorder (MDD). The HiTDIP in MDD was conducted in a sample of 974 cases of recurrent MDD of white German origin collected at the Max‐Planck Institute (MP‐GSK) and 968 ethnically matched controls screened for lifetime absence of depression. Six genes were identified as of interest for a follow‐up, based on the strength of the association and based on the interest as potential candidate target for developing new treatment for depression: Solute Carrier Family 4 Member 10 (SLC4A10), Dipeptidyl Peptidase IV (DPP4), Dopamine Receptor D3 (DRD3), Zinc Finger Protein 80 (ZNF80), Nitric Oxide Synthase 2A (NOS2A) and Peroxisome Proliferator‐Activated Receptor‐Gamma, Coactivator 1, Alpha (PPARGC1A). Within the current study, we attempted to follow‐up these findings in a sample from the UK, the Depression Case Control (DeCC) sample consisting of 1,196 cases and 842 screened controls, phenotyped using exactly the same methods as the MP‐GSK sample. Performing Cochran–Mantel–Haenzel statistics to test for genotypic and/or allelic differences between the DeCC and MP‐GSK samples, we found no significant differences, thus being able to combine the two samples for association testing. In the combined sample of 2,170 MDD cases and 1,810 controls, there were positive findings in the Nitric Oxide Synthase 2A (NOS2A) gene both using single SNP analysis and haplotype analysis.