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Background:GAP(genesandpsychosis) is a case-control studyof first episode psychosis conducted in London and Cambridge, which aims to identify genes conferring susceptibility to psychosis, and associated phenotypes including cognitive dysfunction and cerebral morphology. Methods:First episode psychosis cases have been recruited in South London and Maudsley NHS Trust and in Cambridge. A variety of demographic and clinical data have been collected. In a subset of these, neurocognitive assessments and MRIs have been performed. Samples have been taken for DNA, and in a subset for RNA and proteomic analysis. Genetic association analysis is being undertaken using a candidate gene approach. The genes chosen for the first wave of analysis include the current most promising candidates for suscept-ibility to psychosis (NRG1, dysbindin, DISC1, G72, etc) as well as candidates for susceptibility to cannabis misuse (COMT), cognitive dysfunction, dysregulation of brain morphology or susceptibility to bipolar disorder (e.g. LIS1), and candidates in the dopamine and serotonin neurotransmitter systems. Results:DNA has been collected from 302 patients to date. Of these, 72%aremale, and themeanage is 25 years; 187 areCaucasian; 115 are of black origin; and the rest are of other ormixed ethnicity. Genotyping is being undertaken in this sample and in matched controls. Conclusions:Data is being reported separately for a number of phenotypes forwhich there is already somedata. This presentationwill report the overall genetic association results.

Suicidal behaviour shows evidence of familial clustering and the twin data on completed suicide suggest moderate heritability. The extent to which the genetics of suicidal behaviour overlaps with the genetics of affective disorders is unclear but there is overwhelming evidence that both bipolar and unipolar disorder are substantially influenced by genes. So far, candidate gene studies of suicidality have provoked much interest, but recently, attention has also turned to candidate gene approaches to suicidal ideation emerging during antidepressant treatment. The advent of genome-wide association studies (GWAS) has had a major impact on studies of affective disorder with some provocative new findings. The GWAS approach is also beginning to be applied in the search for genes that underlie suicidal ideation and behaviour.

Response to the treatment with antidepressants escitalopram and nortryptiline in correlation between serotonin transporter polymorphisms was described.

Background and aims: The simultaneous and wide-scale analysis of gene and protein expression provides a powerful strategy for the exploration at molecular level of complex pathophysiological mechanisms, such as the response to treatment with psychotropic agents. GENDEP is an Integrated Project that combines large-scale clinical pharmacogenomic studies on depressed patients with preclinical investigations on animal models, focusing on treatment with proserotonergic and pronoradrenergic antidepressants. Methods: Two different, complementary rat models of depression were used: the flinders sensitive line (FSL) and the learned helplessness. FSL rats were additionally subjected to a maternal separation protocol to investigate the impact of gene-environment interaction. Animals were chronically treated with escitalopram or nortriptyline, with behavioural studies and transcriptomic and proteomic profiling, in order to identify novel genes and gene products differentially expressed in the different paradigms. Transcriptome analyses were performed from prefrontal cortex and hippocampus using Affymetrix GeneChips, whilst for proteomics two-dimensional electrophoresis with mass spectrometry was used. Further proteomic studies, including functional investigations focusing on the detection of protein phosphorylation changes, were performed on both total extracts and purified synaptic terminals. Finally, modifications of synaptic plasticity (LTP) in hippocampus were investigated by electrophysiology with parallel measurements of molecular correlates. Results and conclusions: Preliminary results on proteome and transcriptome analysis of escitalopram treated rats allowed the identification of molecular and functional correlates of vulnerability to the disease, the effect of early-life stress and the response to pharmacological treatment.

The wide-scale analysis of protein expression provides a powerful strategy for the exploration at a molecular level of complex pathophysiological mechanisms, such as the response to treatment with psychotropic agents. GENDEP is an Integrated Project that combines large-scale clinical pharmacogenomic studies on depressed patients with preclinical investigations on animal models of disease, focusing on treatment with antidepressants. In this work, the Flinders Sensitive Line (FSL), a genetically selected rat model of depression displaying good face, predictive and construct validity (Overstreet 2005) was investigated by a two dimensional proteomic approach. As a control, analyses were carried out on the corresponding Flinders Resistant Line (FRL), which does not show the depressive-like behaviour. To evaluate gene–environment interactions, the FSL and FRL animals were subjected to maternal separation (MS), since early life trauma is considered to be an important antecedent of major depression. Following weaning, FSL and FRL rats were treated with escitalopram (ES), a selective serotonin reuptake inhibitor. FSL and FRL rats were subjected to 180 min. maternal separation from postnatal day 2 to 14. Control groups were not maternally separated. Both stressed and control animals were split into groups receiving ES admixed to food pellets (25 mg/kg/day) or vehicle for 30 days. One week before the end of treatments, the animals were subjected to the Porsolt swim test in order to assess the antidepressant effect of ES. After sacrifice, extracts were prepared from frontal cortex and hippocampus and proteins were separated by two-dimensional electrophoresis. Spots were detected by staining with a fluorescent dye. Image analysis was carried out on maps with PDQuest software to compare protein levels in different gels. Protein level comparisons were carried out with both univariate (Student’s t test) and multivariate (Partial Least Squares) statistical analysis methods. Spots displaying statistically significant differences were cut and proteins were identified using peptide fingerprinting mass spectrometry. Comparisons were carried out between groups in different electrophoretic runs to detect changes induced by genetic background, stress exposure and pharmacological treatment in each brain region. Modified proteins were identified. By the comparison FRL vs FSL, information was gathered about genetic differences between the lines, which are probably involved in the depressive-like behaviour. In the comparison (FSL+noMS+vehicle) vs (FSL+no MS+ES) vs (FSL+MS+ES) the different effect of pharmacological treatment was revealed on control and maternally separated FSL. By the comparison (FSL+noMS+vehicle) vs (FSL+MS+vehicle) vs (FSL+MS+ES), information was collected about the effect of the pharmacological treatment on the modifications induced by maternal separation. The same designs were also analysed on the FRL. Proteins involved in the different pharmacological response in different genetic backgrounds were revealed in the comparison (FRL+MS+ES) vs (FSL+MS+ ES). Results on proteome analysis of ES treated rats allowed the identification of molecular correlates of vulnerability to the disease, the effect of early life stress and the response to pharmacological treatment.

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.

The 8th Annual Pharmacogenetics in Psychiatry Meeting was held in New York City on 17 and 18 April 2009 with a series of panel presentations, as well as plenary lectures and a debate on the strengths and weakness of the meta-analytic approach. The following is a report of the meeting presentations.

SCOPUS: ar.j, info:eu-repo/semantics/published

BackgroundTricyclic antidepressants and serotonin reuptake inhibitors are considered to be equally effective, but differences may have been obscured by internally inconsistent measurement scales and inefficient statistical analyses.AimsTo test the hypothesis that escitalopram and nortriptyline differ in their effects on observed mood, cognitive and neurovegetative symptoms of depression.MethodIn a multicentre part-randomised open-label design (the Genome Based Therapeutic Drugs for Depression (GENDEP) study) 811 adults with moderate to severe unipolar depression were allocated to flexible dosage escitalopram or nortriptyline for 12 weeks. The weekly Montgomery–Åsberg Depression Rating Scale, Hamilton Rating Scale for Depression, and Beck Depression Inventory were scored both conventionally and in a more novel way according to dimensions of observed mood, cognitive symptoms and neurovegetative symptoms.ResultsMixed-effect linear regression showed no difference between escitalopram and nortriptyline on the three original scales, but symptom dimensions revealed drug-specific advantages. Observed mood and cognitive symptoms improved more with escitalopram than with nortriptyline. Neurovegetative symptoms improved more with nortriptyline than with escitalopram.ConclusionsThe three symptom dimensions provided sensitive descriptors of differential antidepressant response and enabled identification of drug-specific effects.

Udgivelsesdato: 2009-Aug The objective of the Genome-based Therapeutic Drugs for Depression study is to investigate the function of variations in genes encoding key proteins in serotonin, norepinephrine, neurotrophic and glucocorticoid signaling in determining the response to serotonin-reuptake-inhibiting and norepinephrine-reuptake-inhibiting antidepressants. A total of 116 single nucleotide polymorphisms in 10 candidate genes were genotyped in 760 adult patients with moderate-to-severe depression, treated with escitalopram (a serotonin reuptake inhibitor) or nortriptyline (a norepinephrine reuptake inhibitor) for 12 weeks in an open-label part-randomized multicenter study. The effect of genetic variants on change in depressive symptoms was evaluated using mixed linear models. Several variants in a serotonin receptor gene (HTR2A) predicted response to escitalopram with one marker (rs9316233) explaining 1.1% of variance (P=0.0016). Variants in the norepinephrine transporter gene (SLC6A2) predicted response to nortriptyline, and variants in the glucocorticoid receptor gene (NR3C1) predicted response to both antidepressants. Two HTR2A markers remained significant after hypothesis-wide correction for multiple testing. A false discovery rate of 0.106 for the three strongest associations indicated that the multiple findings are unlikely to be false positives. The pattern of associations indicated a degree of specificity with variants in genes encoding proteins in serotonin signaling influencing response to the serotonin-reuptake-inhibiting escitalopram, genes encoding proteins in norepinephrine signaling influencing response to the norepinephrine-reuptake-inhibiting nortriptyline and a common pathway gene influencing response to both antidepressants. The single marker associations explained only a small proportion of variance in response to antidepressants, indicating a need for a multivariate approach to prediction.

Background: It has been proposed that a history of suicide attempts could be a correlate of severe depressive disorder and that suicide attempters (SA) could represent a particular subtype of subjects suffering from major depressive disorder. We investigated clinical and demographic characteristics associated with SA and tested the hypothesis that a history of suicide attempts predicts poor response to antidepressants. Methods: One-hundred-and-forty-one SA and 670 non-SA subjects with major depressive disorder (MDD) were treated for twelve weeks with escitalopram or nortriptyline in GENDEP, a part-randomized multi-center clinical and pharmacogenetic study. Baseline characteristics were compared using linear and logistic regression. Linear mixed models were used to analyse continuous outcomes during the twelve weeks of follow-up. Results: At baseline, SA subjects suffered from more severe depression (mean Montgomery-Asberg Depression Rating Scale: 30.29 (7.61) vs 28.43 (6.54), p = 0.0002), reported higher level of suicidal ideation (1.21 (0.82) vs 0.73 (0.48), p < 0.0001), had a younger age of onset and experienced more depressive episodes, had higher harm avoidance scores and poorer socio-demographic environment than non-SA individuals. However, during the twelve weeks of treatment and after adjustment for baseline severity of depression there was no difference in treatment response between SA and non-SA. Limitations: Due to its retrospective design, it is possible that more severely depressed subjects might report more suicide attempts than less depressed individuals. Conclusions: While SA differed from non-SA in several clinical and demographic characteristics, the antidepressants were similarly effective in SA as in comparably severely depressed subjects without a history of suicide attempts. © 2009 Elsevier B.V. All rights reserved.

BackgroundAdverse drug reactions are important determinants of non-adherence to antidepressant treatment but their assessment is complicated by overlap with depressive symptoms and lack of reliable self-report measures.AimsTo evaluate a simple self-report measure and describe adverse reactions to antidepressants in a large sample.MethodThe newly developed self-report Antidepressant Side-Effect Checklist and the psychiatrist-rated UKU Side Effect Rating Scale were repeatedly administered to 811 adult participants with depression in a part-randomised multicentre open-label study comparing escitalopram and nortriptyline.ResultsThere was good agreement between self-report and psychiatrists' ratings. Most complaints listed as adverse reactions in people with depression were more common when they were medication-free rather than during their treatment with antidepressants. Dry mouth (74%), constipation (33%) and weight gain (15%) were associated with nortriptyline treatment. Diarrhoea (9%), insomnia (36%) and yawning (16%) were more common during treatment with escitalopram. Problems with urination and drowsiness predicted discontinuation of nortriptyline. Diarrhoea and decreased appetite predicted discontinuation of escitalopram.ConclusionsAdverse reactions to antidepressants can be reliably assessed by self-report. Attention to specific adverse reactions may improve adherence to antidepressant treatment.