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Udgivelsesdato: 2010-Mar-9 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.The Pharmacogenomics Journal advance online publication, 9 March 2010; doi:10.1038/tpj.2010.14.

Udgivelsesdato: 2009-Mar-6 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.

Objectives. Sexual dysfunction (SD) is a frequently reported side-effect of antidepressant treatment, particularly of selective serotonin reuptake inhibitors (SSRIs). In the multicentre clinical and pharmacogenetic GENDEP study (Genome-based Therapeutic Drugs for Depression), the effect of the serotonin transporter gene promoter polymorphism 5-HTTLPR on sexual function was investigated during treatment with escitalopram (SSRI) and nortriptyline (tricyclic antidepressant). Methods. A total of 494 subjects with an episode of DSM-IV major depression were randomly assigned to treatment with escitalopram or nortriptyline. Over 12 weeks, depressive symptoms and SD were measured weekly with the Montgomery-Asberg Depression Rating Scale, the Antidepressant Side-Effect Checklist, the UKU Side Effect Rating Scale, and the Sexual Functioning Questionnaire. Results. The incidence of reported SD after 12 weeks of treatment was relatively low, and did not differ significantly between antidepressants (14.9% escitalopram, 19.7% nortriptyline). There was no significant interaction between the 5-HTTLPR and antidepressant on SD. Improvement in depressive symptoms and younger age were both associated with lower SD. The effect of age on SD may have been moderated by the 5-HTTLPR. Conclusions. In GENDEP, rates of reported SD during treatment were lower than those described in previous reports. There was no apparent effect of the 5-HTTLPR on the observed decline in SD.

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.

Udgivelsesdato: 2010-Aug-18 The risk of weight gain is an important determinant of the acceptability and tolerability of antidepressant medication. To compare changes in body weight during treatment with different antidepressants, body weight and height were measured at baseline and after 6, 8, 12 and 26 wk treatment with escitalopram or nortriptyline in 630 adults with moderate-to-severe unipolar depression participating in GENDEP, a part-randomized open-label study. Weight increased significantly more during treatment with nortriptyline compared to escitalopram. The weight gain commenced during the first 6 wk of nortriptyline treatment, reached on average 1.2 kg at 12 wk (0.44-point BMI increase), and continued throughout the 6-month follow-up period. Participants who were underweight at baseline gained most weight. Participants who were obese at baseline did not gain more weight during treatment. Weight gain occurred irrespective of whether weight loss was a symptom of current depressive episode and was identified as an undesired effect of the antidepressant by most participants who gained weight. There was little weight change during treatment with escitalopram, with an average increase of 0.14 kg (0.05-point BMI increase) over 12 wk of treatment. In conclusion, treatment with the tricyclic antidepressant nortriptyline was associated with moderate weight gain, which cannot be explained as a reversal of symptomatic weight loss and is usually perceived as an undesired adverse effect. While treatment with nortriptyline may be recommended in underweight subjects with typical neurovegetative symptoms, escitalopram is a suitable alternative for subjects at risk of weight gain.

Background The occurrence of stressful life events (SLEs) has been shown to predict response to antidepressants; however, results are inconsistent. There is some evidence to suggest that SLEs prior to treatment are associated with greater cognitive symptoms at baseline and may therefore predict changes in these symptoms specifically. Methods GENDEP, a prospective part-randomised pharmacogenomics trial, collected longitudinal data on the symptoms of patients with major depression treated with either a selective serotonin reuptake inhibitor (SSRI, escitalopram) or a tricyclic antidepressant (TCA, nortriptyline). Data on life events experienced in the 6 months preceding treatment measured using the List of Threatening Experiences Questionnaire (LTE-Q) were available for 728 participants. Results Both the occurrence and number of SLEs were associated with greater cognitive but not mood or neurovegetative symptoms prior to treatment. Those who reported SLEs also experienced a greater decline in cognitive symptoms during treatment with escitalopram, but not with nortriptyline. Limitations Life events were measured retrospectively using a self-report checklist and are therefore subject to a number of biases especially in the context of depressive illness. Conclusions These findings are in line with cognitive theories of depression and suggest that symptomatic heterogeneity may have contributed to inconsistencies in studies reported to date. Our results also tentatively suggest a clinically relevant drug specific effect of SLEs. Specifically, those reporting stress may benefit more from treatment with SSRIs than TCAs.

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.