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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.

BackgroundA number of scales are used to estimate the severity of depression. However, differences between self-report and clinician rating, multi-dimensionality and different weighting of individual symptoms in summed scores may affect the validity of measurement. In this study we examined and integrated the psychometric properties of three commonly used rating scales.MethodThe 17-item Hamilton Depression Rating Scale (HAMD-17), the Montgomery–Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI) were administered to 660 adult patients with unipolar depression in a multi-centre pharmacogenetic study. Item response theory (IRT) and factor analysis were used to evaluate their psychometric properties and estimate true depression severity, as well as to group items and derive factor scores.ResultsThe MADRS and the BDI provide internally consistent but mutually distinct estimates of depression severity. The HAMD-17 is not internally consistent and contains several items less suitable for out-patients. Factor analyses indicated a dominant depression factor. A model comprising three dimensions, namely ‘observed mood and anxiety’, ‘cognitive’ and ‘neurovegetative’, provided a more detailed description of depression severity.ConclusionsThe MADRS and the BDI can be recommended as complementary measures of depression severity. The three factor scores are proposed for external validation.

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.

Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2, 746 cases and 1, 594 screened controls from the RADIANT studies, with replication performed in 1, 471 cases and 1, 403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P

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 Treatments and organizational changes supported by eHealth are beginning to play an important role in improving disease treatment outcome and providing cost-efficient care management. “Improvehealth.eu” is a novel eHealth service to support the treatment of patients with depressive disorder. It offers active patient engagement and collaborative care management by combining Web- and mobile-based information and communication technology systems and access to care managers. Objectives Our objective was to assess the feasibility of a novel eHealth service. Methods The intervention—the “Improvehealth.eu” service—was explored in the course of a pilot study comparing two groups of patients receiving treatment as usual and treatment as usual with eHealth intervention. We compared patients’ medication adherence and outcome measures between both groups and additionally explored usage and overall perceptions of the intervention in intervention group. Results The intervention was successfully implemented in a pilot with 46 patients, of whom 40 were female. Of the 46 patients, 25 received treatment as usual, and 21 received the intervention in addition to treatment as usual. A total of 55% (12/25) of patients in the former group and 45% (10/21) in the latter group finished the 6-month pilot. Available case analysis indicated an improvement of adherence in the intervention group (odds ratio [OR] = 10.0, P = .03). Intention-to-treat analysis indicated an improvement of outcome in the intervention group (ORs ranging from 0.35 to 18; P values ranging from .003 to .20), but confidence intervals were large due to small sample sizes. Average duration of use of the intervention was 107 days. The intervention was well received by 81% (17/21) of patients who reported feeling actively engaged, in control of their disease, and that they had access to a high level of information. In all, 33% (7/21) of the patients also described drawbacks of the intervention, mostly related to usability issues. Conclusions The results of this pilot study indicate that the intervention was well accepted and helped the patients in the course of treatment. The results also suggest the potential of the intervention to improve both medication adherence and outcome measures of treatment, including reduction of depression severity and patients becoming “healthy.”

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.

Success in early detection of harmful stress, mental ill-health, and suicidal behaviour is substantially dependent on system solutions at the macro level. Suicide prevention interventions and strategies can only be effective if cross-disciplinary knowledge and skills, at different stages of the suicidal process and on different vulnerable groups are combined. In this chapter, traditionally well-known vulnerable groups, such as people with depression and alcohol misuse, are discussed at different stages of the suicidal process, in order to increase early detection. Early recognition is also important in demographic groups that have been neglected to date in suicide prevention, such as mothers with pre-natal and post-natal mental disorders, persons with diabetes mellitus, spinal cord injury disabilities and adult childhood cancer survivors, as well as young vulnerable people for whom harmful stress can be a suicidal trigger. In regard to the implementation and process optimization of individual interventions, lessons from management and, in particular, from social marketing, can provide a key contribution.

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.

The main objective of the present study was to obtain an approximate prevalence of depressive symptoms in a community sample of persons with diabetes mellitus and to discover whether social networks could explain comorbidity of diabetes mellitus and depressive symptoms.Subjects were persons with diabetes mellitus, members of the Diabetes Association of Ljubljana (N = 396, average age: 62.9 +/- 13.4, average duration of diabetes: 17.2 +/- 10.6). Firstly, subjects were screened with CESD (Centre for Epidemiological Studies Depression Scale) and demographic data were also gathered. Secondly, two samples (individuals with and without depressive symptoms) were compared on the basis of social network analysis.The prevalence of depressive symptoms was higher among persons with diabetes in comparison with general population. Individuals with depressive symptoms compared with individuals without depressive symptoms were less dissatisfied with diabetes (p = 0.011), and had better informational (p = 0.039) and instrumental support (p = 0.046), relations between them and support givers were closer (p = 0.050), more important and less conflicting (p = 0.042). Compared groups did not differ in quantitative characteristics of social networks (eg. size of the network or the network gender structure).The community sample results in Slovenia support the already reported association between diabetes mellitus and depression. Furthermore, social network analysis offered some potentially relevant explanation for comorbidity of diabetes mellitus and depressive symptoms.