Showing papers by "Rudolf Uher published in 2009"

Protective Effect of CRHR1 Gene Variants on the Development of Adult Depression Following Childhood Maltreatment: Replication and Extension

Abstract: CONTEXT: A previous study reported a gene x environment interaction in which a haplotype in the corticotropin-releasing hormone receptor 1 gene (CRHR1) was associated with protection against adult depressive symptoms in individuals who were maltreated as children (as assessed by the Childhood Trauma Questionnaire [CTQ]). OBJECTIVE: To replicate the interaction between childhood maltreatment and a TAT haplotype formed by rs7209436, rs110402, and rs242924 in CRHR1, predicting adult depression. DESIGN: Two prospective longitudinal cohort studies. SETTING: England and New Zealand. PARTICIPANTS: Participants in the first sample were women in the E-Risk Study (N = 1116), followed up to age 40 years with 96% retention. Participants in the second sample were men and women in the Dunedin Study (N = 1037), followed up to age 32 years with 96% retention. Main Outcome Measure Research diagnoses of past-year and recurrent major depressive disorder. RESULTS: In the E-Risk Study, the TAT haplotype was associated with a significant protective effect. In this effect, women who reported childhood maltreatment on the CTQ were protected against depression. In the Dunedin Study, which used a different type of measure of maltreatment, this finding was not replicated. CONCLUSIONS: A haplotype in CRHR1 has been suggested to exert a protective effect against adult depression among research participants who reported maltreatment on the CTQ, a measure that elicits emotional memories. This suggests the hypothesis that CRHR1's protective effect may relate to its function in the consolidation of memories of emotionally arousing experiences. Language: en

Adverse reactions to antidepressants

Abstract: Background Adverse 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. Aims To evaluate a simple self-report measure and describe adverse reactions to antidepressants in a large sample. Method The 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. Results There 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. Conclusions Adverse reactions to antidepressants can be reliably assessed by self-report. Attention to specific adverse reactions may improve adherence to antidepressant treatment.

Genetic predictors of response to antidepressants in the GENDEP project

Abstract: 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.

Differential efficacy of escitalopram and nortriptyline on dimensional measures of depression

Abstract: Background Tricyclic 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. Aims To test the hypothesis that escitalopram and nortriptyline differ in their effects on observed mood, cognitive and neurovegetative symptoms of depression. Method In 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–Asberg 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. Results Mixed-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. Conclusions The three symptom dimensions provided sensitive descriptors of differential antidepressant response and enabled identification of drug-specific effects.

The role of genetic variation in the causation of mental illness: an evolution-informed framework

Abstract: The role of genetic variation in the causation of mental illness: an evolution-informed framework

Moderation of antidepressant response by the serotonin transporter gene

Abstract: Background There have been conflicting reports on whether the length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) moderates the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is modulated by gender, age and other variants in the serotonin transporter gene. Aims To test the hypothesis that the 5-HTTLPR differently influences response to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline reuptake inhibitor). Method The 5-HTTLPR and 13 additional markers across the serotonin transporter gene were genotyped in 795 adults with moderate-to-severe depression treated with escitalopram or nortriptyline in the Genome Based Therapeutic Drugs for Depression (GENDEP) project. Results The 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more than short-allele homozygotes. A significant three-way interaction between 5-HTTLPR, drug and gender indicated that the effect was concentrated in males treated with escitalopram. The single-nucleotide polymorphism rs2020933 also influenced outcome. Conclusions The effect of 5-HTTLPR on antidepressant response is SSRI specific conditional on gender and modulated by another polymorphism at the 5′ end of the serotonin transporter gene.

An examination of decision making in bulimia nervosa

Abstract: Background: Patients with eating disorders favor immediate gratification and ignore long-term negative consequences. This study investigated decision making in bulimia nervosa using the Iowa Gambling Task (IGT) and skin conductance responses (SCR). Method: A total of 26 bulimia nervosa patients and 51 healthy controls took part in this study; 29 patients with anorexia nervosa were included for comparison. Results: Bulimia nervosa patients performed poorly in the IGT, but showed no decrease in anticipatory SCR, whereas a markedly diminished anticipatory SCR was seen in the anorexia nervosa group. Conclusions: This finding does not support the somatic marker hypothesis. Impaired decision making was associated with obsessive-compulsive traits.

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

Abstract: Background Suicidal 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.

Stability of symptoms across major depressive episodes in bipolar disorder

Abstract: The DSM-IV includes subtypes, or illness specifiers, for major depressive episodes such as atypical and melancholic, which have been suggested to have predictive validity (1, 2). That is, depressive features may be informative about outcome or diagnosis (3). In particular, some investigators have reported that atypical depressive symptoms, most notably reversed neurovegetative symptoms, and melancholic features are more characteristic (and perhaps a hallmark) of bipolar disorder compared to major depressive disorder (MDD) (4-6). This literature makes the implicit, but important, assumption that depressive features are stable across episodes, an assumption rarely examined prospectively in large cohorts. In the only study to examine more than one depressive recurrence, Coryell and colleagues (7) found some stability for psychotic, agitated versus retarded, and ‘endogenous’ depression; this cohort included ~120 subjects with bipolar disorder. Smaller studies in MDD identified modest correlation for neurovegetative symptoms (8), groups of ‘endogenous’ or anxious symptoms (9, 10), melancholia (11), and suicidality (10). To our knowledge, no study has specifically examined stability of these symptoms in bipolar depression, and only one study considered more than one depressive episode. Beyond refining psychiatric nosology, understanding temporal stability may facilitate biological studies by clarifying ‘core’ symptoms of depression in mood disorders. It may also guide clinical practice if certain symptoms such as suicidality demonstrate stability from episode to episode. We therefore examined data from the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort study of bipolar disorder, utilizing the subset of individuals with up to three prospectively observed depressive episodes. We attempted to confirm the stability of neurovegetative symptoms and suicidality between episodes and explore the broader stability of mood symptoms.

Modulation of thermal pain perception by stress and sweet taste in women with bulimia nervosa.

Abstract: OBJECTIVES: To investigate if the increased pain threshold in women with bulimia nervosa (BN) may be due to chronic stress-induced analgesia. METHODS: We measured thermal pain threshold latency, blood pressure and heart rate in 21 women with BN and 21 healthy women (HW) under six consecutive conditions: rest I, mental arithmetic task, rest II, eating sweet food, rest III, cold-pressor test. RESULTS: Thermal pain threshold latency was longer in BN than in HW in all six conditions. It increased during mental arithmetic test and remained increased during the rest of the experiment in both groups. In the BN group, the increase of pain threshold during mental arithmetic was positively correlated with illness duration. The differential modulation of pain threshold by stress in BN and HW could not be explained by autonomic system reactivity. In HW, the pain threshold increased more during eating and blood pressure increased more during mental stress; in BN, the pain threshold was highest in the mental stress condition and blood pressure was most increased during eating. During the cold pressor test, women with BN showed smaller blood pressure increase and tolerated the cold for shorter time than HW CONCLUSION: The observed marked modulation of pain threshold by experimental stress suggests that stress-induced analgesia is unlikely to account for baseline pain insensitivity in BN. Increased pain threshold in BN is a stable yet incompletely understood phenomenon, which may be related to the predisposition to or maintenance of the disorder.