GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

Association between thyroid function, thyroid autoimmunity, and state and trait factors of depression.

OBJECTIVE: The aim of this study was to investigate whether thyroid function and thyroid peroxidase antibodies (TPOAb) are associated with depression, when using both state and trait parameters of depression. METHOD: In 1125 participants of the Nijmegen Biomedical Study, thyroid-stimulating hormone (TSH), free thyroxine (FT4), and TPOAb were measured twice. The Beck Depression Inventory (BDI), a self-reported lifetime diagnosis of depression, and the neuroticism scale of the Eysenck Personality Questionnaire Revised Short Scale (EPQ-RSS) were used to evaluate the presence of state and trait features of depression. RESULTS: We found no association between TSH and FT4 levels and BDI score, current depression, lifetime diagnosis of depression, and EPQ-RSS neuroticism score. Subjects with TPOAb had higher EPQ-RSS neuroticism scores in comparison with subjects without TPOAb, mean score 4.1 vs. 3.2 (regression coefficient 0.70; 95% CI 0.1-1.3; P-value 0.02 after adjustment for confounders). The prevalence of a lifetime diagnosis of depression was higher in subjects with positive TPOAb in comparison with participants without TPOAb: 24.2% vs. 16.7% (relative risk 1.4; 95% CI 1.0-2.1; P-value 0.04 after adjustment for confounders). CONCLUSION: Thyroid peroxidase antibodies are positively associated with trait markers of depression. The presence of TPOAb may be a vulnerability marker for depression.

Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals and may be implicated in the etiology of mood-related phenotypes. However, genetic association studies of the BDNF Val66Met polymorphism (single nucleotide polymorphism rs6265) in major depressive disorder (MDD) have produced inconsistent results. We conducted a meta-analysis of studies comparing the frequency of the BDNF Val66Met-coding variant in depressed cases (MDD) and nondepressed controls. A total of 14 studies involving 2812 cases with DSM-III or -IV defined MDD and 10 843 nondepressed controls met the inclusion criteria. Analyses were stratified either by gender or ethnicity (Asian and Caucasian) because MDD is more prevalent in women and in Caucasians and because BDNF allele frequencies differ by ethnicity. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were provided for allelic analyses (Met versus Val), as well as for genotypic analyses (Met/Met and Val/Met versus Val/Val). In the total sample, the BDNF Val66Met polymorphism was not significantly associated with depression. However, the gender stratified analyses revealed significant effects in both the allelic and genotypic analyses in men (OR(MET), 95% CI; 1.27 (1.10-1.47); OR(MET/MET), 95% CI; 1.67 (1.19-2.36)). Stratification according to ethnicity did not show significant effects of the Val66Met polymorphism on MDD. Our results suggest that the BDNF Val66Met polymorphism is of greater importance in the development of MDD in men than in women. Future research into gender issues will be of interest.

Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine.

OBJECTIVE: It remains unclear whether unipolar psychotic depression should be treated with an antidepressant and an antipsychotic or with an antidepressant alone. METHOD: In a multi-center RCT, 122 patients (18-65 years) with DSM-IV-TR psychotic major depression and HAM-D-17 > or = 18 were randomized to 7 weeks imipramine (plasma-levels 200-300 microg/l), venlafaxine (375 mg/day) or venlafaxine-quetiapine (375 mg/day, 600 mg/day). Primary outcome was response on HAM-D-17. Secondary outcomes were response on CGI and remission (HAM-D-17). RESULTS: Venlafaxine-quetiapine was more effective than venlafaxine with no significant differences between venlafaxine-quetiapine and imipramine, or between imipramine and venlafaxine. Secondary outcomes followed the same pattern. CONCLUSION: That unipolar psychotic depression should be treated with a combination of an antidepressant and an antipsychotic and not with an antidepressant alone, can be considered evidence based with regard to venlafaxine-quetiapine vs. venlafaxine monotherapy. Whether this is also the case for imipramine monotherapy is likely, but cannot be concluded from the data.

Familiality of depression in the community; associations with gender and phenotype of major depressive disorder.

INTRODUCTION: Although associations between family history and depression have been shown in clinical patients, it is unknown if they also apply to subjects living in the community. The present study considers the relationship between family loading and depression phenotype characteristics in a large community-based sample. METHOD: In a Dutch representative population sample of 7,076 individuals, lifetime diagnosis of depression was classified according to severity, course and age of onset. A family loading score of depression (FLSD) was computed by taking the proportion of the first-degree relatives for whom a history of depression was reported. RESULTS: There was a strong association between FLSD and lifetime diagnosis of MDD. Severity, recurrence and early onset of depression were the specific phenotypic characteristics associated with familiality. The effects of FLSD and gender were independent. CONCLUSION: Associations between family history and risk for depression in the community confirm those reported from clinical-based studies using direct interviewing of relatives. A stronger degree of familiality is associated with specific phenotypic characteristics of depression.

Depression in Down syndrome: a review of the literature.

BACKGROUND: Depression has been frequently reported in individuals with Down Syndrome (DS). The aim of this article is to provide a comprehensive, critical review of the clinically relevant literature concerning depression in DS, with a focus on epidemiology, potential risk factors, diagnosis, course characteristics and treatment. METHODS: We searched the PUBMED database (January 2011) using the keywords ("Depressive Disorder [MESH]" OR "Depression [MESH]" OR "depress* [All Fields]") AND ("Down Syndrome [MESH]" OR "Down syndrome [All Fields]" OR "Down's syndrome [All Fields]"). Review articles not adding new information, single case reports and papers focusing on subjects other than depression in DS were excluded. RESULTS: The PUBMED search resulted in 390 articles, of which 30 articles were finally included. Recent information does not support earlier suggestions of an increased prevalence of depression in DS compared to other causes of Intellectual Disability (ID). However, individuals with DS show many vulnerabilities and are exposed to high levels of stressors that could confer an increased risk for the development of depression. Apart from general risk factors, several potential risk factors are more specific for DS, including smaller hippocampal volumes, certain changes in neurotransmitter systems, deficits in language and working memory, attachment behaviours and frequently occurring somatic disorders. Protective factors might play a role in reducing the vulnerability to depression. The diagnosis of depression in DS is mainly based upon observable characteristics, and therefore, the use of modified diagnostic criteria is advised. Although several common treatments, including antidepressants, electroconvulsive therapy and psychotherapy seem effective, there is evidence of undertreatment of depression in DS. CONCLUSIONS: There are important limitations to our current clinical knowledge of depression in DS. Future studies should include systematic evaluations of pharmacotherapeutic and psychotherapeutic interventions.

The course of depressive symptoms in unipolar depressive disorder during electroconvulsive therapy: a latent class analysis.

BACKGROUND: Research examining the course of depressive symptoms during electroconvulsive therapy (ECT) is relatively scarce. OBJECTIVE: To classify patients according to the course of their depressive symptoms while receiving ECT. METHODS: The sample consisted of 156 consecutive patients receiving ECT for unipolar depressive disorder. Depressive symptoms were measured weekly with the Montgomery-Asberg Depression Rating Scale. Latent class analysis was applied to identify distinct trajectories of symptom improvement. RESULTS: We identified five classes of different trajectories (improvement rates) of depressive symptoms, i.e. fast improvement (39 patients), intermediate improvement (47 patients), slow improvement (30 patients), slow improvement with delayed onset (18 patients), and finally a trajectory with no improvement (20 patients). The course of depressive symptoms at the end of the treatment within the trajectories of intermediate improvement, slow improvement and slow improvement with delayed onset, was still improving and did not achieve a plateau. CONCLUSION: The different courses of depressive symptoms during ECT probably contribute to mixed results of prediction studies of ECT outcome. Data suggest that for a large group of patients no optimal clinical endpoint can be identified, other than full remission or no improvement at all, to discontinue ECT.

Measuring depression: comparison and integration of three scales in the GENDEP study.

BACKGROUND: A 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. METHOD: The 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. RESULTS: The 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. CONCLUSIONS: The MADRS and the BDI can be recommended as complementary measures of depression severity. The three factor scores are proposed for external validation.

Depressive symptoms predict slow cognitive decline in mild dementia.

Depression may be a prognostic marker of subsequent cognitive decline in patients with dementia. Earlier investigations did not find support for this hypothesis, but these considered mainly syndromal depression. In this prospective study, 32 subjects with mild dementia were followed up for 12 months. The effects of GMS-AGECAT syndromal depression, subsyndromal depression and dimensions of depressive symptoms were studied. Higher levels of mood symptoms but not (sub)syndromal depression predicted slower cognitive decline during follow-up. It is hypothesized that the report of depressive symptoms by subjects with mild dementia reflects relative intactness of cognitive functions, not accounted for by cognitive screening instruments.