Joost Janzing

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 (ORMET, 95% CI; 1.27 (1.10–1.47); ORMET/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.

Electroconvulsive therapy increases hippocampal and amygdala volume in therapy refractory depression: A longitudinal pilot study

Electroconvulsive therapy (ECT) is the most potent biological therapy in depression. Animal studies suggest that ECT acts via neuroplasticity effects on limbic structures involved in the pathophysiology of depression but in vivo evidence at the human system level is scarce. Therefore, the aim of the present study was to investigate the effect of ECT on hippocampus and amygdala volume in 15 antidepressant-free patients with treatment refractory depression (seven males, range 42-63 years). ECT treatment was successful as indexed by a significant decrease in depressive symptoms (t14=13.6; p<0.001). Analysis of normalized volumetric data before and after ECT treatment revealed a significant volume increase of both hippocampus and amygdala (minimum p<0.005) with no evidence for a change in global brain volume. Though this change in volume cannot be clearly related to treatment effects, ECT is associated with broader neurotrophic effects other than mere adult neurogenesis in the hippocampus, which has been previously suggested as a core mechanism on the basis of animal data.

Genome-wide association uncovers shared genetic effects among personality traits and mood states.

Measures of personality and psychological distress are correlated and exhibit genetic covariance. We conducted univariate genome‐wide SNP (∼2.5 million) and gene‐based association analyses of these traits and examined the overlap in results across traits, including a prediction analysis of mood states using genetic polygenic scores for personality. Measures of neuroticism, extraversion, and symptoms of anxiety, depression, and general psychological distress were collected in eight European cohorts (n ranged 546–1,338; maximum total n = 6,268) whose mean age ranged from 55 to 79 years. Meta‐analysis of the cohort results was performed, with follow‐up associations of the top SNPs and genes investigated in independent cohorts (n = 527–6,032). Suggestive association (P = 8 × 10−8) of rs1079196 in the FHIT gene was observed with symptoms of anxiety. Other notable associations (P < 6.09 × 10−6) included SNPs in five genes for neuroticism (LCE3C, POLR3A, LMAN1L, ULK3, SCAMP2), KIAA0802 for extraversion, and NOS1 for general psychological distress. An association between symptoms of depression and rs7582472 (near to MGAT5 and NCKAP5) was replicated in two independent samples, but other replication findings were less consistent. Gene‐based tests identified a significant locus on chromosome 15 (spanning five genes) associated with neuroticism which replicated (P < 0.05) in an independent cohort. Support for common genetic effects among personality and mood (particularly neuroticism and depressive symptoms) was found in terms of SNP association overlap and polygenic score prediction. The variance explained by individual SNPs was very small (up to 1%) confirming that there are no moderate/large effects of common SNPs on personality and related traits.

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

Wijkstra J, Burger H, van den Broek WW, Birkenhäger TK, Janzing JGE, Boks MPM, Bruijn JA, van der Loos MLM, Breteler LMT, Ramaekers GMGI, Verkes RJ, Nolen WA. Treatment of unipolar psychotic depression: a randomized, double‐blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine.

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

van de Ven AC, Muntjewerff J‐W, Netea‐Maier RT, de Vegt F, Ross HA, Sweep FCGJ, Kiemeney LA, Vos PE, Buitelaar JK, Hermus ARMM, den Heijer M, Janzing JGE. Association between thyroid function, thyroid autoimmunity, and state and trait factors of depression.

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

IntroductionAlthough 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.MethodIn 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.ResultsThere 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.ConclusionAssociations 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.

Familiality of major depressive disorder and gender differences in comorbidity.

Objective:  Gender differences exist in the prevalence and psychiatric comorbidity of major depressive disorder (MDD). This study investigates whether familiality of MDD contributes to observed gender differences in comorbidity.

Effect of the 5-httlpr polymorphism in the serotonin transporter gene on major depressive disorder and related comorbid disorders

Objectives The serotonin transporter gene (5-HTT) has been proposed as a candidate gene for major depressive disorder (MDD). Association studies, however, have revealed inconsistent results. This could be because of the phenotypic heterogeneity of MDD, as it often presents with comorbid disorders such as generalized anxiety disorder (GAD), alcohol-related disorders, and dysthymia. Methods In this exploratory study, we performed regression analyses with generalized estimating equations in patients with familial MDD (n=233) in order to explore whether a polymorphism in the serotonin transporter gene (5-HTTLPR) is differentially associated with MDD and a comorbid disorder compared with MDD without that particular comorbidity. As in general, GAD is more common in females and alcohol-related disorders are more common in males, the analyses were stratified for sex. Results Comorbid dysthymia was less common in s-allele carriers with MDD (P<0.05) than in patients homozygous for the long allele. In the sex-specific analyses, an association between the 5-HTTLPR and comorbid alcohol use disorders was observed in females, with s-carriers reporting significantly less alcohol use disorders. The relationship with comorbid GAD differed by sex with male s-carriers reporting more comorbid GAD than female s-carriers. Conclusion The effect of the 5-HTTLPR polymorphism on MDD is codependent on the presence of comorbid disorders and sex. In this study, the s-allele of the 5-HTTLPR polymorphism was associated with significantly lower rates of particular lifetime comorbid disorders. Therefore, the presence of comorbid psychiatric disorders should be taken into account to clarify the association of the 5-HTTLPR polymorphism with MDD phenotypes.

The course of depression in elderly subjects with and without dementia.

BACKGROUND A persistent course of depression has been described in subjects with and without dementia. Up to the present it is unclear to what extent dementia affects the prognosis of depression. METHOD At baseline and at 6 and 12 months follow-up AGECAT depression diagnoses were made in 49 subjects with and 72 subjects without DSM-III-R dementia living in homes for the elderly. RESULTS Adjusting for demographic characteristics and physical health, dementia was not associated with the severity of depression at follow up. The baseline depression severity and to a lesser extent somatic complaints predicted a bad prognosis of depression in the total sample. LIMITATIONS Because of the high vulnerability of the residents the results cannot be generalised to other populations of elderly subjects. CONCLUSION Depression is persistent in residents of homes for the elderly. Dementia does not affect its course.

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.