Maladaptive mood repair, atypical respiratory sinus arrhythmia, and risk of a recurrent major depressive episode among adolescents with prior major depression.

BACKGROUND: Because depressive illness is recurrent, recurrence prevention should be a mainstay for reducing its burden on society. One way to reach this goal is to identify malleable risk factors. The ability to attenuate sadness/dysphoria (mood repair) and parasympathetic nervous system functioning, indexed as respiratory sinus arrhythmia (RSA), are impaired during depression and after it has remitted. The present study therefore tested the hypothesis that these two constructs also may mirror risk factors for a recurrent major depressive episode (MDE). METHOD: At time 1 (T1), 178 adolescents, whose last MDE had remitted, and their parents, reported on depression and mood repair; youths' RSA at rest and in response to sad mood induction also were assessed. MDE recurrence was monitored until time 2 (T2) up to 2 years later. Mood repair at T1 (modeled as a latent construct), and resting RSA and RSA response to sadness induction (RSA profile), served to predict onset of first recurrent MDE by T2. RESULTS: Consistent with expectations, maladaptive mood repair predicted recurrent MDE, above and beyond T1 depression symptoms. Further, atypical RSA profiles at T1 were associated with high levels of maladaptive mood repair, which, in turn, predicted increased risk of recurrent MDE. Thus, maladaptive mood repair mediated the effects of atypical RSA on risk of MDE recurrence. CONCLUSIONS: This study documented that a combination of behavioral and physiological risk factors predicted MDE recurrence in a previously clinically referred sample of adolescents with depression histories. Because mood repair and RSA are malleable, both could be targeted for modification to reduce the risk of recurrent depression in youths.

Association of the GABRD gene and childhood-onset mood disorders.

The chromosome 1p36 region was previously indicated as a locus for susceptibility to recurrent major depressive disorder based on a linkage study in a sample of 497 sib pairs. We investigated the gamma-aminobutyric acid A (GABA(A)) delta receptor subunit gene, GABRD, as a susceptibility gene to childhood-onset mood disorders (COMD) because of substantial evidence implicating GABAergic dysfunction in mood disorders and the position of this gene near the 1p36 linkage region. Using a sample consisting of 645 Hungarian families with a child/adolescent proband diagnosed with a mood disorder with the onset of the first episode before age 15, we found some evidence for the association of two polymorphisms located within the gene, rs2376805 and rs2376803, as well as significant evidence for biased transmission of the haplotypes of these two markers (global chi(2) test for haplotypes = 12.746, 3 df, P = 0.0052). Furthermore, significant evidence of association was only observed in male subjects (n = 438) when the results were analyzed by sex (chi(2) = 9.000 1 df, P = 0.003 for rs2376805). This was in contrast with the previous linkage findings, as LOD scores exceeding 3 were only in female-female pairs in that study. These findings point to the GABRD gene as a susceptibility gene for COMD; however, this gene may not explain the previous linkage finding.

Mutation screen and association analysis of the glucocorticoid receptor gene (NR3C1) in childhood-onset mood disorders (COMD).

Depressive disorders are highly heterogeneous psychiatric disorders involving deficits to cognitive, psychomotor, and emotional processing. Considerable evidence links disruption to the hypothalamic-pituitary-adrenal (HPA) axis to the etiology of depression, with specific deficits reported in glucocorticoid receptor (GR)-mediated negative feedback. Given the role of GR-mediated negative feedback in mediating response to stress, and the clear link between stress and depression, it is plausible that polymorphisms in the GR gene (NR3C1) act to increase susceptibility. Maternal behavior in rats epigenetically alters a NGF1-A transcription factor binding-site in the promoter region of the GR gene, providing a mechanism by which environmental cues can regulate GR expression and thus response to stress. The analogous region of the human GR gene (NR3C1) has not been studied, but it is possible that polymorphisms in this region may alter the binding of transcription factors known to regulate GR expression. In this study, we have performed bioinformatic analyses on the promoter region of NR3C1 to identify conserved promoter sequences and predicted transcription factor binding sites. These regions were screened with denaturing high-performance liquid chromatography (DHPLC) and direct re-sequencing, and several novel polymorphic variants were identified. We genotyped nine polymorphisms across NR3C1 in a large sample of Hungarian nuclear families ascertained through affected probands with a diagnosis of childhood-onset mood disorders (COMD). Single-marker analysis provided little evidence for an association of this gene with COMD, but multi-marker analysis across a region of high linkage disequilibrium revealed modest evidence for the biased transmission of several haplotypes.

Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and childhood-onset mood disorders.

BACKGROUND/AIMS: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. METHODS: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. RESULTS: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. CONCLUSION: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.

Association study of the adrenergic receptors and childhood-onset mood disorders in Hungarian families.

The adrenergic system has been implicated in the etiology of depression based on a number of lines of evidence, particularly, the mechanism of some classes of antidepressants which increase the synaptic levels of norepinephrine. Further, several genome scans for mood disorders, both unipolar and bipolar, have indicated linkage to the chromosomal regions of 5q23-q33.3, 8p12-p11.2, 4p16, and 10q24-q26, the location of the adrenergic receptors alpha1B (ADRA1B), beta3 (ADRB3), alpha2C (ADRA2C), alpha2A (ADRA2A), and beta1 (ADRB1). In this manuscript, we report on the relationship of the adrenergic receptors and depression using a family based association approach and 189 families (223 affected children) with childhood-onset mood disorder (COMD) collected in Hungary. We found no significant evidence for an association with any of the 24 markers, in total, tested across these genes using single marker analysis or haplotypes of markers across these genes. The results in the present sample indicate that these nine genes are unlikely to be major susceptibility genes contributing to COMD.