Childhood-onset Mood Disorders Research Articles

Maladaptive mood repair predicts suicidal behaviors among young adults with depression histories

BackgroundAs the rates of suicidal behaviors continue to rise, research is needed that can facilitate prevention. The present study therefore examined whether a modifiable process, dysfunctional regulation of sadness (maladaptive mood repair), predicts a range of suicidal behaviors and if its impact is affected by risk and protective factors. MethodsYoung adults with histories of childhood-onset mood disorder (COMD) (n = 173) or no histories of major psychiatric illness (controls, n = 96) were followed for approximately 3 years. Self-rated questionnaires and psychiatric evaluations were administered at study entry (T1) and across the follow-up (T2) and clinicians assessed the DSM-range of non-fatal suicidal behaviors. We hypothesized that the impact of depression on suicidal behaviors was mediated by dysfunctional regulation of sadness. ResultsAt T1, 90% of the COMD group had histories of various suicidal behaviors; 63% had past suicide attempts. During follow-up, 40% exhibited suicidal behaviors; 7% reported suicide attempts. Controlling for prior suicidal behaviors, T1 maladaptive mood repair predicted suicidal behavior during the follow-up and differentiated recurrent thoughts of death from other forms of suicidality. Protective and risk factors lost their predictive power in the presence of maladaptive mood repair. LimitationsFew control cases exhibited suicidal behavior during the follow-up and the high inter-correlations among several key variables constrained the models that could be fitted. ConclusionsPrograms to prevent suicidal behavior among high-risk individuals should include maladaptive mood repair as an intervention target. Further research is needed on whether recurrent thoughts of death constitute a valid index of suicidality.

Family functioning as perceived by parents and young offspring at high and low risk for depression

BackgroundFamily dysfunction has been proposed as one of the environmental mechanisms whereby risk of depression is transmitted from mothers to their children. Using our sample of offspring at high and low familial risk for depression, we hypothesized that: a) high-risk offspring (n = 79) and their mothers will report more extensive family dysfunction than low-risk offspring (n = 82) and their mothers, b) family dysfunction will predict the extent of offspring's depressive symptoms, and c) family dysfunction will mediate the impact of mother's depression on offspring's depressive symptoms. MethodsThe study enrolled 161 offspring of parents who, in a previous study, were ascertained to have either childhood onset mood disorder or no history of a major psychiatric disorder. Parents completed questionnaires and a clinical interview about themselves, their offspring, and the family, while offspring also completed questionnaires about themselves and the family. ResultsWe found support for all three hypotheses. The significant indirect effect between maternal depression and offspring depressive symptoms was driven primarily by offspring's, but not mothers’, reports of family dysfunction. LimitationsAlthough our assessment of mother's early history of depression was done in a previous study, it is important to note that our results do not inform about causality because of the present study's cross-sectional nature. ConclusionsThe results highlight the importance of detecting and treating family dysfunction, particularly via offspring report, as one way to lower the risk of depression transmission from mothers to their children.

Children's responses to cognitive challenge and links to self-reported rumination

We tested the hypothesis that less effective responses during a cognitive challenge would relate to higher levels of self-reported rumination in children. The sample was 100 children (55 boys, 45 girls), aged 7 to 14 years. A portion (n=65) was at high risk for depression due to having a parent with a childhood-onset mood disorder, and 35 were a low-risk comparison group. Using an impossible puzzle task, we assessed children's responses following failure across several domains: emotions (expressed anger, sadness, and negative self-statements), performance (being off-task, the time to solve subsequent puzzles, and the number solved), and physiology (heart rate, respiratory sinus arrhythmia). Results indicated that making negative self-blaming statements during the solvable puzzles and taking more time to solve the puzzles were associated with higher levels of self-reported rumination. Our findings advance the understanding of potential correlates of children's tendency to ruminate and may have implications for children's performance on cognitive tasks.

Association study of early-immediate genes in childhood-onset mood disorders and suicide attempt

Childhood-onset mood disorders (COMD) are serious affective disorders with deleterious developmental sequelae including interpersonal dysfunction, psychotic symptoms and suicidal behavior. The current study examines 10 markers from two early-immediate genes for association with COMD and suicide attempt (SA) — HOMER1 and human neuronal pentraxin II (NPTX2). We examined individuals diagnosed with COMD versus matched controls, as well as individuals with COMD and a history of at least one lifetime SA versus COMD participants with no history of SA. No significant genotypic association was noted between any of the single nucleotide polymorphisms (SNPs) and COMD. Our sample yielded a nominally significant allelic association between the HOMER1 rs7713917 SNP and COMD. We report significant genotype associations between HOMER1 rs2290639 and SA , and between NPTX2 markers rs705315 and rs1681248 and SA, findings that remained statistically significant after multiple test correction. A three-way interaction was observed among HOMER1 rs4704560, rs2290639 and NPTX2 rs705318. The associations we describe for HOMER1 and NPTX2 with SA should be considered preliminary until replicated.

Atypical development of resting respiratory sinus arrhythmia in children at high risk for depression

Compromised respiratory sinus arrhythmia (RSA, i.e., low cardiac vagal control) frequently characterizes clinically depressed adults and also has been detected in infants of depressed mothers; however, its existence has not been established in older at-risk offspring. We investigated developmental patterns of RSA in a sample of 163 5- to 14-year-old children, who were either at high risk for depression (due to having a parent with a childhood-onset mood disorder) or low-risk for depression. We hypothesized that high-risk children have lower resting RSA than do low-risk children, which could reflect atypical developmental trajectories. Children's RSA was assessed during resting baseline periods on multiple occasions, typically 1-year apart. Linear growth modeling indicated a group by age interaction. Low-risk children (but not the high-risk children) exhibited a significantly increasing trajectory in resting RSA with age. Mood disorders in offspring did not account for the Group X Age interaction effect. Our study provides new evidence that children at high risk for depression have an atypical developmental trajectory of RSA across late childhood.

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.

A review of estrogen receptor α gene (ESR1) polymorphisms, mood, and cognition

There are significant individual differences in the extent to which mood and cognition change as a function of reproductive stage, menstrual phase, postpartum, and hormone therapy use. This review explores the extent to which variations or polymorphisms in the estrogen receptor alpha gene (ESR1) predict cognitive and mood outcomes. A literature search was conducted from 1995 to November 2009 through PubMed, Embase, and PsychINFO. Twenty-five manuscripts that summarize investigations of ESR1 in mental health were reviewed. Among studies investigating ESR1 in relation to cognition, 11 of 14 case-control studies reported an association between ESR1 polymorphisms and risk for developing dementia. Three of four prospective cohort studies reported an association between ESR1 polymorphisms and significant cognitive decline. There are inconsistencies between case-control and cohort studies regarding whether specific ESR1 alleles increase or decrease the risk for cognitive dysfunction. The relationships between ESR1 and cognitive impairment tend to be specific to or driven by women and restricted to risk for Alzheimer disease rather than other dementia causes. Three of five studies examining ESR1 polymorphisms in relation to anxiety or depressive symptoms found significant associations. Significant associations have also been reported between ESR1 polymorphisms and childhood-onset mood disorder and premenstrual dysphoric disorder. A strong relationship between ESR1 variants and cognitive outcomes is evident, and preliminary evidence suggests a role of the ESR1 gene in certain mood outcomes. Insights into the discordant results will come from future studies that include haplotype analyses, analyses within specific ethnic/racial populations, and sex-stratified analyses.

No association between oxytocin or prolactin gene variants and childhood-onset mood disorders

Oxytocin (OXT) and prolactin (PRL) are neuropeptide hormones that interact with the serotonin system and are involved in the stress response and social affiliation. In human studies, serum OXT and PRL levels have been associated with depression and related phenotypes. Our purpose was to determine if single nucleotide polymorphisms (SNPs) at the loci for OXT, PRL and their receptors, OXTR and PRLR, were associated with childhood-onset mood disorders (COMD). Using 678 families in a family-based association design, we genotyped 16 SNPs at OXT, PRL, OXTR and PRLR to test for association with COMD. No significant associations were found for SNPs in the OXTR, PRL, or PRLR genes. Two of three SNPs 3' of the OXT gene were associated with COMD (p≤0.02), significant after spectral decomposition, but were not significant after additionally correcting for the number of genes tested. Supplementary analyses of parent-of-origin and proband sex effects for OXT SNPs by Fisher's Exact test were not significant after Bonferroni correction. We have examined 16 OXT and PRL system gene variants, with no evidence of statistically significant association after correction for multiple tests.

No evidence of an association between two genes, EDN1 and ACE, and childhood‐onset mood disorders

Recent evidence supports a pathological link between heart disease and depressive symptoms, suggesting that depression is both etiologic and prognostic to heart disease. Thus, biological molecules which are at the interface between heart and mind are plausible candidate genes for depressive disorders. To investigate this line of enquiry we have investigated two genes, Endothelin 1 (EDN1) and Angiotensin-converting enzyme (ACE) in a family-based sample with childhood-onset mood disorders (COMDs). EDN1 is highly expressed in endothelium where it acts as a potent vasoconstrictor, and is also expressed in the brain where it exhibits neurotransmitter characteristics. ACE acts as a potent vasopressor, and interacts with the hypothalamic-pituitary-adrenocortical (HPA) system, which is often dysregulated in mood disorders. Furthermore, ACE has recently been found to be associated with major depression. Polymorphisms were selected to best capture the genetic variation at the two loci, and to replicate previous associations. The markers were genotyped across EDN1 and ACE in a sample comprised of 382 Hungarian nuclear families ascertained through affected probands diagnosed with a mood disorders before the age of 15. We found no evidence of association between either of these genes and COMD. Consequently, we were unable to support our hypothesis that these two genes, which are involved in both vascular and brain functions are contributing to the susceptibility to mood disorders of children/adolescents.

Further genetic evidence implicates the vasopressin system in childhood‐onset mood disorders

Studies in both animals and humans advocate a role for the vasopressin (AVP) system in the aetiology of depressive symptoms. Attention has particularly focused on the role of AVP in the overactivation of the hypothalamic-pituitary-adrenal (HPA)-axis in mood disorders. Elevated AVP plasma levels have been found in mood disorder patients, which are often positively correlated with the severity of symptoms. We recently reported an association between childhood-onset mood disorders (COMD) and polymorphisms in the receptor responsible for the AVP-mediated activation of the HPA-axis (AVPR1B). As genetic variation in the vasopressinergic system could provide a mechanism to explain the endocrine alterations observed in mood disorders, we investigated other genes in this system. The gene encoding AVP is the strongest candidate, particularly as genetic variation in this gene in rodents is associated with anxiety-related behaviours. Six single-nucleotide polymorphisms (SNPs) were genotyped across the AVP gene in a sample comprised of 586 Hungarian nuclear families ascertained through affected probands with a diagnosis of COMD. In addition, AVP coding and putative regulatory regions were screened for mutations using denaturing high-performance liquid chromatography. One SNP, 3' to the AVP, gene reached significance (P = 0.03), as did the overtransmission of a five-marker haplotype with a frequency of 22% (P = 0.0001). The subsequent mutation screen failed to identify any putative functional polymorphisms. The outcome of this study, combined with our previous association between COMD and AVPR1B, implicates genetic variation in vasopressinergic genes in mediating vulnerability to COMD.

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.

Respiratory sinus arrhythmia reactivity predicts emotion regulation and depressive symptoms in at-risk and control children

We examined respiratory sinus arrhythmia (RSA), emotion regulation (ER), and prospective depressive symptoms in children at risk for depression and controls. Of the 65 children (35 boys; 5–13 years) in the sample, 39 had a parent with childhood-onset mood disorder and 26 had a parent with no history of major psychiatric disorder. RSA during pre- and post-film baselines and RSA reactivity to sad film clip were measured. Later, children's ER responses (focusing on sad/distressing affect) were assessed using a parent-reported questionnaire, and depressive symptoms were measured via clinical ratings. Results indicated that, compared to the initial baseline, a greater decrease in RSA (i.e., more vagal withdrawal) in response to the sad film clip predicted more adaptive ER responses and lower levels of clinician-rated depressive symptoms. However, tests for ER as a mediator of the association between RSA reactivity and depressive symptoms were precluded because maladaptive, but not adaptive, ER was associated with depressive symptoms. Overall, results suggest that cardiac vagal withdrawal (a greater decrease in RSA) in response to an emotional stimulus reflects more adaptive parasympathetic activity, which could facilitate children's ability to effectively manage their sadness and distress and predict lower risk of depressive symptoms over time.

Tagging SNP association study of the IL‐1β gene (IL1B) and childhood‐onset mood disorders

Given substantial evidence for IL-1beta involvement in the etiology of depression, the IL1B gene is a strong candidate for involvement in susceptibility to depressive disorders. However, association studies investigating this, to date, have been limited to just two polymorphisms (rs1143627[-31T/C] and rs16944[-511C/T]) that constitute only a fraction of the genetic variation that is actually present across this gene in the population. Here, in a family-based association study of childhood-onset mood disorders (COMD), characterized by onset of depression before the age of 15, we have used a gene-wide approach, employing a panel of five tagging SNPs spanning the entire gene. Based on TDT analyses of both individual alleles and haplotypes, in a study sample of 646 families (with 782 affected children), none of the SNPs, including those implicated in transcriptional regulation of the gene, showed evidence for association with COMD. This is the largest and most comprehensive study of IL1B in relation to mood disorders that has been carried out, to date. The results do not support the involvement of IL1B as a major factor in genetic risk for early-onset mood disorders.

Association study of N-methyl-D-aspartate glutamate receptor subunit genes and childhood-onset mood disorders

GRIN1 rs4880210 139,143,515 50 G T 0.122 0.878 76 70 0.247 0.619 rs28489906 139,158,220 Intron 2 G A 0.470 0.530 171 170 0.003 0.957 rs6293 139,171,059 Exon 6 A G 0.692 0.303 166 157 0.251 0.616 rs10747050 139,175,697 Intron 11 A G 0.951 0.049 24 33 1.427 0.232 GRIN2A rs1071504 10,187,517 50 C T 0.279 0.721 138 144 0.128 0.721 rs2302711 10,183,199 Intron 2 C T 0.282 0.718 141 140 0.004 0.952 rs1070503 10,172,675 Intron 3 C T 0.866 0.134 67 79 0.987 0.320 rs727605 9,863,065 Intron 5 G A 0.694 0.306 161 133 2.671 0.102 rs8049651 9,851,167 Exon 6 G A 0.726 0.274 153 125 2.825 0.093 rs1014531 9,763,295 Exon 14, 30UTR G A 0.617 0.383 184 163 1.272 0.260 G A 0.797 0.203 117 109 0.283 0.594 rs2284416 13,810,481 Intron 2 T G 0.464 0.536 174 189 0.620 0.431 rs2268115 13,760,992 Intron 3 T G 0.561 0.439 169 170 0.003 0.957 rs2284407 13,733,473 Intron 3 G T 0.582 0.418 186 176 0.276 0.599 rs2268097 13,644,099 Intron 9 A G 0.583 0.417 170 174 0.047 0.829 rs890 13,606,575 Exon 13, 30UTR G T 0.452 0.548 183 172 0.341 0.559

Responses to Depressed Mood and Suicide Attempt in Young Adults With a History of Childhood-Onset Mood Disorder

Although individuals' responses to their depressed mood are hypothesized to play an important role in the development and maintenance of depression, how these responses might impact the likelihood of suicidal behavior in mood disorders remains largely unexplored. The goal of the current study was to examine whether maladaptive responses to depressed mood are associated with suicide attempts in adults with a history of childhood-onset mood disorder (COMD). Participants included 223 young adult probands with COMD meeting DSM-III or DSM-IV criteria for major depressive disorder or bipolar disorder and 112 controls without a history of psychiatric disorders. All participants were recruited between 1996 and 2004. Probands were followed for 6 to 99 months (median = 32 months). The Responses Styles Questionnaire was used to assess 2 adaptive (distraction and problem solving) and 2 maladaptive (dangerous activity and rumination) ways of coping with depressed mood. Compared to controls, COMD probands scored significantly higher on maladaptive response styles and lower on adaptive styles. Compared to their COMD peers, probands with a history of suicide attempt were less likely to report using distracting activities to manage their depressed mood. However, COMD probands who engaged in dangerous activities in response to depressed mood were more likely to attempt suicide during the follow-up period (hazard ratio = 1.8, 95% CI = 1.2 to 2.8). One of the pathways to suicide attempt in mood disorders may involve maladaptive responses to depressed mood. The assessment of how depressed individuals manage their dysphoric moods, therefore, should be considered an important aspect of treatment and prevention of suicidal behavior.

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 Theta EEG Asymmetry and Brain-derived Neurotrophic Factor Gene Variants in Childhood-onset Mood Disorder

Childhood-onset mood disorders (COMD) include various serious, disabling psychiatric conditions that are heterogeneous in presentation and etiology. Because intermediate phenotypes may help to identify genetic contributors to COMD, we tested for an association between variants in the brain-derived neurotrophic factor (BDNF) gene and theta EEG asymmetry, both of which have been independently implicated in affective disorders. Theta EEG asymmetry measures were calculated for a total of 191 individuals with COMD and 93 controls, who were also genotyped at seven BDNF single-nucleotide polymorphism (SNPs), two intergenic flanking SNPs, and one SNP in the lin-7 homolog C (Caenorhabditis elegans) (LIN7C) gene. Adjusting for sex and ethnicity in linear models of asymmetry scores at ten brain regions, significant genotype and genotype-by-ethnicity interactions were observed for marker Val66Met in two parietal (P3/4 and P7/8) regions in the depressed group only. Our results suggest that the functional Val66Met polymorphism affects theta EEG asymmetry in parietal brain regions specifically in individuals with COMD.

Association study of the estrogen receptor alpha gene (ESR1) and childhood‐onset mood disorders

Depressive disorders are heterogeneous psychiatric disorders involving deficits in cognitive, psychomotor, and emotional processing. Depressive disorders have a significant genetic component, with severe, recurrent and early-onset forms demonstrating elevated heritability. In this study we genotyped eleven single nucleotide polymorphisms (SNPs) spanning the estrogen receptor alpha gene (ESR1) in a large family-based childhood-onset mood disorder (COMD) sample. None of the individual SNP or global haplotype analyses was significant in the entire COMD sample, but haplotype analysis of three SNPs in strong linkage disequilibrium (rs746432, rs2077647, and rs532010) uncovered an association with COMD, specifically in females. Our data are consistent with previous studies demonstrating a female-specific association between ESR1 and neurobehavioral phenotypes. These results suggest the existence of sex-specific etiological factors in depressive disorders, related to estrogen, with onset in childhood.

Association study of serotonin system genes in childhood-onset mood disorder

The serotonin system has been implicated in neuropsychiatric disorders, including mood disorders. We investigated polymorphisms in two serotonin-receptor genes, HTR1B and HTR2A, and the serotonin transporter (SLC6A4) in two independent samples of patients with childhood-onset mood disorders (COMD): 203 patients from Pittsburgh, USA with matched controls and 448 small families from Hungary. Case-control and family-based analyses showed no association between COMD and any of the studied polymorphisms (all P values >0.05). Haplotype analysis of SLC6A4 was also negative in both samples. Overall, the examination of genetic variants at the HTR1B, HTR2A, and SLC6A4 loci indicated no association between the selected polymorphisms and COMD.

Association of the Neurotrophic Tyrosine Kinase Receptor 3 ( NTRK3 ) Gene and Childhood-Onset Mood Disorders

Genome scans have revealed significant evidence for linkage of depression to chromosome 15q25.3-q26.2. The gene for neurotrophic tyrosine kinase receptor 3 (NTRK3), the receptor for neurotrophin-3 (trkC) and a key gene in neurotrophin signaling, is located within this region and, given evidence for synaptic plasticity as a mechanism in mood disorders, was considered a prime candidate. The authors investigated NTRK3 as a susceptibility gene for childhood-onset mood disorders. The study sample consisted of 603 families with 723 affected children and adolescents diagnosed with a mood disorder with onset of the first episode by age 15. The authors genotyped 18 polymorphic markers across the NTRK3 gene in this sample and tested for association. Results identified significant evidence for association for five of the markers using the transmission disequilibrium test. Four of the five markers were located in a region of strong linkage disequilibrium and were highly correlated. Haplotype results provided significant evidence for association to haplotypes composed of markers located in two haplotype blocks. The results for NTRK3 as well as the authors' previous finding for association to brain-derived neurotrophic factor in this sample support synaptic plasticity as a mechanism contributing to mood disorders that begin during childhood and adolescence and specifically implicate the NTRK3 gene as a contributing factor in the 15q-linked region.