Family and twin studies have shown a heritable component to seasonal affective disorder (SAD). While a few studies have examined individual genetic variants in SAD, many methodological issues exist in the current literature. First, most studies combined major depression (MDD) and bipolar (BD) cases in the genetic analysis of SAD. This makes it difficult to differentiate the effect from MDD and BD. Second, most studies adopted a candidate gene approach and used fairly small sample sizes. This does not allow for testing across a wide variety of genes, and it yields less robust P-values. Third, healthy controls have been used, but not case comparisons, which makes it difficult to differentiate the effects of seasonality from that of the primary illness (MDD and BD). To overcome these issues, seasonal MDD and BD cases were separated into two different studies in this thesis; sample sizes for both studies are the largest in the current SAD molecular genetics literature; GWAS was used to test for potential risk loci in a hypothesis-free fashion; case comparisons were incorporated to exclude potential genetic contributions related generally to the primary diseases themselves (MDD and BD). For MDD, we performed a GWAS with 562 seasonal MDD cases and 1,225 comparison cases with non-seasonal MDD. Subjects were drawn from two iterations of the Genetics of Recurrent Early Onset Depression (GenRED) study. Seasonal cases were those whose depressive episodes typically started in fall or winter. A mega-analysis of the two GWAS datasets was done using SNPTEST. We found that two single nucleotide polymorphisms (SNPs), rs149882931 and rs77073398, on chromosome 16p12.1 were associated with seasonal depression, at a genome-wide significant level (OR= 1.66, P= 3.59 x 10-8 and OR=1.62, 4.76 x 10-8, respectively). Since SAD is more prevalent in females, a female-specific analysis was carried out. The two variants were more significant in this analysis: P=2.18x10-9 (OR=1.89) and P=2.79x10-9 (OR=1.82), respectively, and a significant sex-by-SNP interaction was observed. These SNPs are located in a conserved intergenic region between the genes HS3ST4 and C16orf82. The protein product of HS3ST4 modifies the side chains of heparan sulfate proteoglycans. We therefore tested the hypothesis that the heparan sulfate biosynthesis pathway would be enriched in nominally significant SNPs using the SNP ratio test, and found evidence for such enrichment (P=0.008, SNP ratio test, P=0.027, SKAT). For BD, the GWAS analysis of 818 seasonal BD cases and 1,515 healthy controls showed that BD-S is most strongly associated with two SNPs within the ZBTB20 genes. BD subjects were drawn from NIMH Bipolar Genetics Study (BIGS), and seasonal cases were defined as those with depressive episodes starting in fall or winter. An association study was carried out with SNPTEST, and we found two single nucleotide polymorphisms (SNPs) in the intronic region of ZBTB20 gene to be associated with BD-S (rs7646282, OR=2.34, P= 7.23 x 10-8 and rs139459337, OR=2.37, 8.05 x 10-8). A similar case-only study was carried out with 818 BD-S cases and 1239 cases without seasonal depressive symptoms (non-BDS), though no SNP was found to be significantly associated in this analysis. rs7646282 is the strongest SNP in cis-association with ZBTB20 gene expression, and ZBTB20 has been shown to affect the neural development of the hippocampus, a brain region implicated in the pathophysiology of BD. Finally, we sought to determine whether there is a role for circadian rhythm genes in BD susceptibility. In this study, we used a discovery set of 189 exome-sequenced BD patients and 105 healthy controls to look for circadian genes associated with BD. We found the DRD2 gene to be the circadian gene most strongly associated with BD. Among the rare damaging variants in the DRD2 gene, the S311C variant was the predominant SNP. To test whether this variant segregates in family members with BD, we genotyped the family members of probands from the discovery sample. This data was used for a linkage and family-based association study. Even though the linkage analysis was only very weakly positive, the family-based association study showed significant segregation of the variant in family members with BD (P< 0.05). To follow up on this finding, we further genotyped 2,185 unrelated BD cases and 1,982 healthy controls. We found no support for the S311C variant in this replication dataset. Sub-phenotype study of psychotic features and mood-incongruence also did not show significant association. Meta-analysis with 2,994 BD cases and 3,661 controls, however, revealed no association between the S311C variant and BD.

Certain electrophysiological markers hold promise in distinguishing individuals with major depressive disorder (MDD) and in predicting antidepressant response, thereby assisting with assessment and optimizing treatment, respectively. This thesis examined resting brain activity via electroencephalographic (EEG) recordings, as well as EEG-derived event-related potentials (ERPs) to auditory stimuli and facial expression presentations in individuals with MDD and controls. Additionally, the utility of resting EEG as well as auditory ERPs (AEPs), and the associated loudness-dependence of AEPs (LDAEP) slope, were assessed in predicating outcome to chronic treatment with one of three antidepressant regimens [escitalopram (ESC); bupropion (BUP); ESC+BUP]. Relative to controls, depressed adults had lower pretreatment cortical activity in regions implicated in approach motives/positive processing. Increased anterior cingulate cortex (ACC)-localized theta was observed, possibly reflecting emotion/cognitive regulation disturbances in the disorder. AEPs and LDAEPs, putative indices of serotonin activity (implicated in MDD etiology), were largely unaltered in MDD. Assessment of ERPs to facial expression processing indicated slightly blunted late preconscious perceptual processing of expressions, and prolonged processing of intensely sad faces in MDD. Faces were rated as sadder overall in MDD, indicating a negative processing bias. Treatment responders (vs. non-responders) exhibited baseline cortical hypoactivity; after a week of treatment, cortical arousal emerged in responders. Increased baseline left fronto-cortical activity and early shifts towards this profile were noted in responders (vs. non-responders). Responders exhibited a steep, and non-responders shallow, baseline N1 LDAEP derived from primary auditory cortex activity. P2 LDAEP slopes (primary auditory cortex-derived) increased after a week of treatment in responders and decreased in non-responders. Consistent with overall findings, ESC responders displayed baseline cortical hypoactivity and steep LDAEP-sLORETA slopes (vs. non-responders). BUP responders also exhibited steep baseline slopes and high ACC theta. These results indicate that specific resting brain activity profiles appear to distinguish depressed from non-depressed individuals. Subtle ERP modulations to simple auditory and emotive processing also existed in MDD. Resting alpha power, ACC theta activity and LDAEP slopes predicted antidepressant response in general, but were limited in predicting outcome to a particular treatment, which may be associated with limited sample sizes.

Background. This article presents prospective longitudinal findings on prevalence, incidence, patterns of change and stability of depressive disorders in a community sample of 1228 adolescents. Methods. Data were collected at baseline and follow-up (20 months later) in a representative population sample of 1228 adolescents, aged 14–17 at baseline. Diagnostic assessment was based on the Munich Composite International Diagnostic Interview (M-CIDI). Results. The overall cumulative lifetime incidence of any depressive condition was 20·0% (major depressive disorder (MDD), 12·2%; dysthymia, 3·5%; subthreshold MDD, 6·3%), of which about one-third were incident depressions in the period between baseline and follow-up. Depressive disorders rarely started before the age of 13. Females were about twice as likely as males to develop a depressive disorder. Overall, the 20-month outcome of baseline depression was unfavourable. Dysthymia had the poorest outcome of all, with a complete remission rate of only 33% versus 43% for MDD and 54% for subthreshold MDD. Dysthymia also had the highest number of depressive episodes, and most psychosocial impairment and suicidal behavioural during follow-up. Treatment rates were low (8–23%). Subthreshold MDD associated with considerable impairment had an almost identical course and outcome as threshold MDD. Conclusions. DSM-IV MDD and dysthymia are rare before the age of 13, but frequent during adolescence, with an estimated lifetime cumulative incidence of 14%. Only a minority of these disorders in adolescence is treated, and more than half of them persist or remit only partly.

Objective: To examine in a nationally representative sample (a) the differential association of specific anxiety and depressive disorders defined according to DSM-IV with pain disorder (PD) and pain symptoms, and (b) whether pain-associated anxiety and depressive disorders and their comorbidity have different implications in terms of impairment, disability, health care utilization, and substance use. Method: A nationally representative community study was conducted in Germany. Symptoms, syndromes and diagnoses of mental disorders, and pain were assessed in N = 4,181 participants aged 18–65 years using the DSM-IV/M-CIDI. Results: Logistic regressions revealed that pain is associated with both specific anxiety and depressive disorders, with increasing significant odds ratios (OR) for medically explained pain symptoms (EPS; OR range: 1.9–2.0), to unexplained pain symptoms (UPS; OR range: 2.4–7.3), to PD (OR range: 3.3–14.8). PD and UPS persistently showed associations after adjusting for comorbid other anxiety and depressive disorders and physical illnesses. All types of pain, particularly PD/UPS, are associated with decreased quality of life, greater impairment in role functioning, disability, health care utilization, and substance use. Depressive disorders, even more so anxiety disorders and their comorbidity account for a substantial proportion of variance in these functional correlates. Conclusions: Pain is strongly associated with specific anxiety and depressive disorders. In light of the individual and societal burden due to pain, and the demonstrated role of comorbid anxiety or/and depression, our results call for further investigation of the underlying mechanisms for this association as well as targeted treatments for these comorbidities.

Our conceptualization and empirical understanding of the course of depression is beginning to change. This is largely a result of recent epidemiological and clinical data that suggest depression has a chronic course for many individuals. Treatment studies for chronic depression have found that response rates are consistently less robust than in studies of acute, episodic depression. As is such, investigators have begun to examine factors that impede treatment response among these patients. One such factor is the presence of comorbid Axis-II personality disorders. This study examined the moderating effects of Depressive Personality Disorder (DPD) on treatment outcome among 680 outpatients with chronic depression. Results suggest that DPD did not serve as a prognostic indicator of worse outcome after 12 weeks of treatment or at last observation carried forward. This was a secondary analysis of the data presented by Keller and colleagues (Keller, McCullough, Klein, Arnow, Dunner, & Gelenberg, 2000).

Social interactions affect the onset and maintenance of major depressive disorder (MDD; e.g., Hammen, 2006). However, little research has examined depressed people’s communications in daily life. This dissertation’s primary aim is to test three models of the association between MDD and everyday communication. The disclosure model suggests that people with MDD, particularly if currently depressed, communicate about themselves and their distress. The social disengagement model suggests that people with MDD, particularly if currently depressed, communicate less. The selectivity model suggests that people with MDD, particularly if currently depressed, communicate more negatively only with people with whom they have closer relationships. This dissertation’s second aim is to investigate associations between communication patterns of individuals with MDD and residual depressive symptoms. Sixteen women with MDD and 15 never-depressed women submitted a year’s worth of their e-mails with up to ten correspondents. For participants with MDD the year included at least one month of depression and one month of remission. E-mails were submitted to computerized text analysis. For the primary research question, the study design was conceptualized as a 2x2 between-subjects (MDD vs. never-depressed) x within-subjects (currently depressed vs. not currently depressed) ANOVA missing one cell (never-depressed individuals with currently depression). Data were e-mails nested within correspondents within participants and were analyzed using multi-level regression. For the second research question, OLS regression analyses were used. People with MDD e-mailed their correspondents marginally more frequently when in a depressive episode, suggesting increased efforts at engagement. During episodes, however, participants showed less verbal synchrony with their correspondents. This suggests that despite reaching out more, currently depressed people are less attuned with others. People with major depressive disorder used more positive emotion words and fewer negative emotion words than never-depressed controls. Although there was a general pattern among participants of using more negative emotion words with correspondents with whom they had closer relationships, this tendency was accentuated in depressed individuals in current major depressive episodes. These findings are consistent with the view that individuals – particularly when depressed – regulate aspects of their communication to protect and manage their social relationships. / text

Representing a major public health concern, suicide is a leading cause of death worldwide. Generally regarded as a behavior with a multitude of state and trait dependent risk factors (e.g. psychiatric disorders, substance abuse, genetics), explanations as to why certain individuals commit suicide while others do not are complex. Of interest is in studying potential trait dependent variables involved in the neurobiology of suicide, particularly at the cellular level. Knowledge of the cellular integrity may aid in explaining the observed macroscopic alterations and ultimately the behavioral correlates associated with suicidality. Therefore we set out to summarize extant knowledge of the cellular alterations occurring in the brains of major depressive and suicide individuals. Following this, we conducted our own cellular investigation in a region known to be altered in major depression and suicide, a supracallosal area of BA24a. Neuronal and glial cell densities as well as neuronal cell sizes were assessed in upper and lower cortical layers between sudden-death controls and MDD suicide subjects. Secondary analyses were also conducted to examine the effect of alcohol on depressed suicides. Analyses of cell densities and neuronal soma sizes between controls and MDD suicide subjects did not reveal any significant differences. Further analyses showed increased glial cell densities in alcoholic depressed suicides. Future studies are necessary to examine explicit changes in the cellular compositions occurring in alcoholic dependent individuals. Staining techniques aimed at targeting specific subtypes of neurons and glial cells will help determine if these cell populations do in fact have an influential role in suicide and MDD.

One of the most difficult and serious challenges facing the mental health professional is the prevention of suicide. Efficient prevention, however, depends on early detection of patients at risk for suicidal behaviour, which in turn depends on a better understanding of the predisposing factors. Over the last years, based on a large volume of data, it has become increasingly clear that subjects who commit suicide present high levels of impulsive and impulsive-aggressive behaviours. / In the first approach, we investigate whether levels of the impulsive aggressive diathesis were more important in suicide occurring at different life stages. In the second, we investigate whether levels of the diathesis predicted when during the course of major depressive disorder suicide occurs. / Family studies have consistently indicated that suicidal behaviour tends to cluster in families. However, relatives also present increased risk for psychiatric morbidity, and therefore, the critical question is whether or not the liability to suicidal behavior is given by the same predisposition to the coexistent psychiatric disorders. / Therefore, in the third study, we examined the independence of familial liability using a three group design. The relatives of deceased suicide probands who died in the context of a major depressive episode are compared to the relatives of living depressed subjects without a history of suicide and to the relatives of healthy controls screened for the absence of major depression and suicide.

Depression is commonly associated with abnormal sleep architecture. This thesis undertook to assess sleep architecture as a biological correlate of self and observer-rated depressive state, and consists of three studies. The first used a categorical approach to examine the association of sleep architecture with subjective mood in a community sample of 74 preoperative patients, and found no association between high depression scores and hypothesized sleep markers. The second followed 16 patients with Major Depression who were treated with the antidepressant mirtazapine in an 8 week longitudinal study during which they underwent polysomnography on 6 occasions. It was found that classes of sleep markers (REM latency or REM, arousal index, and slow wave sleep) tend to predict response when analyzed concurrently. The third study was methodological in nature, and found that commercially available software for automating eye movement counts did not show strong correspondence with visually scored polysomnographic data.

Depression is commonly associated with abnormal sleep architecture. This thesis undertook to assess sleep architecture as a biological correlate of self and observer-rated depressive state, and consists of three studies. The first used a categorical approach to examine the association of sleep architecture with subjective mood in a community sample of 74 preoperative patients, and found no association between high depression scores and hypothesized sleep markers. The second followed 16 patients with Major Depression who were treated with the antidepressant mirtazapine in an 8 week longitudinal study during which they underwent polysomnography on 6 occasions. It was found that classes of sleep markers (REM latency or REM, arousal index, and slow wave sleep) tend to predict response when analyzed concurrently. The third study was methodological in nature, and found that commercially available software for automating eye movement counts did not show strong correspondence with visually scored polysomnographic data.