This dissertation is composed of five major chapters. The first is a comprehensiveliterature review, followed by three chapters of research findings, and a final concludingchapter. Major Depressive Disorder (MDD) is a phenotypically complex andheterogeneous syndrome. This challenge and others faced when investigating the geneticbasis for the susceptibility to MDD are discussed, as are tools used to address andovercome these challenges. Included in this review of the literature is a discussion onfindings of genome-wide analyses of MDD, as well as candidate genes that may play arole in the susceptibility to major depression. Following the literature review, threechapters of studies are presented. The first one demonstrates that in humans, the actualnumber of risk genotypes in the serotonin system accounts for over half of the variance inmood response to tryptophan depletion. There was no association between the dopaminesystem and mood response. The main conclusion from that study is that using a pathwayanalysis, rather than a single gene approach, may lead to more informative results whenstudying the genetics of a complex behavior. The next study demonstrates a similarconclusion, however, is not pathway specific. It is shown that in a group of de pressedsubjects not capable of treatment response, the mean number of risk genotypes is greaterthan in a group without depression. This supports the thought that treatment resistancemay be a more severe form of MDD. This study also presents data on single gene resultswhich demonstrate that the genetic basis for susceptibility to major depression may bedifferent and independent from the genetic basis for the capacity to respond to treatment.Several individual polymorphisms are implicated in each case. The final investigation is apublished manuscript refuting the findings of a previously published article onpolymorphisms in the TPH2 gene and association with treatment resistance. Many otherresearch groups have also been able to replicate the results demonstrated here. A finalchapter discusses the overall conclusions about the three research studies, as well as thefield of psychiatric genetics with a focus on the continuing search for the genetic basis ofsusceptibility to major depressive disorder.

Background. Mindfulness-based Cognitive Therapy (MBCT) is a relapse-prevention treatment for people in remission from major depression (rMDD). The neuropsychological mechanisms of MBCT are largely unknown. The key theoretical mechanisms of MBCT include self-compassion and rumination, with other mindfulness-based studies suggesting mechanisms across domains of attention, emotional processing, and cognitive flexibility. The aims of this thesis were to investigate the neuropsychological and neuroimaging mechanisms of MBCT in rMDD and to investigate relationships with relapse six months beyond MBCT. Paper One. 40 MBCT, 33 Treatment As Usual (TAU), and 42 healthy volunteers (HVs) took part. Experimental tasks for self-compassion and rumination were completed at baseline and post-session, alongside self-report questionnaires. Results showed increases for self-compassion following MBCT, with non-specific reductions for rumination. Paper Two. 40 MBCT, 33 TAU, and 42 HV participants took part. Tasks of attention, emotional processing, and cognitive flexibility were completed at baseline and post-session. Results showed increases in positive emotions post-MBCT, with non-specific changes for face emotion recognition and affective attentional bias tasks both post-MBCT and TAU. There were no changes over time for sustained attention or cognitive flexibility. Paper Three. 16 rMDD participants completed baseline and post-MBCT fMRI tasks of sustained attention and self-blame. Results showed reduced activation over time in the bilateral dACC in self-blame contrasts but no activation changes for sustained attention. Paper Four. 69 rMDD participants (38 MBCT & 31 TAU) completed task-based and self-report assessments up to six months follow-up. Non-relapsing MBCT participants showed increased self-compassion post-session which was maintained in follow-up. MBCT non-relapsing and TAU participants showed reduced rumination post-session and in follow-up. Conclusions. MBCT encourages a move towards more self-compassionate, positive processing but does not alter more automatic, bottom-up levels of processing. MBCT initiates a process for change beyond the course, particularly for self-compassion. Findings have theoretical and clinical implications and extend our understanding of the mechanisms of MBCT in rMDD participants.

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A defined group of medical records was surveyed for patients who showed onset of major depression with melancholic features while taking an antidepressant medication. Nine cases resulted. In all the antidepressants being taken while melancholia began were SSRIs and the melancholic depression remitted rapidly with the first treatment given, bupropion in five males, nortriptyline with triiodothyronine in two females, and ECT in one male and one female. This suggests that patients who take SSRIs and are melancholic respond well to bupropion, nortriptyline, or ECT. These observations complement reports of low responsivity of melancholic depression to SSRIs and distinctions between melancholic and nonmelancholic depressions.

The University of Rhode Island Change Assessment Scale (URICA) is a widely used measure of readiness to change. To evaluate the URICA's ability to discriminate among alcohol abusers with and without co-occurring major depression, the authors administered it to 193 outpatients court-referred for alcohol treatment. Estimates of internal consistency suggest that scoring the URICA using its traditional factors, as well as using the newer Readiness to Change index, produced variable yet adequately reliable scores. Further, the URICA detected statistically significant differences in motivation to change an alcohol problem between an alcohol use disorder group (AD; n = 131) and an alcohol use disorder with co-occurring depression group (AD/D; n = 62) with the AD/D group showing greater readiness to change. For the AD/D group, separate URICAs were given for alcohol use and depressed mood. Confirming previous findings, results suggest the URICA may lack sensitivity to discriminate among two simultaneously occurring psychological disorders.

Many patients suffering from depressive disorders are refractory to treatment with currently available antidepressant medications, while many more exhibit only a partial response. These factors drive research to discover new pharmacological approaches to treat depression. Numerous studies demonstrate evidence of inflammation and elevated oxidative stress in major depression. Recently, major depression has been shown to be associated with elevated levels of DNA oxidation in brain cells, accompanied by increased gene expression of the nuclear base excision repair enzyme, poly(ADP-ribose) polymerase-1. Given these findings and evidence that drugs that inhibit poly(ADP-ribose) polymerase-1 activity have antiinflammatory and neuroprotective properties, the present study was undertaken to examine the potential antidepressant properties of poly(ADP-ribose) polymerase inhibitors.

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Regulatorische T-Zellen (Tregs, CD4+CD25hi-Tregs) haben u. a. die Aufgabe, die Immunantwort sowie die Zytokinfreisetzung zu steuern, um die Immuntoleranz gegenüber körpereigenen Antigenen aufrecht zu erhalten. Es wurde beschrieben, dass depressive Patienten eine erniedrigte Konzentration von Tregs aufweisen. Da es Hinweise darauf gibt, dass Zytokine wie Interleukin (IL)-1IL-6 und Interferon (IFN)-eine Rolle in der Pathophysiologie der Depression spielen, und dass sich die Konzentrationen dieser Zytokine während antidepressiver Therapie ändern, untersuchten wir Veränderungen der Produktion von IL-1IL-6 und IFN- und Veränderungen der Konzentration von CD4+CD25hi-Tregs während antidepressiver Therapie. Wir gewannen dazu das Blut von 16 Patienten mit depressiver Störung in der ersten und sechsten Woche nach stationärer Aufnahme, indem wir die Plasmakonzentrationen von IL-1bestimmten. Ferner wurde die Produktion von IL-1, IL-6 und IFN-in einem Vollblut-Assay unter immunologischer Stimulation mit Lipopolysaccharid (LPS) oder Newcastle Disease Virus (NDV) in-vitro gemessen. Die Lymphozyten wurden differenziert und CD4+CD25hi-Tregs mittels Durchflusszytometrie bestimmt. Der psychopathologische Status wurde mit der Hamilton-Depressionsskala (HAMD-21) erfasst. Der HAMD-21-Score, die IL-1-Plasmakonzentrationen sowie die LPS-induzierte IL1-- und IL-6-Produktion waren nach sechs Wochen antidepressiver Behandlung signifikant gegenüber der Baseline erniedrigt. Dagegen stieg der Anteil der CD4+CD25hi-Tregs unter den Lymphozyten von 2,74% ± 0,88 (Mittelwert ± Standardabweichung) auf 3,54% ± 1,21 signifikant (p = 0,007) an. Es fand sich keine signifikante Änderung der NDV-induzierten IFN--Produktion. Der Anstieg der CD4+CD25hi-Tregs während antidepressiver Therapie könnte mit dem Abfall der Zytokinproduktion und der psychopathologischen Verbesserung der Patienten in einem kausalen Zusammenhang stehen.

The lateral and basal nuclei of the amygdala receive dopaminergic projections from the ventral tegmental area and substantia nigra, and noradrenergic projections from the locus coeruleus (LC). Previously, we demonstrated postmortem indices of altered dopaminergic (amygdala) and noradrenergic (LC) neurochemistry in subjects with major depressive disorder (MDD). For example, decreased levels of dopamine transporter were observed in the amygdala in MDD, while concentrations of tyrosine hydroxylase (TH) were elevated in the LC in MDD. The present study investigated the quantitative distribution of TH in nuclei of the human amygdala from 5 control subjects, and measured amounts of TH in specific amygdaloid nuclei and the LC from 8-10 matched pairs of MDD and psychiatrically normal control subjects. Matched pairs included 3 females and 7 males (controls and MDD), average ages of 50±5 y (controls) and 51±5 y (MDD), average postmortem intervals of 16±2 h (controls) and 21±1 h (MDD), and average pH values of 6.58±0.08 (controls) and 6.59±0.09 (MDD). The lateral, basal, accessory basal, and central nuclei of the amygdala and the LC were punched from frozen sections of postmortem brain. TH-immunoreactivity was measured by quantitative Western blotting. In normal control subjects, TH levels in the LC were between 3000- and 4000-fold higher than TH levels in the nuclei of the amygdala. Within the amygdala, amounts of TH were highest in the basal and central nuclei, and lowest in the lateral nucleus. TH levels in the basal nucleus were highly variable across subjects. TH levels were significantly lower (-50%) in the lateral amygdaloid nucleus in MDD subjects as compared to control subjects. In contrast, TH levels in the LC were significantly higher (+75 %) in MDD subjects. This report is the first demonstration of altered TH levels in the human amygdala. The direction of change associated with MDD of TH in the lateral nucleus of the amygdala was opposite to that found in the LC. Whether abnormal amounts of TH in the amygdala are a result of altered dopaminergic or noradrenergic input to the amygdala requires further study.

Recent postmortem studies have demonstrated deficits in glia in major depressive disorder, including reductions in the astrocyte specific interfilament glial fibrillary acidic protein (GFAP) in the prefrontal cortex and cerebellum of depressed patients. Astrocytes serve important roles in influencing neuronal activity in the CNS, one of which is to remove neurotransmitters from the extracellular space. The present study investigated the levels of GFAP in the locus coeruleus (LC) of human subjects. The LC is the principal source of norepinephrine in the brain and neurochemical pathology of the LC has been demonstrated in major depressive disorder (MDD) and suicide. Tissue punches of the LC were obtained from postmortem brains collected from subjects with MDD who died by suicide and psychiatrically normal control subjects (n=9 per group). The age of the subjects ranged from 17 to 65 years (control 37±4 y; MDD 39±5 y) and postmortem intervals ranged from 17 to 44 h (control 20±1 h; MDD 25±3 h). GFAP-immunoreactivity (ir) was measured by quantitative Western blotting. Alpha-tubulin-ir was used to control for protein loading and transfer. Amounts of GFAP-ir were highly variable within both control and MDD subjects, ranging 15-fold across control subjects and 24-fold across MDD subjects. There was a modest trend for lower GFAP-ir in the LC from MDD subjects relative to control subjects, but this difference was not significantly different. In control subjects, there was no significant correlation of GFAP-ir levels with age. In contrast, GFAP-ir levels were positively correlated with age in MDD subjects. In younger MDD subjects (<40 y), GFAP-ir was consistently lower as compared to matched control subjects. Amounts of GFAP-ir did not correlate with postmortem intervals. These findings are consistent with a previous report demonstrating age effects on GFAP in frontal cortex in depressed but not control subjects. Glia deficits reported in frontal cortex and cerebellum from depressed subjects may also occur in the brainstem, and these deficits may contribute to disruption of monoamine chemistry in depression. Given the variability of GFAP levels in the LC between subjects, other markers of glia should be pursued to evaluate the potential role of glia in brainstem pathology associated with MDD.