Background: Treatment-resistant depression (TRD) encompasses a segment of individuals with major depressive disorder who are severely ill in terms of chronicity, comorbidity, and prognosis. Although functional impairment is a prominent and costly feature of treatment-resistance, very little is known about the factors that contribute to and maintain functional impairment in TRD. Purpose: This study examined the relationships among neurocognition, symptoms, and functional impairment in TRD. Specifically, I examined the neurocognitive impairments that relate to different symptom domains and to level of symptom severity, as well as the predictors of functional outcomes and real-world behaviour in TRD. Method: Patients (N = 29) with a diagnosis of major depressive disorder were recruited from the Mood Disorders Treatment and Research Service at Providence Care Mental Health Services in Kingston, Ontario. Data were collected during a baseline assessment for a neurocognitive enhancement therapy program. Results: Individuals with TRD show mild to moderate impairments across all neurocognitive domains, with a superimposed severe impairment in verbal working memory. Verbal working memory significantly correlated with depressive symptoms and anxiety, such that increased verbal working memory capacity was related to more severe clinical symptoms. Greater response inhibition significantly correlated with less anxiety. Interpersonal competence was predicted by sustained attention and severity of depressive symptoms. Adaptive competence was significantly predicted by age at baseline and set shifting. Real-world work behaviour, interpersonal relations, and general satisfaction were predicted by the severity of depressive symptoms, whereas observed mood and anxiety predicted real-world recreational activity. Conclusions: The current study pioneered some of the first data regarding the relationships among neurocognition, symptoms, and functional outcomes in treatment-resistant depression. Verbal working memory appears to play an important role in the symptomatology of TRD. Neurocognitive variables and depressive symptoms are important in predicting functional competence (what one can do) but only depressive symptoms predict functional performance (what one actually does in the real world). There may be additional intrinsic or extrinsic factors that mediate the relationships among neurocognition, symptoms, and functioning in TRD. / Thesis (Master, Psychology) -- Queen's University, 2011-09-07 11:55:40.708

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BACKGROUND: Major depression is a pervasive condition that affects every aspect of a patient’s life, and many patients are unable to find symptom alleviation with the current available medications. Ketamine has recently shown promise as a rapid-acting antidepressant, yet its mechanisms are not yet well-understood. OBJECTIVE: We sought to understand the change in depression symptom interrelationships, with particular interest in sleep, in the context of ketamine treatment in depression by completing a network analysis. METHODS: 97 patients with treatment-resistant depression were given ketamine over six treatments, and symptoms were examined via the Quick Inventory of Depressive Symptomology (QIDS-SR-16). Two networks were constructed: one prior to the first treatment, and one prior to the sixth treatment. Each symptom of the inventory formed a node, and partial correlations were used to construct the edges of the network. Centrality indices and network structure was then evaluated and compared. RESULTS: Centrality indices measured were unstable, limiting assertions to node strength, but global network structure was revealed to be changed between the networks. CONCLUSION: The data suggests that ketamine may affect the interrelationships between depressive symptoms, by impacting some symptoms more than others.

Background: The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the aetiopathology of depression, and the incidence of HPA dysfunction tends to increase with the severity of treatment resistance. In healthy volunteers (HV), both acute and chronic hypercortisolaemia causes cognitive impairment, including emotional memory. The exact mechanism of this remains unclear; however the action of cortisol on corticosteroid receptors in the hippocampus appears to be crucial and this may also be important in the aetiopathology of depression. The aim of this thesis was to investigate acute and chronic states of the HPA axis, and its role on neurocognition in HV and treatment resistant depression (TRD). Methods: The acute action of cortisol in HV was examined through meta-analysis of the literature. In HV, the acute, non-genomic effects of hydrocortisone on the hippocampus were measured using pharmacological challenge functional magnetic resonance imaging (phMRI) and the effects on the working memory n-back task during functional magnetic resonance imaging (fMRI). Additionally, the neurocognitive effects in TRD patients, who are theorised to have chronically elevated corticosteroids, were compared to age and sex matched HV using the n-back task and a novel emotional encoding-retrieval task. Finally the acute effects of hydrocortisone on the whole brain were measured in TRD compared to HV using phMRI.Results: Meta-analysis results demonstrated an adverse effect on performance in retrieval tasks, but not encoding, after an acute rise in cortisol in HV, with a trend towards sparing of emotional memories. Using phMRI, hydrocortisone caused a time dependent increase in signal in the hippocampus, as well as an increased signal in the ventrolateral prefrontal cortex and a decreased signal in the hippocampus during the n-back task. Patients with TRD, when compared with HV, had a decreased signal in the dorsolateral prefrontal cortex during the n-back task. Additionally, during the emotional encoding-retrieval task, regardless of the emotional content, the patients showed a decrease in signal in the posterior cingulate during encoding and an increase in the posterior insula during retrieval. During retrieval of positive versus neutral images, there was an increase in signal in the anterior cingulate. The earlier phMRI findings were not reproduced in either the TRD or age and sex matched controls. Conclusions: This work developed and examined a new technique to explore the relationship between the HPA axis and depression, as well as exploring the neurocognitive difference between TRD and HV. A non-genomic, acute effect of cortisol on the hippocampus was demonstrated in HV, as well as differences in processing emotional memories both acutely in HV and also in TRD patients. Further work needs to be done to develop the phMRI technique further and explore the aetiopathological role of the HPA axis in depression, focussing on the hippocampus.

In addition to low mood, major depressive disorder (MDD) is characterized by persistent cognitive deficits that impair daily functioning and resist improvement with conventional pharmacotherapies. Repetitive transcranial magnetic stimulation (rTMS) holds promise as an efficacious alternative, offering better outcomes than medication for patients with treatment-resistant depression (TRD). Yet, current rTMS protocols that administer sinusoidal biphasic pulses achieve remission in less than the majority. However, monophasic pulses may yield higher success rates based on greater cortical excitation/neuromodulation strength. MDD is associated with altered P300 event-related potentials (ERPs), indexing decreased attentional resource allocation and slower cortical processing speed. Using a cohort of 20 TRD patients who received high-frequency rTMS, this study aimed to assess the impact of monophasic and biphasic stimulation on attention-related P300 measures and their utility as correlates of clinical/cognitive response. Based on baseline and post-treatment change in P300 components, rTMS-induced increases in automatic attention/passive information processing differed by pulse type and predicted greater clinical improvement in depressed individuals. This study represents an important step towards identifying cognitive changes and underlying cortical mechanisms associated with rTMS response and targeted MDD treatment.

Background: Major depressive disorder is associated with elevated levels of DNA oxidation, DNA damage, and gene expression of DNA repair enzymes including poly (ADP-ribose) polymerase-1 (PARP1). Elevated PARP1 activity is directly linked to neuroinflammation and PARP inhibitors are anti-inflammatory and neuroprotective. We previously showed that PARP inhibitors produce antidepressant-like effects equivalent to fluoxetine in rodent models. Here, we examined whether the PARP inhibitor 3-aminobenzamide (3AB) is effective in a rat model of treatment-resistant depression. Methods: Treatment-resistant depression was modeled with injections of lipopolysaccharide (LPS; 0.1 ug/kg/day) and daily chronic unpredictable stress (CUS) for 28 days. Anhedonia and helplessness were indexed with sucrose preference and forced swim tests, respectively, in 5 groups of rats (n¼6-8 rats/group) including unstressed, CUS, and CUS+LPS rats treated with saline, and CUS+LPS rats treated with either 3AB or fluoxetine. Results: Anhedonia induced by CUS+LPS was significantly attenuated by 3AB (p¼0.01), while fluoxetine failed to do so. Likewise, 3AB was superior to fluoxetine in reducing helplessness, where latency to immobility times were significantly lower in CUS+LPS rats treated with fluoxetine (p¼0.001) compared to unstressed rats, but not significantly different for 3AB-treated CUS+LPS rats. Conclusions: The PARP inhibitor 3AB demonstrated robust and unique antidepressant activity superior to fluoxetine in the TRD rat model. PARP is linked to neuroinflammation through release of microglia-activating factors including poly (ADP-ribose) and HMGB1, and through NF-kB activation, pathways under investigation by our lab. PARP inhibitors are currently used clinically to facilitate cytotoxicity of DNA-damaging anti-cancer treatments. Further research could implicate re-purposing non-cytotoxic PARP inhibitors for treatment-resistant depression.

An increasing amount of research suggests Ketamine in subanaesthetic doses to be an effective antidepressant for Major Depressive Disorder (MDD) and Treatment-Resistant Disorder (TRD). After the finding that NMDA-receptor antagonists may hold antidepressant effect, several studies have suggested Ketamine to have great effect in relief of depressive symptoms. A time lag between biological and behavioural effects have been shown in currently available antidepressants and are not guaranteed to be efficient; only 30% of patients reach adequate response. The aim for this thesis is to systematically review available studies on the efficiency of Ketamine's antidepressant effects in patients with TRD. Scopus, Web of Science, and PubMed were the databases searched for relevant research regarding the subject. Six articles were included in the analysis. A compilation of the results presented a moderate to large effect size for Ketamine compared to placebo at 24 hours through day seven. It is of immense weight that prolonged adverse effects and possible abuse are taken into consideration for future research, as well as how to sustain the dramatic acute antidepressant effect of Ketamine.

Mindfulness-based cognitive therapy (MBCT) is a meditation-based psychotherapeutic intervention suggested to be equally effective as antidepressant medication for preventing depressive relapse. A lot of patients with major depressive disorder (MDD) have preference for psychotherapeutic intervention compared to antidepressant medication, currently being the most common treatment for preventing depressive relapse. The aim of this systematic review was to examine the effectiveness of MBCT compared to antidepressant medication for preventing depressive relapse in individuals with MDD, treatment-resistant depression, or suicidal ideation. After a literature search in the databases Scopus and Web of Science, 16 articles were included in this systematic review. Results were mixed. While two studies demonstrated that MBCT is equally effective as antidepressant medication in preventing depressive relapse, four studies showed evidence of reduced relapse rates after MBCT treatment alone. Further, four studies suggested that MBCT is inferior to antidepressant medication in preventing depressive relapse. Future studies should focus on comparing MBCT alone to specific antidepressant medication in order to further evaluate the effectiveness of MBCT vs antidepressant medication.

Background: Major depressive disorder is a debilitating psychiatric condition with high rates of treatment resistance that may be associated with working memory (WM) deficits. For treatment resistant depression (TRD) patients, deep brain stimulation (DBS) is emerging as an effective therapeutic option. Objective: To determine if electroencephalography signals recorded during DBS ON and OFF states while performing WM tasks can serve as biomarkers of therapeutic efficacy for DBS in TRD patients. Results: DBS stimulation suppressed frontal gamma oscillations (30–50Hz) during the ON state relative to the OFF state, an effect that was more pronounced with higher WM load. This suppression strongly correlated with depressive symptoms reduction. Conclusion: Suppression of gamma oscillations by DBS is likely mediated by indirect activation of inhibitory circuits in the frontal cortex. It represents a potential treatment biomarker for DBS in TRD and may lead to more tailored treatment parameters that can result in enhanced efficacy.

Background: Major depressive disorder is a debilitating psychiatric condition with high rates of treatment resistance that may be associated with working memory (WM) deficits. For treatment resistant depression (TRD) patients, deep brain stimulation (DBS) is emerging as an effective therapeutic option. Objective: To determine if electroencephalography signals recorded during DBS ON and OFF states while performing WM tasks can serve as biomarkers of therapeutic efficacy for DBS in TRD patients. Results: DBS stimulation suppressed frontal gamma oscillations (30–50Hz) during the ON state relative to the OFF state, an effect that was more pronounced with higher WM load. This suppression strongly correlated with depressive symptoms reduction. Conclusion: Suppression of gamma oscillations by DBS is likely mediated by indirect activation of inhibitory circuits in the frontal cortex. It represents a potential treatment biomarker for DBS in TRD and may lead to more tailored treatment parameters that can result in enhanced efficacy.