Lithium (Li+) is the major drug presently prescribed in the treatment of manic depression. Its site of action within the central nervous system is unknown although it has been known for several years to have profound effects upon inositol (poly)phosphate metabolism. The basis of the work presented here is to investigate the effects of Li+ upon the accumulation of labelled and unlabelled inositol (poly)phosphates in muscarinic cholinergically stimulated rat cerebral cortical slices and cultured cell lines. Its effects on the accumulation of CMP-phosphatidic acid (CMP-PA), a precursor to (poly)phosphoinositide lipid resynthesis and upon the inhibition of inositol monophosphatase activity are also described. It has been shown that the presence of Li+ leads to reduced accumulation of, not only Ins(l,3,4,5)P4 but also of Ins(l,4,5)P3, the molecule responsible for the release of intracellular Ca2+. The labelled Ins(l,4,5)P3 and Ins(l,3,4)P3 which accumulate under these conditions were separated in the absence of mg++ using an enzymic preparation from rat cerebral homogenate. This technique allows an effective and accurate separation which circumventss the use of h.p.l.c. It has also been demonstrated that both [3H] InsP1 and [14C]CMP-PA increase with similar EC50 values in the presence of increasing Li+ concentrations and also with increasing time in the presence of Li+. Furthermore, work has indicated that the preincubation of rat cerebral cortical slices with myo-inositol can, at least partially, reverse the accumulation of labelled CMP-PA. However, if the myo-inositol is added subsequent to the Li+ block being established, incomplete reversal is only observed in the presence of very high concentrations of inositol. In addition, similar experiments were conducted to observe the effects of myo-inositol upon the Li+-induced reduced accumulation of both Ins(l,4,5)P3 and Ins(1,3,4,5)P4 as measured by radio-receptor assay. Whilst the presence of 10mM myo-inositol prolonged the lag phase routinely observed between 5 and 10 mins, it could not prevent the fall in accumulation from occurring. Scyllo-inositol, a naturally occurring isomer of myo-inositol, was found to be completely ineffective in reducing the accumulation of [14C]CMP-PA. In other experiments, the effects of Li+ upon the carbachol-stimulated inositol (poly)phosphate fractions were examined in CHO cells transfected with an M1 muscarinic receptor subtype and also in SH-SY5Y cells and the results compared to those obtained in rat cerebral cortical slices. Finally, an assessment of inhibition of the inositol monophosphatase activity was made in a variety of cell free systems. This inhibition was caused using either Li+ or polyclonal antibodies raised to purified inositol monophosphatase. In conclusion, the results obtained verify the profound effects which Li+ can have upon inositol (poly)phosphate metabolism and suggest that whilst the primary intracellular target of Li+ may indeed be the inositol monophosphatase it may also be causing other subtle alterations to the cell functioning. These possibilities and their implications are discussed.

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

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).

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.

Depression is a significant mental health concern with a pivotal increase of incidence during adolescence, specifically for females. Currently, cognitive behavioral therapy (CBT) is the most widely tested treatment for depression. Yet, it is unclear how CBT functions to produce effective outcomes. Adult studies have shown that behavioral components of CBT are more effective than cognitive components in reducing depression at acute treatment. Both behavioral and cognitive components have been shown to be effective in preventing relapse of depressive symptoms at follow up. Yet less is understood about how treatment components work together to provide positive outcomes, particularly for depressed youth. The overall goal of this study was to examine which parts of treatment (cognitive and/or behavioral) aid in symptom reduction and to determine if treatment outcome is mediated by cognitive change. Forty two pre-adolescent girls, aged 9-14, participated in a 20-session manualized group CBT program. The first portion of treatment (session 1-9) focused the behavioral intervention and the second portion of treatment (sessions 11-19) focused on cognitive interventions while continuing to reinforce behavioral interventions when necessary. Self report measures and diagnostic interviews were completed at pre-treatment and post-treatment. Using multiple regression analyses, the findings of this study supported the role of behavioral and cognitive interventions in reducing depression. Behavioral interventions were found to significantly reduce depression at post-treatment. Additionally, cognitive interventions were found to play a small, but significant role in post-treatment outcome, with preliminary evidence that cognitive interventions could also be linked to treatment outcome one year later. Treatment specificity could not be tested, as the cognitive change of depressed girls was not directly influenced by the behavior and cognitive interventions. Exploratory analysis demonstrated the significant role of behavioral techniques such as behavior activation, positive reinforcement, homework review, and skills training in predicting outcome of treatment. Implications of the results, limitations, and recommendations for future research are provided. / text

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.