Introduction: The aim of the project was to investigate the effects of antidepressants on brain networks whilst at rest. My hypothesis was that antidepressants work by reversing persistent activity in the brain’s default mode network (DMN). The DMN is implicated in self-reflection and rumination in MDD. The methodologies and results of studies of resting state networks in MDD and the effects of antidepressants are reviewed in the thesis. Increasing evidence implicates glutamate in the action of antidepressant drugs. Whether there are illness related changes in glutamate function is unresolved, largely because of the lack of techniques for assessing it. Ketamine and other NMDA antagonists have improved MDD symptoms within 24 hours though the effects are short lasting. The molecular neural networks involved in ketamine’s putative antidepressant effects are unclear. The thesis reviews the evidence. Much evidence implicates ACC as a site of action of antidepressant effects but whether this is through its regulation of the DMN or other networks is not known. This thesis compares the effect of ketamine and citalopram on ACC-related systems. Method: The thesis combines two systematic reviews of the effects of MDD and antidepressant drugs on i) resting state networks (53 studies) and ii) glutamate neurotransmission (45 studies of clinical efficacy of ketamine). There are two experimental chapters. The first describes investigation into two rapid acting antidepressant drugs acting via glutamate mechanisms. 54 unmedicated cMDD were scanned across two centres on 3T MRI scanners while being infused with placebo (0.5% saline), 0.5mg/kg ketamine or 100mg AZD6765 over 1 hour. fMRI resting state data between drug treatments was compared for the final 25 minutes of the drug infusion and for a 25 minute resting state scan a day later. The second experimental chapter examines whether these effects were shared by citalopram, a standard antidepressant. 67 unmedicated cMDD, rMDD and HC were administered citalopram 7.5mg i.v. and scanned on a 1.5T MRI scanner. In a second study 63 cMDD and HC were administered i.v. citalopram 7.5mg or placebo (0.5% saline). fMRI resting state data for the final 12 ½ minutes following drug infusion was compared. Independent Component Analysis was performed using the Group ICA for fMRI toolbox. The resting component with the highest spatial correlation to the ACC was used. Brain maps of the intensity of the selected component were constructed for each individual. Group averages were calculated and compared using SPM. Regional analysis was performed using Marseille Boite a Regions d'interet. Results: On day 1 AZD6765 significantly increased mean intensity of ACC resting component in the right insula, right IPL and left cingulate gyrus greater than ketamine or placebo. Ketamine increased mean intensity of ACC resting component greater than placebo in the right lentiform nucleus and left mFG. Significantly decreased mean intensity of ACC resting component in the left insula in the AZD6765 group compared to placebo was noted. On day 2 AZD6765 increased mean intensity of ACC resting component greater than ketamine and placebo in the left and right lentiform nuclei. AZD6765 reduced mean intensity of the ACC resting component in the left and right MFG. The first citalopram study revealed reduced mean intensity of ACC resting component in cMDD compared to rMDD and HC in PCC. rMDD had reduced mean intensity of ACC resting component in the precuneus compared to HC. In the second study, citalopram had no effect in HC but normalised precuneus activity in cMDD producing a significant drug x group interaction. Conclusions: The acute antidepressant effects of citalopram are modulated by changes in the bilateral precuneus. The precuneus is central to connectivity with other regions in MDD. It has a prominent role in the DMN and is linked to rumination. The mechanism of the antidepressant effects of AZD6765 is different from those of ketamine and citalopram. The insula, IPL, MFG, cingulate gyrus and lentiform nuclei are all regions implicated in MDD suggesting antidepressant effects. The rapid antidepressant effects of AZD6765 are possibly due to a resetting of the interface between DMN and salience networks.

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.

Le trouble dépressif majeur est une pathologie qui atteint 20% de la population et qui représente le premier facteur de morbidité et d’incapacité au niveau mondial. Récemment, le canal potassique TREK-1 est une cible potentielle avérée dans le traitement de la dépression. La délétion de ce canal ou son blocage par un peptide dérivé résultant de la maturation de la sortiline, le propeptide (PE) ou son analogue synthétique la Spadine, résulte en un phénotype de résistance à la dépression. La sortiline est une protéine capable de s’associer à TREK-1 mais également au facteur neurotrophique BDNF important pour la viabilité neuronale et la régulation de l’état dépressif. La sortiline est donc impliquée dans la régulation de l’adressage intracellulaire de TREK-1 et du BDNF. Mes travaux se sont d’abords focalisés sur les conséquences de la délétion du gène codant pour la sortiline (Sort1-/-) sur l’adressage de TREK-1 et du BDNF, et également sur le système neurotensinergique. Les résultats révèlent au niveau cérébral une diminution de l’expression membranaire de TREK-1 et une augmentation de BDNF. L’ensemble de ces modifications conduisent les souris Sort1-/- à développer un phénotype de résistance à la dépression. De plus, ces souris présentent une augmentation de la concentration en neurotensine cérébrale ainsi que de son récepteur 2, ce qui entraine une résistance à la douleur. Par la suite, nous avons montré une diminution de la concentration sérique du PE chez les personnes dépressives, un niveau restauré après traitement avec des antidépresseurs. En conclusion, la sortiline joue un rôle prépondérant dans la régulation du trouble dépressif et aussi dans la nociception. / Major depressive disorder is a condition that affects 20% of the population and is the leading cause of morbidity and disability worldwide. Recently, the TREK-1 potassium channel has been shown to be a potential target in the treatment of depression. The deletion of this channel or its blocking by a derived peptide resulting from the maturation of Sortilin, propeptide (PE), or its synthetic analogue Spadin, results in a phenotype of resistance to depression in mice. Sortilin is a protein able to bind with TREK-1 but also with the neurotrophic factor BDNF, an important factor for neuronal viability and depressive state regulation. Sortilin is therefore involved in regulating the intracellular addressing of TREK-1 and BDNF. Initially, my work focused on the consequences of the deletion of the Sortilin gene (sort1-/-) on the TREK-1 and BDNF addressing, and the neurotensinergic system. The results showed a decrease in TREK-1 membrane expression at the cerebral level and an increase in BDNF. All of these changes lead the Sort1-/- mice to develop a phenotype of resistance to depression. In addition, these mice show an increase in brain neurotensin concentration and its receptor 2, leading to increased resistance to pain perception. In a second phase, I was interested in whether PE, a potential antidepressant, showed serum variations in depressed patients and could be an indicator of depressive syndrome. We showed that the serum PE level is significantly reduced in depressed people, a level restored after treatment with antidepressants. In conclusion, Sortilin plays a major key in the regulation of depressive disorder and also in nociception.

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.

A growing body of work links psychopathology to changes in hedonic capacity following stressors. This was the first experimental study of the effects of stress on hedonic capacity in an analog generalized anxiety disorder (GAD) sample (a high worry group). Specifically, we utilized an experimental manipulation of stress and a behavioral index of anhedonia to test the hypothesis that individuals with GAD, who are at higher risk for developing depression symptoms, exhibit greater stress-related deficits in hedonic capacity than do nonanxious controls. Further, this study assessed whether stress-induced hedonic deficits predicted future depression. Controls exhibited the expected reward learning pattern in the baseline condition, demonstrating intact hedonic responding, as well as the expected pattern of behavioral anhedonia under stress. Contrary to predictions, worriers demonstrated intact hedonic capacity under stress. The stress effect in worriers was modulated by past depression diagnostic status; whereas worriers with no past depression demonstrated blunted baseline hedonic capacity and heightened hedonic capacity under stress, worriers with past depression demonstrated the normative response pattern. Blunted baseline response bias predicted higher future depression in both groups. We discuss the differential stress effects on behavioral hedonic capacity found as a function of worry, the role of past depression as a moderator of stress effects among worriers, and the need for future work to further explicate the mechanisms that may modulate reward response under stress.

Major depressive disorder (MDD) is a relevant condition to consider regarding Work Capacity Evaluation (WCE) because of its high prevalence, strong impact on short-term work disability, and low rate of treatment. The challenge that faces occupational therapists (OTs) is that there is no specific guideline and process to follow when conducting Work Capacity Evaluation with clients suffering from MDD. The researcher had also noted conflicting opinions with regard to the outcome of Work Capacity Evaluation (WCE) and recommendations in occupational therapy reports. The researcher is of the opinion that indeed occupational therapy assessments need to be clear about what to measure, and selection of appropriate standardised measures and non-standardised assessments is needed. Therefore, the research question was, what are the perceptions and practices of occupational therapists in determining work capacity of employees suffering from major depressive disorder? The aim of this study was to describe the perceptions and practices of occupational therapists in determining work capacity of employees suffering from major depressive disorder. The literature showed that Work Capacity Evaluation assists to determine the employee’s returnto- work. The Code of Good Practice: Dismissal contained in the Labour Relations Act of 1998, stipulates that incapacity on the ground of ill health or injury may be either temporary or permanent. The nature of this study was a mixed method design including both qualitative and quantitative approaches. The phenomenological strategy was used. The study had a sample size of 68 participants, practising as occupational therapists. Purposive sampling was used. The data were collected in four distinct phases, referred to as sequential exploratory strategy with elements of embedded design. Phase one, used descriptive open-ended questions; phase two was a close-ended questionnaire to confirm findings in phase one; phase three consisted of focus group interviews and phase four was member checking to confirm findings in phase three. During data analysis, five themes related to employees suffering from MDD emerged and they were identified as: (1) the content of comprehensive assessment for work capacity evaluation, (2) the process of work capacity evaluation, (3) the competency requirements of the occupational therapist, (4) occupational performance and (5) formulating return-to-work decision. Recommendations related to the five themes were formulated and suggestions for future research proffered. The study clarified and confirmed that occupational therapists have a major role to play in performing work capacity of employees suffering from major depressive disorder, and that they need to be competent in performing these evaluations. Copyright / Dissertation (MOccTher)--University of Pretoria, 2011. / Occupational Therapy / unrestricted

Several trials have reported rapid antidepressant response from the anesthetic drug ketamine although the mechanism behind this effect is not fully understood. Research has focused mainly on ketamine’s action in the brain, including its effects on chemical balance, connections between brain cells and networks, and cognition. Trials with psychedelic drugs have had similar antidepressant results as ketamine, and the quality of the subjective psychedelic experience seems to mediate antidepressant action. Ketamine causes similar alterations of consciousness, which have been viewed as side effects. This thesis examines whether ketamine works in a similar way as psychedelics, where the ketamine-induced dissociative-like experience has a relationship to antidepressant response. Leading theories of depression and ketamine’s action in the brain are presented, and eight studies examining the relationship between ketamine-induced subjective experience and antidepressant response are reviewed. Three included studies found a relationship between psychedelic- and dissociative-like symptoms and reduction in depression, while five did not. The supposed relationship between psychedelic- and dissociative-like symptoms and antidepressant action has not been adequately explored and needs further examination in clinical trials.

Major depression and suicide are associated with altered concentrations of specific noradrenergic proteins in the human locus coeruleus (LC). Based on experimental studies that can reproduce these LC abnormalities in laboratory animals, we hypothesized that noradrenergic pathobiology in depression is a result of overactivity of the LC. LC activity is under the control of both excitatory and inhibitory inputs. A major inhibitory input to the LC is GABAergic, arising from the nucleus prepositus hypoglossi. Numerous studies demonstrating low levels of GABA in the CSF and plasma of subjects with major depressive disorder (MDD) raise the possibility that LC overactivity in depression may be secondary to reduced GABAergic input to the LC. Here, GABAergic input to the LC in depression was evaluated by studying the binding of [ H]flunitrazepam to GABA receptors at three anatomically defined levels of the human postmortem LC. LC tissues were collected from subjects with MDD, subjects with depressive disorders including MDD that died as a result of suicide, and psychiatrically normal control subjects. A modest rostral-caudal gradient of GABA receptor binding density was observed among all subjects. No significant differences in the amount of binding to GABA receptors were observed between control subjects (n = 21) and MDD subjects (n = 9) or depressed suicide victims (n = 17). These results demonstrate that GABA receptor binding in the LC measured with [ H]flunitrazepam is not altered in subjects with depressive illnesses.

No description available.

Phox2a and Phox2b are two homeodomain transcription factors playing a pivotal role in the development of noradrenergic neurons during the embryonic period. However, their expression and function in adulthood remain to be elucidated. Using human postmortem brain tissues, rat stress models and cultured cells, this study aimed to examine the alteration of Phox2a and Phox2b expression. The results show that Phox2a and Phox2b are normally expressed in the human locus coeruleus (LC) in adulthood. Furthermore, the levels of Phox2a protein and mRNA and protein levels of Phox2b were significantly elevated in the LC of brain donors that suffered from the major depressive disorder, as compared to age-matched and psychiatrically normal control donors. Fischer 344 rats subjected to chronic social defeat showed higher mRNA and protein levels of Phox2a and Phox2b in the LC, as compared to non-stressed control rats. In rats chronically administered oral corticosterone, mRNA and protein levels of Phox2b, but not Phox2a, in the LC were significantly increased. In addition, the corticosterone-induced increase in Phox2b protein was reversed by simultaneous treatment with either mifepristone or spironolactone. Exposing SH-SY5Y cells to corticosterone significantly increased expression of Phox2a and Phox2b, which was blocked by corticosteroid receptor antagonists. Taken together, these experiments reveal that Phox2 genes are expressed throughout the lifetime in the LC of humans and Fischer 344 rats. Alterations in their expression may play a role in major depressive disorder and possibly other stress-related disorders through their modulatory effects on the noradrenergic phenotype.