published_or_final_version / Community Medicine / Master / Master of Public Health

Major depressive disorder (MDD) is a prevalent and disabling disorder worldwide and in Hong Kong. It can occur alone or as a psychiatric sequelae of stroke known as post stroke depression (PSD). Our recent randomized controlled trial (RCT) found that additional dense cranial electroacupuncture stimulation (DCEAS) produced significantly greater improvement on depressive symptoms in patients with MDD compared to conventional antidepressants alone. However, the effectiveness of DCEAS on PSD and the underlying neural mechanism of its antidepressant effects remain unclear and need further investigation. This thesis consisted of three studies aimed to evaluate the efficacy of DCEAS as an additional therapy in PSD and to explore the neuroimaging correlates of DCEAS in MDD using PET and fMRI modalities. The purpose of Study 1 was to examine whether additional DCEAS was effective in treating PSD. A single blind RCT was conducted in 43 PSD patients treated with antidepressants and same body acupuncture combined with sham or active DCEAS with 3 acupuncture sessions per week for 4 weeks. Clinical outcomes included the Hamilton Depression Rating Scale 17-Item (HAMD-17), Clinical Global Impression - Severity Scale (CGI-S), and Barthel Index (BI).The results showed that DCEAS significantly reduced HAMD-17 at week 1, CGI-S at week 1 and endpoint whereas BI was more significantly decreased in control group. A combination of DCEAS and body acupuncture can be considered as an augmenting treatment for PSD. Study 2 aimed to explore the potential effects of DCEAS in regulating abnormal glucose metabolism in patients with MDD using 18F-FDG PET/CT. A single blind RCT was conducted in 25 MDD patients treated with antidepressants combined with sham or active DCEAS with 3 acupuncture sessions per week for 6 weeks. Clinical outcomes were measured using the HAMD-17, Zung Self-Rating Depression Scale (SDS), CGI-S and Insomnia Severity Index (ISI). There was a significant difference on the slope in SDS in linear mixed model analysis, indicating a faster improvement in subjective depressive symptoms by DCEAS. While the increased 18F-FDG signals in the cerebellum were normalized in both groups, the reversion of the reduced 18F-FDG signals in the left prefrontal cortex was only observed in DCEAS-treated patients, suggesting that additional DCEAS could more vigorously improve abnormal brain glucose metabolism in MDD. The purpose of Study 3 was to further investigate the neuropsychological and functional neuroimaging correlates of the antidepressant effects of DCEAS in the same pool of MDD subjects in Study 2 using fMRI with sad-face paradigm. The sad-face stimulation increased BOLD signals in an extensive neural network of the brain, including the frontal, temporal, parietal, limbic system and cerebellum. Additional DCEAS extensively suppressed the abnormal BOLD signals in these brain regions, more apparently in left caudate and cingulate, whereas sham treatment had slightly suppressive effects in fewer brain regions, suggesting that additional DCEAS could more robustly alter the biases towards sadness in MDD. In conclusion, DCEAS additional treatment is more effective in reducing depressive symptoms in patients with PSD, improving brain glucose metabolism and normalizing the abnormal neural activation due to biases towards sadness in patients with MDD. / published_or_final_version / Chinese Medicine / Doctoral / Doctor of Philosophy

Given the pervasive, debilitating nature of major depressive disorder, a large body of clinical research has evaluated the efficacy of short-term treatments for depression. Researchers have attempted to understand the complex mechanism of therapeutic change by examining treatment response, which is typically defined as the extent of symptom change between the intake and termination sessions. However, this approach fails to recognize that therapy is a non-linear, dynamic longitudinal process. An alternative approach involves analysis of longitudinal repeated measures process and outcome indicators in order to examine change both during treatment as well as following treatment. In order to evaluate dynamic, longitudinal hypotheses, it is necessary to use an appropriate analytical framework. A structural modelling technique termed Latent Difference Score Analysis (LDS) is well suited for this purpose, allowing for evaluation of longitudinal growth within a time series, while also considering multivariate relationships and determinants. / The purpose of this research was to evaluate established theories of depression vulnerability as well as theories of psychotherapy process, both during and following depression treatment. The research described in Chapter 2 examined several theories of the longitudinal relationship between depression and perfectionism during depression treatment, while considering the role of the therapeutic alliance. Longitudinal LDS analyses supported a "personality vulnerability" model of depression, in which perfectionism predicted the subsequent rate of depression change throughout treatment. Results indicate that patients with high levels of perfectionism experience less reduction in their depression scores throughout treatment. Furthermore, the strength of the therapeutic alliance significantly predicted the rate of change in personality vulnerability throughout therapy. The research described in Chapter 3 examined several theories of the longitudinal relationship between depression and stress following treatment termination. Results supported a "stress reactivity" model, in which stressful events led to elevations in the rate of depression change following therapy. Multigroup LDS analysis indicated that stress reactivity only occurred for patients who had been treated with medication, and not for those who had received psychotherapy. / These findings have several implications. First, comprehensive analyses of treatment efficacy can move beyond symptom reduction by examining mechanisms underlying treatment response using an appropriate statistical framework. The first paper demonstrates that an efficient route to symptom reduction involves establishing an adequate therapeutic alliance in order to target personality vulnerability. The second paper demonstrates that importance of evaluating treatment efficacy by considering whether a treatment leads to enduring change. Specifically, results indicate that the enduring effects of psychotherapy (in comparison to medication treatments) following treatment termination involves increased resiliency to stressful life events.

No description available.

This study used a qualitative methodology to examine treatment outcome and mechanisms of change from the perspective of the participants in a group cognitivebehavioral therapy intervention for depressed girls (i.e., the ACTION program). Data were collected from seventeen participants using semi-structured interviews. Seventeen initial and seven follow-up interviews were conducted. Interviews were transcribed and analyzed using the grounded theory approach. A theoretical model emerged from the data that explained mechanisms of change in relation to treatment outcome and evaluation. Prior to treatment, all participants were diagnosed with a depressive disorder. At post-treatment, approximately 88% of the sample no longer met criteria for depression. Thus, the ACTION program demonstrated a high rate of efficacy. Additionally, all of the participants described treatment as helpful. Level of helpfulness varied from high to low, with most participants rating treatment as very helpful, and depended on the ways in which the intervention produced positive change in the following areas: stressors, stressor management strategies, emotions, cognitions, and social support. Participants evidenced high levels of pre-treatment stressors, particularly in the interpersonal domain, and low levels of social support. Passive, emotion-focused strategies were used to manage these difficulties; however, they were largely ineffective. Not being able to resolve stressors successfully led participants to experience unpleasant emotions and negative ways of thinking. Together, these variables resulted in high levels depression prior to treatment. At post-treatment, most participants experienced several positive changes, including decreased stressors, increased effectiveness of stressor management strategies, elevated mood, and a more positive outlook. These changes were attributed to the acquisition and application of the core treatment components by the majority of participants. Some participants also experienced an increase in social support, which was associated with characteristics of the treatment structure. Thus, the two most important variables in relation to treatment outcome and evaluation were specific mechanisms of change (i.e., treatment components) and non-specific therapeutic factors (i.e., treatment structure). In addition, treatment outcome was also influenced by participant characteristics. Participants that held unrealistic expectations, were not ready for change, or engaged in limited problem-sharing experienced fewer positive changes over the course of treatment.

published_or_final_version / Nursing Studies / Master / Master of Nursing in Advanced Practice

D.Litt. et Phil. / Within the South African context there seems to be no workable manual-based therapy programme for the treatment of Unipolar Major depression. The need for a workable solution is steadily increasing. This was the aim of this study; to develop a manual driven therapy programme for the treatment of Unipolar Major Depression which is a short term intervention influenced by the Cognitive Behaviourial model, with the inclusion of exercise therapy. The Cognitive Behaviourial model addresses the persons negative cognitions in a structured manner, within the framework of short term therapy. The person is encouraged to become actively involved: helplessness, worthlessness, and powerlessness, among others, are addressed. The approach towards the General Therapy Programme has partly a behaviourial component and partly a cognitive component (Williams, 1992). Past research (Kaplan, Saddock & Grebb, 1994) shows highly successful results achieved by Cognitive Behaviour Therapy. Exercise therapy also addresses the physiological workings of the depressed person (Johnsgard, 1989). Short term therapy is an immediate intervention which lays claim to a higher level of therapeutic activities, along with the identification of a clear focus and the creation of time limitation. There were 34 participants, selected randomly from a population of 85 patients, at TARA, the H. Moross centrum, general practitioners and psychiatrists. Only outpatients were used. The measuring instruments used in this study, were the Hamilton Depression Rating Scale, the Millon's Clinical Multiaxial Inventory II, and the Nowlis Mood Adjective Checklist. The participants were randomly divided into an experimental and control group. The experimental group was subject to a short term Cognitive Behaviourial Intervention, consisting of eight therapy sessions with the goal of decreasing the intensity and occurrence of Unipolar Major Depression. The results of this study, shows an effective decrease in intensity and occurrence of Unipolar Major Depression after the intervention. The influence of the therapy programme on other personality indexes has also become apparent in this study. Cognitive Behaviour Therapy practised on a short term basis, was shown to be an effective intervention, but the impact of other therapeutic models cannot be ignored.

The burden of depression requires modalities other than individual psychotherapy if we are to reduce it. Over the past two decades preventative programs for depression have been developed and refined for different populations. The six years since the last meta-analysis of preventative interventions—inclusive of all program types—have seen a number of new studies. The current study used the greater statistical power provided by these new studies to analyze moderators of, and sub-group differences in, the effect of these interventions on depression. Moreover, this meta-analysis synthesized effect sizes for outcomes other than, but often related to, depression (e.g., anxiety) and for within-group change scores with the goal of better informing program implementation and evaluation. Twenty-nine studies met inclusion criteria and indicated that small, robust effects exist for reductions in depression diagnoses and symptomatology. Significant effects were also observed for anxiety, general health, and social functioning.

The regulation of tryptophan-2,3-dioxygenase (TDO) (EC 1.13.1.12) and, to a lesser extent, pineal indoleamines, both in vitro and in vivo, is examined in this study. Rat liver TDO is a cytosolic enzyme which plays a crucial role in the regulation of circulating tryptophan (TRP) levels. Stimulation of this enzyme by heme enhances the catabolism of TRP, making less TRP available for uptake into the brain and other tissues, and for protein synthesis. At pH 7, the enzyme has an approximate Km of 100μM, is subject to substrate inhibition immediately beyond Sopt([S] at Vmax), and response of the enzyme is cooperative in both uninhibited and inhibited regions. Hill analysis of the uninhibited region reveals a biphasic plot and two classes of binding sites. Negative cooperativity is brought about through deprotonation of the enzyme. Substrate iphibition also occurs at both acidic and basic pH values with concomitant shifts in Sopt. The results obtained indicate that substrate inhibition could be an additional mechanism whereby the flux through the TRP-kynurenine pathway is regulated. TDO is subject to a diurnal rhythm, with peak activity during the pre-dark period and the loweSt activity towards the end of the dark period. It is possible that the enzyme controls the synthesis of the neurotransmitter serotonin (5-HT), and that the circadian rhythm in TDO activity is due to the endogenous rhythm of melatonin (aMT) production by the pineal gland. In the present study, aMT displaces TRP from bovine serum albumin (BSA) in vitro, and it is therefore possible for the indoleamine to regulate the availability of TRP for uptake into the brain for conversion to its derivatives. Chronic intraperitoneal administration of aMT affects physiological hepatic parameters in rats, such as TDO activity and stromal fatty acid composition, whilst no observable effect is demonstrable with respect to protein synthesis, nucleic acid metabolism, membrane fatty acid composition and pineal indole biosynthesis. On the other hand, chronic treatment of rats with antidepressants, the tricyclic desmethylimipramine (DMI) and the selective serotonin reuptake inhibitor (SSRI), fluoxetine, reveals significant negative alterations in TDO concentrations and pineal indole amine synthesis. Combining aMT with any of these two drugs normalises the activity of the hepatic enzyme. DMI is found to be an effective inhibitor of TDO in the micromolar range in vitro, and also affects total enzyme concentrations in vivo. Fluoxetine has no effect on TDO in vitro, but in vivo also reduces total enzyme levels in the liver. However, the SSRI does not affect conjugation between apo- and holoenzyme. Instead, it decreases extant holoenzyme levels. Indoleamine synthesis by the pineal gland, in organ culture, is altered by both antidepressants, although in different ways. DMI increases N-acetylserotonin levels and reduces the output of methoxyindole acetic acid and meth6xytryptophol. Fluoxetine treatment markedly reduces aMT concentrations and also brings about high levels of the 5-HT catabolites, 5-hydroxytryptophol and 5-hydroxyindole acetic acid. Insulin also lowers aMT synthesis significantly in pineal organ cultures, via a mechamsm that involves inhibition of the enzyme, N-acetyl transferase, that regulates aMT synthesis. The effects of insulin on pineal indole metabolism are due to the observation that a carbohydrate rich diet which induces insulin release elevates plasma TRP and brain 5-HT, but has no effect on pineal TRP and indole amine synthesis. It could thus be possible for insulin to have an effect on the pineal, since the latter is outside the blood brain barrier. The finilings of this study support the biogenic amine deficiency hypothesis, implicating some of the major biogenic amines such as noradrenaline (NA), 5-HT and aMT in depression. There is believed to be a deficiency of NA and 5-HT at their respective synapses in the depressed state. The drug DMI could act, firstly, by inhibiting TDO and thus increasing plasma TRP levels, and could, secondly, stimulate NA release and inhibit NA reuptake at the pineal membrane. The combined effect would be to enhance aMT synthesis, with eventual remission. Fluoxetine, on the other hand, appears to utilize a slightly different mode of action to DMI, which seems to focus on the preservation of 5-HT. The fact that aMT counteracts the effects of both antidepressants, and restores the activity of TDO to that of the controls, is also consistent with the observation that the therapeutic action of drugs such as these coincides willi the restoration of normal plasma levels of the neurohormone in depressives. In view of the biogenic amine deficiency hypothesis of depression and the contentious claim that TDO is the major peripheral determinant of brain TRP, brain 5-HT and ultimately aMT, the regulation of TDO is investigated and discussed. The study concludes that TDO activity is regulated by a number of endogenous compounds which are mainly derivatives of TRP, such as aMT and oxidized nicotinamide adenine dinucleotide and exogenous substances, of which DMI and fluoxetine are but two. In addition, modulation of IDO activity in depression appears to be an important aspect of antidepressant action. aMT, the product of the pineal gland, also has the potential to increase plasma TRP and hence forebrain TRP levels, and ultimately 5-HT concentrations, firstly by displacing TRP from serum albumin and secondly by inhibiting TDO.

For over half a century, the monoamine hypothesis has been the dominant theoretical framework guiding depression research and drug development. This hypothesis posits that depression arises from a deficiency in the monoaminergic neurotransmitters serotonin, norepinephrine, and possibly dopamine, and that antidepressants function by increasing extracellular availability of these monoamines in the brain, especially at the synaptic level. It is clear however, that the monoamine hypothesis cannot fully explain either the pathophysiology of depression nor the mechanisms of antidepressant action. Tianeptine is an atypical antidepressant used in Europe to treat patients who respond poorly to selective serotonin reuptake inhibitors (SSRIs). The recent discovery that tianeptine is a mu opioid receptor (MOR) and delta opioid receptor (DOR) agonist has provided a potential avenue for expanding our understanding of antidepressant treatment beyond the monoamine hypothesis. This dissertation aims to understand the neural circuits underlying tianeptine’s antidepressant effects. We first characterized the acute and chronic effects of tianeptine on depressive-like and other opioid-related behaviors in mice, and used genetic and pharmacological models to test whether these behavioral effects are mediated by MOR and/or DOR. We found that acute tianeptine administration produced an antidepressant-like reduction in immobility time in the forced swim test, as well as classic opioid-like effects including analgesia, hypophagia, hyperactivity, and conditioned place preference. These behavioral responses to tianeptine are abolished in MOR knockout (KO) mice and in mice that have been pretreated with an MOR antagonist. By contrast, all responses to tianeptine remained intact in DOR KO mice. Remarkably, unlike other classic opiates such as morphine, chronic tianeptine treatment did not produce tolerance to tianeptine’s analgesic effect, nor naloxone-precipitated withdrawal. The acute behavioral effects of tianeptine (excluding analgesic effects, which were present at 15 minutes, but not 1 hour) were established to occur at 1 hour post-injection and to be largely absent by 3 hours post-injection. Chronically, tianeptine produced an antidepressant effect in corticosterone-treated mice, and prevented the development of restraint-stress-induced depression-like behavior, both in an MOR-dependent manner. Interestingly, tianeptine’s chronic antidepressant-like effects were evident in mice after as little as one week of treatment, rather than several weeks as might be expected for SSRIs. Using tissue-specific MOR knockouts, we further showed that MOR expression on GABAergic cells, specifically somatostatin-positive neurons, is necessary for the acute and chronic antidepressant-like responses to tianeptine. By contrast, tianeptine’s behavioral effects did not require the expression MORs on D1- and parvalbumin-expressing cells, nor the expression of ß-arrestin 2. These experiments also revealed a dissociation between the antidepressant-like phenotype and other opioid-like phenotypes resulting from acute tianeptine administration such as analgesia, conditioned place preference, and hyperlocomotion. Critically, we found that tianeptine’s mechanism of action is distinct from fluoxetine in three important aspects: 1) tianeptine requires MORs but not DORs for its chronic antidepressant-like effect, while fluoxetine is the opposite, 2) unlike fluoxetine, tianeptine does not promote hippocampal neurogenesis, and 3) tianeptine’s effects appear to persist even after serotonin depletion. Taken together, these results suggest a novel entry point for understanding what circuit dysregulations may occur in depression, as well as possible targets for the development of new classes of antidepressant drugs.