The controversy surrounding the use of LSD as an adjunct to psychotherapy for alcoholics in Saskatchewan has not been explored by social or medical historians. From 1950 to 1967, Saskatchewan psychiatrists developed new treatments for chronic alcoholism by using LSD on themselves, on volunteers and finally on patients. Despite early success and praise, the use of LSD in psychotherapy was later condemned by the media, the general public, the medical profession and eventually the federal government and was discontinued after being banned in 1967. The reasons for the ban were far-reaching and diverse. LSD was exploited by the counter-culture for "kicks" and was later abandoned by pharmaceutical companies because of the negative reputation lay-professionals and the media had bestowed upon its therapeutic use. As it turned out, legitimate LSD research became too clouded in controversy to survive the 1960s as researchers failed to convince the masses that the drug did not pose a threat to the well-being of society. In many respects, the LSD controversy can be seen as more of a moral panic than a scientific debate. Nevertheless, the LSD controversy provides a unique and much needed look into the history of medicine from a social perspective, illustrating that social values often have more impact on medical research than empirical validity. As recent evidence suggests, the psychotherapeutic potential of LSD -- as developed by Saskatchewan psychiatrists -- has not been forgotten. Indeed, a renewal of interest in LSD research has surfaced in several U.S. states as American psychiatrists are discovering, once again, that LSD can be a valuable psychiatric research tool. / Arts, Faculty of / History, Department of / Graduate

<p>The development of alcohol use disorder (AUD) is believed to involve functional adaptations in corticostriatal projections which regulate the reinforcing properties of ethanol (EtOH). To further our understanding of how repeated EtOH consumption impacts the corticostriatal circuit, extracellular electrophysiological recordings (local field potentials; LFPs) were gathered from the nucleus accumbens and prefrontal cortex of female and male C57BL/6J mice voluntarily consuming EtOH or water using ‘drinking-in-the-dark’ (DID) procedures. Mice were given 15 consecutive days of two-hours of access to EtOH (20% v/v), three hours into the dark cycle while LFPs were recorded. To determine the impact of repeated EtOH consumption on neural activity between these brain regions, theta phase-locking value (PLV, a measure of synchrony) was calculated. Specifically, theta PLV was calculated during active drinking periods (bouts) and average PLV during the first bout was compared to the last bout to determine within session changes in synchrony. Results indicated significantly lower PLV during the last bout than the first bout. Additionally, longer bouts predicted lower PLV during the last bout, but not the first bout when mice were consuming EtOH. These results may suggest that alcohol intoxication decreases corticostriatal synchrony over a drinking period. Results considering changes in theta power spectral density (PSD) indicated an increase in PSD when mice were given access to water during the typical EtOH access time following the 15-day EtOH drinking history. This effect was not seen when mice were drinking water prior to EtOH access and may be indicative of a successive negative contrast effect. This work identifies unique functional characteristics of corticostriatal communication associated with binge-like EtOH intake and sets the stage for identifying the biological mechanisms subserving them.</p>

Mental illness has been a perplexing mystery for centuries, inciting both fear and stigmatization. Yet, the knowledge that the brain gives rise to the mind transformed the field of psychiatry; biological studies of aberrant human behavior has revealed that mental disorders are rooted in physical abnormalities that may be targeted to alleviate symptoms. Even with recent progress, there remains many open questions, one of which is: how exactly are some individuals more susceptible to developing these disorders than others? Excess, or traumatic, stress can lead to the onset of maladaptive disorders such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). But what if it were possible to prevent these diseases from occurring in the first place? What if there was a prophylactic or vaccine-like approach to increase resilience against environmental stressors? Would we be able to target susceptible populations and administer this prophylactic? In this thesis, I present our work demonstrating the potential for prophylactic pharmaceuticals to enhance stress resilience and protect against stress-induced psychopathology. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been demonstrated to be a viable candidate drug to administer as a prophylactic against stress-induced psychopathology. It was serendipitously discovered to rapidly (in as little as a half hour) and persistently (up to 2 weeks) alleviate depressive symptoms in patients with MDD. Since its discovery as an effective antidepressant, research has been focused on its mechanism of action with the goal of ultimately developing more efficacious, rapid-acting, long-lasting antidepressant drugs. However, in our lab, we made a truly unexpected discovery in 2016, described in Chapter 2: (R,S)-ketamine prevents the development of psychiatric symptoms when administered before a stressor. We found that prophylactic (R,S)-ketamine is effective against behavioral despair and buffers against learned fear in a time- and dose-specific manner, described in Chapter 3. This was the first indication that a drug can be administered before stress to prevent stress-induced psychopathology, opening a novel field of preventative psychopharmaceuticals. Follow-up studies in our and other labs have consistently replicated this effect using different stressors and mouse strains, in rats, and in both males and females. These data demonstrate that (R,S)-ketamine can effectively enhance resilience pre-clinically. To address how (R,S)-ketamine is inducing long-lasting protection, in Chapter 4, I describe a study that used a metabolomics platform to uncover the long-term effects of (R,S)-ketamine in buffering against learned fear. We found that (R,S)-ketamine alters purine and pyrimidine metabolism in brain and, most notably, the periphery. These data suggest the potential to conduct a simple blood test to screen for biomarkers of prophylactic efficacy in the clinic. However, while these data revealed the end-products of therapeutic efficacy, it was unknown what brain mechanisms may mediate such long-lasting protection against a psychological stressor. In a separate study, the ventral CA3 (vCA3) region of the hippocampus was uncovered to be necessary for (R,S)-ketamine’s prophylactic fear buffering effects, and that targeting this region both mimics and occludes its effects. It was then discovered that 1 week after a single administration of (R,S)-ketamine or FENM, AMPA bursts were attenuated in vCA3. These data reveal vCA3 a central node for prophylactic (R,S)-ketamine efficacy. The biggest limitation of these preliminary studies is that they each only assessed changes at single timepoints rather than mapped out what occurs throughout treatment, during stress, and during recall of a stressor. It remained unknown whether (R,S)-ketamine alters the experience or recollection of a stressor to induce long-lasting protection. The next goal was to use in vivo technologies such as 1-photon Ca2+ imaging in freely-moving mice to develop a more thorough understanding of how exactly (R,S)-ketamine is acting on vCA3 to confer its prophylactic fear buffering effects, which is outlined in Chapter 5. Mice were imaged in the ventral hippocampus throughout a prophylactic (R,S)-ketamine administration paradigm. We found that prophylactic (R,S)-ketamine administration buffered against the experience of the stressor specifically in vCA3 and reduced ventral hippocampal correlated network activity to ultimately buffer against learned fear. These data indicate that (R,S)-ketamine actively buffers against learned fear in the ventral hippocampal at the time of stress. The promise of (R,S)-ketamine is that it is also beneficial as a prophylactic in other settings beyond MDD and PTSD, such as in patients with traumatic brain injury (TBI). In Chapter 6, I describe a study that sought to determine whether (R,S)-ketamine can be useful as a prophylactic for TBI-induced neuropsychiatric effects. Here, TBI mice developed fear generalization, or the inability to distinguish between fear-inducing and neutral stimuli. To understand how TBI alters fear memory traces to promote fear generalization, we used the ArcCreERT2 x enhanced yellow fluorescent protein (eYFP) activity-dependent memory tagging strategy developed by Dr. Christine Ann Denny and found that TBI-induced fear generalization is partially mediated by dentate gyrus (DG) memory trace dysregulation. To reverse this fear generalization phenotype, a single administration of (R,S)-ketamine 1 hour after a TBI prevented the fear generalization phenotype. These data reveal the possibility of administering (R,S)-ketamine or other prophylactics in the clinic as part of post-operative care for TBI patients to prevent long-term fear generalization deficits. Altogether, this thesis demonstrates the potential for pharmacotherapies for stress resilience enhancement and reveals potential targets for prophylactic drug development. We have uncovered the long-term metabolomic changes that occur after a single dose of (R,S)-ketamine, revealed a central node for prophylactic efficacy, mapped the dynamic changes that occur throughout treatment, and applied the prophylactic paradigm to a model of TBI to demonstrate the broad range of applications of this approach. This work paves the way for the novel field of preventative psychiatry and opens new avenues to explore ways to reduce the devastating impact of mental illness on individuals and society.

<p>Environmental exposure to lead (Pb) and cannabis use are two of the largest public health issues facing modern society in the United States and around the world. Exposure to Pb in early life has been unequivocally shown to have negative impacts on development, and recent research is mounting showing that it may also predispose individuals for risk of developing substance use disorders (SUD). At the same time, societal and legal attitudes towards cannabis (main psychoactive component delta-9-tetrahydrocannabinol) have been shifting, and many American states have legalized the recreational use of cannabis. It is also the 3^rdmost widely used drug of abuse in the US, and rates of cannabis use disorder are on the rise. This thesis sets out to establish whether there is a link between early life Pbexposure and later THC-related behavior in C57BL6/J mice, as has been demonstrated for other drugs of abuse. The first aim seeks to answer whether Pbexposure affects physiological THC sensitivity (as measured by the cannabinoid-induced tetrad). The secondaimseeks to answer whether Pbexposure affects edible THC self-administration and the development of THC tolerance (also measured by the tetrad).It was hypothesized that Pbexposure would decrease THC sensitivity (Aim 1), would enhance THC self-administration (Aim 2), enhance the development of THC tolerance (Aim 2), and finally that sex-dependent effects of Pb-exposure and THC would be observed (Aims 1 & 2). These hypotheses ended up not being supported, but Aim 1 produced findings indicating that THC sensitivity was increased by Pbexposure, but only in female mice. Future researchwill hopefully be able to fully explore the implications of these findings.</p>

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Dissertation (DSc)-- Stellenbosch University, 2008. / ENGLISH ABSTRACT: The overall aim of these studies was to investigate selected aspects of psychopathology, neurobiological abnormalities and treatment in schizophrenia. The following topics were researched: 1. Psychopathology: We explored the symptom structure of schizophrenia by means of principal components and factor analysis in two separate samples. a. The first study investigated the nature of symptoms in patients with a first-episode of schizophrenia, in a large cohort of patients who were participating in a multinational clinical trial. We compared our findings with similar analyses previously conducted in multi-episode schizophrenia patients. b. We then assessed the influence of culture on the symptom structure of schizophrenia by conducting a principal components and factor analysis of the symptom ratings in a large sample of South African Xhosa patients with schizophrenia, and comparing the results with those in other parts of the world. c. We investigated the occurrence of co-morbid depressive and anxiety symptoms, and their demographic and clinical correlates. The sample for this study comprised acutely psychotic patients who were participants in clinical drug trials conducted at our centre. d. To explore the relationships between obsessive-compulsive disorder and schizophrenia, we conducted a review of the relevant literature. 2. Neurobiological abnormalities: a. We performed a series of studies to investigate disorders of water homeostasis and vasopressin secretion in schizophrenia. To test the hypothesis that acutely psychotic patients have disordered regulation of water homeostasis, we applied a dynamic suppression test - a water loading test, with assessment of excretory capacity (including arginine vasopressin assay) in acutely psychotic patients. To evaluate whether a subset of patients with schizophrenia and co-morbid disordered water homeostasis sustained cerebral damage as a consequence of water intoxication we did the following experiment: We identified a cohort of subjects with schizophrenia and disordered water homeostasis and compared them with patients with schizophrenia without disordered water homeostasis in terms of cerebral ventricular size and cognitive function. To assess the prevalence of disordered water homeostasis in a long-term inpatient sample of psychiatric patients we conducted serum sodium screening tests. Those subjects with dilutional hyponatraemia were then further investigated for dysregulation of water homeostatic mechanisms. b. We studied neurological soft signs in a sample of subjects with first-episode schizophrenia followed up over a two year period. We investigated their occurrence, relationships to psychiatric symptoms and medication effects, their temporal stability and their outcome correlates. We also investigated their potential to predict outcome in schizophrenia 3. Treatment aspects A great deal of our work has focussed on the pharmacological treatment of schizophrenia. The following aspects of treatment are included in this thesis: a. Treatment effects on psychiatric symptoms: i. To assess the effects of ethnicity on treatment outcome in schizophrenia we compared the acute response to antipsychotic treatment in 3 ethnic groups, namely blacks, coloureds and whites. We included patients in this analysis who had participated in clinical trials in our department as well as the Department of Psychiatry in the University of the Free Sate. Patients had been treated under blinded conditions over a 6-week period. ii. After discussions with the late Dr David Horrobin, who had pioneered possible applications of the omega-3 fatty acids in the treatment of various psychiatric disorders, we became interested in further investigating the potential of this group of compounds as an affordable adjunct to treating schizophrenia. We assessed the antipsychotic potential of the omega-3 fatty acid, ethyl-eicosapentaenoic-acid (e-EPA) supplementation versus placebo supplementation in a small sample of subjects with schizophrenia who had been only partially responsive to antipsychotic treatment previously. We also conducted a review of the literature to evaluate the evidence for efficacy for the omega-3 fatty acids in schizophrenia according to published studies. b. Treatment effects on neurological abnormalities: i. In a single-blinded controlled study we compared a new generation antipsychotic to a conventional antipsychotic in the treatment of tardive dyskinesia (TD). This was a long-term (1 yr) study in patients with chronic schizophrenia and established tardive dyskinesia. ii. We also assessed the effect of omega-3 fatty acid (e-EPA) supplementation in treating TD. This was conducted in a larger sample (n=84) of patients with chronic schizophrenia and established TD. The blinded, placebo-controlled phase was 12 weeks. This was followed by an open-label extension for 40 weeks. c. Conventional versus new generation antipsychotic agents. Several evidence-based literature reviews of the efficacy and tolerability of the new generation of antipsychotics compared to the conventional agents were conducted. Some multinational, randomised, controlled clinical trials in which the author was principal investigator, are included in this thesis. Also, studies addressing patients with partial treatment refractoriness are included, as well as studies of the effects of antipsychotics on depressive symptoms, body mass and glycaemic control. Finally, we have included a pharmacoeconomic study comparing a conventional antipsychotic (haloperidol) with a new generation antipsychotic (quetiapine) in partially refractory patients in a South African setting. Findings and conclusions: 1. Psychopathology: Our studies demonstrated that the factor structure for the symptoms of schizophrenia is replicable across samples, and is not greatly influenced by ethnic and cultural factors. However, changes in the factor structures do occur over time. There are symptom domains that are present in first-episode schizophrenia but disappear as a distinct entity as the illness becomes chronic. Particularly, a motor component is evident in untreated patients, but disappears after initiation of treatment. We found that depression and anxiety are common co-morbid symptoms in schizophrenia, and have important clinical and outcome correlates. Depressive symptoms in the acute psychotic phase of schizophrenia are associated with a favourable prognosis and diminish as the symptoms of psychosis improve in response to antipsychotic treatment. However, persistent depressive symptoms are associated with a poorer prognosis, and require additional therapeutic intervention. 2. Neurobiological abnormalities: We investigated the occurrence of disordered water regulation in a population of psychiatric inpatients, and conducted further investigations on those identified, in order to establish mechanisms involved. Polydipsia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) were found to occur in a subset of patients with schizophrenia, and are associated with acute psychosis, as well as with some psychotropic medications. These patients are characterised by more severe cognitive impairment and evidence of cerebral atrophy. The condition can become life-threatening in the presence of other factors impeding water excretion, particularly thiazide diuretics. Neurological soft signs were investigated in a sample of patients with a first-episode of schizophrenia. These soft signs appear to be trait-like (present early in the illness, and stable over time), except for a motor sequencing factor. Patients performing poorly on this latter group of tests have a longer duration of untreated psychosis, and are at significant risk for developing TD. 3. Treatment aspects: Our studies suggest that there are important ethnic differences in antipsychotic treatment response, but that these differences could be explained by a number of environmental and biological factors. As was found with many studies worldwide, we found that the new generation antipsychotics have important efficacy and safety advantages over their predecessors. Risperidone was as effective as haloperidol in first-episode psychosis, but with a more favourable side-effect profile in terms of reduced extrapyramidal symptoms. Quetiapine treatment in partially refractory patients resulted in more responders compared to haloperidol, and fewer extrapyramidal symptoms. However, evidence of a different side-effect profile is emerging. Of particular concern is the finding that some of the new antispychotics cause weight gain, glucose intolerance and dyslipidaemias. We found that one novel antipsychotic, quetiapine, was not associated with significantly more weight gain or disordered glucose metabolism that a conventional agent, haloperidol. The omega-3 fatty acids, particularly EPA may have a role in the treatment of various psychiatric disorders. Our studies provided mixed results – the first found a significant beneficial effect on psychotic symptoms and dyskinesia scores for EPA supplementation, while the second failed to demonstrate a beneficial effect on TD or psychotic symptoms. We explored the early treatment response in first-episode psychosis and found, unlike that reported in multi-episode patients, some patients took a long time to respond. We also found that early treatment response was a significant predictor of later remission, as was duration of untreated psychosis, educational level and baseline excitement factor scores. Finally, our pharmacoeconomic study conducted for South African circumstances in patients with a partial response to conventional antipsychotic treatment showed cost-neutrality or cost-benefits for quetiapine compared with haloperidol treatment for direct costs. / AFRIKAANSE OPSOMMING: Die oorkoepelende doel van hierdie studies was om geselekteerde aspekte van psigopatologie, neurobiologiese abnormaliteite en behandeling in skisofrenie te ondersoek. Die volgende onderwerpe is nagevors: 4. Psigopatologie: Ons het die simptoomstruktuur van skisofrenie ondersoek deur middel van hoofkomponent- en faktoranalise in twee aparte steekproewe. a. Die eerste studie het die aard van simptome in pasiënte, met ʼn eerste-episode van skisofrenie, ondersoek in ʼn groot kohort van pasiënte wat deelgeneem het aan ʼn multi-nasionale kliniese proefneming. Ons het ons bevindinge vergelyk met soortgelyke analises wat voorheen gedoen is in multi-eposode skisofrenie pasiënte. b. Hierna het ons die invloed van kultuur op die simptoom struktuur van skisofrenie geassesseer deur ʼn hoofkomponent- en faktoranalise van die simptoomtellings uit te voer in ʼn groot steekproef van Suid-Afrikaanse Xhosa pasiënte met skisofrenie en die resultate te vergelyk met bevindinge in ander dele van die wêreld. c. Ons het die voorkoms van ko-morbiede depressiewe en angssimptome ondersoek, asook hul demografiese en kliniese korrelate. Die steekproef vir hierdie studie het bestaan uit akute psigotiese pasiënte wat deelnemers was in ʼn kliniese geneesmiddel proef wat uitgevoer is by ons sentrum. d. Om die verband tussen obsessief-kompulsiewe steurnis en skisofrenie te verken, het ons ʼn oorsig van die relevante literatuur gedoen. 5. Neurobiologiese abnormaliteite: a. Ons het ʼn reeks studies uitgevoer om steurnisse in water homeostase en vasopressien sekresie in skisofrenie te ondersoek. Om die hipotese dat akute psigotiese pasiënte versteurde regulering van water homeostase het te ondersoek, het ons ʼn dinamiese onderdrukkingstoets toegepas – ʼn water ladingstoets, met assessering van ekskresiekapasiteit (insluitend arginien vasopressien essai) in akute psigotiese pasiënte. Om te evalueer of ʼn onderafdeling van skisofrenie pasiënte met ko-morbiede versteurde water homeostase serebrale skade opgedoen het as gevolg van water intoksikasie, het ons die volgende eksperiment uitgevoer: Ons het ʼn kohort deelnemers met skisofrenie en versteurde water homeostase geïdentifiseer en hulle vergelyk met skisofrenie pasiënte sonder versteurde water homeostase in terme van serebrale ventrikulêre grootte en kognitiewe funksionering. Om die voorkoms van versteurde water homeostase in ʼn langtermyn binne-pasiënt steekproef van psigiatriese pasiënte te bepaal, het ons serum natrium siftingstoetse uitgevoer. Deelnemers met hiponatremie is hierna verder ondersoek vir disregulering van water homeostatiese meganismes. b. Ons het neurologiese sagte tekens in ʼn steekproef van deelnemers met eersteepisode skisofrenie bestudeer en opgevolg oor ʼn twee jaar tydperk. Ons het hulle voorkoms, verwantskappe met psigiatriese simptome en medikasie effekte, hulle temporale stabiliteit en hul uitkoms korrelate ondersoek. Ons het ook hulle potensiaal om die uitkoms in skisofrenie te voorspel, ondersoek. 6. Behandelings aspekte ʼn Groot meerderheid van ons werk het gefokus op die farmakologiese behandeling van skisofrenie. Die volgende aspekte van behandeling is ingesluit in hierdie tesis: a. Behandelingseffekte op psigiatriese simptome: i. Om die effek van etnisiteit op behandelingsuitkoms in skisofrenie te assesseer, het ons die akute respons op anti-psigotiese behandeling in 3 etniese groepe vergelyk, naamlik swart, gekleurd, en wit. Ons het pasiënte wat deelgeneem het aan kliniese proefnemings in ons departement sowel as die Departement Psigiatrie van die Universiteit van die Vrystaan ingesluit in hierdie analise. Pasiënte is behadel onder geblinde toestande oor ʼn tydperk van 6 weke. ii. Na besprekings met wyle Dr David Horrobin, wie die moontlike toepassings van omega-3 vetsure in die behandeling van verskeie psigiatreise steurnisse gepionier het, het ons begin belangstel in verdere ondersoek na die potensiaal van hierdie groep samestellings as ʼn bekostigbare toevoeging in die behandeling van skisofrenie. Ons het die anti-psigotiese potensiaal van die omega-3 vetsuur, etieleikosapentanoësuur (e-EPA) supplementasie versus plasebo supplementasie ondersoek in ʼn klein steekproef van deelnemers met skisofrenie wat slegs gedeeltelik responsief was op anti-psigotiese behandeling in die verlede. Ons het ook ʼn literatuuroorsig gedoen om die bewyse vir die effektiwiteit vir die omega-3 vetsure in skisofrenie te evalueer volgens gepubliseerde studies. b. Behandelingseffekte op neurologiese abnormaliteite: i. In ʼn enkelblinde kontrole studie het ons ʼn nuwe generasie anti-psigotiese medikasie vergelyk met ʼn konvensionele anti-psigotiese medikasie in die behandeling van tardiewe diskinesie (TD). Hierdie was ʼn langtermyn (1- jaar) studie in pasiënte met chroniese skisofrenie en vasgestelde TD. ii. Ons het ook die effek van omega-3 vetsuur (e-EPA) suplementasie geassesseer in die behandeling van TD. Dit was gedoen in ʼn groter steekproef (n=84) van pasiënte met chroniese skisofrenie en vasgestelde TD. Die blinde, placebo kontrole fase was 12 weke. Dit is gevolg deur ʼn nie-geblinde ekstensie vir 40 weke. c. Konvensionele versus nuwe generasie anti-psigotiese agente. Verskeie bewys-gebaseerde literatuuroorsigte oor die effektiwiteit en toleransie van die nuwe generasie anti-psigotiese agente in vergelyking met die konvensionele agente, is gedoen. Sommige multi-nasionale, ewekansige, kontole kliniese proefnemings waarin die outeur die hoofnavorser was, is ingesluit in hierdie tesis. Verder, studies wat die pasiënte met gedeeltelike behandelingsweerstandigheid aanspreek, is ingesluit, sowel as studies oor die effekte van anti-psigotiese agente op depressiewe simptome, liggaamsmassa en glisemiese kontrole. Laastens, het ons a farmakoekonomiese studie ingesluit wat die konvensionele anti-psigotiese behandeling (haloperidol) met ʼn nuwe generasie anti-psigotiese behandeling (quetiapien) in gedeeltelik weerstandige pasiënte in ʼn Suid-Afrikaanse ligging vergelyk. Bevindinge en gevolgtrekkings: 4. Psigopatologie: Ons studies het gedemonstreer dat die faktor struktuur vir die simptome van skisofrenie herhaalbaar is oor steekproewe, en dat dit nie grootliks beïnvloed word deur etnisiteit en kulturele faktore nie. Veranderinge vind egter in die faktor strukture wel plaas met verloop van tyd. Daar is simptoom domeine wat teenwoordig is in eerste-episode skisofrenie, maar verdwyn as ʼn afsonderlike entiteit soos wat die toestand chronies word. Spesifiek, ʼn motoriese komponent is duidelik in onbehandelde pasiënte, maar verdwyn na die aanvang van behandeling. Ons het gevind dat depressie en angs algemene ko-morbiede simptome in skisofrenie is en het belangrike kliniese en uitkoms korrelate. Depressiewe simptome in die akute psigotiese fase van skisofrenie word geassosieer met ʼn gunstige prognose en verminder soos wat die simptome van psigose verbeter in repons op anti-psigotiese behandeling. Egter, volgehoue depressiewe simptome word geassosieer met ʼn swakker prognose en benodig addisionele terepeutiese intervensie. 5. Neurobiologiese abnormaliteite: Ons het die voorkoms van versteurde water regulering ondersoek in ʼn populasie van psigiatriese binne-pasiënte en verdere ondersoek ingestel op dié wie geïdentifiseer is, om die betrokke meganismes vas te stel. Polidipsie en en die sindroom van onvoldoende antidiuretiese hormoon sekresie (SIADH) is gevind om voor te kom in ʼn onderafdeling van pasiënte met skisofrenie, en word geassosieer met akute psigose sowel as met somige psigotropiese medikasie. Hierdie pasiënte word gekenmerk deur meer ernstige kognitiewe beperking en bewyse van serebrale atrofie. Die toestand kan lewensbedreigend raak in die teenwoordigheid van ander faktore wat water ekskresie hinder, veral tiasied diuretikums. Neurologiese sagte tekens is ondersoek in ʼn steekproef van pasiënte met eerste-episode skisofrenie. Hierdie sagte tekens blyk om kenmerkend (teenwoordig vroeg in die siekte, en stabiel oor tyd) te wees, behalwe vir ʼn motoriese volgorde faktor. Pasiënte wat swak vaar op die laasgenoemde groep toetse, het ʼn langer durasie van onbehandelde psigose, en het ʼn beduidende risko om TD te ontwikkel. 6. Behandeling aspekte: Ons studies stel voor dat daar ʼn belangrigke etniese verskil is in anti-psigotiese behandelingsrespons, maar dat hierdie verskille verduidelik kan word deur ʼn aantal omgewings- en biologiese faktore. Soos wat gevind was vir verskeie studies wêreldwyd, het ons gevind dat die nuwe generasie anti-psigotiese agente belangrike effektiwiteit- en veiligheidsvoordele het bo hulle voorgangers. Risperidoon was net so effektief as haloperidol in eerste-episode psigose, maar met ʼn meer gunstige newe-effkte profiel in terme van verminderde ekstrapirimidale simptome. Quetiapien behandeling in veral refraktêre pasiënte het gelei tot meer respondeerders vergeleke met haloperidol, en minder ekstra pirimidale simptome. Alhoewel, bewyse van ʼn verskillende newe-effekte profiel is besig om na vore te kom. Van spesifieke belang is die bevinding dat sommige van die nuwe anti-psigotiese agente gewigstoename, glukose intoleransie en dyslipidemie veroorsaak. Ons het gevind dat een nuwe anti-psigotiese agent, quetiapien, nie geassosieer was met enige beduidende meer gewigstoename of versteurde glukose metabolisme as ʼn konvensionele agent, haloperidol, nie. Die omega-3 vetsure, spesifiek EPA mag moontlik ʼn rol in die behandeling van verskeie psigiatriese versteurings hê. Ons studies het gemengde resultate voorsien – die eerste het ʼn beduidende voordelige effek op psigotiese simptome en diskinesie tellings vir EPA supplementasie gevind, terwyl die tweede nie ʼn voordelige effek op TD of psigotiese simptome gevind het nie. Ons het die vroeë behandelingsrespons ondersoek in eersteepisode pasiënte en het gevind, in teenstelling met dit wat gerapporteer word in multi-episode pasiënte, dat sommige pasiënte ʼn lang tyd geneem het om te reaggeer. Ons het ook gevind dat vroeë behandelingsrespons ʼn beduidende voorspeller was van latere remissie, so ook die durasie van onbehandelde psigose, opvoedingspeil, en basisvlak opwindings-faktor tellings. Laastens het ons farma-ekonomiese studie, wat uitgevoer is vir Suid-Afrikaanse omstandighede in pasiënte met ʼn gedeeltelike repons op konvensionele anti-psigotiese behandeling, koste-neutraliteit of koste-voordele aangetoon vir quetiapien vergeleke met haloperidol behandeling vir direkte onkostes.

Patients with both depression and anxiety show an increased tendency to deploy attention towards negative information. Cognitive models of the illnesses predict that these negative attentional biases are causally related to the symptoms of the disorders. Consistent with this, modifying attentional bias using either antidepressant medication or simple, computer based training tasks has previously been associated with altered symptomatology in both non-clinical and clinical populations. The current thesis aimed to investigate the mechanisms by which attentional bias training tasks alter attention. The investigations were conducted within an experimental neuroscience framework which has previously been successfully deployed in studies of antidepressant medication. The thesis then sought to use these initial results to improve the basic understanding of attentional control processes and, ultimately, guide the development of novel treatment strategies. The initial studies of the thesis characterised the behavioural and neural effects of attentional bias training. Behaviourally, a high degree of generalisation of the training effect was found across a range of emotional stimuli. Neurally, training was found to alter activity in a network of prefrontal regions known to be involved in the control of attention. Further analysis, utilising a computational learning model, suggested that the attentional control systems identified in this study could be understood in terms of expectation based processes. These studies therefore indicated that, in contrast to the predominately limbic effects of antidepressant medication, training initially altered the response of frontal control circuitry. The later studies of the thesis investigated possible strategies for extending the use of attentional bias training. Firstly, combining training with antidepressant medication was found to produce an interference effect on emotional memory suggesting that administering both interventions concurrently is likely to erode their cognitive impact. Lastly, attentional bias training was found not to alter attention in patients with bipolar disorder, with the results of the study indicating that standard assessments of attentional bias in this clinical population are likely to be unreliable. Overall, these studies indicate that attentional bias training may be used to alter the top-down control of attention to emotional information and suggest that such effects may interfere with the bottom-up effects of antidepressant drugs. More generally the work demonstrates the utility of using a cognitive-neuroscientific framework to explore the mechanisms and impact of novel therapeutic strategies.

Depression in adolescence is a major health problem, associated with poor psychological function and key risk factors both for later illness and suicidal behaviours. The antidepressant fluoxetine is commonly used in this population and it is shown to have a favourable benefit-to-risk profile. However, controversy still exists about the use of antidepressants in young people and there is little research focusing on underlying mechanisms of wanted and unwanted actions in this group. This doctoral thesis aims to investigate, for the first time, the acute effects of fluoxetine on emotional processing, using a combination of behavioural and neuroimaging techniques. The aim is to achieve a greater understanding of the mechanisms underlying fluoxetine use in depressed adolescents, in light of differences seen in their clinical presentation and response to antidepressant drugs. In the first study (Chapter Two), a single dose of fluoxetine was shown to decrease the recognition of anger in a sample of young adult volunteers, an effect not previously seen in acute studies of older participants. This effect may be particularly relevant for the treatment of adolescent depression, in which symptoms of anger and irritability are often prominent. Beyond this, fluoxetine was shown to increase the recognition of positive vs. negative facial information, and also exerted an anxiolytic-like influence, eliminating the emotion-potentiated startle effect. However, no influence was seen in measures of attentional vigilance to threat. In an attempt to overcome methodological limitations of this study, a paradigm was developed that is particularly sensitive to the detection of automatic biases towards threatening information (Chapter Three). Chapter Four describes a neuroimaging study with depressed adolescents, in which a single dose of fluoxetine was found to reduce amygdala activity in response to anger. Early changes in amygdala activity to fear correlated with decreased symptoms of anxiety and depression in the first 7-10 days of treatment. Chapter Five explores the effects of acute fluoxetine in a sample of high trait anger males. This study replicated the finding that fluoxetine acts to increase the recognition of positive information, whilst showing preliminary evidence for a reduction in attentional vigilance to angry faces. Overall, fluoxetine was found to decrease the processing of anger across studies. This effect was seen alongside a broader influence on positive vs. negative information and anxiolytic-like properties. Together, these results indicate that fluoxetine has direct effects on processes that are especially relevant to adolescent depression and suggest a potential cognitive mechanism for the efficacy of this particular antidepressant in adolescent patients.

3,4-methlenedioxymethamphetamine (MDMA), the main constituent of Ecstasy, is a ring-substituted amphetamine commonly abused in recreational users. High doses of MDMA determined by allometric scaling produce serotonin (5-HT) axon deneveration. Studies suggest that this interspecies scaling does not reflect human use. An 'effects' scale comparing similar behavioral and physiological effects between species has been postulated as more accurate for translational studies. Experiment 1 examined the effects of MDMA on serotonergic forebrain innervation using immunohistochemical labeling targeting the serotonin transporter protein (SERT). Experiments 2 and 3 examined low and high doses of MDMA on spatial memory, prefrontal functioning, and serotonergic neurotoxicity using 'effects' scaling. Long Evans rats were given MDMA regimens of: chronic low dose (daily injections of 1.5 mg/kg for 10 days); binge low dose (2 days of 4 x 1.5 mg/kg spaced 2 hours apart), binge high dose (2 x 7.5 mg/kg sp aced 2 hours apart). Acquisition, retention, and spatial reversal (SR) were measured in a water maze task. A 2.0 mg/kg MDMA drug challenge was then given prior to a serial spatial reversal (SSR) task to assess performance while under the effect of the drug. Attentional set shifting and behavioral flexibility were assessed in an intradimensional extradimensionl (IED) task using odor/texture discriminations. MDMA chronic and binge low doses did not impair water maze or IED performance and produced no reductions in SERT expression. MDMA binge high dose resulted in significant reductions of SERT density in the prefrontal cortex, striatum, cortical mantle, hippocampus, amygdala, and many thalamic nuclei. Despite prominent 5-HT denervation, water maze performance was unaffected. Selective impairment in behavioral flexibility on the IED test was found. / This suggests that low doses of MDMA do not produce long-term deleterious effects. But, high doses of MDMA taken in 'binges' produces widespread loss of forebrain SERT fiber innervation and significant impairments in reversal learning, while leaving attentional set shifting and spatial navigation unscathed. / by Stephanie Brooke Linley. / Thesis (Ph.D.)--Florida Atlantic University, 2011. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2011. Mode of access: World Wide Web.