The pathophysiology, etiology, and treatment of schizophrenia remain elusive, but research is closing the gap. Schizophrenia globally affects less than 1% of the population and presents with positive, negative, and cognitive symptoms. As treatment for schizophrenia is not completely and meaningfully effective at treating all of the symptoms, without eliciting side effects, the current thesis aimed to evaluate a new drug candidate. PAOPA is a novel allosteric modulator that increases dopamine binding to the dopamine D2 receptor. It has previously shown positive findings in preventing and reversing behaviours proposed to model phenotypes of schizophrenia. However, it has not yet been tested to improve cognitive deficits in animal models, nor has its effects on other animals models been investigated. Lastly, its mechanism of action has not yet been comprehensively answered. In three separate studies, PAOPA was tested on ameliorating attentional deficits using the 5-choice serial reaction time task in an amphetamine model, deficits in novel objection recognition memory, sensorimotor gating, social interaction, and locomotor activity using a PCP model, and its effects on proteins regulating G protein-coupled receptors (GRK2 and arrestin-3), downstream signalling (ERK1 and ERK2), and synaptic vesicular control (synapsin II) were investigated. Although the sample sizes were too small to draw valid interpretations, the results suggested that PAOPA partially attenuated deficits in attention, novel object recognition memory, social interaction, sensorimotor gating, but not locomotor. Furthermore PAOPA increased the protein expression of GRK2, arrestin-3, ERK1 and 2, and synapsin IIa in the medial prefrontal cortex, striatum, and the nucleus accumbens. The results suggest that PAOPA influences the dopaminergic system in the striatum to change behaviour via receptor internalization and possibly downstream signalling. The present studies illuminate new insights, and point to future explorations for the potential development of PAOPA as a therapeutic for schizophrenia. / Thesis / Master of Science (MSc)

Antipsychotic medications are highly effective in the treatment of patients experiencing first-episode psychosis. However, some patients do not respond to the first antipsychotic medication they are given, and may require trials of several drugs before an effective treatment is found. While antipsychotics may take months to achieve their full effect, recent evidence suggests that it is possible to predict whether a patient will respond to a particular drug by assessing early response after as little as 2 weeks of treatment. Assessing early antipsychotic response has the potential to improve treatment strategies for psychotic patients, but there is still a great deal of uncertainty about what early response can and cannot predict, and how the predictive value of early response differs among drugs and patient populations. The work presented in this thesis addresses some of the most pressing questions about early antipsychotic response in several samples of antipsychotic-naive patients with first-episode psychosis. This work demonstrates that: (1) the appropriate time point at which to assess early response differs between antipsychotic drugs; (2) early improvement in depressive and manic symptoms predicts treatment outcome, while early improvement in anxiety symptoms may not; (3) strong early response is associated with decreased rates of extrapyramidal side-effects; (4) early antipsychotic response can predict long-term treatment outcome at least 2 years after treatment initiation; (5) the appropriate time point at which to assess early response differs in patients who receive antidepressant treatment in addition to antipsychotic treatment; (6) patients with a poor early response may benefit from being switched to another antipsychotic, particularly one with a distinct receptor binding profile. These results highlight several weaknesses of the current literature, suggesting that early antipsychotic response should be assessed differently depending on the psychiatric symptom profile of each patient and the specific medications that are being used. However, the data presented here also emphasize the potential therapeutic value of assessing early response. The ability of early response to predict treatment outcome appears to be even greater than previously thought, and understanding how to appropriately use this important assessment to guide treatment strategies may improve the efficiency and efficacy of treatment for psychotic patients. / Thesis / Doctor of Philosophy (PhD)

Thesis (Ph. D.)--Memorial University of Newfoundland, 2005. / Restricted until May 2006. Includes bibliographical references (leaves 187-207).

<p>Genetically determined differences in drug metabolism and disposition and drug targets play a pivotal role in the interindividual variability in the clinical outcome of antipsychotic treatment. The aim of this thesis was to study the impact of polymorphisms in genes involved in the pharmacokinetics and pharmacodynamics of antipsychotics, with special focus on their extrapyramidal and metabolic adverse effects. </p><p>Polymorphisms in serotonin 2A and 2C receptor coding genes (<i>HTR2A</i> and <i>HTR2C</i>) were found to be associated with the risk to develop extrapyramidal side effects (EPS) in patients on short term perphenazine treatment. A further study in a larger group of patients on long term treatment with various classical antipsychotics confirmed the association between occurrence of EPS and <i>HTR2C</i> polymorphisms. In another study, dose corrected steady state serum clozapine and N-desmethylclozapine concentrations (C/D) and insulin elevation during clozapine therapy were found to correlate with <i>CYP1A2</i> but not with <i>CYP2D6</i> polymorphisms. Furthermore, <i>HTR2C</i> and <i>HTR2A</i> polymorphisms were found to have significant influences on BMI and C-peptide levels in patients treated with olanzapine and clozapine. Evaluation of the impact of polymorphisms in genes encoding CYP3A4, CYP3A5 and P-glycoprotein (<i>ABCB1</i>) in addition to CYP2D6 on the steady state plasma levels of risperidone, 9-hydroxyrisperidone and their active moiety revealed a significant influence of <i>ABCB1 </i>genotype on 9-hydroxyrisperidone and active moiety C/Ds, while <i>CYP2D6</i> genotype associated with risperidone C/Ds but not with 9-hydroxyrisperidone or active moiety C/D. </p><p>We have shown that polymorphisms in genes involved in the pharmacokinetics and the pharmacodynamics of antipsychotic drugs play a role in the occurrence of adverse effects, both EPS and metabolic disturbances, induced by antipsychotic treatment. Genotyping for <i>HTR2A</i>, <i>HTR2C</i>, <i>CYP1A2</i>, <i>CYP2D6</i> and <i>ABCB1</i> polymorphisms may therefore potentially provide useful information to identify patients at higher risk to develop EPS or metabolic adverse during schizophrenia treatment with antipsychotic drugs.</p>

The treatment of schizophrenia today consists of a multi-component system of services. Mental health professionals generally agree that anti-psychotic medications are an essential treatment for schizophrenia. However, adherence to medication regimens by patients with schizophrenia is notoriously poor. To identify correlates and predictors of medication compliance, the Schedule for Affective Disorders and Schizophrenia (SADS), a semi-structured diagnostic interview, was administered to 90 outpatients with schizophrenia. The results suggest that there are specific variables (i.e., mood symptoms, psychotic symptoms, and socio-demographic variables) that predict medication compliance. In addition, the confirmation of these variables was effective (90.0%) at identifying non-compliant patients. The results suggest that schizophrenia is a complex disorder composed of heterogeneous symptoms. However, a specific group of symptoms is proposed which may provide a screening measure for predicting patients who are likely to be non-compliant with their medications.

G protein-coupled receptors (GPCRs) are seven-transmembrane domain receptors that sense extracellular signal and activate intracellular signaling pathways. The serotonin 5HT2A receptor (or 2AR) is one of the GPCRs coupled to Gq proteins, activating PLC and hydrolyzing PIP2. This hydrolysis causes a diffusion of bound PIP2 away from the channel binding site resulting in G protein-gated inwardly rectifying K+ channel (GIRK) inhibition and a downstream stimulation of Ca2+ release from endoplasmic reticulum stores. Previous experiments have demonstrated that the serotonin 5HTA receptor is a target of serotonergic psychedelic drugs, such as LSD, and partially mediates the action of many atypical antipsychotic drugs. However, the portion responsible for the functional activity and response of these drugs is unknown. The purpose of this study was to functionally characterize four deconstructed analogs of risperidone, an atypical antipsychotic agent, using two assays: by application to 5HT2A receptors in Xenopus oocytes and by calcium epifluorescence imaging in a HEK293 cell line stably expressing 2AR. Our experiments revealed that two analogs, RHV-006 and RHV-008, are partial agonists by themselves and greatly antagonize the effects of serotonin. RHV-006 and RHV-008 contain the piperidine and benzisoxizole ring systems of risperidone. RHV-023 and RHV-026, on the other hand, are more efficacious agonists than RHV-006 and RHV-008 but display a non-antagonistic effect with serotonin. RHV-023 and RHV-026 contain both the piperidine and benzisoxizole ring systems in addition to part of the diazabicyclo ring, thus containing more of risperidone’s structure than RHV-006 and RHV-008.

INTRODUÇÃO: Considera-se a clozapina como padrão-ouro para o tratamento de pacientes com esquizofrenia refratária, com base principalmente em sua eficácia comprovadamente superior em relação aos antipsicóticos típicos. No entanto, os dados acerca do uso de outros antipsicóticos atípicos ainda são escassos ou divergentes. Tendo em vista que o uso de clozapina está associado a várias limitações, existe uma necessidade não atendida de alternativas terapêuticas eficazes e seguras para a esquizofrenia refratária. MÉTODOS: Foi realizada uma revisão sistemática de estudos controlados e randomizados (ECRs), comparando clozapina aos outros antipsicóticos atípicos, em pacientes com esquizofrenia refratária. Foram realizadas metanálises avaliando a eficácia das intervenções, medida por meio de escalas de avaliação de sintomas psicóticos. A resposta ao tratamento foi medida por meio da porcentagem de respondedores ou pela mudança média ou valores finais dos escores das escalas. Quando possível, foram realizadas metanálises da comparação entre clozapina e outro antipsicótico atípico específico. Os tamanhos de efeito foram dados pelo risco relativo (RR) ou pela diferença entre médias (DM), ponderada ou padronizada, acompanhados dos respectivos intervalos de confiança de 95%. As metanálises foram realizadas utilizando-se o modelo de efeitos fixos, ou aleatórios, no caso de haver heterogeneidade entre os estudos. Foram realizadas análises de sensibilidade, excluindo-se estudos que haviam incluído pacientes intolerantes junto à população refratária. RESULTADOS: Onze ECRs foram incluídos, representando 1182 pacientes, com 12 comparações entre clozapina e antipsicóticos atípicos: quatro com risperidona, um com ziprasidona e sete com olanzapina. Considerados como um grupo, não foi possível determinar diferenças no tamanho de efeito entre a clozapina e os outros antipsicóticos atípicos em nenhum tipo de medida geral de sintomas psicóticos. A metanálise que combinou as mudanças médias e os valores finais da PANSS e da BPRS apresentou uma diferença de médias de 0,00 (IC95%= -0,12, 011). Foi observada superioridade marginal dos antipsicóticos atípicos para sintomas negativos, medidos pelos valores finais da PANSS (DM= -1,96, IC95%= -3,44, -0,48). Foi observado que os estudos que compararam a clozapina à olanzapina tiveram doses finais médias altas de olanzapina (médias de 17,2 mg/d a 33,6 mg/d), o que pode ter influenciado nos resultados.CONCLUSÕES: Os antipsicóticos atípicos, particularmente a olanzapina em doses altas, podem representar uma alternativa de tratamento para pacientes com esquizofrenia refratária / BACKGROUND: Clozapine is considered as the gold standard for the treatment of patients with refractory schizophrenia, based upon its well established superior efficacy against typical antipsychotics. Nevertheless, data on other atypical antipsychotics are still scarce or divergent for this population. Considering that clozapine use is associated to several caveats, there is an unmet need for safe and efficacious alternative therapeutic approaches for refractory schizophrenia. METHODS: It was conducted a systematic review of randomized clinical trials (RCTs) comparing clozapine to other atypical antipsychotics in patients with refractory schizophrenia. Metanalyses assessing the efficacy of interventions were performed. Efficacy was measured by psychotic symptoms scales. Response to treatment was measured by the percentage of responders or by mean change or endpoints values of such scales. Whenever possible, metanalyses comparing clozapine to other specific atypical antipsychotic were performed. Effect sizes were shown as relative risks (RR) or weighted or standardized mean differences (MD), with 95% confidence intervals. The fixed effect model was used, unless studies were considered heterogeneous. Sensivity analyses were performed with the exclusion of studies which had included intolerant patients along with true refractory patients. RESULTS: Eleven RCTs were included, figuring 1182 patients, with 12 comparisons between clozapine and other atypical antipsychotics: four with risperidone, one with ziprasidone, and seven with olanzapine. Considered as a group, it was not possible to determine different effect sizes between atypical antipsychotics and clozapine for any general measure of psychotic symptoms. Pooled mean change and endpoint PANSS and BPRS scores metanalysis presented a zero mean difference (MD=0.00, CI95%= -0.12, 0.11). Atypical antipsychotics were shown to be marginally superior to clozapine for negative symptoms, measured by PANSS negative symptoms subscale endpoint scores (DM= 1.96, CI95%= -3.44, -0.48). Studies which compared clozapine to olanzapine had relatively high mean final olanzapine doses (means ranging from 17.2 mg/d to 33.6 mg/d), what might have influenced the results. CONCLUSIONS: Atypical antipsychotics, particularly high dose olanzapine, can represent an alternative therapeutic approach to patients with refractory schizophrenia

Aggression and violence pose a significant public health concern to society. Aggression is a highly conserved behavior that shares common biological correlates across species. While aggression developed as an evolutionary adaptation to competition, its untimely and uncontrolled expression is maladaptive and presents itself in a number of neuropsychiatric disorders. A mechanistic hypothesis for pathological aggression links aberrant behavior with heightened dopamine function. However, while dopamine hyper-activity is a neural correlate of aggression, the developmental aspects and circuit level contributions of dopaminergic signaling have not been elucidated. In this dissertation, I aim to address these questions regarding the specifics of dopamine function in a murine model of aggressive behavior. In chapter I, I provide a review of the literature that describes the current state of research on aggression. I describe the background elements that lay the foundation for experimental questions and original data presented in later chapters. I introduce, in detail, published studies that describe the clinical manifestation and epidemiological spread, the dominant categories, the anatomy and physiology, and the pharmacology of aggression, with a particular emphasis on the dopaminergic system. Finally, I describe instances of genetic and environmental risk factors impacting aggression, concluding with studies revealing an important role for interactions among genetics, environmental factors, and age in the development of aggression. In chapter II, I investigate the developmental origins of aggression by examining sensitive periods during which perturbations to the dopaminergic system impact adult aggressive behavior. Previous work in our laboratory has concluded that periadolescent (postnatal days 22-41) elevation in dopamine, via transient dopamine transporter blockade, leads to increased adult aggression and heightened response to amphetamine. I expanded on these findings by temporally refining the opening and closing of this window of sensitivity, specifically to postnatal days 32 to 41, during which increases in dopaminergic tone increase adult aggression and behavioral sensitivity to psychostimulants. The potentiated response to amphetamine indicated to us a state of altered dopaminergic physiology. We next validated this hypothesis and found increased firing rate (in vitro), and increased bursting and population activity (in vivo) at baseline. These data indicate that elevated periadolescent dopamine impacts maturation of the dopamine system, leading to a hyper-active dopaminergic and aggressive predisposition. In conclusion, this chapter introduces a developmental component to the hyper-dopaminergic model of aggression. In chapter III, I report a series of experiments exploring the direct and causal involvement of dopamine in driving aggression. While dopamine hyper-activity is a neural correlate of aggression, the precise brain circuits involved have not been elucidated. Using optogenetics, I established a causal role for the ventral tegmental area (a key source of dopamine) in aggression modulation. I further advanced this finding by demonstrating that the modulatory role of dopamine, is population- and projection-specific. I found that activity of ventral tegmental area, but not substantia nigra, dopamine neurons promotes aggression. Furthermore, controlled stimulation of ventral tegmental area dopaminergic terminals in the lateral septum, but not the nucleus accumbens, mediates increased aggression. I selectively traced connectivity between the lateral septum and the ventral tegmental area using a Cre-driven, population-specific viral vector. I used this virus to show that anatomically distinct clusters of ventral tegmental area dopamine cells send projections to the lateral septum and the nucleus accumbens, thereby dissociating the two target sites both behaviorally and anatomically. Furthermore, I found that while local dopamine release in the lateral septum increases aggression, it has no bearing on reward behaviors thus indicating a stronger association with impulsive, and not motivated, aggression. In conclusion, this chapter offers causal evidence for dopamine’s role in modulating impulsive aggression by identifying a distinct pathway from the ventral tegmental area to the lateral septum that controls aggression. In the work described in chapter IV, my aim was to determine the mechanism underlying ventral tegmental area to lateral septum dopamine-mediated aggression. I first characterized the expression of dopamine receptors in the lateral septum and found that D2 receptors heavily colocalize with the dominant population of neurons in the lateral septum, i.e. GABAergic cells. Moreover, the D2 receptors are perfectly aligned with incoming dopamine afferents. Next we investigated, in acute brain slices, how D2 signaling affects lateral septum function. We revealed that activating D2 receptors hyperpolarizes D2-expressing lateral septum neurons. This effect was abolished with bath application of the D2 receptor antagonist, sulpiride. We validated the functional involvement of post-synaptic D2 signaling in a behavioral test, and found that the aggression induced by direct terminal release of dopamine at the lateral septum is reversed by acutely blocking local D2 receptor signaling. In conclusion, this chapter demonstrates that the ventral tegmental area to lateral septum dopamine pathway, via D2-mediated inhibition of GABAergic lateral septum neurons, is necessary to drive ventral tegmental area-triggered aggression. In chapter V, I engage in a general discussion addressing how the findings from each chapter can be linked to provide a more comprehensive outlook on environmental and genetic risk factors that can modulate ventral tegmental area-triggered aggression. I discuss possible pre- and post-synaptic mechanisms that could impact the functionality of the identified dopaminergic ventral tegmental area to lateral septum pathway. Moreover, in distinguishing this specific dopamine circuit and lateral septum D2 signaling as an underlying correlate of violent pathology, this dissertation aims to evoke deeper understanding of the mechanism of current antipsychotics used to manage aggression. I end this dissertation by proposing new empirical questions, techniques and lines of research that could further develop my findings as well strengthen the links between dominant models of aggression that exist in the field today.

Second-generation antipsychotics (SGAs) are prescribed for treatment of psychosis. A major side effect of SGAs is an increased risk of metabolic syndrome (MetS) with symptoms of hypertension, hyperlipidemia, hyperglycemia, and truncal obesity. A clinic in the northeastern United States was not screening patients for MetS when being treated with SGAs. The purpose of this project was to educate staff on MetS risk factors, signs, symptoms, and patient management with a goal to improve their knowledge of MetS. Lewin's change theory provided a conceptual framework for the project. The project question explored the development and evaluation of an educational module on MetS increased staff knowledge. Educational content was guided by current literature and the American Psychiatric Association and American Diabetic Association practice guidelines. Five expert panel members, consisting of 3 psychiatrists, an advance practice nurse, and a registered nurse reviewed the education program and evaluated content using a Likert-type questionnaire. Expert panel evaluations indicated that the module content contained useful clinical information on MetS screening for patients on SGAs. After panel review, the program was presented to 7 clinic staff. Pretest and posttest questionnaires asked 10 multiple choice questions and results were compared. Questions on SGA side effects, MetS complications, prevalence, baseline assessment measures, lab work, and needed collaboration were answered correctly by 6 of the participants pretest and all questions after receiving the education program. The project has the potential to promote positive social change through staff education on MetS screening for patients, thus improving patient outcomes.

Thesis (M.Cur) --University of Limpopo, 2013 / Adherence to antipsychotic medication is very important to patients with schizophrenia. Therefore, if patients with schizophrenia are non-adherent to treatment, they are at risk of relapse and being re-admitted at a mental health care institution in the Limpopo Province. Despite the proven benefits of antipsychotic medications, half of the patients with schizophrenia do not take their prescribed drugs. The researcher has observed the following occurrences during practice: • Lack of adherence to antipsychotic medications of schizophrenic patients results in symptoms not being relieved, poor drug effectiveness and patients developed other serious or costly consequences, such as being violent and damaging property; • High rate of relapse; and • High rate of re-admissions. This research questions has guided the study: • What are the factors affecting adherence of mentally stable schizophrenic patients to antipsychotic medications at a mental health institution in the Limpopo Province? • Do mentally stable schizophrenic patients adhere to prescribed treatment? • Are there any guidelines used to promote adherence to antipsychotic treatment? The aim of the study has been to determine the level of adherence of mentally stable schizophrenic patients to antipsychotic medication at a mental healthcare institution in the Limpopo Province. The objectives of the study have been to describe adherence of mentally stable schizophrenic patients to antipsychotic medication at a mental health institution in the Limpopo Province. It implies that participants have been given the opportunity to describe their experience while on medication. vi Their responses have led to the development of guidelines to promote adherence of mentally stable schizophrenic patients to antipsychotic medication. The study site has been the Thabamoopo Mental Healthcare Institution in the Capricorn District of the Limpopo Province. A descriptive, exploratory and contextual qualitative research design has been used in this study. The population has consisted of all mentally stable schizophrenic patients and all the carers of such patients. Non-probability purposive sampling has been used to select participants in this study. The researcher has used a semi- structured interview with two schedule guides for the patient and carers/relatives, which have specified the issues and questions covered. It has assisted the researcher with gathering information about the problem studied (De Vos et al. 2005).A total of twenty (n = 20) participants, consisting of fourteen (n = 14) mentally stable schizophrenic patients and six (n = 6) carers/relatives has been included voluntarily in the semi-structured interview sessions. The steps of data analysis as described by Tesch (1990) in Cresswell (1994) have been followed in this study. The findings of this study reveal a central storyline which indicates that participants share the same point of view in connection with aspects of adherence to antipsychotic treatment and also knowledge about the causes of mental illness and its prognosis. The following four themes and their sub-themes have emerged during data analysis: Theme 1: Participants share the same point of view related to aspects of adherence to antipsychotic treatment; Theme 2: Knowledge related to mental illness; Theme 3: Health seeking behaviours of mentally ill patients; and Theme 4: Experiences of relatives caring for mentally stable patients on treatment. Guidelines and recommendations based on the findings of this study are described in Chapter 4. The criteria for establishing the trustworthiness of qualitative data maintained in this study have been: Credibility, dependability, confirmability and transferability. The following ethical principles have been adhered to: The principle of beneficence, justice, the principle of human respect and dignity, permission to conduct the study, informed consent and confidentiality, privacy and anonymity.