Schizophrenia is a debilitating psychiatric condition affecting almost one percent of the US population. Typical antipsychotics (e.g., haloperidol) have been in use for several decades and are generally very effective in treating the emotional and cognitive effects of schizophrenia, but are used as the last line of treatment due to their severe extrapyramidal motor side effects under chronic exposure. The present study was conducted to investigate the role of sex in determining the oromotor side effects of typical antipsychotics via measuring different behavioral dimensions of male and female Sprague-Dawley rats licking sucrose after haloperidol treatment. The results showed a stronger sensitivity in female rats than male rats within total licking responses and inter-lick intervals. The present results suggest closer attention needs to be paid to the role that sexual hormones play in the motor slowing and behavior-reducing effects of antipsychotics.

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Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

The 129S2 inbred mouse strain is often used as a background strain in the production of genetically altered mice (i.e. knockout and transgenic mice). It is important to establish the behavioral phenotype of wild-type mice before making comparisons to genetically altered mice. Also, those comparisons can assist in the evaluation and interpretation of the in vivo effects of drugs. The drug discrimination assay measures the subjective effects of drugs and provides a measure of underlying neuropharmacological mechanisms responsible for the discriminative stimulus properties of drugs. The present study established the atypical antipsychotic drug clozapine as a discriminative stimulus in male 129S2 inbred mice and compared clozapine’s discriminative stimulus properties in 129S2 mice to C57BL/6 and DBA/2 inbred mice. By comparing the discriminative stimulus properties between inbred strains of mice we hope to obtain a fuller picture of the underlying neuropharmacological mechanisms of antipsychotic drugs.

Due to its unique receptor binding profile and its relationship to clozapine, N-desmethylclozapine (NDMC) has been examined as a possible antipsychotic drug (APD). Clozapine has been trained as discriminative stimulus in our lab, but NDMC has not yet been established as a discriminative stimulus. In experiment 1, 12 C57BL/6 mice were trained to discriminate 10.0 mg/kg NDMC from VEH using a standard-two lever operant procedure to assess antipsychotic substitution. The typical APD clozapine fully substituted for NDMC at 2 doses tested (2.5 and 5.0 mg/kg), while typical APD haloperidol failed to substitute for NDMC. In Experiment 2, 11 mice were given repeated administration of NDMC to assess cross-tolerance development to the discriminative stimulus of clozapine. NDMC was successfully trained as a discriminative stimulus and was also shown to induce cross-tolerance to clozapine’s discriminative stimulus, indicating similar underlying pharmacological mechanisms of action between NDMC and clozapine.

Dados pré-clínicos e clínicos indicam que o canabidiol (CBD), um composto não-psicotomimético presente na planta Cannabis sativa, induz efeitos tipoantipsicóticos sem produzir efeitos extrapiramidais. Estudos realizados pelo nosso grupo mostram que o tratamento repetido com CBD atenuou as alterações comportamentais induzidas pelo tratamento repetido com MK-801, uma antagonista dos receptores NMDA, nos testes de reconhecimento de objeto (RO), utilizado no estudo de funções cognitivas, e teste de interação social (IS), utilizado para o estudo dos sintomas negativos da esquizofrenia quando ambas as drogas foram administradas concomitantemente. Estudos mostram que as alterações induzidas por antagonistas NMDA foram observadas até 6 semanas após o tratamento, sendo essas alterações revertidas por antipsicóticos atípicos como clozapina e aripripazol, mas não pelo haloperidol, um antipsicótico típico. Apesar das evidências indicarem o possível efeito tipo-antipsicótico do CBD o mecanismo de ação pelo qual ele exerce este efeito ainda não está elucidado, acredita-se que o sistema endocanabinoide e/ou o sistema serotoninérgico possam estar evolvidos. Assim, no presente estudo, nós avaliamos se o tratamento repetido por 7 dias com CBD seria capaz de reverter as alterações nos testes de IS e RO após o fim do tratamento com MK-801 por 14 dias. Além disso, foi avaliado se o efeito do canabidiol em reverter os prejuízos nos testes de IS e RO seria bloqueado pelo tratamento com AM251, um antagonista dos receptores CB1, e/ou WAY100635, um antagonista dos receptores 5-HT1A. Foi observado que o CBD (15 e 30 mg/kg) atenuou os prejuízos nos testes de IS e RO induzidos por MK- 801 e este efeito foi bloqueado pelo WAY100635 mas não pelo AM251. Estes dados reforçam a proposta de que o CBD tem propriedades antipsicóticas e indicam que o CBD poderia ser uma interessante alternativa para o tratamento de sintomas negativos e cognitivos de pacientes com esquizofrenia. / Preclinical and clinical data indicate that cannabidiol (CBD), a nonpsychotomimetic compound in the Cannabis sativa plant, induces antipsychoticlike effects without producing extrapyramidal effects. Studies conducted by our group show that repeated treatment with CBD attenuated the behavioral changes induced by repeated treatment with MK-801, an NMDA receptor antagonist, in the object recognition (RO) test, used in the study of cognitive functions, and social interaction test (IS), used to study the negative symptoms of schizophrenia when both drugs were administered concomitantly. Studies show that changes induced by NMDA antagonists have been observed up to 6 weeks after treatment, and these changes are reversed by atypical antipsychotics such as clozapine and aripiprazole, but not by haloperidol, a typical antipsychotic. Although the evidence indicates the possible antipsychotic-like effect of CBD, the mechanism of action by which it exerts this effect has not yet been elucidated, it is believed that the endocannabinoid system and / or the serotoninergic system may be involved. Thus, in the present study, we evaluated whether repeated 7-day treatment with CBD would be able to reverse changes in IS and RO tests after the end of MK-801 treatment for 14 days. In addition, it was assessed whether the effect of cannabidiol on reversing impairments in the IS and RO tests would be blocked by treatment with AM251, a CB1 receptor antagonist, and / or WAY100635, a 5-HT1A receptor antagonist. CBD (15 and 30 mg / kg) was observed to attenuate the impairments in the IS and RO tests induced by MK-801 and this effect was blocked by WAY100635 but not by AM251. These data reinforce the proposal that CBD has antipsychotic properties and indicate that CBD could be an interesting alternative for the treatment of negative and cognitive symptoms of patients with schizophrenia.

Dados pré-clínicos e clínicos indicam que o canabidiol (CBD), um composto não-psicotomimético presente na planta Cannabis sativa, induz efeitos tipoantipsicóticos sem produzir efeitos extrapiramidais. Estudos realizados pelo nosso grupo mostram que o tratamento repetido com CBD atenuou as alterações comportamentais induzidas pelo tratamento repetido com MK-801, uma antagonista dos receptores NMDA, nos testes de reconhecimento de objeto (RO), utilizado no estudo de funções cognitivas, e teste de interação social (IS), utilizado para o estudo dos sintomas negativos da esquizofrenia quando ambas as drogas foram administradas concomitantemente. Estudos mostram que as alterações induzidas por antagonistas NMDA foram observadas até 6 semanas após o tratamento, sendo essas alterações revertidas por antipsicóticos atípicos como clozapina e aripripazol, mas não pelo haloperidol, um antipsicótico típico. Apesar das evidências indicarem o possível efeito tipo-antipsicótico do CBD o mecanismo de ação pelo qual ele exerce este efeito ainda não está elucidado, acredita-se que o sistema endocanabinoide e/ou o sistema serotoninérgico possam estar evolvidos. Assim, no presente estudo, nós avaliamos se o tratamento repetido por 7 dias com CBD seria capaz de reverter as alterações nos testes de IS e RO após o fim do tratamento com MK-801 por 14 dias. Além disso, foi avaliado se o efeito do canabidiol em reverter os prejuízos nos testes de IS e RO seria bloqueado pelo tratamento com AM251, um antagonista dos receptores CB1, e/ou WAY100635, um antagonista dos receptores 5-HT1A. Foi observado que o CBD (15 e 30 mg/kg) atenuou os prejuízos nos testes de IS e RO induzidos por MK- 801 e este efeito foi bloqueado pelo WAY100635 mas não pelo AM251. Estes dados reforçam a proposta de que o CBD tem propriedades antipsicóticas e indicam que o CBD poderia ser uma interessante alternativa para o tratamento de sintomas negativos e cognitivos de pacientes com esquizofrenia. / Preclinical and clinical data indicate that cannabidiol (CBD), a nonpsychotomimetic compound in the Cannabis sativa plant, induces antipsychoticlike effects without producing extrapyramidal effects. Studies conducted by our group show that repeated treatment with CBD attenuated the behavioral changes induced by repeated treatment with MK-801, an NMDA receptor antagonist, in the object recognition (RO) test, used in the study of cognitive functions, and social interaction test (IS), used to study the negative symptoms of schizophrenia when both drugs were administered concomitantly. Studies show that changes induced by NMDA antagonists have been observed up to 6 weeks after treatment, and these changes are reversed by atypical antipsychotics such as clozapine and aripiprazole, but not by haloperidol, a typical antipsychotic. Although the evidence indicates the possible antipsychotic-like effect of CBD, the mechanism of action by which it exerts this effect has not yet been elucidated, it is believed that the endocannabinoid system and / or the serotoninergic system may be involved. Thus, in the present study, we evaluated whether repeated 7-day treatment with CBD would be able to reverse changes in IS and RO tests after the end of MK-801 treatment for 14 days. In addition, it was assessed whether the effect of cannabidiol on reversing impairments in the IS and RO tests would be blocked by treatment with AM251, a CB1 receptor antagonist, and / or WAY100635, a 5-HT1A receptor antagonist. CBD (15 and 30 mg / kg) was observed to attenuate the impairments in the IS and RO tests induced by MK-801 and this effect was blocked by WAY100635 but not by AM251. These data reinforce the proposal that CBD has antipsychotic properties and indicate that CBD could be an interesting alternative for the treatment of negative and cognitive symptoms of patients with schizophrenia.

INTRODUÇÃO: Acredita-se cada vez mais que o tempo para se observar a resposta ao antipsicótico é curto, sendo possível nas primeiras duas semanas já prever se o paciente responderá em 12 semanas. Entretanto, a maior parte das evidências que sustentam tal hipótese provém da análise de dados de estudos controlados duplo-cegos, que não definiam o conceito de início de ação de antipsicóticos, o que pode gerar uma certa confusão quanto às expectativas de resposta. Neste estudo, testamos se a ausência de melhora mínima de 20% da PANSS nas primeiras duas semanas correlacionava-se a ausência de resposta em 12 semanas. MÉTODOS: Foi feita a avaliação do tempo de resposta ao tratamento antipsicótico, utilizando o algoritmo de tratamento do IPAP, que recomenda o uso de monoterapia por 4 a 6 semanas, e troca por outro antipsicótico em caso de ausência de resposta. Os pacientes incluídos tinham esquizofrenia de início recente pelos critérios DSM-IV e foram aleatorizados para receber tratamento com antipsicótico de primeira geração (APG) ou de segunda geração (ASG). Foi considerada resposta ao tratamento a redução média de pelo menos 30% dos sintomas, em comparação com a PANSS inicial.Os pacientes foram avaliados pela PANSS a cada 2 semanas, durante 12 semanas. RESULTADOS: Foram incluídos 22 pacientes (APG, N=10 e ASG, N=12). Não houve diferença quanto ao tempo ou taxa de resposta entre os grupos; 20% (4) dos pacientes não responderam ao tratamento, enquanto 65% (13) responderam; 15% (3) abandonaram um tratamento. Um paciente não pôde ser avaliado pela PANSS e não teve seus dados incluídos na análise. Não houve correlação entre melhora nas primeiras 2 semanas e resposta em 12 semanas. A mudança média da 11 PANSS em relação ao basal foi significante a partir da 4a semana (p=0,43), e houve melhora progressiva ao longo das 12 semanas. Ambos os grupos tiveram a mesma proporção de substituições de medicamentos, sendo que não houve diferença, em termos de porcentagem de respondedores, entre os que trocaram o medicamento e entre os que permaneceram com a mesma medicação inicial. CONCLUSÕES: A ausência de resposta nas primeiras duas semanas não prediz ausência de resposta em 12 semanas. O tempo para avaliar a resposta clínica a um medicamento antipsicótico é de pelo menos quatro semanas. Aguardar o efeito do medicamento parece ser mais importante que trocar de medicamento nas primeiras 4 semanas / INTRODUCTION: It has been widely accepted that time to observe response to antipsychotic is short, with a response in 2 weeks predicting response or nonresponse in 12 weeks. However, most evidence for this hypothesis come from controlled doubleblind trials, which did not assess the onset of action, but clinical response, generating some false expectancies regarding clinical response. In this study, we assessed whether the lack of improvement in 2 weeks would predict nonresponse in 12 weeks. METHODS: We assessed time to response to antipsychotic through a treatment algorithm IPAP, which recommends monotherapy during 4-6 weeks and switch to another antipsychotic in case of nonresponse. Subjects with recent onset schizophrenia according to DSM-IV criteria were included and randomized to receive first generation antipsychotic (FGA) or second generation (SGA). Response was considered as at least 30% reduction of PANSS. Subjects were assessed every 2 weeks, during the 12-week study period. RESULTS: 22 subjects were included (FGA: 10; SGA: 12). There was no difference between groups in terms of response rate; overall 20% (4) did not respond in 12 weeks and 65% responded; 15% (3) dropped out. Data from one patient was not included in the analysis due to impossibility of assessment with PANSS. No correlation was found between response in 2 weeks and response in 12 weeks. Significant mean change at PANSS was observed in the fourth week (p= 0,43). The need for switch was similar in both groups, and improvement was progressive throughout the 12 weeks. Response rate was similar in the group that switched and the group that remained with first antipsychotic. CONCLUSIONS: Lack of response in 2 weeks does not predict lack 13 of response in 12 weeks. Time to assess clinical response é at least four weeks. Looking forward to drug effect seems to be more important for the outcome in 12 weeks than switching the drug in the first 4 weeks

This thesis sought to explore the phenomenon of discontinuing neuroleptic medication for psychosis. It comprises three standalone papers. Papers one and two have been prepared for submission to journals and in accordance with the journal guidelines. Paper one is a systematic literature review synthesising studies investigating the association between neuroleptic discontinuation and functional outcomes. Databases were systematically searched and thirteen studies were included in the review. Evidence regarding the association between discontinuation from neuroleptic medication and functional outcomes was mixed. Findings are limited by the scarcity of evidence, diversity in the study methods and designs used, and methodological and design quality issues. Paper two is a qualitative study exploring personal accounts of making choices about neuroleptic medication, specifically considering decisions to discontinue. Twelve participants were interviewed and a constructivist grounded theory approach was used to analyse transcripts. The findings suggest that making sense of choices relates to a continuation-discontinuation spectrum and involves three interrelated tasks. The tasks are: forming a personal theory of the need for, and acceptability of, neuroleptic medication; negotiating the challenges of forming alliances with others; and weaving a safety net to safeguard wellbeing. A theoretical model explaining the processes involved in the tasks and the mediating factors is presented and discussed. The clinical implications of the findings are discussed with reference to existing literature. Paper three is not intended for publication and is a critical review of the research process, in which the strengths and weaknesses of the systematic review and empirical study are evaluated. Personal and professional reflections on the experience of conducting a systematic review and an empirical qualitative study are discussed and the implications of the research for future clinical practice and research are considered.