The impact of antipsychotic drugs on food intake and body weight and on leptin levels in blood and hypothalamic ob-r leptin receptor expression in wistar rats

OBJECTIVES: The aim of our study was to investigate the impact of typical and atypical antipsychotic drugs on leptin concentration in blood and changes in the receptor expression in the hypothalamus of male Wistar rats. METHODS: From the age of 13 to 18 weeks, three groups of 20 animals were fed an average dose of 3.5 + 0.03 mg/ kg body weight (BW) haloperidol; 30.6 + 0.22 mg/kg BW clozapine; or 14.9 + 0.13 mg/kg BW ziprasidone in ground food pellets containing 15 percent fat. Twenty control animals received no drugs. Blood samples were taken at week 14, 16, and 19. Locomotor activity and exploratory behavior were measured using the alcove test at weeks 15 and 17. The expression of the hypothalamic leptin receptor in rat brains was determined by using a Western blot. RESULTS: Rats medicated with haloperidol and ziprasidone showed a significantly decreased percentage weight gain and food consumption. We observed no differences in the alcove test, but locomotor activity was significantly reduced in the haloperidol group. Except for rats in the clozapine and ziprasidone groups, after 2 weeks of drug application, we found no changes in the leptin blood concentrations among the four groups or animals within each group. Moreover, we did not find specific differences in hypothalamic leptin receptor expression among the groups. CONCLUSION: We concluded that in male Wistar rats during this treatment period, the tested drugs did not act directly on the leptin regulatory system. We recommend further studies using long-term treatment of different rat strains.

Avaliação antropométrica e bioquímica em pacientes com esquizofrenia usuários de clozapina / Anthropometric and biochemical assessment of schizophrenic patients taking clozapine

OBJETIVO: Avaliar a proporção de sobrepeso/obesidade e alterações em parâmetros bioquímicos sangüíneos em pacientes com esquizofrenia do sexo masculino, usuários de medicação antipsicótica (clozapina). MÉTODOS: Estudo transversal com 40 pacientes do sexo masculino, diagnosticados com esquizofrenia, em uso de clozapina, atendidos no Hospital de Clínicas de Porto Alegre. Foram verificadas as relações entre o índice de massa corporal, a circunferência abdominal, o percentual de gordura corporal, o perfil lipídico e o exame de glicose de jejum e a dosagem da medicação, o acompanhamento dietoterápico e a monoterapia de clozapina. RESULTADOS: Os pacientes apresentaram freqüências de 71,8 por cento de sobrepeso/obesidade, 76,9 por cento de circunferência abdominal aumentada e 94,1 por cento de percentual de gordura elevada. Foram encontrados 56,8 por cento de pacientes com lipoproteína de baixa densidade-colesterol acima do normal e 64,1 por cento com triglicerídeos elevados. Quanto maior a dosagem de clozapina utilizada maiores foram os níveis de lipoproteína de baixa densidade-colesterol (p=0,01). CONCLUSÃO: Pacientes tratados com clozapina apresentam aumento de peso e significante anormalidade lipídica, necessitando de monitoramento freqüente dos níveis plasmáticos e intervenção nutricional precoce, visando à otimização do tratamento.

OBJECTIVE: The objective was to access the overweight/obesity rates and variations of biochemical blood parameters in male schizophrenic outpatients taking antipsychotic medication (clozapine), treated at the Schizophrenia and Dementia First Aid Station of the Clinics Hospital in Porto Alegre. METHODS: This is a cross-sectional study with 40 male outpatients diagnosed with schizophrenia and taking clozapine, from the Clinics Hospital in Porto Alegre. Associations between body mass index, waist circumference, body fat percentage, lipid levels and fasting glucose and medication dosage, diet therapy and clozapine monotherapy were verified. RESULTS: There was a rate of 71.8 percent of overweight/obesity, 76.9 percent of increased waist circumference and 94.1 percent of high body fat percentage. More than half of the patients (56.8 percent) had low density lipoprotein cholesterol levels above normal and 64.1 percent had high triglycerides. LDL-cholesterol levels increased with increasing clozapine dose (p=0.01). CONCLUSION: Patients on clozapine presented excess weight and significant lipid abnormality, needing frequent monitoring of the biochemical blood parameters and early nutritional intervention to optimize treatment.

Haloperidol and clozapine differentially regulate signals pstream of glycogen synthase kinase 3 in the rat frontal cortex

Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D(2) receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT(2) receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3alpha/beta and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3GSK3alpha/beta. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D(2)- or 5HT(2)- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.

Cinqüenta anos de medicamentos antipsicóticos em psiquiatria: III. fenotiazinas piperidínicas / Fifty years of antipsychotic drugs in psychiatry: III. piperidine phenothiazines

Na iminência de uma nova era na terapêutica psiquiátrica com a redescoberta da clozapina e a introduçäo dos novos antipsicóticos atípicos, é tempo de um inventário das substâncias desenvolvidas nos últimos cinqüenta anos. É feito um breve histórico dos antecedentes dos antipsicóticos tradicionais na era que se encerra. As substâncias introduzidas até o presente poderiam ser reunidas nos grupos tradicionais - fenotiazinas (alifáticas, piperazínicas e piperidínicas), tioxantenos, butirofenonas, difenilbutilpiperidinas, benzaminas, indóis, dibenzoxazepinas - e nos grupos químicos mais recentes - diidroindolonas, dbenzodiazepinas, benzisoxazólicos -, além de compostos ainda em desenvolvimento. Neste artigo, o terceiro de uma série concebida com esta finalidade, säo examinados os derivados fenotiazínicos com cadeia lateral piperidínica que tenham demonstrado utilidade na prática clínica e ou guardem importância histórica: mepazina, mesoridazina, nortioridazina, piperacetazina, propericiazina, sulforidazina e toridazina. Com base em bibliografia básica específica, säo discutidos aspectos técnicos e revisado o conhecimento científico acumulado através da experimentaçäo e utilizaçäo clínica destes compostos, desde seu lançamento até a presente data, com informaçöes sistemáticas sobre fórmula estrutural, fórmula molecular, nomes químicos, nomes de fantasia e códigos de cada composto, além de dados sobre eventual comercializaçäo no país

Clozapina, uma alternativa no tratamento dos transtornos afetivos bipolares resistentes e esquizoafetivos / Clozapine, on option in the therapy in bipolar refractory affective disorders and schizoaffectives

A clozapina é um psicofármico antigo que ainda hoje tem revolucionado o tratamento dos transtornos peiquiátricos. Essa droga foi desenvolvida na década de 60 e aprovada pelo FDA(Food and Drug Administration) em 1984 para o tratamento da esquizofrenia refratária. Dados recentes demonstram que ela também pode ser útil no controle dos quadros afetivos bipolares resistentes nos subtipos de ciclagem rápida, quadros mistos e nos transtornos esquizoafetivos

Antipsychotic profile of alstonine: ethnopharmacology of a traditional Nigerian botanical remedy

Although recently developed drugs have brought significant improvement, the treatment of psychotic disorders still presents serious drawbacks. Since inherent complexity and lack of satisfactory understanding of the underlying pathophysiology impose limits for rational drug design, resourceful approaches in the search for antipsychotics are pertinent. This paper reports pharmacological properties of alstonine, a heteroyohimbine type alkaloid, Which exbitited an antipsychotic-like profile, inhibiting amphetamine-induced lethaly, apomorphine-induced steotypy and potentiating barbiturate-induced slleping time. Atypical features of alstonine were the prevention of haloperidol-induced catalepsy and lack of direct interaction with D1, D2 and 5-HT2A receptors, classically linked to antipsychotic mechanism of action.

Sustained long-term improvement with clozapine in schizophrenia

The present paper reports the long-term use of clozapine in a prospective sample of 46 chronic schizophrenics. In six months, 21 subjects had been excluded for a number of reasons. In four of them the reasons for exclusion were related to lack of response or adverse effects. The median daily clozapine dose was 400 mg in the remaining 25 patients. As a whole, there were remarkable improvements in core dimensions of psychopathology, global cognitive status, and level of functioning. We confirmed that clozapine is effective in a subgroup of schizophrenics with the severest forms of the disease. If tolerated after the first few months it leads to progressive gains in several domains of behavior. Clozapine should be tried in every patient with schizophrenia in whom positive symptoms, disorganization, or bizarre behavior are a matter of incapacitation despite efforts to keep them under control with other drugs.

Síntomas negativos y empleo de antipsicóticos atípicos en la esquizofrenia / Negative symptoms and use of atypical antipsychotic agents in schizophrenia

Se analiza el concepto de síntoma negativo en las concepciones actuales de la esquizofrenia, especialmente los aportes de Crow, Andreasen y Carpenter. Se discute la importancia de los síntomas negativos dentro del cuadro clínico de la esquizofrenia. Se analiza el concepto de atipicidad de los antipsicóticos y se revisan los estudios acerca de su eficacia en el tratamiento de los síntomas negativos. Se concluye que los antipsicóticos atípicos son fármacos seguros y eficaces tanto en el tratamiento de los síntomas positivos como de los síntomas negativos de la esquizofrenia

Preferential blockade by clozapine of hyperlocomotion induced by non-competitive NMDA antagonist MK-801.

Effect of clozapine on MK-801-induced hyperlocomotion and stereotypy as well as open field behavior was studied. Clozapine (0.1-7.5 mg/kg) dose-dependently blocked MK-801(0.5 mg/kg)-induced stereotypy. Both total and ambulatory responses were blocked by even the lower doses (0.1-0.5 mg/kg) of clozapine. In open field test, clozapine selectively blocked hyperambulation induced by MK-801 (0.1 mg/kg) whereas it potentiated MK-801 (0.1 mg/kg)-induced stereotypy at all the doses used. Haloperidol (0.25 and 0.5 mg/kg) and SCH 23390 (0.5 and 1 mg/kg) showed a dose-dependent effect on MK-801-induced behaviors while sulpiride (25 and 50 mg/kg) failed to modify MK-801-induced open field behavior. This study supports the preferential effect of clozapine on dopamine receptors located in mesolimbic area and further suggests the possibility of using open field behavior induced by MK-801 as a model for studying atypical antipsychotics.

Experiencia con clozapina en esquizofrenia resistente / Experience with clozapine in ressistant schizophrenia

Se presenta una experiencia de tratamiento con clozapina en 11 pacientes esquizofrénicos resistentes. Se discute la eficacia del tratamiento y sus efectos adversos, así como la metodología empleada

La esquizofrenia resistente: ilustración mediante 3 casos clínicos del uso de un algoritmo para la elección de medicamentos / Resistant schizophrenia: 3 clinical cases showing the use of an algorithm for drug selection

En este trabajo se analiza el tratamiento de pacientes con esquizofreniaresistente al uso de neurolépticos clásicos, y se sugiere el uso de un árbol de decisión que, consiste en la identificación de síntomas blanco , que guíen la selección de alternativas terapéuticas, que aumenten o potencien el uso de los neurolépticos. Se revisa la literatura sobre el uso de litio, carbamazepina y clozapina en esquizofrenia y se ilustra el uso de estos medicamentos con un caso clínico

Clozapina, um neuroléptico atìpico: Propriedades farmacológicas e uso terapêutico / Clozapine, an atypical antipsychotic drug

Derivado dibenzodiazepìnico, a clozapina é considerada um neuroléptico atìpico por näo desencadear habitualmente reaçöes extrapirâmidais (REP). Sua atividade terapêutica representa um grande progresso no tratamento da esquizofrenia, tendo sido demonstrado que, em doentes refratários e graves, é mais eficaz que a clorpromazina, agindo tanto nos sintomas positivos quanto nos negativos. Além da virtual ausência de REP, näo se observaram, nestes 20 anos, casos confirmados de discinesia tardia com seu uso. Outra caracterìstica que a diferencia dos neuroléticos usuais é a de näo aumentar os nìveis plasmáticos de prolactina. Apesar de seu potencial terapêutico promissor, a incidência relativamente elevada de agranulocitose em 1 a 2//dos casos impöe restriçäo de seu emprego de forma mais ampla na prática psiquiátrica

Caso clínico de agranulocitosis por clozapina / Clínical case of agranulocytosis by clozapin

Se presenta primer caso clínico de agranulocitosis inducida por Clozapina descrito en Chile. Se discuten algunos aspectos farmacológicos y hematológicos involucrados en esta complicación

Role of dopaminergic mechanisms in the central amygdalar nucleus in the regulation of stress-induced gastric ulcer formation in rats.

Microinjections (i/am) of dopamine (DA) antagonists, haloperidol or clozapine (1 and 5 micrograms) into the central amygdalar nucleus (CEA) produced dose-related aggravations in cold-restraint (3 h at 4 degrees C) stress-induced gastric ulcer formation in rats. On the other hand, DA (10 micrograms, i/am), its agonist, apomorphine (5 mg/kg, ip) and its precursor, l-Dopa (100 mg/kg, ip) significantly inhibited stress ulcerogenesis. Pretreatment of rats (i/am) with clozapine antagonized or reversed the gastric cytoprotective effects of DA, apomorphine and l-Dopa. The results indicate that the CEA is important for the observed gastric cytomodulatory effects of both centrally and peripherally administered dopaminergic agents during stressful experiences.