RESUMO
The underlying mechanisms of antipsychotic (AP)-induced weight gain are unknown, but both central and peripheral AP target receptors could potentially be involved. This study used radioligand binding assays to compare the binding affinities of clozapine, olanzapine and haloperidol for candidate receptors potentially involved in AP-induced weight gain. Selected candidates derived from known pathways involved in body weight regulation included receptors classified as anorexigenic (bombesin receptor subtype 3, calcitonin gene-related peptide receptor, cholecystokinin receptor, melanocortin-4 receptor, neurotensin receptor 1) or orexigenic (cannabinoid receptor 1, galanin 1 receptor, melanin-concentrating hormone receptor (MCHR), neuropeptide Y1 receptor) as well as receptors involved in physiological actions related to digestion and fluid homeostasis (angiotensin II type 1 receptor, bradykinin B2 receptor, endothelin receptor, neurokinin 1 receptor, vasoactive intestinal polypeptide receptor 1). Clozapine, olanzapine and haloperidol exhibited negligible affinities to all of these receptors except for the MCHR (Ki=501 nM; haloperidol). With respect to other candidates from (neuro)transmitter systems already suggested to be involved in AP-induced weight gain, the binding profile of olanzapine resembled that of clozapine, with high affinity (Ki<10 nM) for serotonin (5-HT) 5-HT2A, 5-HT2C and 5-HT6, muscarinic M1 and histamine H1 receptors. In contrast, the binding profile of haloperidol was substantially different (high affinity only for the dopamine D1 receptor). In conclusion, we have not identified a novel binding site of the two investigated atypical AP that could contribute to the induced weight gain.
Assuntos
Antipsicóticos/metabolismo , Peso Corporal/efeitos dos fármacos , Clozapina/metabolismo , Haloperidol/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Antipsicóticos/farmacologia , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacologia , Clozapina/farmacologia , Haloperidol/farmacologia , Humanos , Olanzapina , Ligação Proteica , Ensaio RadioliganteRESUMO
We investigated serum ghrelin levels (SGL) in 12 patients with schizophrenia over a 10-week period after initiation of clozapine treatment. In contrast to increments of body mass indices (BMI, kg/m2) and serum leptin levels (SLL), no significant change in SGL was detected. Inverse correlations between delta SGL and delta SLL did not reach statistical significance. Linear mixed model analysis could not detect effects of age, sex, BMI, SLL and serum clozapine levels on SGL. Our results do not support a causal involvement of ghrelin in clozapine-related weight gain.
Assuntos
Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Hormônios Peptídicos/sangue , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/administração & dosagem , Índice de Massa Corporal , Clozapina/administração & dosagem , Feminino , Grelina , Humanos , Leptina/sangue , Estudos Longitudinais , Masculino , Estudos Prospectivos , Esquizofrenia Catatônica/sangue , Esquizofrenia Catatônica/tratamento farmacológico , Esquizofrenia Hebefrênica/sangue , Esquizofrenia Hebefrênica/tratamento farmacológico , Esquizofrenia Paranoide/sangue , Esquizofrenia Paranoide/tratamento farmacológico , Aumento de Peso/efeitos dos fármacosRESUMO
The authors explored the binge eating symptomatology in 74 patients receiving clozapine (N = 57) or olanzapine (N = 17), and compared body mass index (BMI, kg/m(2)) and weight gain in patients with and without binge eating symptomatology. Subjects who screened positively for binge eating were interviewed using a modified version of the Questionnaire on Eating and Weight Patterns (QEWP). Current BMIs were assessed cross-sectionally, BMIs at initiation of clozapine/olanzapine treatment retrospectively. Thirty-seven subjects (50%) screened positively. Taking clozapine and olanzapine together, 6/27 (22.2%) females and 3/47 (6.4%) males fulfilled criteria for binge eating disorder, 3/27 (11.1%) females and 2/47 (4.3%) males for bulimia nervosa. Patients who screened positively showed higher current BMIs (26.8 +/- 3.9 vs. 24.7 +/- 3.7 kg/m(2)) and higher BMI increments during clozapine/olanzapine treatment (3.9 +/- 3.1 vs. 2.6 +/- 3.4 kg/m(2)) than patients who screened negatively. We conclude that clozapine/olanzapine may induce binge eating and full blown eating disorders which may have predictive value for weight gain. For future research in this field we suggest a novel DSM-IV research classification "Medication-induced eating disorders".
Assuntos
Antipsicóticos/efeitos adversos , Bulimia/induzido quimicamente , Clozapina/efeitos adversos , Hiperfagia/induzido quimicamente , Pirenzepina/análogos & derivados , Pirenzepina/efeitos adversos , Adolescente , Adulto , Benzodiazepinas , Índice de Massa Corporal , Feminino , Humanos , Masculino , Olanzapina , Fatores de Risco , Inquéritos e Questionários , Aumento de Peso/efeitos dos fármacosRESUMO
We review the indications, modes of action, effectiveness, side effects, legal and ethical aspects of pharmacological agents which reduce sexual desire. It needs to be emphasized that these agents - regardless of their indication - should never be used without concomitant psychotherapy. Nevertheless, in this review we focus on pharmacotherapy, because it can be an important part of the therapeutic procedure and appropriate knowledge is required. A part of the review pertains to the therapy of male adolescents.
Assuntos
Disfunções Sexuais Fisiológicas/tratamento farmacológico , Adolescente , Antagonistas de Androgênios/uso terapêutico , Acetato de Ciproterona/uso terapêutico , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Masculino , Acetato de Medroxiprogesterona/uso terapêutico , Psicotrópicos/uso terapêuticoRESUMO
Estrogens are known to have an inhibitory effect on food intake in rodents and primates. Decreased estrogen levels that are found for instance in menopausal woman and in ovarectomized rodents result in body weight gain. Estrogen can act both in the periphery and in the central nervous system via at least two different estrogen receptors (alpha and beta). We systematically screened the coding region and part of the 5' and 3'regions of the estrogen receptor beta gene (ER beta) in 96 extremely obese children and adolescents, 50 patients with anorexia nervosa (AN), 28 patients with bulimia nervosa (BN), and 25 healthy underweight individuals. We detected five different sequence variants in the ER beta: a) A 21 bp deletion (codons 238 to 244) was detected in two obese probands and an underweight individual. b) An 846G-->A transition leading to a nonconservative amino acid substitution (G-250-S) was found in two obese male probands. Both a) and b) were located within the flexible hinge region between DNA and ligand binding domain. c) For a 1082G-->A polymorphism we found suggestive evidence for an association between the more common 1082G-allele and anorexia nervosa (nominal p=0.04). d) One silent mutation (1421T-->C) was found solely in two obese probands. e) A common variant is located in the 3' nontranslated region at position 1730(A-->G). We did not detect association of this polymorphism to any of the analyzed phenotypes. We conclude that the ER beta harbors several different mutations and polymorphisms, none of which can readily be associated with the phenotypes under study.
Assuntos
Peso Corporal/fisiologia , Testes Genéticos , Variação Genética/genética , Mutação/genética , Receptores de Estrogênio/genética , Adolescente , Anorexia Nervosa/genética , Bulimia/genética , Criança , Receptor beta de Estrogênio , Feminino , Humanos , Masculino , Obesidade/genéticaRESUMO
Evidence that leptin plays an important role in reproductive function is accumulating rapidly. We hypothesized that low leptin synthesis is associated with amenorrhea. We therefore determined serum leptin levels in 43 underweight female students, who were screened for lifetime occurrence of amenorrhea. We assessed the predictive value of leptin, body mass index (BMI), fat mass and percent body fat, respectively, for lifetime occurrence of amenorrea. Factors predicting amenorrhea were tested for their capability to predict current amenorrhea in a second cohort of 63 inpatients with anorexia nervosa (AN) or bulimia nervosa (BN). Furthermore, the relationships between serum leptin levels and of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol and progesterone, respectively, were evaluated. Only leptin predicted lifetime occurrence of amenorrhea in the student cohort. The critical leptin level was in the range of 1.85 micrograms L-1. This level served to largely separate anorectic from bulimic patients. In patients with AN mean serum log10 leptin levels over the first 4 weeks of inpatient treatment were correlated with mean FSH, LH and estradiol levels, respectively. Evidently, a critical leptin level is needed to maintain menstruation. In affluent populations eating disorders are likely to be a major cause of a low leptin synthesis.
Assuntos
Amenorreia/sangue , Anorexia Nervosa/sangue , Proteínas/metabolismo , Adolescente , Adulto , Índice de Massa Corporal , Estudos de Coortes , Anticoncepcionais Orais/administração & dosagem , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Leptina , Hormônio Luteinizante/sangue , Obesidade/metabolismo , Progesterona/sangue , Redução de PesoRESUMO
We report a null mutation in the first exon of the human dopamine D4 receptor (DRD4) gene. The mutation is predicted to result in a truncated non-functional protein and is the first natural nonsense mutation found in a human dopamine receptor gene. It occurs with a frequency of about 2% in the general population. The distribution of the mutation was found to be similar in healthy controls and patients suffering from psychiatric diseases which included schizophrenia, bipolar affective disorder and Tourette's syndrome, indicating that heterozygosity for this mutation in the DRD4 gene is not causally related to major psychiatric diseases. We also identified an adult male who is homozygous for this mutation. He shows no symptoms of major psychiatric illness, but he displays somatic ailments including acousticous neurinoma, obesity and some disturbances of the autonomic nervous system. Some of these symptoms might be related to the absence of functional DRD4 protein.