mdl-100907 and Weight-Gain

Second generation antipsychotics (SGAs), notably atypical antipsychotics including olanzapine, clozapine and risperidone, can cause weight gain and obesity side effects. Antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling have been identified as a main cause of SGA induced obesity. Here we review the pivotal regulatory role of the 5-HT2cR in ghrelin-mediated appetite signalling. The 5-HT2cR dimerizes with GHSR1a to inhibit orexigenic signalling, while 5-HT2cR antagonism reduces dimerization and increases GHSR1a-induced food intake. Dimerization is specific to the unedited 5-HT2cR isoform. 5-HT2cR antagonism by SGAs may disrupt the normal inhibitory tone on the GHSR1a, increasing orexigenic signalling. The 5-HT2cR and its interaction with the GHSR1a could serve as the basis for discovering novel approaches to preventing and treating SGA-induced obesity.

Topics: Antipsychotic Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Obesity; Protein Binding; Receptor, Serotonin, 5-HT2C; Receptors, Ghrelin; Serotonin 5-HT2 Receptor Antagonists; Weight Gain

Lurasidone is a second-generation antipsychotic newly approved by the U.S. Food and Drug Administration for the treatment of schizophrenia. Similar to most other second-generation antipsychotics, lurasidone is a full antagonist at dopamine D2 and serotonin 5HT2A receptors. Efficacy within the dose range of 40-120 mg/d was established in four 6-week, randomized, controlled trials. The recommended starting dose is 40 mg/d and the maximum recommended dose is 80 mg/d. Doses above 80 mg/d do not appear to confer added benefit and may be associated with a dose-related increase in certain adverse reactions such as somnolence and akathisia. Lurasidone is administered once daily with at least 350 calories of food in order to optimize bioavailability. Lurasidone is primarily metabolized in the liver through the CYP3A4 enzyme system, and coadministration with drugs that are strong inhibitors of CYP3A4 (such as ketoconazole) or strong inducers (such as rifampin) are contraindicated. Lurasidone is associated with minimal weight gain and no clinically meaningful alterations in glucose, lipids, or the ECG QT interval.

Topics: Akathisia, Drug-Induced; Animals; Antipsychotic Agents; Disorders of Excessive Somnolence; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Humans; Isoindoles; Lurasidone Hydrochloride; Randomized Controlled Trials as Topic; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Thiazoles; Treatment Outcome; United States; United States Food and Drug Administration; Weight Gain

Previous studies reported that the co-injection of leptin and cannabinoid CB1 receptor antagonists reduces food intake and body weight in rats, and this effect is more profound than that induced by these compounds individually. Additionally, serotonin mediates the effects of numerous anorectic drugs. To investigate whether serotonin interacts with leptin and endocannabinoids to affect food intake and body weight, we administered 5-hydroxytryptamine(HT)1B and 5-hydroxytryptamine(HT)2C serotonin receptor antagonists (3 mg/kg GR 127935 and 0.5 mg/kg SB 242084, respectively) to male Wistar rats treated simultaneously with leptin (100 μg/kg) and the CB1 receptor inverse agonist AM 251 (1 mg/kg) for 3 days. In accordance with previous findings, the co-injection of leptin and AM 251, but not the individual injection of each drug, resulted in a significant decrease in food intake and body weight gain. Blockade of the 5-HT1B and 5-HT2C receptors completely abolished the leptin- and AM 251-induced anorectic and body-weight-reducing effects. These results suggest that serotonin mediates the leptin- and AM 251-dependent regulation of feeding behavior in rats via the 5-HT1B and 5-HT2C receptors.

Topics: Aminopyridines; Animals; Cannabinoid Receptor Agonists; Drug Synergism; Eating; Indoles; Leptin; Male; Oxadiazoles; Piperazines; Piperidines; Pyrazoles; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Weight Gain

The aim of this prospective observational study was to verify the tolerability and safety profile of risperidone in a sample of antipsychotic-naive children/adolescent patients having a different psychiatric diagnosis. Twenty-two (mean age of 12±3.2) antipsychotic-naive patients who started therapy with risperidone were recruited. The assessment involved anthropometric data (weight, height, BMI, BMI z-score and BMI percentile), cardiovascular parameters (blood pressure and QTc interval) and blood tests (levels of glucose, triglycerides, total cholesterol, glutamic oxaloacetic and pyruvic transaminases, γ-glutamyl transferase, prolactin, free triiodothyronine, free thyroxine, thyroid-stimulating hormone, thyroglobulin, antithyroid peroxidase and antithyroglobulin). After an average follow-up of 6 months of risperidone therapy, a statistically significant increase in weight and body composition was observed. Furthermore, an increase in serum levels of prolactin was observed in 50% of patients. No other significant changes in metabolic and cardiovascular parameters were found. Although an increase in these parameters was detected, it remained in the normal range. This study suggests the use of specific protocols for monitoring children/adolescents treated with second-generation antipsychotics to manage the metabolic long-term complications and progression to more severe disease states.

Topics: Adolescent; Antipsychotic Agents; Attention Deficit and Disruptive Behavior Disorders; Body Composition; Body Mass Index; Child; Child Development Disorders, Pervasive; Diagnostic and Statistical Manual of Mental Disorders; Dopamine Antagonists; Drug Monitoring; Female; Follow-Up Studies; Humans; Male; Prolactin; Risperidone; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Tic Disorders; Up-Regulation; Weight Gain

A recent Finnish study reported that long-term cumulative exposure to any antipsychotic treatment was related to lower mortality than was no drug exposure. We hypothesize that the antipsychotic 5-HT2A receptor blockade might protect from ischemic heart disease and buffer the deleterious metabolic effects of antipsychotics. The 5-HT2A receptor may be involved in vascular smooth muscle contraction, coronary artery spasms, platelet aggregation and thrombus formation. 5-HT2A receptor blockade might protect from ischemic heart disease by decreasing platelet aggregation and myocardium hypertrophy. Long-term follow-up studies are needed to clearly establish the long-term contribution of the various antipsychotic drugs to ischemic heart disease, and to explore our hypothesis that 5-HT2A receptor blockade may be protective for cardiovascular disease.

Topics: Antipsychotic Agents; Cause of Death; Humans; Long-Term Care; Myocardial Ischemia; Receptors, Histamine H1; Risk; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Weight Gain

Central 5-HT2A receptors have been implicated in central volume control by activating a central angiotensinergic pathway to cause the release of vasopressin. Interestingly, to induce DOCA-salt hypertension in rats vasopressin release is required. Thus the present experiments were carried out to determine whether continuous blockade of these receptors over 20 days, with the non-selective 5-HT2 receptor antagonist mianserin would prevent the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Mianserin, given i.c.v. 90 or 60 microg twice daily for 20 days prevented the development of hypertension in conscious rats receiving DOCA-salt but did not affect blood pressure in rats on salt alone. Further, the dose of 30 microg given i.c.v. twice daily had no effect nor did the vehicle, polyethylene glycol (PEG), on the development of the hypertension. Mianserin 90 microg twice daily i.c.v. was also shown to prevent the increase in fluid intake, urinary flow and sodium excretion caused by DOCA-salt treatment. These data indicate that this action of mianserin is not due to an intrinsic hypotensive action but an action which involves interference with the mechanism by which DOCA-salt treatment causes hypertension. Thus the data overall support the view that to induce hypertension with DOCA-salt a central 5-HT-containing pathway needs to be activated, which then activates 5-HT2 receptors to cause the release of vasopressin which has previously been shown to be responsible for the initiation of DOCA-salt treatment hypertension.

Topics: Animals; Blood Pressure; Desoxycorticosterone; Dose-Response Relationship, Drug; Drinking; Heart Rate; Hypertension; Injections, Intraventricular; Male; Mianserin; Rats; Rats, Wistar; Receptors, Serotonin, 5-HT2; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Sodium; Time Factors; Urodynamics; Weight Gain

With the introduction of conventional antipsychotics in the 1950s, clinicians began to expect effective treatment of positive symptoms of schizophrenia. However, these drugs do not resolve negative and cognitive symptoms of schizophrenia and are also associated with serious side effects, including extrapyramidal side effects (EPS) and tardive dyskinesia. In 1989, clozapine was introduced and labeled the first new antipsychotic owing to its improved efficacy and side-effect profile. Clozapine proved effective in alleviating many of the positive, negative, and cognitive symptoms of schizophrenia, without causing inevitable EPS or tardive dyskinesia. Over the past decade, a number of different new antipsychotics have been developed. These drugs have an affinity for multiple dopamine-receptor subtypes as well as serotonin, norepinephrine, and glutamate receptors, allowing for better treatment outcomes. The antagonism of the 5-HT2A receptor may be responsible for improvement in negative symptoms and decrease in EPS. In addition to providing enhanced efficacy, the affinity of the new drugs for multiple receptors introduces new side effects not seen with the conventional agents, including weight gain. Each new antipsychotic has a unique receptor-binding profile that corresponds to its pharmacologic and side-effect profile. Understanding the differences in mechanisms of action of new antipsychotics will allow physicians to better choose treatment that meets the needs of each individual patient.

Topics: Antipsychotic Agents; Brain; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Humans; Schizophrenia; Schizophrenic Psychology; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome; Weight Gain