olanzapine and Hyperphagia

Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain.

Topics: Agouti-Related Protein; Animals; Antipsychotic Agents; Eating; Humans; Hyperphagia; Hypothalamus; Mice; Olanzapine; Receptors, Cytoplasmic and Nuclear; Weight Gain

The dopaminergic partial agonism of the so-called third-generation antipsychotics (TGAs; aripiprazole, brexpiprazole, cariprazine) is hypothesized to cause impulse control disorders (ICDs). Relevant warnings by the Food and Drug Administration (FDA) were posted on aripiprazole (2016) and brexpiprazole (2018). Our study investigated the FDA Adverse Event Reporting System and the pharmacodynamic CHEMBL database to further characterize TGA-induced ICDs.. We downloaded and pre-processed the FDA Adverse Event Reporting System up to December 2020. We adapted Bradford Hill criteria to assess each TGA's -and secondarily other antipsychotics'-causal role in inducing ICDs (pathological gambling, compulsive shopping, hyperphagia, hypersexuality), accounting for literature and disproportionality. ICD clinical features were analyzed, and their pathogenesis was investigated using receptor affinities.. A total of 2708 reports of TGA-related ICDs were found, primarily recording aripiprazole (2545 reports, 94%) among the drugs, and gambling (2018 reports, 75%) among the events. Bradford-Hill criteria displayed evidence for a causal role of each TGA consistent across subpopulations and when correcting for biases. Significant disproportionalities also emerged for lurasidone with compulsive shopping, hyperphagia, and hypersexuality, and olanzapine and ziprasidone with hyperphagia. Time to onset varied between days and years, and positive dechallenge was observed in 20% of cases. Frequently, co-reported events were economic (50%), obsessive-compulsive (44%), and emotional conditions (34%). 5-Hydroxytryptamine receptor type 1a agonism emerged as an additional plausible pathogenetic mechanism.. We detected an association between TGAs and ICDs and identified a new signal for lurasidone. ICD characteristics are behavior specific and may heavily impact on life. The role of 5-Hydroxytryptamine receptor type 1a agonism should be further explored.

Topics: Antipsychotic Agents; Aripiprazole; Disruptive, Impulse Control, and Conduct Disorders; Dopamine; Dopamine Agonists; Humans; Hyperphagia; Lurasidone Hydrochloride; Olanzapine; Pharmacovigilance; Quinolones; Receptors, Serotonin; Thiophenes; United States; United States Food and Drug Administration

Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine-another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice.

Topics: alpha-MSH; Animals; Antipsychotic Agents; Female; Hyperphagia; Hypothalamus; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Models, Animal; Neurons; Obesity; Olanzapine; Potassium; Receptor, Melanocortin, Type 4; Risperidone; Synaptic Potentials; Transcriptome; Weight Gain

Antipsychotic drugs (AP) are used to treat a multitude of psychiatric conditions including schizophrenia and bipolar disorder. However, APs also have metabolic side effects including increased food intake and body weight, but the underlying mechanisms remain unknown. We previously reported that minocycline (MINO) co-treatment abrogates olanzapine (OLZ)-induced hyperphagia and weight gain in mice. Using this model, we investigated the changes in the pharmacometabolome in the plasma and hypothalamus associated with OLZ-induced hyperphagia and weight gain. Female C57BL/6 mice were divided into groups and fed either i) control, CON (45% fat diet) ii) CON + MINO, iii) OLZ (45% fat diet with OLZ), iv) OLZ + MINO. We identified one hypothalamic metabolite indoxylsulfuric acid and 389 plasma metabolites (including 19 known metabolites) that were specifically associated with AP-induced hyperphagia and weight gain in mice. We found that plasma citrulline, tricosenoic acid, docosadienoic acid and palmitoleic acid were increased while serine, asparagine and arachidonic acid and its derivatives were decreased in response to OLZ. These changes were specifically blocked by co-treatment with MINO. These pharmacometabolomic profiles associated with AP-induced hyperphagia and weight gain provide candidate biomarkers and mechanistic insights related to the metabolic side effects of these widely used drugs.

Topics: Animals; Anti-Bacterial Agents; Antipsychotic Agents; Eating; Female; Hyperphagia; Hypothalamus; Metabolome; Mice; Mice, Inbred C57BL; Minocycline; Olanzapine; Weight Gain

Although olanzapine is highly efficacious and most widely used second generation antipsychotic drug, the success of treatment has been hampered by its propensity to induce weight gain. While the underlying neuronal mechanisms are unclear, their elucidation may help to target alternative pathways regulating energy balance. The present study was undertaken to define the role of cocaine- and amphetamine-regulated transcript (CART), a well-known anorexic peptide, in olanzapine-induced hyperphagia and body weight gain in female rats. Olanzapine was administered daily by intraperitoneal route, alone or in combination with CART (intracerebroventricular) for a period of two weeks. Immediately after drug administrations, preweighed food was offered to the animals at the commencement of the dark phase. The food intake and body weight were measured daily just prior to next injection. Furthermore, the brains of olanzapine-treated rats were processed for the immunohistochemical analysis of CART-containing elements in the hypothalamus. Treatment with olanzapine (0.5 mg/kg) for the duration of 14 days produced a significant increase in food intake and body weight as compared to control. However, concomitant administration of CART (0.5 µg) attenuated the olanzapine-induced hyperphagia and weight gain. Olanzapine administration resulted in a significant reduction in CART immunoreactivity in the hypothalamic arcuate, paraventricular, dorsomedial and ventromedial nuclei. We suggest that decreased CART contents in the hypothalamus may be causally linked with the hyperphagia and weight gain induced by olanzapine.

Topics: Animals; Antipsychotic Agents; Body Weight; Eating; Feeding Behavior; Female; Hyperphagia; Hypothalamus; Neuropeptides; Olanzapine; Rats, Sprague-Dawley; Weight Gain

Atypical antipsychotics such as olanzapine often induce excessive weight gain and type 2 diabetes. However, the mechanisms underlying these drug-induced metabolic perturbations remain poorly understood. Here, we used an experimental model that reproduces olanzapine-induced hyperphagia and obesity in female C57BL/6 mice. We found that olanzapine treatment acutely increased food intake, impaired glucose tolerance, and altered physical activity and energy expenditure in mice. Furthermore, olanzapine-induced hyperphagia and weight gain were blunted in mice lacking the serotonin 2C receptor (HTR2C). Finally, we showed that treatment with the HTR2C-specific agonist lorcaserin suppressed olanzapine-induced hyperphagia and weight gain. Lorcaserin treatment also improved glucose tolerance in olanzapine-fed mice. Collectively, our studies suggest that olanzapine exerts some of its untoward metabolic effects via antagonism of HTR2C.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Hyperphagia; Male; Mice; Mice, Inbred C57BL; Olanzapine; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Weight Gain

Excessive weight gain is a major metabolic side effect of second-generation antipsychotics (SGAs) in the treatment of schizophrenia. Ghrelin is an orexigenic hormone secreted mainly from the stomach, which can induce weight gain and hyperphagia through regulating neuropeptides at the hypothalamus. Accumulating evidence implicates a relationship between ghrelin signalling and SGA-induced hyperphagia and weight gain. We report that olanzapine (a SGA with high weight gain liability) potently and time-dependently up-regulate ghrelin and ghrelin signalling, leading to hyperphagia and weight gain in female Sprague-Dawley rats, an action reversed by i.c.v. injection of a ghrelin receptor (GHS-R1a) antagonist. These findings indicate a crucial role of ghrelin signalling in hyperphagia induced by olanzapine, supporting the notion that GHS-R1a antagonist may be useful for pharmacological treatment of SGA-induced weight gain resulted from hyperphagia.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Central Nervous System Agents; Eating; Female; Ghrelin; Hyperphagia; Hypothalamus; Neuropeptides; Olanzapine; Oligopeptides; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; RNA, Messenger; Signal Transduction; Time Factors; Transcription Factors; Up-Regulation; Weight Gain

Although second-generation antipsychotics induce severe weight gain and obesity, there is a lack of detailed knowledge about the progressive development of antipsychotic-induced obesity. This study examined the hypothalamic histamine H1 receptor and AMP-activated protein kinase (H1R-AMPK) signaling at three distinctive stages of olanzapine-induced weight gain (day 1-12: early acceleration, day 13-28: middle new equilibrium, and day 29-36: late heavy weight maintenance). At the early acceleration stage, the rats were hyperphagic with an underlying mechanism of olanzapine-increased H1R mRNA expression and AMPK phosphorylation (pAMPK), in which pAMPK levels positively correlated with H1R mRNA expression and food intake. At the middle stage, when the rats were no longer hyperphagic, the changes in H1R-AMPK signaling vanished. At the late stage, olanzapine increased H1R mRNA expression but decreased pAMPK which were positively and negatively correlated with weight gain, respectively. These data suggest a time-dependent change of H1R-AMPK signaling, where olanzapine activates AMPK by blocking the H1Rs and causing hyperphagia in the acute phase. The chronic blockade of H1R may contribute to the late stage of olanzapine-induced heavy weight maintenance. However, pAMPK was no longer elevated and actually decreased. This indicates that AMPK acts as an energy sensor and negatively responds to the positive energy balance induced by olanzapine. Furthermore, we showed that an H1R agonist, 2-(3-trifluoromethylphenyl) histamine, can significantly inhibit olanzapine-induced hyperphagia and AMPK activation in the mediobasal hypothalamus in a dose dependent manner. Therefore, lowering H1R-AMPK signaling is an effective treatment for the olanzapine-induced hyperphagia associated with the development of obesity.

Topics: Adenylate Kinase; Animals; Antipsychotic Agents; Benzodiazepines; Female; Hyperphagia; Olanzapine; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Signal Transduction; Time Factors; Weight Gain

Weight gain and its related metabolic disorders are major side effects associated with second generation antipsychotic drug treatment. The dorsal vagal complex (DVC) and AMP-activated protein kinase (AMPK) are implicated in the regulation of food intake and body weight. Blocking the histamine H1 receptor contributes to antipsychotic-induced weight gain. The present study investigated the time-dependent effect of olanzapine treatment (8, 16, and 36 d) on DVC AMPK signaling in olanzapine-induced weight gain and whether these changes are associated with olanzapine-induced H1 receptor antagonism. During the 8-day olanzapine treatment, the rats were hyperphagic and rapidly gained weight. The phosphorylation of AMPK (pAMPK) (activated AMPK) as well as its directly downstream phospho-acetyl-coenzyme A carboxylase was significantly increased. The pAMPK/AMPK ratio, an indicator of AMPK activity, was significantly positively correlated with feeding efficiency and weight gain. As treatment was prolonged (16 and 36 d of olanzapine treatment), the rats were no longer hyperphagic, and there were no longer any changes in DVC AMPK signaling. Although the DVC H1 receptor protein expression was not significantly altered by olanzapine, the pAMPK expression was significantly positively correlated with the H1 receptor level after the 8-, 16-, and 36-day olanzapine treatments. Moreover, we showed that an H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine, significantly inhibited the olanzapine-induced hyperphagia and DVC AMPK activation in a dose-dependent manner. These results suggest a time-dependent role of DVC AMPK in olanzapine-induced obesity. Thus, olanzapine-induced DVC AMPK activation may be at least partially related to olanzapine's antagonistic effect on the H1 receptor.

Topics: AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Drinking; Eating; Female; Histamine Agonists; Hyperphagia; Medulla Oblongata; Obesity; Olanzapine; Random Allocation; Rats, Sprague-Dawley; Receptors, Histamine H1

Metabolic adverse effects such as weight gain and dyslipidaemia represent a major concern in treatment with several antipsychotic drugs, including olanzapine. It remains unclear whether such metabolic side-effects fully depend on appetite-stimulating actions, or whether some dysmetabolic features induced by antipsychotics may arise through direct perturbation of metabolic pathways in relevant peripheral tissues. Recent clinical and preclinical studies indicate that dyslipidaemia could occur independently of weight gain. Using a rat model, we showed that subchronic treatment with olanzapine induces weight gain and increases adipose tissue mass in rats with free access to food. This effect was also observed for aripiprazole, considered metabolically neutral in the clinical setting. In pair-fed rats with limited food access, neither olanzapine nor aripiprazole induced weight gain. Interestingly, olanzapine, but not aripiprazole, induced weight-independent elevation of serum triglycerides, accompanied by up-regulation of several genes involved in lipid biosynthesis, both in liver and in adipose tissues. Our findings support the existence of tissue-specific, weight-independent direct effects of olanzapine on lipid metabolism.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Weight; Female; Gene Expression Regulation; Hyperphagia; Lipid Metabolism; Lipogenesis; Olanzapine; Piperazines; Quinolones; Rats; Rats, Sprague-Dawley; Triglycerides; Weight Gain

Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug's antagonistic affinity to histamine H₁ receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H₁ receptor agonist and H₃ receptor antagonist) could reduce the body weight/obesity induced by olanzapine. Female Sprague Dawley rats were treated orally with olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings demonstrate that olanzapine-induced body weight gain can partially be reduced by co-treatment with betahistine. Betahistine has H₃ receptor antagonistic effects to increase histamine release, which may augment its direct agonistic effects on H₁ receptors. These findings have important implications for clinical trials using betahistine to control antipsychotic-induced obesity side effects.

Topics: Animals; Antipsychotic Agents; Appetite Depressants; Behavior, Animal; Benzodiazepines; Betahistine; Disease Models, Animal; Drug Interactions; Exploratory Behavior; Feeding Behavior; Female; Histamine Agonists; Histamine H3 Antagonists; Hyperphagia; Motor Activity; Olanzapine; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Weight Gain

Body weight gain is one of the most serious side effects associated with clinical use of antipsychotics. However, the mechanisms by which antipsychotics induce body weight gain are unknown, and no reliable animal models of antipsychotics-induced weight gain have been established. The present studies were designed to establish male rat models of weight gain induced by chronic and acute treatment with antipsychotics. Six-week chronic treatment with olanzapine (5, 7.5, and 10mg/kg/day) in male Sprague-Dawley rats fed a daily diet resembling a human macronutrient diet, significantly increased body weight gain and weight of fatty tissues. In contrast, ziprasidone (1.25, 2.5, and 5mg/kg/day) administration caused no observable adverse effects. We then investigated feeding behavior with acute antipsychotic treatment in male rats using an automated food measurement apparatus. Rats were allowed restricted access to normal laboratory chow (4h/day). With acute olanzapine (0.5, 1, and 2mg/kg, i.p.) treatment in the light phase, food intake volume and duration were significantly increased, while treatment with ziprasidone (0.3, 1, and 3mg/kg, i.p.) did not increase food intake volume or meal time duration. Findings from the present studies showed that chronic treatment with olanzapine in male rats induced body weight gain, and acute injection induced hyperphagia, suggesting that hyperphagia may be involved in the weight gain and obesity-inducing properties of chronically administered olanzapine. These animal models may provide useful experimental platforms for analysis of the mechanism of hyperphagia and evaluating the potential risk of novel antipsychotics to induce weight gain in humans.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Feeding Behavior; Hyperphagia; Male; Olanzapine; Piperazines; Rats; Rats, Sprague-Dawley; Thiazoles; Weight Gain

Olanzapine is known to be advantageous with respect to outcome and drug compliance in patients with schizophrenia. However, olanzapine has adverse effects, including a higher incidence of weight gain and metabolic disturbances, when compared with those of other antipsychotic agents. The mechanisms underlying these adverse events remain obscure. Female rats were orally administered olanzapine (2 mg/kg) or vehicle once a day for 2 weeks to ascertain if hypothalamic AMP-activated protein kinase (AMPK) mediates olanzapine-induced weight gain and hyperphagia. Body weight and food intake in each rat were evaluated every day and every two days, respectively. After the termination of drug treatment, we measured the protein levels of AMPK and phosphorylated AMPK in the hypothalamus using western blot analyses. Olanzapine significantly increased body weight and food intake. The phosphorylation levels of AMPK were significantly elevated by olanzapine. These results suggest that activation of hypothalamic AMPK may mediate hyperphagia and weight gain induced by chronic treatment with olanzapine.

Topics: AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Eating; Female; Hyperphagia; Hypothalamus; Olanzapine; Rats; Rats, Sprague-Dawley; Weight Gain

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance.

Topics: Agouti-Related Protein; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Arcuate Nucleus of Hypothalamus; Benzodiazepines; Clozapine; Feeding Behavior; Female; Gene Expression Regulation; Hyperphagia; Hypothalamus; Injections, Intraventricular; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Neuropeptide Y; Neuropeptides; Olanzapine; Orexins; Phosphorylation; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Ribonucleotides; Signal Transduction; Weight Gain

Olanzapine is a novel antipsychotic drug known to induce clinically significant weight gain. Although the cause of such weight gain is not fully known, drug-induced changes in appetite and food intake are likely to play a significant role together with other possible mechanisms enhancing weight and/or adiposity. We assessed acute drug effects on 1 hour intake and behavioural expression in female rats. Low doses of olanzapine (0.5 and 1 mg/kg) enhanced acute mash intake. Marked drug effects were seen on a number of behaviours following olanzapine over a range of doses. These effects included dose-related reductions in activity and exploratory behaviours and associated substantial dose-related increases in resting behaviour. Behavioural data were also used to plot drug effects over time, including behavioural satiety sequence (BSS) profiles, to evaluate whether olanzapine's hyperphagic effects might be a consequence of altered satiety development. BSS profiles reflected enhanced eating behaviour at low doses (0.5 and 1 mg/kg) but showed dose-related increases in resting, indicative of drug-induced sedation, which meant that it was impossible to fully discern olanzapine's effects on satiety. Acute olanzapine induces both hyperphagia and sedation, both of which may promote weight gain and adiposity, but which interact competitively.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Dose-Response Relationship, Drug; Energy Intake; Exploratory Behavior; Feeding Behavior; Female; Hyperphagia; Olanzapine; Rats; Rats, Wistar; Satiety Response; Weight Gain

This is the first study to examine the effect of subchronic olanzapine (OLZ) on energy homeostasis in rats, covering all aspects of energy balance, including energy intake as metabolizable energy, storage, and expenditure. We further analyzed whether, and by which mechanism, the CB1-antagonist AVE1625 might attenuate OLZ-induced body weight gain. For this purpose, we selected juvenile female Hanover Wistar rats that robustly and reproducibly demonstrated weight gain on OLZ treatment, accepting limitations to model the aberrations on lipid and carbohydrate metabolism. Rats received 2 mg/kg OLZ orally twice daily for 12 days. Body weight and body composition were analyzed. Moreover daily food intake, energy expenditure, and substrate oxidation were determined in parallel to motility and body core temperature. OLZ treatment resulted in substantial body weight gain, in which lean and fat mass increased significantly. OLZ-treated rats showed hyperphagia that manifested in increased carbohydrate oxidation and lowered fat oxidation (FO). Energy expenditure was increased, motility decreased, but there was no indication for hypothermia in OLZ-treated rats. Coadministration of OLZ and AVE1625 (10 mg/kg orally once daily) attenuated body weight gain, diminishing the enhanced food intake while maintaining increased energy expenditure and decreased motility. Our data reveal that energy expenditure was enhanced in OLZ-treated rats, an effect not critically influenced by motility. Energy uptake, however, exceeded energy expenditure and led to a positive energy balance, confirming hyperphagia as the major driving factor for OLZ-induced weight gain. Combination of OLZ treatment with the CB1-antagonist AVE1625 attenuated body weight gain in rats.

Topics: Animals; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Dietary Carbohydrates; Dietary Fats; Energy Intake; Energy Metabolism; Female; Hydrocarbons, Halogenated; Hyperphagia; Obesity; Olanzapine; Oxidation-Reduction; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Sulfonamides; Weight Gain

Atypical antipsychotic-induced weight gain is a significant impediment in the treatment of schizophrenia.. In a putative model of antipsychotic drug-induced weight gain, we investigated the effects of sub-chronic olanzapine on body weight, meal patterns, the expression of genes encoding for hypothalamic feeding-related neuropeptides and the contribution of hyperphagia to olanzapine-induced weight gain in rats.. In experiment 1, female rats received either olanzapine (1 mg/kg, p.o.) or vehicle, twice daily for 7 days, while meal patterns were recorded. At the end of the treatment regimen, we measured the levels of hypothalamic messenger RNAs (mRNAs) encoding neuropeptide-Y (NPY), hypocretin/orexin (HCRT), melanin concentrating hormone and pro-opiomelanocortin. NPY and HCRT mRNA levels were also assessed in a separate cohort of female rats treated acutely with olanzapine (1 mg/kg, p.o.). In experiment 2, we investigated the effect of a pair-feeding paradigm on sub-chronic (1 mg/kg, p.o.) olanzapine-induced weight gain.. In experiment 1, sub-chronic olanzapine increased body weight, food intake and meal size. Hypothalamic neuropeptide mRNA levels were unchanged after both acute and sub-chronic olanzapine treatment. In experiment 2, the restriction of food intake to the level of vehicle-treated controls abolished the sub-chronic olanzapine-induced increase in body weight.. Hyperphagia mediated by drug-induced impairments in satiety (as evidenced by increased meal size) is a key requirement for olanzapine-induced weight gain in this paradigm. However, olanzapine-induced hyperphagia and weight gain may not be mediated via alterations in the expression of the feeding-related hypothalamic neuropeptides examined in this study.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Eating; Female; Hyperphagia; Intracellular Signaling Peptides and Proteins; Neuropeptide Y; Neuropeptides; Olanzapine; Orexins; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Weight Gain

A mouse model of atypical antipsychotic-associated adverse effects was used to compare the liability to induce weight gain, food intake, and metabolic alterations after chronic olanzapine (OL; LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5] benzodiazepine) and ST2472 (ST; 9-piperazin-1-ylpyrrolo[2,1-b][1,3]benzothiazepine) administration. By adding two equipotent doses (3 and 6 mg/kg) of either OL or ST to a high-sweet, high-fat (HS-HF) diet, mice were allowed to self-administer drugs up to 50 days. Body weight and food intake were evaluated daily. Locomotor activity was recorded over 48 h at two different time points. Dyslipidemia was measured by central visceral obesity. Blood serum levels of insulin (IN), glucose (Glu), triglycerides (TGs), nonesterified fatty acids (NEFAs), cholesterol (Ch), and ketone (Ke) bodies were quantified. OL treatment at 3 mg/kg enhanced body weight, whereas at the highest dose, the increase became evident only during the last 10 days of treatment. OL (3 mg/kg) increased HS-HF intake over time, whereas the highest dose reduced intake during the second 10 and final 10 days of administration. Both compounds induced nocturnal hypomotility at the highest dose. In contrast to ST, 3 mg/kg OL elevated serum levels of IN, Glu, TG, NEFA, Ch, and Ke, whereas 6 mg/kg OL elevated those of Glu, TG, and Ch. In contrast, ST did not affect weight gain, food intake, and metabolic markers. Given the similarities between OL-induced obesogenic effects and medical reports, this study further supports the view that ST may represent a new class of agents characterized by a low propensity to induce side effects with promising clinical safety.

Topics: Animals; Benzodiazepines; Body Weight; Hyperphagia; Metabolic Diseases; Mice; Olanzapine; Piperazines; Pyrroles; Thiazepines; Weight Gain

The ability of clozapine to induce weight gain in female rats was investigated in three studies with progressively lowered doses of clozapine. In an initial preliminary high dose study, clozapine at 6 and 12 mg/kg (i.p., b.i.d.) was found to induce weight loss. In a subsequent intermediate dose study, we obtained no evidence for clozapine-induced weight gain despite using identical procedures and doses of clozapine (1-4 mg/kg, i.p., b.i.d.) with which we have observed olanzapine-induced weight gain, hyperphagia, enhanced adiposity and metabolic changes [Cooper G, Pickavance L, Wilding J, Halford J, Goudie A (2005). A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology; 181: 80-89.]. Instead, clozapine induced weight loss without alteration in food intake and muscle mass or changes in levels of glucose, insulin, leptin and prolactin. However, these intermediate doses of clozapine enhanced visceral adiposity and elevated levels of adiponectin. In a final study, low doses of clozapine (0.25-0.5 mg/kg, i.p, b.i.d.) induced weight loss. These data demonstrate that clozapine-induced weight gain can be much more difficult to observe in female rats than olanzapine-induced weight gain. Moreover, these findings contrast with clinical findings with clozapine, which induces substantial weight gain in humans. Clozapine-induced enhanced adiposity appears to be easier to observe in rats than weight gain. These findings, along with other preclinical studies, suggest that enhanced adiposity can be observed in the absence of antipsychotic-induced weight gain and hyperphagia, possibly reflecting a direct drug effect on adipocyte function independent of drug-induced hyperphagia [e.g. Minet-Ringuet J, Even P, Valet P, Carpene C, Visentin V, Prevot D, Daviaud D, Quignard-Boulange A, Tome D, de Beaurepaire R (2007). Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Molecular Psychiatry; 12: 562-571.]. These and other findings which show that the results of studies of antipsychotic treatment in animals do not always mimic clinical findings have important implications for the use of animal models of antipsychotic-induced weight gain. With regard to weight gain the results obtained appear to depend critically on the experimental procedures used and the specific drugs studied. Thus such models are not without limitations. However, they do consistently demonstrate the ability of various ant

Topics: Adiponectin; Adiposity; Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Dose-Response Relationship, Drug; Eating; Female; Hyperinsulinism; Hyperphagia; Models, Animal; Olanzapine; Rats; Rats, Wistar; Research Design; Sex Factors; Weight Gain; Weight Loss

Weight gain induced by some second-generation anti-psychotics such as olanzapine has emerged as a most debilitating side-effect. This study investigates whether co-administration with either ziprasidone or aripiprazole, which have little propensity to induce weight gain, can attenuate the hyperphagic effect of olanzapine. Female hooded-Lister rats (n=8 per group) were treated acutely with either vehicle, olanzapine (1 mg/kg), ziprasidone (1 mg/kg), aripiprazole (2 mg/kg) or olanzapine in combination with ziprasidone or aripiprazole and placed in automated locomotor activity (LMA) boxes with preweighed palatable mash. Food intake and LMA were measured for 60 min postdrug treatment. All olanzapine-treated groups demonstrated significant increases in food intake (P<0.001). This effect was attenuated following co-administration of olanzapine with either ziprasidone or aripiprazole (P<0.001), neither of which affected food intake alone. The lack of hyperphagia induced by aripiprazole and ziprasidone may reflect an inherent pharmacological mechanism preventing weight gain.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Eating; Female; Hyperphagia; Motor Activity; Olanzapine; Piperazines; Quinolones; Rats; Thiazoles; Weight Gain

Olanzapine (OLZ), one of the second-generation atypical antipsychotics (SGAs), has shown relative advantages in patient adherence and outcomes. However, OLZ has also been associated with a higher incidence of weight gain than most other SGAs. Excessive weight gain may in turn contribute to long-term health concerns for some individuals. Zonisamide (ZNS), a medication approved in the United States as an adjunct in the management of epilepsy, has a diverse pharmacological profile, including sodium channel blockade, monoamine enhancement, and inhibition of carbonic anhydrase. ZNS has also been reported to cause weight loss in both humans and rodents. We hypothesized that this profile might be beneficial when co-administered with OLZ. To test this hypothesis, we evaluated the effects of OLZ on body weight, as well as the pathways known to regulate feeding behavior and arousal in the Sprague-Dawley rat. As indicated via c-Fos expression, we found an OLZ-induced activation in the nucleus accumbens and orexin neurons in the lateral hypothalamus. An OLZ-associated development of hyperphagia, weight gain and elevated blood glucose in the rat was also found. These outcomes were attenuated and reversed in the presence of concomitant ZNS. These results suggest the hypothesis that ZNS may effectively treat or prevent weight gain or metabolic changes associated with the SGAs. Future studies of this combination in patients through appropriately designed human clinical studies are encouraged.

Topics: Animals; Anticonvulsants; Appetite Regulation; Benzodiazepines; Biomarkers; Body Weight; Diabetes Mellitus; Female; Hyperglycemia; Hyperphagia; Hypothalamic Area, Lateral; Intracellular Signaling Peptides and Proteins; Isoxazoles; Neurons; Neuropeptides; Nucleus Accumbens; Obesity; Olanzapine; Orexins; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Weight Gain; Zonisamide

Many of olanzapine's (OLZ) actions in humans related to weight regulation can be modelled in female rats (Cooper et al., 2005). Such effects include weight gain, hyperphagia, enhanced visceral adiposity and elevated Levels of insulin and adiponectin. As sex differences have been reported in the effects of antipsychotic drugs, including OLZ, in rats, the current study extended our study in female rats by directly comparing the actions of OLZ in maLes using identical methodology. Individually housed male Han Wistar rats were administered OLZ twice daily (i.p.), at 0, 1, 2, and 4 mg/kg over 21 days. Both differences from, and simiLarities to, the data obtained in females were obtained. Males treated with OLZ showed reduced weight gain, enhanced visceral adiposity and reduced lean muscle mass. There were no accompanying changes in food or water intake. OLZ did not induce changes in plasma levels of insulin, leptin or glucose. Significant elevation of adiponectin was observed. OLZ-treated males displayed elevated prolactin and suppressed testosterone. OLZ's effects in humans can very clearly be most validly modelled in female rats, although the cause(s) of the sex difference in OLZ's actions in rats are not clear. However, the finding that significantly enhanced adiposity is seen in both male and female rats, in other animal species (mice and dogs) and in humans suggests that studies in male rats of OLZ's effects may be of value, by highlighting the consistent ability of OLZ to increase visceral adiposity. It is hypothesized that such adiposity is a key, clinically relevant, common component of OLZ's actions which may be, at Least partially, independent of both OLZinduced weight gain and hyperphagia, and which is induced reliably in male and female rats and other animal species. Possible mechanisms involved in the effects reported are discussed.

Topics: Adiponectin; Adiposity; Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Dose-Response Relationship, Drug; Drinking; Eating; Female; Hyperphagia; Insulin; Leptin; Male; Metabolic Diseases; Olanzapine; Prolactin; Rats; Rats, Wistar; Sex Factors; Testosterone; Weight Gain

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".

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Bulimia; Clozapine; Female; Humans; Hyperphagia; Male; Olanzapine; Pirenzepine; Risk Factors; Surveys and Questionnaires; Weight Gain