Induced Weight Gain Research Articles

Su1917 Chronic Omeprazole Treatment Induces Weight Gain in Mice When Combined to High Energy Diet

of corticosterone level to baseline in 4 h after indomethacin administration. Indomethacininduced corticosterone rise was inhibited by NBI 27914 injection and these results confirm the critical role of CRF1 receptors in the activation of the HPA axis. Both astressin and astressin2-B injection resulted in a delay of the recovery to basal circulating corticosterone levels. The impaired termination of corticosterone response to indomethacin caused by astressin2-B was followed by aggravation of indomethacin-induced gastric injury. Conclusions: The results suggest that CRF injected into the periphery at the dose, which markedly increased plasma corticosterone levels, may induce protection against indomethacin-produced gastric injury through both CRF1 and CRF2 receptors. CRF2 receptor signaling pathway contributes to the appropriate termination of indomethacin-induced corticosterone secretion and the maintainance of gastric mucosal integrity during ulcerogenic action of indomethacin in rats. The study was supported by grants from RFBR N13-04-01680a and PRAS 5 and 7.

Almost all antipsychotics result in weight gain: a meta-analysis.

IntroductionAntipsychotics (AP) induce weight gain. However, reviews and meta-analyses generally are restricted to second generation antipsychotics (SGA) and do not stratify for duration of AP use. It is hypothesised that patients gain more weight if duration of AP use is longer.MethodA meta-analysis was conducted of clinical trials of AP that reported weight change. Outcome measures were body weight change, change in BMI and clinically relevant weight change (7% weight gain or loss). Duration of AP-use was stratified as follows: ≤6 weeks, 6–16 weeks, 16–38 weeks and >38 weeks. Forest plots stratified by AP as well as by duration of use were generated and results were summarised in figures.Results307 articles met inclusion criteria. The majority were AP switch studies. Almost all AP showed a degree of weight gain after prolonged use, except for amisulpride, aripiprazole and ziprasidone, for which prolonged exposure resulted in negligible weight change. The level of weight gain per AP varied from discrete to severe. Contrary to expectations, switch of AP did not result in weight loss for amisulpride, aripiprazole or ziprasidone. In AP-naive patients, weight gain was much more pronounced for all AP.ConclusionGiven prolonged exposure, virtually all AP are associated with weight gain. The rational of switching AP to achieve weight reduction may be overrated. In AP-naive patients, weight gain is more pronounced.

Phosphorylation of hypothalamic AMPK on serine(485/491) related to sustained weight loss by alpha-lipoic acid in mice treated with olanzapine.

Alpha-lipoic acid (ALA) was shown to suppress atypical antipsychotic drug (AAPD)-induced weight gain. However, its mode of action has remained unidentified. We aimed to identify mechanisms underlying anti-obesity effects of ALA in mice treated with olanzapine. We compared body weight and food intake among vehicle-, olanzapine-, and olanzapine plus ALA-treated mice, and measured hypothalamic AMP-activated protein kinase (AMPK) activity by detecting levels of Thr(172) and Ser(485/491) phosphorylation, which indicate activation and inhibition of AMPK, respectively. Body weights were increased by olanzapine in parallel with increased levels of Thr(172) phosphorylation of hypothalamic AMPK. Initially increased rate of weight gain was diminished as Thr(172) phosphorylation levels were decreased to control levels after 10days of olanzapine treatment. ALA successfully not only prevented olanzapine-induced weight gain but also induced additional weight loss even relative to control levels throughout the treatment period. During the initial stage, ALA's action was indicated by both suppression of olanzapine-induced Thr(172) phosphorylation and an increase in Ser(485/491) phosphorylation levels. However, in the later stage when no more increases in Thr(172) phosphorylation and weight gain by olanzapine were observed, ALA's action was only indicated by increased levels of Ser(485/491) phosphorylation. Our data suggest that anti-obesity effects of ALA may be related to modulation of both Ser(485/491) phosphorylation and Thr(172) phosphorylation of hypothalamic AMPK, while olanzapine-induced weight gain may be only associated with increase in Thr(172) phosphorylation. This might be an important mechanistic clue for thefuture development of anti-obesity drugs beyond control of AAPD-induced weight gain.

(‐)‐Epicatechin: cardiometabolic clinical effects supported by preclinical model (829.2)

Background. Obesity associates with cardiometabolic disruptions. Lifestyle changes and pharmacologic therapies show moderately effective results. (‐)‐Epicatechin (EPI), the most abundant flavanol in cacao, has been associated with better cardiometabolic health.Objective. To assess the effect of EPI in humans and explain findings through a preclinical study.Methods. In humans, we performed a single‐dose of EPI oral metabolic tolerance test and a 1‐week trial, measuring cardiometabolic endpoints. In rats, we induced weight gain and cardiometabolic disruptions by a high‐fat diet; afterwards, EPI was daily administered for 15 days. Weight gain, glycemia, arterial pressure, triglyceridemia, and HDL‐cholesterol were measured; also, immonublot in skeletal muscle and adipose tissue were performed.Results. EPI enhanced lipid oxidation and attenuated hyperglycemia and hypertriglyceridemia during postprandial metabolism. EPI induced weight‐loss, fat loss, and improved cardiometabolic endpoints in humans. In rats, EPI reduced weight gain, blood triglycerides, and hyperglycemia. EPI increased the expression of sirtuins, PCG‐1α, mitofilin, UCP.Conclusions. EPI improved several cardiometabolic risk factors in both humans and animals by modulating energy metabolism. These findings make EPI an attractive candidate for human use in regards of treating obesity and its associated comorbidities.

Randomized controlled clinical trial of a combination therapy of vildagliptin plus an α-glucosidase inhibitor for patients with type II diabetes mellitus.

The aim of this study was to assess the efficacy of a combination therapy of vildagliptin plus an α-glucosidase inhibitor for patients with type II diabetes mellitus. Type II diabetic patients exhibiting poor glycemic control following α-glucosidase inhibitor treatment for at least two months were selected and randomly distributed into vildagliptin and placebo groups. The body weight, fasting blood glucose (FBG), postprandial glucose (PPG), glycated hemoglobin (HBA1c) and blood lipid levels and hepatorenal functions of the patients were determined before and 12 weeks after the trial. Following the trial, the FBG, PPG, HbA1c, cholesterol (CHOL) and triglyceride (TG) levels in the vildagliptin group were significantly decreased compared with the pretreatment levels (P<0.05), whereas only the PPG level in the placebo group decreased (P<0.05). The FBG, PPG and HbA1c levels in the vildagliptin group were markedly lower than those in the placebo group 12 weeks after the trial. A comparison of the body weights and hepatorenal functions before and after the trial or between groups did not show statistically significant differences. The combination therapy of vildagliptin plus an α-glucosidase inhibitor effectively reduced the FBG, PPG and HbA1c levels in patients without inducing weight gain or hepatorenal dysfunction. However, the therapy may have caused a reduction in the blood lipid levels.

Nebivolol induces, via β3 adrenergic receptor, lipolysis, uncoupling protein 1, and reduction of lipid droplet size in human adipocytes

Most β-blockers may induce weight gain, dysglycemia, and dyslipidemia. Nebivolol is a third-generation β1-blocker with vasodilating properties mediated by β3 adrenergic receptors (β3AR). We investigated whether nebivolol is able to induce β3AR-mediated lipolysis, uncoupling protein 1 (UCP1), and size-reduction in human adipocytes. Human visceral (n = 28) and subcutaneous adipose tissue (n = 26) samples were used to obtain differentiated subcutaneous and visceral preadipocytes. Adipocytes were used to verify the effects of nebivolol onlipolysis, uncoupling protein 1 (UCP1) and other genes of the thermogenic program. Lipolysis was induced by isoproterenol and specific β3AR agonist, as expected,and also by nebivolol at 100 nmol/l and by its L-enantiomer at 10 nmol/l (P < 0.01). Nebivolol-mediated lipolysis was blocked by SR59230A, a specific β3AR antagonist, suggesting that nebivolol acts through β3AR in human adipocytes. Interestingly, in human adipocytes, nebivolol activated UCP1, PPARγ coactivator-1α (PGC-1α) and cytochrome c (CYCS) gene expression in a p38 MAPK-dependent manner. Using propranolol (β1 and β2 antagonist) together with nebivolol we showed that the induction of these genes was still present suggesting again β3AR activation. Moreover, nebivolol significantly reduced the diameter of lipid droplets in cultured adipocytes. In summary, nebivolol, through β3AR, is able to induce lipolysis and promote thermogenic and mitochondrial genes. The induction of lipolysis and the thermogenic program could explain the reduction of lipid droplets size. In conclusion, the lower dysmetabolic effects of nebivolol in humans may depend on its β3 agonist activity and the consequent induction of thermogenic program in human adipocytes.

Hypothalamic ghrelin signalling mediates olanzapine-induced hyperphagia and weight gain in female rats

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.

Metabolic issues in schizophrenic patients receiving antipsychotic treatment.

Schizophrenia is a psychotic disorder with a complex pathophysiology and requires treatment that includes long term administration of antipsychotics that is said to be associated with metabolic syndrome. This study was designed to evaluate the impact of seven different antipsychotics prescribed to schizophrenic patients, on development of metabolic syndrome in the patients. A total of 210 patients with schizophrenia (30 patients in each drug therapy group) were recruited according to ICD-10 criteria and were assigned to receive the drug for 16weeks. Measurement of anthropometric (body weight, waist circumference, blood pressure) and biochemical parameters (glucose, insulin, HOMA-IR, triglycerides, LDL, HDL) was done and the patients were subjected to ATP-III defined criteria for metabolic syndrome. Patients undergoing treatment with olanzapine were more prone to metabolic syndrome as the drug induces weight gain after 16weeks of treatment. It also induces dyslipidemia (P<0.001) and hyperglycemia (P<0.01). Clozapine was found to be second most potent drug in inducing metabolic syndrome as the weight in clozapine treated patients increased after 16weeks, along with a significant increase in glycemic (P<0.001) and lipid parameters (P<0.01). Aripriazole and amisulphride are comparatively safer drugs as their role in inducing metabolic abnormalities in schizophrenic patients was insignificant, although the impact of long term administration of these drugs needs to be explored. It is clear from the study that antipsychotic treatment induces metabolic syndrome so, it becomes important that the metabolic and cardiovascular risk factors should be surveillance regularly in schizophrenic patients undergoing antipsychotic treatment.

Long-Term Antidepressant Use and the Risk of Type 2 Diabetes Mellitus

Antidepressant drugs might induce weight gain and increase diabetes risk. We examined the diabetes risk with long-term antidepressant use in a general population. This study was a population-based, nested case-control study using Taiwan's National Health Insurance Research Database between 1998 and 2009. A total of 47,885 patients with type 2 diabetes mellitus (ICD-9 codes: 250.x; excluding 250.x 1 and 250.x 3) and 95,770 controls were identified. We used a conditional logistic regression model for data analysis and 1-year latent period before the diabetes diagnosis to account for the quantification of treatment duration of antidepressant (defined by Anatomic Therapeutic Chemical classification code N06A). Sensitivity analyses were performed using a propensity score matching method, as well as different lengths of latent periods. Compared with nonusers, patients with cumulative antidepressant use (> 2 years) had an increased risk of diabetes (adjusted OR = 1.20; 95% CI, 1.05-1.37). Moreover, increasing mean daily dose or use of selective serotonin reuptake inhibitors or serotonin antagonist and reuptake inhibitors was associated with increased diabetes risk. The increased diabetes risk with long-term antidepressant therapy in patients aged 44 years or less (adjusted OR = 2.39; 95% CI, 1.46-3.90) was higher than that in older adults (adjusted OR = 1.15; 95% CI, 1.00-1.32). The findings suggest that long-term antidepressant use may be associated with an increased risk of type 2 diabetes mellitus, especially for young adults. Therefore, long-term antidepressant use should be evaluated more cautiously for its benefits and the potential risk of diabetes.

EPA-1390 – CRTC3 polymorphisms are not associated with obesity in swiss psychiatric populations

Weight gain and obesity are serious problems associated with psychiatric diseases, in which psychotropic treatments play an important role. The CREB-regulated transcription coactivator 3 ( CRTC3 ) gene was linked to energy balance in animal models, and in humans CRTC3 rs8033595 polymorphism was associated with obesity markers only in Mexican-Americans, a population with a high prevalence of obesity. To determine whether polymorphisms within the CRTC3 gene are associated with adiposity markers in Caucasian psychiatric patients, a population with also a high prevalence of obesity. The association of the CRTC3 rs8033595 and 2 other selected CRTC3 polymorphisms (rs3743401 and rs3902286) was investigated in three independent groups of Caucasian psychiatric patients taking weight gain-inducing psychotropic drugs such as atypical antipsychotics, lithium and valproate (n 1 =168, n 2 =188, and n 3 =448). Body mass index (BMI) was chosen as a marker for obesity. Generalized Additive Mixed Model (GAMM) was used to test the association of CRTC3 polymorphisms with BMI. Obesity prevalence was high in the three psychiatric populations (n 1 :40%, n 2 :28% and n 3 :19%). The three CRTC3 polymorphisms did not deviate from Hardy-Weinberg equilibrium and the minor allelic frequency (MAF) was 44%, 25% and 19% for CRTC3 rs8033595, rs3743401 and rs3902286 , respectively. None of the CRTC3 polymorphisms were found to be associated with BMI in any of the three psychiatric samples and when analyzing the combined samples together. CRTC3 polymorphisms seem not to have an influence on adiposity markers (BMI) in Caucasian psychiatric patients receiving drugs inducing weight gain.

Quinoline- and Isoquinoline-Sulfonamide Analogs of Aripiprazole: Novel Antipsychotic Agents?

The introduction of typical antipsychotics over six decades ago signaled an important milestone in psychiatry. However, second-generation antipsychotics ameliorated the positive symptoms of schizophrenia but displayed limited effectiveness for the negative and cognitive symptoms. In addition, while the newer antipsychotics produced fewer motor side effects, the atypical antipsychotics still induced weight gain and endocrinopathies. In recent years, a third generation of antipsychotics was identified. Aripiprazole was the first approved drug acting as a D2 partial agonist/functionally selective ligand. This review presents the state of the development of novel antipsychotic dopaminergic and non-dopaminergic agents, supported by an overview of the compounds evaluated under advanced preclinical and clinical development (e.g., cariprazine and brexpiprazole). In line with the recent trends in the development of modern atypical antipsychotics, we present our strategic development of long-chain arylpiperazine-derived quinoline- and isoquinoline-sulfonamide displaying a multireceptor binding profile and partial D2 receptor agonism.

In Vivo Pharmacological Evaluations of Novel Olanzapine Analogues in Rats: A Potential New Avenue for the Treatment of Schizophrenia

Olanzapine (Olz) is one of the most effective antipsychotic drugs commonly used for treating schizophrenia. Unfortunately, Olz administration is associated with severe weight gain and metabolic disturbances. Both patients and clinicians are highly interested in the development of new antipsychotics which are as effective as atypical antipsychotics but which have a lower propensity to induce metabolic side effects. In the present study, we examined two new derivatives of Olz; OlzEt (2-ethyl-4-(4′-methylpiperazin-1′-yl)-10Hbenzo[b]thieno[2,3-e][1,4]diazepine), and OlzHomo (2-ethyl-4-(4′-methyl-1′,4′-diazepan-1′-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine), for their tendency to induce weight gain in rats. Weight gain and metabolic changes were measured in female Sprague Dawley rats. Animals were treated orally with Olz, OlzEt, OlzHomo (3 or 6 mg/kg/day), or vehicle (n = 8), three times daily at eight-hour intervals for 5 weeks. Furthermore, a phencyclidine (PCP)-treated rat model was used to examine the prevention of PCP-induced hyperlocomotor activity relevant for schizophrenia therapy. Male Sprague Dawley rats were pre-treated with a single dose (3 mg/kg/day) of Olz, OlzEt, OlzHomo, or vehicle (n = 12), for 2 weeks. Locomotor activity was recorded following a subcutaneous injection with either saline or PCP (10 mg/kg). Olz was found to induce weight gain, hyperphagia, visceral fat accumulation, and metabolic changes associated with reduced histamatergic H1 receptor density in the hypothalamus of treated rats. In contrast, OlzEt and OlzHomo presented promising antipsychotic effects, which did not induce weight gain or fat deposition in the treated animals. Behavioural analysis showed OlzEt to attenuate PCP-induced hyperactivity to a level similar to that of Olz; however, OlzHomo showed a lower propensity to inhibit these stereotyped behaviours. Our data suggest that the therapeutic effectiveness of OlzHomo may be delivered at a higher dose than that of Olz and OlzEt. Overall, OlzEt and OlzHomo may offer a better pharmacological profile than Olz for treating patients with schizophrenia. Clinical trials are needed to test this hypothesis.

Cerebral Blood Flow and Glucose Metabolism in Appetite-Related Brain Regions in Type 1 Diabetic Patients After Treatment With Insulin Detemir and NPH Insulin

OBJECTIVETo test the hypothesis that insulin detemir, which is associated with less weight gain than other basal insulin formulations, exerts its weight-modulating effects by acting on brain regions involved in appetite regulation, as represented by altered cerebral blood flow (CBF) or cerebral glucose metabolism (CMRglu).RESEARCH DESIGN AND METHODSTwenty-eight male type 1 diabetic patients (age 36.9 ± 9.7 years, BMI 24.9 ± 2.7 kg/m2, A1C 7.5 ± 0.6%) successfully completed a randomized crossover study, consisting of two periods of 12-week treatment with either insulin detemir or NPH insulin, both in combination with prandial insulin aspart. After each treatment period, patients underwent positron emission tomography scans to measure regional CBF and CMRglu.RESULTSAfter 12 weeks, A1C, daily insulin doses, fasting insulin, and blood glucose levels were similar between treatments. Insulin detemir resulted in body weight loss, whereas NPH insulin induced weight gain (between-treatment difference 1.3 kg; P = 0.02). After treatment with insulin detemir relative to NPH insulin, CBF was higher in brain regions involved in appetite regulation, whereas no significant difference in CMRglu was observed.CONCLUSIONSTreatment with insulin detemir versus NPH insulin resulted in weight loss, paralleled by increased CBF in appetite-related brain regions in the resting state, in men with well-controlled type 1 diabetes. These findings lend support to the hypothesis that a differential effect on the brain may contribute to the consistently observed weight-sparing effect of insulin detemir.

Chronic treatment with olanzapine increases adiposity by changing fuel substrate and causes desensitization of the acute metabolic side effects

Atypical antipsychotic drugs such as olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these metabolic side-effects are unknown at the moment. In this study, we investigated the metabolic changes induced by a chronic treatment, as well as the influence of a preceding chronic treatment on the acute effects of olanzapine on glucose metabolism. The effect of chronic olanzapine treatment (±6.5mg/kg/day, administered via drinking water) on body weight, locomotor activity, body temperature, fat distribution and energy expenditure was investigated in male rats. After 5weeks, the animals received an acute olanzapine challenge (intragastric, IG) at 3mg/kg/h during 160min to investigate the acute effects of olanzapine on glucose metabolism. Chronic olanzapine-treated animals showed a slight decrease in nocturnal body temperature, and increased perirenal fat pad weights as well as plasma leptin. In addition, chronic olanzapine-treated animals showed hyperinsulinaemia with unchanged blood glucose concentrations. The acute challenge with IG olanzapine elevated blood glucose levels and endogenous glucose production in control animals, but not in chronic olanzapine-pre-treated rats. Chronic olanzapine-treated animals also showed reduced locomotor activity and a higher respiratory exchange ratio. Thus, chronic treatment with olanzapine in rats causes desensitization to its acute effects on glucose metabolism but promotes adiposity probably due to a shift from lipids to carbohydrates as an energy source. Chronic exposure to olanzapine changes body fat distribution and insulin sensitivity in an unfavourable direction, but it is still unclear what the primary mechanism is.

Suppression of Adipogenesis and Obesity in High-Fat Induced Mouse Model by Hydroxylated Polymethoxyflavones

This study demonstrated that hydroxylated polymethoxyflavones (HPMFs) effectively and dose-dependently suppressed accumulation of lipid droplets in adipocytes by approximately 51-55%. Western blot analysis revealed that HPMFs markedly down-regulated adipogenesis-related transcription factors peroxisome proliferator-activated receptor (PPAR) γ and sterol regulatory element-binding protein (SREBP)-1c as well as downstream target fatty acid binding protein 2 (aP2), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). In addition, HPMFs also activated adenosine monophosphate-activated protein kinase (AMPK) signaling in 3T3-L1 adipocytes. In the early phase of adipogenesis, HPMF-treated preadipocytes displayed a delayed cell cycle entry into G2/M phase at 24 h (35.5% for DMI group and 4.8% for 20 μg/mL HPMFs-treated group) after initiation of adipogenesis. Furthermore, administration of HPMFs (0.25 and 1%) decreased high-fat diet (HFD) induced weight gain (15.3 ± 3.9 g for HFD group, 10.3 ± 0.3 g and 7.9 ± 0.7 g for 0.25 and 1% HPMFs groups, respectively) and relative perigonadal, retroperitoneal, mesenteric fat weight in C57BL/6 mice. Administration of HPMFs reduced serum levels of aspartate aminotransferase (GOT), alanine aminotransferase (GPT), triglycerides (TG), and total cholesterol (T-cho). The results suggested that HPMFs may have a potential benefit in preventing obesity.

Dysfunctional Cardiac Lipid Metabolism in Cystathionine-Beta-Synthase Deficient Mice With Diet-Induced Weight Gain

Obesity is characterized by ectopic cardiac lipid deposition. Excess cardiac lipid accumulation is associated with lipotoxicity and eventually cardiac dysfunction. The molecular mechanisms linking obesity and the development of cardiac lipotoxicity are unknown. Cysteine is a sulfur-containing amino acid required for synthesis of the antioxidant glutathione. Cysteine is supplied by the diet or the transsulfuration of homocysteine by cystathionine-beta-synthase (Cbs). We previously reported mice heterozygous for targeted disruption of Cbs (Cbs +/-) with diet-induced weight gain and glucose intolerance have enhanced cardiac lipotoxicity. We hypothesize that Cbs +/- mice diet-induced weight gain have altered myocardial fatty acid uptake, activation, and oxidation. To address our hypothesis, Cbs +/+ and Cbs +/- mice were fed a high-fat diet (HFD) from weaning for 20 weeks to induce weight gain and glucose intolerance. Cbs +/- mice fed HFD had higher fasting blood glucose concentrations (P<0.01) and greater glucose intolerance (P<0.01) than Cbs +/+ mice fed the HFD. Cbs +/+ and Cbs +/- mice fed the HFD had higher fasting insulin concentrations (P<0.01) compared to mice fed chow diet. Cbs +/- mice had lower total adiponectin concentrations (P<0.06) in plasma compared to Cbs +/+ mice. An interaction was observed between diet and genotype for high molecular weight (HMW) adiponectin concentrations in plasma, with lower HMW adiponectin concentrations (P<0.01) in Cbs +/- mice than Cbs +/+ mice fed chow diet. When assessing the heart, Cbs +/- mice had higher heart weights (P<0.01) compared to Cbs +/+ mice. Interventricular septum thickness in Cbs +/+ and Cbs +/- fed HFD was greater during both end systole (P<0.01) and diastole (P<0.01). Left ventricle performance was also higher for measurements such as ejection fraction (P<0.01) and fractional shortening (P<0.01) than in chow fed mice. This was accompanied by increased expression of markers of fatty acid uptake (CD36, P<0.01); activation (long-chain acyl CoA synthetase 1, P<0.01); and oxidation (carnitine palmitoyltransferase 1 and acyl CoA oxidase, P<0.01) in heart. These findings demonstrate a novel role for Cbs in the pathology of cardiac lipotoxicity.

FDA Approves Antipsychotic to Treat Bipolar Depression

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessFDA Approves Antipsychotic to Treat Bipolar DepressionAaron LevinAaron LevinSearch for more papers by this authorPublished Online:8 Aug 2013https://doi.org/10.1176/appi.pn.2013.8a13AbstractThe Food and Drug Administration opens an additional door for treating depression in patients with bipolar I disorder.The Food and Drug Administration (FDA) has approved new indications for the atypical antipsychotic medication lurasidone (Latuda; manufactured by Sunovion) in the treatment of patients with depressive episodes associated with bipolar I disorder. The approval covers use of the medication alone and in conjunction with lithium or valproate.“Its utility as monotherapy and adjunctive therapy places the drug in a select position in an area with few other medication choices,” said Roger McIntyre, M.D., a professor of psychiatry and pharmacology at the University of Toronto, in an interview with Psychiatric News. Lurasidone is already approved for use in patients with schizophrenia.Clinical trials indicated that the drug appeared to cause fewer metabolic problems or weight gain than other drugs in its class, said McIntyre, who formerly consulted with Sunovion's Canadian affiliate but does not do so now. “It's as close to weight-neutral as possible.”The existing alternatives, quetiapine (Seroquel) and an olanzapine/fluoxetine combination (Symbyax), both induce weight gain, and the latter is also difficult to titrate, said McIntyre.At APA's 2013 annual meeting in San Francisco in May, McIntyre called weight gain a “brain hazard,” because obesity in bipolar patients lessens chances for recovery from manic episodes and increases their risk for depression.In two six-week clinical trials submitted to the FDA, lurasidone was tested over its complete daily dosing range of 20 mg to 120 mg, and average weight gain was 0.3 kg with monotherapy and 0.1 kg with adjunctive use, said psychiatrist Antony Loebel, M.D., chief medical officer at Sunovion. Trial results were presented in poster sessions at APA's 2012 annual meeting and have been submitted for publication.The new indication should help fill an unmet need for more treatment options that clinicians can use in patients with bipolar depression, Loebel told Psychiatric News. There currently is a mismatch between symptoms and treatment choices, he said. “Most medications approved by the FDA for bipolar disorder address the manic stage. However, patients spend most of their time in the depressive phase and find it more distressing but have fewer options for treatment.”The clinical trials recorded effects on body mass index, lipids, glucose, and insulin. The trials included patients with bipolar I disorder who had a history of depression and at least one manic episode, said Loebel.As with other drugs in its class, the new indications come with black-box warnings noting that lurasidone is not approved for treating elderly patients with dementia-related psychosis. And as is the case with antidepressants, it also includes warnings that clinicians need to monitor patients closely for suicidality as treatment begins. Lurasidone is not approved for use in patients under age 18. ■More about treating depression in bipolar I patients is posted at http://psychnews.psychiatryonline.org/newsarticle.aspx?articleid=1702075. ISSUES NewArchived

Role of Ethnicity in Antipsychotic-Induced Weight Gain and Tardive Dyskinesia: Genes or Environment?

This study explored the role of self-reported ethnicity and genetic ancestry on antipsychotic (AP)-induced weight gain and tardive dyskinesia (TD) in schizophrenia. Ethnicity was determined by self-report as well as Structure analysis of 190 SNPs selected from HapMap3, genotyped using a customized Illumina BeadChip. Age, gender, baseline weight and AP response using Brief Psychiatric Rating Scale were assessed. Multivariate regression models for AP-induced weight gain and TD, based on the Abnormal Involuntary Movement Scale were constructed. African-American ethnicity (self-report, p = 0.021 and Structure analysis, p = 0.042) predicted AP-induced weight gain but not TD (self-report, p = 0.408 and Structure analysis, p = 0.714). Self-reported African-American ethnicity seemed to better predict AP-induced weight gain in schizophrenia compared with genetic ancestry, suggesting a possible role of environmental in addition to genetic factors. Future larger studies are needed to clarify specific gene-environment mechanisms mediating the effect of ethnicity on AP-induced weight gain.

Olanzapine-induced changes in glucose metabolism are independent of the melanin-concentrating hormone system

Atypical antipsychotic drugs such as Olanzapine (Ola) induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these undesired side-effects are currently unknown. Chagnon et al. showed that the common allele rs7973796 of the prepro-melanin-concentrating hormone (PMCH) gene is associated with a greater body mass index in Ola-treated schizophrenic patients. As PMCH encodes for the orexigenic neuropeptide melanin-concentrating hormone (MCH), it was hypothesized that MCH is involved in Ola-induced metabolic changes. We have recently reported that the intragastric infusion of Ola results in hyperglycaemia and insulin resistance in male rats. In order to test in vivo the possible involvement of the PMCH gene in the pathogenesis of Ola side-effects, we administered Ola intragastrically in wild-type (WT) and PMCH knock-out (KO) rats. Our results show that glucose and corticosterone levels, as well as endogenous glucose production, are elevated by the infusion of Ola in both WT and KO animals. Thus, the lack of MCH does not seem to affect the acute effects of Ola on glucose metabolism. On the other hand, these effects might be obliterated by compensatory changes in other hypothalamic systems. In addition, possible modulatory effects of the MCH KO on the long term effects of Ola, i.e. increased adiposity, body weight gain, have not been investigated yet.

Central administration of an orexin receptor 1 antagonist prevents the stimulatory effect of Olanzapine on endogenous glucose production

Atypical antipsychotic drugs such as Olanzapine (Olan) induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these undesired side-effects are currently unknown. It has been shown that peripheral injections of Olan activate neurons in the lateral hypothalamus/perifornical area and that a large part of these neurons are orexin (Ox) A-positive. We investigated further the possible involvement of the central Ox system in the metabolic side-effects of Olan by comparing the hyperglycaemic effects of an intragastric (IG) Olan infusion between animals treated intracerebroventricularly (ICV) with an Ox-1 receptor antagonist (SB-408124) or vehicle. As observed in previous studies IG Olan caused an increase in blood glucose, endogenous glucose production and plasma glucagon levels. ICV pre-treatment with the Ox-1 receptor antagonist did not affect the Olan-induced hyperglycaemia or increased plasma glucagon concentrations, but the increased endogenous glucose production was blunted by the ICV SB-408124 treatment. From these results we conclude that the metabolic side-effects of Olan are partly mediated by the hypothalamic Ox system.