Weight Gain Side Research Articles

Worth the Weight? Olanzapine Prescribing in Schizophrenia. A Review of Weight Gain and Other Cardiometabolic Side Effects of Olanzapine.

About 80% of patients who experience a first episode of psychosis (FEP) will have another within 5 years (1). In a large meta-analysis of randomized controlled trials (RCTs), 12 months of antipsychotic treatment reduced the rate of relapse from 61 to 26% in FEP, and from 64 to 27% in chronic cases (2). Long-term antipsychotic treatment has been associated with a decrease in mortality rates, compared to untreated cases (3). However, compared to the general population, those with schizophrenia still die, on average, 14.5 years earlier (3, 4). Most life years lost relate to poor physical health outcomes—specifically mortality related to cardiovascular disease (CVD) (4). Adverse cardiometabolic side effects of antipsychotics, particularly second-generation antipsychotics (SGA), represent an undeniable contributor to the burden of cardiovascular morbidity and mortality amongst this cohort (5). Olanzapine, a SGA with one of the most significant cardiometabolic side effect profiles (5, 6), continues to be one of the most popular antipsychotics prescribed in schizophrenia (7–9). This commentary will consider some of the most pertinent research assessing the efficacy of olanzapine in schizophrenia management; suggest potential reasons for incongruence observed between guideline recommendations and prescribing practices; and finally, make suggestions as to how olanzapine-induced weight gain—a side effect that often represents the beginning of a series of escalating cardiometabolic derangements–can be recognized and its effects ameliorated. Olanzapine and Weight Gain Amongst those prescribed olanzapine early in psychosis management, 80% experience an increase of ≥7% of their baseline body weight (10, 11). With the exception of clozapine, whether short- or long-term anthropometric outcomes are being assessed, olanzapine is invariably listed as causing the most significant increases amongst users (6). This is not new information–the first review that aggregated data on weight changes following SGA use was published in 1999 (12). In a 2019 meta-analysis of 402 RCTs including data from 53,463 participants with multi-episode schizophrenia, olanzapine remained the antipsychotic most likely to induce clinically significant weight gain after clozapine and zotepine, the latter of which is not licensed in many countries (6). Antipsychotic-induced weight gain (AIWG) is a particularly important side effect, as it mediates cardiometabolic outcomes, including development of type 2 diabetes mellitus (T2DM) and subsequent CVD–the latter being responsible for approximately 60% of the excess mortality amongst those with schizophrenia previously highlighted (13). Aside from drastically reducing life expectancy, such high rates of physical comorbidity increases the personal, social and economic burden on mental illness across the lifespan. Significant weight gain may also influence outcomes related to mental health. AIWG is consistently listed as one of the most distressing side effects of antipsychotic treatment, frequently resulting in partial or complete antipsychotic non-adherence, and future reluctance to engage with treatment (14, 15). Furthermore, research is now emerging suggesting that obesity and metabolic syndrome may be independent predictors of relapse and re-hospitalization amongst those with a Severe Mental Illness (SMI) (16). Due to its significant association with weight gain and other cardiometabolic abnormalities, since 2009 several international guidelines in Europe, the United States, Australia and New Zealand have advised against olanzapine's use as part of first-line psychosis management (17). However, today olanzapine continues to be one of the most popular antipsychotics, extensively prescribed in both FEP and chronic cases, across the spectrum of illness severity and in many jurisdictions (7–9). Considering the cardiometabolic adverse effects of olanzapine are well-documented, what might be the reasons underlying its popularity? Does its prevalent use reflect poor translation of evidence and subsequent guideline recommendations into clinical practice? Or does its popularity reflect an “availability bias”, whereby clinicians ascribe greater efficacy to olanzapine compared to other antipsychotics, simply based on their more familiar and frequent use of olanzapine? It is worth first assessing efficacy data supporting olanzapine, both in symptom reduction and relapse prevention.

Erasing m6A-dependent transcription signature of stress-sensitive genes triggers antidepressant actions

Emerging evidence has shown that stress responsivity and psychiatric diseases are associated with alterations in N6-methyladenosine (m6A) mRNA epigenetic modifications. Fat mass and obesity-associated protein (FTO) is an m6A demethylase that has been linked to increased body mass and obesity. Here, we show that tricyclic antidepressants (TCAs) with weight-gain side effects, such as imipramine and amitriptyline, directly increased FTO expression and activated its epigenetic function in the ventral tegmental area (VTA). VTA-specific genetic disruption of FTO increased stress vulnerability and abolished the antidepressant activity of TCAs, whereas erasing m6A modification in the VTA by FTO overexpression or cycloleucine led to significant antidepressant activity. Mechanistically, both transcriptome sequencing and quantitative PCR revealed that overexpression of FTO in the VTA decreased the transcription of stress-related neuropeptides, such as cocaine- and amphetamine-regulated transcript peptide and urocortin, in the social defeat model, which was mimicked by imipramine, suggesting an m6A-dependent transcription mechanism of stress-related neuropeptides may underlie the responses to antidepressant. Collectively, our results demonstrate that inhibiting m6A-dependent transcription of stress-related genes may work as a novel antidepressant strategy and highlight a previously unrecognized activator of FTO-dependent epigenetic function that may be used for the treatment of other neurological diseases.

Melatonin for Reducing Weight Gain Following Administration of Atypical Antipsychotic Olanzapine for Adolescents with Bipolar Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial.

We aimed to evaluate melatonin effectiveness in weight gain reduction following olanzapine use for 11-17-year-old bipolar disorder patients. Seventy-seven adolescent outpatients, subsequent to their initial diagnosis of bipolar I disorder by a psychiatrist, entered this study. After assessing inclusion and exclusion criteria, 48 patients consented to participate. Twenty-four patients were allocated to receive olanzapine, lithium carbonate, and melatonin, and 24 patients were allocated to receive olanzapine, lithium carbonate, and placebo by simple randomization. The Young Mania Rating Scale (YMRS) was performed at baseline. Before treatment and after 6 and 12 weeks of treatment, weight, height, and body mass index (BMI) were measured. Analysis of variance (ANOVA) with repeated measure and t-test were used to analyze data. Nineteen patients in each group finished the study and their data were entered for analysis. Mean rise in BMI in the melatonin group compared with placebo (2.45 vs. 3.25 respectively) was marginally significant (t = 1.936; df = 36; p = 0.061). ANOVA with repeated measure also showed a marginally significant difference (F = 3.74; df = 1; p = 0.061) between groups and across time in regard to BMI. Mean body weight rise in the melatonin group compared with the placebo group (5.8 kg vs. 8.2 kg respectively) was marginally significant (t = 1.923; df = 28; p = 0.065). ANOVA with repeated measure also showed a marginally significant difference (F = 3.73; df = 1.1; p = 0.056) between groups and across time for body weight. Coadministration of melatonin with olanzapine and lithium carbonate in adolescents with bipolar disorder could reduce the sharp weight gain side effect of these drugs to near significance.

A Complex Case of Suspected Serotonin Syndrome

A Complex Case of Suspected Serotonin Syndrome

Electroacupuncture Reduces Weight Gain Induced by Rosiglitazone through PPARγ and Leptin Receptor in CNS.

We investigate the effect of electroacupuncture (EA) on protecting the weight gain side effect of rosiglitazone (RSG) in type 2 diabetes mellitus (T2DM) rats and its possible mechanism in central nervous system (CNS). Our study showed that RSG (5 mg/kg) significantly increased the body weight and food intake of the T2DM rats. After six-week treatment with RSG combined with EA, body weight, food intake, and the ratio of IWAT to body weight decreased significantly, whereas the ratio of BAT to body weight increased markedly. HE staining indicated that the T2DM-RSG rats had increased size of adipocytes in their IWAT, but EA treatment reduced the size of adipocytes. EA effectively reduced the lipid contents without affecting the antidiabetic effect of RSG. Furthermore, we noticed that the expression of PPARγ gene in hypothalamus was reduced by EA, while the expressions of leptin receptor and signal transducer and activator of transcription 3 (STAT3) were increased. Our results suggest that EA is an effective approach for inhibiting weight gain in T2DM rats treated by RSG. The possible mechanism might be through increased levels of leptin receptor and STAT3 and decreased PPARγ expression, by which food intake of the rats was reduced and RSG-induced weight gain was inhibited.

Impact of caffeine on weight changes due to ketotifen administration.

Prescription of ketotifen as an effective antihistamine in asthma and allergic conditions is associated with side effect of weight gain. Caffeine is an agent which increases thermogenesis and improves energy expenditure and also effective in asthma. The aim of current study was to evaluate caffeine impact in reducing weight gain side effect of ketotifen. Male mice at the weight limit of 20-30 gr in 8 groups were randomly chosen and injected following drug dosages for 45 days intraperitoneally: control group (normal saline 10 ml/kg), three groups of ketotifen (4, 8, 16 mg/kg), three groups of caffeine (4, 8, 16 mg/kg) and one group of ketotifen (4 mg/kg) in combination with caffeine (4 mg/kg). Weight changes have been recorded and assessed every 3 days for 45 days. The results showed that in all dosages of the two drugs, significant weight loss occurred in comparison with the control group. The effect of caffeine on weight loss according to our results, matches with human studies, while ketotifen contradictory to our assumption, resulted in weight loss which probably was related to the difference in metabolic pathways in mice and humans, or maybe the used doses of ketotifen in this study were insufficient to reduce TNF-α production or influence in serotonin release and be effective on appetite or weight gain.

Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia

The present study aimed to examine the changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia. Sixty-two drug naïve, first-episode schizophrenia (SZ group) and 60 healthy individuals (control group) were enrolled in the study. Serum interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) levels, and body weight were measured at baseline for both groups, and repeated for the SZ group at five different time points during 6-month risperidone treatment. At baseline, serum IL-1β, IL-6, and TNF-α levels in the SZ group (53.28 ± 12.62, 33.98 ± 14.13, 50.08 ± 12.86pg/mL, respectively) were significantly higher than those in the control group (23.49 ± 15.27, 15.53 ± 7.16, 32.12 ± 15.23pg/mL, respectively) (p's < 0.001). Within the SZ group, serum IL-1β levels decreased significantly at 2weeks (48.02 ± 16.00pg/mL, p < 0.01) and 1month (44.70 ± 16.63pg/mL, p < 0.001), but then gradually increased at 2months (48.49 ± 18.87pg/mL), 3months (50.59 ± 18.48pg/mL) and 6months (53.64 ± 16.22pg/mL) to the levels comparable to baseline; serum IL-6 levels changed significantly over the course of treatment (p = 0.001), but reached the levels comparable to baseline at 6months (37.13 ± 13.23pg/mL); serum levels of TNF-α increased significantly at 3months (55.02 ± 16.69pg/mL, p < 0.01) and 6months (58.69 ± 13.57pg/mL, p < 0.001); steady and significant weight gain was observed at each follow-up time point (p's < 0.001), from 56.71 ± 9.25kg at baseline to 62.72 ± 9.53kg at 6months. Risperidone treatment is associated with changes in serum pro-inflammatory cytokines levels and weight. There is an initial anti-inflammatory effect that reduces with treatment, potentially due to its weight gain side effect.

Reducing olanzapine-induced weight gain side effect by using betahistine: a study in the rat model

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.

Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: A 12-month randomized, prospective, open- label trial

Medication combinations that improve the efficacy of thiazolidinediones or ameliorate weight-gain side effects of therapy represent an attractive potential treatment for (NASH). The aim of this randomized, open-label trial was to assess the efficacy of rosiglitazone and metformin in combination versus rosiglitazone and losartan, compared to rosiglitazone alone, after 48 weeks of therapy. A total of 137 subjects with biopsy-proven NASH were enrolled and randomly assigned to receive either 4 mg twice-daily of rosiglitazone, 4 mg of rosiglitazone and 500 mg of metformin twice-daily, or 4 mg of rosiglitazone twice-daily and 50 mg of losartan once-daily for 48 weeks. Patients were screened for other etiologies of chronic liver disease, including daily alcohol intake in excess of 20 g. Repeat liver biopsy was performed after 48 weeks of therapy and reviewed in a blinded fashion by a single expert hepatopathologist. The primary aim of the study was to assess for differences between treatment groups in the improvement of steatosis, hepatocellular inflammation, and fibrosis. In total, 108 subjects completed the trial. Primary outcome revealed no significant difference between treatment groups in all histologic parameters (steatosis, P = 0.137; hepatocellular inflammation, P = 0.320; fibrosis, P = 0.229). Overall improvement in steatosis, hepatocellular inflammation, ballooning degeneration, and fibrosis was observed (P ≤ 0.001). Serum aminotransferases were reduced in all three groups (P < 0.001 within treatment, P > 0.05 between groups). Metformin did not significantly mitigate weight gain (P = 0.051). Forty-eight weeks of combination therapy with rosiglitazone and metformin or rosiglitazone and losartan confers no greater benefit than rosiglitazone alone with respect to histopathology.

Medication Adherence and Subjective Weight Perception in Patients with First-Episode Psychotic Disorder

Medication adherence is critical to the management of psychotic disorder. Different factors associated with medication adherence have been investigated in previous studies. However, the association with subjective weight perception, which is related to the weight gain side effect of antipsychotics, has not been thoroughly investigated. Subjective weight perception may not equal objective weight status. This study tests the hypothesis that medication adherence is related to subjective weight perception in a group of patients with first-episode psychotic disorder who have taken antipsychotics for one year. This study recruited 160 participants with one-year histories of first-episode psychotic disorder and measured their actual and perceived weights, amount of weight gain in the past year, body size satisfaction and medication adherence levels. The associations between medication adherence and both the actual and perceived weight status were analyzed controlling for other confounding factors including insight, drug attitude, illness severity and other medication side effects. Stepwise multiple regression analysis found that the participants' perceived weight status, negative attitude toward their drugs and insight were the major factors associated with poor medication adherence. Of the participants who perceived themselves as being overweight, 86% believed that antipsychotics were responsible. Among those who had such beliefs, 72% had reduced their antipsychotic dosages on their own. About half of the participants had gained more than 7% of their baseline weight and 43.1% of the participants were found to be overweight after one year of treatment with antipsychotics. The results of this study indicate that medication adherence is associated with perceived weight status. Healthcare professionals should be aware of this relationship and address this issue early in the management of patients. Apart from weight management programs, education on a correct weight perception should be carried out with the promotion of proper drug attitudes and better insight for the improvement of medication adherence in the early course of psychotic disorder.

The Role of Sleep Dysfunction in Physical Inactivity and its Relationship to Obesity

Natural selection defined our genotype as athletes who sleep 8-9 h each night. Physical activity and sleep exhibit positive synergy, whereby each optimizes quality of and capability for the other. Our sedentary, sleep-restricted lifestyle conflicts with our genotype to generate pathophysiologic phenotypes, especially obesity. Insufficient sleep is pandemic, and other sleep disorders are increasingly common. Sleep dysfunction promotes obesity due to inactivity from sleepiness and to metabolic changes. Obesity is the primary risk factor for obstructive sleep apnea, which commonly disrupts sleep. This represents one of many pathophysiologic vicious cycles involving inactivity, sleep disorders, and obesity. Solutions include better education of the medical community, which remains surprisingly ignorant about these disease processes and therapeutic advantages of exercise and sleep repletion. Doctors commonly prescribe medications with sleep disruption or weight-gain side effects instead of lifestyle modifications. Lifestyle improvements often provide superior treatment to medications and impose no side effects.

EFFECTS OF SECOND GENERATION ANTIPSYCHOTICS ON LEPTIN AND GHRELIN

Abstract Background Weight gain is a major side effect of antipsychotic treatment. Some atypical antipsychotic agents have profound effects on weight. Body weight is regulated by a complex system, including both peripheral and central factors. Two of the hormones that seem to play an important role in the regulation of food intake, energy metabolism, and body weight are leptin and ghrelin. Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation. In this present study it is aimed to compare the effects of five different atypical antipsychotic medications on leptin and ghrelin. Method 112 patients who were treated either with clozapine ( n = 20), olanzapine ( n = 28), risperidone ( n = 22), quetiapine ( n = 20) or amisulpride ( n = 22) as monotherapy for at least one year and age, gender, and body mass index (BMI) matched control group ( n = 23) were assessed cross-sectionally. Ghrelin and leptin levels were measured with enzyme-immunoassay. Results When fasting serum leptin levels were compared between groups, control group had the highest mean value (9.2 ± 6.7) and amisulpride group had the lowest mean value (3.7 ± 2.1) but still there was no statistically significant difference between six groups ( F = 1993, p = 0.084). In the comparison of the mean values of fasting serum ghrelin levels there was a statistically significant difference between groups ( F = 11,473, p = 0.00). In post-hoc analysis it was seen that the control group had the lowest ghrelin level (194.5 ± 86.8). Quetiapine treated group (378.1 ± 260.4) had similar fasting serum ghrelin levels to control group. All the other antipsychotic treatment groups had significantly higher levels of fasting serum ghrelin compared to control group, highest in amisulpride treated group (597.0 ± 150.0). Conclusion The weight-gain side effect of atypical antipsychotics can be related with the orexigenic effect of elevated serum ghrelin rather than leptin deficit. Among the five widely used atypical antipsychotics quetiapine is the only one which does not elevate the ghrelin level.

Effects of second generation antipsychotics on leptin and ghrelin

Background Weight gain is a major side effect of antipsychotic treatment. Some atypical antipsychotic agents have profound effects on weight. Body weight is regulated by a complex system, including both peripheral and central factors. Two of the hormones that seem to play an important role in the regulation of food intake, energy metabolism, and body weight are leptin and ghrelin. Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation. In this present study it is aimed to compare the effects of five different atypical antipsychotic medications on leptin and ghrelin. Method 112 patients who were treated either with clozapine ( n = 20), olanzapine ( n = 28), risperidone ( n = 22), quetiapine ( n = 20) or amisulpride ( n = 22) as monotherapy for at least one year and age, gender, and body mass index (BMI) matched control group ( n = 23) were assessed cross-sectionally. Ghrelin and leptin levels were measured with enzyme-immunoassay. Results When fasting serum leptin levels were compared between groups, control group had the highest mean value (9.2 ± 6.7) and amisulpride group had the lowest mean value (3.7 ± 2.1) but still there was no statistically significant difference between six groups ( F = 1993, p = 0.084). In the comparison of the mean values of fasting serum ghrelin levels there was a statistically significant difference between groups ( F = 11,473, p = 0.00). In post-hoc analysis it was seen that the control group had the lowest ghrelin level (194.5 ± 86.8). Quetiapine treated group (378.1 ± 260.4) had similar fasting serum ghrelin levels to control group. All the other antipsychotic treatment groups had significantly higher levels of fasting serum ghrelin compared to control group, highest in amisulpride treated group (597.0 ± 150.0). Conclusion The weight-gain side effect of atypical antipsychotics can be related with the orexigenic effect of elevated serum ghrelin rather than leptin deficit. Among the five widely used atypical antipsychotics quetiapine is the only one which does not elevate the ghrelin level.