Pharmacological interventions for prevention of weight gain in people with schizophrenia.

BACKGROUND: Antipsychotic-induced weight gain is an extremely common problem in people with schizophrenia and is associated with increased morbidity and mortality. Adjunctive pharmacological interventions may be necessary to help manage antipsychotic-induced weight gain. This review splits and updates a previous Cochrane Review that focused on both pharmacological and behavioural approaches to this problem. OBJECTIVES: To determine the effectiveness of pharmacological interventions for preventing antipsychotic-induced weight gain in people with schizophrenia. SEARCH METHODS: The Cochrane Schizophrenia Information Specialist searched Cochrane Schizophrenia's Register of Trials on 10 February 2021. There are no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that examined any adjunctive pharmacological intervention for preventing weight gain in people with schizophrenia or schizophrenia-like illnesses who use antipsychotic medications. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data and assessed the quality of included studies. For continuous outcomes, we combined mean differences (MD) in endpoint and change data in the analysis. For dichotomous outcomes, we calculated risk ratios (RR). We assessed risk of bias for included studies and used GRADE to judge certainty of evidence and create summary of findings tables. The primary outcomes for this review were clinically important change in weight, clinically important change in body mass index (BMI), leaving the study early, compliance with treatment, and frequency of nausea. The included studies rarely reported these outcomes, so, post hoc, we added two new outcomes, average endpoint/change in weight and average endpoint/change in BMI. MAIN RESULTS: Seventeen RCTs, with a total of 1388 participants, met the inclusion criteria for the review. Five studies investigated metformin, three topiramate, three H2 antagonists, three monoamine modulators, and one each investigated monoamine modulators plus betahistine, melatonin and samidorphan. The comparator in all studies was placebo or no treatment (i.e. standard care alone). We synthesised all studies in a quantitative meta-analysis. Most studies inadequately reported their methods of allocation concealment and blinding of participants and personnel. The resulting risk of bias and often small sample sizes limited the overall certainty of the evidence. Only one reboxetine study reported the primary outcome, number of participants with clinically important change in weight. Fewer people in the treatment condition experienced weight gains of more than 5% and more than 7% of their bodyweight than those in the placebo group (> 5% weight gain RR 0.27, 95% confidence interval (CI) 0.11 to 0.65; 1 study, 43 participants; > 7% weight gain RR 0.24, 95% CI 0.07 to 0.83; 1 study, 43 participants; very low-certainty evidence). No studies reported the primary outcomes, 'clinically important change in BMI', or 'compliance with treatment'. However, several studies reported 'average endpoint/change in body weight' or 'average endpoint/change in BMI'. Metformin may be effective in preventing weight gain (MD -4.03 kg, 95% CI -5.78 to -2.28; 4 studies, 131 participants; low-certainty evidence); and BMI increase (MD -1.63 kg/m2, 95% CI -2.96 to -0.29; 5 studies, 227 participants; low-certainty evidence). Other agents that may be slightly effective in preventing weight gain include H2 antagonists such as nizatidine, famotidine and ranitidine (MD -1.32 kg, 95% CI -2.09 to -0.56; 3 studies, 248 participants; low-certainty evidence) and monoamine modulators such as reboxetine and fluoxetine (weight: MD -1.89 kg, 95% CI -3.31 to -0.47; 3 studies, 103 participants; low-certainty evidence; BMI: MD -0.66 kg/m2, 95% CI -1.05 to -0.26; 3 studies, 103 participants; low-certainty evidence). Topiramate did not appear effective in preventing weight gain (MD -4.82 kg, 95% CI -9.99 to 0.35; 3 studies, 168 participants; very low-certainty evidence). For all agents, there was no difference between groups in terms of individuals leaving the study or reports of nausea. However, the results of these outcomes are uncertain given the very low-certainty evidence. AUTHORS' CONCLUSIONS: There is low-certainty evidence to suggest that metformin may be effective in preventing weight gain. Interpretation of this result and those for other agents, is limited by the small number of studies, small sample size, and short study duration. In future, we need studies that are adequately powered and with longer treatment durations to further evaluate the efficacy and safety of interventions for managing weight gain.

Acute effects of single-dose olanzapine on metabolic, endocrine, and inflammatory markers in healthy controls.

Atypical antipsychotics may "directly" influence glucose homeostasis, increasing risk of type 2 diabetes independently of changes in adiposity. Animal models suggest direct effects after even a single dose of certain atypical antipsychotics on glucose dysregulation. Here, we investigated effects of a single-dose olanzapine (OLA) on glucose metabolism in healthy volunteers, thereby minimizing confounding effects of the illness of schizophrenia and adiposity. In a randomized double-blind crossover design, 15 subjects were administered 10 mg of OLA or placebo at 7:00 A.M. on separate study dates. A frequently sampled intravenous glucose tolerance test was initiated 4.25 hours later to assess changes in glucose homeostasis, including an index of insulin sensitivity, disposition index, glucose effectiveness, and acute insulin response to glucose. We also examined effects on cortisol, prolactin, fasting free fatty acids (FFAs), insulin-mediated suppression of FFAs, and adipocytokines (leptin, adiponectin, C-reactive protein, interleukin 6, and tumor necrosis factor α). Complete data for both visits were analyzed for 12 subjects. Olanzapine treatment significantly decreased glucose effectiveness (P = 0.041) and raised fasting glucose over 4.25 hours (P = 0.03) as compared to placebo. Olanzapine was associated with lower serum cortisol (P = 0.003), lower fasting FFA (P = 0.042), and increased prolactin levels (P < 0.0001). We therefore suggest that a single dose of OLA may invoke early changes in some parameters of glucose and lipid metabolism, as well as endocrine indices.

Smoking cessation in women with severe mental illness: exploring the role of exercise as an adjunct treatment.

OBJECTIVE: The aim of this study was to investigate the potential role of exercise in smoking cessation in women with severe mental illness (SMI). METHODS: Semistructured interviews with 12 women diagnosed with SMI receiving smoking cessation treatment were conducted. RESULTS: Participants perceived three roles for exercise in assisting smoking cessation--addressing fears with preexisting chronic health conditions, emotion management and distraction, and weight management. Most participants identified health care providers (HCPs) as needing to play a supportive role in integrating exercise into smoking cessation attempts. CONCLUSION: Findings support a potential role for exercise in facilitating smoking cessation among women with SMI. PRACTICE IMPLICATIONS: HCPs should consider developing referral links with exercise specialists to facilitate smoking cessation in women with SMI.

Topiramate augmentation in clozapine-treated patients with schizophrenia: clinical and metabolic effects.

Clozapine represents the treatment of choice for refractory psychosis, although a significant number of individuals demonstrate suboptimal response to it as well, leading to clozapine augmentation strategies. A variety of agents have been investigated in this regard, including mood stabilizers, such as anticonvulsants. Within this group of medications, topiramate is unique in that it is associated with weight loss, making it an attractive option because of clozapine's notable risk for associated metabolic disturbance. A 12-week naturalistic, open study was carried out to examine the potential benefits of topiramate in clozapine-treated individuals with schizophrenia demonstrating a suboptimal clinical response. We were specifically interested in clinical symptoms, changes in metabolic parameters, and tolerability. A total of 20 subjects were enrolled, and 16 completed the study, including 5 individuals with type 2 diabetes. Topiramate augmentation led to a 14% improvement in total Brief Psychiatric Rating Scale scores (P = 0.0003), a 2.5% decrease in body weight (P = 0.015), and was generally well tolerated, paraesthesia being the most common side effect. These findings support topiramate as a viable augmentation strategy in clozapine partial responders, with evidence of both clinical and metabolic benefits.

Antipsychotic switching for people with schizophrenia who have neuroleptic-induced weight or metabolic problems.

BACKGROUND: Weight gain is common for people with schizophrenia and this has serious implications for a patient's health and well being. Switching strategies have been recommended as a management option. OBJECTIVES: To determine the effects of antipsychotic medication switching as a strategy for reducing or preventing weight gain and metabolic problems in people with schizophrenia. SEARCH STRATEGY: We searched key databases and the Cochrane Schizophrenia Group's trials register (January 2005 and June 2007), reference sections within relevant papers and contacted the first author of each relevant study and other experts to collect further information. SELECTION CRITERIA: All clinical randomised controlled trials comparing switching of antipsychotic medication as an intervention for antipsychotic induced weight gain and metabolic problems with continuation of medication and/or other weight loss treatments (pharmacological and non pharmacological) in people with schizophrenia or schizophrenia-like illnesses. DATA COLLECTION AND ANALYSIS: Studies were reliably selected, quality assessed and data extracted. For dichotomous data we calculated risk ratio (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. The primary outcome measures were weight loss, metabolic syndrome, relapse and general mental state. MAIN RESULTS: We included four studies for the review with a total of 636 participants. All except one study had a duration of 26 weeks or less. There was a mean weight loss of 1.94 kg (2 RCT, n = 287, CI -3.9 to 0.08) when switched to aripiprazole or quetiapine from olanzapine. BMI also decreased when switched to quetiapine (1 RCT, n = 129, MD -0.52 CI -1.26 to 0.22) and aripiprazole (1 RCT, n = 173, RR 0.28 CI 0.13 to 0.57) from olanzapine.Fasting blood glucose showed a significant decrease when switched to aripiprazole or quetiapine from olanzapine. (2 RCT, MD -2.53 n = 280 CI -2.94 to -2.11). One RCT also showed a favourable lipid profile when switched to aripiprazole but these measures were reported as percentage changes, rather than means with standard deviation.People are less likely to leave the study early if they remain on olanzapine compared to switching to quetiapine or aripiprazole.There was no significant difference in outcomes of mental state, global state, and adverse events between groups which switched medications and those that remained on previous medication. Three different switching strategies were compared and no strategy was found to be superior to the others for outcomes of weight gain, mental state and global state. AUTHORS' CONCLUSIONS: Evidence from this review suggests that switching antipsychotic medication to one with lesser potential for causing weight gain or metabolic problems could be an effective way to manage these side effects, but the data were weak due to the limited number of trials in this area and small sample sizes. Poor reporting of data also hindered using some trials and outcomes. There was no difference in mental state, global state and other treatment related adverse events between switching to another medication and continuing on the previous one. When the three switching strategies were compared none of them had an advantage over the others in their effects on the primary outcomes considered in this review. Better designed trials with adequate power would provide more convincing evidence for using medication switching as an intervention strategy.

Exploring the construct validity of the transtheoretical model to structure physical activity interventions for individuals with serious mental illness.

OBJECTIVE: Physical activity intervention research involving individuals with serious mental illness are often not based on any theoretical framework. This study examined the construct validity of the Transtheoretical Model (TTM) in individuals with serious mental illness to guide future physical activity interventions. METHODS: Fifty-four individuals completed surveys that asked about their current stage of change for physical activity, self-efficacy, and perceived advantages and disadvantages of being more physically active. RESULTS: Most individuals reported being in the preparation stage of the TTM. As individuals approached the action and maintenance stages, self-efficacy and perceived benefits of physical activity increased significantly. Although perceived disadvantages decreased with each successive stage, this change was not significant. CONCLUSIONS: This study's findings support the TTM's application in this population to structure physical activity interventions given that self-efficacy, perceived benefits of and barriers to physical activity differed across stages and changes were in the direction predicted by theory.

Insulin resistance and decreased glucose-stimulated insulin secretion after acute olanzapine administration.

The newer atypical antipsychotics, as a class, have been associated with an increased risk of weight gain and metabolic abnormalities. The mechanisms underlying this phenomenon are currently unclear, but there are data to suggest the possibility of an immediate (as opposed to chronic) effect of these drugs. The aim of the present study was to assess the acute effects of olanzapine on specific measures of insulin sensitivity and secretion. Healthy animals were tested in either the hyperinsulinemic-euglycemic or the hyperglycemic clamp. After reaching steady state in the hyperinsulinemic-euglycemic clamp, rats were injected with olanzapine (3 mg/kg sc) and monitored for an additional 130 minutes. In the hyperglycemic clamp, olanzapine was injected approximately 90 minutes before receiving a glucose bolus, and hyperglycemia was maintained via exogenous glucose infusion for an additional 90 minutes. Insulin and C-peptide levels were monitored throughout this clamp.Acute administration of olanzapine significantly lowered the glucose infusion rate due to an increase in hepatic glucose production and a decrease in glucose utilization. Olanzapine pretreatment induced hyperglycemia and markedly decreased plasma insulin and C-peptide in response to the glucose challenge. These findings indicate that olanzapine can directly induce metabolic changes that occur rapidly and well in advance of the changes that might be anticipated as a result of its weight-gain liability. We present novel findings highlighting an olanzapine-induced deficit in beta-cell functioning.

Body mass index, waist circumference and quality of life in individuals with schizophrenia.

OBJECTIVE: The primary objective was to examine the differential relationship between waist circumference, body mass index, and self-reported quality of life in patients with schizophrenia. METHOD: Individuals with DSM-IV schizophrenia (n=90) were interviewed to obtain sociodemographic data, complete a Quality of Life questionnaire (the MOS SF-12) and have measurements taken of height, weight (kg), and waist circumference (cm). Multiple regression analysis was used to assess the associations between adiposity measures (BMI, WC) and quality of life outcomes (PCS, MCS). RESULTS: Mental component score (MCS) was not significantly related to either of the weight related measures. After adjustment for gender and age, both BMI alone and WC alone were significant predictors of PCS. When both BMI and WC were included in the same regression model, only WC remained a significant predictor of PCS. CONCLUSIONS: Quality of life in schizophrenic patients is related to measures of body weight. The relationship is strongest using waist circumference as the primary measure. This provides further support for routinely incorporating this measure within research and clinical assessments.

Validation of a physical activity assessment tool for individuals with schizophrenia.

OBJECTIVE: Increasing physical activity must be one component of lifestyle interventions designed to prevent or treat obesity in schizophrenia and there is now a need to develop low cost, practical and accurate measures of physical activity in this population to identify the prevalence of physical (in)activity and to assess the effectiveness of physical activity interventions. The objective of this study was to provide preliminary validation of the Short-Form International Physical Activity Questionnaire (IPAQ), a measurement tool that could prove useful for both clinicians and researchers in the field. METHOD: Reliability and validity data were collected from a sample of 35 outpatients with a DSM-IV diagnosis of schizophrenia. Test-retest repeatability was assessed within the same week and criterion validity was assessed against an RT3 accelerometer. Spearman's correlation coefficients are reported based on the total reported physical activity (minutes) and estimated energy expenditure. RESULT: We found a correlation coefficient of 0.68 for reliability and 0.37 for criterion validity based on total reported minutes of physical activity. There was a nonsignificant correlation (0.30; p>0.05) between the RT3 data and estimated energy expenditure derived from the IPAQ. CONCLUSION: Although not without limitations, the Short-Form IPAQ, when used with individuals with schizophrenia, exhibits measurement properties that are comparable to those reported in the general population and can be considered as a surveillance tool to assess levels of physical activity.

Use of atypical antipsychotics during pregnancy and the risk of neural tube defects in infants.

OBJECTIVE: Folate deficiency in early pregnancy and maternal adiposity, independent of folate intake, lead to a greater risk of neural tube defects in infants. Atypical antipsychotics cause various degrees of weight gain. The authors assessed folate status and obesity among patients with schizophrenia receiving atypical antipsychotics. METHOD: A sample of 70 inpatients and outpatients (21 of them women) who were taking antipsychotics was randomly selected. Body weight, body mass index, daily folate intake, and folate serum concentrations were determined. RESULTS: The majority of the patients were overweight. Only eight of 37 patients had folate intake above 400 microg/day, the level shown to be protective against neural tube defects. Mean serum folate was significantly lower than in a general hospital group of 810 patients. CONCLUSIONS: Women with schizophrenia who take atypical antipsychotics have a higher risk of neural tube defects in their infants because of the associated low intake of folate and obesity.

Examining strategies to improve accelerometer compliance for individuals living with schizophrenia.

OBJECTIVE: This study examined the feasibility and effect of 2 investigator-based and 2 participant-based strategies on accelerometer wear time in individuals living with schizophrenia in order to improve accelerometry compliance. METHOD: Four adults with schizophrenia were asked to wear an accelerometer for 1 week during the baseline, intervention, and follow-up phases of a study that evaluated exercise counseling. To encourage participants to wear their accelerometers, investigators modeled proper accelerometer use, provided verbal and written instructions, and placed reminder phone calls. Participants were also given wear time logs and reminder magnets. RESULTS: All participants wore their accelerometers for the required amount of time during the study. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Researchers should use multiple techniques to help ensure compliance. Research is needed to identify the most effective combination of strategies for this population.

Effects of intracerebroventricular (ICV) olanzapine on insulin sensitivity and secretion in vivo: an animal model.

The atypical antipsychotics (AAPs) have been associated with an increased risk of type 2 diabetes. While weight gain associated with AAPs is a risk factor for diabetes, preclinical work suggests that among these medications, olanzapine, when given peripherally in a single dose, causes pronounced effects on insulin sensitivity and secretion. Given a critical role of the hypothalamus in control of glucose metabolism, we examined the effect of central administration of olanzapine. Sprague-Dawley rats were treated with a single 75 µg intracerebroventricular (ICV) dose of olanzapine and tested using separate hyperinsulinemic-euglycemic and hyperglycemic clamps. Dosing of olanzapine was established based on inhibition of amphetamine-induced locomotion. In contrast to the single dosing peripheral paradigm, there was no effect of central olanzapine on insulin sensitivity, either with respect to hepatic glucose production or peripheral glucose uptake. Analogous to the peripheral model, a single ICV dose of olanzapine followed by the hyperglycemic clamp decreased insulin (p=0.0041) and C-peptide response (p=0.0039) to glucose challenge as compared to vehicle, mirrored also by a decrease in the steady state glucose infusion rate required to maintain hyperglycemia (p=0.002). In conclusion, we demonstrate novel findings that at least part of the effect of olanzapine on beta-cell function in vivo is central.

Topiramate in schizophrenia: a review of effects on psychopathology and metabolic parameters.

Less than half of patients with schizophrenia obtain full response to antipsychotic drugs and, while clozapine represents the treatment of choice for refractory psychosis, a significant number of individuals remain only partially responsive. Despite a need for augmentation in this subpopulation, to date clear choices have not been forthcoming. Because clozapine, along with the majority of second-generation agents (SGAs), are linked to metabolic disturbances, augmentation strategies that do not further exacerbate these side effects are needed. Topiramate, unlike other anticonvulsants used for augmentation purposes, has been associated with weight loss. This article reviews the safety and efficacy of topiramate in treatment-refractory schizophrenia, including effects on metabolic disturbances, which burden this population. While current evidence specifically examining improvements in psychopathology demonstrates small to moderate benefits with topiramate augmentation, a growing body of evidence suggests that topiramate may have beneficial effects on antipsychotic-induced weight gain. We conclude that topiramate's metabolic profile, taken together with a current lack of evidence supporting a particular augmentation strategy, argues for further well-controlled studies examining its potential as an augmentation strategy in schizophrenia.

Atypical antipsychotics and diabetic ketoacidosis: a review.

RATIONALE: Atypical antipsychotics have been linked to weight gain and type 2 diabetes, but are also associated with diabetic ketoacidosis (DKA), which can occur more acutely and in the absence of weight gain. OBJECTIVES: Our aim was to review current case reports of DKA in the context of atypical antipsychotic treatment to better understand (a) the scope of the problem, (b) its relationship to different atypical agents, (c) risk factors, (d) long-term outcome, and (e) putative mechanisms of action. METHOD: Searches in PubMed/Medline, as well as the University of Toronto's Scholar Portal, were performed for all relevant articles/abstracts in English. RESULTS: Sixty reports, yielding 69 cases, affirm that DKA is a rare but serious risk with almost all atypical antipsychotics; however, liability seems to vary between agents, at least partially mirroring risk of weight gain. Mean age of onset was 36.9 years (range 12-80), with 68 % of cases occurring in males, and 41 % in individuals of African American or African Caribbean descent. Over one third of cases present with either no weight gain or weight loss, and 61 % of these require ongoing treatment for glycemic control. Death occurred in 7.25 % of cases. CONCLUSION: While the underlying mechanisms are not well understood, antipsychotic-related DKA can occur soon after treatment onset and in the absence of weight gain. Although rare, clinicians must remain vigilant given its acute onset and potential lethality.

Atypical antipsychotics and effects of muscarinic, serotonergic, dopaminergic and histaminergic receptor binding on insulin secretion in vivo: an animal model.

The atypical antipsychotics (AAPs) have been associated with increased risk of type-2 diabetes. Evidence suggests direct, drug-related effects independent of weight gain and although mechanisms underlying this phenomenon are unclear, it has been suggested that the heterogeneous receptor binding profile of the AAPs may influence receptors implicated in glucose metabolism. This study aimed to clarify weight gain-independent mechanisms of AAP-induced changes in insulin secretion by deconstructing their binding profile with representative antagonists. Healthy rats were pretreated with a single subcutaneous dose of darifenacin 6 mg/kg (n=10), a selective M(3) muscarinic antagonist; ketanserin 2mg/kg (n=10), a 5HT(2A) antagonist; raclopride 0.3mg/kg (n=11) a selective D(2)/D(3) antagonist; terfenadine 20mg/kg (n=9) a selective H(1) antagonist; or, vehicle (n=11). Hyperglycemic clamps were employed following injection, providing an index of secretory capacity of pancreatic ß-cells. Acute treatment with darifenacin and ketanserin significantly decreased insulin response to glucose challenge as compared to controls, which was confirmed in the darifenacin group by reduced C-peptide levels. Treatment with raclopride resulted in an increased insulin response and a strong tendency to increased C-peptide levels. H(1) blockade did not result in effects on insulin or C-peptide. Results suggest that the effects of antipsychotics on glucose dysregulation may be related to direct inhibitory effects of muscarinic (M(3)) and serotonergic (5HT(2)) antagonism on insulin secretion. Based on the expression of D(2)-like receptors in ß-cells, which mediate inhibition of insulin secretion, we propose that prolonged D(2) blockade with antipsychotics may predispose to depletion of insulin stores and an eventual defect in pancreatic compensation.

Psychiatric illness and obesity: recognizing the "obesogenic" nature of an inpatient psychiatric setting.

OBJECTIVE: The prevalence of obesity and obesity-related diseases is higher among individuals with psychiatric illness than in the general population. This study examined environmental factors that contribute to obesity in one psychiatric hospital in Canada. METHODS: Semistructured interviews were conducted with 25 key stakeholders from multiple professional disciplines at the hospital. Transcribed interviews were analyzed through content analysis with the analysis grid for environments linked to obesity (ANGELO) framework as a categorical template. RESULTS: Factors contributing to obesity in this setting were related to increased energy intake, such as easy access to high-calorie snacks and beverages, and reduced energy expenditure, such as lack of access to staircases. CONCLUSIONS: Psychiatric settings may contribute to the high prevalence of obesity among individuals with psychiatric illness. Ecologically framed interventions are required to address obesity in this population.

Schizophrenia and the incidence of cardiovascular morbidity: a population-based longitudinal study in Ontario, Canada.

OBJECTIVE: Despite the high rates of cardiovascular mortality among people with schizophrenia, little is known about the incidence of cardiovascular morbidity in this population. We assessed whether individuals diagnosed with schizophrenia, in comparison to a population-proxy comparison group (comprised of individuals receiving an appendicitis-related primary diagnosis), would have a significantly greater risk of subsequent readmission to an inpatient or Emergency Department setting with a cardiovascular condition. DESIGN: Using inpatient hospital discharge records from April 1, 2002 to March 31, 2006 in Ontario, Canada, we constructed a population-based cohort study of patients who were followed for a period up to 4 years. Individuals with a primary ICD-10 (F20) schizophrenia diagnosis (n=9815) were matched with persons with a primary ICD-10 appendicitis-related diagnosis (K35-37) on sex, age, average neighbourhood income level, and amount of follow-up time available. We used a Cox regression procedure to estimate group differences in time-to-readmission with a cardiovascular-related diagnosis. RESULTS: Individuals in the Schizophrenia group had a significantly greater adjusted risk of readmission for a cardiovascular event in comparison to individuals in the Appendicitis group [adjusted hazard ratio (AHR)=1.43, 95% CI, 1.22-1.69]. CONCLUSIONS: Given the elevated risk of cardiovascular morbidity among individuals with schizophrenia, our findings add to the importance of screening and intervention programs for metabolic disorders and known cardiovascular risk factors among patients with schizophrenia.