Version July 2025
INTRODUCTION —
Individuals with serious mental illness (SMI; ie, a mental illness such as schizophrenia or bipolar disorder resulting in serious functional impairment) are at greater risk of developing cardiovascular disease than the general population [1]. Cardiovascular disease remains the primary cause of death in most resource-abundant countries, particularly among individuals with SMI. Factors contributing to this include obesity, sedentary or unhealthy lifestyle, diets with more saturated fats and fewer fruits and vegetables, adverse effects of antipsychotic medications, and higher rates of tobacco use [2-17]. The goal of managing increased risk for cardiovascular disease is to prevent the associated early morbidity and mortality associated with it [18]. The lifespan of individuals with SMI is reduced by 15 to 25 years compared with the general population [1].
This topic discusses the factors contributing to cardiovascular disease in individuals with SMI, and the initial interventions (ie, lifestyle change, adjustment in antipsychotic medication, adjunctive medication) aimed at managing antipsychotic-associated obesity. The management of other modifiable risk factors (eg, prevention of type 2 diabetes mellitus, lipid lowering, and antihypertensive therapy) in individuals with or without SMI is found elsewhere. (See "Overview of established risk factors for cardiovascular disease", section on 'Hypertension' and "Overview of established risk factors for cardiovascular disease", section on 'Lipids and lipoproteins' and "Overview of established risk factors for cardiovascular disease", section on 'Diabetes mellitus'.)
PREVALENCE IN MENTAL ILLNESS —
Individuals with serious mental illness (SMI) appear to have a greater biologic predisposition for cardiovascular disease than the general population [19-26]. Cardiovascular disease is a major contributor to the increased mortality in these individuals. The prevalence and relative risk of modifiable risk factors for cardiovascular disease are shown on the table (table 1).
The estimated prevalence of obesity, type 2 diabetes mellitus, hypertension, and dyslipidemia are each higher in individuals with SMI as compared with the general population:
●In a meta-analysis including 120 studies from 43 countries individuals with SMI were three times more likely to have obesity as compared with individuals in the general population (odds ratio 3, 95% CI 2.4-3.8) [27].
●The prevalence of type 2 diabetes mellitus is four to five times higher in individuals with SMI as compared with the general population [28,29].
●Hypertension is two to three times more frequent among people with schizophrenia or bipolar disorder than in the general population [30].
●Individuals with schizophrenia as compared with the general population have higher estimated percentage of individuals with dyslipidemia. It is estimated that 25 to 69 percent of people with schizophrenia have some degree of dyslipidemia [30,31].
MONITORING —
For all individuals with serious mental illness (SMI), we obtain baseline metabolic parameters, provide education about the risks of cardiovascular disease, and review factors that may be contributing to this risk. We monitor individuals with SMI who are taking antipsychotic medication for weight gain, body mass index (BMI), and metabolic abnormalities at regular intervals. The table provides our suggested schedule for monitoring these risk factors (table 2) [11,12].
LIFESTYLE INTERVENTION —
Our preference for first-line treatment of antipsychotic-associated obesity in individuals with serious mental illness (SMI) is with a comprehensive lifestyle intervention including psychoeducation, dietary modification, exercise and behavior modification skills. (See 'Components of lifestyle intervention' below.)
Who we treat — We encourage all individuals who we are treating with antipsychotic medications to engage in lifestyle intervention [32-39]. This is particularly true in individuals with antipsychotic-associated weight gain or obesity (body mass index [BMI] ≥25).
However, patient preference is the determining factor. In individuals who are not immediately amenable to lifestyle interventions, or are unable to participate in lifestyle interventions, we typically offer medication intervention while continuing open discussion and encouraging more gradual adaptations of the intervention that the individual is willing to accomplish (eg, less intensive exercise). (See 'Medication intervention' below.)
Components of lifestyle intervention — A comprehensive lifestyle intervention includes psychoeducation, dietary modification, exercise, and behavior modification skills.
●Psychoeducation – We educate the individual about the risk for cardiovascular disease and review behaviors or activities that may attenuate the risk. (See "Overview of primary prevention of cardiovascular disease in adults".)
●Dietary modification – We review dietary options that are associated with modest weight loss (eg, Mediterranean diet). (See "Obesity in adults: Dietary therapy" and "Healthy diet in adults".)
●Exercise – We review the benefits of regular exercise including weight loss and improved cardiovascular health. (See "Obesity in adults: Overview of management", section on 'Exercise' and "Overview of primary prevention of cardiovascular disease in adults".)
●Self-management skills – We encourage individuals to practice self-management skills including setting realistic goals within a timeframe, regular weigh-ins, self-monitoring of daily food intake, portion control and exercise.
●Address tobacco smoking – We recommend that all patients stop smoking. In the United States, individuals with SMI have a high prevalence of tobacco smoking as compared with the general population [40-45]. Furthermore, individuals with SMI appear to have lower quit rates than the general population [46,47]. For those that are willing to take action, treatment is discussed elsewhere. (See "Overview of smoking cessation management in adults", section on 'Treatment considerations for specific populations' and "Pharmacotherapy for smoking cessation in adults", section on 'Psychiatric illness'.)
Addressing challenges in serious mental illness — Individuals with SMI, as compared with those without SMI, may have unique challenges that make lifestyle change more difficult and place them at greater risk of cardiovascular disease. These include a challenging socioeconomic status, psychiatric symptoms, cognitive impairments, side effects from medications, sedentary lifestyle, diets that are less health conscious, and high rates of tobacco use. The presence of co-occurring disorders and ambivalence about lifestyle change may also contribute to the challenges [1,8-10,30,48-51].
●Socioeconomic status – Persons with SMI are disproportionally affected by poverty and other barriers to routine exercise and healthy eating. These may include difficulty obtaining appropriate athletic shoes or clothing, transportation to sites offering lifestyle change, lack of safe environment to exercise outdoors, limited access to fresh fruits or other healthy food choices [52-54]. Potential strategies to address these issues include [35,55-67]:
•Use of local and community resources (eg, senior centers, community centers, YMCA, churches, local schools)
•Distribution of exercise tutorials or videos
•Organization of group outdoor recreational activities
•Accompany patients to shopping trips at local grocery stores to demonstrate healthy options, obtain local menus, highlight healthy choices, and encourage portion control
●Psychiatric symptoms – Psychiatric symptoms (eg, paranoia, depression, or amotivation) may interfere with patients establishing a therapeutic alliance with lifestyle intervention facilitators [68,69]. This may interfere with consistent treatment and lead to missed appointments and treatment dropout. Potential strategies to address this include:
•Group treatment settings – We encourage treatment in group settings when possible. Group setting may increase motivation, offer peer encouragement, and decrease attrition [59].
•Health-promoting incentives – We encourage the use of health-promoting incentives (eg, pedometers or blood glucose logs) to improve outcomes [58,64].
•Engage support system – We attempt to engage the patient’s support system to enhance motivation. In underserved populations, family involvement is associated with increased engagement in lifestyle interventions. The use of facilitators who call patients to encourage completion of food and exercise logs and problem-solve around program nonadherence may be helpful [59,70].
•Incorporate lifestyle interventions into patient visits – Greater therapeutic alliance may be forged by incorporating lifestyle interventions into visits with established case managers and other known mental health providers, or through the use of peer leaders [64,71]. For example, a peer support specialist may offer to meet the patient in a park and the appointment could be conducted while walking.
●Cognitive impairment – Patients with SMI may also have cognitive impairments. Neuropsychiatric testing in this population reveals deficits in memory, executive function, attention, and processing speed [72]. Techniques that may help individuals with cognitive impairment to overcome limitations include simplification of language, use of visual material (eg, charts, pictures), large font size in printed material, lesson repetition, and use of educational games and mnemonic devices [35].
●Adverse medication effects – Antipsychotic medications are first-line treatment for schizophrenia and are widely used in other mental disorders. Adverse effects of antipsychotic medication add to the challenges faced by individuals with SMI [30,31,73-82].
Adverse effects of commonly used antipsychotic medications are shown on the associated table and discussed further elsewhere (table 3). (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation and other antipsychotic medications: Pharmacology, administration, and side effects".)
•Weight gain – Prolonged use of almost all antipsychotics is associated with weight gain to varying degrees. The weight gain tends to be greater during treatment of antipsychotic-naïve patients compared with patients with a prior history of antipsychotic use [76]. Many second-generation antipsychotics, as compared with first-generation antipsychotics are associated with greater risk of obesity and related cardiometabolic. However, their benefits include fewer extrapyramidal symptoms and movement disorders (table 3) [83-85]. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Metabolic dysregulation'.)
•Sedation – Most antipsychotic medications are sedating. This may make exercise challenging and could inhibit attention during education sessions. Activities may need to be scheduled for the time of day when sedating effects have worn off.
•Anticholinergic effects – Many antipsychotics also have anticholinergic effects, leading in part to dry mouth. Patients often increase consumption of sugar-sweetened beverages to counteract this side effect, and counseling may need to directly address this behavior.
●Co-occurring disorders – Individuals with SMI may have co-occurring disorders (eg, substance use disorder) that affect engagement in treatment. We address these disorders to help improve program engagement. A study of correlates of attendance in a healthy lifestyle intervention shows that as compared with those without any substance use, the odds of attending at least one session were lower for those who reported any drug use [68,69,86].
●Ambivalence – Individuals with SMI may express ambivalence about lifestyle changes. We often use techniques of motivational interviewing to assist in exploring and resolving the ambivalence [51]. When using motivational techniques, we typically use open-ended questions (which allow for the patient to express themselves fully), make affirmative statements supporting positive behaviors, repeat back to the patient their concerns (ie, allow them to feel heard), close with a positive statement that emphasizes the patient strengths, and make concrete suggestions for change.
Further discussion of the use of motivational enhancement in the treatment of substance use disorders is discussed elsewhere. (See "Substance use disorders: Motivational interviewing" and "Overview of psychotherapies" and "Behavioral approaches to smoking cessation".)
Benefits of lifestyle intervention — Aggressive lifestyle modification focused on weight reduction and increased physical activity is the primary therapy for the management of cardiovascular risk in patients in the general population [87-90]. For those individuals that embrace lifestyle intervention we encourage beginning the intervention early in the treatment and continuation of the lifestyle change indefinitely (with or without pharmacotherapy).
In our clinical experience, a lifestyle intervention can help patients with SMI reduce body weight and improve other metabolic abnormalities. However, among patients with SMI, clinical trials of the efficacy of lifestyle interventions have been mixed and the quality of the available efficacy data are limited by methodologic limitations (eg, small sample size, short duration intervention, and variability in intervention components). Specific elements of lifestyle interventions associated with better outcomes in individuals with SMI include: longer duration of treatment (three or more months), active monitoring of both nutrition and exercise, education, and exercise-based sessions [90].
●In a meta-analysis including 17 trials and approximately 2000 participants with SMI, lifestyle interventions (addressing both nutrition and physical activity) produced weight loss compared with control when followed for both <6 and ≥12 months duration, although studies more consistently showed a benefit with ≥12 months duration [91].
●In a randomized trial, 133 participants with obesity (BMI >25) and SMI were assigned to lifestyle modification with the In SHAPE program (consisting of one year of weekly sessions with a fitness trainer and resources for establishing a healthy diet) versus control (one year of fitness club membership plus education) [92]. Patients in the treatment group, as compared with the control group, were more likely to meet predetermined measures of fitness (an increase of >50 meters on the six-minute walk test) or ≥5 percent weight loss (49 versus 41 percent). More participants in the treatment group achieved both fitness and weight objectives (24 versus 9 percent). The In SHAPE intervention was also replicated in a community setting with similar outcomes [93].
●Other reviews and individual studies of lifestyle interventions in those with SMI report mixed results with regards to obesity and metabolic outcomes [71,90,94-107].
Lifestyle intervention has not been directly compared with medication management. Furthermore, the combination of these interventions has not been compared with either as monotherapy.
MEDICATION INTERVENTION
Indications for medication intervention — We prefer a medication intervention (eg, adjustment/change in antipsychotic regimen or dose, addition of adjunctive medication) for individuals under the following circumstances:
●Ongoing weight gain or body mass index (BMI) ≥25 despite three months of lifestyle intervention.
●A weight gain of ≥5 percent of baseline weight within one month of starting an antipsychotic.
●The individual is unable to execute lifestyle change or is unwilling to engage in lifestyle change and is willing to take medication.
●Patient preference to start adjunctive medication at the same time as starting any antipsychotic medication to maximize the potential preventive benefits of adjunctive treatment. (See 'Metformin as first choice for most' below.)
The decision to add a medication intervention to address weight gain can be hastened or delayed, depending on patients’ relative ability and/or willingness to participate in lifestyle interventions. We do not withhold medication treatment if an individual refuses to engage in lifestyle change. All treatment decisions are made using shared decision-making. (See 'Lifestyle intervention' above and 'Medication intervention' above.)
Change antipsychotic dose or agent — We are always cautious in making changes to antipsychotic medications due to concerns of relapse or exacerbation of psychotic symptoms. (See 'Reasons to avoid dose reduction or agent change' below.)
●Dose reduction – For individuals in which it is clinically reasonable to lower an otherwise effective antipsychotic medication dose, we prefer this as the first medication intervention. We carefully review the patient’s medication history, clinical status, and efficacy of current antipsychotic treatment. If clinically reasonable, we gradually reduce the dose (eg, 25 percent or less) while monitoring closely for recurrence of psychiatric symptoms. We monitor on the reduced dose for at least three months to ensure continued clinical stability prior to making further changes. (See 'Reasons to avoid dose reduction or agent change' below.)
If symptoms recur, we rapidly titrate back to the previously effective dose.
The evidence for a dose-dependent relationship with weight gain for most antipsychotics is limited [108]. Doses of antipsychotic medications are found on the table (table 4 and table 5).
●Change agent – Switching antipsychotic medication may be effective in promoting weight loss and addressing increased risk for cardiovascular disease. For example, switching from a medication with a relatively high risk of weight gain and dyslipidemia (eg, quetiapine, olanzapine) to an antipsychotic with lower risk of dyslipidemia (eg, aripiprazole or ziprasidone) may be effective [12,109,110]. When doing this we typically taper one medication while simultaneously titrating the new medication over at least two to three weeks. We monitor closely for adverse effects and psychotic symptom exacerbation. Weight loss may not occur immediately. We observe the patient for at least three months before assessing the effectiveness of the change.
Adverse effects of antipsychotics can be found on the table and are discussed elsewhere (table 3). (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Implementation of medication changes' and "Psychosis in adults: Initial management", section on 'Antipsychotic therapy'.)
Reasons to avoid dose reduction or agent change — For each individual with antipsychotic-associated weight gain we carefully weigh the potential risks (exacerbation of symptoms) and benefits of medication reduction or change. In most cases, we do not lower the dose of the effective medication or change medication. In these cases, we skip this step and consider adjunctive medication. (See 'Adjunctive medications' below.)
●Individuals with prominent suicidality
●Individuals whose symptoms were difficult to stabilize or caused significant psychosocial impairment
●Individuals who have had past recurrence of symptoms with medication change or reduction
●Individuals treated with clozapine for refractory symptoms
Adjunctive medications — Adjunctive medications to reduce antipsychotic-induced weight gain are typically considered after lifestyle intervention and medication dose reduction or agent change are unsuccessful or clinically unreasonable. Additionally, patient preference is strongly considered and in individuals who request starting adjunctive medication at the time of initiation of a new antipsychotic, we agree to this. (See 'Indications for medication intervention' above and 'Metformin as first choice for most' below.)
Metformin as first choice for most — For most individuals who will be treated with adjunctive medications, metformin is our first choice.
Of the adjunctive treatments that have reported efficacy for treatment of antipsychotic-associated weight gain, metformin represents the best-studied and in our clinical experience demonstrates the best combination of tolerability and efficacy. Metformin is widely identified as the most appropriate first-line agent taking into consideration its efficacy for both weight control and long-term benefits of diabetes prevention as well as its favorable side effect profile.
●Metformin as early intervention – Preventive use of metformin in antipsychotic-naïve individuals who are starting an antipsychotic is under investigation. We provide education regarding the risks of antipsychotic-associated weight gain and the potential benefits of pharmacologic intervention and allow the patient to make a decision regarding taking metformin at the time the individual begins treatment with any antipsychotic.
While some evidence supports early intervention with adjunctive medication to prevent antipsychotic-associated weight gain, the evidence is too limited at this time to recommend an adjunctive medication to be started with every new antipsychotic initiation [111,112].
Meta-analyses and practical guidelines have supported metformin as adjunctive treatment for antipsychotic-associated weight gain including weight gain due to clozapine treatment [112-119].
●In a meta-analysis including 21 trials and 1547 patients taking antipsychotic medications, treatment with metformin, as compared with treatment with placebo, led to a greater mean body weight loss (standardized mean difference -0.61, 95% CI -0.77 to -0.44) [115].
●In a randomized trial investigating metformin for weight loss in individuals with schizophrenia or schizoaffective disorder, 148 outpatients (without diabetes) with BMI ≥27 were assigned to 16 weeks of metformin, titrated up to 2000 mg per day, or placebo [117]. All participants also received weekly diet and exercise counseling during the study. Over 16 weeks, individuals treated with metformin as compared with those treated with placebo showed a greater mean reduction in weight (-3.0 versus -1.0 kg). Metformin was also associated with improvements in triglycerides and hemoglobin A1c. Metformin was well tolerated, with only diarrhea reported more frequently for metformin than for placebo.
The following small trial supports the use of metformin in attenuating weight gain in individuals without prior antipsychotic treatment:
●In a small randomized trial, 40 nonobese inpatient participants with first episode schizophrenia were assigned to treatment with olanzapine (15 mg/day) plus metformin (750 mg per day) or olanzapine (15 mg/day) plus placebo [112]. After 12 weeks, the individuals in the metformin group experienced a lower mean weight gain compared with the placebo group (1.9 versus 6.9 kg).
Discussion of the use of metformin including pretreatment treatment testing, dosing, adverse effects, and contraindications are reviewed in detail elsewhere (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Suggested approach to the use of metformin'.)
Other agents — Other agents that have shown evidence of effect in the treatment of antipsychotic-associated weight gain include liraglutide, olanzapine-samidorphan combination, and topiramate [113,114,120-130]. However, limited data support the use of these agents in patients with SMI. Our choice from among these agents is based on prior history, patient preference, the presence of co-occurring conditions, and is made using shared decision-making.
Glucagon-like peptide agents — For individuals in whom metformin is ineffective (eg, failure to lose >5 percent of baseline weight after a three-month trial of metformin in overweight or obese individuals taking an antipsychotic, or the failure to prevent >5 percent weight gain within three months of starting metformin in conjunction with the initiation of a new antipsychotic), or clinically undesirable, our next choice is treatment with the glucagon-like peptide receptor agonist, liraglutide. Semaglutide or tirzepatide are reasonable alternative agents. The need for frequent subcutaneous injections may limit the use of each of these agents as viable options in individuals with SMI.
When administering liraglutide, we begin 0.6 mg subcutaneously per day on week 1. We increase to 1.2 mg per day for week 2 and then to a final target dose of 1.8 mg per day starting week 3, as tolerated. Common side effects include nausea, abdominal discomfort, and diarrhea. In our experience, the titration may need to be slowed due to gastrointestinal side effects. Rarely, liraglutide has been associated with hypoglycemia, pancreatitis, cholelithiasis, and cholecystitis. Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2.
In a randomized trial investigating the effect liraglutide on individuals with schizophrenia, obesity and prediabetes, 103 participants who were taking either olanzapine or clozapine were assigned to treatment with liraglutide versus placebo for 16 weeks [121]. Subjects receiving liraglutide, as compared with those receiving placebo lost more weight (-4.7 versus 0.5 kg, respectively), and had a greater reduction in BMI (-1.6 versus 0.08, respectively).
Glucagon-like peptide agents (eg, liraglutide, semaglutide, tirzepatide) have each demonstrated remarkable efficacy for weight loss in the general population [122,123,125], especially for semaglutide and tirzepatide. However, evidence of efficacy for weight loss in persons taking antipsychotic medication or with SMI is currently limited to liraglutide [121,126].
While the limited evidence suggests potentially greater efficacy compared with metformin, studies to date with liraglutide are limited to approximately 150 participants. Furthermore, the need for daily subcutaneous injections limits the acceptability and feasibility for a substantial number of people with schizophrenia, and issues with affordability/insurance coverage represents another hurdle for the use of this class of medication.
Guidance on the use of glucagon-like peptide agonists in the treatment of obesity in adults is found elsewhere. (See "Obesity in adults: Drug therapy", section on 'Preferred medications'.)
Topiramate — Although less well studied than metformin, topiramate shows evidence of efficacy for weight loss in patients with SMI with antipsychotic-associated weight gain. However, tolerability of topiramate is often problematic, with sedation, cognitive slowing, and paresthesias in extremities among the more limiting side effects. In particular, we avoid topiramate in individuals taking valproate due to increased risk of hyperammonemia.
Information on prescribing topiramate including dosing and side effects are found elsewhere. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Topiramate' and "Stimulant use disorder: Treatment overview", section on 'Topiramate as first choice' and "Preventive treatment of episodic migraine in adults", section on 'Topiramate' and "Alcohol use disorder: Pharmacologic management", section on 'Topiramate'.)
Topiramate as compared with placebo appears to be associated with greater weight reduction in individuals with schizophrenia who are overweight.
●In a meta-analysis including seven trials with 327 participants with schizophrenia spectrum disorder patients were treated with either topiramate or placebo for up to 24 weeks. At treatment end, individuals treated with topiramate as compared with placebo, led to a greater mean weight reduction (standardized mean difference 3.17 kg, 95% CI -5.55 to -0.73) [127]. Topiramate was well tolerated with a trend towards more paresthesias than in those taking placebo (four trials; relative risk 2.03, 95% CI 0.99-4.18). However, all cause discontinuation was similar between groups.
●In a randomized trial, 66 overweight individuals hospitalized for schizophrenic symptoms were randomly assigned to treatment with topiramate (200 or 100 mg/day) versus placebo [128]. After 12 weeks, weight reduction was greater among patients treated with 200 or 100 mg/day of topiramate compared with placebo (-5.35 or -1.68 versus -0.3 kg). Paresthesia was the only side effect more common in the active treatment groups compared with placebo.
For specific patient populations — We use the following agents based on clinical presentation.
Subjects responding to olanzapine — We typically use olanzapine-samidorphan in individuals with good response to olanzapine who are gaining weight and have failed to respond to metformin. The combination of olanzapine with the opioid antagonist, samidorphan, has been reported to attenuate olanzapine-induced weight [120,130].
However, since samidorphan is only available in a proprietary combination with olanzapine, the decision to use samidorphan is limited to patients for whom olanzapine is also appropriate.
In a randomized trial 561 patients with schizophrenia were assigned to treatment with olanzapine-samidorphan versus olanzapine only for 24 weeks [120]. At study end, the mean percent weight gain from baseline was 4.2 and 6.6, respectively. Additionally, subjects in the olanzapine-samidorphan group were less likely to gain 10 percent or more of their body weight (odds ratio 0.5, 95% CI 0.31-0.80) and had smaller increases in waist circumference (a proxy for central fat accumulation and risk of greater cardiovascular disease and diabetes). Treatment with combined olanzapine-samidorphan resulted in similar improvements in symptoms of schizophrenia compared with olanzapine only group with similar adverse effects including somnolence, increased appetite, and dry mouth.
There are no head-to-head comparisons with other available treatments (eg, metformin). However, in clinical trials, olanzapine-samidorphan, in contrast to metformin, was not associated with any improvements in laboratory-based metabolic endpoints including cholesterol, triglyceride, glucose, HbA1C, or insulin levels [120,130].
Partial response to olanzapine or clozapine — In an individual with SMI and obesity, who has not fully responded (ongoing psychiatric symptoms) to treatment with olanzapine or clozapine, we occasionally augment with aripiprazole.
Aripiprazole appears to be modestly effective in the treatment of antipsychotic-induced weight gain when due to clozapine or olanzapine [113,129].
●In a meta-analysis including three trials and 266 patients who experienced olanzapine and clozapine-induced weight gain, treatment with aripiprazole, as compared with placebo, led to a greater mean weight reduction (standardized mean difference -2.13 kg, 95% CI -2.87 to -1.39) [113].
●In a trial, 207 participants with schizophrenia taking stable doses of clozapine and who had gained at least 2.5 kg with clozapine were randomized to 16 weeks of aripiprazole 5 to 15 mg/day (dosed flexibly, mean dose 11 mg/day) or placebo [129]. Weight change was greater with aripiprazole compared with placebo (-2.53 versus -0.38 kg). Total cholesterol and low-density lipoprotein levels also improved with aripiprazole.
Further discussion of treatment with aripiprazole including indications, dosing and side effects are found elsewhere. (See "Second-generation and other antipsychotic medications: Pharmacology, administration, and side effects".)
ADDRESSING OTHER RISK FACTORS —
We refer individuals with persistent abnormalities of other metabolic parameters such as fasting glucose, HbA1c, lipid profile, or blood pressure change, to a clinician with expertise in treating these disorders (eg, primary care, endocrinologist). Assessment and treatment of metabolic syndrome including managing risk factors, treatment of hypertension, prevention of diabetes, and lowering of serum cholesterol is discussed elsewhere. (See "Overview of established risk factors for cardiovascular disease" and "Overview of primary prevention of cardiovascular disease in adults" and "Metabolic syndrome (insulin resistance syndrome or syndrome X)" and "Overview of hypertension in adults" and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Smoking cessation, e-cigarettes, and tobacco control".)
SUMMARY AND RECOMMENDATIONS
●Cardiovascular disease in serious mental illness (SMI) – Individuals with SMI are at greater risk of developing cardiovascular disease than the general population. Factors contributing to this include obesity, sedentary or unhealthy lifestyle, diets with more saturated fats and fewer fruits and vegetables, adverse effects of antipsychotic medications, and higher rates of tobacco use (table 1).
This topic discusses the factors contributing to cardiovascular disease in individuals with SMI, and the initial interventions aimed at managing antipsychotic-associated obesity. (See 'Introduction' above.)
●Lifestyle intervention – To mitigate the risk of obesity and cardiovascular disease, we regularly counsel patients on the value of lifestyle interventions. We encourage dietary modification, regular exercise, behavior modification skills, and cessation of tobacco smoking. (See 'Lifestyle intervention' above and 'Components of lifestyle intervention' above.)
●Addressing specific challenges – We address the unique challenges to lifestyle intervention that individuals with SMI may face. These include socioeconomic barriers to healthy exercise and diet, psychiatric symptoms, cognitive impairment, adverse medication effects, co-occurring disorders, ambivalence, and high rates of tobacco use (table 3). (See 'Addressing challenges in serious mental illness' above.)
●Medication intervention – We prefer a medication intervention (eg, dose adjustment, change in medication, or adjunctive medication) in the following circumstances (see 'Medication intervention' above):
•Ongoing weight gain after three months of lifestyle intervention
•Weight gain ≥5 percent over their baseline weight within one month of starting medication
•The individual is unwilling or unable to execute a lifestyle intervention
•Patient prefers to start adjunctive medication at the same time as starting an antipsychotic
●Changes to antipsychotic dose or agent – We are always cautious in making changes to antipsychotic medications due to concerns of relapse or exacerbation of psychotic symptoms.
In select individuals in which it is clinically reasonable, we attempt a reduction of up to 25 percent of the antipsychotic dose. We monitor for symptom recurrence for at least three months prior to further changes. (See 'Change antipsychotic dose or agent' above.)
Another option is to change to another agent with a more favorable side effect profile (table 3). (See 'Change antipsychotic dose or agent' above.)
●Reasons to avoid dose reduction or change in agent – We do not make changes to dose or agent in individuals with any of the following. In these cases, we skip these steps and prefer adjunctive medication (see 'Reasons to avoid dose reduction or agent change' above):
•Prominent suicidality
•Symptoms that were difficult to stabilize or caused significant psychosocial impairment
•Recurrence of symptoms with past medication changes
•Treatment with clozapine for refractory schizophrenia
●Adjunctive medication – Adjunctive medications to reduce antipsychotic-induced weight gain are typically used after lifestyle intervention and medication dose reduction or agent change are unsuccessful or clinically unreasonable. (See 'Adjunctive medications' above.)
●Metformin as first choice for most – For individuals with antipsychotic-associated obesity who will be treated with adjunctive medication, we suggest initial treatment with metformin rather than other medications (Grade 2C). (See 'Metformin as first choice for most' above.)
●Glucagon-like peptide agents and others – Other agents that have shown evidence of effect in the treatment of antipsychotic-associated weight gain include glucagon-like peptide agents (eg, liraglutide, semaglutide, tirzepatide) and the antiseizure medication, topiramate. (See 'Other agents' above.)
Additionally, in specific patient populations olanzapine-samidorphan or aripiprazole are alternative options. (See 'For specific patient populations' above.)
●Addressing other risk factors – We refer patients with ongoing weight gain despite lifestyle change and medication intervention and those with other persistent risk factors (ie, dyslipidemia, hypertension, hyperglycemia) for further evaluation and consultation with a provider having expertise in treating these conditions (eg, endocrinologist). (See 'Addressing other risk factors' above.)
