Acta Psychiatr Scand 2015: 132: 97–108 All rights reserved DOI: 10.1111/acps.12445

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA PSYCHIATRICA SCANDINAVICA

Clinical overview

Weight gain and obesity in schizophrenia: epidemiology, pathobiology, and management Manu P, Dima L, Shulman M, Vancampfort D, De Hert M, Correll CU. Weight gain and obesity in schizophrenia: epidemiology, pathobiology, and management.

P. Manu1,2,3, L. Dima4,

M. Shulman1, D. Vancampfort5, M. De Hert6, C. U. Correll1,2,3 1

Objective: To review recent advances in the epidemiology, pathobiology, and management of weight gain and obesity in patients with schizophrenia and to evaluate the extent to which they should influence guidelines for clinical practice. Method: A Medline literature search was performed to identify clinical and experimental studies published in 2005–2014 decade. Results: Weight gain and obesity increase the risk of adult-onset diabetes mellitus and cardiovascular disorders, non-adherence with pharmacological interventions, quality of life, and psychiatric readmissions. The etiology includes adverse effects of antipsychotics, pretreatment/premorbid genetic vulnerabilities, psychosocial and socioeconomic risk factors, and unhealthy lifestyle. Patients with schizophrenia have higher intake of calories in the form of high-density food and lower energy expenditure. The inverse relationship between baseline body mass index and antipsychotic-induced weight gain is probably due to previous antipsychotic exposure. In experimental models, the second-generation antipsychotic olanzapine increased the orexigenic stimulation of hypothalamic structures responsible for energy homeostasis. Conclusion: The management of weight gain and obesity in patients with schizophrenia centers on behavioural interventions using caloric intake reduction, dietary restructuring, and moderate-intensity physical activity. The decision to switch antipsychotics to lower-liability medications should be individualized, and metformin may be considered for adjunctive therapy, given its favorable risk-benefit profile.

The Zucker Hillside Hospital, New York, NY, USA, Albert Einstein College of Medicine, New York, NY, USA, 3Hofstra North Shore – LIJ School of Medicine, Hempstead, NY, USA, 4Faculty of Medicine, Transilvania University, Brasov, Romania, 5KU Leuven Department of Rehabilitation Sciences, Leuven, Belgium and 6 University Psychiatric Centre KU Leuven, Kortenberg, Belgium 2

Key words: schizophrenia; weight gain; obesity; pathobiology; management Peter Manu, Medical Services, The Zucker Hillside Hospital, North Shore – LIJ Health System, 75-59 263rd Street, Glen Oaks, New York, NY, USA. E-mail: [email protected]

Accepted for publication April 27, 2015

Clinical recommendations

• Weight gain is greatest in patients with schizophrenia treated with the second-generation antipsychotics clozapine and olanzapine.

• The antipsychotic-induced weight gain is inversely related to the baseline body mass index, a finding that likely reflects prior antipsychotic exposure or regression to the mean.

• The management of weight gain and obesity in patients with schizophrenia requires frequent monitoring, early recognition, and multidisciplinary treatment. With the exception of metformin, pharmacological interventions to improve the cardiometabolic status are generally not recommended for broad clinical usage.

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Manu et al. Additional comments

• Stigma, negative discrimination, and low socioeconomic status hinder training, education and close • •

personal relationships and limit opportunities for achieving physical fitness and access to healthier food. Poor illness self-management skills, deficits in executive function and memory, residual psychotic symptoms, and substance misuse limit the effectiveness of behavioural intervention and weight reduction. The drugs associated with weight loss in patients with antipsychotic-induced weight gain are metformin, d-fenfluramine, sibutramine, topiramate, and reboxitine. Treatment with amantadine, dextroamphetamine, famotidine, fluoxetine, fluvoxamine, nizatidine, orlistat, phenylpropanolamine, and rosiglitazone was not superior to placebo.

Introduction

Weight gain and obesity are critical issues in patients with schizophrenia. Both can adversely affect the risk of adult-onset diabetes mellitus and cardiovascular disorders, non-adherence with pharmacological interventions, quality of life (1), and psychiatric readmissions (2). Treatment with second-generation antipsychotics is frequently invoked as the cause of weight gain in schizophrenia, but the explanation is multifactorial and includes pretreatment and premorbid genetic vulnerabilities, socioeconomic disadvantages, and unhealthy lifestyle (3, 4). The need for early detection of weight gain is great, because weight gain occurs early during antipsychotic exposure (5, 6). The abnormal nutritional status (7) and ‘developmental’ obesity in schizophrenia (8) have been described more than half-century ago. To date, there are over 2600 papers indexed by Medline on the topic of weight gain and obesity in schizophrenia, and the space constraints of this special issue allows only a circumscribed update. Aims of the study

To identify recent clinical and experimental data that have advanced the understanding of obesity in schizophrenia with regard to its genetic, neurotransmitter, hormonal, and psychosocial mechanisms and to clarify the ways in which these data contribute to a rational approach for the prevention and management of weight gain in this patient population. Material and methods

For this narrative review, we performed a Medline literature search to identify the most recent comprehensive descriptions of advances in the epidemi98

ology, pathobiology, and management of weight gain and obesity in the community. We then aimed to find clinical and experimental studies published in the last decade that investigated advances in these areas in patients with schizophrenia and to evaluate the extent to which they should influence guidelines for clinical practice.

Results Epidemiology

From 1980 to 2013, the proportion of adults with a BMI ≥25 kg/m2 has increased worldwide from 29.8% to 38.0% in females and from 28.8% to 36.9% in males (9). In children and adolescents, the prevalence of overweight and obesity has increased by 47.1% in the same interval, which is almost double the change (27.5%) recorded for adults (9). In both developed and developing countries, successive cohorts became heavier most rapidly in the 20–40 years of age group (9). Longterm trends were similar in countries that had low and high rates of obesity in 1980, and no country has shown a significant decrease in the past 33 years (9). Obesity contributes to the increased morbidity for type 2 diabetes mellitus, coronary artery disease, dyslipidemia, arterial hypertension, stroke, sleep apnea, osteoarthritis, and some solid tumors, and is associated with increased all-cause mortality (10). In the United States, obese persons incur 80% higher spending on prescription drugs and 46% higher hospitalizations costs (10). Compared with the general population, patients with early-stage or previously untreated schizophrenia and bipolar disorder have a substantially higher risk to be classified as overweight (BMI = 25–102 cm in men and >88 cm in women) (11, 12).

Weight gain and obesity in schizophrenia Individual antipsychotics have different weight gain potentials (13–19). Among first-generation antipsychotics, low-potency agents, such as chlorpromazine and thioridazine, are associated with a higher risk of weight gain than either mid-potency or high-potency agents (4). Weight gain is greatest with the second-generation antipsychotics, clozapine, and olanzapine. Iloperidone, quetiapine, risperidone, paliperidone, sertindole, and zotepine confer an intermediate risk, whereas amisulpride, aripiprazole, asenapine, lurasidone, and ziprasidone are generally associated with small increases in body weight (4, 12, 13). A post hoc analysis of 4626 patients with schizophrenia, who had completed 3 years of naturalistic antipsychotic monotherapy with clozapine, olanzapine, quetiapine, risperidone, amisulpride, and oral and depot firstgeneration antipsychotics (20), indicated that the mean weight gain was highest with olanzapine (4.2 kg) and lowest with amilsulpride (1.8 kg). Weight accrual was fastest during the first 6 months of treatment and, depending of the drug, 7–15% of patients moved from normal weight to the overweight or obese status (20). All antipsychotics are associated with notable weight gain in antipsychotic-na€ıve and first-episode patients (6, 14, 21–24). For example, in a 12month trial involving patients with first-episode schizophrenia who received antipsychotics considered body weight neutral (amisulpride, ziprasidone, and low-dose haloperidol), each drug was associated with relevant weight gain (9.7, 4.8 and 6.3 kg respectively) (17). These findings are supported by a recent 3-year study of treatment with quetiapine, ziprasidone, and aripiprazole in patients with a first psychotic episode (25). The proportion of patients gaining ≥7% baseline weight was 23% for ziprasidone, 32% for quetiapine, and 45% for aripiprazole. The greatest amount of weight gain associated with antipsychotics in previously drug-naive patients with schizophrenia occurs in the first few months (4). For example, a meta-analysis reported a mean weight gain of about 3.8 kg and a mean gain in BMI of 1.2 kg/m2 within the first 12 weeks of antipsychotic treatment in previously drugnaive patients who were >15 years old (21). In patients with schizophrenia and bipolar disorder treated for ≥48 weeks with olanzapine, 64%, 32%, and 12% of patients gained ≥7%, ≥15%, and ≥25%, respectively, of their baseline body weight (26). Subsets of patients treated with second-generation antipsychotics have a particularly rapid and marked weight gain after exposure. In a retrospective analysis of 1191 patients diagnosed with schizophrenia or schizoaffective disorder treated

with olanzapine (27), approximately 15% of subjects had a rapid change of ≥7% body weight during the first 6 weeks of treatment, with a mean weight gain of 1.8–3.2 kg (about 4% of the baseline body weight) during the first 2 weeks. The mean weight change in this subgroup was higher at the end of the 52 weeks compared with subjects with a slower or no weight increase at 6 weeks. The rapid weight gainers were younger, had a lower baseline BMI, and more likely to report increased food craving (27). Increasing evidence indicates that antipsychotics have greater orexigenic weight gain potential in children and adolescents than in adults (5, 17, 28) and that young patients receiving antipsychotics are at increased risk of being or becoming overweight or obese (5, 29–32). A recent comparison of pooled long-term studies (median followup = 201 days) of patients treated with olanzapine indicated a mean weight gain of 4.8 kg in adults, but 11.2 kg for adolescents (33). The proportion of patients gaining ≥7% of their baseline weight was 55.4% among adults and 89.4% in patients 40 kg/m2 and for patients with obesity-related morbidity with BMI ≥35 kg/m2 after dietary and behavioural interventions. The weight-lowering drugs approved for use in the United States work by reducing appetite through enhanced neurotransmission in the central nervous system (i.e., the 5HT2C agonist lorcaserin, phentermine/topiramate extended release, and naltrexone/bupropion) or by decreasing intestinal fat absorption (orlistat) and should be used only as an adjunct to lifestyle interventions (10, 82, 83). Orlistat is also approved for pediatric patients (84). Compliance is reduced by gastrointestinal adverse effects and increased risk of nephrolithiasis and liver failure for orlistat; headache, dizziness, and increased risk of serotonin syndrome for lorcaserin; and insomnia, irritability, anxiety, and disturbance of attention for phentermine/topiramate; (82) and nausea, constipation, xerostomia, amne-

Weight gain and obesity in schizophrenia sia, seizures, and hepatotoxicity for naltrexone/ bupropion (82). Among promising drugs awaiting completion of regulatory trials are liraglutide, a glucagon-like peptide-1 receptor agonist; and beloranib, a drug that increases fat oxidation and lipolysis (83). However, while these agents are approved for weight loss in obese people in the general population, only orlistat has been studied in randomized trials in patients treated with antipsychotics, and orlistat was not more effective than placebo (85). While the majority of studies have been conducted in adults, in pediatric obese patients, encouraging data have emerged for metformin, exenatide, topiramate, and zonisamide (84). Initiating the discussion about weight gain should be straightforward and use questions such as ‘Do you have any concerns about your weight’ or ‘Do you think your body weight is making your health problems worse’ (86). The patient’s readiness and motivation to participate in a weight reduction programme must be carefully explored taking into account the barriers to behavioural and lifestyle changes. The clinician may need to consciously avoid confrontation and imposing their authority or ideas, but instead rely on collaboration and enhanced patient autonomy (86). Readiness can be tested by the question ‘Some people don’t mind talking about their weight, others don’t want to talk about it at all. How do you feel about this?’ (86). Non-pharmacological interventions. Strategies to minimize or reverse cardiovascular and metabolic adverse effects associated with antipsychotics include foremost healthy lifestyle promotion (Fig. 1a,b). Healthy lifestyle education, instruction, or intervention should always be used prior to considering switching to lower-risk antipsychotics for the sole reason of cardiometabolic risk stabilization or adding medications that reduce weight and/or reverse metabolic abnormalities (1, 22, 85, 87). Psychiatrists should educate patients and those most involved in their care about healthy lifestyle behaviours and should use effective behavioural interventions to motivate patients to make the necessary changes, including smoking cessation, adoption of a healthy diet, and regular physical exercise (85, 88, 89). A meta-analysis of 17 controlled studies reporting the effect of behavioural interventions in 810 patients with schizophrenia spectrum disorders indicated significant reductions in weight ( 3.12 kg), BMI ( 0.94 kg/m2), waist circumference ( 3.6 cm), and body fat ( 2.82%) (1). The interventions were also remarkably suc-

cessful in preventing further weight accrual, as an increase ≥7% was observed in 61.3% of control patients, but in only 29.7% of those receiving behavioural treatment. Follow-up 3.6 months after the intervention ended indicated enduring benefits with regard to weight, but not BMI, suggesting that behavioural interventions to prevent or reduce weight gain should remain part of a comprehensive treatment plan. The attenuation of benefit over time was observed in a recently completed STRIDE trial, a controlled weight loss and lifestyle intervention for individuals taking antipsychotic medications (90). Moderate caloric reduction, a low-fat high-fiber diet, and at least 24 min of moderate-intensity physical activity/day led to a 4.4 kg more weight loss than in the control group after 6 months, but only 2.6 kg after 1 year. In a recent trial of a behavioural weight loss intervention in 291 persons with serious mental illness, of whom 58.1% had schizophrenia or schizoaffective disorder, the mean difference in weight was 3.2 kg at 18 months compared with a control group (75). The goals for the intervention group were moderate-intensity aerobic exercise, choosing healthy snacks, and smaller portions, at least five daily servings of vegetables and fruits, avoid junk food and sugar-sweetened beverages, which were reinforced throughout the trial by targeting deficits in memory and executive function (75). Switching or adding antipsychotics. Antipsychotic switching to a lower-risk agent is another evidencebased approach to addressing antipsychoticrelated weight gain and metabolic abnormalities (Fig. 1a,b). However, the decision to switch antipsychotics should consider the patient’s entire psychiatric and physical condition and the pharmacological profiles of current and proposed drugs (91). In the largest randomized controlled efficacy trial in schizophrenia to date confirmed that weight gain was not associated with clinically relevant efficacy advantages and that switching to agents that were associated with weight loss was associated with similar efficacy outcomes as switching to more weight gain-promoting agents (92). Older switch studies indicated that replacing a high weight gain propensity antipsychotic with a lower-risk antipsychotic (93–97) or switching from antipsychotic polypharmacy to antipsychotic monotherapy (98) is associated with statistically and clinically relevant weight loss, mostly associated with metabolic improvements. For example, in a head-to head prospective, open-label, 12month switch trial, ziprasidone (40–160 mg/day)

103

Manu et al. (a) Baseline: Check body weight, BMI, waist circumference, blood pressure, fasting glucose and lipids, HgA1c, and start lowest risk agent at lowest effective dose

4 week visit:

12 week visit:

8 week visit:

Gauge clinical response, Weight Check

Check weight and blood pressure, and repeat every 3 months. Check, fasting glucose and lipids, HbA1c, and repeat annually*

Gauge clinical response, Weight Check

Do observed clinical benefits outweigh risks of metabolic side effects

Stop antipsychotic or switch to lower risk agent.

No

Yes

Continue to monitor as above

No

>7% weight gain or metabolic complications

Yes

Patient motivated to lose weight?

No

Yes *Repeat more frequently if significant weight gain or symptoms/ signs of diabetes onset (polyuria, polydipsia)

Educate and aggressively manage risk factors, consider referral to medical specialist, continue to monitor as above

Weight loss intervention- see table 1b (75)

(b) Antipsychotic-induced weight gain: BMI 25–30

Hypertension?

Dyslipidemia?

Dysglycemia?

No Yes No

Reinforce healthy lifestyle education and instruction.

BMI over 40?

Insufficient response* after 3–6 months

Yes

Address abnormalities and/or refer to specialist

Insufficient

Start evidence based Refer for supported or response* adjunctive structured behavior after 6 months pharmacotherapy for modification, nutritional antipsychotic induced consult weight gain (ie (tailored to patient and metformin or topiramate) stepped according to risk ** factor levels)

Sufficient response

Sufficient response

Continue to monitor as in figure 1a

Consider combination therapy or referral t for bariatric surgery if indicated due to obesity related complications.

* Response defined as weight loss of >5% and improvement in cardiovascular risk factors (lipids, glucose, HbA1C) ** If on clozapine, adjunctive use of aripiprazole is also an option

led to a decrease in BMI from 35.1 to 32.8 kg/m2, while aripiprazole (5–30 mg/day) decreased the BMI from 35.1 to only 34.9 (99). The absence of a control group continuing their prestudy antipsychotic, lack of standardized psychosocial support during the intervention, and statistical processing that ignored the duration of prior antipsychotic treatment complicates interpretation of this study. Aripiprazole and ziprasidone received the most intense scrutiny for their role in attenuating antipsychotic-related weight gain. A recent metaanalysis of three studies of adjunctive aripiprazole indicated a 2.13 kg mean difference compared 104

Insufficient response* after 3–6 months

Figure 1. (a) Suggested algorithm for cardiometabolic monitoring of patients treated with antipsychotics. (b) Suggested algorithm for managing antipsychotic-related weight gain.

with placebo and a concomitant decrease in cholesterol and triglyceride levels (100). Pharmacological treatment of antipsychotic-related weight gain. When switching to a lower-risk antipsychotic is not an option, medications can also be added to counteract antipsychotic-related cardiometabolic adverse events (Fig. 1a,b). In a metaanalysis of pharmacological strategies in patients with any diagnosis who had gained weight with antipsychotics, only 5 of 15 studied drugs were associated with greater weight loss than placebo: metformin ( 2.94 Kg), d-fenfluramine ( 2.60 kg),

Weight gain and obesity in schizophrenia sibutramine ( 2.56 kg), topiramate ( 2.52 kg) and reboxitine ( 1.90 kg) (85, 87). Treatment with amantadine, dextroamphetamine, famotidine, fluoxetine, fluvoxamine, nizatidine, orlistat, phenylpropanolamine, and rosiglitazone was not superior to placebo (85, 87). The results were confirmed by a recent meta-analysis of 40 trials of 19 unique pharmacological interventions restricted to patients with schizophrenia spectrum disorders. Again, metformin was the most effective drug ( 3.17 kg weight loss) compared with placebo (100). There is no clear evidence that prevention, that is, metformin given together with a newly started antipsychotic, is more effective than intervention after the weight gain has occurred (101). Discussion

Weight gain and obesity in patients with schizophrenia and other mental disorders are associated with a host of adverse physical and psychiatric outcomes. Therefore, body weight and related metabolic indices need to be monitored routinely and targeted as part of a comprehensive and integrated care programme. As severely mentally ill patients seek out or receive less optimal care than the general population (102) despite their higher risk for adverse physical outcomes (102, 103), mental healthcare providers should take on at least the orchestration of integrated education, assessment, and care. Nevertheless, it is also important to consider that antipsychotics are currently the only medication class with evidence for effective treatment of psychosis (104). Moreover, in nationwide database studies, patients with schizophrenia not receiving antipsychotics had the highest all-cause mortality (105, 106). Furthermore, other medications, including mood stabilizers and antidepressants, often used in patients with schizophrenia, can also lead to weight gain, and adversely affect lipid and glucose metabolism (107), and antipsychotics have diverging weight gain and metabolic risk potentials (4, 102). These differences should be considered when making treatment choices (91). Ideally, a treatment algorithm should start with healthy lifestyle education/instruction and lower cardiometabolic risk antipsychotics, and only consider higher risk agents when it has become clear that the physically safer medication is not sufficiently effective or tolerated. Psychiatric care providers should aim for balancing acute and long-term efficacy as well as tolerability, and engage other medical specialists as needed to improve the overall well-being of patients with schizophrenia.

Declaration of interest Dr. De Hert has been a consultant for, received grant and/or research support and honoraria from, and been on the speakers’ bureaus and/or advisory boards of Janssen-Cilag, Lundbeck, and Takeda. Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Alkermes, Bristol-Myers Squibb, Eli Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, MedAvante, Medscape, Otsuka, Pfizer, ProPhase, Reviva, Roche, Sunovion, Supernus, and Takeda. He has received grant support from the American Academy of Child and Adolescent Psychiatry BMS, Janssen/J&J, National Institute of Mental Health (NIMH), Novo Nordisk A/S, Otsuka, Takeda and the Thrasher Foundation. Drs. Manu, Dima, Shulman, and Vancampfort have nothing to declare.

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