Rohan Ganguli, MD, FRCP, is Professor of Psychiatry and Canada Research Chair, University of Toronto, Department of Psychiatry; and Executive Vice President for Clinical Programs, Center for Addiction and Mental Health, Toronto.
Dr. Ganguli has disclosed the following relevant financial relationships: grants —Janssen, Lilly, Pfizer, Bristol Myers-Squibb; honoraria — Janssen, Lilly, Bristol Myers-Squibb, AstraZeneca.
Address correspondence to: Rohan Ganguli, MD, FRCP, via email: firstname.lastname@example.org.
Obesity is two to three times higher in those suffering from serious mental illness, and many psychotropic medications carry significant risk of causing weight gain. Moreover, serious mental illness is associated with a 20- to 25-year reduction in lifespan, primarily from premature coronary heart disease, and cerebrovascular disease.
Since obesity is one of the leading risk factors for heart disease, prevention of obesity is an important goal in the efforts to reduce the mortality gap between those with serious mental illness (SMI) and the general population.1,2,3
In public health and preventive medicine, it has been customary to distinguish between primary, secondary, and tertiary prevention. Primary prevention applies to interventions, such as vaccines, that reduce the risk of a disease occurring. In the area of obesity, primary prevention is possible, since many of the risk factors are potentially modifiable (quantity and composition of food intake, physical activity, etc), but the efforts so far in the general population, have met with limited success.4
Secondary prevention refers to early detection of illness, followed immediately by treatment, so as to limit progression to full-blown disease and complications. Metabolic monitoring of patients on antipsychotics is an example of secondary prevention with regard to obesity and metabolic syndrome in people with psychiatric illnesses.5
Tertiary prevention is intervention initiated after disease onset, with the goals of preventing damage and disablement, preventing or limiting complications, and restoring health to the greatest extent possible. Weight loss programs fall mainly into this tertiary prevention category.
When treating psychiatric disorders, prescribing medication with the lowest risk factors for weight gain, dyslipidemia, and insulin resistance is one of the rare opportunities treating clinicians have to exercise primary prevention of obesity. Almost all antipsychotics carry some risk of causing weight gain, however, the risk factors differ across the classes of medication.2,6 Clozapine and olanzapine consistently have been found to cause weight gain in the largest proportion of users, as well as to cause the greatest mean weight gain, in comparison to other available anti-psychotics. Aripiprazole, ziprasidone, and molindone, have the lowest risk of associated weight gain. The rest of the antipsychotic class of medications fall between these two along the continuum.6 The practice most consistent with a primary preventive approach would be to offer medications with the least weight gain potential as first-line agents when initiating treatment. Medications with greater potential for causing weight gain and its attendant comorbidities, should be reserved for nonresponse to low-risk agents and other special circumstances.
Behavioral and dietary strategies have been used to evaluate whether weight gain can be prevented or alleviated. In a clinical trial involving patients starting olanzapine, Evans and colleagues7 adopted a dietary intervention delivered by a trained dietician. In this study, patients were randomly assigned to either six dietician-delivered nutrition sessions or to usual care. At 6 months after initiation of olanzapine, both groups had gained weight, but there was significantly less weight gain in the group that received dietary counseling.7 In a pilot study using a stepped behavioral strategy, self-monitoring was combined with other behavioral and cognitive strategies to decrease food intake, and increase physical activity, for those starting on novel antipsychotics. Those randomly assigned to the stepped intervention experienced less weight gain than those randomly assigned to treatment as usual; many of them experienced no weight gain at all.8 Skouraliakou and colleagues9 employed an individualized nutritional approach in obese patients, who were taking olanzapine (mean BMI 33.12). This latter study did not have a control group, but reported that after 3 months, there was a significant decrease in body mass and waist circumference.9
There have also been a number of attempts to investigate whether administration of concomitant medications can counteract antipsychotic-induced weight gain. Most studies of this approach involve olanzapine, which is associated with the most weight gain among antipsychotics. Cavazzoni and colleagues10 reported that co-administration of nizatidine with olanzapine was associated with less early weight gain than placebo, but the results were not statistically significant after 6 weeks of treatment. A second study investigating nizatidine given concurrently with olanzapine was unable to find any benefit over placebo.11 It is worth noting that Cavazzoni’s study, which favored nizatidine (Cavazzoni et al) was funded by Lilly, which manufactures both nizatidine and olanzapine, while the second negative study was funded by Bristol Myers-Squibb which manufactures aripiprazole. A study without these potential conflicts of interest has yet to be undertaken.
In a small study (n = 21), Graham and colleagues found that, compared with placebo, administration of amantadine resulted in no further weight gain in patients taking olanzapine, whereas patients receiving placebo gained a mean 1.24 kg of weight.12 Perhaps this is a potential agent for secondary prevention, but more research is necessary.
The medication with the best evidence for success in preventing olanzapine-associated weight gain is metformin, an insulin-sensitizing biguanide. In a 2008 double blind trial, Wu and colleagues,13 randomly assigned 40 patients starting olanzapine to either 750 mg of concomitant metformin or placebo, in double blind fashion. At the end of 12 weeks, there was less mean weight gain and a smaller proportion of patients with clinically significant weight gain in the metformin group, compared with those who received placebo (weight change in kg: mean −3.2; 95% CI, −3.9 to −2.5 with metformin; mean 3.1, 95% CI, 3.8–2.4 with placebo [P = .05]).
This review also concludes that the greatest weight loss or prevention of weight gain benefits have been demonstrated in those studies that combined behavioral weight-loss treatment with adjunctive medication.14 In a recent systematic review and meta-analysis of 32 studies of 15 adjunctive medications used to avoid or attenuate antipsychotic-related weight gain and metabolic abnormalities, the data was most robust in favor of metformin.14 Other effective drugs were D-fenfluramine, sibutramine, topiramate, and reboxetine; however, fenfluramine and sibutramine have been withdrawn in the US and Canada, due to cardiovascular safety concerns.
Several recent studies have shown that a significant proportion of patients who develop metabolic syndromes while taking antipsychotics might show improvement in metabolic syndrome components when switched to antipsychotic agents with lower risk of weight gain. Several clinical trials have shown reductions in body weight when patients were switched to ziprasidone from olanzapine or risperidone,15 olanzapine to aripiprazole,16 or aripiprazole.17 When switching patients from antipsychotic agents, side effects need to be carefully balanced,18 because some of the antipsychotics with the greatest efficacy might also be associated with the greatest metabolic side effects.19,20
Despite the high rates of obesity and metabolic syndrome in the population of those with serious mental illness. In the CATIE trial, involving approximately 1,450 participants, Nasrallah and colleagues21 reported that the point prevalence of hypertension was 33.2%, of diabetes 10.9%, and of dyslipidemia 47.3%. Thirty percent of those with diabetes, 62% of those with hypertension, and 88% of those with abnormal lipids were not treated for these conditions.21 Since these were all patients under the care of a physician, the opportunity for prevention of complications was lost.
A Canadian study of re-hospitalization after a cardiac event found that those with schizophrenia were significantly more likely than those with no mental illness to be re-hospitalized in the following 4 years (adjusted hazard ratio = 1.43; 95% CI, 1.22–1.69) for a cardiac event.22 These differences in outcome for heart disease treatment suggest that there are problems with access or delivery of care to people with serious mental illnesses, and that it is likely this contributes to worse nonpsychiatric medical outcomes. A system that integrates psychiatric and non-psychiatric care may result in improved health outcomes for the seriously mentally ill.23 Druss and colleagues tested the benefits of a medical case management model in 407 people, randomly assigned to medical care management or usual care.24 At the end of 1 year, the intervention group (n = 205), compared with the controls (n = 202), were found to have received significantly more recommended preventive services (58.7% vs. 21.8%); have received more “evidence-based services for cardiometabolic conditions” (34.9% vs. 27.7%); were more likely to have a PCP (71.2% vs. 51.9%). A subset of patients (n = 100) had sufficient data to calculate the Framingham Cardiovascular Risk Index; and the scores were significantly lower for those with medical case managers as compared to the controls (6.9% vs. 9.8%; z = 2.23, P = 0.03).24
In a randomized controlled clinical trial of those recruited from a VA hospital, Kilbourne and colleagues25 studied a self-management program for patients with bipolar disorder. The psychoeducational program (bipolar disorder medical care model, BCM) addressed symptom management and behavior change related to both mood disorder and risk factors for cardiovascular disease. They found that the controls showed worsening of both the mental and physical components of the Medical Outcomes Study Short-Form Health Survey (SF-12), whereas those randomized to the self-management group showed some improvement in both components.
These studies demonstrate that a variety of nonpharmacologic approaches could actually prevent some nonpsychiatric comorbidities prevalent in those with serious mental illness. To determine whether there is an effect on actual cardiovascular disease outcomes will also require funding of long-term studies, since such outcomes take years to develop. People with serious mental illness have also been systematically excluded from large trials involving prevention of cardiovascular disease and diabetes, thus preventing collection of data on the efficacy of those interventions in these highly vulnerable people.
Obesity and metabolic complications are highly prevalent in those suffering from serious mental illness. This undoubtedly accounts for a large proportion of premature mortality and morbidity for these patients. Some of these complications, and obesity itself, appear to be associated with the psychotropic medications. Regular monitoring of the development of new risk factors in the patient will allow intervention before comorbidities become manifest. When metabolic syndrome is detected, lifestyle management to reduce weight and increase physical activity and fitness is the initial recommended intervention. These interventions should be available wherever people with serious mental illness receive psychiatric services.
If these measures fail, switching antipsychotic medication should be considered and discussed with patients and their caregivers. If the prior measures fail, specific pharmacological interventions, such as statins, antihypertensives, antidiabetics, etc, will need to be considered in collaboration with a primary care practitioner. Given the high risk of developing diabetes and cardiovascular disease in people with serious mental illness, psychiatrists who treat these patients should be familiar with these risks and educate their patients and caregivers about how to prevent them.
- Hwang MY, Nasrallah HA. Psychiatric and physical comorbidity in schizophrenia. Psychiatr Clin North Am. 2009;32(4):xiii–xv. doi:10.1016/j.psc.2009.10.002 [CrossRef]
- Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19Suppl 1:1–93. doi:10.2165/00023210-200519001-00001 [CrossRef]
- Hennekens CH, Hennekens AR, Hollar D, Casey DE. Schizophrenia and increased risks of cardiovascular disease. Am Heart J. 2005;150(6):1115–1121. doi:10.1016/j.ahj.2005.02.007 [CrossRef]
- Ruth S, Chan M, Woo J. Prevention of Overweight and Obesity: How Effective is the Current Public Health Approach. Int J Environ Res Public Health. 2010; 7(3): 765–783. doi:10.3390/ijerph7030765 [CrossRef]
- Cohn TA, Sernyak MJ. Metabolic monitoring for patients treated with antipsychotic medications. Can J Psychiatry. 2006;51(8):492–501.
- Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156 :1686–1696.
- Evans S, Newton R, Higgins S. Nutritional intervention to prevent weight gain in patients commenced on olanzapine: a randomized controlled trial. Aust N Z J Psychiatry. 2005;39(6):479–86
- Ganguli R, Brar JS. Prevention of weight gain, by behavioral interventions, in patients starting novel antipsychotics. Schizophr Bull. 2005;31(2):561–562.
- Skouroliakou M, Giannopoulou I, Kostara C, Hannon J. Effects of nutritional intervention on body weight and body composition of obese psychiatric patients taking olanzapine. Nutrition. 2009;25(7–8):729–735. doi:10.1016/j.nut.2008.12.009 [CrossRef]
- Cavazzoni P., Tanaka Y., et al. , (2003). “Nizatidine for prevention of weight gain with olanzapine: a double-blind placebo-controlled trial.”Eur Neuropsychopharmacol. 13(2): 81–85. doi:10.1016/S0924-977X(02)00127-X [CrossRef]
- Assunção SS, Ruschel SI, Rosa Lde C, et al. Weight gain management in patients with schizophrenia during treatment with olanzapine in association with nizatidine. Rev Bras Psiquiatr. 2006;28(4):270–276. doi:10.1590/S1516-44462006005000007 [CrossRef]
- Graham KA, Gu H, Lieberman JA, Harp JB, Perkins DO. Double-blind, placebo-controlled investigation of amantadine for weight loss in subjects who gained weight with olanzapine. Am J Psychiatry. 2005;162(9):1744–1746. doi:10.1176/appi.ajp.162.9.1744 [CrossRef]
- Wu RR, Zhao JP, Guo XF, et al. Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study. Am J Psychiatry. 2008;165(3):352–358. doi:10.1176/appi.ajp.2007.07010079 [CrossRef]
- Maayan L, Vakhrusheva J, Correll CU. Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis. Neuropsychopharmacol. 2010;35(7):1520–1530. doi:10.1038/npp.2010.21 [CrossRef]
- Weiden PJ, Newcomer JW, Loebel AD, et al. Long-term changes in weight and plasma lipids during maintenance treatment with ziprasidone. Neuropsychopharmacol. 2008;33(5):985–994. doi:10.1038/sj.npp.1301482 [CrossRef]
- Newcomer JW, Campos JA, Marcus RN, et al. A multicenter, randomized, double/blind study of the effects of aripiprazole in overweight subjects with schizophrenia or schizoaffective disorder switched from olanzapine. J Clin Psychiatry. 2008; 69(7), 1046–1056. doi:10.4088/JCP.v69n0702 [CrossRef]
- Kolotkin RL, Corey-Lisle PK, Crosby RD, et al. Changes in weight and weight-related quality of life in a multicentre, randomized trial of aripiprazole versus standard of care. Eur Psychiatry. 2008;23:561–566. doi:10.1016/j.eurpsy.2008.01.1421 [CrossRef]
- Buckley PF. Olanzapine: a critical review of recent literature. Expert Opin Pharmacother. 2005;6(12):2077–2089. doi:10.1517/14656518.104.22.1687 [CrossRef]
- Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223. doi:10.1056/NEJMoa051688 [CrossRef]
- Fenton WS, Chavez MR. Medication-induced weight gain and dyslipidemia in patients with schizophrenia. Am J Psychiatr. 2006;163(10):1697–1704. doi:10.1176/appi.ajp.163.10.1697 [CrossRef]
- Nasrallah HA. An overview of common medical comorbidities in patients with schizophrenia. J Clin Psychiatry. 2005;66Suppl 6:3–4.
- Callahan RC, Boire MD, Lazo RG, McKenzie K, Cohn T. Schizophrenia and incidence of cardiovascular morbidity: a population-based longitudinal study in Ontario, Canada. Schizophrenia Research. 2009;115:325–332. doi:10.1016/j.schres.2009.07.018 [CrossRef]
- Druss BG, Bradford DW, Rosenheck RA, Radford MJ, Krumholtz HM. Quality of medical care and excess mortality in older patients with mental disorders. Arch Gen Psychiatry. 2001;58:565–572. doi:10.1001/archpsyc.58.6.565 [CrossRef]
- Druss BG, von Esenwein SA, Compton MT, Rask KJ, Zhao L, Parker RM. A randomized trial of medical care management for community mental health settings: the Primary Care Access, Referral, and Evaluation (PCARE) study. Am J Psychiatry. 2010;167(2):151–159. doi:10.1176/appi.ajp.2009.09050691 [CrossRef]
- Kilbourne AM, Post EP, Nossek A, Drill L, Cooley S, Bauer MS. Improving medical and psychiatric outcomes among individuals with bipolar disorder: a randomized controlled trial. Psychiatr Serv. 2008;59:760–768. doi:10.1176/appi.ps.59.7.760 [CrossRef]