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Weight Issues in Schizophrenia

Anita H. Clayton, MD


Primary Psychiatry. 2006;13(3):22-24


Dr. Clayton is professor of psychiatric medicine at the University of Virginia in Charlottesville.


Disclosure: Dr. Clayton is a consultant to and on the advisory boards of Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pfizer, Vela, and Wyeth; is on the speaker’s bureaus of and receives honorarium from Eli Lilly, GlaxoSmithKline, Pfizer, and Wyeth; and receives grants and/or research support from Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Neuronetics, Pfizer, and Wyeth.



Disease-Related Concerns


Weight gain in adulthood appears to have significant negative effects on physical health. Among women, weight gain, regardless of baseline weight, is associated with decreased physical function, diminished vitality, and increased body pain.1 In a large naturalistic study,2 nearly 40% of women 45–72 years of age gained >5 lbs in 4 years, with the leanest women who gained >20 lbs having twice the likelihood of developing role limitations due to physical problems. No difference was seen between older and younger women. In addition, adults who gain >10 lbs are at increased risk for medical illnesses and premature death.2 Adults in this group have nearly twice the risk of type II diabetes mellitus and ischemic stroke and 1.25 times the risk of coronary heart disease, compared to adults who lose or maintain a stable weight. Breast cancer risk also appears to be increased with weight gain. Impairments in physical functioning, reduced quality of life, and poor mental health are also associated with weight gain and are an additional burden for patients with schizophrenia.


Among individuals with schizophrenia, effects of both the disease and its treatment may contribute to weight gain, metabolic syndrome, and subsequent other impairments and functional limitations. This may be particularly true for women, as women with schizophrenia (from the National Health Interview Survey) had a significantly higher mean body mass index (BMI) than women without schizophrenia (from the National Health and Nutrition Examination Survey III [NHANES III]), 27.36 versus 24.50, respectively (P<.001).3


Treatment-Related Issues


Very few studies have examined gender differences in weight and metabolic effects in patients with schizophrenia. In addition, separating out the effects of the illness from the effects of the antipsychotic agents has been difficult. It is clear that both men and women with severe and persistent mental illness (Maryland Medicaid recipients with severe and persistent mental illness) had a higher prevalence of obesity than individuals in the general population (NHANES III and Maryland Behavioral Risk Factor Surveillance System), but only men demonstrated a 4-fold greater association between atypical antipsychotics and prevalent obesity.4 However, in a study examining several antipsychotics in patients with schizophrenia, clinically significant weight gain (>7% of baseline body weight) was experienced by 46% of patients receiving olanzapine, 31% of patients receiving risperidone, and 22% of patients receiving haloperidol.5 No subjects treated with quetiapine gained >7% of their baseline body weight. The risk of weight gain was higher in women (odds ratio [OR] 4.4), overweight patients (OR 3.0), and in women receiving risperidone (OR 2.6). Perhaps women with schizophrenia have a greater risk of obesity related to their disease, whereas men may have that risk further increased by treatment with atypical antipsychotics not associated with elevations in prolactin levels.


To sort out the effect of disease versus treatment, 15 men and 4 women with drug-naïve, first-episode schizophrenia were evaluated for obesity/fat distribution parameters and 24-hour plasma cortisol levels, and compared to age- and sex-matched controls.6 Patients were treated with olanzapine or risperidone for 6 months, followed by reassessment of the adiposity parameters. At baseline, the patients with schizophrenia had significantly more intra-abdominal fat as measured by computerized tomography and anthropometry, which did not change with treatment. Higher baseline cortisol levels significantly decreased with antipsychotic treatment. No differences were demonstrated between the two antipsychotics. In an open-label study involving the use of olanzapine in six men and three women experiencing their first psychotic episode, a median increase in body weight of 4.7 kg was seen within 12 weeks, a significant increase of >7% from first assessment (within 7 weeks of diagnosis).7 Body fat also increased significantly, primarily as central fat deposits. Fasting insulin, C-peptide, and triglyceride levels significantly increased within 3 months of treatment initiation, but glucose levels did not. Neither did cholesterol or leptin levels. This may suggest insulin resistance, with a decrease in fat oxidation as a secondary or predisposing mechanism for weight gain with antipsychotics, explaining how weight gain and metabolic effects may occur together or independently in patients receiving antipsychotics. Similar outcomes were seen with clozapine in one study (11 women and 8 men),8 with early increases in circulating leptin levels inversely correlated with weight gain over the following 6–8 months (13 men and 9 women) in another trial.9


Long-term studies are important, as most patients with schizophrenia require life-long therapy. In one naturalistic 5-year study, patients with schizophrenia were at increased risk of weight gain through month 46 from initiation of clozapine, and of developing diabetes mellitus (36.6%). Weight gain was not a significant risk factor for the onset of diabetes, so these factors appear independent, but co-occurring.10 In addition, calculations reveal that the lives saved from suicide through treatment with clozapine are essentially offset by the additional deaths associated with a 10 kg weight gain.11


The Clinical Antipsychotic Trials of Intervention Effectiveness data support these concerns with some of the atypical antipsychotics, as 30% of patients receiving olanzapine gained >7% of their baseline body weight versus 7% to 16% with other antipsychotics.12 Average weight gain with olanzapine was 2 lbs/month. Comparable problems were seen with blood glucose, cholesterol, triglycerides, and hemoglobin A1c. Discontinuation secondary to weight gain and metabolic side effects over the 18 months of the trial was 9% with olanzapine versus 1% to 4% with the other drugs. Other differences among agents included improvement in metabolic effects with ziprasidone and an increase in prolactin levels with risperidone. However, only 25% of the subjects in the trial were women.


Women may have a different propensity for weight gain with antipsychotics than men because premenopausal women with schizophrenia require lower medication doses for effective treatment and because women have less of a predisposition for visceral fat storage. However, since 1987, the mean BMI for women with schizophrenia 18–30 years of age has increased dramatically and significantly when compared to women in the general population.13 One factor may be a combination of medications, which can further contribute to weight gain. Women are more likely to have an associated mood disorder requiring additional medication intervention, which may result in subsequent weight gain. However, in an 8-week trial of patients with borderline personality disorder, the combination of fluoxetine with olanzapine was associated with less weight gain than olanzapine alone.14 Women also appear more likely to suffer with hyperprolactinemia secondary to antipsychotics than men, and as a result may experience abnormal menstrual cycles and weight gain. However, iatrogenic weight gain (mean weight increase of 27%) does not explain the emergence of irregular menses (23%) among premenopausal women with psychotic illness taking clozapine.15 Other factors contributing to weight gain may include diet, smoking, exercise, substance use, and hormonal transitions.16


Management Options


Use of the lowest possible dose of antipsychotic medication may reduce the likelihood of weight gain, as insulin levels have been positively correlated to serum concentration of clozapine.17 Premenopausal women generally require lower doses than men or postmenopausal women. Minimizing additional concomitant medications will also reduce potential weight gain. When other medications are required, utilizing those not associated with weight gain is recommended. Such medications may include lamotrigine, bupropion, and topiramate. Education about interventions such as nutrition, exercise, and living a healthy lifestyle may limit weight gain, as a 6-month study demonstrated a mean weight change in the intervention group of -0.06 lbs versus +9.57 lbs in the standard care group.18 Good general health maintenance may also mitigate against weight gain, so routine monitoring of weight, blood pressure, fasting blood glucose, and lipids is recommended. Once problems with weight gain or metabolic syndrome have been identified, treatment should be instituted immediately, and consideration should be given to change of antipsychotic medication to ziprasidone, quetiapine, and possibly aripiprazole. A long-term view is required, as patients with schizophrenia will require life-long treatment with a goal to maintain general health status. PP




1. Fine JT, Colditz GA, Coakley EH, et al. A prospective study of weight change and health-related quality of life in women. JAMA. 1999;282(22):2136-2142.


2. Kawachi I. Physical and psychological consequences of weight gain. J Clin Psychiatry. 1999;60(suppl 21):5-9.


3. Allison DB, Fontaine KR, Heo M, et al. The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry. 1999;60(4):215-220.


4. Daumit GL, Clark JM, Steinwachs DM, Graham CM, Lehman A, Ford DE. Prevalence and correlates of obesity in a community sample of individuals with severe and persistent mental illness. J Nerv Ment Dis. 2003;191(12):799-805.


5. Bobes J, Rejas J, Garcia-Garcia M, et al. Weight gain in patients with schizophrenia treated with risperidone, olanzapine, quetiapine or haloperidol: results of the EIRE study. Schizophr Res. 2003;62(1-2):77-88.


6. Ryan MC, Flanagan S, Kinsella U, Keeling F, Thakore JH. The effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naive patients with schizophrenia. Life Sci. 2004;74(16):1999-2008. Erratum in: Life Sci. 2004;75(23):2851.


7. Graham KA, Perkins DO, Edwards LJ, Barrier RC Jr, Lieberman JA, Harp JB. Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis. Am J Psychiatry. 2005;162(1):118-123.


8. Kivircik BB, Alptekin K, Caliskan S, et al. Effect of clozapine on serum leptin, insulin levels, and body weight and composition in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(5):795-799.


9. Monteleone P, Fabrazzo M, Tortorella A, La Pia S, Maj M. Pronounced early increase in circulating leptin predicts a lower weight gain during clozapine treatment. J Clin Psychopharmacol. 2002;22(4):424-426.


10. Henderson DC, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry. 2000;157(6):975-981.


11. Fontaine KR, Heo M, Harrigan EP, et al. Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate. Psychiatry Res. 2001;101(3):277-288.


12. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.


13. Homel P, Casey D, Allison DB. Changes in body mass index for individuals with and without schizophrenia, 1987–1996. Schizophr Res. 2002;55(3):277-284.


14. Zanarini MC, Frankenburg FR, Parachini EA. A preliminary, randomized trial of fluoxetine, olanzapine, and the olanzapine-fluoxetine combination in women with borderline personality disorder. J Clin Psychiatry. 2004;65(7):903-907.


15. Feldman D, Goldberg JF. A preliminary study of the relationship between clozapine-induced weight gain and menstrual irregularities in schizophrenic, schizoaffective, and bipolar women. Ann Clin Psychiatry. 2002;14(1):17-21.


16. Seeman MV. Gender differences in the prescribing of antipsychotic drugs. Am J Psychiatry. 2004;161(8):1324-1333.


17. Melkersson KI, Hulting AL. Insulin and leptin levels in patients with schizophrenia or related psychoses—a comparison between different antipsychotic agents. Psychopharmacology (Berl). 2001;154(2):205-212.


18. Littrell KH, Hilligoss NM, Kirshner CD, Petty RG, Johnson CG. The effects of an educational intervention on antipsychotic-induced weight gain. J Nurs Scholarsh. 2003;35(3):237-241.