Obesity in Schizophrenia The Epidemic of Obesity Obesity in Schizophrenia Psychopharmacology of Weight Gain Weight Monitoring for Schizophrenia Behavioral Treatment Pharmacological Treatment of Obesity in Schizophrenia Obesity and Mental Illness

Obesity in Patients With Schizophrenia

Obesity and its related sequelae represent a growing epidemic in the United States. Overweight is defined by the World Health Organization as a body mass index (BMI) of 25.0­29.9 kg/m², and obesity as BMI ≥ 30 kg/m². Recent data estimate that more than 50% of U.S. adults are overweight, with 31% of men and 35% of women considered obese, or at least 20% above their ideal body weight (Yanovski and Yanovski 1999).

Results of the 1999 National Health and Nutrition Examination Survey (NHANES), released in December 2000 by the National Center for Health Statistics, noted that the proportion of obese individuals in the United States in 1999 was 80% greater than the proportion measured by NHANES II in 1976­1980, and 17% greater than that measured by NHANES III in 1997 (Flegal and Troiano 2000).

Similarly, the Centers for Disease Control (CDC) performed a telephone survey in 1991 that found that only 4 of the 47 states surveyed had obesity rates of 15% or greater, whereas the 2000 survey, which was repeated in all 50 states, found that every state except Colorado had an obesity rate ≥ 15%

Obesity in Schizophrenia

In the pre-antipsychotic era, Kraepelin noted that some patients with schizophrenia exhibited bizarre eating habits, and not uncommonly were obese. "The taking of food fluctuates from complete refusal to the greatest voracity. The body weight usually falls at first often to a considerable degree. . . . [L]ater, on the contrary we see the weight not infrequently rise quickly in the most extraordinary way, so that the patients in a short time acquire an uncommonly well-nourished turgid appearance" (Kraepelin 1919, p. 125).

It is worth noting that this tendency to weight loss during more active phases of the illness has been borne out by results from a recent meta-analysis of multiple antipsychotic drug trials, which noted that placebo-treated patients on average lost weight (Allison et al. 1999a). Nevertheless, there are a number of reasons that patients with schizophrenia might be prone to obesity, including the effect of symptoms such as paranoia and negative symptoms such as apathy and social withdrawal, which may independently contribute to schizophrenic patients' lack of adherence to proper diet and their overall sedentary lifestyle (Davidson et al. 2001).

Moreover, the economic conditions of chronically mentally ill individuals also contribute to poor dietary habits. One theory about the major vector of the obesity epidemic in this country and abroad correlates obesity trends with the growth of the fast-food industry (Schlosser 2001). Fast food is an affordable option for those on limited budgets, yet unfortunately is often very high in saturated fat and total calories ..

Weight Monitoring for Schizophrenia

The effects of antipsychotic-related weight gain have both medical and psychiatric components. In particular, medication compliance is adversely affected by excessive weight gain, with weight gain being a wellknown cause of treatment nonadherence (Bernstein 1988; Silverstone et al. 1988) and subsequent psychotic relapse (Rockwell et al. 1983).

During the 2000 American Psychiatric Association meeting, investigators at the Columbia­St. Luke's Obesity Research Center released survey data examining this link between obesity and antipsychotic medication compliance. They found that obese patients were 13 times as likely to request discontinuation of their current antipsychotic agent because of concerns about weight gain and 3 times as likely to be noncompliant with treatment compared with nonobese individuals (Weiden et al. 2000).

Patients who gain weight on antipsychotics also utilize health care resources more than patients who do not experience weight gain (Allison and Mackell 2000).

Pharmacological Treatment of Obesity in Schizophrenia

The literature thus far suggests that some of the novel antipsychotic medications cause less weight gain than others; thus it may be possible to switch patients on agents associated with the most weight gain to those with lower weight gain liability (Allison et al. 1999a; Wirshing et al. 1999); however, prior to switching, it is important to recall that the most difficult symptoms to control are those of psychosis.

A switch of antipsychotic medication makes sense particularly if the patient is nonresponsive to the current antipsychotic. As discussed, weight gain can be a significant cause of nonadherence with a medication regimen; thus, in cases where a patient refuses to take medication due to weight gain concerns, a switch is advisable (Bernstein 1988; Silverstone et al. 1988). A switch study sponsored by Pfizer demonstrated that subjects switched from olanzapine to ziprasidone lost a statistically significant 2.2 kg on average over 6 weeks (Kingsbury et al. 2001).

Obesity in schizophrenia: what can be done about it? Obesity is a common problem for people with schizophrenia, with an estimated 40-60% of this population being obese or overweight. Obesity among the mentally ill may contribute to adverse medical and psychological consequences as well as medication non-compliance and poorer quality and enjoyment of life. This review discusses the issues related to obesity in schizophrenia and the role of pharmacological and behavioural treatments in the reduction of obesity and maintenance of gains. Lisa Catapano; David Castle Affiliations: George Washington University, Washington, DC, USA Mental Health Research Institute and University of Melbourne, Melbourne, Vic., Australia DOI: 10.1046/j.1039-8562.2003.02054.x Published in: Australasian Psychiatry, Volume 12, Issue 1 March 2004 , pages 23 - 25

Although most persons with schizophrenia do not have a family history of it, genetic factors have been implicated. Persons who have a first-degree relative with schizophrenia have about a 15% risk of developing the disorder, compared with a 1% risk among the general population. A monozygotic twin whose co-twin has schizophrenia has a > 50% probability of developing it. Sensitive neurologic and neuropsychiatric tests often indicate that aberrant smooth-pursuit eye tracking, impaired performance on tests of cognition and attention, and deficient sensory gating occur more commonly among patients with schizophrenia than among the general population. These psychophysiologic markers also occur among first-degree relatives of persons with schizophrenia and may indicate vulnerability before overt onset of illness.

Various environmental stressors can trigger the emergence or recurrence of symptoms in vulnerable persons. Examples are stressful life events such as ending a relationship or leaving home for the armed forces, work, or college and biologic stressors such as substance abuse. Stressful family relations can cause or result from frequent illness exacerbation. Protective factors that may mitigate the effect of stress on symptom formation or exacerbation are discussed under Treatment, below.

Behavioral Treatment

Behavioral interventions such as calorie restriction, exercise, and behavioral modification are key elements to successful, sustained weight loss (NHLBI 2000; NHLBI also has posted on its Web site a practical guide for obesity evaluation and management: www.nhlbi.nih.gov/guidelines/ obesity/practgd_c.pdf). There is little in the way of published data on behavioral interventions for weight loss in psychotic patients, and the few studies tend to be methodologically weak. In one small (n = 14) 14-week study, patients in a residential setting achieved, on average, 10 pounds more weight loss when given behavioral interventions compared with a control group (Rotatori 1980).

Work by Wirshing and colleagues demonstrated that simple stepwise behavioral interventions were modestly successful in risperidone- and olanzapine-treated subjects, but had little effect in clozapine-treated subjects (Wirshing et al. 1999). The interventions are listed below ....

The Effects of Antipsychotic Medications on Weight

Antipsychotic medications have been the mainstay of treatment for schizophrenia for over half a century. A link between weight gain and treatment with chlorpromazine and other low-potency conventional antipsychotic agents, such as thioridazine, was noted in early studies of the metabolic effects of these agents. (Bernstein 1988; Rockwell et al. 1983). A recent study by Allison et al. (1999b) based on 1989 National Health Interview Survey data revealed that a significantly greater proportion of female patients with schizophrenia had BMI distributions in the overweight and obese spectrum compared with their counterparts in the general medical population, with a trend toward greater BMI seen among male schizophrenic patients.

Donna A. Wirshing, M.D.
Jonathan M. Meyer, M.D.

References

1. Allison DB, Mentore JL, Heo M, et al: Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156:1686-1696, 1999a
2. Allison D, Fontaine K, Moonseong H, et al: The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry 60:215- 220, 1999b
3. Allison D, Mackell J: Healthcare resource use and body mass index among individuals with schizophrenia. Poster presented at the annual meeting of the New Clinical Drug Evaluation Unit, Boca Raton, FL, May 2000
4. Aronne LJ: Epidemiology, morbidity, and treatment of overweight and obesity. J Clin Psychiatry 62 (suppl 23):13-22, 2001
5. Aulakh CS, Hill JL, Yoney HT, et al: Evidence for involvement of 5-HT1C and 5-HT2 receptors in the food intake suppressant effects of 1-(2,5-dimethoxy- 4-iodophenyl)-2-aminopropane (DOI). Psychopharmacologia 109:444-448, 1992
6. Ball MP, Coons VB, Buchanan RW: A program for treating olanzapine-related weight gain. Psychiatr Serv 52:967-969, 2001
7. Baptista T, Hernandez L, Prieto LA, et al: Metformin in obesity associated with antipsychotic drug administration: a pilot study. J Clin Psychiatry 62:653-655, 2001
8. Basson BR, Kinon BJ, Taylor CC, et al: Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol or risperidone. J Clin Psychiatry 62:231-238, 2001
9. Bernstein JG: Psychotropic drug induced weight gain: mechanisms and management. Clin Neuropharmacol 11 (suppl 1):S194-S206, 1988
10. Berry SA, Mahmoud RA: Normalization of olanzapine associated abnormalities of insulin resistance and insulin release after switch to risperidone: the risperidone rescue study. Poster presented at the 40th annual meeting of the American College of Neuropsychopharmacology, Kona, HI, December 2001
11. Brecher M, Melvin K: Effect of long term quetiapine monotherapy on weight in schizophrenia. Poster presented at the annual meeting of the American Psychiatric Association, New Orleans, Louisiana, May 2001
12. Bromel T, Blum W, Ziegler A, et al: Serum leptin levels increase rapidly after initiation of clozapine treatment. Mol Psychiatry 3:76-80, 1998
13. Bustillo JR, Buchanan RW, Irish D, et al: Differential effect of clozapine on weight: a controlled study. Am J Psychiatry 153:817-819, 1996
14. Cerulli J, Lomaestro B, Malone M: Update on the pharmacotherapy of obesity.Ann Pharmacother 32:88-102, 1998
15. Colditz GA: Economic costs of obesity and inactivity. Med Sci Sports Exerc 31 (suppl 11):S663-S667, 1999
16. Correa N, Opler LA, Kay SR, et al: Amantadine in the treatment of neuroendocrine side effects of neuroleptics. J Clin Psychopharmacol 7:91-95, 1987
17. Davidson S, Judd F, Jolley D, et al: Cardiovascular risk factors for people with mental illness. Aust N Z J Psychiatry 35:196-202, 2001
18. DeFronzo RA, Goodman AM: Multicenter Metformin Study Group: efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333:541-549, 1995
19. Eder U, Mangweth B, Ebenbichler C, et al: Association of olanzapine-induced weight gain with an increase in body fat. Am J Psychiatry 158:1719-1722, 2001
20. Flegal KM, Troiano RP: Changes in the distribution of body mass index of adults and children in the US population. Int J Obes Relat Metab Disord 24:807-818, 2000
21. Fontaine KR, Heo M, Harrigan EP, et al: Estimating the consequences of antipsychotic induced weight gain on health and mortality rate. Psychiatry Res 101(3):277-288, 2001
22. Fontbonne A, Charles MA, Juhan-Vague I, et al: The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution. Diabetes Care 19:920-926, 1996
23. Furst BA, Champion KM, Pierre JM, et al: Possible association of QTc interval prolongation with co-administration of quetiapine and lovastatin. Biol Psychiatry 51:264-265, 2002
24. Garattini S, Mennini T, Samain R: Reduction of food intake by manipulation of central serotonin: current experimental results. Br J Psychiatry 155 (suppl 8):41-51, 1989
25. Geodon. New York, Pfizer, 2001 [package insert]
26. Goodall E, Oxtoby C, Richards R, et al: A clinical trial of the efficacy and acceptability of D-fenfluramine in the treatment of neuroleptic-induced obesity. Br J Psychiatry 153:208-213, 1988
27. Green AI, Patel JK, Goisman RM, et al: Weight gain from novel antipsychotic drugs: need for action. Gen Hosp Psychiatry 22:224-235, 2000
28. Groop L, Orho-Melander M: The dysmetabolic syndrome. J Intern Med 250:105- 120, 2001
29. Gupta S, Droney T, Al-Samarrai S, et al: Olanzapine: weight gain and therapeutic efficacy. J Clin Psychopharmacol 19:273-275, 1999
30. Henderson DC, Cagliero E, Gray C, et al: Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry 157:975-981, 2000
31. Hilgar E, Quiner S, Ginzel I, et al: The effect of orlistat on plasma levels of psychotropic drugs in patients with long-term psychopharmacotherapy. J Clin Psychopharmacol 22:68-70, 2002
32. Jones AM, Rak IW, Raniwalla J, et al: Weight changes in patients treated with quetiapine. Poster presented at the annual meeting of the American Psychiatric Association, Chicago, IL, May 2000
33. Kingsbury SJ, Fayek M, Trufasiu D, et al: The apparent effects of ziprasidone on plasma lipids and glucose. J Clin Psychiatry 62:347-349, 2001
34. Kinon BJ, Basson BR, Gilmore JA, et al: Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry 62:92-100, 2001
35. Knapp M: Schizophrenia costs and treatment cost-effectiveness. Acta Psychiatrica Scand Suppl 102:15-18, 2000
36. Knight A: Astemizole: a new, non-sedating antihistamine for hay fever. J Otolaryngol 14:85-88, 1985
37. Kolokowska T, Gadhvi H, Molyneux S: An open clinical trial of fenfluramine in chronic schizophrenia: a pilot study. Int Clin Psychopharmacol 2:83-88, 1987
38. Kraepelin E: Dementia Praecox and Paraphrenia. Edinburgh, E & S Livingstone, 1919
39. Kraus T, Haack M, Schuld A, et al: Body weight and leptin plasma levels during treatment with antipsychotic drugs. Am J Psychiatry 156:312-314, 1999
40. Leadbetter R, Shutty M, Pavalonis D, et al: Clozapine-induced weight gain: prevalence and clinical relevance. Am J Psychiatry 149:68-72, 1992
41. Luque C, Rey J: Sibutramine: a serotonin-norepinephrine reuptake-inhibitor for the treatment of obesity. Ann Pharmacother 33:968-978, 1999
42. Marder S, Davis JM, Chouinard G, et al: The effects of risperidone on the five dimensions of schizophrenia. J Clin Psychiatry 58:538-546, 1997
43. McElroy S, Suppes T, Keck P, et al: Open-label adjunctive topiramate in the treatment of bipolar disorders. Biol Psychiatry 47:1025-1033, 2000
44. McIntyre RS, Trakas K, Lin D, et al: Risk of adverse events associated with antipsychotic treatment: results from the Canadian National Outcomes Measurement Study in Schizophrenia (CNOMSS). Abstract presented at the 40th annual meeting of the American College of Neuropsychopharmacology, Kona, HI, December 2001
45. Meyer JM: Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 21:369-374, 2001
46. Meyer JM: A retrospective comparison of lipid, glucose and weight changes at one year between olanzapine and risperidone treated inpatients. J Clin Psychiatry 63: 425-433, 2002
47. Mokdad AH, Ford ES, Bowman BA, et al: Diabetes trends in the U.S.: 1990-1998. Diabetes Care 23:1278-1283, 2000a
48. Mokdad AH, Serdula MK, Dietz WH, et al: The continuing epidemic of obesity in the United States. JAMA 284:1650-1651, 2000b
49. Morrison JA, Cottingham EM, Barton BA: Metformin for weight loss in pediatric patients taking psychotropic drugs. Am J Psychiatry 159:655-657, 2002
50. Must A, Spadano J, Coakley EH, et al: The disease burden associated with overweight and obesity. JAMA 282:1523-1529, 1999
51. Myers A, Rosen JC: Obesity stigmatizationa and coping: relation to mental health symptoms, body image, and self-esteem. Int J Obes Relat Metab Disord 23:221-230, 1999
52. National Heart, Lung and Blood Institute (NHLBI): Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Available at: http://www.nhlbi.nih.gov/guidelines/obesity/practgd_c.pdf. November 2000
53. Nemeroff CB: Dosing the antipsychotic medication olanzapine. J Clin Psychiatry 58 (suppl 10):45-49, 1997
54. Norton J, Potter D, Edward K: Sustained weight loss associated with topiramate. Epilepsia 38 (suppl 3):S60, 1997
55. Park YW, Allison DB, Heymsfield SB, et al: Larger amounts of visceral adipose tissue in Asian Americans. Obes Res 9:381-387, 2001
56. Pelleymounter M, Cullen M, Baker M, et al: Effects of the obese gene production body weight regulation in ob/ob mice. Science 269:240-243, 1995
57. Petrie J, Saha A, McEvoy J: Aripiprazole, a new atypical antipsychotic: phase II clinical trial result. Eur Neuropsychopharmacol 7 (suppl 2):S227, 1997
58. Pfizer: Briefing document for ziprasidone HCl presented at the FDA Psychopharmacological Drugs Advisory Committee, July 19, 2000
59. Reinstein M, Sirotovskaya L, Jonas L, et al: Effect of clozapine-quetiapine combination therapy on weight and glycaemic control. Clin Drug Invest 18:99-104, 1999
60. Risperdal. Titusville, NJ, Janssen Pharmaceutica, 1999 [package insert]
61. Rockwell WJ, Ellinwood EH, Trader DW: Psychotropic drugs promoting weight gain: health risks and treatment implications. South Med J 76:1407-1412, 1983
62. Rosenfeld W, Schaefer P, Pace K: Weight loss patterns with topiramate therapy. Epilepsia 38 (suppl 3):S58, 1997
63. Rotatori AF, Fox R, Wicks A: Weight loss with psychiatric residents in a behavioral self-control program. Psychol Rep 46:483-486, 1980
64. Samanin R, Garattini S: The pharmacology of serotonergic drugs affecting appetite, in Nutrition and the Brain, Vol 8. Edited by Wurtman RJ, Wurtman JJ. New York, Raven, 1990, pp 163-192
65. Sacchetti E, Guarner L, Bravi D: H2 antagonist nizatidine may control olanzapine-associated weight gain in schizophrenic patients. Biol Psychiatry 48:167-168, 2000
66. Schlosser E: Fast Food Nation: The Dark Side of the All-American Meal. Boston, Houghton Mifflin, 2001
67. Schotte A, Janssen PF, Megens AA, et al: Occupancy of central neurotransmitter receptors by risperidone, clozapine, and haloperidol measured ex vivo by quantitative autoradiography. Brain Res 631:191-202, 1993
68. Seroquel. Wilmington, DE, AstraZeneca, 2000 [package insert]
69. Silverstone T, Smith G, Goodall E: Prevalence of obesity in patients receiving depot antipsychotics. Br J Psychiatry 153:214-217, 1988
70. Taylor DM, McAskill R: Atypical antipsychotics and weight gain: a systematic review. Acta Psychiatr Scand 101:416-432, 2000
71. Tecott L, Sun L, Arkana S: Eating disorder and epilepsy in mice lacking 5-HT_2C serotonin receptors. Nature 374:542-546, 1995
72. Theisen FM, Linden A, Geller F, et al: Prevalence of obesity in adolescent and young adult patients with and without schizophrenia and in relationship to antipsychotic medication. J Psychiatr Res 35:339-345, 2001
73. Umbricht DS, Pollack S, Kane JM: Clozapine and weight gain. J Clin Psychiatry 55 (suppl B):157-160, 1994
74. Weiden PJ, Allison DB, Mackell JA, et al: Obesity as a risk factor for antipsychotic noncompliance. Poster presented at the annual meeting of the American Psychiatric Association, Chicago, IL, May 2000
75. Werneke U, Taylor D, Sanders TA: Options for pharmacological treatment of obesity in patients treated with atypical antipsychotics. Int Clin Psychopharmacol 17:145-160, 2002
76. Wirshing D, Wirshing W, Kysar L, et al: Novel antipsychotics:comparison of weight gain liabilities. J Clin Psychiatry 60:358-363, 1999
77. Wirshing DA, Pierre JM, Eyeler J, et al: Risperidone associated new-onset diabetes. Biol Psychiatry 50:1489-1489, 2001a
78. Wirshing D, Boyd J, Meng L, et al: Antipsychotic medication: impact on coronary artery disease risk factors. Biol Psychiatry 49:175S, 2001b
79. Wolf A, Colditz G: Current estimates of the economic cost of obesity in the United States. Obes Res 6:97-106, 1998
80. Yanovski J, Yanovski S: Recent advances in basic obesity research. JAMA 282:1504-1506, 1999
81. Yanovski S, Yanovski J: Obesity. N Engl J Med 346:591-602, 2002
82. Zyprexa. Indianapolis, IN, Eli Lilly, 2000 [package insert]