The impact of weight gain associated with atypical antipsychotic use in schizophrenia

Authors

  • Pierre Chue,

    Corresponding author
    1. Department of Psychiatry, University of Alberta;
      *Dr P. Chue, 3rd Floor, 9942-108 Street, Edmonton, Alberta T5K 2J5, Canada. Tel: (780) 401 4189; Fax: (780) 425 9317; E-mail: pchue@ualberta.ca
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  • Raphael Cheung

    1. South-western Ontario Medical Education Network Windsor, Faculty of Medicine and Dentistry, University of Western Ontario, Canada
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*Dr P. Chue, 3rd Floor, 9942-108 Street, Edmonton, Alberta T5K 2J5, Canada. Tel: (780) 401 4189; Fax: (780) 425 9317; E-mail: pchue@ualberta.ca

Abstract

Background:  Atypical antipsychotics offer clear advantages in the management of schizophrenia, compared with conventional neuroleptics, but weight gain is a significant adverse effect with some of these agents.

Objective:  To review the literature on weight gain associated with atypical antipsychotic treatment in schizophrenia.

Methods:  Relevant sources were identified from Medline searches to February 2003 using combinations of keywords including ‘schizophrenia’, ‘antipsychotics’, ‘weight gain’, ‘adverse events’, ‘obesity’, and ‘diabetes’.

Results:  Most atypical antipsychotics induce some weight gain, but the magnitude of the effect varies markedly. The greatest increases are seen with clozapine and olanzapine: risperidone has a slight effect, comparable with that of conventional neuroleptics, while ziprasidone and aripiprazole appear from current data to have little effect. In addition, atypical antipsychotics have been associated with metabolic disturbances, particularly glucose dysregulation and dyslipidemia. These effects tend to be more marked with olanzapine and clozapine than with other agents. Weight gain associated with atypical antipsychotics imposes substantial morbidity, in addition to that associated with schizophrenia itself. Furthermore, weight gain can significantly impair patients' quality of life, and leads to non-adherence with treatment. Effective weight management should include the selection of an appropriate atypical antipsychotic and for effective weight management, as well both diet and exercise, formal weight management programs tailored to the needs of schizophrenic patients may be useful, and some patients may benefit from weight-reducing drugs.

Conclusions:  Weight gain associated with atypical antipsychotics is a common problem that requires effective management. The selection of an agent with a low risk of weight gain, such as risperidone or ziprasidone, is central to such management.

Introduction

Atypical antipsychotics offer a number of advantages in the treatment of schizophrenia, notably a reduced incidence of extrapyramidal adverse effects and better efficacy against negative symptoms, compared with conventional neuroleptics (1). During the past decade, however, it has become apparent that some of these agents can cause substantial weight gain in a significant number of patients. Moreover, this problem is compounded since patients with schizophrenia are often receiving other medications, such as lithium or sodium valproate, which themselves may cause weight gain.

Although weight gain has attracted less attention than other adverse events associated with antipsychotics (2), it nevertheless constitutes an important clinical problem. In addition to the health hazards associated with excess weight and obesity, weight gain has a substantial impact on patients' general well-being, and is a major cause of non-adherence with antipsychotic medication (3–6). These considerations apply not only to patients with schizophrenia, but also to patients with bipolar disorder, a condition in which atypical antipsychotics are increasingly being used. The propensity to increased weight is compounded in the latter group of patients by the use of mood stabilizers, which are also associated with weight gain.

Atypical antipsychotics differ markedly in their propensity to induce weight gain (3–6) and hence careful choice of agent is necessary in order to minimize weight gain. The choice of the most appropriate antipsychotic agent for an individual patient will therefore depend on both efficacy and the risk of weight gain and other potential adverse effects, as well as the patient's specific circumstances.

This paper reviews the extent of weight gain associated with atypical antipsychotics, the impact of weight gain on patients' well-being and quality of life, and the management of antipsychotic-induced weight gain. Relevant sources were identified from Medline searches to February 2003 using combinations of keywords including ‘schizophrenia’, ‘antipsychotics’, ‘weight gain’, ‘adverse events’, ‘obesity’ and ‘diabetes’.

Weight gain associated with atypical antipsychotics

Weight gain is becoming accepted as one of the most significant adverse effects associated with some atypical antipsychotics (1). Almost all of the atypical antipsychotics currently available induce weight gain to some extent (5,7–12) and there is evidence that 40–80% of patients may experience weight gain that exceeds their ideal body weight by 20% or more (13). Thus, it is appropriate for clinicians to consider using agents with a lower propensity for inducing weight gain, particularly when atypical antipsychotics are to be used in patients who are receiving other medications associated with weight gain, such as sodium valproate or certain antidepressants.

The potential consequences of weight gain associated with atypical antipsychotics can be estimated by extrapolating from data on cardiovascular mortality in the Framingham study; for example, a 10 kg weight gain during treatment with an atypical antipsychotic would be associated with approximately 416 additional deaths over 10 years, a figure that largely offsets the 492 suicide deaths that could be prevented during that time (10). Furthermore, the consequences of weight gain may be particularly significant in psychiatric patients given the high prevalence of smoking in such patients, which greatly compounds cardiovascular mortality (14) and poorer detection and treatment of physical illnesses in these patients (15). The high incidence of weight gain, together with the attendant burden of morbidity and impaired well-being, creates a strong case for effective management of the problem (13).

Although most atypical antipsychotics induce some degree of weight gain, it is important to recognize that this is not an inevitable consequence of their antipsychotic activity. Although some studies have reported an association between body weight gain and clinical response (7,16), more recent data suggest that there is no relationship between weight gain and symptomatic improvement. This view is supported by the findings that even for a given drug, weight gain is variable and unpredictable (2) and that newer atypical antipsychotics of comparable efficacy differ markedly in their capacity to induce weight gain. Further information comes from a recent analysis of data from two large double-blind trials with risperidone, which showed that there was no significant interaction between the degree of weight gain and clinical improvement (17).

Extent of weight gain

Comparisons of body weight gain during treatment with atypical antipsychotics are complicated by differences in study design (e.g. prospective vs. retrospective, randomized vs. open, non-comparative vs. controlled), patient characteristics and inclusion criteria, study duration, and the use of different measures of body weight gain (7). Furthermore, the question of how much weight gain should be considered clinically relevant in schizophrenic patients is also important, since obesity is about two to three times more common among patients with schizophrenia than in the general population (18–20). In general, increases of more than 3 kg, or 5% or more of initial body weight, within 12 weeks can be considered clinically relevant (7). The distribution of weight gain during treatment with atypical antipsychotics is also important. Patients with schizophrenia who gain weight on antipsychotic treatment tend to gain abdominal fat, which is an independent risk factor for coronary artery disease (21–24).

Prospective studies

Many of the studies investigating weight gain during treatment with atypical antipsychotics have been retrospective or naturalistic in nature and very few prospective studies have been performed. One such study compared the weight gain in 66 patients treated with olanzapine, risperidone, ziprasidone or haloperidol for up to 48 weeks (25). At the end of the study, the mean weight gains with the four drugs were approximately 5.4, 2.5, 1.9 and 1 kg, respectively. In a second study, 377 patients received flexible doses of risperidone 2–6 mg, or olanzapine 5–20 mg, for 8 weeks (26). Risperidone was associated with significantly less weight gain than olanzapine (mean 1.5 vs. 3.3 kg, respectively, P < 0.001), and significantly fewer patients experienced a weight gain of 7% or more with risperidone (12 vs. 27%, P < 0.001). Moreover, in risperidone-treated patients, weight gain was mainly seen in patients with a low body mass index (BMI) at baseline, whereas with olanzapine weight gain occurred irrespective of the patients' baseline BMI. There are, however, other data suggesting that olanzapine-related weight gain may be greatest in patients with the lowest BMI. The combined data from four studies showed that 41% of a total of 1455 olanzapine-treated patients experienced clinically significant weight gain (> 7%); the incidence of weight gain was highest (32%) among patients who were underweight at baseline and lowest (11%) among those who were overweight (27). A recent study measured body weight in 180 elderly schizophrenic patients before and after 1 year's treatment with risperidone, at a mean dose of 3.7 mg/day (28). No significant weight gain occurred in these patients during risperidone treatment.

Naturalistic studies

The effects on weight gain of olanzapine, risperidone and haloperidol were compared in a large prospective naturalistic study involving a total of 2967 patients (29). The incidence of weight gain, reported as a treatment-emergent adverse event, during the first 6 months of treatment was significantly higher with olanzapine (6.9%) than with risperidone (1.9%, P = 0.001 vs. olanzapine) or haloperidol (0.9%, P = 0.013). A second study compared changes in body weight and BMI in 100 patients treated for 4 months with risperidone or olanzapine (30). There was no significant change in either measure in risperidone-treated patients. By contrast, patients receiving olanzapine showed a mean weight gain of approximately 2 kg from baseline, and a significant increase in BMI. Similarly, the proportion of patients in whom weight decreased or remained unchanged was 66% with risperidone, compared with 26% with olanzapine.

Meta-analyses

Allison et al. (9) compared the weight gain associated with conventional neuroleptics and atypical antipsychotics in a meta-analysis that included data from 81 studies. The analysis estimated the weight gain following treatment with each agent for 10 weeks at a standard dose. Among the atypical agents, the largest weight gains were seen with clozapine and olanzapine, which produced mean increases of 4.45 and 4.15 kg, respectively. Risperidone and sertindole were associated with moderate weight gains (mean increases of 2.1 and 2.92 kg, respectively), which were within the range of those seen with conventional neuroleptics. Ziprasidone produced the smallest weight gain (mean 0.04 kg); there were insufficient data to evaluate the effects of quetiapine. The authors pointed out that larger weight gains would be expected during longer periods of treatment, and that many patients might experience clinically significant weight gain.

Systematic reviews

A subsequent systematic review included data from 80 reports of weight changes associated with a wider range of atypical antipsychotics (31). The greatest weight gains were seen with clozapine, olanzapine and quetiapine; weight gain with risperidone was less common, but more frequent than with haloperidol and amisulpride. Zotepine appeared to be linked with significant weight increases, while ziprasidone was not associated with clinically relevant weight gain.

Retrospective reviews

Similar results have been obtained in retrospective reviews (11,32,33). In one such study, the mean monthly weight gain in the short term (< 10 weeks) ranged from 2.28 kg with olanzapine to 0.8 kg with ziprasidone (11). A second study found significant weight gains over 6 months during treatment with clozapine, olanzapine or quetiapine, but not with risperidone or haloperidol (32).

In summary, studies have consistently shown that clozapine and olanzapine produce the greatest weight gains, while ziprasidone produces the least; risperidone has an intermediate effect, comparable with that of conventional neuroleptics (Fig. 1).

Figure 1.

Mean weight gains during treatment with atypical antipsychotics and haloperidol (9,11,25,32).

Time course of weight gain

As noted above, the meta-analysis by Allison et al. (9) highlighted the possibility that weight gain may continue during long-term treatment with atypical antipsychotics, resulting in clinically significant increases in weight. Evidence that weight gain may persist for up to several years comes from a naturalistic study in 82 clozapine-treated patients, in whom significant weight gain continued for approximately 46 months (it should be noted, however, that some patients in this study were also receiving sodium valproate, which may have contributed to the observed weight gain) (34,35). Similarly, weight gain with olanzapine has been shown to continue for up to 1 year in extension studies (36). It is well known that ‘real world’ clinical populations may show even greater changes in body weight, given the self-selected nature of clinical trial participants.

The time course of weight gains associated with different atypical antipsychotics was investigated in a retrospective review of clinical records from 92 patients with schizophrenia who were treated with clozapine, olanzapine, risperidone, haloperidol or sertindole (37). Patients treated with olanzapine or clozapine showed the greatest and most prolonged weight gains; the mean weight gains associated with these agents were 6.8 and 6.9 kg, respectively, and the mean times to maximum weight was 21.2 and 24.9 weeks, respectively. By contrast, in risperidone-treated patients, the mean weight gain was 5 kg, which was not significantly different from that in haloperidol-treated patients, and the mean time to maximum weight was 15 weeks (P = 0.04).

Mechanisms of weight gain

Clearly, atypical antipsychotics differ in their ability to induce weight gain, and in the duration of this effect. This presumably reflects differences in their pharmacological properties, and calls into question the mechanisms by which these agents act on body weight regulation. At present, these remain unclear, although it seems likely that multiple mechanisms are involved. Potential mechanisms include effects on neurotransmitters, principally serotonin (5-hydroxytryptamine, 5-HT), dopamine and norepinephrine, antihistaminergic effects, effects on leptin, and changes in insulin resistance.

Serotonergic effects

The serotonergic system in the lateral hypothalamus appears to play a key role in regulating food intake (4) and agonists of different 5-HT receptor subtypes have been shown to decrease feeding in animal models (38). Atypical antipsychotics have a variety of antagonistic effects at 5-HT receptors, and a correlation has been reported between antagonist potency at 5-HT2A-2C receptors (which is associated with increased appetite) and body weight gain (5).

Antidopaminergic effects

Stimulation of dopamine D2 receptors in the brain is associated with decreased food intake. Most antipsychotic drugs act as D2-receptor antagonists, and there is a significant correlation between this antagonist activity and antipsychotic effect (39). However, there is no clear evidence for a relationship between the D2-receptor antagonist activity of atypical antipsychotics and the extent of weight gain (11).

Noradrenergic effects

Noradrenergic receptors also appear to play a role in appetite and body weight control. Blockade of α- and β-noradrenergic receptors is associated with weight gain, although the β3-receptor has been shown to decrease food intake and increase energy expenditure (40). Mutations of the β3 receptor gene have been associated with the development of weight gain and type 2 diabetes mellitus (41) and it is possible that a similar genetic predisposition may exist in schizophrenia; increased expression of genes coding for the β3 and α1a receptors has been reported in patients with schizophrenia treated with clozapine (2).

Antihistaminergic effects

It is well known that antihistaminergic agents stimulate appetite and weight gain in humans, and hence it seems likely that the antihistaminergic properties of atypical antipsychotics contribute to their effects on body weight (4). The available agents, however, differ markedly in their capacity for binding to histamine H1 receptors. Drugs such as clozapine, olanzapine and zotepine show a higher affinity for histamine H1 receptors than for serotonergic or dopaminergic receptors (42); hence, binding to these receptors is likely to be highly relevant to the weight gain associated with these compounds. By contrast, risperidone has a lower affinity for H1 receptors than for dopaminergic or 5HT2A receptors (42).

Leptin

Leptin is a hormone derived from adipose tissue that plays an important role in the development of obesity and eating disorders (43). Short-term (4–6 weeks) treatment with atypical antipsychotics results in significant increases in circulating leptin concentrations, whereas haloperidol has no such effect (44,45). The magnitude of this effect varies between agents: olanzapine and clozapine increase leptin concentrations to a similar extent (44), whereas quetiapine has less effect than olanzapine (45). A further study found a correlation between serum leptin concentrations and weight gain during long-term treatment with atypical antipsychotics; patients receiving olanzapine showed the highest concentrations, whereas risperidone-treated patients had the lowest concentrations (46).

Insulin resistance

Insulin resistance forms part of a cluster of cardiovascular risk factors, together known as the metabolic syndrome or syndrome X, which is believed to contribute to the development of coronary artery disease and diabetes (47). Some atypical antipsychotics, notably clozapine and olanzapine, have been shown to increase insulin resistance (35,48–50).

Impact of weight gain on health and well-being

The health risks associated with excess body weight are well recognized (Table 1) (51). In addition to symptoms such as dyspnea on exertion, sleep disturbances, lower back pain and hip or knee pain, obesity is associated with substantial long-term morbidity and mortality. Moreover, recent data suggest an association between obesity and increased cancer mortality (52). Weight gain associated with atypical antipsychotics therefore represents a significant threat to patients' welfare, particularly when these agents are added to other weight-increasing drugs. Furthermore, the problem is compounded since people with schizophrenia are at increased risk of cardiovascular disease and death from cardiovascular causes, compared with the general population (14,53,54). This can be at least partly attributed to an increased prevalence of obesity (18,19) and other cardiovascular risk factors, such as smoking and a high-fat diet (53,55). among people with schizophrenia.

Table 1.  Diseases with documented or suggested links to obesity (51)
Documented
Coronary heart disease and congestive heart failure
Type 2 diabetes mellitus
Gout
Osteoarthritis
Degenerative joint disease
Hypertension
Endometrial carcinoma
Varicose veins (women)
Suggested
Gallbladder disease
Kidney stones
Breast cancer (postmenopausal)
Menstrual irregularities
Pulmonary and respiratory disorders (e.g. sleep apnea)
Renal disease
Skin complications
Psychosocial problems
Hemorrhoids

One potential consequence of weight gain following treatment with atypical antipsychotics is diabetes mellitus. People with schizophrenia have a higher incidence of diabetes than non-schizophrenic individuals (56) and there is growing evidence that atypical antipsychotics are themselves associated with the development of glucose intolerance and overt diabetes (57–71). Evidence that this is a direct effect of treatment comes from the finding that in approximately 50% of cases, hyperglycemia resolves when the drug is withdrawn and recurs following its reintroduction (63). Weight gain appears to be a risk factor for the development of glucose intolerance and diabetes (57,60,64,67), although in many cases diabetes can occur in the absence of significant weight gain (63,68).

The risk of diabetes varies between atypical antipsychotics. Most reports have involved clozapine and olanzapine, with much fewer cases being reported with risperidone, quetiapine, or ziprasidone (63,65,67,68,70). In a retrospective review of cases of new-onset diabetes among 7933 patients with psychosis, the incidence of diabetes in patients treated with olanzapine or clozapine was approximately three and seven times higher, respectively, than in untreated patients (58). By contrast, the incidence of diabetes in risperidone-treated patients was not significantly different from that in untreated patients. Similarly, in a retrospective review of over 34 700 patients treated with either olanzapine or risperidone, the incidence of diabetes was significantly higher with olanzapine than with risperidone (59). More recently, a case–control study involving almost 20 000 schizophrenic patients found that olanzapine-treated patients had a significantly greater risk of developing diabetes than untreated patients or patients receiving conventional neuroleptics (66). In patients treated with risperidone, the risk of diabetes was not significantly different from that in untreated patients or those receiving conventional neuroleptics. In view of such differences between atypical antipsychotics, it may be appropriate to substitute an agent with a low risk of weight gain or diabetes should hyperglycemia occur with olanzapine or clozapine (62).

In addition to disturbances of glucose metabolism, cases of dyslipidemia have also been reported during treatment with some atypical antipsychotics (34,57,69,70,72–79). These most commonly involve increases in circulating triglycerides and cholesterol. As with hyperglycemia and diabetes, dyslipidemia appears to be more marked with olanzapine and clozapine, whereas risperidone and ziprasidone have little or no effect on circulating lipids (70,73,75–79). From the cardiovascular perspective, elevation of lipids such as triglycerides and LDL-cholesterol contribute to significantly increased cardiovascular mortality, and there is evidence that these lipid changes may not only precede the development of diabetes but may also be a contributory cause (63).

In addition to the substantial burden of morbidity it imposes, weight gain can also markedly affect a patient's quality of life and psychological well-being (80,81). In a recent study, for example, weight gain was significantly correlated to impaired quality of life, as measured by the Psychological Well-being Index, and with poor general health and vitality; patients with the greatest weight gains tended to show the greatest reductions in quality of life, although this trend did not reach statistical significance (82). Weight gain is consistently cited by patients as one of the most troublesome adverse effects of atypical antipsychotics, and this has important implications for the management of schizophrenia (see below). There is thus a strong clinical need for weight management in patients treated with atypical antipsychotics with a high capacity for inducing weight gain.

Impact of weight gain on the management of schizophrenia

Adherence

Adherence with therapy is often poor in patients with schizophrenia. Studies suggest that approximately 40–50% of patients stop taking their medication within 1 year, and about 75% do so within 2 years (83,84). This non-adherence is a principal cause of relapse and hospitalization for schizophrenia (84).

Poor adherence is often related to adverse effects of medication (83–85). Side-effects of antipsychotic therapy that have been linked to poor adherence include extrapyramidal symptoms, neuroleptic dysphoria, akathisia, sexual dysfunction and weight gain (84). Although surveys have found strong patient preferences for atypical antipsychotics over conventional neuroleptics (86), the weight gain associated with some agents is often perceived as a major disadvantage. In a survey conducted in the UK, for example, weight gain was the second most commonly reported adverse effect associated with atypical antipsychotics, and almost two-thirds of patients who reported weight gain considered it to be ‘bad’ or ‘very bad’ (86) (Fig. 2). In a further study (87), weight gain was ranked third of 16 adverse events in terms of the subjective discomfort caused to patients. More recently, a survey of 341 patients with psychosis found that weight gain was rated as ‘quite’ or ‘extremely’ distressing by a higher proportion of patients (74%) than any other adverse event (88). Moreover, studies that have specifically examined the impact of weight gain on treatment adherence suggest that weight gain may increase the risk of non-adherence (83). In one such study, obese patients were three times more likely than non-obese patients to miss doses of atypical antipsychotics, and 13 times more likely to discontinue treatment because of weight gain (89). Other studies have found that, when patients were informed about the risks associated with different antipsychotic medications, they preferred agents that did not produce weight gain, even if these were less effective or associated with other adverse effects (90).

Figure 2.

Patients' perceptions of weight gain during treatment with atypical antipsychotics (86).

Use of health care resources

Overweight and obesity are themselves associated with increased use of health care resources, and this compounds the already substantial costs involved in the management of schizophrenia. In one study, involving 277 patients with schizophrenia, obese patients were significantly more likely to use emergency room or general medical services, and there were linear relationships between BMI and the number of days hospitalized for reasons unrelated to mental health problems, and the number of general medical visits (91). Moreover, 46% of obese patients reported two or more comorbidities, compared with only 26% of normal weight or overweight patients. In a second study (92), patients who reported significant weight gain (> 6.8 kg) were significantly more likely to use acute medical services than those with no or moderate weight gain. Furthermore, total medical costs were highest in patients with significant weight gain.

Management of weight gain during treatment with atypical antipsychotics

In general, patients with schizophrenia who are at risk of weight gain during treatment with atypical antipsychotics are appropriate candidates for weight management in view of the potential consequences of drug-induced weight gain, which may be exacerbated by the often unhealthy lifestyle of people with schizophrenia (20,55,81). The decision on whether to treat an individual patient will depend on the patient's relative weight and their general state of health. Assessment of weight is commonly performed by calculation of the BMI (defined as weight in kilograms divided by the square of height in meters). For an obese person [defined as a BMI of 30 or above (20)], even a moderate weight loss of 5–10 kg can markedly improve symptoms, reduce the risk of disease, and improve quality of life (51,93).

Clinical guidelines for weight management identify the aims of management as prevention of weight gain, weight reduction where necessary, and control of other risk factors such as poor diet, lack of exercise, dyslipidemia, and smoking (51). In general, these are as applicable to patients with schizophrenia as to the general population, although motivation and adherence are likely to be particularly problematical in this situation.

The key elements of weight management in schizophrenic patients are summarized in Table 2. An initial evaluation should assess the patient's body weight and BMI and likelihood of weight gain, together with risk factors for cardiovascular disease and diabetes. Baseline investigations should include fasting blood glucose and lipids (total cholesterol, HDL- and LDL-cholesterol, and triglycerides). Initial counseling should include discussion of the risk of weight gain during treatment and, where appropriate, realistic weight loss goals (81,94). Subsequent management may involve non-pharmacological interventions and, where appropriate, drug therapy to control body weight. Weight should be monitored regularly during treatment.

Table 2.  Elements of management of atypical antipsychotic-induced weight gain (81)
Screening measures
Baseline weight
Blood pressure
Weight-related laboratory measures (glucose, lipids, etc.)
Risk factors for diabetes mellitus and cardiovascular disease
Additional risk factors (smoking, alcohol and drug abuse)
Non-pharmacological measures
Diet
Exercise
Behavioral therapy
Pharmacological options
Change of antipsychotic medication
Dose reduction
Weight-reducing drugs, in selected patients

Non-pharmacological measures

Preventative measures to control weight gain during treatment with atypical antipsychotics may be appropriate if weight increases by more than 5% (94) or if a patient gains 3 kg or more over 3 years (95). Non-pharmacological measures that can be beneficial in patients with schizophrenia include improvements in diet, exercise, and participation in weight reduction programs (13,81,95).

Ideally, dietary measures should involve the adoption of a low-fat, high-fiber diet that avoids the high-calorie foods often associated with weight gain in patients taking antipsychotic medication (94). Low-calorie diets can produce rapid initial weight loss, but should only be undertaken under medical supervision (94). It is clearly important that dietary recommendations should be within the patient's capabilities in order to ensure adherence; for most patients, the simplest dietary regimens possible are to be preferred (94).

Patients should be encouraged to exercise regularly, since exercise is often considered the most important (but least addressed) element of weight control (81,94) and has a beneficial effect on insulin sensitivity (13). Regular walking provides a simple and convenient form of exercise – even walking for just 20 min three times a week can be beneficial (94).

Several studies have shown that formal weight management programs emphasizing diet and exercise can produce short-term weight loss in patients with schizophrenia treated with atypical antipsychotics (96–98) Such programs, however, should be specifically tailored to the needs of schizophrenic patients; commercial programs aimed at the general public may not focus on issues important to people with schizophrenia (13).

Pharmacological options

If weight gain occurs during treatment with an atypical antipsychotic, it may be appropriate to substitute an alternative drug with a lower risk of weight gain, such as risperidone (81,95). The use of intermittent or low-dose treatment has also been suggested, but this approach remains controversial given the potential risk of relapse (81).

Weight-reducing drugs may have a role in selected patients in whom non-pharmacological interventions have proved unsuccessful. This approach, however, should be used with caution due to the risk of interactions with existing psychoactive medications and worsening of schizophrenia symptoms (13,16,81,94). Potential options that have been shown to be effective in the general population include sibutramine, a noradrenergic and serotonergic reuptake inhibitor, and orlistat, which acts by inhibiting the intestinal absorption of dietary fat (13,95). To date, however, these have not been studied in patients with schizophrenia. An open study found that amantadine, a dopamine agonist, produced some weight loss in patients who had gained an average of 7.3 kg during treatment with olanzapine (99). However, the use of this class of drug carries the theoretical risk of worsening psychosis. Other potential strategies, such as the use of antidepressants with appetite-suppressing properties, have proved disappointing, although one small study has reported a reduction in olanzapine-induced weight gain following treatment with nizatidine, a histamine H2-receptor antagonist (100).

The role of surgery in the management of weight gain and obesity is limited to patients with severe obesity (BMI > 35) treated in specialized centers with facilities for long-term follow-up. Moreover, gastric surgery should be followed by a strict liquid diet for 3 months, and this could be difficult for schizophrenic patients living in the community.

Conclusions

Although atypical antipsychotics offer clear advantages in the treatment of schizophrenia, compared with conventional neuroleptics, weight gain constitutes a significant limitation with some agents. The substantial morbidity associated with excess body weight, together with the marked impact of weight gain on patients' quality of life and well-being, means that early intervention with effective strategies for controlling weight gain is essential for patients being treated with atypical antipsychotics. Furthermore, the selection of agents with a low capacity for inducing weight gain, such as risperidone or ziprasidone, is central to such strategies.

Acknowledgments

This work was supported by an unrestricted educational grant from Janssen.

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