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Increasing experience with the atypical antipsychotics (AAPs) in real-world clinical settings has demonstrated that the use of these drugs can be associated with adverse metabolic changes including diabetes mellitus (DM) (1–9), weight gain (10–21), and dyslipidemia (22–29). These effects are particularly important for patients with schizophrenia who are at greater risk of developing DM as well as suffering from more cardiovascular (CVS) disease than the general population (30). Further, patients with schizophrenia experience increased rates of medical comorbidity and are often inadequately treated (31,32). This review discusses a practical approach to the management of metabolic problems in psychiatric patients. However, it should be noted that the treatment of such problems is particularly complex, and referral to family practice and specialist physicians is recommended. DiabetesDM is a common chronic disease associated with premature macrovascular and microvascular disease and affecting > 7% of Canadians, yet it remains significantly underdiagnosed (33, 34). Groups at higher risk of DM include women, particularly those with a history of gestational DM (GDM), macrosomic babies (> 4 kg), or polycystic ovarian syndrome (PCOS); the obese, particularly those aged 40 years or over with abdominal obesity and sedentary lifestyle; those with early vascular disease, hypertension, or dyslipidemia; individuals with a family history of DM or a personal history of hyperglycemia; and certain ethnic groups. Patients with schizophrenia are also at increased risk because of their psychiatric illness and their medications (certain AAPs, mood stabilizers, and antidepressants); this risk appears to extend to bipolar disorder patients, although to a lesser extent (35,36). The diagnostic criteria for DM have been recently revised (34). Currently, the diagnosis of DM is made if there are symptoms of DM present (polyuria, polydipsia, and unexplained weight loss), together with a random plasma glucose (PG) value > 11.1 mmol/L; or a 2-hour oral glucose tolerance test (OGTT) PG value > 11.1 mmol/L; or a fasting PG (FPG) value > 7.0 mmol/L on 2 different days (Table 1). Accurate fasting blood investigations may be particularly difficult to achieve in psychiatric patients, since patients may not eat, smoke, chew, or drink anything except water for 12 hours prior to the investigations (no alcohol for 24 hours). The glycosylated hemoglobin (HbA1C) test is not sufficiently sensitive for screening, because it reflects glucose control over the previous months and is not standardized. While a FPG is the recommended screening test, a proportion of patients with DM can have a normal FPG (37). Screening for DM with a FPG is recommended every 3 years in individuals aged 40 years or over but more frequently and (or) earlier, together with an OGTT, in those individuals with additional risk factors (34).
The first steps in management are prevention and early detection. All risk factors should be modified where possible, and this encompasses both the choice and use of psychotropic drugs. The risk of metabolic disturbance may possibly be minimized by using AAPs at the lowest optimized therapeutic dosages; initially using or substituting lower-risk drugs; and avoiding concomitant drugs, such as tricyclic antidepressants and sodium valproate, that also affect glucose metabolism. However, it may not be clinically appropriate to change to an alternative AAP because of the risk of relapse or partial response, and dosage reduction once a metabolic disturbance has occurred may be of limited benefit. Occasionally, careful use of antipsychotics (APs) in combination may allow a lower dosage of both, but in general polypharmacy should be avoided (15). Nonetheless, a study of 82 clozapine-treated patients with schizophrenia reported improvement in glucose regulation and weight loss with reduced clozapine dosage and added quetiapine (38). Impaired glucose tolerance (IGT) is now considered to be a stage in the development of DM, and individuals with IGT are at increased risk of cardiovascular disease, which may present before the onset of DM (39,40). The development of a syndrome of insulin resistance (IR) (metabolic syndrome, syndrome X, or cardiovascular dysmetabolic syndrome) has been identified as a key process in the dysregulation of glucose metabolism and is associated with a cluster of CVS risk factors that include central or android obesity (waist circumference > 102 cm for male patients and > 88 cm for female patients); hypertension, dyslipidemia, hyperinsulinemia, or endothelial dysfunction; disorders of coagulation and fibrinolysis; hyperuricemia; and acanthosis nigricans (41,42). It is now well recognized that the treatment of DM is not just about glucose control, it is also important to target lipid levels, blood pressure (BP), and smoking cessation to prevent the complications of DM. First-line therapy for DM is primarily lifestyle modification incorporating improvement in diet (by reducing fat and if appropriate caloric intake, eating healthy balanced meals, and increasing fiber intake), weight reduction or maintenance of healthy weight, and increased physical activity. Both hypocaloric diets and physical activity can reduce IR, even without reduction in body weight, although weight loss further reduces IR and has a significant effect on decreasing BP (42). All diabetics should receive individualized professional dietary advice. Increasing evidence suggests that early intervention with diet and exercise, as well as certain drugs such as metformin, acarbose, rosiglitazone, ramipril, losartan, captopril, orlistat, and possibly sibutramine can reduce the progression of IGT to DM (43–51). Recommended glycemic control targets (that is, HbA1C < 7.0%; preprandial PG 4.0 to 7.0 mmol/L, 2-hour postprandial PG 5.0 to 10.0 mmol/L) should be tailored on an individual basis according to risk factors, and recent data suggest that postprandial PG elevations represent an independent predictor of CVS mortality (34). Further, there does not appear to be a glycemic control target at which the CVS risk of a diabetic is reduced to that of a nondiabetic (52). This reflects the severity of DM as a systemic and progressive disease process requiring aggressive and comprehensive interdisciplinary management. The physician plays an important role in improving outcome in DM, and many of the strategies for improving adherence are cognitive-behavioural techniques familiar to psychiatrists (53). If lifestyle changes fail to achieve glycemic targets within 2 to 3 months or if marked hyperglycemia occurs (HbA1C > 9.0%), medications should be initiated together with lifestyle counselling. Currently there are 5 classes of oral agents used in the treatment of type 2 DM, including biguanides (metformin), sulphonylureas (glyburide, glicazide, and glimepride), meglitinides (repaglinide and nateglinide), alpha-glucosidase inhibitors (acarbose), and thiazolidinediones (rosiglitazone and pioglitazone). The differences among these agents are beyond the scope of this article, but metformin remains the optimal first-line therapy for obese patients with type 2 DM from a simple and practical perspective and is not associated with weight gain or hypoglycemia (34,54). Metformin is also used in the treatment of PCOS to restore fertility (55). Acarbose, which must be taken just before eating, is also not associated with hypoglycemia or weight gain. The thiazolidinediones act directly to improve IR, and their benefits beyond glucose reduction are being investigated, including their use in women who have had GDM. These women (and their children) are at increased risk of developing DM in later life (56). This may be particularly relevant with AAPs that have been associated with GDM (57,58). Liver-function tests (LFTs) are recommended with metformin, acarbose, and the thiazolidinediones. The presence of hypertension and DM significantly increase both macrovascular and microvascular complications. Target BP values are lower than for nondiabetic hypertensives at 130/80 mmHg; however, BP is often measured inaccurately (59). A complete blood count, serum electrolytes and creatinine, urinalysis, and ECG are recommended in addition to FPG and lipid profile. The management of hypertension is complex and depends on overall CVS risk, not just BP; treatment includes lifestyle modification (that is, weight loss, low-sodium diet, physical activity, and smoking cessation) and pharmacotherapy (60). Further, in the presence of microalbuminuria, an angiotensin-converting–enzyme (ACE) inhibitor (if creatinine clearance > 60 mL/min) or, if not tolerated (or if creatinine clearance < 60 mL/min), an angiotensin- receptor blocker (ARB) is recommended, even in normo- tensive diabetics. Patients receiving an ACE inhibitor or ARB should have their serum creatinine and potassium levels checked within 2 weeks and regularly thereafter. Unless contraindicated, low-dosage acetylsalicylic acid is recommended for all diabetics with evidence of CVS risk factors. Weight GainWeight gain leads to an increased risk of DM, CVS disease (that is hypertension and coronary artery disease), cancers (specifically, uterus, prostate, kidney, and gall bladder), arthritis (osteoarthritis and inflammatory), low back pain, and obstructive sleep apnea (61). Further, weight gain has particular implications for women in terms of hormonal changes associated with menstrual irregularity, early menopause, sexual dysfunction, infertility, and an increased risk of GDM and neural tube defects (62). There are also negative impacts on self-esteem, stigma, quality of life, treatment adherence, and health care resource utilization (13, 65). Patients with untreated obstructive sleep apnea may demonstrate daytime fatigue, irritability, and anergia and thus be diagnosed with depressive or negative symptoms, leading to potentially inappropriate pharmacotherapy. The index of overweight and obesity that is most commonly used is the body mass index (BMI; BMI = weight in kilograms / [height in metres]2) (Table 2) (63). However, BMI is not standardized for ethnicity; for young, elderly, or muscular individuals; or for pregnant or lactating females (64). Waist circumference (measured as the midpoint between lowest rib margin and iliac crest) is a more sensitive measure for abdominal fat, which is an independent risk factor for morbidity even in persons of normal weight (63). However, it is a more intrusive measurement than BMI and requires palpation of anatomical landmarks to be performed correctly.
Antipsychotic-associated weight gain appears to be influenced by drug, duration of treatment, and concomitant medications, as well as by patient characteristics that include younger age, female sex, ethnicity, and psychiatric diagnosis (12,14,15,65). Baseline weight, clinical response, and drug dosage are less clearly related to weight-gain potential. There are few directly comparative data for the AAPs; most of the data are derived from short-term clinical trials in which olanzapine, clozapine, sertindole, and zotepine appear to be associated with the greatest weight gain, while ziprasidone, amisulpride, and molindone appear to cause the least (16–19,21). The trajectory of weight gain is different among the AAPs, and the plateau representing the final total amount of weight gained may only be reached after 9 to 60 months’ treatment, depending on the drug (66,67). Prevention of weight gain is particularly important in the first place because excess weight is very difficult to manage, especially in psychiatric populations (68–70). Given the serious health consequences, weight gain must be managed aggressively; thus, it is important to identify those patients at risk and the drugs that are most likely to be associated with weight gain when used in such patients. Baseline assessment should include BP, FPG, fasting lipids, serum thyroid-stimulating hormone, and a LFT. It is possible to minimize weight gain by choosing AAPs with less weight-gain liability where possible and by implementing a diet and exercise regimen from the outset. Switching to an alternative AAP can reverse weight gain and other metabolic disturbances, including adverse lipid and glucose profiles (71,72). It is important to review other medications associated with weight gain; for example, sodium valproate can be associated with weight gain, IR, and PCOS when used in women as an anticonvulsant or mood stabilizer (73,74). Many prescription medications, including insulin and others used to treat DM, can cause weight gain (75). Concomitant psychiatric and physical illnesses should be treated. Published clinical guidelines for weight management are generally appropriate for the management of patients with schizophrenia, although adherence may be problematic (76). Patients with schizophrenia often lead an unhealthier lifestyle than the general population, perhaps because of limited finances and health education. The key steps of management are to avoid weight gain; to lose weight when appropriate; and to manage other risk factors such as smoking, DM, poor diet, and physical inactivity. Energy intake must be less than energy expenditure; to achieve and maintain this, a realistic weight-loss goal should be no more than 1 to 2 kg monthly, but even modest weight loss in obese individuals can decrease the risk of disease (77). Dietary change often requires substantial lifestyle adjustment, and caloric restriction alone leads to decreased energy expenditure. Weight gain with olanzapine has been shown to be related to decreased energy expenditure (78). Exercise is critical in the management of weight and has additional benefits in reducing BP, IR, dyslipidemia, stress, and cardiovascular risk (79). Regular exercise distinguishes people who are successful at maintaining weight loss from those who are not successful, and a maintenance program must be practiced indefinitely (and at the same intensity) to prevent regain of weight. Establishing the patient’s motivation to lose weight and providing regular support are essential components of any treatment plan. Although several studies have shown weight management in patients with schizophrenia with behavioural interventions, these have been small, short-term studies not representative of the resources available to most patients (80–85). In general, the most effective methods incorporate a highly structured, stepwise approach of incremental weight management interventions that should be implemented as early as possible and maintained for the duration of AP treatment; in 1 study the average time to peak weight loss was 2 years (84). Other behavioural changes accompanying AP treatment may modify potential weight gain; thus, Frankenburg and colleagues found that a reduction in smoking, and not increased appetite or sedation, contributed significantly to the weight gain occurring with clozapine (86). However, another study found that, for olanzapine, there was no difference in weight gain between smokers and nonsmokers (87). Ethnicity and sex influence weight loss: women generally show less improvement with behavioural strategies than men (81,88,89). In both psychiatric and nonpsychiatric populations, African Americans lose significantly less weight than whites (88,90). There are few reviews of the pharmacologic approaches to obesity specific to weight management in schizophrenia (68,69). In general, centrally acting pharmacologic agents should be approached with caution in schizophrenia because of potential interactions with AP therapy, and most are indicated for short-term use only (91). Further, antiobesity drugs are rarely covered by drug reimbursement plans, and patients with schizophrenia are unlikely to be able to afford them, especially over the long term. Sibutramine, a noradrenergic and serotonin reuptake inhibitor, is contraindicated in patients on antidepressants or with CVS problems, and its use and safety in the general population are currently being reviewed (92). The use of orlistat, a lipase inhibitor that blocks up to 30% of intestinal fat absorption, can be effective, particularly in patients who are able to follow the required low-fat diet and thus avoid the gastrointestinal side effects (93). Although orlistat can impair the absorption of fat-soluble vitamins, an adverse effect on the serum levels of psychotropic drugs, such as clozapine, has not been shown (94). The use of concomitant antidepressants associated with weight loss or weight neutrality, such as fluoxetine, moclobemide, and bupropion, has been suggested. However, weight loss effects tend to be short term, and there are risks of increased adverse effects and drug–drug interactions. Further, certain combinations (for example, fluoxetine and olanzapine) may even exacerbate weight gain (95). Histamine H2 receptor antagonists can reduce appetite and mitigate weight gain, but again, limited benefits are described with the use of nizatidine in the treatment of AP-associated weight gain (96,97). Recent data suggest that topiramate is associated with weight loss or weight stabilization (98,99). Both D2 agonists and antagonists in animal studies are associated with a dosage-dependent biphasic response in which low dosages stimulate food intake and high dosages are inhibitory (100,101). However, there are few studies of dopamine agonists in AP-treated patients. Amantadine did attenuate olanzapine-associated weight gain without worsening of mental state (102,103). Finally, although metformin has been used in obese diabetics, there are few data for psychiatric patients other than 1 small study demonstrating weight loss in adolescents on olanzapine or valproic acid (104). Surgical (bariatric) techniques for treating obesity may be considered in patients with a BMI > 35 who fail to respond to other treatments and have significant obesity-related complications. This is generally only possible in specialized centres and may not be covered by health care. In addition, there are strict requirements related to anesthetic risk (for example, cessation of smoking) and the ability to adhere to lifelong follow-up to avoid chronic complications (105). DyslipidemiaAbnormalities of lipid metabolism can precede the development of glucose dysregulation, and the increased flux of free fatty acids from adipose depots exacerbates many of the fundamental derangements seen in IR (105,106). Certain AAPs have been associated directly with dyslipidemia, particularly hypertriglyceridemia (22–29). Since many individuals are asymptomatic, it is recommended that, in the general population, men over age 40 years and women over age 50 years should be screened regularly (107). For higher-risk populations, earlier and more frequent screening is suggested. The fasting lipid profile consists of total cholesterol (TC), high- density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and TC/HDL ratio; the latter is the index of choice (34). The same requirements as for the OGTT apply to obtaining a fasting lipid profile. Overall, CVS risk is influenced by age, presence of DM, lipid values, systolic BP, and smoking status; thus, target lipid values are stratified by level of risk (Table 3). Any patient over age 30 years with DM or clinical evidence of atheroclerosis, and any patient who has already suffered a CVS event, is automatically at very high risk.
Ideally, a 3- or 6-month trial of nonpharmacological treatment for moderate-risk and low-risk patients, respectively, should be initiated where possible, but this may need to be combined with early drug therapy for patients at high or very high risk (107). Nonpharmacologic interventions include treatment of secondary causes of hyperlipidemia such as hypothyroidism, DM, and alcoholism; switching AAPs to reverse adverse lipid changes (23,71); and implementing lifestyle changes such as dietary modification, increased physical activity, weight control, and smoking cessation. The choice of lipid-lowering drug is complex and depends on the type of lipid abnormality. There are 5 classes of lipid- lowering agents that include statins or 3-hydroxy- 3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, and rosuvastatin), fibrates (bezafibrate, clofibrate, microionized, and microcoated fenofibrate, and gemfibrozil), bile acid sequestrants or resins (cholestyramine and colestipol), niacin (nicotinic acid), and ezetimibe. Omega-3 fatty acids (docosapentoic and eicosapentoic acids) found in salmon oil supplements also lower TG (cod liver oil has no effect). Rhabdomyolysis has been reported with the combination of lovastatin and gemfibrozil or niacin; the latter can also increase IR (108). Bile acid sequestrants can elevate TG in diabetic dyslipidemia, and fibrates may paradoxically raise LDL-C in 10% to 15% of patients. Monitoring of LFTs, creatine kinase, and serum creatinine is recommended 6 weeks after starting fibrate therapy and regularly thereafter (109). ConclusionIt is important to keep in perspective that, despite the adverse metabolic effects of AAPs, they offer many significant benefits in the treatment of schizophrenia. Although a favourable risk–benefit ratio can be argued for clozapine, given its efficacy in treatment-refractory patients, the same does not necessarily hold true for some of the other AAPs (110). Patients with schizophrenia are at greater risk of cardiovascular disease and DM than the general population, and increasing experience of AAPs in real-world clinical situations suggests that these risks are compounded by the use of certain AAPs. Effective strategies to reduce these risks need to be studied. In light of the current knowledge, psychiatrists must be more proactive in the management of AP side effects (111). This requires careful selection and use of all the relevant psychotropic drugs. It is recommended that all patients receiving AAPs (especially those with identified risk factors) should have weight, BP, FPG, and fasting lipids monitored at baseline and regularly. Consideration should also be given to evaluation of serum creatinine, uric acid, electrolytes, LFTs, and ECG. Appropriate management strategies should be initiated early, given the serious long-term health implications. In view of the complexity of the management of the medical consequences of AP side effects, regular health screens and early referral to primary care and specialist physicians should be encouraged. Psychiatrists should discuss serious potential health-risk side effects with patients prior to initiating treatment, where possible, and provide adequate psychoeducation concerning the management of side effects. AcknowledgementsDr Phil Hardin and Dr Raphael Cheung are gratefully acknowledged for their expert advice. 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CMAJ 2001;165:632. 109. Fung MA, Frohlich JJ. Common problems in the management of hypertriglyceri- demia. CMAJ 2002;167:1261–6. 110. Fontaine KR, Heo M, Harrigan EP, Shear CL, Lakshminarayanan M, Casey DE, Allison DB. Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate. Psychiatry Res 2001;101:277–88. 111. Wirshing DA, Boyd JA, Meng LR, Ballon JS, Marder SR, Wirshing WC. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry 2002;63:856–65. Author(s)Manuscript received February 2003, revised, and accepted May 2003. 1. Associate Clinical Professor, Department of Psychiatry, University of Alberta, Edmonton, Alberta. Address for correspondence: Dr P Chue, Community Living Program, 3rd Floor, 9942 108 Street, Edmonton, AB T5K 2J5 e-mail: pchue@ualberta.ca
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