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Metabolic issues in patients with severe mental illness.

This article reviews the epidemiology of weight gain and diabetes mellitus in general and in patients with severe mental illness in particular. Body mass index is defined, and possible predictors for weight gain in patients receiving antipsychotic medications are also enumerated. Information on risk of association with type 2 diabetes mellitus is described, as well as information on dyslipidemias within the rubric of the metabolic syndrome. Recent consensus panel reports and their recommendations for ongoing patient monitoring are reviewed. The issue of switching antipsychotic medication in the context of a developing metabolic disorder is discussed with regard to appropriately balancing risk and benefits. Collaborative treatment between a psychiatrist and an endocrinologist is encouraged. The primary care physician may be required to fulfill both roles.

Key Words: diabetes mellitus, metabolic syndrome, obesity, schizophrenia


The introduction of second-generation antipsychotic agents has led to an improvement in the treatment of patients with serious mental disorders. Approved by the United States Food and Drug Administration (FDA) for both schizophrenia and bipolar mania (Table 1), they have demonstrated efficacy for a number of symptom domains, including positive symptoms (such as hallucinations and delusions), negative symptoms (such as amotivation), cognitive symptoms (such as attention and memory), mood (including both dysphoria and mania), and aggressive behavior. (1) Also of great benefit is a decreased propensity for extrapyramidal side effects and tar-dive dyskinesia compared with the older first-generation antipsychotic agents (such as haloperidol).

The second-generation antipsychotic agents are not free of burdensome side effects, however. Issues that have recently become a focus of much attention have been weight gain, a risk for the development of diabetes mellitus, and/or the metabolic syndrome (Fig. 1). This article reviews these three adverse outcomes by examining their causes among the general population and among patients with schizophrenia and reviews the information regarding association of these adverse events with the use of second-generation antipsychotic agents. Current recommendations for assessment and monitoring of these problems are outlined. Basic lifestyle interventions (medical nutrition therapy and appropriately prescribed physical activity) are discussed, as well as the need for a collaborative relationship between psychiatrist and endocrinologist. In some cases, when specialists are not available, primary care practitioners may have to fill both roles. The importance of a careful individual risk-benefit assessment is underscored.

Weight Gain

In the past decade, the prevalence of obesity has increased across the United States. (2) As weight increases, so does the risk for many medical problems, including type 2 diabetes mellitus, coronary heart disease, osteoarthritis, hypertension, and gallbladder disease. (3) Abdominal or visceral obesity is particularly associated with increased risk for insulin resistance and/or the metabolic syndrome and for type 2 diabetes mellitus, and patients with schizophrenia have increased visceral fat when compared with control subjects, even in the absence of treatment with antipsychotic medication. (4) Therefore, the seriously mentally ill may fundamentally be at higher risk for metabolic problems.

Body mass index (BMI), calculated as the quotient of body weight (kg) divided by the square of height (m), is a better measure of obesity than is body weight. Printed and on-line calculators for BMI are readily available (for example, the website from the Centers for Disease Control and Prevention, BMI-related health risks are well established, with health risk considered "high" for BMI of 30 to 34.9, "very high" for BMI 35 to 39.9, and "extremely high" for BMI greater than 40. (5)


It is estimated that 30% of the general population are obese (BMI > 30). (6) Individuals with schizophrenia are, on the whole, as or more obese than individuals without schizophrenia. (7) Second-generation antipsychotic medications have been associated with an increase in weight. In a comprehensive meta-analysis of weight change after 10 weeks of treatment at a standard dose, (8) mean increases were as follows: clozapine, 4.45 kg; olanzapine, 4.15 kg; risperidone, 2.10 kg; and ziprasidone, 0.04 kg. Insufficient data were available to evaluate quetiapine at 10 weeks, but subsequent studies have indicated that quetiapine also has a high propensity toward gain, particularly over the long term, as demonstrated in a prospective, naturalistic study. (9) Aripiprazole, the newest second-generation antipsychotic medication to become commercially available, is generally considered to be weight neutral. Other psychotropic medications have also been associated with weight gain, notably antidepressants such as paroxetine (a serotonin-specific reuptake inhibitor), (10) and mood stabilizers such as valproate. (11) Possible mechanisms for medication-associated weight gain include weight loss before drug treatment, food craving, alteration in resting metabolic rate, change in neurotransmitters (in general, [alpha]-adrenergic neurotransmission is thought to stimulate appetite, whereas [beta]-adrenergic, histaminergic, dopaminergic, and serotoninergic signal transduction confers satiety) and alteration of neuropeptides such as leptin and cytokines such as tumor necrosis factor. (12) The relative importance of these mechanisms may differ from medication to medication and individual to individual but may explain how histamine-1 receptor blockade as seen with quetiapine can be associated with sedation and gradual weight gain over time, and 5-HT2C receptor blockade as seen with olanzapine can be associated with an increase in appetite (resulting in rapid weight gain) and improvement in negative and depressive symptoms. A further discussion about receptor affinity predicting weight gain among antipsychotic medications can be found elsewhere. (13)

One major effort has been to characterize weight gain profiles for the different antipsychotic medications and to identify predictors. There is evidence that weight gain is associated with clinical response for clozapine and olanzapine. (14) However, among the patients with schizophrenia in that study, (14) only about half of the subjects who responded to clozapine or olanzapine (defined as a 20% improvement in the Positive and Negative Syndrome Scale score) gained a significant amount of weight (10% increase from baseline) over the 14-week period. (14) One can use the time course for weight gain with olanzapine (weight gain occurring in the first 40 weeks and then reaching a plateau) for early identification of those at risk before substantial weight gain has occurred. (15,16) Patients taking olanzapine who gain 5% or more of their body weight within the first 4 to 12 weeks of treatment will require more active behavioral and pharmacologic interventions than patients who gain weight more slowly or not at all. (16) Approximately one quarter of patients receiving olanzapine do not gain weight or may actually lose weight, with almost one half gaining up to 10 kilograms over a period of 39 weeks or more. (15) The dose of antipsychotic does not appear to be predictive of weight gain for olanzapine (15) but may be related to weight gain with risperidone (17) or quetiapine. (18) Low initial BMI (BMI < 25 kg/[m.sup.2]) may be a predictor of some future weight gain in some patients with any of the second-generation antipsychotic medications.

Diabetes Mellitus

An epidemic of type 2 diabetes mellitus is currently underway in the United States. The number of adult persons in the United States in 1999 to 2000 with diagnosed type 2 diabetes mellitus was estimated to be approximately 12 million, with another 5.2 million reportedly undiagnosed, and 20 million with prediabetes (using the old definition of a normal fasting plasma glucose [FPG] < 110 mg/dL). (19) Now that the American Diabetes Association (ADA) has lowered the definition of a normal FPG to less than 100 mg/dL, about 41 million people are estimated to have prediabetes. (20) The estimated lifetime risk of development of diabetes for individuals born in 2000 is 32.8% for men and 38.5% for women, with risk even higher among Hispanics (men, 45.4%; women, 52.5%). (21) Well-recognized risk factors include advancing age, weight gain, lack of physical activity, and family history, to name a few. (22) Although weight gain and obesity are risk factors for type 2 diabetes mellitus, not all patients with obesity will have diabetes and not all people with diabetes are obese (Fig. 1). Recent evidence points to schizophrenia and bipolar disorder being independent diabetes risk factors, even in the absence of treatment with antipsychotic medication. (23) Thus, the Canadian Diabetes Association recently added schizophrenia to the list of risk factors in its new clinical guidelines for the treatment and prevention of type 2 diabetes mellitus. (24)

A major issue is the impact of second-generation anti-psychotic medications in the development of type 2 diabetes mellitus. Although clear differences exist among second-generation antipsychotic medications in the potential for both weight gain and dyslipidemias, quantifiable risk differences in the association with diabetes mellitus have been less consistent in large published pharmacoepidemiologic studies. (25) For this reason, the FDA has notified the manufacturers of the second-generation antipsychotic medications that product labeling for all drugs in that class will require a new warning about hyperglycemia and diabetes. (26) In contrast to this position, a recent consensus development conference conducted by the ADA, the American Association of Clinical Endocrinologists, the American Psychiatric Association, and the North American Association for the Study of Obesity (27) did conclude that the data regarding risk of association with diabetes are more consistent for clozapine or olanzapine versus risperidone or quetiapine, where some studies showed an increased risk for diabetes whereas others did not. The panel also concluded that although the two most recently approved second-generation antipsychotic medications, aripiprazole and ziprasidone, have relatively limited epidemiologic data, available clinical trial experience with these drugs has not shown an increased risk for diabetes. A more complete discussion regarding the individual pharmacoepidemiologic studies may be found elsewhere. (25, 28)

Putative mechanisms contributing to a risk for diabetes include insulin resistance related to an increase in body weight or caused by direct effects of antipsychotic agents on glucose transporters, elevation of serum leptin, and antagonism of serotonin 5-HT1A receptors decreasing pancreatic [beta]-cell responsiveness. (29-31) However, no significant change in insulin response or insulin sensitivity was detected using either a hyperglycemic clamp (32) or a hyperinsulinemic euglycemic clamp (33) model in healthy volunteers. Other studies have demonstrated higher fasting and postprandial plasma glucose levels in patients treated with olanzapine or clozapine than those treated with first-generation antipsychotic medications, even when controlling for body weight. (34)

The absolute risk directly attributable to individual antipsychotic medications in an individual patient is difficult to determine from available data. As mentioned, schizophrenia itself is a risk factor. Multiple other risk factors may also be present, such as advancing age or a family history of diabetes mellitus. Recent attempts to quantify attributable risk of prescribing clozapine, risperidone, olanzapine, or quetiapine, compared with prescribing first-generation antipsychotic medications, revealed attributable risk percentages of 2.03%, 0.05%, 0.63%, and 0.80%, respectively. (35) It appears that choice of an antipsychotic may not necessarily predict or guarantee the development of type 2 diabetes mellitus. However, the effect of prolonged exposure to an antipsychotic agent and how it may affect attributable risk is unknown, and one might expect that risk would increase with increasing duration of exposure to agents that increase weight and or other diabetes risk factors, particularly in patients with a genetic predisposition to development of diabetes.

Early identification and treatment of diabetes mellitus are important to prevent acute illness, prevent or ameliorate symptoms attributable to diabetes, reduce macrovascular disease risk, prevent the development or the progression of microvascular and/or neuropathic disease, and increase life expectancy. (36) The FPG (no caloric intake for at least 8 hours) criteria for diagnosing diabetes mellitus were lowered from 140 mg/dL or greater to 126 mg/dL or greater several years ago. Two other diagnostic criteria for diabetes are (1) symptoms of diabetes (such as polyuria, polydipsia, and unexplained weight loss) plus plasma glucose concentration of 200 mg/dL or greater at any time of day or (2) 2-hour plasma glucose of at least 200 mg/dL during an oral glucose tolerance test, using the equivalent of 75 g anhydrous glucose dissolved in water. (22) In the absence of unequivocal hyperglycemia with acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day. The oral glucose tolerance test is not generally recommended for routine clinical use.

In the past year, the definition of a normal FPG was reduced from less than 110 mg/dL to less than 100 mg/dL. (37) Currently, an FPG between 100 and 125 mg/dL is termed impaired fasting glucose. People with impaired fasting glucose and/or impaired glucose tolerance (a plasma glucose between 140 and 199 mg/dL 2 hours after the ingestion of a 75-g glucose load) are said to have prediabetes. They have a significantly increased risk of development of type 2 diabetes mellitus. It is important to identify people with prediabetes because the Diabetes Prevention Program study (38) demonstrated that one could prevent or at least delay the progression from prediabetes to type 2 diabetes by 58% through the implementation of lifestyle changes including attempting to lose 7% or more of body weight and exercising 30 minutes per day on 5 days of each week at the intensity of brisk walking. Treatment with metformin decreased the progression to type 2 diabetes mellitus by 31%.

The Metabolic Syndrome

The metabolic syndrome is another way to identify people with increased cardiovascular risk, many of whom will have an increased risk for diabetes mellitus. It is important to note that not all people with the metabolic syndrome have prediabetes. Moreover, there have been no trials focused on people with the metabolic syndrome demonstrating the potential to prevent the development of type 2 diabetes mellitus.

The metabolic syndrome is defined as being present when three or more of the following criteria are fulfilled: (1) abdominal obesity (more highly correlated with metabolic risk than elevations in BMI), as measured by waist circumference greater than 102 cm (>40 in) for men or greater than 88 cm (>35 in) for women, (2) triglyceride plasma level of 150 mg/dL or greater, (3) HDL-cholesterol plasma level less than 40 mg/dL for men or less than 50 mg/dL for women, (4) blood pressure of 130/85 mm Hg or greater, and (5) FPG of 110 mg/dL or greater (although the threshold might be lowered to 100 mg/dL to coincide with the ADA change in the definition of a normal FPG). (39) It is estimated that approximately 25% of the population in the United States has metabolic syndrome. (40)

In addition or possibly related to weight increases observed among patients receiving antipsychotic medication, second-generation antipsychotic medications can also be associated with dyslipidemia. In a randomized clinical trial, subjects receiving olanzapine or clozapine had elevations in fasting cholesterol (although on average they remained <200 mg/dL) that were correlated with weight. (41) Regarding the metabolic syndrome, a study presented at the 63rd Scientific Sessions of the American Diabetes Association estimated increased risk for development of the metabolic syndrome among patients treated with olanzapine using data from two randomized, double-blinded, controlled clinical trials comparing olanzapine and aripiprazole. (42) Pharmacoepidemiologic studies regarding dyslipidemia and exposure to antipsychotic agents, similar in design to the studies evaluating the association with diabetes mellitus (and with similar methodological flaws), have also demonstrated an association with dyslipidemia (as demonstrated by the presence of the diagnostic code[s] or prescription of a lipid-lowering agent) for agents such as olanzapine (43) and clozapine (among patients 20 to 34 years of age). (44)

Monitoring and Managing

The report from the Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes (27) contains valuable advice for the appropriate and prudent monitoring of patients who are at risk for type 2 diabetes mellitus (Table 2). The recommendations made are similar to a prior consensus conference (Table 3), (45) and, if they are followed, will benefit our vulnerable patients by early identification and hence early intervention to address metabolic disorders.

Treatment programs include diet and exercise (which may also serve as a preventive measure), and medication treatment that includes oral antidiabetic agents (monotherapy or combination therapies), insulin, antihypertensive agents, and medications to treat dyslipidemia, depending on the presenting problems, but often used simultaneously. At present, pharmacologic antihyperglycemic therapy is presently only FDA approved for use in patients with a diagnosis of diabetes mellitus and not for the prevention of diabetes.

The value of nutritional intervention (46) and the benefits of exercise are well documented, especially in subjects with diabetes and prediabetes. Modest weight loss is associated with increased life expectancy and may be associated with reduction in parameters such as blood pressure, glucose, hemoglobin A1c, and lipids. (47,48) Exercise may also improve these factors. (49) The benefits of a combination of intensified integrated behavior modification and targeted polypharmacy addressing hyperglycemia, hypertension, dyslipidemia, and microalbuminuria can be significant, as described in a open parallel trial (n = 160; mean follow up, 7.8 years) examining cardiovascular disease in patients with type 2 diabetes mellitus and microalbuminuria. (50,51) In that study, 44% of patients in the conventional treatment group had a cardiovascular event compared with 24% in the intensive treatment group; thus, a relative risk reduction of approximately 50% was observed.

The initial choice of a second-generation antipsychotic medication is dependant on many factors and ultimately must balance risk versus benefits for each individual. Risk for the development of obesity, dyslipidemia, and diabetes is one concern that needs to be considered, together with other potential side effects. When weight gain follows a predictable pattern (such as with olanzapine), aggressive early intervention should be initiatied. (16) When a problem is identified and it persists despite efforts at nutritional and other lifestyle interventions, deciding whether or not to switch antipsychotic medication can be a significant clinical dilemma. Although clinical trials may not show big differences in efficacy between groups among antipsychotic agents, one large meta-analysis suggests that modest differences may exist in some patients, which may favor not only clozapine but also risperidone and olanzapine. (52) Efficacy considerations may be even more important among chronic patients with treatment-resistant schizophrenia, (53) particularly in terms of medication effect in ameliorating cognitive dysfunction (clearly favoring risperidone and olanzapine over haloperidol) (54) and persistent aggressive behavior (favoring clozapine), (55) as assessed in a double-blinded clinical trial. (56) Further complicating the risk-benefit equation is the observation that weight gain may be associated with response in about half of responders to clozapine or olanzapine. (14) In addition, interindividual differences in response may be large, leading to patients receiving several sequential medication trials over the years to find the optimal regimen for that individual.

For many patients, later on in their disease course and after failing a number of medication trials, obtaining an adequate antipsychotic medication response is a major challenge. When such a response is achieved, a major focus is to manage somatic problems, should they emerge. A premature switch in medications may expose the patient to the risk of deterioration in their symptoms and ultimately, relapse. This is also a public safety issue, particularly for patients with persistent aggressive behavior (where clozapine has well-documented advantages), and for patients with recurrent suicidal ideation/behavior (an indication for which clozapine has received FDA approval). Thus, for some patients it may actually be easier to manage the metabolic syndrome than it is to manage a chronic psychotic illness. Here, collaborative treatment between a psychiatrist and an endocrinologist will be crucial in optimizing the overall health outcome of the patient. The primary care physician may need to fulfill one or both roles, but consultation, when available, is desirable in complicated cases.

If a switch in antipsychotic medication is believed by both the clinician and the patient to be the most appropriate course of action, the change should be gradual, using a cross-titration technique, unless there are other overriding concerns that require an immediate discontinuation (such as a low granulocyte count in a patient receiving clozapine). The clinician needs to be mindful that a switch in medication may or may not lead to a reversal in the weight gained or in any other metabolic parameter, and continued vigilance and efforts at implementing lifestyle changes are required.

Ziprasidone and aripiprazole are two newer second-generation antipsychotic agents that appear to have a more favorable profile regarding metabolic effects including weight gain and dyslipidemia. This may also favorably affect treatment adherence. However, these agents, like all medications, are not immune from potential adverse effects. For example, there is a bolded warning in the product label for ziprasidone regarding prolongation of the QTc interval, although the actual clinical significance of this is in doubt. (57) Moreover, efficacy is not guaranteed, and, as mentioned earlier, individual patients may respond better to one agent than another. Thus, clinicians and patients benefit from having a variety of medications to use with these often difficult-to-treat disorders. Further experience with both ziprasidone and aripiprazole will better place these agents into clinical perspective.


The United States has an epidemic of obesity, type 2 diabetes mellitus, and the metabolic syndrome. Patients with serious mental disorders such as schizophrenia may be even more vulnerable to development of these problems. Routine screening for all patients with schizophrenia, as recommended by the Canadian Diabetes Association, is poised to become a standard of care. Second-generation antipsychotic medications have been associated with weight gain (in particular clozapine, olanzapine, quetiapine, and to a lesser extent, risperidone), type 2 diabetes mellitus, and the metabolic syndrome. Preserving gains made in the management of schizophrenia requires clinicians to be vigilant for the metabolic issues and intervene early when appropriate. Interventions include nutritional counseling, exercise, medication treatment, and possibly a switch of the antipsychotic medication being prescribed. Second-generation antipsychotic medications that have a more favorable weight-gain profile will have an increasingly important role, but their use, like all treatments, will also be dependent on an individual's therapeutic response.


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Leslie Citrome, MD, MPH, Lawrence Blonde, MD, FACP, FACE, and Cristina Damatarca, MD

From the New York University School of Medicine, Department of Psychiatry, and the Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY; Ochsner Clinic Foundation, New Orleans, LA; and Neuroscience Education Institute, Carlsbad, CA.

Reprint requests to Leslie Citrome, MD, MPH, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962. Email:

Accepted June 21, 2004.

Leslie Citrome, MD, MPH, is a consultant for, has received honoraria from, or has conducted clinical research supported by the following: Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Janssen Pharmaceuticals, Novartis Pharmaceuticals, Pfizer Inc, and Repligen Corp. Lawrence Blonde, MD, is a consultant for, has received honoraria from, or has conducted clinical research supported by the following: Amylin Pharmaceuticals, Inc, AstraZeneca, Aventis Pharmaceuticals, Inc, BD, Bristol-Myers Squibb, Eli Lilly and Company, EMD, GlaxoSmithKline, LifeScan, Inc, Merck & Co, Inc, Merck/Scherring Plough Corporation, Novo Nordisk A/S, Novartis Pharmaceuticals Corporation, Pfizer, Inc, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc, and Wyeth Pharmaceuticals. Cristina Damatarca, MD, is Executive Director, Medical Education and CME for the Neuroscience Education Institute, which has, or has had financial relationships with Abbott Laboratories, Asahi Kasei, AstraZeneca, Bristol-Myers Squibb, Cephalon Inc, Eli Lilly & Company, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceuticals, Lundbeck, Meiji, Pfizer, Sanofi-Synthelabo, and Wyeth Pharmaceuticals.


* The seriously mentally ill patient may fundamentally be at higher risk for metabolic problems.

* Second-generation antipsychotic medications have been associated with an increase in weight, but this varies from agent to agent and from patient to patient.

* Recent evidence points to schizophrenia and bipolar disorder as being independent diabetes risk factors, even in the absence of treatment with antipsychotic medication.

* When a problem is identified and it persists despite efforts at nutritional and other lifestyle interventions, deciding whether or not to switch antipsychotic medication can be a significant clinical dilemma.

* Second-generation antipsychotic agents that have a more favorable weight-gain profile will have an increasingly important role, but their use, like all treatments, will also be dependent on an individual's therapeutic response.
Table 1. Second-generation antipsychotic agents

 US Food and Drug
Antipsychotic Year introduced Administration-approved
agent in the US indication(s) (a)

Clozapine 1989 Treatment-resistant
 recurrent suicidal
 behavior in
Risperidone 1994 Schizophrenia, bipolar
Olanzapine 1996 Schizophrenia, bipolar
 mania, bipolar
Quetiapine 1997 Schizophrenia, bipolar
Ziprasidone 2001 Schizophrenia, bipolar
Aripiprazole 2002 Schizophrenia, bipolar

(a) As listed in the Physicians' Desk Reference, Montvale, Thomson PDR,
2004, ed 58.

Table 2. American Diabetes Association, American Psychiatric
Association, American Association of Clinical Endocrinologists, North
American Association for the Study of Obesity: Guidelines from the
consensus development conference on antipsychotic drugs and obesity and
diabetes (27)

Baseline Personal and family history of obesity, diabetes,
 dyslipidemia, hypertension, or cardiovascular disease
 Weight and height (calculate body mass index)
 Waist circumference (at the level of the umbilicus)
 Blood pressure
 Fasting plasma glucose
 Fasting lipid profile
Follow up Weight reassessed at 4, 8, and 12 weeks, and then quarterly
 Fasting plasma glucose, lipid levels, and blood pressure at
 3 months, and then fasting plasma glucose and blood
 pressure annually, and fasting lipid levels every 5 years

Table 3. Guidelines from the Mount Sinai Conference on the
pharmacotherapy of schizophrenia (45)

Body mass index Weigh at every visit for the first 6 months after
 should be monitored starting new prescription of an antipsychotic
 for all patients agent, then quarterly
 Weight gain of 1 body mass index unit should lead
 to an intervention
Diabetes A baseline measure of glucose should be collected
 before new prescription of an antipsychotic
 medication and then repeated if weight
 increases by at least 7% from baseline, then
 Patients with significant risk factors for
 diabetes mellitus should have fasting glucose
 or hemoglobin A1c monitored 4 months after
 starting an antipsychotic medication, then
Lipids Baseline measure, and repeat if weight gain is
 greater than 7%, then yearly
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Title Annotation:risk factors of mental disorders
Author:Damatarca, Cristina
Publication:Southern Medical Journal
Date:Jul 1, 2005
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