Schizophrenia: Metabolic Changes and Their Management
Udaya M. Kabadi, MD, FACP, FRCP(C), FACE, Adjunct Professor of Medicine, University of Iowa, Iowa City, and Des Moines University,Des Moines, IowaUdaya M. Kabadi, MD,
Sarah L. Tragesser, PhD,Associate Professor of Psychology, Washington State University,Richland, WA
Schizophrenia (SCH) is a psychiatric disorder characterized by disruption of both the normal thought process and the appropriate emotional response. Common clinical manifestations include hallucinations, delusions, disorganized thought, and inappropriate speech. The disorder frequently causes a marked impairment in social and occupational behavior, requiring lifelong intervention with antipsychotic medications and/or counseling. Antipsychotic drugs are effective in ameliorating symptoms and improving overall function and, therefore, are deemed to be the cornerstone of therapy in SCH subjects. However, these drugs are implicated in onset and perpetuation of obesity and a variety of metabolic abnormalities.1-19
This psychiatric disorder requires persistent vigilance and lifelong monitoring with individual psychological counseling and administration of antipsychotic drugs. Subjects with SCH, their families, and their caregivers require education and management skills including recurrent close monitoring with a detailed history, a thorough physical examination, and appropriate laboratory tests for onset of metabolic abnormalities as recommended by a consensus development conference conducted by several organizations.
Obesity is well documented to predispose to disorders of almost every organ system in the body and therefore contributes to morbidities, including disorders such as prediabetes or diabetes, hypertension, and dyslipidemia constituting metabolic syndrome, and increases mortality in the population at large. Subjects with SCH are no exception. In fact, the presence of these disorders more than doubles the relative risks of mortality in SCH patients in comparison to the general population. The mortality risk rises further with a recent documentation of increasing prevalence of cancer among subjects with both obesity and diabetes. Unfortunately, in some SCH subjects, the initial presentation of diabetes is diabetic ketoacidosis or hyperglycemic hyperosmolar state with a change in state of consciousness including coma requiring hospitalization. Thus, the severity of the clinical manifestations induced by metabolic abnormalities is often more pronounced at diagnosis in subjects with SCH as compared to non-SCH subjects and is attributed to lack of recognition of symptoms and/or neglect on the part of SCH subjects or their caregivers, leading to increased mortality. Increased prevalence of smoking in subjects with SCH contributes to recurrent infections and respiratory disorders, promoting further rise in morbidity and mortality. Finally, some of the newer antipsychotic drugs, especially olanzapine and quetiapine, are well documented to induce or exacerbate all disorders constituting metabolic syndrome, thus ensuing additional risk of morbidity and mortality.
It is well established that SCH subjects have a greater occurrence of metabolic syndrome disorders prior to treatment in comparison to the healthy population. The prevalence of these metabolic alterations rises significantly following administration of antipsychotic drugs, especially second-generation drugs. The presence of obesity, especially of visceral type as defined by several indices, was noted to be significantly higher in SCH patients prior to drug therapy in comparison to age-matched, healthy subjects — e.g., body mass index (BMI, 26.7 kg/m2 for SCH vs 22.8 kg/m2 for healthy subjects, P < 0.003); waist:hip ratio (0.99 for SCH vs 0.86 for healthy subjects, P < 0.005); total body fat (34,681 mm2 in SCH vs 27,692 mm2 in healthy subjects, P < 0.01); and intra-abdominal fat (13,232 mm2 in SCH vs 3880 mm2 in healthy subjects, P < 0.005).
The occurrence of obesity and these metabolic abnormalities appears to rise on initiation of antipsychotic therapy.2 Unfortunately, metabolic aberrations are documented to manifest more frequently in SCH subjects even prior to treatment, and the prevalence continues to rise following treatment with antipsychotic drugs, especially the newer ones.1-27
The advent of obesity and the metabolic derangements constitute the metabolic syndrome and hence enhance the risk for cardiovascular and all-cause morbidities and mortality.28-33 Thus, SCH subjects are at a much greater risk for adverse cardiovascular outcomes, including mortality.34-40 In actuality, cardiovascular mortality is documented to be increased more than two-fold among subjects with SCH as compared to the general population. Moreover, multiple other factors also contribute to the increased mortality (see Table 1). The causes include lifestyle factors, such as a greater incidence of substance abuse, smoking, poor nutrition, and inactivity; coexisting illnesses, such as HIV and hepatitis C; as well as adverse effects of efficacious drugs.41-54
|Table 1: Main Causes of Mortality in SCH Patients40|
|Ratio of Observed Deaths in Patients with Schizophrenia to Expected Deaths in the General Population|
|Cause of Deathin||Mortality Ratio in Men||Mortality Ratio in Women|
|*Since cardiovascular disease is the most common cause of death in the general population and is more than twice as common in patients with schizophrenia, it accounts for most of the excess mortality in schizophrenia.|
In one study, 15 SCH subjects were compared with 15 age-matched healthy volunteers. Seven SCH subjects were drug-naïve, and the remaining eight had not received oral drug therapy for at least 6 weeks and intramuscular drug administration for at least 6 months. The study documented the presence of generalized obesity as expressed by BMI and total body fat content, as well as visceral obesity as defined by waist:hip ratio and greater intra-abdominal fat in SCH patients during the drug-free period (see Table 2) compared to age-matched healthy volunteers.3
|Table 2: Adiposity in Patients with Untreated SCH3|
|Measure||Patients with schizophrenia*(n=15)||Healthy Controls(n=15)||P value|
|Mean age (years)||33.7||30.1||NS|
|BMI (kg/m2)||26.7||22.8||< 0.003|
|Waist:hip ratio||0.99||0.86||< 0.005|
|Total body fat (mm2)||34,680.9||27,692.5||NS|
|Intra-abdominal fat (mm2)||13,232.0||3879.9||< 0.005|
*Patients were either drug-naive (n = 7) or had been free of oral neuroleptics for ≥ 6 weeks and IM neuroleptics for ≥ 6 months (n = 8).
NS = not significant
Ryan et al also demonstrated increased prevalence of visceral fat as well as prediabetes manifested by glucose intolerance or impaired fasting glucose attributed to insulin resistance as measured by a homeostasis model assessment in SCH subjects compared to normal subjects.8,21
A meta-analysis of more than 80 studies examined the impact of 10-week, antipsychotic drug therapy on body weight in SCH subjects.1 The studies were divided into two groups according to drugs: 1) typical first-generation antipsychotic agents, e.g., molindone, fluphenazine, haloperidol, chlorpromazine, and thioridazine/mesoridazine; and 2) second-generation atypical antipsychotic drugs, e.g. ziprasidone, risperidone, olanzapine, and clozapine. Both groups were placebo-controlled. Weight gain was noted following treatment with all antipsychotic drugs. The only exceptions were molindone in the first-generation group and ziprasidone in the newer atypical agents; both apparently were weight-neutral. In contrast, olanzapine and clozapine appeared to induce the maximum weight gain (4.0-4.5 kg) over the course of the study. However, the weight gain was not only limited to the short-term use of the drugs.
Long-term studies confirm the lack of weight gain with ziprasidone. The weight gain with quetiapine and risperidone appeared to reach a plateau at approximately 2.0-5.6 kg (4-12 lbs), with the weight gain with olanzapine reaching peak and stabilizing at approximately 12 kg (26 lb), an increase well documented to induce significant aberrations in carbohydrate and lipid metabolism, contributing to adverse cardiovascular outcomes.55
Another long-term study examined weight changes with initial treatments of risperidone and olanzapine therapy over 1 year. The mean weight gain was 10.7 lbs and 17.5 lbs for patients receiving risperidone and olanzapine, respectively, at the end of 1 year, with body weights being significantly higher at the end of 1 year compared to prior initiation of either therapy.5 Weight gain associated with antipsychotics may ensue soon after initiation of therapy; the subjects randomized to receive both olanzapine and ziprasidone gained weight within 6 weeks. However, in subjects administered ziprasidone, the weight gain was 2 lbs, significantly lower (P < 0.001) than the 8 lbs noted in subjects receiving olanzapine.13
Weight gain following therapy with certain antipsychotics (e.g., risperidone and olanzapine) may be halted or even reversed within a short period of 6 weeks on withdrawal of these drugs and initiating therapy with ziprasidone.6 This study involved subjects in whom therapy with either first-generation conventional antipsychotics (e.g., haloperidol) or with second-generation agents (risperidone and olanzapine) was discontinued and ziprasidone was initiated. One hundred two subjects who had prior treatment with conventional antipsychotics experienced an insignificant gain of 0.27 kg, whereas subjects who were changed from risperidone experienced a weight loss of 0.86 kg (P < 0.0001 vs baseline). Moreover, subjects with prior therapy with olanzapine showed a greater weight loss: 1.76 kg (P < 0.05 vs baseline). However, the weight loss appeared to be dependent on the body weight at the time of initiation of treatment with ziprasidone — the higher the initial body weight, the greater the weight loss.
Other Clinical Disorders
Serious clinical disorders, including hypertension, type 2 diabetes, osteoarthritis, sleep apnea, cardiovascular disorders (coronary heart disease and stroke), and cancers involving several organs, are attributed to weight gain and obesity.34 In addition, subjects with SCH are predisposed to being overweight and obese due to lack of adequate physical activity. Moreover, the stigmatization, social rejection, and loss of self-esteem accompanying both obesity and SCH make these patients more susceptible to isolation, unfortunately leading to diminution of the interpersonal and cognitive skills required to cope with these consequences. Finally, weight gain tends to perpetuate social withdrawal and further impairs quality of life, predisposing these subjects to an additional risk for discontinuation of treatment resulting in recurrent relapses of the disorders.34
An increase in disorders such as hypertension, glucose intolerance including diabetes, and premature mortality secondary to weight gain similar to that induced by antipsychotic drugs is well documented in the Framingham study.35,36 It is apparent that these disorders ensue earlier in life and with a greater prevalence, leading to enhanced risk of premature death with rising BMI > 27 kg/m2 in subjects with SCH. The risk is further exacerbated in those receiving therapy with certain antipsychotic drugs; the death rate reaches more than 2000 excess fatalities per 100,000 individuals.35,36 It is estimated that the lives saved due to prevented suicides may be equal to the deaths caused by disorders as a result of weight gain induced by certain drugs such as clozapine.35,36,44
Glucose Intolerance and Insulin Sensitivity
More frequent onset of diabetes in comparison to the general population remains after elimination of other risk factors (e.g., obesity, family history, concomitant use of other drugs, etc.) in SCH patients.14-27 A retrospective analysis documented changes in fasting glucose levels in patients administered either risperidone or olanzapine for 1 year.5 Risperidone did not induce a significant change from baseline, but use of olanzapine was associated with an increase of 7.26 mg/dL in fasting plasma glucose concentration (P ≤ 0.05 vs baseline). Moreover, among subjects < 60 years old, the rise in fasting glucose level with olanzapine was even greater (10.8 mg/dL) and the difference between these two age groups was statistically significant (P = 0.03), indicating that younger subjects may be more susceptible to prediabetes and diabetes following administration of olanzapine.5
To define the pathogenesis of rising plasma glucose following olanzapine treatment, an examination of glucose regulation was conducted to determine fasting plasma insulin and glucose levels in subjects with SCH or another schizoaffective disorder.56,57 Participants were randomized to receive therapy with ziprasidone or olanzapine for 6 weeks. Plasma glucose did not change significantly with either drug, However, mean fasting plasma insulin rose by 3.3 µU/mL in olanzapine-treated subjects (P < 0.0001 vs baseline), whereas no significant alteration (0.25 µU/mL) from baseline was noted in patients receiving ziprasidone; the difference between insulin levels for the two drugs at the end of the observation period was significant (P = 0.05). Therefore, it is apparent that insulin sensitivity as determined by insulin × glucose product, a reliable index of insulin sensitivity,58 declined following therapy with olanzapine but not with ziprasidone.56,57
Similar findings regarding the role of insulin resistance in glucose dysregulation following short- and long-term administration of several antipsychotic drugs are reported in several studies.4,5,10,14-16 In an extensive retrospective study, a multivariate analysis examined the influence of other variable factors (e.g., patients’ age, duration of antipsychotic treatment, use of other drugs known to affect glucose metabolism) and established that use of olanzapine, clozapine, and haloperidol induced significant glucose elevations.
Moreover, the clinical significance of the change in plasma glucose concentration is underscored by the fact that 13% of the patients treated with clozapine required a glucose-lowering agent after starting the antipsychotic, and 6% of the olanzapine group required a dose increase in their glycemic therapy. In contrast, none of the subjects in the risperidone, quetiapine, haloperidol, or fluphenazine groups required glucose-lowering intervention.1 Mean glucose levels were higher following a long-term, continuous treatment for 2.5 years with antipsychotic drugs (e.g., olanzapine, clozapine, risperidone, quetiapine, haloperidol, or fluphenazine).2
Another literature review reported a markedly greater adverse impact on onset of diabetes mellitus and mortality following therapy with olanzapine (52 subjects, 3 deaths) and clozapine (30 subjects, 1 death) in comparison to subjects treated with other agents (e.g., four with quetiapine, two with risperidone, one with ziprasidone, and none with aripiprazole).7 However, the single case reported with ziprasidone was transient hyperglycemia. This difference between various agents in occurrence of diabetes was confirmed by the FDA Medwatch surveillance system, and a greater mortality with clozapine and olanzapine was attributed to metabolic acidosis or ketosis.7
Diabetes is deemed "cardiovascular risk equivalent" because type 2 diabetes increases the odds of SCH patients developing macrovascular disease by 2- to 4-fold compared to age-matched subjects without diabetes. The occurrence of initial myocardial infarction (MI) in subjects with diabetes is almost identical to recurrence of MI in subjects without diabetes.28,31-33,38,39 Moreover, the fatal outcome during initial MI in subjects manifesting diabetes is not significantly different from the subjects without diabetes with a prior MI.28 A similar pattern is also observed regarding the incidence of stroke; patients with diabetes without a prior MI manifest approximately the same risk (10.3%) as those without diabetes but with a prior MI (7.2%).28,31,38,39 Therefore, the importance of early diagnosis and aggressive treatment to achieve prompt desirable glycemic control in delaying or preventing both micro- and macrovascular complications is never over-emphasized.
It is apparent that changes in lipids following therapy with various antipsychotic agents follows a similar path as diabetes.2,5 The changes in total cholesterol levels were relatively small, with fluphenazine alone inducing a significant decrease of 6% from the baseline concentration. However, the alterations in triglyceride levels were more pronounced with both olanzapine and clozapine with significant rises from baseline (38% and 34%, respectively) compared to those associated with haloperidol and fluphenazine.
Fortunately, low-density lipoprotein (LDL) levels did not rise significantly when patients took the antipsychotic agents. Indeed, the patients taking olanzapine, risperidone, and quetiapine manifested significant declines of similar magnitude. Finally, the majority of the drugs apparently induced a modest, though not a significant, decline in high-density lipoprotein (HDL); the lone exception was olanzapine, which induced a significant decrease of 10%. This undesirable effect of olanzapine on HDL level may neutralize its apparent benefit regarding LDL concentration.
However, in another study, olanzapine increased fasting cholesterol by 23.6 mg/dL, a significantly greater rise than that induced by risperidone, 7.2 mg/dL. An identical pattern was found in fasting triglycerides. Olanzapine was also associated with a markedly greater increase of 88.2 mg/dL than the 29.7 mg/dL noted with use of risperidone.4 Fortunately, antipsychotic-induced dyslipidemia may be at least partially reversed within weeks by switching to a metabolically neutral antipsychotic agent such as ziprasidone or aripiprazole.5-7,9,56,57,59
In a similar nested, case-control study involving more than 1000 subjects, the use of conventional antipsychotic agents was accompanied by a small but significant increase in the risk of developing hyperlipidemia, whereas olanzapine more than quadrupled the risk with risperidone, showing no aberrant effect compared with nonuse of antipsychotics.4 Therefore, the potential cardiovascular consequences of olanzapine therapy and its association with the metabolic syndrome warrant a serious consideration of its risk/benefit ratio prior to initiation. Another recently approved antipsychotic agent, asenapine, also presents the same dilemma regarding adverse influence on body weight, cardiovascular outcomes, and metabolic outcomes, including glycemia and serum lipid concentrations, especially because of lack of data on long-term use.60,61
Thus, it is apparent that subjects with SCH are more prone to manifest weight gain and its consequences, including metabolic derangements, raising the risk of adverse cardiovascular outcomes.55 Furthermore, the risk is exaggerated with the use of various antipsychotic agents required for attaining and maintaining remission of clinical manifestations and improving quality of life in these subjects (see Table 3). The exact pathophysiologic mechanism responsible for occurrence of metabolic syndrome, including glycemic dysregulation with the use of these agents, may be attributed to weight gain and change in body composition and their impact on insulin sensitivity as well as beta cell dysfunction.1,3,5,8,26,34,35
|Table 3: Metabolic Abnormalities with Atypical Antipsychotics55|
|Drug||Weight Gain||Risk of Diabetes||Worsening Lipid Profile|
+ = increase, = no effect, D = discrepant results
* Newer drugs with limited long-term data
Therefore, management strategies to treat and prevent or delay onset of these metabolic disorders deserve priority, especially because of their impact on all-cause mortality and specifically on cardiovascular outcomes. Several paradigms have been tested. Educational programs that involve therapeutic lifestyle changes and nutrition and exercise counseling with SCH subjects and their caregivers assist in preventing weight gain.55,62-65 Treatment with insulin sensitizers (e.g., metformin and rosiglitazone) appears to effectively decrease BMI and body weight as well as fasting plasma insulin, which is indicative of improvement in insulin sensitivity.66-71 Concurrent therapy with metformin and sibutramine, a weight-lowering agent, also looks promising.72 In addition, therapy with the angiotensin receptor blockers (ARBs) valsartan and telmisartan has been shown to be beneficial with a decline in BMI, abdominal circumference, fasting insulin, and insulin resistance.73
Finally, a recent clinical trial using topiramate was effective in preventing weight gain and therefore delaying or decreasing the consequences of weight gain, the major one being metabolic syndrome.74 Thus, the treatment for antipsychotic-induced metabolic syndrome is multifaceted and identical to the metabolic syndrome manifesting in the general population. Strategies should include implementing recurrent behavioral modification techniques involving therapeutic lifestyle changes and adherence to administration of drugs including metformin, ARBs, statins, and aspirin.75
A Consensus Development Conference that included psychiatrists, endocrinologists, cardiologists, and experts in management of obesity was held to raise awareness and devise an algorithm for managing SCH subjects.55 The panel concluded that atypical or second-generation antipsychotics offer significant benefits to patients with a variety of psychotic disorders. However, the panel also affirmed the greatest risk of weight gain, glucose dysregulation including diabetes and its complications such as DKA, as well as dyslipidemia following treatment with clozapine, olanzapine, and quetiapine. It noted an intermediate risk to administration of risperidone and the lowest risk with the use of aripiprazole and ziprasidone. Finally, the panel provided an algorithm of guidelines for assessing and monitoring subjects manifesting SCH prior to and following use of these effective agents to prevent and/or treat ensuing consequences of short- and long-term use of these agents (see Table 4).
|Table 4: Recommended Frequency of Follow-up Monitoring55|
|Measurement||Baseline||4 Weeks||8 Weeks||12 Weeks||Every Quarter||Every Year||Every 5 Years|
|Fasting lipid profile||X||X||X|
|Consider switching to a different atypical antipsychotic if patient gains ≥ 5% of initial body weight or develops worsening glycemia or dyslipidemia|
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