COMMENTARIES

The Metabolic Syndrome, Schizophrenia, and Antipsychotics

Jonathan M. Meyer, M.D., Assistant Professor of Psychiatry, University of California, San Diego

The Public Health Issue: High Metabolic Syndrome Prevalence in Patients with Schizophrenia

 

In the past decade there has been increasing recognition that schizophrenia patients represent a population at high risk for cardiometabolic disorders. As the focus of diabetes prevention has shifted to identification of prediabetic conditions, data has emerged on metabolic syndrome (MS) prevalence in patients with schizophrenia. The largest U.S. data set to examine this issue derives from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, an NIH-funded study exploring outcomes in a broadly representative group of chronic schizophrenia patients entering the trial on a variety of medications (with 28% on no antipsychotic medication), and randomized in a double-blind manner to one of four newer, so-called second generation or atypical antipsychotics (olanzapine [Zyprexaò], quetiapine [Seroquelò], risperidone [Risperdalò], or ziprasidone [Geodonò]) or a typical antipsychotic (perphenazine). Of the 1,460 subjects enrolled at study baseline, 689 had fasting laboratory measures to examine all MS parameters, and each member of this sample was compared with an age-, gender-, and race/ethnicity-matched peer drawn from the general population using data from the third National Health and Nutrition Examination Survey (NHANESIII) [1]. Among this cohort of CATIE subjects, the mean age was 40.4, and MS prevalence was 40.9% using 2001 ATPIII criteria: 51.6% for females, and 36.0% for males. The odds ratio for MS among the schizophrenia patients compared to the NHANESIII peers was 2.38 (95% CI, 1.77-3.18) for CATIE males, and 3.51 (95% CI, 2.19-5.62) for CATIE females. The discrepancy was most marked in the younger age deciles. For those ages 20-29, MS prevalence for CATIE males was 27.0%, and 47.1% for CATIE females.

 

Is it the Disease?

 

The public health impact of this high MS prevalence and the early onset is undeniable, but important questions remain regarding possible etiologies. Aside from drug therapy, there are significant environmental factors that contribute to metabolic risk. Smoking is a known risk for type 2 diabetes mellitus (DM) [2], and the odds for smoking among schizophrenia patients is 3 times greater than national averages, with current US estimates close to 70% [3]. By virtue of the negative symptoms of their mental disorder, patients with schizophrenia are less active and often obese; moreover, due to limited income or semi-structured housing, many have poor dietary habits [4]. These lifestyle issues are obvious risk factors, but there is compelling data to suggest that, at time of first diagnosis, prior to drug exposure or the expected physiology changes from sedentary habits and poor diet, patients with schizophrenia have abnormalities in glucose-insulin homeostasis. Several recent studies in first-episode, neuroleptic-naïve patients evince demonstrable differences when compared to matched controls [5-8]. The most sophisticated of these studies involved a euglycemic-hyperinsulinemic protocol, with labeled tracer to measure endogenous glucose production, combined with dexascan and CT measurements of adiposity [8]. The investigators found that endogenous glucose production during the clamp was 6.7 ± 2.7 μmol/kg.min in the schizophrenia patients versus 4.1 ± 1.6 μmol/kg.min in the matched controls (p = 0.02). Insulin-mediated peripheral glucose uptake was not different between patients and controls. Visceral and total adiposity did not differ, but subcutaneous abdominal fat was 104.6 ± 28.6 cm³ in patients and 63.7 ± 28.0 cm³ in controls (p = 0.04).

 

The Impact of Antipsychotics

 

The most significant environmental factor, one surrounded by acrimonious debate and litigation, relates to the adverse metabolic effects of antipsychotics. The earliest antipsychotics, referred to as typical, conventional, or first-generation agents, possessed a single therapeutic mechanism: antagonism of postsynaptic dopamine D₂ receptors. These were broadly divided into two classes, low potency antipsychotics (e.g. chlorpromazine) and high potency antipsychotics (e.g. haloperidol). While the low potency compounds were known to induce weight gain [9], increase serum triglyceride (TG) levels [10], and adversely impact glycemic control [11], these agents gradually fell out of favor for the less sedating and less anticholinergic high potency agents that also happened to be metabolically neutral. The advent of atypical antipsychotics, with their weaker affinities for D₂ receptors, promised adequate symptom control but with markedly decreased risk for extrapyramidal side effects caused by excessive D₂ antagonism. These agents were first marketed starting in 1994, and were all modeled after the first atypical antipsychotic, clozapine, whose pharmacology included potent antagonism of serotonin 5HT₂ receptors combined with weak D₂ receptor affinity.

          These second generation medications lacked clozapine’s unique efficacy for refractory schizophrenia, but also spared clozapine’s risk for agranulocytosis, and soon gained widespread use in schizophrenia and other behavioral disorders. With increasing use came the recognition that patients with schizophrenia exposed to atypical antipsychotics, particularly clozapine and olanzapine, suffered extreme weight gain (mean > 12 kg during first year of exposure), along with, at times severe elevations of serum TG, and new onset type 2 DM, including cases of diabetic ketoacidosis (DKA) [12,13]. By early 2004, a consensus panel led by the American Diabetes Association and American Psychiatric Association published a joint statement commenting on the differential metabolic risk among these newer antipsychotics, and the need for ongoing monitoring and judicious use of agents with greater metabolic liabilities [14].

          The CATIE trial spanned the years 2001-04, and provided one of the only large scale, non-industry sponsored, randomized studies to incorporate most of the newer antipsychotic medications. The detailed analysis of CATIE confirmed prior impressions regarding the significant metabolic risk imposed by exposure to olanzapine, while ziprasidone appeared metabolically benign, and risperidone and quetiapine associated with intermediate effects [15]. After only 3 months of treatment, MS prevalence increased from 34.8% to 43.9% in the olanzapine group but decreased from 37.7% to 29.9% in the ziprasidone (p = 0.001 for ziprasidone versus olanzapine). The analysis of MS criteria found differences between antipsychotics primarily in the areas of central adiposity and serum TG levels, with limited effects on blood pressure, serum glucose, and HDL cholesterol. Olanzapine is known to adversely impact glycemic control, but in the relatively short timeframe of CATIE (e.g. months), effects on fasting glucose were not evident; however, the increases in fasting TG seen with olanzapine points to interference with insulin sensitivity. Since olanzapine exposure was also associated with increased waist circumference, the CATIE data imply an adiposity-dependent mechanism underlying the impact on glucose-insulin homeostasis. Perphenazine is 5 times less potent than haloperidol on a milligram basis, but behaved like a high potency typical antipsychotic, and appeared metabolically quite favorable in nearly all analyses of MS components where between-treatment differences were found.

          Given the recent interest in nonfasting TG levels as a predictor of cardiovascular events [16-18], a second set of 3-month analyses was performed using data exclusively from CATIE subjects with nonfasting TG obtained at baseline and 3 months post-randomization [19]. The greatest increases in median and adjusted mean nonfasting TG levels were seen among those randomized to quetiapine (mean +54.7 mg/dl, median +26 mg/dl) and olanzapine (mean +23.4 mg/dl, median +26.5 mg/dl). Pairwise comparisons indicated a significant between-group difference for perphenazine versus olanzapine (p = 0.002) and a trend for perphenazine versus quetiapine (p = 0.006) that was not significant due to the Bonferroni correction.

 

Postulated Mechanisms

 

The basis for antipsychotic-induced weight derives predominantly from central histamine H₁ antagonism. Antipsychotics with higher affinities for H₁ receptors are associated with both sedation and impaired satiety [20,21]. Among the atypical antipsychotics, clozapine and olanzapine have the greatest H₁ affinity, while the newer atypicals ziprasidone and aripiprazole have the least, and are close to weight neutral. There is also evidence from animal models and human studies that antagonism of serotonin 5HT_2C receptors, or certain polymorphisms of this receptor [22-24], may play a role in weight gain liability among agents with marked H₁ antagonism, but 5HT_2C receptor antagonism by itself is insufficient to induce weight gain in humans. Ziprasidone is the most potent 5HT_2C receptor antagonist among all antipsychotics studied, yet is weight neutral by virtue of its low H₁ affinity.

          Those antipsychotics associated with greatest increases in central adiposity are also associated with greatest impact on TG levels, yet there is compelling data to suggest that medications like olanzapine and clozapine may interfere with glycemic control by adiposity-independent mechanisms. Anecdotal case reports have emerged over the years of individuals without known diabetes developing abrupt onset of type 2 DM, at times with DKA, within weeks of starting an atypical antipsychotic, predominantly clozapine and olaznapine [12]; moreover, in 78% of these cases, DM or DKA was reversible upon antipsychotic discontinuation, implying a direct drug effect. Recently, Houseknecht and colleagues performed a series of euglycemic-hyperinsulinemic clamp studies in laboratory animals using escalating doses of risperidone, ziprasidone, clozapine, and olanzapine [25]. These studies revealed marked effects of olanzapine and clozapine, but not the other agents, on whole body insulin sensitivity and hepatic glucose production within 2 hours after exposure to single doses. This basis for this adiposity-independent metabolic effect is unknown, but provides further reasons for clinicians to be careful in the use of antipsychotics with adverse metabolic profiles, especially in patients with risk conferred by lifestyle, family history, race, or ethnicity, or perhaps the biology of mental illness itself.

 

Conclusions

 

Schizophrenia patients have 2-3 times greater MS prevalence for a variety of reasons, including the very agents used to manage the illness. Use of antipsychotic medications with significant deleterious effects on MS parameters has decreased significantly, yet clozapine remains an important part of the treatment armamentarium as it is the only effective agent for schizophrenia patients refractory to other neuroleptics. Data from the CATIE Schizophrenia Trial highlight the significant metabolic disease burden seen in patients with schizophrenia, and the need for aggressive monitoring for and treatment of cardiometabolic disease, along with preferential use of antipsychotics carrying lower metabolic risk. Ongoing research is examining the possible benefits (and psychiatric costs) that may accrue from switching schizophrenia patients to more metabolically neutral medications, and means to manage those with MS for whom switching is not an option. The use of metformin, pioglitazone, or other strategies to improve glycemic control in nondiabetics with MS are intriguing options, both to forestall DM onset, and to possibly reduce complications rates from related problems such as nonalcoholic steatohepatitis, but await controlled trials to determine their relative merits. For now, early recognition and treatment remain the mainstays of care for mentally ill patients with metabolic syndrome.

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