Elsevier

Schizophrenia Research

Volume 80, Issue 1, 1 December 2005, Pages 9-18
Schizophrenia Research

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial: Clinical comparison of subgroups with and without the metabolic syndrome

https://doi.org/10.1016/j.schres.2005.07.015Get rights and content

Abstract

The metabolic syndrome (MS) is highly prevalent among patients with schizophrenia (current estimates 35–40%), yet no data exist on the correlation of this diagnosis with illness severity, neurocognitive or quality of life measures in this population.

Methods

Using baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, assignment of MS status was performed using an updated definition derived from the National Cholesterol Education Program (NCEP) criteria. Those with and without MS were compared on the basis of primary and secondary variables of interest from baseline data encompassing psychiatric, neurocognitive and quality of life measures.

Results

Of 1460 subjects enrolled at baseline, MS status could be reliably assigned for 1231 subjects, with a prevalence of 35.8% using the NCEP derived criteria. After adjustment for age, gender, race, ethnicity and site variance, those with MS rated themselves significantly lower on physical health by SF-12 (p < .001), and scored higher on somatic preoccupation (PANSS item G1) (p = .03). There were no significant differences between the two cohorts on measures of symptom severity, depression, quality of life, neurocognition, or self-rated mental health. Neither years of antipsychotic exposure nor alcohol usage were significant predictors of MS status when adjusted for age, gender, race, and ethnicity.

Conclusions

The metabolic syndrome is highly prevalent in this large cohort of schizophrenia patients and is strongly associated with a poor self-rating of physical health and increased somatic preoccupation. These results underscore the need for mental health practitioners to take an active role in the health monitoring of patients with schizophrenia to minimize the impact of medical comorbidity on long-term mortality and on daily functioning. Outcomes data from CATIE will provide important information on the metabolic and clinical impact of antipsychotic treatment for those subjects with MS and other medical comorbidities.

Introduction

More than any period in the past 50 years, there has been a resurgence of interest in medical comorbidity among patients with schizophrenia, with numerous papers (Goldman, 1999, Le Fevre, 2001, Lambert et al., 2003, Jones et al., 2004, Marder et al., 2004) and an edited book (Meyer and Nasrallah, 2003) solely devoted to this topic. One stimulus has been the recent concern regarding the metabolic effects of atypical antipsychotics (Allison and Casey, 2001, Jin et al., 2004, Meyer and Koro, 2004), and the differential impact of these newer therapies on cardiovascular risk and overall health of patients with schizophrenia (American Diabetes Association et al., 2004, Melkersson et al., 2004). There is also a body of literature on excess mortality related to the diagnosis of schizophrenia, with recent methodologically rigorous data confirming excess mortality from natural causes, particularly cardiovascular disease (Allebeck, 1989, Mortensen and Juel, 1990, Newman and Bland, 1991, Mortensen and Juel, 1993, Simpson and Tsuang, 1996, Brown, 1997, Brown et al., 2000, Osby et al., 2000a, Osby et al., 2000b).

While mortality and side effect researches have been published consistently since the mid-20th century, a more recent addition to the literature on medical comorbidity in schizophrenia has focused on the underdiagnosis and treatment of common medical conditions among patients with schizophrenia (Druss et al., 2000, Druss et al., 2001, Cradock-O'Leary et al., 2002). In addition to the direct physiological burden, patients with schizophrenia suffer functional sequelae from medical comorbidity. Data from the large Patient Outcomes Research Team (PORT) study revealed that, among the 719 patients with schizophrenia studied, the number of medical problems present at time of interview was associated with worse perceived physical health, greater severity of psychotic and depressive symptoms, and greater likelihood of a history of a suicide attempt (Dixon et al., 1999). Moreover, the effect of medical comorbidity was significant even after controlling for psychiatric disease severity. Among acute inpatients, medical comorbidity is associated with longer hospital stays and more psychiatric symptoms and functional impairment at discharge, effects which also persisted after statistical adjustment for clinical severity at time of admission (Lyketsos et al., 2002). Persistent medication related medical side effects, such as weight gain, also play an active role in schizophrenia treatment outcomes by affecting adherence (Robinson et al., 2002, Weiden et al., 2004).

Given this confluence of findings, investigators have sought to study the functional impact of specific disease entities among patients with schizophrenia, particularly those which are highly prevalent in this population. Type 2 diabetes mellitus has received significant attention in the recent literature, in part related to the association with atypical antipsychotic therapy, and concern over long-term health burden in patients with schizophrenia, especially the marked increase in cardiovascular disease risk (Jin et al., 2002, Jin et al., 2004). The prevalence of this disorder in patients with schizophrenia is approximately 10–15%, or twice that of the general population (Dixon et al., 2000, Bushe and Holt, 2004), and retrospective analysis of the PORT data sample confirmed a linkage between a diagnosis of diabetes, other medical comorbidities, and poor self-perception of physical health (Dixon et al., 2000).

With this recent focus on metabolic disorders in patients with schizophrenia, investigators have turned their attention to another clinical entity, the metabolic syndrome, which may be up to three times more prevalent than diabetes among schizophrenia patients, and poses a substantial risk of cardiovascular morbidity and mortality. The metabolic syndrome, also called the insulin resistance syndrome, dysmetabolic syndrome or Syndrome X, is diagnosed in those who meet 3 or more of the clinical criteria: increased abdominal or visceral adiposity (measured by waist circumference), low serum high density lipoprotein (HDL), elevated fasting triglycerides, hypertension, impaired fasting glucose or overt diabetes mellitus (DM) (Expert Panel, 2001). The definition from the National Cholesterol Education Program (NCEP) is commonly used (Table 1), although recent consensus panels suggest incorporating the new lower threshold for impaired fasting glucose of 100 mg/dl (Grundy et al., 2004). The age-adjusted prevalence of metabolic syndrome in the U.S. population is 23.7%, with the lowest prevalence (6.7%) in the cohort ages 20–29, and the highest (43.5%) in those ages 60 and over (Ford et al., 2002). Most importantly, those diagnosed with the metabolic syndrome are at significant future risk for development of type 2 diabetes mellitus (if not already diabetic), and cardiovascular mortality. Cross-sectional data obtained in the U.S. found the prevalence of coronary heart disease to be significantly higher among nondiabetic patients with the metabolic syndrome (13.9%) than in diabetic patients who did not meet criteria for the syndrome (7.5%), implying that the metabolic syndrome poses a greater risk from cardiovascular disease than DM (Alexander et al., 2003). Moreover, prospective data reveal that a diagnosis of the metabolic syndrome was associated with a 3-fold increased risk for both coronary heart disease and stroke over a median of 6.2 years of follow-up (Isomaa et al., 2001).

The metabolic syndrome is of interest to those who care for patients with schizophrenia for two important reasons: 1) it appears to be highly prevalent in this patient population; and 2) it is associated with increased risk for future diabetes and cardiovascular mortality. There are three published prevalence studies of the metabolic syndrome in schizophrenia patients as of this writing, two of which have small samples sizes which call into question the reliability of the data; nonetheless, these published estimates correlate with unpublished meeting abstracts, and indicate that among schizophrenia patients ages 40–49, the prevalence of the metabolic syndrome may be as high as 50%, or more than twice the prevalence of the age-matched U.S. cohort ages 40–49 of 24% for males and 20% for females (Ford et al., 2002, Ford et al., 2004, Cohn et al., 2004). The first estimate is from Heiskanen et al., who published metabolic syndrome prevalence data among from a sample of 35 Finnish outpatients with schizophrenia using the NCEP criteria for the metabolic syndrome (Heiskanen et al., 2003). The sample prevalence of 37% was 2 to 4 times higher than the prevalence reported for the surrounding geographical area in Eastern Finland. The second published study assessed 33 outpatients with schizoaffective disorder (mean age 44.5 years) enrolled in a clinical trial, and noted a prevalence of 42.4% (Basu et al., 2004). The best published estimate is from Cohn et al. Canadian study of 240 subjects with schizophrenia or schizoaffective disorder (65% male, mean age 43.3 years), which found a prevalence of 42.6% for males and 48.5% for females using the NCEP criteria (Cohn et al., 2004).

The mechanism for this increased prevalence is not entirely clear, but hypotheses include lifestyle factors which promote obesity (e.g., poor dietary habits, lack of exercise or limited activity due to negative symptoms of schizophrenia), the direct metabolic effects of antipsychotic medications (Basu et al., 2004), increased propensity for storing excess fat as intraabdominal (visceral) adiposity (Ryan and Thakore, 2002, Thakore et al., 2002), or abnormalities of the hypothalamic–pituitary–adrenal (HPA) axis (Elman et al., 1998, Kaneda et al., 2002) leading to hypercortisolemia and its phenotypic expression of truncal obesity, poor glycemic control (Rosmond, 2002) and possible effects on hippocampal volume (Starkman et al., 1999, Brown et al., 2004).

The HPA hypothesis in particular has been considered by a number of investigators as a means of unifying the features of truncal obesity and glucose intolerance (Chrousos, 2000, Ryan et al., 2003), with recent data indicating an association between depression and the metabolic syndrome, all of which may be mediated by elevated serum cortisol levels. While the association between metabolic syndrome and abnormal glucocorticoid feedback has not been definitively established, an association with this syndrome and psychological stress or depression has emerged in recent studies. In one prospective study of middle-aged women, those with high baseline levels of depression, tension and anger, and ongoing anger during the 7.4 years of follow-up had significantly elevated risk for developing the metabolic syndrome (Raikkonen et al., 2002). Analysis of data from the Third National Health and Nutrition Examination Survey comprising 3186 men and 3003 women, ages 17 to 39, also revealed that women with a history of depression, but not men, were twice as likely to have the metabolic syndrome (Kinder et al., 2004).

Given the association between medical comorbidity and poor self-perceived physical health, and the likelihood that the metabolic syndrome is highly prevalent in patients with schizophrenia, there is a need for studies with large sample sizes to more appropriately assess the impact on clinical and quality of life variables in this patient population. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial is a large multicenter study, sponsored by the National Institute of Mental Health (NIMH), designed to examine a multitude of variables in patients with schizophrenia (Stroup et al., 2003, Swartz et al., 2003). With the broad recruitment strategy of the CATIE Schizophrenia Trial, its multisite design, and large sample size, the baseline data obtained offers an excellent opportunity to explore the impact of the metabolic syndrome among U.S. patients with schizophrenia. Specifically, we hypothesized that those with the metabolic syndrome, as has been described with diabetes, might report worse quality of life and self-perceived physical health; moreover, if the metabolic syndrome is related to HPA axis dysfunction, we hypothesized that this might result in greater psychiatric symptom severity and neurocognitive impairment than in patients without the metabolic syndrome.

Section snippets

Methods

The methods for the CATIE Schizophrenia Trial have been published in detail previously (Stroup et al., 2003). Briefly, the CATIE Schizophrenia Trial is a national, multisite, NIMH-sponsored prospective trial of antipsychotic effectiveness in patients with schizophrenia which broadly assesses metabolic, symptom, neurocognitive and functional outcomes. Institutional Review Board approval was obtained at each site, and subjects voluntarily enrolled after having been provided informed consent in

Results

For the 1231 subjects who could be classified on the basis of metabolic syndrome status, the metabolic syndrome prevalence was 35.8%. When compared on the basis of demographics (Table 2), those with the metabolic syndrome, were older, had higher proportion of female gender, and also were more likely to be white. There was no significant difference in the proportion of those with Hispanic ethnicity based upon metabolic syndrome status. Table 3 provides data on the primary and secondary variables

Discussion

The results of this study, from the baseline CATIE Schizophrenia Trial sample, represent the first data set to systematically examine the impact of the metabolic syndrome on clinical, cognitive, and quality of life variables in patients with schizophrenia. While much of the recent literature on metabolic dysfunction in patients with schizophrenia has focused on diabetes (Dixon et al., 2000), the metabolic syndrome is much more prevalent, and deserving of increased scrutiny. The metabolic

Acknowledgement

Supported by NIMH grant #N01MH90001.

References (59)

  • C.M. Alexander et al.

    NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older

    Diabetes

    (2003)
  • P. Allebeck

    Schizophrenia: a life-shortening disease

    Schizophrenia Bulletin

    (1989)
  • D.B. Allison et al.

    Antipsychotic-induced weight gain: a review of the literature

    Journal of Clinical Psychiatry

    (2001)
  • American Diabetes Association et al.

    Consensus development conference on antipsychotic drugs and obesity and diabetes

    Journal of Clinical Psychiatry

    (2004)
  • R. Basu et al.

    The prevalence of the metabolic syndrome in patients with schizoaffective disorder-bipolar subtype

    Bipolar Disorders

    (2004)
  • S. Brown

    Excess mortality of schizophrenia. A meta-analysis

    British Journal of Psychiatry

    (1997)
  • S. Brown et al.

    Causes of the excess mortality of schizophrenia

    British Journal of Psychiatry

    (2000)
  • C. Bushe et al.

    Prevalence of diabetes and glucose intolerance in patients with schizophrenia

    British Journal of Psychiatry

    (2004)
  • G.P. Chrousos

    The role of stress and the hypothalamic–pituitary–adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes

    International Journal of Obesity and Related Metabolic Disorders: Journal of the International Association for the Study of Obesity

    (2000)
  • T. Cohn et al.

    Characterizing coronary heart disease risk in chronic schizophrenia: high prevalence of the metabolic syndrome

    Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie

    (2004)
  • J. Cradock-O'Leary et al.

    Use of general medical services by VA patients with psychiatric disorders

    Psychiatric Services

    (2002)
  • L. Dixon et al.

    The association of medical comorbidity in schizophrenia with poor physical and mental health

    Journal of Nervous and Mental Disease

    (1999)
  • L. Dixon et al.

    Prevalence and correlates of diabetes in national schizophrenia samples

    Schizophrenia Bulletin

    (2000)
  • B.G. Druss et al.

    Mental disorders and use of cardiovascular procedures after myocardial infarction [see comments]

    JAMA

    (2000)
  • B.G. Druss et al.

    Quality of medical care and excess mortality in older patients with mental disorders

    Archives of General Psychiatry

    (2001)
  • I. Elman et al.

    Effect of acute metabolic stress on pituitary–adrenal axis activation in patients with schizophrenia

    American Journal of Psychiatry

    (1998)
  • Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults

    Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)

    JAMA

    (2001)
  • E.S. Ford et al.

    Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey

    JAMA

    (2002)
  • E.S. Ford et al.

    Increasing prevalence of the metabolic syndrome among US adults

    Diabetes Care

    (2004)
  • Cited by (178)

    View all citing articles on Scopus
    View full text