The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial: Clinical comparison of subgroups with and without the metabolic syndrome
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)
- et al.
Association of depression with medical illness: does cortisol play a role?
Biological Psychiatry
(2004) - et al.
Atypical antipsychotics and glucose dysregulation: a systematic review
Schizophrenia Research
(2004) - et al.
The hypothalamic–pituitary–adrenal axis in chronic schizophrenic patients long-term treated with neuroleptics
Progress in Neuro-Psychopharmacology and Biological Psychiatry
(2002) - et al.
Medical comorbidity in psychiatric inpatients: relation to clinical outcomes and hospital length of stay
Psychosomatics
(2002) - et al.
The effects of antipsychotic therapy on serum lipids: a comprehensive review
Schizophrenia Research
(2004) - et al.
Mortality and causes of death in schizophrenia in Stockholm county, Sweden
Schizophrenia Research
(2000) - et al.
Predictors of medication discontinuation by patients with first-episode schizophrenia and schizoaffective disorder
Schizophrenia Research
(2002) - et al.
Physical consequences of schizophrenia and its treatment: the metabolic syndrome
Life Sciences
(2002) - et al.
Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease
Biological Psychiatry
(1999) - et al.
Obesity as a risk factor for antipsychotic noncompliance
Schizophrenia Research
(2004)
NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older
Diabetes
Schizophrenia: a life-shortening disease
Schizophrenia Bulletin
Antipsychotic-induced weight gain: a review of the literature
Journal of Clinical Psychiatry
Consensus development conference on antipsychotic drugs and obesity and diabetes
Journal of Clinical Psychiatry
The prevalence of the metabolic syndrome in patients with schizoaffective disorder-bipolar subtype
Bipolar Disorders
Excess mortality of schizophrenia. A meta-analysis
British Journal of Psychiatry
Causes of the excess mortality of schizophrenia
British Journal of Psychiatry
Prevalence of diabetes and glucose intolerance in patients with schizophrenia
British Journal of Psychiatry
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
Characterizing coronary heart disease risk in chronic schizophrenia: high prevalence of the metabolic syndrome
Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie
Use of general medical services by VA patients with psychiatric disorders
Psychiatric Services
The association of medical comorbidity in schizophrenia with poor physical and mental health
Journal of Nervous and Mental Disease
Prevalence and correlates of diabetes in national schizophrenia samples
Schizophrenia Bulletin
Mental disorders and use of cardiovascular procedures after myocardial infarction [see comments]
JAMA
Quality of medical care and excess mortality in older patients with mental disorders
Archives of General Psychiatry
Effect of acute metabolic stress on pituitary–adrenal axis activation in patients with schizophrenia
American Journal of Psychiatry
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
Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey
JAMA
Increasing prevalence of the metabolic syndrome among US adults
Diabetes Care
Cited by (178)
A miR-137–Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing
2024, Biological Psychiatry: Cognitive Neuroscience and NeuroimagingPsychiatric drugs impact mitochondrial function in brain and other tissues
2020, Schizophrenia ResearchRelationship of metabolic syndrome and neurocognitive deficits in patients with schizophrenia
2019, Psychiatry ResearchAging of the body and the brain in schizophrenia
2018, Schizophrenia Research