This prospective, randomized study provides an opportunity to study change in overall coronary heart disease risk across antipsychotic treatments for patients with schizophrenia in a large clinical trial. At baseline, study participants had high estimated 10-year CHD risk compared to matched controls from the general population and had been treated for schizophrenia for an average of 14 years. (Goff, Sullivan et al. 2005
) In the relatively short study time frame consisting of a maximum treatment exposure of 18 and mean of 9.5 (SD 7.0) months, overall differences in estimated 10-year CHD risk between antipsychotics were significant. Olanzapine and quetiapine were associated with increased risk; whereas risk decreased in patients treated with perphenazine, risperidone, and ziprasidone. The difference in 10-year CHD risk between olanzpaine and risperidone was statistically significant (p=0.004). Differences between medication effects on risk were seen particularly in patients with at least 10% baseline CHD risk, in subjects younger than 40 and older than 49, and in men. Coronary heart disease risk increased, on average, for subjects with baseline risk estimated at less than 10%, whereas average estimated risk was reduced in subjects entering the study with estimated 10-year CHD risk of 10% or greater. Overall differences in CHD risk between treatments appeared to result largely from lowering of total cholesterol in subjects treated with risperidone and ziprasidone, and elevation of HDL cholesterol among Whites treated with perphenazine and non-whites treated with ziprasidone.
While other work documents changes in individual CHD risk factors such as diabetes mellitus and cholesterol from particular antipsychotics (Allison, Fontaine et al. 1999
; 2004; Meyer and Koro 2004
; Newcomer and Haupt 2006
), this analysis is distinctive in examining overall CHD risk across several antipsychotics in the setting of a large, randomized clinical trial. Our results also are consistent with those from a recent post-hoc analysis using the Framingham equation to compare change in CHD risk in patients treated with olanzapine and ziprasidone in a 6 week randomized clinical trial. (Del Valle, Loebel et al. 2006
Differences in individual antipsychotic drug effects on CHD risk in the CATIE study appear to be due principally to changes in total and HDL cholesterol. Whereas other agents tended to decrease total cholesterol, olanzapine was associated with relative increases. Prior reports have demonstrated large increases in triglyceride levels with olanzapine (Meyer 2002
; Wirshing, Boyd et al. 2002
; Atmaca, Kuloglu et al. 2003
), whereas risperidone and ziprasidone have been associated with small or neutral effects on triglycerides and total cholesterol. (Kingsbury, Fayek et al. 2001
; Meyer 2002
; Atmaca, Kuloglu et al. 2003
; Weiden, Daniel et al. 2003
) While risperidone’s effects on weight gain and glucose elevation are similar to quetiapine, (Lieberman, Stroup et al. 2005
) because risperidone was associated with decreases in total cholesterol in this study, its estimated CHD risk is comparable to that of ziprasidone and perphenazine.
Consistent with our hypothesis, effects on HDL cholesterol differed significantly among antipsychotics, with only olanzapine associated with a consistent mean decrease (or worsening) in HDL levels. To our knowledge, the mediating effect of race observed on perphenazine-associated changes in HDL cholesterol has not been previously reported. Whites treated with perphenazine exhibited a mean increase in HDL cholesterol, whereas levels decreased in other races. If replicated, identification of physiologic or molecular mechanisms underlying race differences in antipsychotic effects on HDL will be of considerable interest.
The mechanisms for antipsychotic-related dyslipidemia are not fully understood. Certainly weight gain and glucose intolerance are well known to increase risk of hyperlipidemia, yet we also know that these factors are not necessary for antipsychotic-induced adverse changes in lipid profiles to occur. (Meyer, Koro et al. 2005
While we found significant differences in lipids across antipsychotic medications, we did not see changes in the dichotomous risk factors of diabetes between drugs over the study. In part, this may be due to our definition and the study’s limited duration. A patient could only obtain a new diagnosis of diabetes but could not revert from diabetic to non-diabetic if blood sugars decreased. In addition, any changes in glucose not meeting the threshold for diabetes did not influence the calculation of CHD risk using the Framingham score. While the definition of diabetes used for this analysis differs from that used in the original Framingham Study (i.e., two casual blood glucoses of 150 mg/dl or fasting of >140), it reflects the investigators’ best attempt to categorize risk factors according to currently accepted definitions using available study data.
We also did not see changes in hypertension status across antipsychotics. However, while the hypertension definition we used also was dichomotous and does not reflect smaller, potentially significant changes in blood pressure, hypertension in the Framingham score is more sensitive and incorporates changes in JNC-V blood pressure stages (e.g., change from systolic 140–159 mmHg to 160 mmHg) We found qualitative differences in changing blood pressure stage by antipsychotic, with approximately 36% of patients taking olanzapine, quetiapine or ziprasidone worsening their blood pressure stage, and 27% of patients taking perphenazine or risperidone worsening blood pressure stage. Fourteen percent of participants took anti-hypertensives at baseline, and three percent initiated anti-hypertensives during the study; these did not differ significantly by antipsychotic assignment. Meyer et.al. provides a more detailed analysis of blood pressure and other components of the metabolic syndrome. (Meyer, Davis et al. in press
) We also clarify that the blood pressure criteria for the baseline CHD-risk CATIE sample used systolic of >140 mmHg and diastolic >90 mmHg. (Goff, Sullivan et al. 2005
) Blood pressure criteria for the metabolic syndrome are systolic >=135 and diastolic >=85 mmHg. (McEvoy, Meyer et al. 2005
We found particular benefit in CHD risk reduction in those patients with greater than 10% CHD risk at baseline treated with perphenazine, risperidone and ziprasidone. Using these medications could have positive consequences in patients who already have clinical risk for coronary disease including possible metabolic side effects from prior antipsychotics. While there was no difference across treatment groups in patients with less than 10% baseline CHD risk, it is notable that risk appeared to increase from baseline in almost all treatment groups.
To explore if switching or staying on an antipsychotic influenced CHD risk, we examined the subsample of patients (n=216) who were on either olanzapine or risperidone prior to randomization and were randomized to either of these two treatments. We found no statistically significant difference in CHD risk between remaining or switching to the other antipsychotic in this limited sample (results not shown).
In addition to results presented here, the Appendix includes results from the subpopulation of participants with fasting laboratory samples at baseline and 3 months in order to approximate our original baseline CHD risk analysis. (Goff, Sullivan et al. 2005
) Numerically, findings were similar overall, although the sample size for each treatment was very small.
This study has limitations. First, although the CATIE Schizophrenia Trial is unique in its large sample size and its examination of several antipsychotic therapies, CATIE was not designed to examine CHD risk as a primary outcome. We attempted to match the Framingham definitions of CHD risk factors, but definitions for hypertension, tobacco smoking and diabetes did differ somewhat. Second, while the Framingham formula is valid across many populations, the equation has not been validated in populations taking antipsychotics. The rapid and large weight change associated with some antipsychotics substantially differs from typical weight change patterns in the general population from which the risk equation was derived. Because weight is not a variable in the Framingham equation, it is possible that the long-term impact on cardiac health of rapid antipsychotic-induced weight gain may not be sufficiently captured. Moreover, although triglycerides are part of total cholesterol which is in the Framingham equation, the model does not specifically incorporate risk for triglycerides, which are increasing in acceptance as an independent risk factor for coronary disease (Nordestgaard, Benn et al. 2007
) and often the lipid fraction most affected by antipsychotics. We would expect inclusion of weight and triglycerides in a CHD risk model would influence and likely enhance the differences we found between antipsychotics with the Framingham model.
In conclusion, we found different antipsychotic treatments did indeed confer varying levels of CHD risk in the CATIE Schizophrenia Trial. Subjects were treated with psychotropics 14 years on average before joining the study, and much cardiovascular risk may have been expected to have accumulated prior to the trial; this is supported by the high baseline Framingham risk scores. Despite this high initial risk factor burden, CHD risk changes differed significantly in magnitude across antipsychotic agents after only a few months of exposure. The absolute magnitude of changes in CHD risk found with antipsychotic medications are comparable to those seen in an intensive lifestyle modification program for adults with cardiac risk factors and thus should be clinically important. (Ellsworth, O'Dowd et al. 2004
) Olanzapine conferred the highest risk of the antipsychotics, with quetiapine appearing to have similar risk. Risperidone, ziprasidone and perphenazine were associated with lower overall risk. The largest treatment differences in 10-year CHD risk were seen in participants with at least 10% baseline CHD risk and in older subjects. When initiating or changing antipsychotic therapy, clinicians should consider these changes in likelihood of coronary heart disease, particularly for older patients and those with baseline coronary risk factors.