While atypical antipsychotics share common pharmacodynamic properties, namely, potent antagonism of serotonin 5-HT2 receptors and weaker dopamine D2 antagonism than typical agents, there are differential effects on serum lipids depending on the underlying chemical structure. What has emerged from data released over the past decade is the association between use of a dibenzodiazepine-derived atypical antipsychotic (i.e., clozapine, olanzapine, quetiapine) and profound effects on serum triglyceride levels, far greater than those seen during treatment with phenothiazine derivatives. This association between dibenzodiazepine structure and hyper-triglyceridemia had emerged as early as 1986 with clinical studies of fluperlapine, a compound modeled on clozapine, in which severe elevations of serum triglyceride were noted, with one patient reaching a triglyceride concentration level of 900 mg/dL after 1 week of therapy (Fleischhacker et al. 1986; Muller-Oerlinghausen 1984). The first significant data on clozapine revealed that patients treated for 1 year had mean fasting serum triglyceride concentration of 264.0 mg/dL, compared with 149.8 mg/dL for those on typical agents, with three individuals in the clozapine cohort registering serum triglyceride levels greater than 500 mg/dL; however, there was no significant effect on TC (clozapine 217.0 mg/dL vs. typical 215.0 mg/dL) (Ghaeli and Dufresne 1996). A 1998 study comparing Israeli patients on clozapine (n=30) and typical antipsychotics (n=30) for at least 1 year confirmed the presence of hypertriglyceridemia in the clozapine group (202.9 mg/dL) but not the typical group (134.4 mg/ dL), again without significant differences in total cholesterol (clozapine 197 mg/dL vs. typical 194.9 mg/dL) (Spivak et al. 1999). Yet a small retrospective study of clozapine patients (n =19) treated for 2 years found a 17.9% increase in total cholesterol, with a strong (r =0.9, P=0.009) correlation with serum LDL (Cato et al. 2000).
Olanzapine, another dibenzodiazepine compound, is also associated with significant elevations in serum triglyceride concentrations, with one case series documenting fasting serum levels in separate individuals of 2,061 mg/dL, 2,811 mg/dL, and 7,668 mg/dL (Meyer 2001b). In a 1-year study of chronic nongeriatric adult inpatients, the olanzapine group exhibited a mean increase in serum triglyceride concentration of 104.8 mg/dL compared with 31.7 mg/dL for the risperidone cohort (P=0.037), and a 30.4 mg/dL increase was seen in TC compared with only 7.2 mg/dL for the risperidone cohort (P =0.004) (Meyer 2002). One prospective study comparing risperidone and olanzapine in a group of males (n =22 each) showed 10.3% greater serum LDL after 17 months of therapy for the olanzapine cohort, but this was not significant at the 0.05 level; however, there was a trend (P= 0.06) for higher TC to HDL ratio for the olanzapine group (Bouchard et al. 2001). Finally, prospective data presented from a large 6-week randomized study revealed a nonsignificant decrease in fasting LDL for the ziprasidone arm (n = 106), whereas the olanzapine cohort (n = 105) exhibited a significant 12.0% increase in fasting LDL (Glick et al. 2001). After adjusting for baseline differences, the serum LDL in the olanzapine cohort was 13.0% greater than in the ziprasidone group. Moreover, there was not a consistent finding in these and other studies that lipid elevations were closely correlated with dose or changes in weight. Ethnicity also appears not to be a factor, because both Caucasians and African Americans exposed to olanzapine experienced substantial increases in serum triglyceride concentrations (81% and 65%, respectively) (Nasrallah et al. 2001).
Both risperidone and ziprasidone are nondibenzodiazepine atypical antipsychotics and, as indicated here, appear to have minimal effects on serum lipids. Between these two compounds, ziprasidone is the more lipid neutral, with data from 6-week open-label studies of patients switched from olanzapine, risperidone, and typicals showing statistically significant decreases in median nonfasting TC and triglycerides (Daniel et al. 2000; Kingsbury et al. 2001). One short-term study (average treatment 15-25 days) associated ziprasidone and risperidone with decreases in fasting triglyceride concentration, although the magnitude of decrease was much greater for the ziprasidone cohort (P<0.05) (Pfizer 2000).
Limited data exist for quetiapine, yet as a dibenzothiazepine it appears to share a propensity for hyperlipidemia with its structural analogues. Among Meyer's case series of severe hypertriglyceridemia patients were two receiving quetiapine therapy, one of whom achieved a fasting triglyceride concentration of 1,911 mg/dL (Meyer 2001b). Quetiapine therapy was also associated with an elevated TC to HDL ratio compared with ziprasidone (P<0.01) in the short-term study noted previously (Pfizer 2000).
The effects of dibenzodiazepine-derived compounds on cardiovascular risk can be seen in Table 4-3, which presents data from a 26-year-old male state hospital patient treated with olanzapine. Utilizing the point scale from the risk chart in Table 4-2, one can see that the use of olanzapine quadrupled his risk for a major coronary event over the next decade. Moreover, if this patient had been 46 and not 26, the risk of a major coronary event would have increased 100%, giving him a 20% chance of a major coronary event in the next 10 years. It is worth noting that the peak serum triglyceride concentration in this patient occurred after 11 months of therapy (408 mg/dL), a characteristic clinical course observed when serum lip-ids are serially monitored after the onset of dibenzodiazepine treatment. Peak triglyceride levels typically occur within the first year of therapy during the course of dibenzodiazepine therapy, followed by a decrease and subsequent period of stabilization. Wide interindividual variation exists in both the timing of peak triglyceride levels and the magnitude of lipid elevations, and this has implications for monitoring of serum lipids during therapy with the dibenzodiazepine-derived agents (Meyer 2001a).
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