Objectives There is substantial comorbidity between serious mental illness and cocaine abuse. Available evidence indicates that chronic neuroleptic treatment and withdrawal can lead to neural changes that confer differential sensitivities to cocaine. Thus, the purpose of this work is to investigate and characterize effects of chronic ziprasidone therapy and withdrawal on acute cocaine toxicity in the mouse.
Methods Male CF-1 mice were randomly assigned to 3 treatment groups: 1) subcutaneous (SC) injections of 0.13 mg ziprasidone daily for 10 days (n=40); 2) SC ziprasidone injections (as in #1) + 2 days of withdrawal (n=45); 3) daily SC injections of saline as placebo control (n=40). Following these treatment regimens, all mice received 102 mg/kg cocaine HCl in saline by intra-peritoneal injection and blinded observers recorded times for death/moribundity and seizure.
Results Survival analysis indicated significantly reduced time to death for mice in the ziprasidone withdrawal group (Chi-square=4.22, 1 DoF, P=0.0399). Apparent, though not statistically significant, trends of increasing mortality and seizure frequency with more rapid onset were observed in both treatment groups as compared to control animals. Mortality proportions were 37% (RR=1.8, 95% CI 0.9 to 4.0, p=0.14) in group 1; 40% (RR=2.0, 95% CI 0.98 to 4.0, p=0.06) in group 2; versus 20% mortality in controls. Seizure frequencies were 90% (RR=1.2, 95% CI 1.0 to 1.5, p=0.08) for group 1; 84% (RR=1.2, 95% CI 0.9 to1.5, p=0.2) in group 2; versus 72% in controls. Analysis of seizure free proportions over time yielded Chi-sq 3.8, 1 DoF, p=0.05 for group 1 vs. control; and chi-sq 2.4, 1 DoF, p=0.12 for group 2 vs. control.
Conclusions Presumably through changes within CNS neurotransmitter systems, chronic ziprasidone treatment and withdrawal appears to confer increased susceptibility to acute cocaine toxicity in mice. While our study cannot detect the specific mechanisms involved, these findings are of clinical concern and raise questions for future study.
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