Effects of antipsychotics on cortisol, interleukin-6 and hippocampal perfusion in healthy volunteers

This randomized within-subject, double blind study aimed to compare the effects of a single dose of two different antipsychotics (haloperidol and aripiprazole) on cortisol, interleukin (IL)-6 and hippocampal regional Cerebral Blood Flow (rCBF) in the same 17 healthy male individuals. Subjects received a single dose of haloperidol (3mg), aripiprazole (10mg) and placebo, in a randomized order on three study appointments. We measured salivary cortisol levels at multiple time points, IL-6 levels from plasma samples, and resting cerebral blood flow (rCBF), using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T). We found significantly lower cortisol levels in the haloperidol condition (F(2,32)=5.78, p=0.007), than in either placebo (p=0.013; CI=0.45, 0.406) or aripiprazole (p=0.037; CI=-0.520, -0.014). Interleukin-6 levels were also lower following haloperidol (F(2,22)=4.19, p=0.048) in comparison with placebo (p=0.02; CI=0.14, 1.8), but not with aripiprazole. Finally, we found a greater rCBF in the right (peak voxel: T=6.47, p<0.0001) and left (peak voxel T=5.17, p<0.01) hippocampus following haloperidol compared with placebo, and at trend level also in the left hippocampus following aripiprazole compared with placebo (T=4.07, p=0.057). These differences in hippocampal rCBF after both antipsychotics were no longer evident (haloperidol) or present at trend level (aripiprazole), after controlling for cortisol and IL-6 levels. Our findings suggest that haloperidol can directly regulate the hypothalamic-pituitary-adrenal (HPA) axis and immune system through a pharmacological action via D2 receptor antagonism. Finally, our data suggest that the increased hippocampal rCBF is a manifestation of the reduction in IL-6 and cortisol which follows the administration of haloperidol.