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 (3 mg), aripiprazole (10 mg) 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.