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.
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, London, UK; Medical Science Manager at Bristol-Myers Squibb Pharmaceuticals Ltd., UK. Electronic address: valeria.mondelli@kcl.ac.uk.
Rowena
R
Handley
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, London, UK; National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, UK.
Valeria
V
Mondelli
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Neuroimaging, London, UK.
Fernando
F
Zelaya
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, London, UK.
Tiago
T
Marques
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, London, UK.
Heather
H
Taylor
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, London, UK.
Antje A T S
AATS
Reinders
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, London, UK.
Christopher
C
Chaddock
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, London, UK.
Grant
G
McQueen
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, London, UK.
Kathryn
K
Hubbard
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, London, UK.
Andrew
A
Papadopoulos
National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, UK; King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Neuroimaging, London, UK.
Steve
S
Williams
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, London, UK.
Philip
P
McGuire
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, London, UK; National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, UK.
Carmine
C
Pariante
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, London, UK; National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, UK.
Paola
P
Dazzan
D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000068180:Aripiprazole / Q000009:adverse effects / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology*; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D012146:Rest; D012463:Saliva / Q000187:drug effects / Q000378:metabolism; D013113:Spin Labels; D055815:Young Adult
D014150:Antipsychotic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; D013113:Spin Labels; D000068180:Aripiprazole; D006220:Haloperidol; D006854:Hydrocortisone
Antipsychotic; Cerebral blood flow; Cortisol; Dopamine; Hippocampus; Inflammation