Genotype and dose-frequency may critically determine the therapeutic efficacy of chronic oxytocin treatment in humans

BackgroundThere is considerable interest in therapeutic application of intranasal oxytocin in psychiatric disorders, but while clinical trials typically use daily dosing protocols it has not been established whether this is optimal or if there are moderating influences of oxytocin receptor genotype. MethodsIn a randomized, placebo-controlled pre-registered trial on 138 adult male subjects we investigated effects of single and repeated (24IU daily versus alternate days for 5 days) doses of oxytocin on two neural biomarkers (attenuated amygdala fear reactivity and increased intrinsic amygdala-prefrontal functional connectivity) and modulating effects of oxytocin receptor polymorphisms rs53576 and rs2254298 strongly associated with autism. ResultsFindings confirmed that after a single dose, amygdala responses to fear faces were reduced and its resting state connectivity with medial frontal cortex increased. Suppression of amygdala responses to fear faces was restricted to AA homozygotes of rs53576 and A+ carriers of rs2254298, whereas resting state effects were not genotype-dependent. Importantly, amygdala responses to fear faces were absent after daily oxytocin treatment but maintained after treatment every other day with infrequent dosing additionally resulting in reduced behavioral ratings of emotional arousal and intensity after 5 days. In contrast, oxytocin effects on intrinsic amygdala-prefrontal coupling were similar following daily or infrequent dose protocols after 5 days. ConclusionsOverall, results suggest that infrequent rather than daily doses of oxytocin may be more effective therapeutically and that its actions in reducing amygdala responses to fear are strongly genotype-dependent. The study was pre-registered at Clinical Trials.gov (NCT03610919).