AbstractCyclin-dependent kinase-5 (CDK5) and p35/p25 activators, interacting with the exocytotic machinery (e.g. munc18-1 and syntaxin-1A), play critical roles in neurosecretion. The basal status of CDK5/p35/p25 and the effect of psychotropic drugs (detected in blood/urine samples) were investigated in post-mortem prefrontal cortex (PFC)/Brodmann's area 9 of schizophrenia (SZ) and major depression (MD) subjects. In SZ (all subjects, n = 24), CDK5 and p35, but not p25, were reduced (−28 to −58%) compared to controls. In SZ antipsychotic-free (n = 12), activator p35 was decreased (−52%). In SZ antipsychotic-treated (n = 12), marked reductions of CDK5 (−47%), p35 (−76%) and p25 (−36%) were quantified. In MD (n = 13), including antidepressant-free/treated subgroups, CDK5, p35 and p25 were unaltered. In SZ (n = 24), CDK5, p35 or p25 correlated with munc18-1a, but not with syntaxin-1A. The results demonstrate reduced p35 basal content and down-regulation of CDK5/p35/p25 by antipsychotics in SZ. The suggested CDK5/munc18-1a functional interaction may lead to dysregulated neurosecretion in SZ PFC.