Abstract
Use of antipsychotic medication is related to thinning of the cerebral cortex, but the underlying mechanisms of this effect remain largely unknown. Here, we investigated potential mechanisms across multiple levels of description by comparing antipsychotic medication related cortical thinning to atlases of normative neurotransmitter distributions, structural and functional organization of the brain, and meta-analyses of functional activation from the Neurosynth database. We first analyzed a single-site discovery sample of patients (N = 131) with early psychosis for whom antipsychotic related cortical thinning was estimated based on lifetime exposure to antipsychotics. Findings were replicated using data from a large (N ≥ 2168) ENIGMA meta-analysis on schizophrenia patients. We discovered that antipsychotic related cortical thinning is associated with a number of neurotransmitter systems, most notably the serotonin system, as well as physiological measures, functional networks and neural oscillatory power distributions typical for regions subserving higher cognition. At the functional level, antipsychotic related cortical thinning affects regions involved in executive function and motivation, but not perception. These results show how molecular, physiological, and large-scale functional patterns may underlie antipsychotic related cortical thinning.