RATIONALE: Changes in the cortical expression of small non-coding microRNA (miRNA) have been observed in postmortem analysis of psychotic disorders. Antipsychotic drugs (APDs) are the most effective treatment option for these disorders and have been associated with changes in gene expression. MicroRNA regulate numerous genes involved in brain development and function. It is therefore plausible to question whether miRNA expression is also altered and hence whether they take part in the neuroleptic mechanism of action. OBJECTIVES: We sought to investigate whether treatment with APDs induces changes in miRNA expression and query the functional implications of such changes. Furthermore, we investigated the possible functional interplay of miRNA-gene regulatory interactions. METHOD: High-throughput miRNA profiling of the whole brain of C57BL/6 mice treated with haloperidol, olanzapine or clozapine for 7 days was performed. Functional analysis was conducted on the putative targets of altered microRNA. Significant miRNA-gene regulatory interactions were evaluated by the integration of genome-wide mRNA expression analysis using the Bayesian networks with splitting-averaging strategy and functional analysis conducted. RESULTS: Small subsets of miRNA were altered with each treatment with potential neurologically relevant influence. Metabolic pathways were enriched in olanzapine and clozapine treatments, possibly associated with their weight gain side effects. Neurologically and metabolically relevant miRNA-gene interaction networks were identified in the olanzapine treatment group. CONCLUSION: This study is the first to suggest a role for miRNA in the mechanism of APD action and the metabolic side effects of the atypical ADPs, and adds support for their consideration in pharmacogenomics.