BACKGROUND Severe mental disorders like schizophrenia are a leading cause of disability in people in the prime years of their lives (aged 15 to 44 years). Relapse is a primary contributor to schizophrenia disease burden and is frequently attributed to medication noncompliance and inadequate doses. Currently, a patient's neuroleptic dose is titrated to clinical response within recommended dose ranges. Use of unbiased biomarkers of effective neuroleptic treatment-response would greatly facilitate the identification of a person's lowest effective dose to minimize unsafe side effects and improve compliance. Biomarkers may allow precisely tailored adjustments of neuroleptic dose to reduce relapse due to variable disease course. METHODS AND FINDINGS Biomarkers of active psychosis were sought among persons with schizophrenia hospitalized with acute psychosis. The transcriptional response of peripheral blood mononuclear cells (PBMCs) to treatment of psychosis was measured using RNA expression profiling in 12-paired samples from patients with schizophrenia. The paired samples were collected early after treatment initiation and again just before patients were released from the hospital. Patients showed significant improvement in positive symptoms of psychosis assessed at each sample collection using a brief psychiatric rating scale (BPRS) (P<0.05). Preliminary evidence is presented indicating that decreased transcript levels of isoforms of disrupted in schizophrenia 1 (DISC1) measured in PBMCs were associated with treatment in 91% of samples (P=0.037). CONCLUSION Further studies are warranted to identify neuroleptic-response biomarkers and to replicate this initial finding of association of DISC1 transcript levels with treatment of psychosis.