Brain Reward Abnormalities and Antipsychotic Monotherapy in Schizophrenia

Research has linked schizophrenia to dysfunction of dopamine neurotransmission and the brain reward system. It is possible that a dysregulated hyperdopaminergic state may lead to the development of psychoses through altered reward processing. It is believed that antipsychotic medication normalizes the altered transmission via D₂ antagonism.

According to researchers, it is not clear whether antipsychotic treatment that blocks transmission of dopamine improves, alters, or worsens the reward-related abnormalities in patients with schizophrenia. To examine changes in reward-related brain activations in schizophrenia before and after antipsychotic monotherapy with a dopamine D₂/D₃ antagonist, the researchers recently conducted a longitudinal cohort study of psychiatric patients. Study results were reported in Archives of General Psychiatry [2012;69(12):1195-1204].

Participants were 23 antipsychotic-naïve patients with schizophrenia 18 to 45 years of age, recruited from inpatient and outpatient psychiatric centers in the Capital Region of Denmark. International Classification of Diseases, 10th Revision diagnoses of schizophrenia or schizoaffective psychoses were based on a structured interview. Patients with a current diagnosis of drug dependency were excluded, but previous diagnoses of drug dependency or current occasional use of drugs was accepted. There were 24 healthy controls matched on age, sex, and parental socioeconomic status.

Patients and controls were examined with functional magnetic resonance imaging (MRI) while playing a variant of the monetary incentive delay task. Patients were treated for 6 weeks with the antipsychotic compound amisulpride. Controls were followed up without treatment.

The primary outcome measures were task-related blood oxygen level-dependent activations as measured by functional MRI before and after antipsychotic treatment.

During the time between the examinations, there was a significant improvement in total Positive and Negative Syndrome Scale (PANSS) scores, PANSS positive score, and PANSS general score (P<.001 for all measures). The patients also improved in function and depressive symptoms.

At baseline, compared with controls, patients demonstrated an attenuation of brain activation during reward anticipation in the ventral striatum, bilaterally. After 6 weeks of treatment, patients showed an increase in the anticipation-related functional MRI signal and were no longer statistically distinguishable from healthy controls.

Among the patients, there was a correlation between the improvement of positive symptoms and normalization of reward-related activation. Those who showed the greatest clinical improvement in positive symptoms also showed the greatest increase in reward-related activation after treatment.

The researchers cited several limitations to the study, among them was allowing previous drug abuse and current occasional drug use as well as the possibility of a selection bias because a degree of patient collaboration was required.

In stating their conclusions, the researchers said, “To our knowledge, this is the first controlled, longitudinal study of reward disturbances in schizophrenic patients before and after their first antipsychotic treatment. Our results demonstrate that alterations in reward processing are fundamental to the illness and are seen prior to any treatment. Antipsychotic treatment tends to normalize the response of the reward system; this was especially seen in the patients with the most pronounced treatment effect on the positive symptoms.”