Characterization of fluoxetine plus olanzapine treatment in rats: a behavior, endocrine, and immediate-early gene...

A large number of individuals afflicted with psychiatric disorders, particularly depression with psychotic features, do not respond to conventional drug therapy. An option for this phenomenon is to augment a standard selective serotonin (5-HT) reuptake inhibitor with an atypical antipsychotic agent. In this regard, fluoxetine and olanzapine have been used concomitantly for treatment-resistant depression and bipolar depression. Although highly efficacious in terms of producing superior improvement of symptoms across a variety of psychological measures, the motor patterns, endocrine profiles, and intracellular signaling pathways affected by drug augmentation have not been determined. Here we show that fluoxetine (10 mg/kg) plus olanzapine (5 mg/kg) given to rats for 7 consecutive days (i.e., subchronic treatment) alters motor activity and diminishes spontaneous behaviors as measured by spatial position and angular path analyses. In addition, the same drug combination pattern sensitizes peak adrenal corticosterone secretion without altering serum glucose levels. We also show that subchronic fluoxetine and olanzapine exposure suppresses the induction of two immediate-early gene transcription factors (e.g., pCREB and FOS) that are associated with long-lasting changes in synaptic efficacy and structural modifications in the prefrontal cortex, piriform cortex, and hippocampus. These results suggest that fluoxetine plus olanzapine can interact in a fashion not predicted by the currently accepted model of fluoxetine monotherapy and provide insight into the synergistic actions of drug augmentation in patients with treatment-resistant depression.