Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex

To understand the mechanism of the clinical efficacy of olanzapine and fluo xetine combination therapy for treatment-resistant depression (TRD), we stu died the effects of olanzapine and other antipsychotics in combination with the selective serotonin uptake inhibitors fluoxetine or sertraline on neur otransmitter release in rat prefrontal cortex (PFC) using microdialysis. Th e combination of olanzapine and fluoxetine produced robust, sustained incre ases of extracellular levels of dopamine ([DA](ex)) and norepinephrine ([NE ](ex)) up to 361 +/- 28% and 272 +/- 16% of the baseline, respectively, whi ch were significantly greater than either drug alone. This combination prod uced a slightly smaller increase of serotonin ([5-HT](ex)) than fluoxetine alone. The combination (o)f clozapine or risperidone with fluoxetine produc ed less robust and persistent increases of [DA](ex) and [NE](ex). The combi nation of haloperidol or MDL 100907 with fluoxetine did not increase the mo noamines more than fluoxetine alone. Olanzapine plus sertraline combination increased only [DA](ex). Therefore, the large, sustained increase of [DA]( ex), [NE](ex), and [5-HT](ex) in PFC after olanzapine-fluoxetine treatment was unique and may contribute to the profound antidepressive effect of the olanzapine and fluoxetine therapy in TRD. (C) 2000 American College of Neur opsychopharmacology. Published by Elsevier Science Inc. All rights reserved .