title: Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex.
abstract: To understand the mechanism of the clinical efficacy of olanzapine and fluoxetine combination therapy for treatment-resistant depression (TRD), we studied the effects of olanzapine and other antipsychotics in combination with the selective serotonin uptake inhibitors fluoxetine or sertraline on neurotransmitter release in rat prefrontal cortex (PFC) using microdialysis. The combination of olanzapine and fluoxetine produced robust, sustained increases of extracellular levels of dopamine ([DA](ex)) and norepinephrine ([NE](ex)) up to 361 +/- 28% and 272 +/- 16% of the baseline, respectively, which were significantly greater than either drug alone. This combination produced a slightly smaller increase of serotonin ([5-HT](ex)) than fluoxetine alone. The combination of clozapine or risperidone with fluoxetine produced less robust and persistent increases of [DA](ex) and [NE](ex). The combination of haloperidol or MDL 100907 with fluoxetine did not increase the monoamines 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.
authors.affiliation: Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: K W
authors.initials: KW
authors.lastname: Perry
authors.forename: D T
authors.initials: DT
authors.lastname: Wong
authors.forename: B D
authors.initials: BD
authors.lastname: Potts
authors.forename: J
authors.initials: J
authors.lastname: Bao
authors.forename: G D
authors.initials: GD
authors.lastname: Tollefson
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001569:Benzodiazepines; D001921:Brain / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004357:Drug Synergism; D005110:Extracellular Space / Q000378:metabolism; D005473:Fluoxetine / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism*; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013268:Stimulation, Chemical
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D004298:Dopamine; D005473:Fluoxetine; D009638:Norepinephrine; D000077152:Olanzapine; D010890:Pirenzepine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors