Zhang W, Perry K W, Wong D T, Potts B D, Bao J, Tollefson G D, Bymaster F P
Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA.
Neuropsychopharmacology. 2000 Sep;23(3):250-62. doi: 10.1016/S0893-133X(00)00119-6.
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) and norepinephrine (NE) 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) than fluoxetine alone. The combination of clozapine or risperidone with fluoxetine produced less robust and persistent increases of DA and NE. 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. Therefore, the large, sustained increase of DA, NE, and 5-HT in PFC after olanzapine-fluoxetine treatment was unique and may contribute to the profound antidepressive effect of the olanzapine and fluoxetine therapy in TRD.
为了解奥氮平与氟西汀联合治疗难治性抑郁症(TRD)的临床疗效机制,我们使用微透析技术研究了奥氮平及其他抗精神病药物与选择性5-羟色胺再摄取抑制剂氟西汀或舍曲林联合应用对大鼠前额叶皮质(PFC)神经递质释放的影响。奥氮平与氟西汀联合用药使细胞外多巴胺(DA)和去甲肾上腺素(NE)水平显著且持续升高,分别达到基线水平的361±28%和272±16%,显著高于单药治疗。该联合用药使5-羟色胺(5-HT)水平的升高幅度略小于单用氟西汀。氯氮平或利培酮与氟西汀联合用药使DA和NE的升高幅度较小且不持久。氟哌啶醇或MDL 100907与氟西汀联合用药对单胺类递质的升高作用不超过单用氟西汀。奥氮平加舍曲林联合用药仅使DA升高。因此,奥氮平-氟西汀治疗后PFC中DA、NE和5-HT大幅且持续升高具有独特性,可能是奥氮平与氟西汀联合治疗TRD产生显著抗抑郁作用的原因。