Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
Pharmacol Rep. 2013;65(5):1144-51. doi: 10.1016/s1734-1140(13)71472-5.
Several clinical reports have documented a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants, in particular selective serotonin reuptake inhibitors, in the treatment of drug resistant depression. The aim of our study was to understand the mechanism of the clinical efficacy of a combination of fluoxetine (FLU) and risperidone (RIS) in drug-resistant depression. We studied the effect of FLU and RIS, given separately or jointly on the extracellular levels of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) in the rat frontal cortex.
Animals were given single intraperitoneal injections of RIS at a doses of 0.1 or 1 mg/kg and FLU at a dose of 10 mg/kg. The release of DA, 5-HT and NA in the rat frontal cortex was investigated using microdialysis in freely moving animals. The extracellular level of DA, 5-HT and NA was assayed by HPLC with coulochemical detection.
RIS (0.1 and 1 mg/kg) and FLU (10 mg/kg) increased the extracellular level of cortical DA, 5-HT and NA. Co-treatment of both drugs was more effective in increasing DA release than administration of each of the drugs alone at doses of RIS 1 mg/kg and FLU 10 mg/kg. Co-treatment of FLU and RIS 0.1 mg/kg was more potent than FLU alone, while the effect of joint injection of FLU and RIS 1 mg/kg was stronger than RIS 1 mg/kg alone on 5-HT release. The combination of FLU with both doses of RIS was not effective in increasing NA release as compared to drugs given alone.
Our data indicate that the effect of the combined administration of RIS and FLU on DA and 5-HT release in the rat frontal cortex may be of crucial importance to the pharmacotherapy of drug resistant depression.
有几项临床报告记录了在抗抑郁药治疗中，特别是选择性 5-羟色胺再摄取抑制剂（SSRIs）治疗中，加入低剂量利培酮对耐药性抑郁症的有益效果。我们研究的目的是了解氟西汀（FLU）和利培酮（RIS）联合治疗耐药性抑郁症的临床疗效的机制。我们研究了单独或联合给予 FLU 和 RIS 对大鼠前额皮质细胞外多巴胺（DA）、5-羟色胺（5-HT）和去甲肾上腺素（NA）水平的影响。
动物单次腹腔内注射 RIS（0.1 或 1mg/kg）和 FLU（10mg/kg）。使用微透析法在自由活动的动物中研究大鼠前额皮质中 DA、5-HT 和 NA 的释放。通过 HPLC 与库仑电化学检测法测定细胞外 DA、5-HT 和 NA 的水平。
RIS（0.1 和 1mg/kg）和 FLU（10mg/kg）增加了皮质 DA、5-HT 和 NA 的细胞外水平。与单独给予每种药物相比，联合给予两种药物时，RIS 1mg/kg 和 FLU 10mg/kg 更能有效增加 DA 释放。与单独给予 FLU 相比，联合给予 FLU 和 RIS 0.1mg/kg 更有效，而联合给予 FLU 和 RIS 1mg/kg 比单独给予 RIS 1mg/kg 更能有效增加 5-HT 释放。与单独给予药物相比，联合给予 FLU 和两种剂量的 RIS 并不能有效增加 NA 释放。
我们的数据表明，联合给予 RIS 和 FLU 对大鼠前额皮质中 DA 和 5-HT 释放的影响可能对耐药性抑郁症的药物治疗至关重要。
