Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Kraków, Poland; The Podhale State Higher Vocational School, Nowy Targ, Poland.
Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Kraków, Poland.
Pharmacol Rep. 2017 Oct;69(5):885-893. doi: 10.1016/j.pharep.2017.02.022. Epub 2017 Mar 4.
Recently, several clinical studies have suggested a beneficial effect of a combination of antidepressants (ADs) with antipsychotic drugs in drug-resistant depression. Moreover, preclinical and clinical studies indicated a role of brain-derived neurotrophic factor (BDNF) in the pathology of depression, as well as in the mechanism of action of ADs.
In the present study, we investigated the effect of repeated administration of ADs, escitalopram, fluoxetine or mirtazapine and a low dose of risperidone (an atypical antipsychotic drug) given separately or in combination, on the mRNA and protein levels of BDNF or cAMP response element binding (p-CREB) in the hippocampus and frontal cortex of male Wistar rats. ADs were given repeatedly (once daily for 14 days), separately or in combination with a low dose of risperidone. The tissue for biochemical assays was dissected 24h after the last dose of ADs.
The obtained results showed that repeated co-treatment with an inactive dose of risperidone and escitalopram or mirtazapine but not fluoxetine increased the BDNF mRNA expression in the hippocampus and frontal cortex. Moreover, combined treatment with an inactive dose risperidone and escitalopram elevated the protein levels of p-CREB in the frontal cortex. While, co-treatment with risperidone and fluoxetine or mirtazapine increased the protein levels of BDNF and p-CREB in both examined regions of the brain.
Our present findings suggest that enhancement levels of BDNF may be essential for the therapeutic effect of co-treatment with ADs and a low dose risperidone in patients with drug-resistant depression.
最近，几项临床研究表明，抗抑郁药（ADs）与抗精神病药物联合治疗耐药性抑郁症有一定的疗效。此外，临床前和临床研究表明脑源性神经营养因子（BDNF）在抑郁症的发病机制中以及 ADs 的作用机制中发挥作用。
在本研究中，我们研究了重复给予 ADs（艾司西酞普兰、氟西汀或米氮平）和低剂量利培酮（一种非典型抗精神病药物），单独或联合使用，对雄性 Wistar 大鼠海马体和前额皮质中 BDNF 或 cAMP 反应元件结合蛋白（p-CREB）的 mRNA 和蛋白水平的影响。ADs 重复给予（每日一次，共 14 天），单独或与低剂量利培酮联合给予。ADs 最后一次给药后 24 小时分离用于生化测定的组织。
研究结果表明，重复给予低剂量利培酮与艾司西酞普兰或米氮平合用但不与氟西汀合用可增加海马体和前额皮质中的 BDNF mRNA 表达。此外，联合治疗用低剂量利培酮可增加前额皮质中 p-CREB 的蛋白水平。而利培酮与氟西汀或米氮平合用可增加大脑两个检查区域的 BDNF 和 p-CREB 蛋白水平。
我们目前的研究结果表明，增强 BDNF 水平可能是 ADs 与低剂量利培酮联合治疗耐药性抑郁症患者的治疗效果的关键。
