Molecular Neuropsychiatry Unit, Sha'ar Menashe Brain Behavior Laboratory, Sha'ar Menashe Mental Health Center, and Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
Int J Neuropsychopharmacol. 2011 Jun;14(5):573-84. doi: 10.1017/S1461145710001471. Epub 2010 Dec 16.
Clinical studies have shown that negative symptoms of schizophrenia unresponsive to antipsychotic given alone can improve after augmentation with SSRI antidepressant. Laboratory investigations into the mechanism of this synergism showed that co-administration of SSRI and antipsychotic produces changes in GABA(A) receptor and related systems, which differ from the effects of each drug alone. To examine the clinical relevance of these findings, the current study examined the effects of SSRI augmentation treatment on GABA(A) receptor and related systems in schizophrenia patients. Schizophrenia patients with high levels of negative symptoms unresponsive to antipsychotic treatment received add-on fluvoxamine (100 mg/d). Blood was taken before and 1, 3 and 6 wk after adding fluvoxamine and peripheral mononuclear cells (PMC) isolated. RNA encoding for GABA(A)β3, 5-HT2A, and 5-HT7 receptors, PKCβ2, and brain-derived neurotrophic factor (BDNF) was assayed with real-time RT-PCR. Plasma BDNF protein was assayed using ELISA. Clinical symptoms were assessed with validated rating scales. We found significant increase in mRNA encoding for GABA(A)β3 and 5-HT2A, 5-HT7 receptors and BDNF and a reduction in PKCβ2 mRNA. Plasma BDNF protein concentrations were increased. There were significant correlations among the genes. Clinical symptoms improved significantly. mRNA expression of PKCβ2, 5-HT2A and 5-HT7 showed significant associations with clinical symptoms. Combined SSRI+antipsychotic treatment is associated with changes in GABA(A) receptor and in related signalling systems in patients. These changes may be part of the mechanism of clinically effective drug action and may prove to be biomarkers of pharmacological response.
临床研究表明，对于单独使用抗精神病药物治疗无效的精神分裂症阴性症状，在加用选择性 5-羟色胺再摄取抑制剂（SSRI）抗抑郁药后可以改善。对这种协同作用机制的实验室研究表明，SSRI 与抗精神病药物联合使用会导致 GABA(A) 受体和相关系统发生变化，这些变化与每种药物单独使用的效果不同。为了检验这些发现的临床相关性，本研究检测了 SSRI 增效治疗对精神分裂症患者 GABA(A) 受体和相关系统的影响。对接受抗精神病药物治疗但仍有高水平阴性症状且无反应的精神分裂症患者，加用氟伏沙明（100mg/d）。在加用氟伏沙明前和加用后 1、3 和 6 周时采血，并分离外周血单核细胞（PMC）。采用实时 RT-PCR 检测 GABA(A)β3、5-HT2A 和 5-HT7 受体、PKCβ2 和脑源性神经营养因子（BDNF）的 RNA 编码。采用 ELISA 法检测血浆 BDNF 蛋白。采用经过验证的评分量表评估临床症状。我们发现 GABA(A)β3 和 5-HT2A、5-HT7 受体以及 BDNF 的 mRNA 编码显著增加，PKCβ2 mRNA 减少。血浆 BDNF 蛋白浓度增加。这些基因之间存在显著相关性。临床症状显著改善。PKCβ2、5-HT2A 和 5-HT7 的 mRNA 表达与临床症状显著相关。联合 SSRI+抗精神病药物治疗与患者 GABA(A) 受体和相关信号转导系统的变化有关。这些变化可能是临床有效药物作用机制的一部分，并且可能被证明是药物反应的生物标志物。
