Fabbri Chiara, Souery Daniel, Calati Raffaella, Crisafulli Concetta, Chierchia Armando, Albani Diego, Forloni Gianluigi, Chiesa Alberto, Martines Rosalba, Sentissi Othman, Mendlewicz Julien, De Girolamo Giovanni, Serretti Alessandro
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123, Bologna, Italy.
J Neural Transm (Vienna). 2015 Jan;122(1):43-58. doi: 10.1007/s00702-014-1290-3. Epub 2014 Aug 17.
The treatment of bipolar disorder (BD) usually requires combination therapies, with the critical issue of the emergence of adverse drug reactions (ADRs) and the possibility of low treatment adherence. Genetic polymorphisms are hypothesized to modulate the pharmacodynamics of psychotropic drugs, representing potential biological markers of ADRs. This study investigated genes involved in the regulation of neuroplasticity (BDNF, ST8SIA2), second messenger cascades (GSK3B, MAPK1, and CREB1), circadian rhythms (RORA), transcription (SP4, ZNF804A), and monoaminergic system (HTR2A and COMT) in the risk of neurological, psychic, autonomic, and other ADRs. Two independent samples of BD patients naturalistically treated were included (COPE-BD n = 147; STEP-BD n = 659). In the COPE-BD 34 SNPs were genotyped, while in the STEP-BD polymorphisms in the selected genes were extracted from the genome-wide dataset. Each ADRs group was categorized as absent-mild or moderate-severe and logistic regression with appropriate covariates was applied to identify possible risk genotypes/alleles. 58.5 and 93.5 % of patients were treated with mood stabilizers, 44.2 and 50.7 % were treated with antipsychotics, and 69.4 and 46.1 % were treated with antidepressants in the COPE-BD and STEP-BD, respectively. Our findings suggested that ST8SIA2 may be associated with psychic ADRs, as shown in the COPE-BD (rs4777989 p = 0.0017) and STEP-BD (rs56027313, rs13379489 and rs10852173). A cluster of RORA SNPs around rs2083074 showed an effect on psychic ADRs in the STEP-BD. Trends supporting the association between HTR2A and autonomic ADRs were found in both samples. Confirmations are needed particularly for ST8SIA2 and RORA since the few available data regarding their role in relation to psychotropic ADRs.
双相情感障碍（BD）的治疗通常需要联合疗法，存在药物不良反应（ADR）出现以及治疗依从性低的关键问题。基因多态性被认为可调节精神药物的药效学，是ADR的潜在生物学标志物。本研究调查了参与神经可塑性调节（BDNF、ST8SIA2）、第二信使级联反应（GSK3B、MAPK1和CREB1）、昼夜节律（RORA）、转录（SP4、ZNF804A）以及单胺能系统（HTR2A和COMT）的基因与神经、精神、自主神经及其他ADR风险的关系。纳入了两个自然治疗的BD患者独立样本（COPE - BD组n = 147；STEP - BD组n = 659）。在COPE - BD组中对34个单核苷酸多态性（SNP）进行了基因分型，而在STEP - BD组中从全基因组数据集中提取所选基因的多态性。每个ADR组分为无 - 轻度或中度 - 重度，并应用带有适当协变量的逻辑回归来识别可能的风险基因型/等位基因。在COPE - BD组和STEP - BD组中，分别有58.5%和93.5%的患者接受心境稳定剂治疗，44.2%和50.7%的患者接受抗精神病药物治疗，69.4%和46.1%的患者接受抗抑郁药物治疗。我们的研究结果表明，ST8SIA2可能与精神性ADR相关，如在COPE - BD组（rs4777989 p = 0.0017）和STEP - BD组（rs56027313、rs13379489和rs10852173）中所示。rs2083074周围的一组RORA SNP在STEP - BD组中显示出对精神性ADR的影响。在两个样本中均发现了支持HTR2A与自主神经性ADR之间关联的趋势。由于关于ST8SIA2和RORA在精神药物ADR方面作用的现有数据较少，尤其需要对它们进行进一步验证。
