Bertollo Amanda Gollo, Mocelin Ricieri, Ignácio Zuleide Maria
Graduate Program in Neurosciences, Federal University of Santa Catarina, Florianópolis 88040-900, SC, Brazil.
Laboratory of Physiology, Pharmacology, and Psychopathology, Graduate Program in Biomedical Sciences, Federal University of Fronteira Sul, Chapecó 89815-899, SC, Brazil.
Pharmaceuticals (Basel). 2025 Sep 11;18(9):1360. doi: 10.3390/ph18091360.
Genetic polymorphisms within specific genes play a role in both the genetic predisposition to Major Depressive Disorder (MDD) and the variation observed in responses to antidepressant treatments. Pharmacogenetics examines how these polymorphisms affect medication response. This review highlights significant disparities in the pharmacogenetic influences on antidepressant response, with a focus on ethnic and sex-based differences. This review synthesizes findings from a comprehensive literature search conducted between 2000 and 2025. It utilized databases such as PubMed, Scopus, and Web of Science, using search terms including "pharmacogenetics", "antidepressants", "Major Depressive Disorder", "CYP450", "neuroplasticity", and "genetic variations". This review integrates pharmacogenetics with neurotransmitters and their transporters, neuroplasticity, growth factors, and the cytochrome P450 family, providing promising insights for personalized MDD treatment strategies. We analyzed and synthesized findings from over 50 relevant studies, focusing on those with a clear emphasis on genetic associations with antidepressant efficacy and adverse effects. Pharmacogenetic analysis facilitates personalized antidepressant prescriptions by identifying key genetic variants that influence treatment outcomes. Specifically, variations in CYP2D6 and CYP2C19 can significantly impact drug metabolism and tolerability. A high percentage of patients with non-normal metabolizer phenotypes are predisposed to adverse drug reactions or ineffective responses. Furthermore, this review identifies significant ethnic and sex-based disparities in treatment response. For example, the L allele of the 5-HTTLPR polymorphism confers a higher likelihood of response and remission following SSRI treatment in white people compared to Asians. Additionally, in women, specific 5-HTTLPR polymorphisms have a more pronounced influence on mood and MDD pathophysiology, with a significant reduction in mood in response to tryptophan depletion. Integrating pharmacogenetic insights, encompassing genetic factors, neurotransmitter pathways, neuroplasticity, and the influence of ethnicity and sex, is crucial for developing personalized antidepressant treatment strategies. This will ultimately optimize patient recovery and minimize adverse effects.
特定基因内的遗传多态性在重度抑郁症（MDD）的遗传易感性以及抗抑郁治疗反应的个体差异中均发挥作用。药物遗传学研究这些多态性如何影响药物反应。本综述着重阐述了药物遗传学对抗抑郁反应影响方面的显著差异，重点关注基于种族和性别的差异。本综述综合了2000年至2025年间全面文献检索的结果。检索使用了PubMed、Scopus和Web of Science等数据库，检索词包括“药物遗传学”、“抗抑郁药”、“重度抑郁症”、“CYP450”、“神经可塑性”和“基因变异”。本综述将药物遗传学与神经递质及其转运体、神经可塑性、生长因子和细胞色素P450家族相结合，为个性化的MDD治疗策略提供了有前景的见解。我们分析并综合了50多项相关研究的结果，重点关注那些明确强调基因与抗抑郁疗效及不良反应关联的研究。药物遗传学分析通过识别影响治疗结果的关键基因变异，有助于实现个性化的抗抑郁药物处方。具体而言，CYP2D6和CYP2C19的变异可显著影响药物代谢和耐受性。高比例的非正常代谢者表型患者易发生药物不良反应或无效反应。此外，本综述还确定了治疗反应中基于种族和性别的显著差异。例如，与亚洲人相比，5-HTTLPR多态性的L等位基因使白人在接受SSRI治疗后有更高的反应和缓解可能性。此外，在女性中，特定的5-HTTLPR多态性对情绪和MDD病理生理学有更显著的影响，色氨酸耗竭会导致情绪显著降低。整合包括遗传因素、神经递质途径、神经可塑性以及种族和性别的影响等药物遗传学见解，对于制定个性化的抗抑郁治疗策略至关重要。这最终将优化患者康复并最大限度减少不良反应。
