Major depression is one of the most disabling health conditions internationally. In recent years, new generation antidepressant medicines have become very widely prescribed. While these medicines are efficacious, side effects are common and frequently result in discontinuation of treatment. Compared with specific pharmacological properties of the different medications, the relevance of individual vulnerability is understudied. We used data from the Australian Genetics of Depression Study to gain insights into the aetiology and genetic risk factors to antidepressant side effects. As expected, the most commonly reported longer-term side effects were reduced sexual function and weight gain. Importantly, participants reporting a specific side effect for one antidepressant were more likely to report the same side effect for other antidepressants, suggesting the presence of shared individual or pharmacological factors. Depression Polygenic Risk Scores (PRS) were associated with side effects that overlapped with depressive symptoms, including suicidality and anxiety. Body Mass Index PRS were strongly associated with weight gain from all medications. PRS for headaches were associated with headaches from sertraline. Insomnia PRS showed some evidence of predicting insomnia from amitriptyline and escitalopram. Our results suggest a set of common factors underlying the risk for antidepressant side effects. These factors seem to be, at least in part, explained by genetic liability related to depression severity and the nature of the side effect. Future studies on the genetic aetiology of side effects will enable insights into their underlying mechanisms and the possibility of risk stratification and prophylaxis strategies.

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了解抗抑郁药物常见副作用的遗传风险因素

重度抑郁症是国际上最致残的健康状况之一。近年来，新一代抗抑郁药物已成为非常广泛的处方。虽然这些药物有效，但副作用很常见，经常导致治疗中断。与不同药物的特定药理特性相比，个体脆弱性的相关性尚未得到充分研究。我们使用来自澳大利亚抑郁症遗传学研究的数据来深入了解抗抑郁药副作用的病因和遗传风险因素。正如预期的那样，最常报告的长期副作用是性功能下降和体重增加。重要的是，报告一种抗抑郁药有特定副作用的参与者更有可能报告其他抗抑郁药有相同的副作用，表明存在共同的个体或药理因素。抑郁症多基因风险评分 (PRS) 与与抑郁症状重叠的副作用有关，包括自杀和焦虑。体重指数 PRS 与所有药物的体重增加密切相关。头痛的 PRS 与舍曲林引起的头痛有关。失眠 PRS 显示了一些证据表明阿米替林和依他普仑可预测失眠。我们的研究结果表明，抗抑郁药副作用风险背后的一系列共同因素。这些因素似乎至少部分是由与抑郁症严重程度和副作用性质相关的遗传责任来解释的。