Understanding genetic risk factors for common side effects of antidepressant medications

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.