Abstract
BackgroundMajor 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.MethodsWe used data from the Australian Genetics of Depression Study to gain insights into the aetiology and genetic risk factors to antidepressant side effects. To this end, we employed structural equation modelling, polygenic risk scoring and regressions.ResultsHere we show that participants reporting a specific side effect for one antidepressant are more likely to report the same side effect for other antidepressants, suggesting the presence of shared individual or pharmacological factors. Polygenic risk scores (PRS) for depression associated with side effects that overlapped with depressive symptoms, including suicidality and anxiety. Body Mass Index PRS are strongly associated with weight gain from all medications. PRS for headaches are associated with headaches from sertraline. Insomnia PRS show some evidence of predicting insomnia from amitriptyline and escitalopram.ConclusionsOur results suggest a set of common factors underlying the risk for antidepressant side effects. These factors seem to be partly 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.
Highlights
Major depression is one of the most disabling health conditions internationally
Our study has several insights, including (1) providing prevalence estimates for side effects outside of a controlled clinical trial; (2) assessing drug-class specificity of antidepressant side effects; (3) testing and providing evidence for non-specific factors, which is of particular interest for some side effects such as suicidality; and 4) testing for genetic factors underlying the aetiology of side effects using Polygenic risk scores (PRS)
It is hypothesised that testosterone and dopamine neurotransmitters are dysregulated by selective serotonin reuptake inhibitors (SSRIs), a plausible hypothesis considering the role that testosterone plays in sexual function and the high amounts circulating in males compared to females[40,41]
Summary
We aim to bridge this research gap by leveraging data from the Australian Genetics of Depression Study (AGDS) to gain insights into the prevalence, aetiology and genetic underpinnings of adverse side effects associated with antidepressant use
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