Advances in technology and transparency have greatly accelerated the ability of clinicians to remain current with regards to being informed and informing patients about the risk/benefit ratio when considering antidepressant medication. In spite of this, the current climate of pharmaceutical industry influence on medical practice does much to hinder informed consent processes. Recent findings of previously unknown and potentially dangerous adverse effects of the second- and third-generation classes of antidepressants underscore the importance of enhancing the practice of informed consent. After considering the concept of informed consent as it has evolved over time, the authors summarize some of the newer side effects associated with second- and third-generation antidepressants and then move on to describe impediments in the way of achieving adequate informed consent at the clinical encounter. Among these impediments, the authors discuss the impact of industry influence, cognitive bias in decision-making, and time constraints. These obstacles and the notion that modern antidepressants are not as safe as once thought offer an opportunity to revisit the process of informed consent. A dynamic concept of informed consent is proposed with the acknowledgement that a mere listing of side effects or pro forma approach to informed consent is inadequate, and that a deep and ongoing conversation with patients will more likely result in patient empowerment and a strengthening of the therapeutic alliance. This process is analogized to an “n=1” approach where patients’ idiosyncratic responses to second- and third-generation antidepressants can be used to update prior beliefs based on large-scale trials and allow patient and doctor to shoulder the burden of uncertainty together, thereby enhancing placebo and minimizing nocebo response and leading to more optimal treatment outcomes.