The development of new antidepressants is a complicated process requiring significant financial investment and extensive clinical research. Even so, the use of medicinal drugs in a real world setting presents challenges for clinicians that cannot always be fully understood in the context of clinical trials. Multiple medical, psychiatric and substance use comorbidities are frequently encountered amongst patients treated with antidepressants. Polypharmacy creates the potential for significant pharmacokinetic and pharmacodynamic drug interactions, and the patterns of adverse effects observed in the post-marketing surveillance phase can be quite different to that observed in clinical trials. Antidepressants can behave differently "in the wild," and awareness of the potential issues can help clinicians to make treatment safer and more effective for patients.