In this chapter, we will discuss studies that have evaluated evidence for various antidepressants, their benefits, and drawbacks. Their use will be reviewed considering concerns about antidepressant adverse effects and efficacy that have prompted a notable shift to nonpharmacological treatments. Questions have arisen about placebo substitution trials, publication bias, and selective screening in clinical trials. Pharmacogenetic insights offer promising avenues for tailoring antidepressant therapy to individual patient profiles, potentially enhancing treatment response rates and reducing adverse events. We emphasize the importance of clinicians familiarizing themselves with the diverse array of antidepressant medications, considering their varying side effect profiles and widespread usage across different conditions and populations. Personalized approaches in MDD management are highlighted, recognizing the variability in patient responses and associated risks with antidepressant medications. Such individualized strategies are vital in optimizing treatment care and minimizing potential adverse reactions.