Comparative Evaluation of Sertraline and Fluoxetine in Major Depressive Disorder: A Structured Review of Safety, Pharmacokinetics, and Clinical Dosing

Abstract

Major depressive disorder is a prevalent psychiatric condition and a prominent cause of disability around the world. Selective serotonin reuptake inhibitors remain the first-line pharmacological options and are the most frequently used, with sertraline and fluoxetine shown to be effective and safe. Although both drugs inhibit serotonin reuptake, they have distinct pharmacokinetic and safety profiles that can affect clinical decision-making. This structured narrative review compares sertraline and fluoxetine regarding their pharmacokinetic properties, such as absorption, distribution, metabolism, elimination, peak plasma concentration, time to peak concentration, area under the concentration–time curve, and elimination half-life (t1/2), and adverse effect profiles. Systematic searches were conducted in electronic databases, such as PubMed, Scopus, ScienceDirect, Google Scholar, and the Cochrane Library, for publications from 2000 to 2025. After screening and quality assessment, 78 studies were included in the review. The synthesized evidence suggests that both drugs are equally effective in treating depression. Fluoxetine, however, has a longer half-life and more potent inhibition of cytochrome P450 2D6 (CYP2D6), which could increase drug–drug interactions, enhance adherence, and decrease discontinuation effects. In contrast, sertraline has a lower inhibition potential for the CYP450 system, fewer clinically important drug-drug interactions, and a better cardiovascular safety profile. In summary, the choice of antidepressant should be individualized based on patient-specific factors, comorbidities, tolerability, cardiovascular parameters, hepatic function, and any other drugs the patient is taking to achieve the best therapeutic effect.