The Limitations of Antidepressants: Toward Etiology-Based Psychiatry

Despite the widespread use of antidepressants, depression remains a leading cause of global disability, revealing fundamental limitations in current psychiatric paradigms. This chapter critically examines the diagnostic and therapeutic frameworks that underlie antidepressant use. The prevailing symptom-centered system of the Diagnostic and Statistical Manual of Mental Disorders (DSM) has produced biologically heterogeneous patient populations, undermining treatment precision and efficacy. Empirical evidence shows that antidepressants offer minimal benefit beyond placebo for mild-to-moderate depression, with only modest advantages in severe cases. Major trials such as STAR*D reveal remission rates below 50%, and relapse is frequent. Moreover, publication bias has distorted perceptions of efficacy, as negative or null studies are often unpublished. Safety concerns—particularly regarding suicidality and aggression among younger patients—underscore the necessity of nuanced clinical assessment and diagnostic vigilance, especially for undetected bipolarity. Meanwhile, the serotonin deficiency hypothesis, long considered central to depression, lacks robust empirical support, prompting interest in novel agents such as ketamine that target alternative neurobiological pathways. These developments call for a paradigm shift from symptom suppression toward etiology-based psychiatry, integrating neurobiological, psychological, and environmental determinants. A Hippocratic approach that intervenes only when the underlying pathophysiology is understood may reduce overtreatment and enhance long-term outcomes. Ultimately, antidepressants should be employed judiciously within a broader, individualized framework that prioritizes disease mechanisms and patient-specific context rather than categorical diagnosis alone. For conceptual clarity, it is important to distinguish between symptom-centered treatment and etiology-based care. Symptom-centered treatment refers to a clinical approach in which therapeutic decisions are guided primarily by the presence and severity of observable symptoms, often independent of their underlying causes. This model, exemplified by current DSM-based practice, prioritizes symptom reduction and functional relief, frequently through pharmacological means. By contrast, etiology-based care emphasizes identification and modification of the underlying mechanisms that give rise to psychiatric symptoms, including neurobiological vulnerabilities, psychological processes, and environmental stressors. Within this framework, symptomatic improvement is regarded as a consequence of addressing causal pathways rather than as the primary therapeutic target. This distinction underlies the present critique of antidepressant overuse and supports a more selective, mechanism-informed application of pharmacotherapy.