Psychiatric Pharmacotherapy and the Problem of Mechanistic Validation: A Critical Review

Abstract

Psychiatric pharmacotherapy is among the most widely practiced and epistemically contested domains of contemporary medicine. Antidepressant consumption has risen significantly across OECD countries over the past decade, yet the neurobiological hypotheses used to justify these prescriptions remain unvalidated. This critical review examines the principal psychiatric drug classes, including antidepressants, antipsychotics, mood stabilizers, benzodiazepines and related anxiolytics, and psychostimulants. For each, the pharmacological composition, proposed mechanism, clinical goals, and evidence of effectiveness are reviewed. The central argument is that virtually none of these agents treats a confirmed biological cause of the disorder for which it is prescribed. The serotonin hypothesis of depression lacks consistent evidentiary support, the dopamine hypothesis of schizophrenia remains mechanistically inconclusive, and the catecholamine hypothesis underlying stimulant use in attention-deficit/hyperactivity disorder has not established a causal deficit. The serendipitous discovery of foundational psychiatric drugs, the substantial placebo response in antidepressant trials, publication bias, weak diagnostic validity, the physical health burden of long-term antipsychotic use, and benzodiazepine dependence are examined as compounding weaknesses in the field’s scientific foundations. Emerging treatments, including ketamine and psilocybin, show early promise alongside unresolved mechanistic questions. The review concludes with a call for epistemic transparency: symptomatic improvement, while clinically valuable, should not be presented to patients as mechanistic cure, and the gap between pharmacological effect and biological understanding should be openly acknowledged.