Treatment-resistant depression (TRD) refers to major depressive disorder (MDD) that has not responded adequately to standard antidepressant treatments. While definitions vary, the most widely accepted criterion is failure to achieve adequate response (≥50% reduction in depressive symptoms) after at least two adequate trials of antidepressants from different mechanistic classes, given for sufficient duration (typically 6-8 weeks each) at therapeutic doses. TRD affects 30-40% of patients with MDD and is associated with substantial morbidity, mortality (particularly suicide), functional impairment, and economic burden. Risk factors include early age of onset, comorbid anxiety, substance use disorders, medical comorbidity, suicidal ideation, and certain personality disorders.
Ketamine, originally developed as a general anesthetic, was discovered to have rapid and profound antidepressant effects through NMDA receptor antagonism, AMPA receptor activation, increased glutamate release in the prefrontal cortex, BDNF upregulation, and synaptic plasticity enhancement. Unlike traditional monoamine-based antidepressants requiring weeks for full effect, ketamine produces antidepressant effects within hours, with peak response at 24 hours and sustained effects for 1-2 weeks. Intravenous racemic ketamine (0.5 mg/kg over 40 minutes) has been used off-label, while the S-enantiomer esketamine intranasal spray (Spravato) received FDA approval in 2019 specifically for TRD in conjunction with an oral antidepressant.
Modern protocols include induction phase with twice-weekly dosing for 4 weeks, followed by maintenance phase with weekly or biweekly administration based on response, with strict monitoring requirements including REMS (Risk Evaluation and Mitigation Strategy) program enrollment for esketamine. During and after each session, patients require monitoring for dissociative effects (typically peak 40 minutes post-dose, resolving within 2 hours), elevated blood pressure, sedation, and rare but serious effects including suicidal ideation, hepatotoxicity, and cystitis. Patients should not drive or operate machinery for the rest of treatment day. Comprehensive evaluation prior to initiation includes psychiatric assessment, suicide risk evaluation, substance use history, cardiovascular evaluation (especially with elevated BP), and discussion of benefits and risks. Emerging therapies include psilocybin-assisted therapy (FDA breakthrough therapy designation), MDMA-assisted therapy for PTSD, dextromethorphan-bupropion (Auvelity, FDA-approved 2022), and continued investigation of other novel mechanisms.