Antidepressant drugs, starting with iproniazid and imipramine, entered psychiatry in the 1950s. Since then, dozens of other antidepressant drugs have been marketed and many withdrawn. These drugs include tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, norepinephrine reuptake inhibitors, and others. Despite the variety in mechanism of action, efficacy, adverse effect profile, metabolic pathways, and drug interactions, there is little difference in antidepressant efficacy between drugs, with dual serotonin and norepinephrine mechanisms potentially being marginally more effective than selective serotonin reuptake inhibitors.

The clinical outcomes with antidepressant drugs remain disappointing. For instance, the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial reported overall remission rates of 28%, 25%, 18%, and 10% for medication options at treatment steps 1, 2, 3, and 4, respectively. Despite many treatment options for medication-refractory patients, a breakthrough antidepressant akin to clozapine for schizophrenia has yet to be found. Ketamine, while not this breakthrough, has shown promise in recent years for its antidepressant properties, and this article will explore its use, focusing on efficacy, adverse effects, and mechanisms of action.

USES OF KETAMINE IN CLINICAL PRACTICE

Ketamine was introduced as an anesthetic drug about half a century ago. Since then, ketamine in subanesthetic doses has demonstrated efficacy for other off-label indications in adult and pediatric practice, including pain management in emergency settings, postoperative pain treatment, medication-refractory headache, reduction of agitation and violence in prehospital and emergency settings, and pediatric sedation in various settings. Additionally, subanesthetic doses of ketamine have shown rapid-onset efficacy in patients with severe and treatment-refractory depression.

KETAMINE FOR DEPRESSION: EFFICACY OUTCOMES

The psychotomimetic and other effects of subanesthetic doses of intravenous (iv) ketamine (0.1 and 0.5 mg/kg infused across 40 minutes) were demonstrated in healthy volunteers in 1994. Following this, Berman et al. conducted a small randomized, double-blind, placebo-controlled crossover trial of ketamine in patients experiencing a major depressive episode, finding a marked early antidepressant effect identifiable at 4 hours post-ketamine and persisting at 72 hours. Subsequent studies confirmed these findings, showing significant response and remission rates in patients with treatment-resistant major depressive disorder.

A meta-analysis of nine ketamine RCTs (pooled N = 234) found that ketamine significantly attenuated depression more than control treatments, with benefits peaking at day 1 and lasting up to 10-12 days. Although most efficacy data come from studies on major depressive disorder, some studies included patients with bipolar disorder as well.

THE EFFECT OF KETAMINE ON SUICIDALITY IN DEPRESSION

Open studies and RCTs have shown that ketamine can attenuate measures of suicidality in patients with treatment-resistant depression, though benefits may wear off within a week. It remains unclear whether ketamine has a specific antisuicidal effect beyond its general antidepressant properties.

USE OF KETAMINE AS AN AUGMENTATION AGENT

A study by Hu et al. examined the possibility of iv ketamine improving escitalopram outcomes in a 4-week RCT, finding significantly greater response and remission rates in the ketamine group. However, a meta-analysis of ketamine use during electroconvulsive therapy (ECT) found no improvement in antidepressant outcomes.

ADVERSE EFFECTS OF KETAMINE IN ANTIDEPRESSANT TRIALS

Subanesthetic doses of ketamine can produce transient dissociative symptoms, cognitive impairment, and psychotomimetic symptoms, though these effects are typically short-lasting and not clinically significant. Hemodynamic changes, such as transient increases in blood pressure and heart rate, can occur but are usually manageable. The adverse effects are dose-dependent and typically resolve within 4-24 hours.

STRATEGIES FOR ELICITING AND PROLONGING EFFICACY

For patients not responding to initial ketamine sessions, continuing treatment or increasing the dose may be effective. Maintenance treatment strategies involving repeated dosing at intervals can extend the antidepressant benefits for months to years.

STRATEGIES FOR THE CONTAINMENT OF KETAMINE ADVERSE EFFECTS

Managing neuropsychiatric and cardiovascular adverse effects often involves symptomatic intervention, such as administering antihypertensive drugs. Strategies like lowering the dose or extending the infusion duration can mitigate adverse effects, though this may compromise efficacy. Intranasal dosing may offer greater tolerability.

THE MECHANISM OF ANTIDEPRESSANT ACTION OF KETAMINE

Ketamine’s antidepressant action is thought to involve NMDA receptor antagonism and glutamatergic facilitation, though the exact mechanism remains uncertain. AMPA receptor up-regulation and activation of downstream neuroplasticity signaling pathways may also play a role.