Ketamine and Esketamine in Depression

Introduction and Overview

In recent years, ketamine and its active enantiomer esketamine have revolutionized the approach to treatment-resistant depression, offering a rapid-acting alternative for patients unresponsive to conventional treatments. Originally developed as an anesthetic, ketamine is a compound with dose-dependent psychoactive effects and a mechanism of action entirely different from traditional antidepressants. Unlike SSRIs, SNRIs, or TCAs, ketamine does not act on monoaminergic systems, but exerts its effects through glutamate modulation and rapid neuroplasticity.

Esketamine, the S-enantiomer of ketamine, has received regulatory approval (e.g., FDA, EMA) in a nasal spray formulation (Spravato®) for the treatment of treatment-resistant depression and, in some cases, depression with acute suicidal ideation, in combination with an oral antidepressant.

Mechanism of Action

Ketamine is a non-competitive NMDA receptor antagonist (N-methyl-D-aspartate), a subtype of glutamatergic receptor. Blocking NMDA receptors on GABAergic neurons leads to disinhibition of glutamate release, which in turn activates postsynaptic AMPA receptors, stimulating the mTOR pathway (mammalian target of rapamycin) and promoting the rapid synthesis of neuroplastic proteins such as BDNF.

This effect results in synaptic remodeling, increased neuronal connectivity, and normalization of brain circuits involved in mood regulation, such as the prefrontal cortex and the limbic system. These changes occur within hours, explaining the rapid onset of antidepressant effect.

Indications and Clinical Use

The main clinical indications for ketamine/esketamine use include:

• Treatment-resistant major depression: lack of response to at least two antidepressants of different classes, at adequate doses and durations;
• Acute suicidal ideation: when immediate antidepressant effects are needed to reduce risk;
• Depression with severe vegetative symptoms (anergia, psychomotor retardation, abulia), often associated with significant fronto-limbic dysfunction.

Intranasal esketamine is approved in combination with an oral antidepressant for:

• Acute treatment of treatment-resistant depression (in controlled outpatient settings);
• Treatment of major depression with acute suicidal ideation (in monitored and protected environments);
• In adult patients, following multidisciplinary assessment and informed consent.

Administration

Ketamine can be administered in several ways, but the most studied and used psychiatric route is intravenous (IV), in subanesthetic doses (0.5 mg/kg over 40 minutes). The treatment is conducted in monitored hospital or outpatient settings, with medical staff present throughout the procedure.

Intranasal esketamine is administered via a single-use medical device, with doses of 56–84 mg per session, according to a tapering protocol (twice weekly in the initial phase, then weekly or biweekly for maintenance).

In both cases, a post-administration monitoring period of at least 2 hours is required to observe any acute adverse effects, including blood pressure changes, dissociation, anxiety, or nausea. Patients must not drive or operate heavy machinery for 24 hours after treatment.

Clinical Efficacy

Ketamine and esketamine have demonstrated rapid antidepressant effects in numerous studies, observable within hours of administration, peaking at 24–48 hours. Clinical response occurs in approximately 50–70% of resistant patients, with remission rates of 30–40%.

The duration of the effect varies: after a single dose, it may last several days; repeated cycles allow for more sustained stabilization. Esketamine, when used with antidepressants, has shown significant improvement in depression scores compared to placebo and a rapid reduction in suicidal ideation.

Side Effects and Safety

The most common acute side effects include:

• Dissociation (altered perception of body, space, or time);
• Dizziness and nausea, often transient;
• Increased blood pressure (systolic and diastolic), reversible;
• Acute anxiety or feeling of losing control, especially during the first session.

Long-term side effects are less well known but may include:

• Tolerance and loss of efficacy with prolonged use;
• Urothelial damage (with chronic high-dose use, as seen in recreational abuse);
• Psychological dependence, though rare under monitored clinical use.

For this reason, treatment should always be limited to specialized clinical settings, with active monitoring, regular reassessment of indications, and maintenance strategies including non-pharmacological approaches (psychotherapy, integrated follow-up).

References
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