Ketamine for depression: Where experts agree, and where they don’t

Clinical takeaway: Use supervised treatment, track symptom improvement, and reassess IV ketamine when benefit remains limited after eight infusions. Avoid high-dose benzodiazepines when feasible, and discourage compounded oral ketamine lozenges between sessions.

An American Society of Clinical Psychopharmacology (ASCP) task force reached consensus on just 35 of 105 questions about ketamine and esketamine, exposing substantial disagreement about everyday prescribing decisions. Published in The Journal of Clinical Psychiatry, the new statement reflects two Delphi rounds involving 21 international experts, with consensus requiring at least 75% agreement or disagreement.

“These findings should not be interpreted as clinical practice guidelines,” the authors caution. The report combines clinical experience with available evidence, and lack of consensus does not necessarily mean a treatment is ineffective or inappropriate.

Panelists supported IV ketamine or intranasal esketamine for treatment-resistant depression (TRD), either as adjunctive treatment or monotherapy, although they primarily favored adjunctive use. They also supported treatment for bipolar depression and major depressive disorder (MDD) with significant suicidal ideation, but opposed use for bipolar mania and advised discontinuation if manic symptoms emerge.

These expert opinions extend beyond approved indications: Ketamine’s psychiatric use and esketamine’s use for bipolar depression are off-label. Intranasal esketamine is approved for adult TRD as monotherapy or with an oral antidepressant; its separate indication for depressive symptoms in MDD with acute suicidal ideation or behavior does not establish suicide prevention or reduction of suicidal ideation or behavior.

Comparative efficacy remains unresolved: Experts could not establish whether IV ketamine and intranasal esketamine provide similar benefit or duration of response. The findings underscore the need to discuss uncertainty with patients rather than treat variable community prescribing practices as established standards.

Key Recommendations

• Start IV ketamine at 0.5 mg/kg infused over 40 minutes, twice weekly for a 3–4-week induction phase. Individualize subsequent doses; some patients may benefit above 0.5 mg/kg, but experts did not agree on dosing between 0.75 and 2 mg/kg and rejected claims of greater efficacy at doses of 2 mg/kg or higher.
• Reassess inadequate response after eight IV infusions; the panel supported stopping treatment when improvement from baseline is 25% or less. Long-term treatment is appropriate when benefit persists without concerning adverse effects, using the lowest effective maintenance frequency.
• Reduce intranasal esketamine frequency to no more than weekly after the first four weeks. The panel did not reach consensus supporting doses above 84 mg or on whether switching from IV ketamine prevents relapse.
• Avoid high-dose benzodiazepines when feasible because of potential interactions. Experts did not agree that benzodiazepines must be discontinued before treatment or that lamotrigine, opioid antagonists, memantine, or stimulants diminish antidepressant efficacy.
• Discourage compounded oral ketamine lozenges between sessions because high-quality safety and efficacy data are insufficient. Evidence also left experts divided on oral or intramuscular ketamine and the added benefit of ketamine-assisted psychotherapy.
• Do not initiate ketamine or esketamine at home, even with in-home monitoring. Check blood pressure before and during sessions; routine laboratory testing, ECGs, and urine toxicology did not achieve consensus.

Source: Sanacora G, et al. (2026 Nov 2) J Clin Psychiatry. Ketamine/esketamine in clinical practice: areas of consensus and non-consensus from an American Society of Clinical Psychopharmacology (ASCP) Delphi panel Task Force