Reading the Esketamine Evidence for Treatment-Resistant Depression

Esketamine is the S-enantiomer of ketamine and an N-methyl-D-aspartate receptor antagonist, and in the United States, the branded nasal spray is approved under a restricted program for adults with treatment-resistant depression, as monotherapy or with an oral antidepressant. It is also approved, with an oral antidepressant, for depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior. Those indications should not be generalized to every ketamine formulation or depression presentation.

Define treatment-resistant depression#

Trials generally required major depressive disorder without psychotic features and inadequate response to at least two antidepressant treatments in the current episode, with additional prospective confirmation in some studies. “Inadequate” depends on dose, duration, adherence, and outcome definition. The label you meet in a clinic may be applied less rigorously.

Before interpreting effect, ask whether bipolar disorder, psychosis, or substance-use conditions were excluded. Ask whether unstable medical illness, imminent suicide risk, or other common complexities were excluded. Trial participants with severe symptoms can still be more selected and more closely monitored than the patients you meet in routine care.

Treatment resistance is not one biology. Misdiagnosis, unrecognized bipolarity, and trauma may contribute. So may medical illness, sleep disorder, and adherence. So may medicine interactions and social conditions. A trial entry rule does not settle an individual's diagnosis.

TRANSFORM-2 established an adjunctive short-term effect#

TRANSFORM-2 randomized 223 adults with treatment-resistant depression to flexible-dose intranasal esketamine or matching nasal placebo twice weekly for four weeks. Both groups also began a new open-label oral antidepressant.

Mean MADRS scores improved substantially in both groups: at day 28, the least-squares mean change was -21.4 with esketamine plus oral antidepressant and -17.0 with placebo spray plus oral antidepressant. The adjusted between-group difference was -4.0 points, 95% confidence interval -7.31 to -0.64, p=0.020.

The comparison is not esketamine versus no treatment. It estimates adding esketamine in a structured program while initiating an oral antidepressant, and the improvement in both groups reflects the new antidepressant, repeated care, expectation, natural course, and measurement as well as any spray-placebo effect.

Four points on MADRS can be meaningful to some people, but it is a group mean and smaller than the total improvement within either arm. Read it beside response, remission, and function. Read it beside quality of life, burden, and harms.

The initial trial program was mixed#

TRANSFORM-1 tested fixed 56 mg and 84 mg doses with a new oral antidepressant and did not meet its primary day-28 endpoint under the prespecified testing procedure. TRANSFORM-3 in adults 65 and older also did not meet its primary endpoint in the overall population. A failed trial is not erased by a later positive one.

FDA considered the total evidence, including short-term efficacy, a randomized relapse-prevention study, and safety data. That evidence also included rapid onset and the unmet need. When you see TRANSFORM-2 quoted on its own, remember that the rest of the program is part of the same evidence. Registration, analysis hierarchy, and multiplicity all matter here, because several doses, time points, response thresholds, and subgroups leave plenty of room to highlight a favorable finding after a primary failure.

The 2025 monotherapy trial answered a new question#

After an antidepressant-free period, the phase 4 TRD4005 study randomized adults in a 1:1:2 ratio to esketamine 56 mg, esketamine 84 mg, or matching placebo twice weekly for four weeks. It included 378 treated participants across 51 U.S. outpatient centers.

At day 28, the adjusted mean difference from placebo was -5.1 MADRS points, 95% confidence interval -7.91 to -2.33, for 56 mg and -6.8, -9.48 to -4.07, for 84 mg. Differences were also present about 24 hours after the first dose: -3.8 and -3.4 points, respectively.

This trial supports short-term efficacy without a concurrent oral antidepressant and underlies the expanded U.S. monotherapy indication, but it does not show that everyone should discontinue an existing antidepressant, that benefits persist without maintenance, or that other ketamine products are equivalent.

Common treatment-emergent events in the combined esketamine groups included nausea, dissociation, dizziness, and headache. The study was sponsored by the manufacturer, and many investigators reported financial relationships; disclosure does not invalidate the trial but heightens the value of protocol adherence and independent replication.

Rapid change creates both value and masking challenges#

Symptom differences can emerge within a day, much faster than the traditional expectation for many oral antidepressants. Rapid benefit may matter greatly in severe depression. The durability of that early change and the care required around each dose remain separate questions.

Esketamine commonly causes transient dissociation, perceptual changes, dizziness, sedation, and taste disturbance. Participants and staff may infer assignment despite a matching spray. This functional unmasking can influence symptom reporting, clinician ratings, co-interventions, and expectations.

So when you read “double-blind” here, it does not guarantee that masking succeeded. Trials should report guesses about assignment where collected and use trained raters separated from dosing when possible; an active placebo that fully mimics effects raises ethical and methodological complications and was not used in the pivotal program.

SUSTAIN-1 tested continuation among responders#

SUSTAIN-1 used a randomized-withdrawal design. Participants first received esketamine plus an oral antidepressant and had to achieve stable remission or stable response, and those who qualified were randomized to continue esketamine or switch to placebo spray while maintaining the oral antidepressant.

Among stable remitters, 26.7% continuing esketamine and 45.3% switching to placebo relapsed; the hazard ratio was 0.49, 95% confidence interval 0.29 to 0.84. Among stable responders without remission, the corresponding relapse proportions were about 25.8% and 57.6%, hazard ratio 0.30, 0.16 to 0.55.

This supports continuation for people who respond and tolerate induction; it does not tell you the probability that an unselected person starting esketamine will reach stable response, tolerate treatment, and remain well. That is enrichment.

Withdrawal designs can also be influenced by discontinuation effects, loss of treatment-related care, and functional unmasking after switching. The relapse definition and timing should be examined. The design answers a real maintenance question but not every long-term comparison.

Safety requirements are part of the intervention#

The FDA label has a boxed warning for sedation, dissociation, and respiratory depression. The warning also covers abuse and misuse, along with suicidal thoughts and behaviors applicable to antidepressant treatment in younger people. Blood pressure can rise after dosing, and people with conditions where an increase poses serious risk may not be candidates.

The product is administered only in certified healthcare settings under the SPRAVATO REMS. Patients self-administer under supervision and are monitored for at least two hours until clinically stable. They are instructed not to drive or operate machinery until the next day after restful sleep. Nasal dosing technique, pre-dose assessment, and blood-pressure checks are treatment burdens and safety components. So are respiratory monitoring, transport home, and staffing.

Esketamine is Schedule III and has abuse and misuse potential. Urinary symptoms, cognitive effects, and pregnancy require context-specific assessment. So do liver impairment, interactions, and long-term frequent use. Short randomized trials cannot exclude uncommon or cumulative harms.

Acute suicidal symptoms are a distinct indication#

Trials in major depressive disorder with acute suicidal ideation or behavior found rapid improvement in depressive symptoms when esketamine was added to comprehensive standard care and an oral antidepressant. Improvement on a depression scale is not the same as proven prevention of suicide or elimination of suicidal intent.

The FDA label explicitly states that effectiveness in preventing suicide or reducing suicidal ideation or behavior has not been demonstrated and that use does not preclude hospitalization when clinically warranted. Marketing language should preserve that limitation.

Anyone in immediate danger or considering self-harm needs urgent local crisis or emergency support, not interpretation of a trial article.

Esketamine nasal spray is not generic ketamine#

Racemic ketamine contains R- and S-enantiomers and is FDA-approved as an anesthetic, not for depression. Intravenous, oral, sublingual, and compounded nasal ketamine protocols differ. They differ in molecule, formulation, and bioavailability. They differ in dose, monitoring, and evidence.

Evidence for one cannot simply be transferred to another. Compounded products do not go through the same FDA approval review for safety, efficacy, manufacturing, and labeling. A clinic offering “ketamine therapy” should state exactly what product and regulatory status it uses. If it does not, ask.

Access and cost affect effectiveness#

Twice-weekly induction visits, observation, and transportation restrictions can limit uptake and continuity. So can certified-site availability, insurance authorization, and time away from work or caregiving. Trial adherence under sponsored, structured conditions may not represent routine care.

NICE did not recommend esketamine for treatment-resistant depression in its U.K. technology appraisal, based on uncertainties in clinical and cost effectiveness within that health system. FDA approval and a health-technology assessment answer different questions; one is not proof that the other is mistaken.

A practical appraisal sequence#

Identify indication, exact product, monotherapy or adjunctive use, prior treatment failures, and excluded conditions. Read the prespecified primary MADRS contrast rather than within-group improvement. Examine all pivotal trials, not one positive headline.

For maintenance, separate induction response from randomized continuation. Check masking, rater separation, and missing data. Check relapse definition, adverse events, and blood pressure. Check discontinuation, abuse monitoring, and sponsor role. Compare symptom change with function, quality of life, patient burden, and durability.

Finally, apply the label and local regulatory status as currently written. Do not generalize to other ketamine formulations or claim suicide prevention.