When several depression treatments have not helped enough, the next option can arrive wrapped in breakthrough language. Comparative trials support a more useful message: further improvement is possible, but no headline rate can select treatment for an individual. The population, comparison, outcome, adverse effects, and follow-up matter as much as the name of the intervention.
Key findings
27.1% versus 17.6%: eight-week remission in the 2023 ESCAPE-TRD comparison of esketamine and quetiapine strategies, each alongside an antidepressant. [1]
4.2% versus 11.0%: discontinuation because of adverse events in the corresponding safety populations. [2]
55.4% versus 41.2%: response in the separate three-week ELEKT-D comparison of intravenous ketamine with electroconvulsive therapy.
Response is not remission: these trials used different populations and endpoints. Their rates cannot form a single treatment ranking. [3]
A remission advantage is not a guarantee
Remission was reached by 91 of 336 participants versus 60 of 340. The absolute difference between the rounded percentages is 9.5 percentage points. Source: Reif and colleagues. [1]
The trial was open-label with blinded raters and funded by Janssen EMEA. It compared specified treatment strategies, not every ketamine-related product or delivery setting.
A family can recognize the between-group advantage while asking what happened to those who did not reach remission. A positive trial does not make remaining symptoms or later care needs disappear.
The adverse-effects table belongs beside the benefit
| Measure | Esketamine strategy | Quetiapine strategy |
|---|---|---|
| Received at least one dose | 334 | 336 |
| Any treatment-emergent adverse event | 91.9% | 78.0% |
| Stopped because of adverse events | 4.2% | 11.0% |
| Median proportion of days with adverse events | 11.9% | 21.3% |
Safety denominators differ from the randomized efficacy populations. Exploratory safety comparisons were not adjusted for multiple testing. Source: McIntyre and colleagues. [2]
More participants in the esketamine group reported an adverse event, while fewer discontinued because of one. Many events were mild or moderate and transient, with different duration and burden.
Neither percentage alone summarizes tolerability. Frequency, severity, duration, and reasons for stopping should all inform an individual discussion.
A second trial asked a different question
ELEKT-D randomized 403 people with nonpsychotic treatment-resistant major depression to intravenous ketamine or electroconvulsive therapy, known as ECT. After withdrawals before starting, 195 and 170 received the assigned treatments.
During the three-week phase, response occurred in 55.4% versus 41.2%. The reported difference was 14.2 percentage points, with a 95% confidence interval of 3.9 to 24.2. The trial supported noninferiority under its specified design. [3]
Response meant substantial symptom reduction. It was not the remission endpoint used in ESCAPE-TRD. Different populations, time windows, routes, and comparators prevent a simple ranking of all four rates.
| Feature | ESCAPE-TRD | ELEKT-D |
|---|---|---|
| Comparison | Esketamine versus quetiapine augmentation | Intravenous ketamine versus ECT |
| Headline endpoint | Eight-week remission | Response during a three-week phase |
| Population boundary | Defined treatment-resistant depression population | Nonpsychotic depression referred to ECT clinics |
| Cannot establish | The same result for all ketamine interventions | The same result for psychotic depression or every ECT pathway |
Before choosing the next treatment, reconstruct the previous ones
NICE’s further-line depression guidance recommends reviewing reasons for limited response and discussing appropriate next options. The assessment includes whether earlier treatment was adequately delivered, acceptable, and affected by other relevant factors. [4]
For someone treated in several countries, a list of medication names or therapy labels may be incomplete. Duration, dose, attendance, benefit, adverse effects, and reasons for change can all matter.
The proposed standard is one coherent history that supports the next decision. A label of treatment resistance should not replace that work or leave the patient repeatedly reconciling disconnected accounts.
The comparator matters as much as the intervention
Beating a waiting list is different from matching or outperforming an active treatment. Likewise, evidence for an intervention alongside ongoing medication should not be presented as evidence for the intervention alone.
A branded private package cannot borrow an entire trial result because one component shares the intervention’s name. The formulation, route, supervision, background treatment, and patient eligibility are part of what was tested.
For media coverage, the standfirst and chart caption should identify those boundaries. Readers should not need to reach the appendix to discover what the treatment was compared with.
Funding disclosure informs scrutiny, not a verdict
Commercial funding and conflicts should be visible. They do not automatically make a result false. Design, analysis, endpoint selection, and independent scrutiny still need examination.
A provider should not hide sponsorship when a study is favorable or invoke it selectively to dismiss an inconvenient result. Consistent standards are more useful than deciding whether evidence counts according to its conclusion.
Fast access should not bypass clinical fit
An affluent family may be able to obtain an appointment quickly or travel for a new option. Those resources change logistics, not the need for assessment.
The service should explain why the intervention fits, what benefits and burdens are expected, and which alternatives were discussed. It should also make the review plan clear if improvement is partial or absent.
None of these trials supplies an HNW-specific effect estimate. The relevance to your family’s decision is the quality of the assessment, not a claim that wealth changes the biological effect of treatment.
International availability is a separate question
A treatment studied in one country may have different authorization, prescribing, or funding arrangements elsewhere. A foreign trial is not evidence that the same pathway is permitted or appropriate in every market.
This article does not list current permissions for the UK, the United States, Europe, or GCC countries. Before cross-border treatment, the provider should check local requirements and explain monitoring and continuity after the person returns home.
Access to an intervention without an appropriate continuation plan deserves scrutiny. The initial appointment and the later pathway should be considered together.
A decision record is more useful than a breakthrough label
| Area | What should be clear |
|---|---|
| Clinical question | Which needs remain insufficiently addressed? |
| Evidence fit | How similar is the patient to those studied? |
| Expected benefit | Which outcome improved, by how much, and when? |
| Harms and burden | What adverse effects and monitoring are relevant? |
| Alternatives | Which other suitable options were considered? |
| Continuity | Who reviews progress and changes the plan? |
Progress should distinguish symptoms, functioning, unwanted effects, and the patient’s priorities. A predefined review point is different from continuing indefinitely without reassessment.
The same principle applies to reporting. Include people who stopped treatment and explain missing follow-up. A favorable result among responders should not be presented as the outcome for everyone admitted.
What the evidence cannot tell us
The trial percentages do not rank all depression treatments or predict an individual’s outcome. Response and remission differ. The routes, combinations, and clinical settings cannot be swapped without changing the question. Treatment changes should be discussed with the treating clinician, not made independently after reading a comparison.
The bottom line
Treatment resistance is not proof that further care is futile. Nor does a favorable trial guarantee recovery. The strongest next step is an informed, monitored decision that preserves the details behind the numbers and makes a plan for what happens next.
For journalists
Key contrast: comparative depression trials show meaningful differences, but their endpoints, populations, and safety findings cannot be reduced to one ranking.
Important caveat: eight-week remission and three-week response are not equivalent measures.
Suggested attribution: THE BALANCE analysis of published ESCAPE-TRD and ELEKT-D findings.
Methodology and sources
This narrative analysis compares selected trials and outcome definitions. Safety and efficacy denominators remain separate. No combined response rate, universal hierarchy, or THE BALANCE outcome estimate was produced.
