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Yes. In this randomized trial, adding a structured 16-week CBT course to esketamine was associated with greater improvement in several longer-term measures of suicidal ideation and depression than esketamine with treatment as usual alone. By week 18, least squares mean change in BSSI was −6.01 with CBT versus −4.10 with TAU (mean difference −1.91; 95% CI, −3.57 to −0.24; P=.025), and composite MADRS change was −11.29 versus −7.52 (mean difference −3.77; 95% CI, −6.62 to −0.93; P=.009).

Clinician-rated suicide outcomes also favored CBT: CGI improvement changed by −1.00 versus −0.63 (mean difference −0.37; 95% CI, −0.68 to −0.05; P=.023), and CGI severity changed by −0.81 versus −0.49 (group difference −0.33; 95% CI, −0.58 to −0.08; P=.011).

Benefit was detected on the BSSI and CGI suicide severity measures, but not on the MADRS suicidal ideation item or the C-SSRS ideation score. At week 18, BSSI improved more with CBT than TAU (mean difference −1.91; 95% CI, −3.57 to −0.24; P=.025). CGI improvement and CGI severity also favored CBT, with mean differences of −0.37 (95% CI, −0.68 to −0.05; P=.023) and −0.33 (95% CI, −0.58 to −0.08; P=.011), respectively.

By contrast, the MADRS suicidal ideation item did not reach significance (mean difference −0.39; 95% CI, −0.84 to 0.06; P=.088), and the C-SSRS ideation-only score showed no group difference (0.13; 95% CI, −0.39 to 0.65; P=.623). The authors noted that the C-SSRS was the least sensitive of the suicidality measures for detecting group differences in ideation in this trial.

Across both groups combined, the mean MADRS score improved by 14.1 points from baseline to week 5 after the index esketamine course. The mean change was −14.1 points (SD=11.1), with an overall response rate of 26.5% and a remission rate of 10.8% at week 5.

The authors described these acute outcomes as modest in the context of severe baseline illness, which was one reason the trial examined a continuation strategy after the 4-week esketamine course.

Yes. The trial met its prespecified feasibility target for enrollment and retention, and CBT completion rates were high. Of 110 screened patients, 93 were randomized, which exceeded the protocol requirement of at least 80% of the target enrollment of 100. Retention was 84/93 (90.3%) through week 4, 72/93 (77.4%) through week 18, and 69/93 (74.2%) through week 26, meeting the prespecified retention threshold of 70% through week 18.

Among participants assigned to CBT, overall completion of all CBT sessions was 80.7%, and completion of the 9 computer-assisted CBT modules was 76.7%.

The CBT intervention was a 16-week program that combined individual face-to-face sessions with computerized lessons, starting in week 3 of esketamine treatment. It included 16–20 face-to-face sessions plus 9 computer-based modules integrated across the 16 weeks.

The therapy was based on the Beck model and included psychoeducation, cognitive restructuring, behavioral activation, and schema change. Sessions also incorporated mood check-ins, agenda setting, homework review, risk assessment, safety planning, and adaptation of CBT principles for suicide prevention.

No difference between groups was detected in the event-based survival analysis. The predefined event composite included suicide death, attempted suicide, hospitalization for a psychiatric indication, or a 75% or greater worsening from baseline in BSSI for 2 consecutive ratings, and the survival analysis showed no group difference (P=.790).

The authors stated that the trial was not fully powered to detect group differences in events, so this analysis was intended mainly to inform future study design.

This was a severely ill, high-risk sample that included many hospitalized patients and many with prior suicidal behavior. In the modified intent-to-treat sample (n=84), mean age was 38.0 years, 64.3% were female, and 61.9% were inpatients at enrollment. The mean baseline MADRS score was 39.0 (SD, 7.7), the mean 17-item Hamilton Depression Rating Scale score was 25.6 (SD, 3.8), and the mean number of antidepressant failures in the current episode was 3.9 (SD, 3.0).

In addition, 59.5% had a prior history of hospitalization and 45% had a lifetime suicide attempt, indicating that the study population was highly clinically relevant to settings managing acute suicide risk.

Serious adverse events occurred, but no serious adverse event was judged related or possibly related to CBT, and none was judged probably or definitely related to esketamine. There were 2 deaths during the trial: 1 suicide and 1 unintentional motor vehicle accident. Overall, 24 serious adverse events occurred, and 19/24 (79.2%) were psychiatric in nature.

Most psychiatric serious adverse events occurred in participants who were inpatients at enrollment (14/18, 77.8%). Seven serious adverse events were judged possibly related to esketamine. The most common adverse events were headache, nausea, and COVID-19–related symptoms or infections.

The main limitations were lack of patient blinding, limited statistical power, and potential confounding from differences in care between inpatients and outpatients. Although raters were blinded for MADRS and C-SSRS assessments, patients could not practically be blinded to whether they were receiving additional therapy, so expectation effects may have influenced outcomes.

The sample size was constrained by funding and was not fully powered to detect group differences in suicide-related events or even continuous outcome measures. The authors also noted that inpatients and outpatients received substantially different amounts of care, which may have confounded results, although randomization was stratified by inpatient versus outpatient status to mitigate this issue.

The findings suggest that when esketamine is used for major depression with suicidal ideation, adding evidence-based psychotherapy such as CBT may help improve longer-term outcomes. The authors concluded that esketamine combined with CBT led to better longer-term outcomes than esketamine without CBT on several measures of suicidal ideation and depression, while acknowledging that the trial was not large enough to be definitive.

They also noted that relapse risk after abrupt esketamine discontinuation is relatively high and that the period after psychiatric hospitalization carries extraordinarily high suicide risk, which supports including adjunctive psychotherapy in the treatment plan.