Which Patients Respond to Ketamine vs ECT for Treatment-Resistant Depression?

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Outpatients and those with less severe depressive symptoms improved more with ketamine than electroconvulsive therapy (ECT) in a post-hoc analysis of the ELEKT-D trial¹ of the interventions for patients with treatment-resistant depression (TRD). Inpatients with more severe symptoms demonstrated greater initial improvement with ECT than ketamine, but those responses were comparable by the end of treatment.

"There is decisional uncertainty for patients with TRD and clinicians when selecting between ketamine and ECT," observed Manish Jha, MBBS, Center for Depression Research and Clinical Care, Department of Psychiatry, the University of Texas Southwestern Medical Center, Dallas, and colleagues.

"Therefore, identifying baseline, ie, pretreatment, features that may be associated with differential improvement with ketamine vs ECT may be helpful in shared decision-making approaches for patients with TRD," they explained.

The investigators considered a range of patient characteristics, from previous studies suggesting their potential for differential response to the interventions, including depression severity, cognitive functioning, concurrent use of benzodiazepine or of an atypical antipsychotic, obesity, history of attempted suicide, inpatient vs outpatient status at first treatment, and presence of anxious features or of comorbid posttraumatic stress disorder.

In discussing the study with Psychiatric Times, Jha explained that the distinction between inpatient and outpatient status reflected more than different levels of symptom severity.

"I believe that they are overlapping but not redundant, as inpatient hospitalization is often preferred for those with concern for safety risk, such as imminent risk of suicide,” Jha commented. "However, it is important to recognize that only 10% of the sample in the ELEKT-D study were inpatients, which likely reflects the practice of ECT in the US, where most courses of ECT for non-psychotic, treatment-resistant depression are initiated in outpatient setting."

Distinguishing Between Responders

Among the 365 participants in the analysis, 195 were randomized to receive ketamine and 170 to ECT. All had inadequate response to at least 2 courses of antidepressants and had initially been referred for possible ECT. Participants met criteria for major depressive disorder without psychotic features, with the current episode of at least 4 weeks duration and severity corresponding to Montgomery-Åsberg Depression Rating Scale (MADRS) score of >20.

The course of ketamine comprised a total of 6 infusions over 3 weeks, with each infusion over 40 minutes containing a subanesthetic dose of 0.5 mg/kg body weight. ECT was administered as a right unilateral ultrabrief pulse width at 6 times the seizure threshold (determined during titration at first visit), in 3 treatments per week for a total of 9 over 3 weeks. The ketamine dosage, and the settings and electrode placements in ECT could be modified as clinically indicated.

The primary outcome of the ELEKT-D trial was change from baseline on the Quick Inventory of Depressive Symptomatology (QIDS-SR16). Response was defined as a decrease of at least 50% from baseline at the end of treatment visit, and remission corresponded to a QIDS-SR16 score of <5 and MADRS of <10.

The investigators reported that those with less severe symptoms at baseline, corresponding to QIDS-SR16 of <20, and those starting treatment as outpatients had greater score reduction with ketamine (-7.7 and -8.4, respectively) than with ECT (-5.6 and-6.2 respectively). Conversely, inpatients with more severe symptoms marked by higher QIDS-SR15 at baseline responded better initially to ECT (-8.4) than ketamine (-6.7), but the measured improvement with each intervention was similar at the end-of-treatment visit (-9.0 and-9.9, respectively).

Additional characteristics which appeared to favor improvement with ECT over ketamine included comorbid PTSD diagnosis and higher premorbid intelligence, estimated with the North American Adult Reading Test-35 (NAART-35).

"While ketamine always had numerically higher response and remission rates compared with ECT, the difference between these 2 treatment groups was lower among those with an NAART-35 score of 85 or more,” the investigators reported.

Among nonstatistically significant, but intriguing numerical trends of differential response was higher BMI, related to obesity, associated with higher likelihood of remission with ketamine. In their mixed-effects model analyses, a higher BMI was also associated with greater reduction in both the QIDS-SR16 and the MADRS with ketamine.

"Given that obesity, as indexed by BMI, is associated with a pro-inflammatory state, I would like to see if elevated c-reactive protein (CRP)—an easy-to-measure and clinically available biomarker of inflammation—is associated with response to ketamine," Jha remarked. "We and others have previously shown² that elevated levels of CRP are associated with poorer outcomes with SSRI antidepressants."

In the final analysis, choosing between the 2 interventions for patients with TRD may rest more on differences in access than in baseline characteristics, Jha acknowledged. "In my personal experience, the strongest consideration in making this choice in clinical practice is the availability of off-label IV ketamine infusions at academic medical centers and their coverage by insurance.”

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. Jha MK, Wilkinson ST, Krishnan K, et al. Ketamine vs electroconvulsive therapy for treatment resistant depression. A secondary analysis of a randomized clinical trial. JAMA Netw Open. 2024; 7(6):e2417786.

2. Jha MK, Minhajuddin A, Gadad BS, et al. Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED Trial. Psychoneuroendocrinology. 2017;78:105-113.