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

paryati/AdobeStock

Outpatients and those with less severe depressive symptoms improved more with ketamine than with electroconvulsive therapy (ECT) in a post hoc analysis of the ELEKT-D trial (NCT03113968),¹ which evaluated interventions for patients with treatment-resistant depression (TRD). Inpatients with more severe symptoms demonstrated greater initial improvement with ECT than with ketamine, but those responses were comparable by the end of treatment.

“There is decisional uncertainty for…clinicians when selecting between ketamine and ECT [for patients with TRD],” said Manish Jha, MBBS, and colleagues. “Therefore, identifying baseline—ie, pretreatment [and] features that may be associated with differential improvement with ketamine vs ECT—may be helpful in shared decision-making approaches for patients with TRD.”

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 benzodiazepines or an atypical antipsychotic, obesity, history of attempted suicide, inpatient vs outpatient status at first treatment, and presence of anxious features or comorbid posttraumatic stress disorder (PTSD).

In discussing the study with Psychiatric Times, Jha, an associate professor of psychiatry at the Center of Depression Research and Clinical Care at the University of Texas Southwestern Medical Center in Dallas, 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 nonpsychotic, treatment-resistant depression are initiated in outpatient settings.”

Distinguishing Between Responders

Among the 365 participants in the analysis, 195 were randomly assigned to receive ketamine and 170 to ECT. All had an inadequate response to at least 2 courses of antidepressants and had initially been referred for possible ECT. Participants met the criteria for major depressive disorder without psychotic features, with the current episode of at least 4 weeks duration and severity corresponding to a Montgomery- Åsberg Depression Rating Scale (MADRS) score of greater than 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 treatments over 3 weeks. The ketamine dose 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-SR-16). Response was defined as a decrease of at least 50% from baseline at the end-of-treatment visit, and remission corresponded to a QIDS-SR-16 score of less than 5 and a MADRS score of less than 10.

The investigators reported that those with less severe symptoms at baseline, corresponding to a QIDS-SR-16 score of less than 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-SR-16 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 that 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).

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

Among nonstatistically significant but intriguing numerical trends of differential response was higher body mass index (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-SR-16 and the MADRS with ketamine.

“Given that obesity, as indexed by BMI, is associated with a proinflammatory 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 said. “We and others have previously shown² that elevated levels of CRP are associated with poorer outcomes with [selective serotonin reuptake inhibitor] 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 explained. “In my personal experience, the strongest consideration in making this choice in clinical practice is the availability of off-label [intravenous] 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.