Esketamine nasal spray superior in achieving remission in patients with treatment-resistant depression

Reviewed by Megan Craig, M.Sc.Oct 5 2023

Both severe depression and treatment-resistant depression are common. Up to one third of patients do not respond to conventional therapy with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Treatment-resistant depression (in short TRD) leads to increased rates of comorbidity, suicide attempts and completions, all-cause mortality and hospitalization. In addition, the relapse rate among those affected is high, highlighting the need for effective and targeted therapies for TRD. Janssen Pharmaceutical Companies of Johnson & Johnson has recently completed an international randomized Phase IIIb study in scientific collaboration with University Hospital Frankfurt. The study compared the drugs and dosage forms of two combination therapies: One group was treated with SSRI/SNRIs in combination with esketamine nasal spray. In the comparison group, SSRI/SNRIs were administered together with quetiapine extended-release, as recommended by the National Disease Management Guideline on Unipolar Depression. The researchers established that the efficacy of esketamine nasal spray was superior in achieving remission at Week 8 (while still on study treatment) and in remaining relapse-free through Week 32 after remission at Week 8 (while still on study treatment) in patients who have TRD when both treatments were taken in combination with a continuing SSRI/SNRI.

Enhanced pharmacological effect

"If a patient does not show any improvement after two different antidepressant therapies over several weeks, we call this treatment-resistant depression, or TRD. Studies have shown that administering an additional drug can then be effective," explains Professor Andreas Reif, Principal Investigator in the study, first author of the primary manuscript now published and director of the Department of Psychiatry, Psychosomatics and Psychotherapy at University Hospital Frankfurt. "In the first instance, such an added drug does not need to have an antidepressant effect, but it can often improve or enhance the effect in combination with the previous SSRI or SNRI therapy. This is what was done in the comparison arm, using quetiapine XR in addition to ongoing SSRI/SNRI treatment." Esketamine, as known from Anesthesiology, has an analgesic effect, but at doses used here and with the kinetics of application through a nasal spray, it also has a distinct antidepressant effect, which is thought to happen through counteraction of reduced neuronal plasticity in the brain, which is generally observed in patients with TRD. 27.1 percent of patients in the esketamine nasal spray arm, who had on average been ill for over a year, went into remission at Week 8 while on study treatment, that is, experienced improvement to an extent that their depression severity reached the non-depressed range. In the quetiapine extended-release study arm, only 17.6 percent who achieved remission at Week 8. Both treatments were taken in combination with a continuing SSRI/ SNRI.

Retaining the edge with esketamine

Esketamine nasal spray is already used as a potent antidepressant. In previous studies, however, it was only compared in combination with a newly started SSRI/SNRI antidepressant therapy together with a placebo nasal spray, where it was already clear that the efficacy in the esketamine nasal spray group was significantly superior to that in the placebo group. In the study now published in the NEJM, quetiapine extended-release tablets serve as the comparator because they are already used for augmentation therapy and are also recommended in the guidelines. "In the group receiving esketamine nasal spray were 54% relatively more patients to experience remission at Week 8 than those receiving quetiapine extended-release. This is a good result for a group with treatment-resistant depression, that is, who have a poor prognosis," says Profesor Reif. "In the relapse rate, too, which we monitored after six months, those patients treated with esketamine retained the edge over those treated with quetiapine."

About the ESCAPE-TRD Ph 3b study

The Janssen Pharmaceutical Companies of Johnson & Johnson, respectively the Belgium-based affiliate, Janssen Pharmaceutica NV, was responsible for designing and coordinating the study. Scientists from Janssen's research departments in several European countries and the US made a significant contribution to implementing the study. A total of 171 facilities took part in the open-label, randomized, rater-blinded and multicenter study. Hospitals, inpatient and outpatient departments as well as research centers in 24 countries were able to incorporate almost 700 patients in the study. Alongside the Department of Psychiatry, Psychosomatics and Psychotherapy at University Hospital Frankfurt, the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP in Frankfurt was also involved. The joint objective was to assess the efficacy, safety and tolerability of esketamine nasal spray in comparison to quetiapine extended-release, both in combination with ongoing SSRI/SNRI therapy, in patients with TRD. As predicted and hoped, patients in the esketamine nasal spray study arm showed better results across the study endpoints.