The real-life treatment-resistant depression population is far more severe than what we expected

May 28, 2024

Written by Joao L. de Quevedo, MD, PhD

Treatment-resistant depression, a debilitating condition that affects millions worldwide, presents a formidable challenge in psychiatric care due to its resistance to conventional therapies. Despite advancements in pharmacological interventions, psychotherapy, and neuromodulation techniques, a significant subset of individuals with depression fails to achieve remission or adequate symptom relief. This persistent resistance not only prolongs suffering but also heightens the risk of functional impairment, disability, and even suicidal ideation. Addressing treatment-resistant depression requires a multifaceted approach, often involving careful medication adjustments, augmentation strategies, psychotherapeutic interventions tailored to individual needs, and emerging modalities such as ketamine infusion therapy or transcranial magnetic stimulation. Additionally, ongoing research into the neurobiological underpinnings of treatment resistance holds promise for developing more effective interventions, offering hope for those enduring the relentless grip of this challenging condition.

Vagus nerve stimulation (VNS) represents a cutting-edge therapeutic approach for various treatment-resistant neuropsychiatric disorders, including depression, epilepsy, and chronic pain. This innovative technique involves the implantation of a small device that delivers electrical impulses to the vagus nerve, a crucial component of the autonomic nervous system in regulating mood, cognition, and bodily functions. By modulating neural activity along the vagus nerve, VNS can profoundly affect brain circuits implicated in mood disorders, alleviating symptoms in individuals who have not responded adequately to traditional treatments. While the precise mechanisms underlying its therapeutic effects remain the subject of ongoing research, clinical studies have demonstrated promising outcomes, highlighting VNS as a valuable adjunctive therapy for those grappling with the challenges of treatment-resistant conditions.

RECOVER is a randomized sham-controlled trial of vagus nerve stimulation, the largest trial conducted with a psychiatric neuromodulation intervention. To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine.

Study investigators and an independent Study Eligibility Committee reviewed medical, psychiatric, and treatment records before qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus those not qualified (N = 228) for RECOVER and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE).

Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had more significant suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials.

RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance, with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT.

While we continue enrolling patients for the treatment-resistant bipolar depression arm, our team of statisticians is analyzing the data from the unipolar depression sample. We hope the upcoming results might facilitate patient access through streamlined insurance coverage.

Trial registration: Identifier NCT03887715.

Keywords: Electroconvulsive therapy (ECT); Esketamine; Ketamine; RECOVER trial; Transcranial magnetic stimulation (TMS); Treatment-resistant depression (TRD); Vagus nerve stimulation (VNS).

Reference: Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report. Conway CR, Aaronson ST, Sackeim HA, Duffy W, Stedman M, Quevedo J, Allen RM, Riva-Posse P, Berger MA, Alva G, Malik MA, Dunner DL, Cichowicz I, Luing H, Zajecka J, Nahas Z, Mickey BJ, Kablinger AS, Kriedt CL, Bunker MT, Lee YL, Shy O, Majewski S, Olin B, Tran Q, Rush AJ. Brain Stimul. 2024 Mar-Apr;17(2):448-459. doi: 10.1016/j.brs.2024.03.016. Epub 2024 Apr 2. PMID: 38574853