Durability of symptomatic responses obtained with adjunctive vagus nerve stimulation in treatment-resistant depression

Abstract

Objective

To compare the durations of response achieved with adjunctive vagus nerve stimulation (VNS + TAU) vs treatment as usual (TAU) alone in treatment-resistant depression (TRD) over a 5-year period in the TRD registry.

Materials and methods

Data from 271 participants on TAU and 328 participants on VNS + TAU were analyzed. Response was defined as ≥50% decrease in baseline Montgomery–Åsberg Depression Rating Scale (MADRS) score at postbaseline visit and was considered retained until the decrease was <40%. MADRS was obtained quarterly in year 1 and biannually thereafter. Time-to-events were estimated using Kaplan–Meier method and compared using log-rank test. HR was estimated using Cox proportion hazard model.

Results

In the VNS + TAU arm, 62.5% (205/328) of participants had a first response over 5 years compared with 39.9% (108/271) in TAU. The time to first response was significantly shorter for VNS + TAU than for TAU (P<0.01). For responders in the first year, median time to relapse from first response was 10.1 months (Q1=4.2, Q3=31.5) for VNS + TAU vs 7.3 months (Q1=3.1, Q3=17.6) for TAU (P<0.01). HR=0.6 (95% CI: 0.4, 0.9) revealed a significantly lower chance for relapse in VNS + TAU. Probability of retaining first response for a year was 0.39 (0.27, 0.51) for TAU and 0.47 (0.38, 0.56) for VNS + TAU. Timing of the onset of the response did not impact the durability of the response.

Conclusion

VNS therapy added to TAU in severe TRD leads to rapid onset and higher likelihood of response, and a greater durability of the response as compared to TAU alone.

Keywords:

• depressive disorder
• treatment-resistant depression
• vagus nerve stimulation
• longitudinal study
• durability of response

Supplementary materials

Figure S1 A Kaplan–Meier plot for durability of first response in the first year for VNS + TAU participants by early and late responder.

Note: The trend in the probability of retaining the first response beyond 1 year was higher in the early responder group (ie, first response at 3 or 6 months after VNS initiation) compared with the late responder group (ie, first response at 9 or 12 months after VNS initiation).

Abbreviations: TAU, treatment as usual; VNS, vagus nerve stimulation.

Figure S2 A Kaplan–Meier plot shows the chance of a second response after relapse following the first response within the first year in both VNS + TAU and TAU.

Abbreviations: TAU, treatment as usual; VNS, vagus nerve stimulation.

Figure S3 A Kaplan–Meier plot demonstrates that the second response may be more durable with VNS + TAU versus TAU.

Abbreviations: TAU, treatment as usual; VNS, vagus nerve stimulation.

Figure S4 A Kaplan–Meier plot demonstrates that there was no difference in durability of the response in either treatment group based on the polarity of the depression.

Abbreviations: TAU, treatment as usual; VNS, vagus nerve stimulation.

Acknowledgments

The authors would like to thank the patients who participated in the TRD registry study, as well as the principal investigators and study staff. The registry was sponsored by Cyberon-ics, Inc. (currently LivaNova, PLC), through contracts to investigative sites. The authors appreciate the editorial support of Karishma Manzur, PhD, employee of Lenimen Consulting, Inc. ClinicalTrials.gov Identifier: NCT00320372.

Disclosure

Dr Kumar is an employee of LivaNova USA PLC. Dr Bunker is a former employee and a current consultant of LivaNova USA PLC. Mr Mordenti is an employee of LivaNova PLC. Dr Aaronson has received consulting fees from Genomind, LivaNova PLC, Alkermes PLC, and Neuronetics; research support from Neuronetics; and speaking fees from Neuro-crine Biosciences, Inc., Otsuka Pharmaceuticals Co., Ltd., and Sunovion Pharmaceuticals, Inc. Dr Conway has received research support from Bristol–Myers Squibb, The Stanley Medical Research Institute, the National Institute of Mental Health, NeoSync, Inc., Cyberonics, Inc., Taylor Family Institute for Innovative Psychiatric Research, American Foundation for Suicide Prevention, Assurex Health, Inc., August Busch IV Foundation, and The Foundation for Barnes-Jewish Hospital. He is currently serving as a research consultant for LivaNova PLC. Dr Rothschild has received grant or research support from Allergan PLC, Janssen, the National Institute of Mental Health, Takeda, Eli Lilly and Company (medications for a NIH-funded clinical trial), and Pfizer Inc. (medications for a NIH-funded clinical trial), is a consultant to Alkermes, GlaxoSmithKline, Sage Therapeutics, and Sanofi Aventis LLC, and has received royalties for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)^®; Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009; The Evidence-Based Guide to Antipsychotic Medications, American Psychiatric Press, 2010; The Evidence-Based Guide to Antidepressant Medications, American Psychiatric Press, 2012; and UpToDate^®. Dr Rush has received consulting fees from Akili, Brain Resource Inc., Compass Inc., Curbstone Consultant LLC, Emmes Corp., Johnson and Johnson (Janssen), Liva-Nova, Mind Linc, Sunovion, Taj Medical; speaking fees from LivaNova; and royalties from Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the inventory of depressive symptoms and its derivatives). He is also named coinventor on two patents: US Patent No 7,795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S, Wilson AS; and US Patent No 7,906,283: Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S. The authors report no other conflicts of interest in this work.