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ABSTRACT
Treatment-resistant depression (TRD) is a problematic and prevalent public health and societal concern. Although electroconvulsive therapy (ECT) is the gold standard TRD intervention, the treatment evokes apprehension due to public perceptions, feasibility, and tolerability. Despite significant medical advancements, few medications have been approved by the U.S. Food and Drug Administration for TRD. In 2019, intranasal esketamine, the S-isomer of racemic ketamine, was approved for TRD, garnering significant excitement about the potential for the drug to act as an alternative treatment to ECT. The goal of this narrative review is to compare the safety, efficacy, and tolerability of ketamine and ECT; clarify whether ketamine is a reasonable alternative to ECT; and to facilitate improved treatment assignment for TRD. Empirical quantitative and qualitative studies and national and international guidelines for these treatments are reviewed. The field awaits the results of two ongoing large comparative effectiveness trials of ECT and IV ketamine for TRD, which should help guide clinicians and patients as to the relative risk and benefit of these interventions. Over the next five years we anticipate further innovations in neuromodulation and in drug development which broadly aim to develop more tolerable versions of ECT and ketamine, respectively.
Article highlights
The Food and Drug Administration has recently approved intranasal esketamine as a treatment for treatment resistant depression (TRD) and for depressive symptoms in adults with major depressive disorder with suicidal thoughts or actions.
In a narrative review, we compare electroconvulsive therapy (ECT) and ketamine in domains of safety, efficacy, and tolerability to determine whether ketamine provides a viable alternative to ECT for TRD. We also compare safety in pregnant, geriatric, and pediatric populations.
With the caveat that there are gaps in the research as to longstanding effects of ketamine, and to a certain extent ECT maintenance treatments, both treatments are determined to be associated with relatively low mortality rates in the general population. For both treatments, risk of suicide in this sometimes fatal disorder must be weighed with potential risk.
ECT may exert higher risk than ketamine in elderly populations due to higher comorbidities, and larger randomized comparative effectiveness trials are in progress.
Research examining ECT<apos;>s effectiveness is scarce for children under 12 years of age. However, ECT has been found to be relatively safe in children older than 12 years. Preliminary evidence suggests that ketamine is relatively safe in children older than 12 years in the short-term, particularly considering ketamine<apos;>s use as an anesthetic in children for many decades. Ketamine<apos;>s long-term safety remains to be determined, particularly considering the vulnerability of the developing human brain in childhood.
In pregnant individuals, ECT has a preferable safety profile, with ketamine not considered a viably safe option due to possible fetal effects.
Both treatments present with significant challenges in terms of feasibility, with considerable inconveniences incurred. Ketamine has a disadvantage in terms of accessibility and cost, and for the esketamine nasal spray restricted distribution practices under the Risk Evaluation and Mitigation System.
ECT appears to have better short-term tolerability, but worse long-term tolerability due to complaints of memory and other cognitive problems. Ketamine may have worse short-term tolerability given side effects such as nausea and dissociation, but better long-term tolerability than ECT. In contrast to ECT, there is evidence for immediate pro-cognitive effects. Ketamine also has better perceived tolerability compared to ECT, which may improve likelihood of treatment seeking in TRD.
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Declaration of interests
SJ Mathew reports consulting for Allergan, Alkermes, Axsome Therapeutics, BioXcel Therapeutics, Clexio Biosciences, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, and Signant Health; and research support from Biohaven Pharmaceuticals, Merck, NeuroRx, Sage Therapeutics, and VistaGen Therapeutics. SJ Mathew is supported using facilities and resources at the Michael E. Debakey VA Medical Center, Houston, Texas and receives support from The Menninger Clinic, Houston, Texas. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.