Side Effect Profiles and Discontinuation Rates of NMDA Receptor Antagonists in Treatment Resistant Depression

In this episode, Dr Anita Clayton and experts discuss safety profile and discontinuation of glutamatergic agents in TRD.

Panelists compared the side effect profiles of newer glutamatergic treatments against traditional antidepressants, highlighting important distinctions in both the nature and duration of adverse effects. Esketamine's side effects — including dissociation and sedation — are largely transient, occurring during the monitored in-office treatment session rather than persisting at home. Panelists noted that esketamine's strict REMS protocol, requiring a minimum two-hour post-administration monitoring period and a licensed healthcare professional on-site, exists precisely to manage these risks safely. Six-and-a-half-year long-term safety data was cited as providing strong reassurance — a level of evidence not available for adjunctive antipsychotics.

Discontinuation rates further distinguished these treatments. Esketamine demonstrated remarkably low discontinuation due to adverse events — approximately 2.8% in short-term monotherapy trials and under 6% in six-year open-label safety data. The five-year SUSTAIN3 data similarly showed only around 5–6% stopping due to lack of efficacy or tolerability concerns. Dextromethorphan-bupropion's discontinuation rate was somewhat higher at just above 10%, while certain adjunctive antipsychotics saw 10% discontinuation due to sedation alone.

Panelists emphasized that proactively educating patients about expected side effects — rather than allowing them to encounter surprises via online searches — is essential for maintaining trust, adherence, and overall treatment success.

In the next episode, “Esketamine Administration in Clinical Practice for Treatment Resistant Depression,” panelists discuss the practical realities of implementing esketamine in clinical practice, detailing the REMS protocol requirements, safety monitoring procedures, and administrative considerations that make in-office administration both manageable and rewarding.