Intranasal Esketamine versus Intravenous Ketamine: An observational pilot study assessing efficacy and tolerability of two novel 'standard of care' treatments for treatment resistant depression in naturalistic clinical practice. Protocol for an observational pilot study (Preprint)

BACKGROUND Intravenous (IV) ketamine and intranasal (IN) esketamine have been studied as novel alternatives to manage treatment resistant depression (TRD). The objective of this observational pilot study is to compare the real-world effectiveness and tolerability of IV ketamine versus IN esketamine in the management of unipolar TRD. OBJECTIVE Compare the effectiveness (primary outcome measure) and tolerability (secondary outcome measure) of racemic ketamine and esketamine in the management of treatment-resistant depression in adults. Then, provide an expert qualitative commentary on the application of IV ketamine and IN esketamine in clinical practice (exploratory objective), focusing on recruitment process, patient retention, effectiveness, and tolerability of the treatments. METHODS This is a multicenter prospective observational study of naturalistic clinical practice. We expect to recruit 10 patients per treatment arm – IV ketamine or IN esketamine, per center (2 centers, total 40 subjects). Patients experiencing moderate to severe TRD and who are candidates for receiving low dose IV ketamine treatments or IN esketamine as part of their standard of care treatments will be recruited. We will measure the effectiveness of each treatment arm by measuring severity of depression symptoms using the Montgomery and Åsberg Depression Rating Scale (MADRS), tolerability, side effects, and the appearance of dissociation symptoms using the simplified 6-Item version of the Clinician Administered Dissociative Symptom Scale (CADSS-6) and potential for abuse using a Likeability and Craving Questionnaire (LCQ). RESULTS Change in depressive symptoms severity (by MADRS total scores) over time by treatment (IV ketamine or IN esketamine) will be evaluated by within-subject repeated measures ANOVA. Logistic regression will examine odds ratios, number needed to treat (NNT) for response and remission, number needed to harm (NNH) and likelihood to be helped or harmed (LHH) of each treatment. Covariate analysis will assess the impact of site and demographic variables on treatment efficacy. CONCLUSIONS We hypothesize both treatments will have comparable rapid and robust antidepressant effects and similar tolerability profiles in real world setting for the management of TRD.