Meta-analysis finds intranasal esketamine boosts remission in MDD and TRD fast, but side effects and short trials leave long-term questions.
TRANSLATING RESEARCH INTO PRACTICE
Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, Column Editor
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Oraee S, Alinejadfard M, Golsorkh H, et al.
None.
To evaluate the effectiveness and safety of intranasal esketamine in treating MDD and TRD.
This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and included a search of 3 core databases (PubMed, Cochrane Library, and Embase) to identify relevant studies published in English language up until January 15, 2024. Eligible studies were randomized controlled trials (RCTs) of intranasal esketamine in adults with MDD or TRD diagnosed according to DSM‑IV‑TR or the DSM‑5 criteria. To be included, trials had to compare intranasal esketamine plus a newly started oral antidepressant with placebo plus the same kind of newly started antidepressant, and they had to report remission (primary outcome), response, and adverse events.
Remission was defined as participants achieving a total score of 12 or lower or 10 or lower on the Montgomery-Åsberg Depression Rating Scale (MADRS). The included studies variably assessed MADRS scores on days 8, 25, or 28. Response was defined as a MADRS total score reduction by at least 50% compared with baseline, which was also measured on days 8, 25, or 28.
Two reviewers independently assessed study quality using the Cochrane risk-of-bias tool, and a third reviewer was consulted for any discrepancies. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method was used to categorize the quality of evidence as high, moderate, low, or very low by assessing meta-analyses for risk of bias, inconsistency, indirectness, imprecision, and publication bias. The Egger regression test was also used to evaluate publication bias. A random-effects model was applied to handle heterogeneity.
A total of 9 RCTs were included in the study, totaling 1752 participants from across 16 countries. Six of the RCTs were focused on TRD, and 3 RCTs were focused on MDD with suicidal ideation. Study durations varied between 8 days (1 RCT), 25 days (3 RCTs), and 28 days (5 RCTs), and esketamine dosing ranged from 28 mg to 84 mg (some flexibly dosed) with all trials involving twice-weekly administration. All studies included random sequence generation, allocation concealment, and blinding of participants, personnel, and outcome assessment. All studies received funding from the same pharmaceutical company. Three studies showed discrepancies between their protocols and presented outcomes. Because of potential sources of bias from study funding and discrepancies in presented outcomes, the overall quality of included studies was determined to be low.
Intranasal esketamine significantly induced remission over placebo (relative risk [RR] = 1.371; 95% CI, 1.194-1.574; P < .0001). Subgroup analysis showed significant induction of remission with 84 mg (RR = 1.345; 95% CI, 1.136-1.591; P = .001) and flexible (RR = 1.662; 95% CI, 1.230-2.248; P = .001) doses but did not show significant induction of remission with 28-mg (RR = 1.186; 95% CI, 0.587-2.396; P = .635) or 56-mg (RR = 1.055; 95% CI, 0.654-1.703; P = .827) doses. Intranasal esketamine also demonstrated a significantly higher response rate in comparison with placebo (RR = 1.274; 95% CI, 1.108-1.465; P = .001). Subgroup analysis by dose showed a significantly higher response rate at day 25 or 28 only with the flexible dosing group (RR = 1.356; 95% CI, 1.105-1.664; P = .004). Meta-regression analysis showed no statistically significant correlation between different doses and either remission rate (P = .350) or response rate (P = .698). The Egger regression test found no evidence of bias for remission or response rate. GRADE scores were low (56-mg and 84-mg subgroups) or moderate (28-mg and flexible dose subgroups).
The following adverse events were more frequently observed in the intranasal esketamine group compared with placebo group: dissociation, nausea, vertigo, dysgeusia, dizziness, headache, somnolence, paresthesia, vomiting, blurred vision, anxiety, sedation, hypoesthesia, and elevated blood pressure.
1. The included RCTs were methodologically strong, and all studies used the MADRS as an outcome variable, which is a thoroughly validated tool.
2. The low statistical heterogeneity allowed for more reliable calculation of combined effect sizes.
3. The analysis included dosage subgroups, which allowed a more nuanced assessment of esketamine efficacy.
1. The overall quality of included trials evidence was low due to risk of bias, particularly regarding reporting and funding.
2. Short follow-up duration (≤ 28 days) limits the assessment of long-term efficacy and safety of esketamine.
3. Included studies carried a high risk of functional unblinding due to the acute dissociative effects of esketamine.
This meta-analysis demonstrated that intranasal esketamine in combination with oral antidepressant therapy rapidly and significantly reduces MADRS scores compared with a placebo group that was also receiving oral antidepressant therapy. Although certain adverse effects were more common in the esketamine group, these effects were typically transient and often resolved on the same day of administration.
For adults with MDD or TRD, intranasal esketamine used to augment oral antidepressant therapy may provide rapid symptom relief. However, clinicians should carefully consider cost, accessibility, and real-world feasibility, as treatment requires frequent clinic visits during initiation, Risk Evaluation and Mitigation Strategies monitoring, and supervised administration.
Intranasal esketamine is associated with short-term improvements in remission and response rates among individuals with MDD and TRD. However, independent studies with longer follow-up periods are needed to better establish long-term efficacy and safety of esketamine among individuals with TRD and MDD.
Dr Ratzloff is a first-year psychiatry resident at Creighton University in Omaha, Nebraska. Dr Coskun is a second-year psychiatry resident at Creighton University. Dr Wolatz is a third-year psychiatry resident at Creighton University. Dr Dickan is a fourth-year psychiatry resident at Creighton University. Dr Schuster is an assistant clinical professor of psychiatry at Creighton University School of Medicine. Dr Mullen is an assistant professor of psychiatry at Saint Louis University School of Medicine in Missouri. Dr Tampi is a professor and chair of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut, and a member of the Psychiatric Times editorial board.
Reference
Oraee S, Alinejadfard M, Golsorkh H, et al.
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