Esketamine: A Novel Option for Treatment-Resistant Depression

Summary & key facts

This review summarizes evidence on intranasal esketamine for adults with treatment-resistant depression. When given along with an oral antidepressant, some short-term trials found small but statistically significant drops in depression scores at day 28 (about 3–4 points on the MADRS). Longer trials suggested benefits could be maintained with continued treatment. Common side effects included dizziness, altered taste, sleepiness, dissociation, suicidal thoughts or behaviors, and raised heart rate and blood pressure. The authors note cost, the need for supervised use, and diversion concerns may limit its role.

Key facts:

• The US Food and Drug Administration approved intranasal esketamine for adults with treatment-resistant depression, to be used together with an oral antidepressant.
• In the short-term trials TRANSFORM-1 and TRANSFORM-2, the fixed 56-mg esketamine arm reduced MADRS scores by −4.1 (95% CI = −7.69 to −0.49; P = 0.027 [exploratory]) at day 28.
• The flexible-dose arms in those trials showed a MADRS change of −4.0 (95% CI = −7.31 to −0.64; P = 0.02) at day 28.
• An 84-mg fixed-dose arm in TRANSFORM-1 had a MADRS change of −3.2 (95% CI = −6.88 to 0.45; P = 0.088), and another reported −3.6 (95% CI = −7.2 to 0.07; P = 0.059); these did not reach conventional statistical significance.
• Two longer trials (SUSTAIN-1 and SUSTAIN-2) suggested that symptom improvement could be maintained with continued esketamine use.
• Reported adverse effects included dizziness, dysgeusia (bad or changed taste), somnolence (sleepiness), dissociation, suicidal thoughts and behaviors, and increases in heart rate and blood pressure.
• The review states that tolerability concerns, cost, supervised administration requirements, and potential diversion are likely to limit esketamine's place in therapy.

Abstract

Objective:To review the pharmacology, pharmacokinetics, efficacy, safety, use requirements, and place in therapy of esketamine for treatment-resistant depression (TRD). Data Sources: A comprehensive PubMed search (1966 to October 2019) was conducted using the search terms depression, treatment-resistant, suicide, intranasal, esketamine, and JNJ-54135419. Additional data were obtained from references of identified articles, governmental sources, manufacturer product labeling, and Clinicaltrials.gov . Study Selection and Data Extraction: All English-language trials evaluating intranasal esketamine for TRD were included and discussed. Data Synthesis: Intranasal esketamine was approved by the US Food and Drug Administration, in conjunction with an oral antidepressant, for treating TRD in adults. Two short-term trials (TRANSFORM-1 and -2) found statistically significant reduction in the Montgomery-Asberg Depression Rating Scale score at day 28 for the fixed 56-mg dose (-4.1; 95% CI = -7.69 to -0.49; P = 0.027 [exploratory]) and flexible-dosed arms (-4.0; 95% CI = -7.31 to -0.64; P = 0.02), though the fixed-dose 84-mg arm (-3.2; 95% CI = -6.88 to 0.45; P = 0.088) of TRANSFORM-1 and TRANSFORM-3 did not (-3.6; 95% CI = -7.2 to 0.07; P = 0.059). Two long-term trials (SUSTAIN-1 and -2) suggested maintenance of response with continued use. Esketamine's adverse effects include dizziness, dysgeusia, somnolence, dissociation, suicidal thoughts and behaviors, and increased heart rate and blood pressure. Relevance to Patient Care and Clinical Practice: Although providing a novel antidepressant mechanism and formulation for TRD, esketamine's role in treatment will likely be limited by cost, administration, and diversion concerns. Conclusion: Intranasal esketamine significantly reduced depression symptoms in TRD, though with tolerability issues.

Topics

Neurotransmitter Receptor Influence on Behavior Treatment of Major Depression Tryptophan and brain disorders

Categories

Health Sciences Medicine Pharmacology

Tags

Adverse effect Anesthesia Antidepressant Clinical trial Depression (economics) Dysgeusia Economics Hippocampus Internal medicine Macroeconomics Medicine Somnolence Tolerability Treatment-resistant depression

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Sadness or low mood