Esketamine: A Novel Option for Treatment-Resistant Depression

Summary & key facts

Researchers reviewed evidence on intranasal esketamine as a new option for adults whose depression did not get better with usual treatments. They looked at short-term and long-term trials and found that, when used together with an oral antidepressant, esketamine gave a small but real extra drop in depression scores in some trials. Ongoing use seemed to help keep the benefit in longer trials. However, the drug can cause dizziness, strange tastes, sleepiness, feeling detached from yourself, raised heart rate and blood pressure, and even new or worse suicidal thoughts. Its real-world use will also be limited by cost, the need for supervised dosing, and concerns about people diverting the drug for misuse.

Key facts:

• Esketamine is an intranasal medicine approved for adults with treatment-resistant depression when given with an oral antidepressant.
• Two short-term trials found a small but statistically significant improvement in depression scores for some dosing groups, roughly a four-point greater drop on a standard depression scale compared with control.
• One higher-dose group and one of the short-term trials did not show a clear benefit, so results were not the same across every dose and study.
• Two longer trials suggested that people who kept using esketamine maintained their improvement over time.
• Common side effects reported included dizziness, changed taste, sleepiness, and a sense of dissociation or feeling detached.
• Serious concerns reported included increases in suicidal thoughts or behavior, higher heart rate and blood pressure, plus practical limits such as cost, required supervised administration, and risk of diversion or misuse.

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 Poor sleep Sadness or low mood