Ketamine and Esketamine for Treatment-Resistant Depression

Introduction to Ketamine and Esketamine

The FDA has approved esketamine (Spravato®) for treatment-resistant depression in adults, with a critical limitation that its effectiveness in preventing suicide or reducing suicidal ideation/behavior has not been established, as stated by the FDA and supported by the Annals of Internal Medicine 1

The 2022 VA/DoD Clinical Practice Guidelines suggest ketamine or esketamine as treatment options for patients who have failed at least 2 adequate antidepressant trials, representing a major shift from their 2016 position, according to the Annals of Internal Medicine 1, 2
The American College of Physicians, as reflected in the Annals of Internal Medicine, recommends that both ketamine and esketamine are explicitly NOT recommended as initial treatment but are reserved exclusively for patients who have failed at least 2 adequate pharmacologic trials at appropriate doses and durations 1, 3

Significant improvement in depressive symptoms occurs within 24 hours after single-dose ketamine administration, with effects persisting for 3-7 days when ketamine is added to ongoing antidepressant treatment, as reported in the Annals of Internal Medicine 1, 2
Esketamine as augmentation therapy (twice-weekly dosing) improves symptoms and remission rates up to 28 days, according to the Annals of Internal Medicine 1, 2
The most significant limitation is the absence of long-term safety and efficacy data for both formulations in MDD, as noted in the Annals of Internal Medicine 1, 3

Short-term adverse effects include dissociative symptoms, hypertension requiring blood pressure monitoring, sedation, and potential respiratory depression, as reported in Praxis Medical Insights: Practical Summaries of Clinical Guidelines 4
Concerns requiring ongoing surveillance include potential for abuse and misuse, unknown neurocognitive effects with long-term use, possible urologic toxicity with chronic administration, and risk of substance use disorder development, although these are not directly cited, the importance of monitoring is emphasized by the Annals of Internal Medicine 1, 3

The American Psychiatric Association acknowledges that standard antidepressant treatments do not provide robust and rapid relief of suicidal ideation, and even ECT may not reduce suicidal ideation for 1-2 weeks, highlighting the need for alternative interventions like esketamine 5, 6
Ketamine appears promising as a rapid-acting option in patients at imminent risk of suicide, with preliminary evidence from 2016 requiring further controlled trials for meaningful clinical recommendations 7

Open-label studies showed reduction in suicidal ideation with ketamine, with largest effect sizes at 40 minutes (d = 1.05), particularly in patients with high baseline suicidal ideation (d = 2.36) 6

The National Institute of Mental Health suggests that ketamine should be considered for patients with treatment-resistant depression who are at high risk of suicide, due to its rapid antidepressant effects 5, 6

The American College of Physicians recommends ketamine for acute symptom control in major depressive disorder only after the patient has failed at least 2 adequate antidepressant trials at appropriate doses and durations 8
Patients should continue or initiate second-generation antidepressants alongside ketamine, as recommended by the American College of Physicians 9, 10
The American College of Physicians guidelines explicitly state that ketamine should not be used as first-line therapy, and using it as such represents inappropriate use 8, 11

The American Psychiatric Association notes that while preliminary evidence suggested rapid reduction in suicidal ideation, studies had mixed results at different timepoints and were underpowered 9, 10, 12
The FDA explicitly states that the effectiveness of ketamine in preventing suicide or reducing suicidal ideation/behavior has not been established, as noted by the National Institute of Mental Health 9, 10, 12