Spravato (Esketamine) and Suicidality
Spravato is FDA-approved for treating depressive symptoms in adults with major depressive disorder who have acute suicidal ideation or behavior, but its effectiveness in preventing suicide or reducing suicidal ideation/behavior has NOT been demonstrated. 1
Critical FDA Limitation
The FDA explicitly states that the effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated, despite its approval for this indication. 1 This represents a fundamental paradox in the drug's labeling—it is approved for use in patients with acute suicidal ideation or behavior, yet lacks proven efficacy for the very outcome that matters most: preventing suicide or reducing suicidal thoughts. 2
Approved Indication and Dosing for Suicidality
Spravato is indicated for depressive symptoms in adults with MDD who have acute suicidal ideation or behavior, used in conjunction with an oral antidepressant. 1
The recommended dosage is 84 mg twice per week for 4 weeks, with possible reduction to 56 mg twice per week based on tolerability. 1
Treatment beyond 4 weeks has not been systematically evaluated in patients with acute suicidal ideation or behavior. 1
Use of SPRAVATO does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose. 1
Evidence for Rapid Antidepressant Effects
Esketamine plus comprehensive standard of care demonstrated significantly greater improvement in depressive symptoms at 24 hours compared to placebo plus standard of care (least square mean difference -3.8), with effects observed as early as 4 hours. 3
The between-group difference for suicidality reduction at 24 hours was modest (-0.20) for all patients, but more pronounced (-0.31) in those with a history of suicide attempt. 3
Single-dose ketamine administration produces significant improvement in depressive symptoms within 24 hours, with effects persisting for 3-7 days when added to ongoing antidepressant treatment. 2
Critical Safety Requirements and Monitoring
Spravato carries a boxed warning for sedation, dissociation, respiratory depression, abuse/misuse potential, and suicidal thoughts/behaviors. 1
Mandatory Monitoring Protocol
Patients must be monitored for at least 2 hours at each treatment session under direct healthcare provider supervision, including pulse oximetry for respiratory status. 1
Blood pressure must be assessed before dosing and at approximately 40 minutes post-dose (corresponding with peak concentration), with continued monitoring until clinically stable. 1
Patients cannot be discharged until they are clinically stable, and must be instructed not to drive or operate machinery until the next day after restful sleep. 1
Contraindications
Absolute contraindications include aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage, and hypersensitivity to esketamine or ketamine. 1
Do not administer if baseline blood pressure is significantly elevated (e.g., >140/90 mmHg) and an increase in blood pressure poses serious risk. 1
Patient Selection Criteria
Esketamine should be reserved exclusively for patients who have failed at least 2 adequate antidepressant trials of different mechanisms of action at appropriate doses for at least 4 weeks each. 2, 4
It is NOT recommended as initial treatment for depression—patients who have not failed adequate antidepressant trials should not receive esketamine. 2, 4
For the suicidality indication specifically, patients must have MDD with acute suicidal ideation or behavior, and treatment must be combined with comprehensive standard of care including hospitalization when warranted. 1, 3
Common Adverse Effects
The most common adverse events (≥20%) include dizziness, dissociation, nausea, somnolence, and headache. 3, 5
48% to 61% of patients develop sedation, and respiratory depression has been observed in postmarketing experience. 1, 5
Most side effects are mild, transient, dose-dependent, and attenuate with subsequent treatments. 5
Long-Term Safety Concerns
The most significant limitation is the absence of long-term safety and efficacy data for both ketamine and esketamine in major depressive disorder. 2
Ongoing surveillance is necessary for potential abuse and misuse, unknown neurocognitive effects with long-term use, possible urologic toxicity with chronic administration, and risk of substance use disorder development. 2, 4
Case reports document drug-seeking behaviors and craving symptomatology in esketamine-treated patients, though the overall addictive potential remains controversial. 6
Clinical Context from Earlier Ketamine Literature
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. 7
Ketamine appears promising as a rapid-acting option in patients at imminent risk of suicide, but the evidence from 2016 was considered preliminary, 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). 7
Practical Implementation Algorithm
Confirm acute suicidal ideation or behavior in a patient with MDD who has failed at least 2 adequate antidepressant trials. 4, 1
Screen for contraindications (vascular disease, intracerebral hemorrhage history, significantly elevated baseline blood pressure). 1
Ensure comprehensive standard of care is in place, including hospitalization if clinically warranted and concurrent oral antidepressant therapy. 1
Initiate esketamine 84 mg twice weekly for 4 weeks (or 56 mg if tolerability concerns), administered under direct supervision with mandatory 2-hour post-dose monitoring. 1
Monitor for abuse potential, dissociative symptoms, blood pressure changes, and respiratory status at every treatment session. 1
Reassess therapeutic benefit at 4 weeks to determine need for continued treatment, recognizing that use beyond 4 weeks lacks systematic evaluation in this population. 1