How to Administer Ketamine or Esketamine for Bipolar Depression
How should clinicians structure an off-label ketamine or esketamine treatment course for patients with bipolar depression in a clinical setting?
Patients with refractory bipolar depression often have limited effective treatment options and may be considered for off-label ketamine or esketamine in specialty care. This guide applies to clinicians setting up or delivering a real-world treatment course modeled on the protocol described in Efficacy and Safety of Ketamine/Esketamine in Bipolar Depression in a Clinical Setting.
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Confirm appropriateness and complete pretreatment clearance
Evaluate the patient with an attending psychiatrist and confirm bipolar depression by clinical evaluation based on DSM criteria. Before treatment, obtain signed informed consent, emphasize that both ketamine and esketamine use for bipolar disorder are not FDA approved, and complete medical clearance including basic laboratory work, urine toxicology, electrocardiogram, and history and physical examination. If esketamine is used, enroll the patient in the FDA-required REMS program.
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Give pretreatment instructions
Instruct patients to fast for 2 hours before treatment. In general, advise them to avoid benzodiazepines in the 8 to 12 hours prior to dosing because the clinic protocol was based on theoretical concerns and limited prior evidence that benzodiazepines may attenuate ketamine's antidepressant effects. Most other medications are continued as normal on treatment days, and patients receiving either ketamine or esketamine should not drive on treatment days.
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Obtain baseline treatment-day measures
On arrival to the treatment suite, measure baseline blood pressure, heart rate, pulse oxygenation, respiratory rate, and temperature. For IV ketamine, insert a peripheral IV catheter before starting the infusion.
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Administer the selected formulation and dose
For IV ketamine, administer 0.5 mg/kg over 40 minutes. If body mass index is 30 or higher, adjust the ketamine dose based on ideal body weight. For intranasal esketamine, use 56 mg or 84 mg; the clinic generally used 56 mg as the starting dose for treatment-resistant depression and 84 mg for major depression with suicidal ideation.
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Use a twice-weekly acute series
Deliver treatments twice weekly during the initial course. Earlier in the clinic's history, some patients received 2 to 4 treatments twice weekly, but the protocol later shifted to twice weekly for up to 4 weeks, aligned with esketamine practice, for a total of up to 8 treatments.
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Monitor during and after each treatment
During ketamine or esketamine administration, monitor blood pressure, heart rate, and oxygen saturation intermittently. Observe patients after treatment initiation until they return to their pretreatment mental state. Assess dissociation with a modified Clinician Administered Dissociative State Scale immediately prior to discharge or return to the inpatient unit to help confirm discharge readiness.
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Track depressive symptom change across the series
Measure symptom severity with the Quick Inventory of Depressive Symptomatology-Self Report scale and the Montgomery-Asberg Depression Rating Scale at baseline and every fourth treatment thereafter. In this cohort, clinical response was defined as at least 50% improvement on MADRS and remission as MADRS 10 or lower following the acute series.
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Manage acute anxiety or nausea if needed
During treatment, lorazepam can be given as needed for severe anxiety and ondansetron can be given as needed for nausea. These were the as-needed supportive medications specifically described in the clinical protocol.
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Continue only if there is meaningful improvement
After the 4-week initial course, recommend weekly treatments for an additional 4 weeks for patients who achieve meaningful improvement. After that, taper to less frequent maintenance treatments as needed to maintain response or remission, generally every 2 to 4 weeks.
Clinical Considerations
- Both ketamine and esketamine were used off label for bipolar depression in this report.
- The study was a small, naturalistic, nonrandomized clinical cohort, so the protocol reflects real-world practice rather than a controlled comparative trial.
- Most patients received ketamine or esketamine with concurrent antipsychotics, lithium, or mood stabilizers rather than as monotherapy.
- Response and remission rates in this cohort were 39% and 13.2% after the acute series, lower than some prior small randomized ketamine trials in bipolar depression.
Bottom Line
In specialty practice, off-label ketamine or esketamine for bipolar depression was delivered as a medically cleared, monitored, twice-weekly acute series with structured symptom tracking and optional continuation only for patients with meaningful improvement.
