What are ketamine's other off-label uses?

Ketamine's Off-Label Uses in Psychiatry

Ketamine's primary off-label use is for rapid reduction of suicidal ideation and treatment-resistant depression, with emerging evidence supporting its use in bipolar depression, PTSD, anxiety disorders, and substance use disorders. 1

Primary Off-Label Applications

Treatment-Resistant Depression (TRD)

• Ketamine at 0.5 mg/kg IV over 40 minutes produces rapid antidepressant effects in patients who have failed at least two adequate antidepressant trials. 1, 2
• The 2022 VA/DoD guidelines now support ketamine/esketamine for TRD, representing a significant shift from the 2016 recommendation against use outside research settings. 1
• Response rates reach 61% when used as add-on therapy to mood stabilizers. 1
• Antidepressant effects begin within hours, peak after approximately one day, and typically last 3-12 days after a single infusion. 2
• Serial dosing at 2-4 day intervals can maintain benefits for weeks to months. 2

Acute Suicidal Ideation

• Ketamine produces rapid reductions in suicidal ideation beginning as quickly as 40 minutes post-infusion, with effect sizes of d=1.05 at 40 minutes. 1
• In patients with high baseline suicidal ideation, effect sizes are substantially larger (d=2.36 at 40 minutes and d=1.27 at 230 minutes). 1
• The antisuicidal effects may be partially independent of ketamine's general antidepressant effects. 3, 1
• The VA/DoD guidelines specifically support ketamine for short-term reduction in suicidal ideation in patients with MDD. 1

Emergency Department Applications

• Lower doses of 0.2 mg/kg IV over 1-2 minutes have shown significant reductions in suicidal ideation lasting up to 10 days in ED settings. 3, 1
• In one ED study of 14 patients, suicidal ideation decreased significantly at 40,80,120, and 240-minute time points with no recurrence during 10-day follow-up. 3
• A separate ED trial of 49 patients showed 94% reported no suicidal ideation at day 10 following a single 0.2 mg/kg dose. 3
• This provides a bridge treatment for acutely suicidal patients until traditional treatments take effect. 1

Secondary Off-Label Applications

Bipolar Depression

• Ketamine/esketamine should be used as add-on therapy to mood stabilizers (lithium or valproate) to mitigate manic switch risk in bipolar depression. 1
• The American College of Physicians supports this approach with 61% response rates. 1
• Ketamine produces rapid and robust reduction in suicidal ideation in bipolar depression, with effects beginning within 40 minutes. 1
• Antidepressant effects persist for 2-3 days after single infusion and remain significant through day 7 when added to ongoing treatment. 1

PTSD and Anxiety Disorders

• Oral ketamine has shown potential benefits for PTSD and anxiety disorders, though evidence remains preliminary. 4
• Additional research is needed to establish optimal dosing protocols for these conditions. 4

Substance Use Disorders

• Intravenous ketamine has shown benefits in reducing relapse rates in substance use disorders. 4
• This represents an emerging area requiring further investigation. 4

Alternative Routes of Administration

Oral Ketamine

• Oral ketamine has 20-25% bioavailability but can be compensated by administering appropriately higher doses. 5
• Doses have ranged from 0.25 to 7 mg/kg and from 50-300 mg per occasion in various dosing schedules. 5
• Three randomized controlled trials show oral ketamine is effective for severe depression, depression with suicidal ideation, and treatment-resistant depression. 5
• Oral ketamine was well tolerated in all studies with dropout rates similar to control arms. 5
• This route is the most practical for mainstream psychiatry despite being less monetarily promising than IV or intranasal routes. 5

Other Routes

• Safety and efficacy have been demonstrated with sublingual, transmucosal, intranasal, intramuscular, subcutaneous, and rectal routes. 6
• Bolus administration is safe and effective when administered intramuscularly or subcutaneously. 6
• From a clinical practicability standpoint, subcutaneous, intranasal, and oral ketamine warrant further study. 6

Dosing Flexibility

Dose Range

• While 0.5 mg/kg is the standard dose, some patients respond to doses as low as 0.1 mg/kg, while others require up to 0.75 mg/kg. 6
• Lower doses (0.2-0.25 mg/kg) may provide antisuicidal benefits while minimizing psychotomimetic effects. 1
• Infusion duration can range from 2 to 100 minutes, though 40 minutes is conventional. 6

Maintenance Strategies

• Ketamine can be dosed a little before the effect of the previous session is expected to wear off for optimal maintenance. 6
• Treatment may be continued for weeks to years to extend and maintain treatment gains in refractory cases. 6
• Optimal maintenance strategies remain not well-established, representing a key limitation. 1

Critical Caveats

Abuse Liability

• Ketamine is a scheduled drug with significant abuse liability, and substance abuse is commonly comorbid with depressive disorders. 7
• The risk of substance abuse after repeat prescription cannot be ruled out with current evidence. 7
• Clinicians should attempt all standard antidepressant therapies before considering off-label ketamine use. 7

Monitoring Requirements

• Esketamine requires Risk Evaluation and Mitigation Strategy (REMS) certification and mandatory 2-hour post-treatment monitoring. 1
• Transient dissociative and psychotomimetic changes occur but are almost always mild and well tolerated. 2
• Transient elevation of heart rate and blood pressure often occur but very seldom cause treatment discontinuation. 2

Evidence Limitations

• Long-term efficacy and safety data remain limited, with most evidence from small sample sizes. 1
• The effectiveness of esketamine in preventing suicide has not been established despite FDA approval for acute suicidal ideation. 1
• Findings from tightly controlled research settings cannot be easily translated to clinical practice. 7