What are the indications, dosing regimens, contraindications, and alternative therapies for intravenous ketamine infusion in adults with treatment‑resistant mood disorders or refractory chronic pain?

Ketamine Infusion: Indications, Dosing, and Clinical Implementation

Primary Indications

Ketamine infusion is indicated for treatment-resistant depression (TRD) in adults who have failed at least 2 adequate antidepressant trials, and for acute suicidal ideation requiring rapid symptom reduction. 1, 2, 3 The 2022 VA/DoD guidelines represent a significant shift from 2016, now supporting ketamine/esketamine as a treatment option for patients with TRD, marking this as a major change in clinical practice. 1, 2

Treatment-Resistant Depression

• Ketamine should be considered when patients have failed at least 2 adequate trials of antidepressants (minimum 4-6 weeks at therapeutic doses). 1, 3
• Moderately severe depression on standardized rating scales is required before initiating therapy. 3
• For bipolar depression, ketamine must be added to mood stabilizers (lithium or valproate) to mitigate manic switch risk. 2, 3
• Response rates range from 25-85% at 24 hours and 14-70% at 72 hours post-infusion. 4

Acute Suicidal Ideation

• Ketamine produces rapid reduction in suicidal ideation beginning within 40 minutes, with effects lasting up to 10 days. 2, 3
• The VA/DoD guidelines specifically support ketamine for short-term reduction in suicidal ideation in patients with MDD. 1, 2
• The antisuicidal effects may be partially independent of general antidepressant effects. 2, 3
• Effect sizes are largest at 40 minutes (d=1.05) and remain moderate at 230 minutes (d=0.45). 2
• In patients with high baseline suicidal ideation, effect sizes are substantially larger (d=2.36 at 40 minutes). 2

Refractory Chronic Pain

• Ketamine has modest analgesic potential as an adjuvant to opioids in cancer-related pain, though evidence is limited. 1
• The NCCN guidelines note that ketamine may limit central sensitization, hyperalgesia, and opioid tolerance at sub-anesthetic doses. 1
• A double-blind RCT found no significant difference between ketamine and placebo for cancer pain, though systematic reviews suggest modest benefit. 1
• Ketamine may improve mood in individuals with depressive disorders comorbid with pain. 1
• For erythromelalgia and other chronic pain syndromes, ketamine infusion evidence is limited and controversial given adverse effects and abuse potential. 1

Treatment-Refractory PTSD

• A single IV infusion of ketamine 0.5 mg/kg over 40 minutes produces rapid reduction in PTSD symptom severity within 24 hours. 5
• Sub-anesthetic dosing yields therapeutic improvement with tolerable dissociative symptoms. 5
• Higher anesthetic-level doses may exacerbate PTSD symptoms through heightened psychomimetic effects. 5

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Standard Dosing Regimens

Intravenous Administration (Primary Route)

The standard evidence-based protocol is 0.5 mg/kg IV infused over 40 minutes, supported by the American Psychiatric Association. 2, 3, 6

Acute Phase Treatment

• Administer twice weekly until remission or completion of 4-6 total infusions. 2, 3
• Alternative schedule: three times per week for 2 weeks has been studied. 2, 3
• Response assessment should evaluate for ≥50% reduction in depressive symptoms at 24 hours post-infusion. 2, 3
• Antidepressant effects persist for 2-3 days after single infusion. 1, 2, 3
• Significant improvements remain through day 7 when added to ongoing antidepressant treatment. 1, 2

Alternative Dosing Strategies

• Lower doses (0.1-0.25 mg/kg) may be effective in some patients, particularly for acute suicidal ideation in emergency settings. 2, 3, 7
• Emergency department protocol: 0.2 mg/kg over 1-2 minutes has shown significant reductions in suicidal ideation for up to 10 days. 2, 3
• Higher doses up to 0.75 mg/kg may be required in non-responders. 7
• Slower infusion rates (0.5 mg/kg over 100 minutes) may provide similar efficacy with potentially better tolerability. 2

Maintenance Treatment

• Optimal maintenance frequency should be determined by monitoring for symptom return, typically occurring 2-7 days after single infusion. 2, 3
• Ketamine should be dosed a little before the effect of the previous session is expected to wear off. 7
• Treatment may be continued for weeks to years in refractory cases. 7

Intranasal Esketamine

• Esketamine requires REMS certification and mandatory 2-hour post-treatment monitoring. 2, 3, 8
• Twice-weekly dosing as augmentation to ongoing oral antidepressant improved depressive symptoms and remission rates at up to 28 days. 1
• Results were only seen in patients with TRD and those with new or optimized antidepressant therapy. 1
• Intranasal esketamine is less bioavailable than IV ketamine. 9

Other Routes (Less Studied)

• Intramuscular, subcutaneous, oral, sublingual, and transmucosal routes have demonstrated safety and efficacy but lack robust comparative data. 7
• Bolus administration is safe and effective when administered intramuscularly or subcutaneously. 7

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Contraindications and Precautions

Absolute Contraindications

• Uncontrolled hypertension or cardiovascular instability (ketamine causes transient increases in blood pressure and heart rate). 4
• Active psychosis or schizophrenia (risk of exacerbating psychotomimetic symptoms). 6
• History of ketamine abuse or active substance use disorder. 8, 6

Relative Contraindications and Monitoring Requirements

• Patients must be monitored for psychotomimetic effects, including hallucinations (20% at 0.5 mg/kg) and nightmares (12% at 0.5 mg/kg). 2, 3, 5
• Brief changes in blood pressure, heart rate, or respiratory rate may occur but are generally mild. 4
• Dissociative symptoms, hypertension, and confusion/agitation are tolerable and limited to around the time of treatment. 8
• Unlike benzodiazepines and opioids, ketamine preserves respiratory drive and functions as a bronchodilator. 5

Long-Term Safety Concerns

• Relatively little is known about longer-term effects, including increased risks of abuse and/or dependence. 1, 2, 3, 8, 6
• Concerns exist about potential excitotoxic neuronal injury at higher doses and with repeated use. 6
• Most evidence comes from small sample sizes with limited long-term follow-up. 1, 2, 3

Administration Requirements

• Ketamine administration requires trained professionals and hospitalization for at least 24 hours post-infusion in initial studies. 4
• An anesthesiologist typically infuses the medication in controlled settings. 4
• Esketamine requires administration under medical supervision per REMS requirements. 2, 3, 8

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Alternative Therapies

For Treatment-Resistant Depression

• Repetitive transcranial magnetic stimulation (rTMS) shows benefit for TRD with minimal adverse events, though access is limited due to frequent onsite visit requirements. 1
• Electroconvulsive therapy (ECT) is the most highly efficacious antidepressant treatment but may not provide reduction in suicidal ideation for 1-2 weeks. 2
• Traditional antidepressants like venlafaxine require weeks to months for therapeutic effect and do not provide rapid relief. 2

For Refractory Chronic Pain

• Intravenous lidocaine (1-3 mg/kg bolus over 20-30 minutes, then 0.5-2 mg/kg/hr continuous infusion) is an alternative for opioid-refractory cancer pain. 1
• Lidocaine may be especially useful for cancer-related neuropathic pain. 1
• Gabapentinoids (gabapentin and pregabalin) are first-line for chronic neuropathic pain. 1
• Topical analgesics have high safety due to low systemic absorption and should be considered whenever feasible. 1

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Clinical Pitfalls and Caveats

Common Mistakes to Avoid

• Do not use ketamine without confirming at least 2 failed adequate antidepressant trials (4-6 weeks at therapeutic doses). 1, 3
• Do not administer ketamine for bipolar depression without concurrent mood stabilizer therapy. 2, 3
• Do not assume antisuicidal effects will persist beyond 7-10 days without maintenance dosing. 2, 3
• Do not use ketamine outside supervised medical settings given REMS requirements and monitoring needs. 2, 3, 8, 4

Evidence Limitations

• The effectiveness of esketamine in preventing suicide or reducing suicidal ideation/behavior has not been established despite FDA approval for acute suicidal ideation. 1, 2, 3
• All controlled trials for depression have used within-subject crossover designs with inactive placebo, raising questions about placebo effects. 1, 4
• Optimal maintenance strategies are not well-established. 1, 2, 3
• For chronic pain, evidence is particularly limited with mixed results. 1

Practical Considerations

• Ketamine's redistribution half-life is about 2.5 hours, yet clinical effects last 2-3 days, reflecting sustained neuroplastic changes. 5
• The rapid onset makes ketamine particularly valuable as a bridge treatment for acutely suicidal patients until traditional treatments take effect. 2
• Treatment guidelines are needed to standardize ketamine use in psychiatric disorders. 6