Ketamine Infusion for Treatment-Resistant PTSD
Direct Recommendation
For adults with chronic PTSD refractory to trauma-focused psychotherapy and SSRIs/SNRIs, off-label IV ketamine at 0.5 mg/kg over 40 minutes, administered twice weekly for 2 weeks (total of 6 infusions), is an appropriate evidence-based intervention that produces rapid and clinically significant symptom reduction. 1
Evidence Base and Appropriateness
The first randomized controlled trial of repeated ketamine infusions in chronic PTSD (N=30) demonstrated that six infusions of ketamine 0.5 mg/kg over 2 consecutive weeks produced significantly greater PTSD symptom reduction than active placebo (midazolam), with a large effect size (d=1.13) and 67% response rate versus 20% for placebo. 1
A prior proof-of-concept RCT (N=41) established that single-dose ketamine 0.5 mg/kg produces rapid reduction in PTSD symptom severity within 24 hours compared to midazolam, with benefits evident across intrusion, avoidance, and negative cognition/mood symptom clusters. 2
While the 2022 VA/DoD guideline recommends ketamine/esketamine for treatment-resistant depression in patients who have failed multiple adequate antidepressant trials, this recommendation does not extend to PTSD specifically—ketamine for PTSD remains off-label but is supported by emerging RCT evidence. 3
Recommended Dosing Schedule
Standard protocol: Ketamine 0.5 mg/kg infused intravenously over 40 minutes, administered twice weekly for 2 consecutive weeks (total of 6 infusions). 1, 2
Continue all existing psychiatric medications (SSRIs/SNRIs, mood stabilizers) during ketamine treatment; discontinuation is not required and may reduce efficacy. 3
Clinical response typically manifests within 24 hours after the first infusion, with cumulative benefit building across the 2-week course. 1, 2
Expected Outcomes and Durability
Response rate: Approximately 67% of patients achieve clinically significant PTSD symptom reduction (defined as ≥30% decrease in CAPS-5 total score) after completing six infusions. 1
Durability: Among responders, the median time to loss of response is 27.5 days following completion of the 2-week infusion series, indicating that maintenance strategies are necessary to sustain benefit. 1
Ketamine demonstrates efficacy across multiple PTSD symptom domains including intrusions, avoidance, negative alterations in cognition/mood, and comorbid depressive symptoms. 2, 4
Mandatory Monitoring Requirements
Pre-Infusion Assessment
Screen for contraindications: uncontrolled hypertension, severe cardiovascular disease, increased intracranial pressure, acute psychosis, or active substance use disorder (particularly alcohol). 5, 4
Obtain baseline vital signs (blood pressure, heart rate, oxygen saturation) and document baseline PTSD symptom severity using a validated measure (e.g., CAPS-5 or Impact of Event Scale-Revised). 1, 2
During Infusion
Continuous monitoring of blood pressure, heart rate, and oxygen saturation throughout the 40-minute infusion, as ketamine causes transient sympathomimetic effects including hypertension and tachycardia. 5
Observe for emergence of dissociative symptoms, which are expected and typically peak during infusion but resolve within 1-2 hours post-infusion. 1, 2
Post-Infusion
Monitor vital signs and mental status for at least 2 hours after infusion completion until dissociative effects fully resolve and patient is ambulatory without assistance. 3
Assess for delayed adverse effects including persistent dissociation, perceptual disturbances, or mood changes before discharge. 1
Contraindications
Absolute Contraindications
Uncontrolled hypertension or severe cardiovascular disease, as ketamine produces dose-dependent increases in blood pressure and heart rate that may precipitate cardiovascular events. 5
Conditions associated with elevated intracranial pressure (e.g., intracranial mass, hydrocephalus), as ketamine increases cerebrospinal fluid pressure. 5
Active psychotic disorder or acute mania, as ketamine's psychotomimetic properties may exacerbate psychotic symptoms. 5
Relative Contraindications Requiring Careful Risk-Benefit Assessment
History of substance use disorder, particularly alcohol or sedative dependence, given ketamine's abuse potential and risk of psychological dependence. 5
Severe hepatic impairment, as ketamine has been associated with drug-induced liver injury in rare cases. 5
Pregnancy, as ketamine crosses the placenta and animal studies suggest potential neurotoxic effects on the developing fetus. 5
Adverse Effects Profile
Common Acute Effects (Occurring During or Immediately After Infusion)
Dissociative symptoms (depersonalization, derealization, perceptual distortions) occur in the majority of patients but are transient, peaking during infusion and resolving within 1-2 hours post-infusion. 1, 2
Hemodynamic changes including transient hypertension and tachycardia are expected pharmacologic effects that typically do not require intervention in patients without cardiovascular disease. 5, 1
Nausea occurs in a minority of patients and can be managed with antiemetics if needed. 1
Serious Adverse Events
No serious adverse events were reported in the two published RCTs of ketamine for PTSD, indicating a favorable safety profile when administered in controlled medical settings with appropriate monitoring. 1, 2
Respiratory depression is rare at subanesthetic doses (0.5 mg/kg) but requires monitoring, particularly in patients receiving concomitant CNS depressants. 5
Emergence reactions (agitation, confusion, hallucinations upon awakening) can occur but are minimized by allowing patients to recover in a quiet, low-stimulation environment. 5
Critical Pitfalls to Avoid
Do Not Use Ketamine as Monotherapy
- Ketamine should be administered as an adjunct to ongoing psychiatric medications (SSRIs/SNRIs, mood stabilizers), not as a replacement; discontinuing existing medications may reduce efficacy and increase relapse risk. 3, 1
Do Not Expect Sustained Remission Without Maintenance Planning
The median duration of response is only 27.5 days after completing six infusions, meaning that most patients will relapse within one month without a maintenance strategy. 1
Plan for maintenance treatment before initiating the acute infusion series; options include transitioning to intranasal esketamine (which has stronger long-term maintenance data) or continuing periodic ketamine infusions. 3
Do Not Administer Without Adequate Monitoring Capacity
- Ketamine must be administered in a setting equipped for continuous vital sign monitoring and management of potential cardiovascular or respiratory complications; outpatient office settings without monitoring equipment are inappropriate. 5, 1
Do Not Use in Patients with Active Suicidal Intent Without Appropriate Safety Planning
- While ketamine reduces suicidal ideation in depression, the PTSD trials excluded patients with acute suicidality; ensure adequate safety planning and support systems are in place before initiating treatment. 3, 1
Alternative and Complementary Treatments
Intranasal Esketamine
Esketamine (the S-enantiomer of ketamine) is FDA-approved for treatment-resistant depression and has stronger evidence for long-term maintenance compared to IV ketamine, though it is not FDA-approved for PTSD. 3
Esketamine requires REMS certification for the pharmacy and treatment site, plus mandatory 2-hour post-administration monitoring, making it more logistically complex than off-label IV ketamine. 3
Consider transitioning responders to esketamine for maintenance after completing the acute IV ketamine series, as esketamine has demonstrated sustained efficacy with twice-weekly dosing for up to 28 days. 3
Trauma-Focused Psychotherapy Remains First-Line
Even in treatment-refractory cases, do not abandon trauma-focused psychotherapy; evidence demonstrates that patients with complex PTSD, multiple traumas, and comorbidities benefit from trauma-focused treatment without requiring prolonged stabilization phases. 3
Consider combining ketamine with trauma-focused psychotherapy to harness ketamine-induced neuroplasticity for enhanced fear extinction and memory reconsolidation, though this approach requires further study. 6
Medications to Avoid
- Benzodiazepines should be avoided in PTSD treatment, as evidence shows 63% of patients receiving benzodiazepines developed PTSD at 6 months compared to only 23% receiving placebo. 3
Practical Implementation Algorithm
Verify treatment resistance: Document failure of at least one adequate trial of trauma-focused psychotherapy (e.g., Prolonged Exposure, Cognitive Processing Therapy, EMDR) plus trials of at least two SSRIs/SNRIs at therapeutic doses for adequate duration. 1, 2
Screen for contraindications: Assess cardiovascular status, intracranial pressure risk factors, active psychosis, and substance use history. 5
Obtain informed consent: Discuss off-label use, expected dissociative effects, need for post-infusion monitoring, and limited durability of response requiring maintenance planning. 1
Administer acute series: Ketamine 0.5 mg/kg IV over 40 minutes, twice weekly for 2 weeks (6 total infusions), with continuous vital sign monitoring and 2-hour post-infusion observation. 1
Assess response: Measure PTSD symptom severity 24 hours after the first infusion and weekly thereafter using a validated scale; response is defined as ≥30% reduction in symptom severity. 1
Plan maintenance: For responders, transition to intranasal esketamine or continue periodic IV ketamine infusions (e.g., weekly or biweekly) to prevent relapse, as median time to loss of response is only 27.5 days without maintenance. 3, 1
Continue psychotherapy: Maintain or reinitiate trauma-focused psychotherapy during and after ketamine treatment to maximize long-term outcomes. 6