What is the recommended weekly dosing frequency of ketamine for treatment‑resistant depression and chronic pain?

Ketamine Dosing Frequency for Treatment-Resistant Depression

For treatment-resistant depression, ketamine should be administered 2–3 times per week during the acute induction phase (typically 6 infusions over 2 weeks), followed by once-weekly maintenance infusions for responders. 1

Acute Treatment Phase (Induction)

• Administer ketamine 3 times per week for 2 weeks (total of 6 infusions) during the initial treatment course for treatment-resistant depression. 1
• The median number of infusions required to achieve response (≥50% reduction in depression scores) is 3 infusions, with 59% of patients meeting response criteria after completing the full 6-infusion course. 1
• A single ketamine infusion produces rapid antidepressant effects within 24 hours, but these effects are transient, lasting only 3–12 days, necessitating repeated dosing. 2, 1
• Repeated infusions produce cumulative antidepressant effects, with response rates doubling compared to single-dose administration. 1

Maintenance Phase

• Once-weekly ketamine infusions maintain antidepressant response in patients who achieved remission during the acute phase, with no further improvement but sustained benefit during weekly maintenance. 1
• For long-term maintenance, dose ketamine a little before the effect of the previous session is expected to wear off, which typically translates to intervals of 2–4 days for most patients requiring extended treatment. 3
• Some patients may require maintenance treatment for weeks to months (or even years in refractory cases) to sustain therapeutic gains. 3

Standard Dosing Protocol

• The standard dose is 0.5 mg/kg IV infused over 40 minutes, though some patients respond to doses as low as 0.1 mg/kg, while others may require up to 0.75 mg/kg. 3
• Patients who do not benefit after the initial dose may respond to serial dosing or higher doses within this range. 2

Safety and Tolerability

• Adverse effects—including dissociative symptoms, psychotomimetic changes, and transient elevations in heart rate and blood pressure—are almost always mild, transient, and well-tolerated, rarely leading to treatment discontinuation. 2
• Co-administration with benzodiazepines (e.g., midazolam 0.05–0.1 mg/kg) minimizes psychotomimetic effects such as dysphoria, nightmares, and hallucinations. 4
• Continuous cardiac monitoring, pulse oximetry, and regular assessment of sedation level and respiratory status are required during infusion. 4

Contraindications

• Uncontrolled cardiovascular disease is an absolute contraindication. 4, 5
• Avoid ketamine in pregnancy, active psychosis, severe liver dysfunction, and elevated intracranial or intraocular pressure. 5

Clinical Algorithm

1. Screen for contraindications (uncontrolled hypertension, active cardiac disease, pregnancy, psychosis). 4, 5
2. Initiate acute treatment: 0.5 mg/kg IV over 40 minutes, 3 times per week for 2 weeks (6 total infusions). 1, 3
3. Assess response after 3 infusions; continue to 6 infusions if partial response is observed. 1
4. Transition responders to maintenance: Once-weekly infusions to sustain benefit. 1
5. Individualize maintenance frequency based on symptom recurrence, typically dosing before the previous session's effect wears off (every 2–4 days if weekly dosing is insufficient). 3
6. Monitor continuously during each infusion and consider benzodiazepine prophylaxis to reduce emergence phenomena. 4, 2

Important Caveats

• The evidence base for ketamine in depression is robust for short-term efficacy but limited for long-term safety, particularly regarding abuse potential and dependence with extended use. 6
• Esketamine (intranasal) is FDA-approved for treatment-resistant depression and requires administration under medical supervision per REMS guidelines, offering an alternative to IV ketamine. 6
• Oral ketamine has been studied in depression with doses ranging from 0.25–7 mg/kg, but bioavailability is poor (20–25%), and this route remains less well-established than IV administration. 7