What are the contraindications for using ketamine in patients with severe depression, particularly those with a history of schizophrenia, substance abuse, uncontrolled hypertension, cardiovascular disease, or increased intracranial pressure?

Ketamine Contraindications

Ketamine is absolutely contraindicated in patients for whom significant blood pressure elevation would constitute a serious hazard, and in those with known hypersensitivity to ketamine or its excipients. 1

Absolute Contraindications

• Conditions where blood pressure elevation poses serious risk 1:

  • Uncontrolled hypertension
  • Severe cardiovascular disease with hemodynamic instability
  • Recent myocardial infarction or unstable angina
  • Severe aortic stenosis
  • Dissecting aortic aneurysm

• Known hypersensitivity to ketamine or any excipient 1

• Elevated intracranial pressure - Ketamine increases cerebrospinal fluid pressure and should only be used in monitored settings with frequent neurologic assessments if intracranial pressure is already elevated 1

Relative Contraindications and Special Populations

History of Psychosis or Schizophrenia

Contrary to traditional assumptions, emerging evidence suggests ketamine may be both safe and effective in patients with psychotic features, though data remain limited. 2, 3

• Multiple case reports and pilot studies (41 patients total) demonstrate that short-term ketamine treatment in patients with psychotic depression or schizophrenia can be safe and effective, with mild, self-limiting side effects 2

• One case report showed robust anti-suicidal and antidepressant effects of S-ketamine in a patient with schizophrenia and severe post-psychotic depression, with no relevant psychotic or dissociative symptoms during treatment 4

• The current literature does not support the assumption that ketamine will exacerbate psychotic symptoms in predisposed patients, though further trials are needed 2

• Most clinical trials have historically excluded patients with psychotic features based on theoretical concerns rather than empirical evidence 3

Cardiovascular Disease and Hypertension

Ketamine produces transient, clinically insignificant blood pressure elevations in most patients, but requires careful monitoring in those with cardiovascular disease. 5, 6

• Blood pressure increases peak at 30-40 minutes during infusion, with mean increases of 7.4/6.0 mmHg systolic/diastolic 6

• In a large series of 684 infusions, no infusions were discontinued due to vital sign instability or adverse cardiovascular consequences 5

• Patients with pre-existing hypertension experience higher blood pressure peaks during infusions but these remain well-tolerated 5, 6

• Older patients (age ≥50 years), hypertensive patients, and those experiencing dissociative symptoms show greater maximal blood pressure changes 6

• Blood pressure returns to baseline during post-infusion monitoring 5

• Close monitoring of vital signs is mandatory when ketamine is co-administered with sympathomimetics or vasopressin, as these may enhance ketamine's sympathomimetic effects 1

Substance Abuse History

Substance abuse history is not an absolute contraindication, though concerns exist regarding repeated ketamine administration and abuse potential. 7

• Guidelines note concerns about repeated ketamine administration in patients with substance use disorders, but do not list this as an absolute contraindication 7

• The risk-benefit analysis should weigh ketamine's rapid antisuicidal effects against potential abuse liability 7

Critical Drug Interactions Requiring Caution

CNS Depressants

Concomitant use with opioids, benzodiazepines, or other CNS depressants may result in profound sedation, respiratory depression, coma, and death. 1

• Close monitoring of neurological status and respiratory parameters (including respiratory rate and pulse oximetry) is mandatory 1

• Consider dose adjustment based on individual clinical situation 1

Theophylline or Aminophylline

Consider using an alternative to ketamine in patients receiving theophylline or aminophylline, as concomitant administration may lower the seizure threshold 1

Additional Safety Considerations

Respiratory Depression

• Respiratory depression may occur with overdosage or rapid administration 1

• Adequate oxygenation and ventilation must be maintained 1

Procedures of Pharynx, Larynx, or Bronchial Tree

• Avoid ketamine as a sole anesthetic agent for procedures involving the pharynx, larynx, or bronchial tree, as it does not suppress pharyngeal and laryngeal reflexes 1

Hepatobiliary Dysfunction

• Ketamine is associated with hepatobiliary dysfunction (typically cholestatic pattern) with recurrent use 1

• Obtain baseline liver function tests (including alkaline phosphatase and gamma-glutamyl transferase) in patients receiving recurrent ketamine dosing 1

• Monitor liver function at periodic intervals during treatment with repeated dosing 1

Pediatric Neurotoxicity

• Published animal studies show that NMDA receptor antagonists may increase neuronal apoptosis in the developing brain when used for longer than 3 hours 1

• The window of vulnerability extends from the third trimester through approximately three years of age 1