Ketamine Guidelines

Ketamine guidelines have recently been published by American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments. They highlight what we know and what we don’t know about this treatment.

What We Know

1. “Several studies now provide evidence of ketamine hydrochloride’s ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment.”
2. “To date, the strongest data supporting ketamine’s clinical benefit in psychiatric disorders are in the treatment of major depressive episodes without psychotic features associated with major depressive disorder. Even these data are limited by the fact that most of those studies evaluated efficacy only during the first week following a single infusion of ketamine. However, emerging studies suggest that repeated dosing can extend the duration of effect for at least several weeks… Most studies and case reports published to date on this topic have examined the effects of less than 1 month of treatment.”
3. Ketamine is being used more and more frequently in routine clinical care, including in Kaiser San Francisco.
4. Ketamine has a reasonable number of adequately designed short term research studies to support its effects.  See table below.

What We Don’t Know

1. “Although some limited data on the use of ketamine in treating other psychiatric diagnoses exist (eBox 1 in the Supplement), we do not believe there are sufficient data to provide a meaningful review of the assessment of risks and benefits of ketamine use in these other disorders at present.”
2. We don’t know what the effects of repeated ketamine infusion is beyond the first month… “there are extremely limited published data on the longer-term effectiveness and safety of ketamine treatment in mood disorders. This literature is confined to a few case series that do not allow us to make a meaningful statement about the longer-term use of ketamine. Several clinics providing such treatments are currently using a 2- or 3-week course of ketamine delivered 2 or 3 times
   per week, followed by a taper period and/or continued treatments based on empirically determined duration of responses for each patient. However, there remain no published data that clearly support this practice, and it is strongly recommended that the relative benefit of each ketamine infusion be considered in light of the potential risks associated with longer-term exposure to ketamine and the lack of published evidence for prolonged efficacy with ongoing
   administration. “
3. We particularly don’t know about cognitive effects… “Although there is strong evidence that ketamine can have transient adverse effects on cognitive function, and that chronic ketamine abuse is associated with cognitive impairment in several domains including verbal fluency, verbal memory, verbal learning, visual recognition memory, cognitive processing speed and deficits in working and episodic memory, the available studies examining the effects of ketamine treatment of mood disorders on cognition have not demonstrated any evidence of cognitive decline. However, these studies have a number of limitations including small numbers of subjects, and treatment periods of less than 1 month, limiting the ability to make strong claims on the relative risks of the treatment on cognitive performance. Considering the preclinical literature suggesting that ketamine could produce cognitive dysfunction and potentially even excitotoxic degeneration, and the limited safety data currently available, it is recommended that some assessment of cognition, probing several different domains function be used to follow patients receiving ongoing ketamine for the treatment of mood disorders.”
4. We know almost nothing about who will respond… “There is
   limited data to suggest slower processing speeds and increased baseline
   anxiety may predict greater response to ketamine treatment.”
5. We don’t know about drug interactions, but benzodiazepines may be a problem… “Based on a proposed mechanism of ketamine’s antidepressant action, whereby ketamine selectively inhibits the activation of subsets of GABAergic interneurons leading to increased levels of presynaptic glutamate release, it has been hypothesized that the concomitant use of benzodiazepines or other gamma amino butyric acid A (GABA A) potentiating agents may attenuate the antidepressant effects of ketamine.”

Recommendations

1. “Based on the known or suspected risks of cognitive impairment and cystitis associated with chronic high-frequency use of ketamine and the known substance abuse liability of the drug, assessments of cognitive function, urinary discomfort, and substance use should be considered if repeated administrations are provided.”
2. “Considering the known potential for abuse of ketamine and recent reports of abuse of prescribed ketamine for the treatment of depression, clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder. Close clinical follow-up with intermittent urine toxicology screening for drugs of abuse and inquiries about attempts to receive additional ketamine treatments at other treatment centers should be implemented when clinical suspicion of ketamine abuse is present.”
3. “…The number and frequency of treatments should be limited to the minimum necessary to achieve clinical response. Considering the evidence suggesting that the mechanism of action requires some delayed physiological effect to the treatment and does not appear to require sustained blood concentrations of the drug to be present, there is no evidence to support the practice of frequent ketamine administration.”
4. “Discontinuation of ketamine treatment is recommended if the dosing cannot be spaced out to a minimum administration of 1 dose per week by the second month of treatment. The goal remains to eventually taper and discontinue treatment until more long-term safety data can be collected.”
5. “A comprehensive diagnostic assessment should be completed to establish current diagnosis and evaluate history of substance use and psychotic disorders.”
6. “Assessment of baseline symptom severity should be completed to allow later assessments of clinical change with treatment”
7. “A thorough history of antidepressant treatment should be collected and documented to confirm previous adequate trials of antidepressant treatments”
8. “A thorough review of systems should be performed to evaluate potential risk factors associated with ketamine treatment”
9. Decisions on the specific physical examination and laboratory screening assessments should be made according to established guidelines and advisories issued by the American College of Cardiology Foundation/American Heart Association and the American Society of Anesthesiologists and should be based on a patient’s individual clinical characteristics… it is important to screen for baseline hypertension and tachycardia in order to anticipate potential cardiovascular complications of treatment, and to ensure that the patient has received adequate treatment for these conditions, if they do exist, prior to initiating treatment. It is also advised that some assessment of a patients’ exercise capacity be collected and documented.”
10. “A careful review of past medical and psychiatric records and/or corroboration of the past history by family members are strongly encouraged; all current medications and allergies should be reviewed, including histories of opiate and benzodiazepine use; the use of a baseline urine toxicology screen is strongly encouraged to ensure the accuracy of the reported substance use and medication record”
11. “An informed consent process, including discussion of the risks associated with the treatment, the limits of the available information pertaining to the potential benefits of the treatment, the fact that this is an off-label use of ketamine, and a discussion of alternative treatment options should be completed; this discussion should be complemented with written materials, and the patient should provide written informed consent before initiating treatment”

References

Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, Summergrad P, Nemeroff CB, for the American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry. 2017;74(4):399-405. doi:10.1001/jamapsychiatry.2017.0080