Ketamine – The Next Breakthrough for Depression?

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A Modern Epidemic

Major Depressive Disorder (MDD) affects an estimated 320 million individuals worldwide (16 million in the U.S. alone), and the incidence of this condition has increased substantially in the last decade. Further challenging psychiatrists, current pharmacologic therapies (MAO inhibitors, tricyclic antidepressants, and SSRIs) are limited by therapeutic lag times of up to weeks or months, and high refractory rates of approximately 30%. Patients with treatment-resistant depression face limited options, such as transcranial magnetic stimulation (r-TMS) or electroconvulsive therapy (ECT), and patients with suicidal ideation may remain at risk while they wait for a newly-prescribed antidepressant to take effect. In treating acute and treatment-resistant MDD, there is an unmet need for a rapidly-acting antidepressant.


Anesthetic Turned Club Drug

Ketamine was first synthesized in 1962 and approved by the FDA in 1970 for use as a short-acting general anesthetic. Since then, it has gained popularity as an anesthetic in the military and in acute care settings due to its rapid onset, short duration, and safety profile. However, ketamine has also gained popularity as a drug of abuse, due in large part to its dissociative and hallucinogenic effects, and it is listed as a Schedule III controlled substance.

In the 1990’s, the psychiatric community began to investigate the role of glutamate in depression, and a growing body of evidence pointed to disruptions in the glutamate system as a possible mechanism of depression. Ketamine, an NMDA receptor antagonist, was further studied under this mechanism, and in 2000 a placebo-controlled, double-blinded study demonstrated that patients receiving intravenous ketamine in subanesthetic doses experienced significant improvement in symptoms of depression within 72 hours of infusion.


A New Tool for Psychiatrists

Starting in 2016, MIEC began receiving inquiries from our members about the off-label use of ketamine either as an adjunctive treatment to facilitate psychotherapy sessions, or as a stand-alone antidepressant. Anecdotally, members reported that the dissociative effects of ketamine seemed to facilitate patients in making breakthroughs in therapy, and those patients tended to experience antidepressant effects that lasted for days after their treatment sessions.

Our research revealed that ketamine infusion clinics were quickly being established across the country. Some of these facilities were affiliated with pain clinics, and staffed by physicians experienced in the administration of ketamine in acute care settings, such as anesthesiologists and emergency medicine physicians; others were extensions of mental health centers and/or staffed by psychiatrists and psychologists.

Ketamine is typically administered in subanesthetic dosages through either IV infusion or intramuscular injection. More recently, ketamine has been available in sublingual lozenges produced by compounding pharmacies; this has become a popular route of off-label administration due to its ease of use and slower onset, as well as the ability to discontinue administration if the effect is not well-tolerated by the patient.

Based on discussions with MIEC members, there is some provider-to-provider variability in how these patients are managed. Patients receive IV or IM ketamine in a medical office or clinic, under the supervision of a licensed health care provider, with monitoring of vital signs and mental status. The patient may undergo psychotherapy with a psychiatrist or clinical psychologist while under the effect of the medication, or they may simply be monitored while under the effects which can last for several hours. With patients who self-administer ketamine in lozenge form, some physicians supervise those patients in the office with or without concurrent psychotherapy, which could be provided by a psychiatrist or clinical psychologist. After patients have demonstrated tolerance to ketamine, some providers have elected to provide them with lozenges to use at home for ongoing maintenance therapy.


Some Direction for Providers

In March 2017, the American Psychiatric Association (APA) issued a consensus statement on the use of ketamine in treating mood disorders.  The statement, based on research conducted to date on IV ketamine, made note of the relatively small sample sizes, lack of long-term efficacy data, and limited safety data associated with those earlier studies; based on this, the APA urged that providers remain cautious while exploring the possible benefits of ketamine in treating MDD.

The APA recommended the following:

  • Careful patient selection in terms of diagnosis and risks/benefits, noting that ketamine is most effective in the treatment of major depressive episodes without psychotic features associated with MDD.
  • Full Informed consent for patients including discussion of the risks/benefits and alternatives.
  • Managing clinician should be able to administer a Schedule III medication, manage potential blood pressure changes, and treat cardiovascular events requiring ACLS certification.
  • Managing clinician should be able to manage changes in mental status and emergency behavioral situations.
  • Mental health provider available on-site to evaluate patients for behavioral risks, including suicidality, before discharge.
  • Monitoring of patients during administration for basic cardiovascular (BP, ECG) and respiratory (O2, end-tidal CO2) function and ability to stabilize/treat any events (supplemental O2, medications, restraints).
  • “At this point of early clinical development, we strongly advise against the prescription of at-home self-administration of ketamine; it remains prudent to have all doses administered with medical supervision until more safety information obtained under controlled situations can be collected.”


Regulatory Approval, With Conditions…

On March 5, 2019 the U.S Food and Drug Administration (FDA) announced approval of Spravato (esketamine) nasal spray, which is the first ketamine-derived medication approved for the treatment of depression. Esketamine, which is the s-enantiomer of racemic ketamine, has been shown to exhibit greater affinity for the NMDA receptor and therefore a greater potential antidepressant effect.

Importantly, the FDA approved Spravato for use under the following conditions:

  • Eligible patients must have treatment-resistant MDD, defined as having failed at least two prior antidepressants.
  • Patients must be concurrently taking an oral antidepressant while undergoing treatment with esketamine.
  • Esketamine must be self-administered in a medical office, and the medication cannot be taken home.
  • Patients must be monitored by a health care provider for two hours following administration.
  • Esketamine will be controlled through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS).


Optimistic Caution

While there has been much optimism around both the off-label use of ketamine and FDA-approved esketamine for treatment-resistant depression, there remain some concerns about the long-term effects and risks surrounding this treatment.

First, the FDA approved Spravato on a fast track application, and the underlying Phase 3 study on which the FDA based its approval included some concerning findings. Out of three clinical trials included in the FDA study, only one study demonstrated a statistically significant effect compared to placebo. The most significant effect was noted at 24-48 hours, compared with lesser changes over the 4-week course of treatment. This evidence, when also considering the study included a concurrent oral antidepressant, potentially raises the question of whether ketamine has any utility beyond a bridging treatment when starting a new oral antidepressant.

Potentially more worrisome is the 40% relapse rate after discontinuing esketamine, and the three suicides that occurred in esketamine recipients following discontinuation of the study. While the FDA did not attribute the suicides to esketamine, this raises questions about appropriate length of therapy and the risks patients may face after discontinuation of treatment, potentially due to withdrawal syndrome.

There is also some evidence that ketamine’s antidepressant effects are mediated through opioid receptor activity. A study published in August 2018 found that patients receiving the opioid antagonist naltrexone experienced significantly less antidepressant effects (but undiminished dissociative effects) with subsequent IV ketamine infusion. This study adds to the concern around potential abuse and/or addiction issues around ketamine and esketamine.

To date, the APA has not issued any revised statements or guidelines since the 2017 consensus statement regarding IV ketamine.

On the other hand, there is an acknowledgement that limiting ketamine/esketamine treatment to formal medical settings might present a barrier to those that otherwise would benefit from treatment but cannot travel repeatedly to a physician’s office, due to logistical or other reasons. Currently, there are several efforts underway to seek FDA approval of similar medications; these include a sublingual ketamine lozenge for at-home use, and an oral NMDA antagonist that can be taken as a pill.


MIEC Recommends

MIEC recommends that esketamine, or ketamine when used off-label for the treatment of depression, should ideally be administered under the supervision of a psychiatrist. Advanced practice providers or physicians from non-mental health specialties who administer ketamine/esketamine for MDD should be working closely with a psychiatrist to manage patients’ underlying depression, the behavioral aspects of ketamine/esketamine administration, and transitioning patients off treatment when appropriate.

Until more research is completed, physicians administering ketamine or esketamine should consider doing the following to increase patient safety and minimize liability risk:

  • Screen patients carefully to ensure that they are appropriate candidates for treatment, and that they are not at increased risk for adverse events.
  • Conduct a full informed consent discussion including risks, benefits, and alternatives, and have patients sign a detailed patient information/consent form.
  • Depending on route of administration, monitor patients’ vital signs and/or mental status during sessions.
  • Develop a plan for responding to patients who poorly tolerate treatment.
  • Monitor patients for an appropriate amount of time (2hrs or so) following administration.
  • Store ketamine/esketamine in a safe, secure location.
  • Avoid providing ketamine/esketamine directly to patients for self-administration at home.