Psychedelic Club Drug: A New Antidepressant?

Ketamine, used by club goers to hallucinate and trip, is being studied to treat depression. In fact, Allergan and Johnson & Johnson are studying drugs very similar to ketamine in late-stage clinical trials.^1,2

According to clinicaltrials.gov, Janssen Research & Development, LLC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, is the sponsor of several phase 3 clinical trials studying esketamine, all of which have been completed. For a list of clinical trials, refer to Table 1.³

In addition, several phase 3 clinical trials, sponsored by Allergan, are recruiting patients for rapastinel studies and are listed in Table 2.³

DEPRESSION THROUGH THE YEARS

The symptoms that define depressive conditions date back to the fifth century BC. Hippocrates attributed melancholia to the excess of black bile, from the spleen, one of the 4 basic humors.⁴ And through the years, the explanation for depression changed. It wasn’t until the 1950s that people started to be treated with medications for depression, helping to move the field of psychiatry away from electroconvulsive therapy. In 1952, Hoffmann-La Roche developed iproniazid to treat tuberculosis but serendipitously discovered its ability to improve people’s moods, and it became the first antidepressant.⁵

Dozens of antidepressants were approved in the decades that followed, including Eli Lilly’s “blockbuster” drug, Prozac, in 1987.¹

Chittaranjan Andrade, MD, a professor and head of the Department of Psychopharmacology at the National Institute of Mental Health and Neurosciences in Bangalore, India, noted that there is little difference in antidepressant efficacy among the available antidepressants, despite their differences in mechanism of action, adverse effects profile, and drug interactions.⁶

KETAMINE IN CLINICAL PRACTICE

Ketamine, approved and used as an anesthetic drug, when given in subanesthetic doses has demonstrated other off-label uses, such as the management of pain in emergency settings. In addition, ketamine, when given in subanesthetic doses, has been demonstrated as efficacious in treating severe and treatment-refractory depression. Ketamine’s antidepressant benefits have shown to be rapid onset. The benefits are typically seen within hours of administration, whereas conventional antidepressants typically take weeks to show antidepressant benefits. Ketamine’s antidepressant benefits typically peak after about a day and are lost between 3 and 12 days later.⁶

The most common dose of ketamine is 0.5 mg/kg intravenously. However, other patients may respond to doses as low 0.1 mg/kg, while some may require higher doses (up to 0.75 mg/kg).⁷ However, it is important to note that adverse effects are dose dependent, with the most common ones seen in clinical trials being blurred vision, dizziness, drowsiness, a feeling of unreality, and a lack of coordination.⁶ The dose is typically given intravenously over 40 minutes. Bolus administration of ketamine is possible if given intramuscularly or subcutaneously. Although ketamine can be administered by other routes, such as intranasally, orally, sublingually, and transmucosally, the intravenous therapy route has been the most extensively studied.⁷

Several studies have shown that a single treatment of ketamine given intravenously is effective. However, the studies have also shown that not everyone responds to a single administration. Based on several studies, if the initial session does not produce an adequate response, ketamine can be given once in 2 to 3 days for 4 to 6 treatment sessions. In patients who require continuation or maintenance, the dosing intervals are to be individualized (typically, once in 3 to 4 days in a modal patient). Because there are limited randomized controlled trials that compare different doses, the number of sessions, the intercession intervals, the rates of administration, and the routes of administration, definitive recommendations cannot be determined.⁷

(S)-KETAMINE VERSUS (R)-KETAMINE: DOES CHIRALITY REALLY MATTER?

Ketamine is a racemic mixture of (R) and (S) enantiomers in which (S)-ketamine (esketamine) has greater analgesic and anesthetic properties than its enantiomer. Some evidence has shown that (S)-ketamine, when administered either intranasally or intravenously, is effective in treating patients with treatment-refractory depression. However, it is important to note that no studies have been done to compare the (R) and (S) ketamine enantiomers with each other or with racemic ketamine.⁸

ESKETAMINE: THE ANTIDEPRESSANT OF THE FUTURE?

In the fall of 2016, the FDA granted a Breakthrough Therapy designation for Johnson & Johnson’s esketamine for the indication of major depressive disorder with imminent risk for suicide. This is not the first time that esketamine was granted this particular designation. In November 2013, the FDA granted a Breakthrough Therapy designation for esketamine for treatment-resistant depression.⁹ The recent Breakthrough Therapy designation was based on the phase 2 clinical trial data that Janssen presented at the Society of Biological Psychiatry 71st Annual Scientific Meeting in May 2016.⁹

Esketamine, a noncompetitive and subtype nonselective activity-dependent N-methyl-d-aspartate receptor antagonist, has a novel mechanism of action and is being studied as an intranasal formulation in several phase 3 clinical trials.⁹

It will be interesting to see the results from the several clinical trials sponsored by Allergan and Janssen Research & Development, LLC, that have either been completed or are recruiting. If esketamine and rapastinel are approved, they would be among the first new approaches to treat depression in the past 50 years.⁹

Anyssa Garza, PharmD, BCMAS, received her doctor of pharmacy degree from The University of Texas at Austin. She is the vice president of Content and Patient Education Programs at Digital Pharmacist and an adjunct assistant professor at The University of Texas at Austin College of Pharmacy.

References

• Oaklander M. New hope for depression. Time. time.com/4876098/new-hope-for-depression/. Published July 27, 2017. Accessed December 6, 2017.
• An expert's view on new CNS drugs, including Esketamine, SAGE-547, and SAGE-217 in PPD and MDD. Seeking Alpha. Published May 12, 2017. Accessed January 11, 2018. https://seekingalpha.com/article/4072727-experts-view-new-cns-drugs-including-esketa. mine-sageminus-547-sageminus-217-ppd-mdd. Accessed December 15th, 2017.
• ClinicalTrials.gov website. clinicaltrials.gov/ct2/home. Accessed December 6, 2017.
• Telles-Correia D, Marques JG. Melancholia before the twentieth century: fear and sorrow or partial insanity? Front Psychol. 2015;6:81. doi: 10.3389/fpsyg.2015.00081.
• Kreston R. The psychic energizer!: the serendipitous discovery of the first antidepressant. Discover. blogs.discovermagazine.com/bodyhorrors/2016/01/27/2081/#.WjWDCMMrJ-U. Published January 27, 2017. Accessed December 15, 2017.
• Andrade C. Ketamine for depression, 1: clinical summary of issues related to efficacy, adverse effects, and mechanism of action. J Clin Psychiatry. 2017;78(4):e415-e419. doi: 10.4088/JCP.17f11567.
• Andrade C. Ketamine for depression, 4: in what dose, at what rate, by what route, for how long, and what frequency. J Clin Psychiatry. 2017;78(7): e852-e857. doi: 10.4088/JCP.17f11738.
• Andrade C. Ketamine for depression, 3: does chirality matter? J Clin Psychiatry. 2017; 78(6):e674-e677. doi: 10.4088/JCP.17f11681.
• Esketamine receives breakthrough therapy designation from U.S. Food and Drug Administration for major depressive disorder with imminent risk for suicide [news release]. Titusville, NJ: Johnson & Johnson; August 16, 2016. jnj.com/media-center/press-releases/esketamine-recieves-breakthrough-therapy-designation-from-us-food-and-drug-administration-for-major-depressive-disorder-with-imminent-risk-of-suicide. Accessed December 6th, 2017.