By: Daniel Levin, PharmD candidate c/o 2022

              Depression is a terrible beast of an illness to battle with, and there are nearly 14 million individuals at any given moment fighting it. Only around 50% of patients struggling with depression will get some form of treatment. Sixty to seventy percent of patients who do get treatment will show an adequate response, with 10-30% of patients showing an inadequate response. The latter group of patients are said to have treatment resistant depression. This is more accurately defined as experiencing a poor or unsatisfactory response to two trials of two different classes of antidepressants at optimal dosing and duration. This failure in treatment, just like that seen with untreated depression, can greatly affect the patient and lead to functional impairment, poor quality of life, suicide ideation and attempts, and self-injurious behavior.¹ For this reason, any “weapons”, so to speak, that we can develop and use against treatment resistant depression would be a great victory.

Treatment resistant depression is managed by either changing, increasing, or adding antidepressant regimens. Currently, there are few options targeted for treatment resistant depression. Ketamine and esketamine, schedule III analgesics, are two such examples. Ketamine has been shown to be effective, off-label, in treating severe resistant depression. It is administered initially as a single intravenous injection of 0.5 mg/kg over 40 minutes or can also be given as a course of repeated infusions administered 2 to 3 times per week for a total of 4 to 8 infusions.⁹ It should not be used in patients with substance use disorders, due to its high risk for abuse. Ketamine can additionally cause profound sedation and respiratory depression. Esketamine (Spravato®) has Food and Drug Administration (FDA) approval for treatment for resistant depression, and is given as a series of intranasal doses. More specifically, it is given as an adjunct to an oral antidepressant and is given as a loading dose of 56 mg intranasally on day 1 followed by 56 or 84 mg twice weekly for 4 weeks. As maintenance therapy, it is dosed as 56 or 84 mg once weekly during weeks 5 through 8, then 56 or 84 mg every 2 weeks or once weekly starting week 9 and onward. Esketamine is contraindicated in patients with a history of intracerebral hemorrhages or aneurysmal vascular disease. Like ketamine, esketamine has potential for abuse and respiratory depression. It is important to note that because of the above-mentioned safety concerns, patients cannot simply pick up a month supply of this medication from their neighborhood pharmacy. Esketamine is subject to REMS program requirements, and must be administered in a physician’s office by a healthcare provider enrolled in the REMS program. After receiving a dose, the patient must be monitored for 2 hours for emergence of adverse effects.^6,9

Recent studies have showed the potential for another treatment option for treatment resistant depression. AXS-05 is an investigational drug combination of dextromethorphan and bupropion, developed by Axsome Therapeutics. Dextromethorphan acts as an NMDA receptor antagonist, an ionotropic glutamate receptor, and a sigma-1 receptor agonist. Bupropion, which is a norepinephrine and dopamine reuptake inhibitor, serves primarily to increase the bioavailability of dextromethorphan.² The MERIT (Mechanistic Evaluation of Response in TRD) trial was a randomized, double-blind, placebo-controlled multicenter study in the United States. This study included 44 adults recruited from a long-term open label phase 3 trial for AXS-05, who were stable for at least 12 months after treatment and were randomly assigned to a placebo group or the AXS-05 group (45 mg dextromethorphan/105 mg bupropion twice daily). Stable remission was defined as 2 or more consecutive Montgomery-Åsberg Depression Rating Scale (MADRS) scores of  ≤12, separated by at least 4 weeks.^7,8 The participants were tracked for at least 26 weeks or until a relapse of symptoms occurred.^5,8

AXS-05 met its primary endpoint of significantly delaying time to depression relapse by up to at least 6 months (p = 0.002), with no relapses observed over at least 6 months of double-blind treatment. AXS-05 also met its secondary endpoint of preventing depression relapses (0.0% of AXS-05 patients, 36.4% of patients switched from AXS-05 to placebo, p=0.004).^7,8 Furthermore, the medication was well tolerated, with no treatment related adverse events recorded in more than one participant in the AXS-05 group, according to the company. One patient had experienced gout and bacteremia, but this was deemed unrelated to the study medication.⁸ Currently, AXS-05 has breakthrough therapy designation for the treatment of major depression disorder. This is a process created to expedite the development of medications that are intended to treat serious conditions, and is based on preliminary clinical evidence that shows substantial benefit over currently available options.⁷

              Based on these positive results, Axsome Therapeutics has submitted a New Drug Application (NDA) to the FDA. Despite all this positive news, according to Axsome, the FDA has found “deficiencies that preclude labeling discussions at this time.” The FDA informed Axsome of “two deficiencies related to analytical methods in the Chemistry, Manufacturing, and Controls (CMC) section of the NDA”.⁴ The CEO of Axsome, Herriot Tabuteau, MD, has noted that this may lead to a delay in the potential approval of AXS-05.”⁵ While it may take some time for all the details to be worked out, AXS-05 seems to be a promising potential addition to the armory of medications for treatment resistant depression.

References:

1. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2;6:369-88. doi: 10.2147/PPA.S29716
2. Axsome Therapeutics. AXS-05. Axsome Therapeutics. https://www.axsome.com/axs-pipeline/about-axs-05. Accessed September 2, 2021.
3. Axsome Therapeutics, Inc. Axsome Therapeutics Receives FDA Breakthrough Therapy Designation for AXS-05 for the Treatment of Alzheimer’s Disease Agitation. GlobalNewsWire. https://www.globenewswire.com/en/news-release/2020/06/26/2053960/33090/en/Axsome-Therapeutics-Receives-FDA-Breakthrough-Therapy-Designation-for-AXS-05-for-the-Treatment-of-Alzheimer-s-Disease-Agitation.html. Accessed December 3,
4. Axsome Therapeutics, Inc. Axsome Therapeutics Reports Third Quarter 2021 Financial Results and Provides Business Update. GlobalNewsWire. https://www.globenewswire.com/en/news-release/2021/11/08/2329090/33090/en/Axsome-Therapeutics-Reports-Third-Quarter-2021-Financial-Results-and-Provides-Business-Update.html. Accessed December 3,
5. Brooks M. Novel Antidepressant Shines in Phase 2 Trial, but FDA Has Issues With Its NDA. Medscape.com. https://www.medscape.com/viewarticle/956445. Published 08/11/2021. Accessed September 2, 2021
6. Esketamine. Micromedex Solutions. Greenwood Village, CO: Truven Health Analytics. http://micromedex.com/. Updated November 06, 2021. Accessed 12/05/2021.
7. FDA. Breakthrough Therapy. FDA.gov. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy. Published 01/04/2018.
8. Jacobson M. Axsome Therapeutics Announces AXS-05 Achieves Primary and Key Secondary Endpoints in the MERIT Phase 2 Trial in Treatment Resistant Depression. GlobalNewsWire. https://www.globenewswire.com/news-release/2021/08/09/2276951/33090/en/Axsome-Therapeutics-Announces-AXS-05-Achieves-Primary-and-Key-Secondary-Endpoints-in-the-MERIT-Phase-2-Trial-in-Treatment-Resistant-Depression.html. Published 08/09/2021. Accessed September 2, 2021
9. Ketamine. Micromedex Solutions. Greenwood Village, CO: Truven Health Analytics. http://micromedex.com/. Updated November 22, 2021. Accessed 12/05/2021.

Published by Rho Chi Post