Antidepressants remain some of the most widely prescribed drugs, but most popular antidepressants are now available as generics. While selective serotonin reuptake inhibitors (SSRIs) and SNRIs (serotonin and norepinephrine reuptake inhibitors) remain the most commonly prescribed antidepressants, various new types of drugs may be available in the future. For example, drug companies are working on getting everything from an selective antagonist of human orexin-2 receptors to an oral neuroactive steroid on the market for depressive disorders.  

Here, we survey 10 antidepressants that may change the mental health landscape in the coming years.  

1. Esmethadone

The (S)-enantiomer of methadone, esmethadone (dextromethadone; REL-1017) from Relmada Therapeutics (Nasdaq:RLMD) is headed to a Phase 3 study for major depressive disorder (MDD). The drug candidate was efficacious on days 4, 7 and 14 (one week after the last dose) in a placebo-controlled, double-blind, randomized Phase 2a clinical study focused on treatment-resistant MDD. An editorial in The American Journal of Psychiatry concludes that the Phase 2a study findings are “novel, exciting, and certainly worth exploring as are additional, well-powered studies of longer duration.” The (S)-enantiomer of methadone, esmethadone has low affinity for opioid receptors and thus likely as low abuse potential.

2. R-ketamine

In recent years, the dissociative anesthetic ketamine has made waves for its off-label use as a rapid-acting antidepressant. In 2019, FDA approved a related drug, Spravato (esketamine/S-ketamine), for major depressive disorder. Now, a handful of companies are developing arketamine (R-ketamine) as a novel antidepressant. Preclinical research indicated that R-ketamine had more potent and longer-lasting antidepressant effects than S-ketamine. In addition, R-ketamine may also lack the psychotomimetic side effects of other ketamine forms.

In general, ketamine also appears to have faster-acting effects than SSRI antidepressants. 

Originated by Atai Life Sciences’ (Nasdaq:ATAI) subsidiary Perception Neuroscience, R-ketamine is also the focus of a collaborative program with Otsuka Pharmaceutical Co., Ltd., which is seeking to commercialize the drug candidate in Japan.  

3. Ansofaxine hydrochloride

The investigational antidepressant ansofaxine hydrochloride (LY03005, LPM570065) from Luye Pharma would be a triple reuptake inhibitor of serotonin, norepinephrine and dopamine. LY03005 had positive top-line results in a Phase 2 clinical trial. According to the sponsor, LY03005 had a comprehensive antidepressant efficacy and a good safety profile in the initial results from the Phase 2 clinical study, which did not find adverse effects related to sexual function or weight change. A Phase 3 study of the drug is also ongoing. 

4. SEP-4199 

A non-racemic ratio of amisulpride from Sumitomo Pharma subsidiary Sunovion could be a potential new therapy for bipolar depression. The company notes that SEP-4199 has a superior antidepressant activity to amisulpride. The developer claims that an 85:15 ratio of aramisulpride to esamisulpride offers an antidepressant benefit and reduces D2 receptor-related extrapyramidal side effects. The drug still retains D2 receptor binding-related benefits for bipolar disorder.

5. Psilocybin 

Although not patentable in its original form, the psychedelic molecule psilocybin has shown promise in a handful of small studies, including a 2021 study featured in NEJM. In May, Compass Pathways released positive data from the biggest randomized, controlled, double-blind study of psilocybin therapy to date. Coupled with psychological support, a single 25 mg dose of psilocybin led to a 6.6 point decrease in the Montgomery-Åsberg depression rating scale (MADRS) over those who received a 1 mg dose. Those receiving the lower dose served as the control group. The numbers fell short of statistical significance by weeks 9 and 12, however. While psilocybin remains a Schedule I substance in the U.S., many companies are testing its potential to treat depression and other mental health disorders. Legitimizing psilocybin in a medical context, however, could be challenging, given the potentially high cost of administering it in a safe clinical setting. A single course of therapy involving psilocybin could cost multiple thousands of dollars, according to analysts’ estimates.  

6. Zuranolone 

The neuroactive steroid zuranolone (SAGE-217) from Sage Therapeutics’ (NSDQ:SAGE) and Biogen offers promise for both MDD and postpartum depression. The drug candidate was featured in a study in JAMA, which found that the drug candidate showed “significant reductions in depressive symptoms” in treating postpartum depression. In a Phase 3 study, Patients who received a 50 mg daily dose of zuranolone had a significant reduction in scores on the Hamilton Rating Scale for Depression (HAM-D-17) scale on Day 15. Biogen and Sage plan on filing a new drug application for zuranolone for MDD to the FDA in the second half of 2022. In addition, the companies plan on filing a new drug application for postpartum depression (PPD) in the first half of 2023. Zuranolone differs from Zulresso (brexanolone) from Sage Therapeutics in that it would be an oral rather than an infused drug.

7. Seltorexant 

The seltorexant (MIN-202, JNJ-42847922, JNJ-922) is now in a Phase 3 study focused on major depressive disorder with insomnia symptoms. That study specifically focuses on patients who have had an inadequate response to prior antidepressants. Seltorexant is a selective antagonist of human orexin-2 receptors. Seltorexant was initially developed jointly by Janssen and Minerva, but the latter opted out of a joint development agreement with Janssen in 2020. 

8. XEN1101 

The differentiated Kv7 potassium channel modulator XEN1101 from Xenon Pharmaceuticals (Nasdaq:XENE) is the focus of the X-NOVA Phase 2 study focused on major depressive disorder. The company aims to complete the study in June 2023. Preclinical studies involving mice showed that the drug promoted the increased activity of KCNQ-type potassium channels, reversing depressive phenotypes related to chronic social defeat stress. 

9. AXS-05

A combination of bupropion and dextromethorphan, AXS-05 is an oral, investigational NMDA receptor antagonist with multimodal activity that could potentially treat MDD, Alzheimer’s disease agitation and smoking cessation. Developed by Axsome Therapeutics (Nasdaq:AXSM), AXS-05 consists of a proprietary formulation and dose of dextromethorphan (DM) and bupropion. Earlier this year, Axsome announced the publication results from the pivotal ASCEND Phase 2 clinical trial of AXS-05 in MDD in the American Journal of Psychiatry. The study found that the drug candidate significantly improved depressive symptoms compared with bupropion, also known as Wellbutrin.

10. NRX-101

Developed by NRx Pharmaceuticals (Nasdaq:NRXP), Cyclurad (NRX-101) is a combination of the antibiotic D-cycloserine and lurasidone, an atypical antipsychotic under development for bipolar depression. The company believes D-cycloserine inhibits the brain’s NMDA receptor and raises glutamate/glutamine levels in the anterior cingulate cortex. NRx is testing the drug candidate in a Phase 2 study in bipolar depression in patients with sub-acute suicidal ideation and behavior. A separate Phase 3 study tests the combination of NRX-100 (ketamine HCl) and NRX-101 in patients with severe bipolar depression with acute suicidal ideation and behavior. NRX-101 has won Fast Track and Breakthrough Therapy Designation from FDA. 

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Filed Under: clinical trials, Drug Discovery, Psychiatric/psychotropic drugs
Tagged With: ansofaxine hydrochloride, antidepressants, AXS-05, esmethadone, NRX-101, psilocybin, R-ketamine, seltorexant, SEP-4199, XEN1101, zuranolone
 

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