How can we develop more effective antidepressants?

“REL-1017 (dextromethadone), if approved could change the way depression is treated – with a different mechanism of action, potential advances in onset of action, efficacy and safety,” said Sergio Traversa, Chief Executive Officer of Relmada Therapeutics.

When speaking with European Pharmaceutical Review’s Victoria Rees, Traversa explained how a new kind of antidepressant could provide depressed patients with an alternative to current therapies.

Current antidepressant therapies

Traversa explained that at present, there are approximately 30 drugs approved for the treatment of depression. With the exception of Johnson & Johnson’s (J&J) Spravato (esketamine) and a few antipsychotics used as adjunctive treatments, there have been few recent mechanistic advances in the field. Most currently approved products target well known neurotransmitter or enzyme pathways, such as serotonin, norepinephrine and monoamine oxidase.

J&J’s Spravato is approved as a nasal spray in the US and in Europe. According to Traversa, the drug is effective and also works rapidly. However, despite its high efficacy rate, because of the challenging safety and tolerability profile, its use is restricted to patients who have failed at least two previous therapies. It also has to be administered in a clinical setting, where patients are rigorously monitored by medical professionals.

Many antidepressants inhibit the re-uptake of serotonin or serotonin and norepinephrine. Traversa said that approximately one in three patients responds well to these selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs). Another one in three patients responds only slightly to traditional SSRI and SNRI antidepressants. The last third of patients do not respond to this kind of treatment at all.

“There is a major unmet need; that is to find a class of drug that works very differently from the existing antidepressants and can effectively and with a rapid onset, treat patients who do not respond well or at all to current treatment,” said Traversa.

A major concern that Traversa highlighted is that the efficacy of the currently available oral drugs is delayed for three or six weeks from the start of treatment. This is a great challenge, he said, due to the nature of the condition. Informing patients that they have to wait approximately one month before their depression is alleviated is demanding.

Therefore, a swift onset of action is critical in developing the next generation of antidepressant therapies.

REL-1017 (dextromethadone)

Traversa commented that the compound REL-1017, which recently completed its Phase II clinical trial, could offer a new treatment paradigm for patients with depression.

As an N-methyl-D-aspartate (NMDA) antagonist, he explained that the new compound works in similar way to Spravato, giving researchers hope that it will be effective and gain regulatory approval but with a more benign safety, tolerability and administration profile. 

“This class of drug definitely addresses the two major unmet needs,” said Traversa. In the completed Phase II clinical trial, he said, “REL-1017 showed over 50 percent response rate in patients that failed at least one previous treatment in the current depression episode and its efficacy was statistically significant and clinically meaningful after four days of treatment.”

Another potential benefit to the REL-1017 therapy that Traversa highlights is that it is expected to be sold in pharmacies and administered as a once-daily pill, which he said is easier for patients to take than intravenously or a nasal spray NMDA antagonist at a hospital or clinic.

Mechanism of action

The NMDA receptor is located in the spine, central nervous system (CNS), brain and other areas of the body, such as the heart and skin.

It has a critical function in many diseases including depression but is also required for the normal working of the body, therefore making it a challenging drug target as it cannot be completely shut off without incurring severe unwanted side effects.

Traversa explained that when the NMDA receptor is over-stimulated, too much calcium can enter the cell. This then becomes toxic, resulting in dysfunctional nerve activity, which is typical of many diseases such as Alzheimer’s and depression.

Dextromethadone is a low affinity blocker of the NMDA receptor, reducing the inflow of calcium into the cell, which then results in a more proper cell metabolism and functioning and ultimately in a fast improvement of the disease symptomatology.

The future of antidepressants

Traversa said that if approved, dextromethadone could “change the way depression is treated.” However, the next step is to move on to Phase III trials.

In more general terms, Traversa said that there are two or three drugs in development that could potentially disrupt the antidepressant market, including dextromethadone.  Currently, this is being developed as an adjunctive therapy when at least one existing treatment fails in a patient.

Traversa emphasised that the antidepressant market is quite large and there is so much unmet need that there is ample room for new products.