'A wild west': Patients seek new depression treatments with different mechanisms of action

Key takeaways:

• There is a plethora of new depression medications that are enticing for patients.
• Knowledge of these new options is important for PCPs, but they should focus on the tried-and-true treatment methods first.

Patients have become increasingly disillusioned with traditional depression treatments, and the search for new therapies has created some chaos in the field, according to experts.

“It’s a bit of a wild west, frankly,” David J. Hellerstein, MD, director of the New York State Psychiatric Institute Depression Evaluation Service and a professor of clinical psychiatry at Columbia University, told Healio.

The typical medications prescribed for depression — selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) — “take weeks to months to work,” Hellerstein said. So, alternatives with new mechanisms of action that can promise benefits like fast-acting results may be enticing for patients.

“If a person has not responded well to, say, the SSRIs, then there are other classes of medicines that might be worth trying because the problem that person has might not be a problem in the serotonin system,” Hellerstein said. “I think it's similar to if you're trying to treat hypertension or cardiac conduction problems, you may use drugs from different classes and often in combination because you get the best result using drugs that work through more than one mechanism at the same time.”

Another major shift in the field is a focus on specific types of depression, Gary Sachs, MD, clinical vice president at Signant Health and founder of the Bipolar Clinic and Research Program at Massachusetts General Hospital, told Healio.

“We're beginning to see an approach that is less global, [from treatments for] everybody with depression no matter what your subtype is, to being able to define subgroups who are very likely to respond better to one kind of treatment or another,” Sachs said.

New FDA-approved treatments

In the past few years, the FDA has been making headway with these new treatment prospects, Hellerstein and Sachs told Healio.

In August 2023, the FDA approved Zurzuvae (zuranolone; Sage Therapeutics and Biogen) as the first and only oral, once-daily treatment for postpartum depression. Previously, medication treatment for postpartum depression was available only through IV injection in certain facilities.

“Postpartum depression is a very serious condition and can be life threatening,” Hellerstein said. “A drug that potentially helps treat it quickly and through hormonal mechanisms seems very appealing.”

More recently, in October 2023, the FDA approved Exxua (gepirone hydrochloride, Fabre-Kramer Pharmaceuticals) for adults with major depressive disorder. As an oral selective serotonin 1a receptor agonist, Exxua is one of the medications with a new mechanism of action, but Hellerstein said he does not think the drug will be “a big blockbuster.”

“My understanding is it does show signs of benefit and effectiveness, but not particularly for treatment-resistant depression,” Hellerstein said. “It’s not clear if that’s going to be a big step forward in any way. It may find a niche as a supplemental medicine, or some subgroups of patients might benefit from it.”

Hellerstein also mentioned Auvelity, a combination of dextromethorphan and bupropion manufactured by Axsome Therapeutics that works through the glutamate and NMDA pathways and “supposedly has a more rapid onset of action than the other antidepressant medications,” he said.

Outside of medications, in April the FDA also cleared the first prescription digital tool to help treat depression. The app, called Rejoyn (Otsuka Pharmaceutical and Click Therapeutics) — which is intended for use as adjunct therapy alongside clinician-managed outpatient care — involves a 6-week brain-training program that helps adults with major depressive disorder process their emotions.

Hellerstein also mentioned transcranial magnetic stimulation, which, while unconventional, generally uses FDA-approved devices to “directly impact brain circuits that could be related to depression,” he said.

Psychedelics

However, many of the depression treatments patients are interested in are not FDA approved, Hellerstein and Sachs said. Psychedelic drugs, for example, have seen a major resurgence in interest as a depression treatment.

“There are lots of psychedelics being tested,” Sachs said.

He said there are studies that have demonstrated “some very encouraging responses to single doses of psilocybin,” with mixed data also coming out of microdosing studies. Also, esketamine nasal spray (Spravato, Janssen), a variation of a ketamine treatment, has been available since 2019.

Hellerstein also mentioned the possibility of 3,4-methylenedioxymethamphetamine, or MDMA, gaining FDA approval “as soon as later this year” for PTSD.

“I think the biggest thing in recent years has been the expansion of ketamine treatments,” Hellerstein said. “Ketamine is being used off-label for treatment of depression and there are many practitioners who provide ketamine infusions or other methods of ketamine administration that are off-label use; it's not covered by insurance. That's the biggest clinically relevant thing that people see in practice. Every town seems to have a ketamine clinic.”

Both Sachs and Hellerstein said current studies have been quite promising and seem to improve symptoms, but Sachs noted that it is unknown “whether the psychedelic experience per se is what is required to have that kind of therapeutic response.”

“When you have an awe-inspiring, majestic, psychedelic experience, it really may well open you up to a lot of other changes that can activate a therapeutic response,” he said. “That’s an important aspect of the research that is ongoing. I think that will get sorted out in the next 10 years.”

If and when psychedelics are FDA approved, Hellerstein said there will be an interesting question as to where they fit into practice; will they be the “first, second, third, fourth choices?”

“They might be something where you only need one or two treatments as opposed to taking daily medicine, but we're just not there yet,” he said. “Managing people's expectations and preventing people from making bad choices, I think, is more key right now.”

The issues

As exciting as the new treatments may be, Hellerstein cautioned that “each of these things has some caveats.” Cost, insurance coverage and availability are some examples of major hurdles many patients might face accessing these treatments.

“A lot of these new treatments are very costly and/or insurance coverage may be slow to be initiated for a number of them,” he said.

For most psychedelic treatments “availability is very, very, very limited,” Hellerstein added.

“Most psychedelic treatments are only legally available through clinical trials, though there are state-based programs, such as in Oregon, which provide psilocybin treatment clinically,” he said.

Availability for brain stimulation treatments may also be challenging “because not every location has a good brain stimulation center,” he said.

Similarly, it is well-known that patients often face difficulties when seeking new medications.

“Copays, insurance coverage, cost and prior authorizations — those all come up,” Hellerstein said.

Sachs also mentioned legality as a concern for psychedelic use.

“In most places in the country, they're now legally available, and in a lot of places where it's not legal, people are accessing them,” Sachs said. “These are not trivial experiences for people to have, especially without medical supervisoin.”

Take-home message

For primary care providers, “most of these new treatments are fairly far down the line for discussion with patients,” Hellerstein said. What is more important, he said, is ensuring accurate diagnoses and giving adequate treatments — asking “well, have the tried-and-true drugs really been tried?”

“The issue that psychiatrists often see when we're doing consults on patients referred from primary care is that the person may have been on an antidepressant for many years, but perhaps at a subtherapeutic dose, or they got to a full therapeutic trial but the drug didn't work and then we never switched to a second one,” he said. “I think the novel drugs, the really cool, headline-grabbing ones, are really interesting, but they're less relevant for primary care practices than well-established medicine that is generic, cheap and covered by the insurance. In primary care, it’s more important to give a person an adequate trial of a full dose to really see if their symptoms are going to respond.”

In rarer cases, “there are reasons to start using new treatments,” he said. If a patient is unresponsive to several conventional treatments at an adequate dose for an adequate amount of time, for example, a PCP might look into these other therapies.

“Treatment-resistant depression has different definitions, but nonresponsive to two to four adequate trials of established antidepressant medicine, that’s the point where you say, ‘What can we do next?’” Hellerstein said. “Augmentation with a second drug? There's a whole plethora of options.”

References:

• Axsome therapeutics announces FDA approval of AUVELITY, the first and only oral NMDA receptor antagonist for the treatment of major depressive disorder in adults. https://www.multivu.com/players/English/9034852-axsome-therapeutics-announces-fda-approval-auvelity/. Published Aug. 19, 2022. Accessed May 5, 2024.
• Otsuka and Click Therapeutics announce the U.S. Food and Drug Administration (FDA) clearance of Rejoyn, the first prescription digital therapeutic authorized for the adjunctive treatment of major depressive disorder (MDD) symptoms. https://otsuka-us.com/news/rejoyn-fda-authorized. Published April 1, 2024. Accessed May 8, 2024.

For more information:

Gary Sachs, MD, can be reached at Gary.Sachs@SignantHealth.com