Dr. Michael Banov: Hi, I’m Michael Banov. I’m a board-certified psychiatrist and I’m the medical director of Psych Atlanta in the Atlanta, Georgia area. We are a large behavioral health practice. We conduct clinical trials as well as have a clinical practice. I’m also on the faculty at Augusta University School of Medicine [Augusta, Georgia], I’m clinical faculty there.
So, what’s unique about what our practice is we have the opportunity of not only treating what I call real world patients, but also seeing patients in a research setting. We have the unique opportunity to see what is kind of coming down the pike in pharmacologic treatment for major depression.
'So what’s new in the antidepressant marketplace?' That’s something a lot of my patients are always asking me. “Is there anything better out there? Anything new coming out that I should know about?”
Yes, the antidepressants we have work OK. But they have their share of side effects and they don’t work for everyone. And when they do help, they don’t always help as much as we would like them to. You might get better with one of the currently available antidepressants, but the reality is you may not get completely well.
We know that remission rates are still low, 30% or less with currently available antidepressants. We have newer antidepressants that work differently from our previously most commonly used. We call these newer ones multimodal antidepressants, like vortioxetine and vilazodone. And they’ve been advances, but maybe not the next or third generation that us clinicians and researchers have been hoping for.
And then the next development phase has been augmentation strategies using things like aripiprazole or brexpriprazole to be used adjunctively with antidepressants. Then, esketamine—medications that work on the NMDA receptor— they’ve been another recent, interesting new development but there are some limitations: the in-office delivery, the cost, the access, risks. Those have limited the pervasive use of this medicine. And then there’s the recent flurry of news about the psychedelic medicines: Psilocybin, LSD, MDMA, etc.
But unfortunately, there is far more news and hype than science on these treatments and there remain extensive questions about durability of effect of these new treatments and how they are going to be used.
The other piece of news frustrating clinicians and researchers like myself is the divestment in big pharma research in new antidepressants. Government funding for basic research into depression, and charitable funding, has declined significantly over the last decade. In 2010, some of the really big pharma companies that were leaders in the area of CNS disorders like GSK, AstraZeneca, Pfizer, Merck and Sanofi, all announced that they had stopped looking for new antidepressants altogether.
So given that somewhat pessimistic introduction, I do have some good news:
There are several compounds that are in fairly late-stage development in clinical trials that look very promising. Now, they may not have the flashy news-making qualities of taking a psychedelic trip with magic mushrooms to make your depression and anxiety go away, but they hold a lot of promise: good tolerability, good safety profiles, and unique mechanisms of action that differ from the traditional monoamine activity we currently have.
Sage Therapeutics is a relatively new pharmaceutical company that is taking a very innovative approach by looking at different brain circuitry and how it regulates mood and anxiety. They brought a medication to market in 2019 called Zulresso, or brexanolone, for postpartum depression, the first drug for postpartum depression. What’s unique about that medication is its mechanism of action - it’s an analog of a hormone that’s produced in the body, pregnanolone. The challenge with the drug is it has to be given as a continuous IV infusion over 60 hours.
Most psychiatrists really aren’t equipped or experienced in giving IV infusions and OB/GYN‘s, who may be more comfortable with such medical interventions, aren’t so comfortable treating postpartum depression. In response, the company has developed an oral medication with a somewhat related mechanism of action. This compound is known as SAGE-217 or zuranolone. The drug has similar pharmacology and pharmacokinetics [to brexanolone] but is an oral once-a-day drug.
They have a number of studies both currently enrolling and completed. The mechanism of action is unique because it’s an oral neuroactive active steroid. It’s a GABA a receptor positive allosteric modulator similar to brexanolone. We know the GABA system is the major inhibitory signaling pathway of the brain and central nervous system. Because of its unique mechanism of action, it’s been granted breakthrough therapy designation by the FDA.
The idea of this medicine would be that it could be taken alone or in combination with an antidepressant for a 14-day course. Then, if a patient relapses, they could be rechallenged at another time. This is a very unique concept in antidepressant therapy. What’s nice for patients is they would not have to take the medication all the time and maybe could avoid any issues, side effects, or problems you may have by taking a daily medication over an extended period of time.
There’s some interesting recent data from a phase 3 open label naturalistic study looking at the safety and tolerability of zuranolone. There’s a 30 mg dose in adults for up to one year. The protocol was later amended to include a 50 mg dose due to some findings from other studies. Both doses were tolerated very well.
What was unusual in this is that patients that received a 14-day course of zuranolone, if their depression came back, they were allowed to get another rechallenge for another 14 days. Seventy percent of the patients in the study needed only one or two treatment courses, which meant a total of 2 to 4 week treatment over a year.
There were 725 patients who came into the study that got the 14 days of zuranolone. 20% did not respond at all so they were kicked out or discontinued from the study. 72% percent of the remainder of the subjects in the study responded, and 40% remitted. 42% percent were on a pre-existing antidepressant, which was continued, meaning about 58% were on no antidepressant therapy.
Interestingly, there was no difference in the outcome between the two groups. The drug was well tolerated, the most common side effect was somnolence at about 9% and headaches at about 8.5%. Most side effects were mild to moderate, there were very few dropouts as a result of side effects.
What is unusual about this study is this concept of retreatment. So, 55% were retreated one or more times whereas 44.5% were not retreated at all. So they are looking at indications in both major depression, and possibly, postpartum depression.
There was one setback to development of this medicine. In one of the trials the drug did not beat placebo but when they re-looked at the data and did a re-analysis, they found that some of the folks who enrolled who had more mild symptoms may not have done as well compared to placebo. A post-hoc analysis showed that 9% of patients in the 30 mg group had no measurable drug concentration, which means they basically they weren’t compliant. If you took those patients out, the drug met significance at all timepoints though, including up to Day 15.
That is a problem with clinical trials is making sure people are compliant while they’re in the study.
There is another company called Axsome Therapeutics, it’s a small pharmaceutical company that is focused on CNS disorders. They have several compounds in the pipeline but one specifically for depression is called AXS -05. This is a novel oral investigational NMDA receptor antagonist, also a glutamate receptor modulator. This is a new mechanism of action that we see affiliated with ketamine and Spravato [esketamine], and those types of medications. It seems to enhance synaptic connections and improve the connection between brain cells in people with major depression.
There’s a lot of other activity that we see with this compound, including sigma-1 receptor agonism; it enhances brain levels of serotonin, norepinephrine, and dopamine, which are key neurotransmitters involved in the regulation of mood; and also very interesting, may display some anti-inflammatory properties that may have some relevance to treating [major depressive disorder] MDD. The multimodal actions of this compound may be complementary and synergistic.
So, this is a proprietary formulation that actually consists of 2 older medicines, dextromethorphan, and if that sounds familiar, it’s because that is an ingredient in cough syrup and also in another compound that’s used for pseudobulbar affect, and bupropion, which commonly known by its brand name Wellbutrin. The dextromethorphan has the NMDA activity, and the bupropion serves to increase the bioavailability of the dextromethorphan since that compound has a very short half-life. Of course, there’s some synergy, because the bupropion can also impact norepinephrine and dopamine levels as well.
The AXS-05 was granted Breakthrough Therapy designated by the FDA in March of 2019. They have positive results from a study with 327 adults. The drug was given once a day for the first three days, then twice a day for 6 weeks after. It met its primary endpoint with a significant reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) compared to placebo at Week 6.
But they also met a number of other interesting secondary measurements including remission rates doing better than placebo, seeing improvement by Week 1, improvements in Clinical Global Impression of improvement, QIDS-SR-16, Sheehan Disability Scale and a number of other secondary outcome measures.
Another very interesting study related to this compound is the phase 2 study called the COMET-SI trial. Here they enrolled patients with major depression who had suicidal ideation (SI). Now, keep in mind in most every clinical trial if someone has suicidal ideation they are excluded. But here they were included specifically to be in this study. The compound showed a very rapid reduction of suicidal ideation, rapid functional improvement, and very rapid, substantial, and durable improvements in all depressive symptomatology. They looked at 37 patients with suicidal ideation, that was a score of 3 or more on Montgomery-Åsberg Depression Rating Scale (MADRS-SI) Suicide Item.
They were given this compound, and the safety profile was quite remarkable: saw improvement in dizziness, nausea, headache, dry mouth, and decreased appetite within a few days after taking the compound, if they developed any of those side effects. But again, most of the side effects were pretty mild in intensity and resolved pretty quickly.
A third compound generating a lot of interest is dextromethadone, this is also known by REL-1017. They give a lot of names and initials to these new compounds. This is under development for the treatment of major depression by a company called Relmada.
They are also focused on central nervous system (CNS) diseases. This is actually the (S)-enantiomer of methadone. It also works on the N-methyl-D-aspartate receptor, it’s an (NMDAR) antagonist.
Now, when we think of methadone, we think opiates. Opiates have been studied in the past as antidepressants, but the safety profile and abuse potential have always been major impediments to development of these medications. However, this compound has very low affinity for opioid receptors, and we believe lacks significant respiratory depressant action and abuse liability.
In a phase 2 trial, REL-1017 had a rapid and sustained antidepressant effect with statistically significant improvements compared to placebo on efficacy measures, including the MADRS. The phase 2 study also showed a very favorable safety and tolerability profile of this compound.
The study involved 62 patients and we saw depression improve as as early as four days after treatment began. Also, there was no dissociative or psychotic type of symptoms that emerged with this drug, or any withdrawal signs or symptoms upon treatment discontinuation.
Now, the phase 2 study was only three weeks, and it really wasn’t looked at long enough to assess long-term dependency, which will remain a question before this drug gets approved.
Nonetheless, in April 2017, the FDA granted it Fast Track designation for adjunctive treatment of major depression. They have two phase 3 registration trials being conducted studying the drug as adjunctive treatment [in MDD patients] who have failed at least 1 prior treatment in their current depressive episode.
So, here’s the summary: there’s lot to get excited about. But anyone who has followed the world of medical discovery and the challenges of bringing new medications to market, are aware there can always be surprises that impact these compounds coming to market, or maybe there’s going to be something else coming along that’s going to replace these agents as the next promising depression treatment.
But it’s a really exciting area to watch, and it gives us and our patients the clear message that we haven’t given up on the treatment of depression and that hope is around the corner.
Thanks for listening.
The views and opinions expressed are those of the author(s) and do not necessarily reflect the official policy or position of Clinical Topics in Depression or HMP Global, their employees, and affiliates. Any content provided by our bloggers or authors are of their opinion and are not intended to malign any religion, ethnic group, club, association, organization, company, individual, anyone, or anything.