Dr. Craig Chepke, MD, is Medical Director at Excel Psychiatric Associates in Huntsville, North Carolina, adjunct professor of psychiatry at SUNY Upstate Medical University in Syracuse, New York, and an adjunct associate professor of psychiatry at Atrium Health. In this video, Dr. Chepke discusses emerging mechanisms of action for drugs that psychiatric illness, most notably schizophrenia and major depressive disorder (MDD), and highlights the ways in which harnessing these mechanisms can help target target specific symptom clusters and provide more rapid treatment response than is possible with currently available medications.
Hi, my name's Dr. Craig Chepke. I'm a psychiatrist in private practice at Excel Psychiatric Associates in Huntersville, North Carolina, where I'm the medical director. I'm also a clinical adjunct professor of psychiatry at SUNY Upstate Medical University in Syracuse, New York, and an adjunct associate professor of psychiatry for Atrium Health.
I'm excited to talk about new mechanisms of action that are coming down the pipeline in psychiatry. This is really why I wanted to be a psychiatrist in the first place. I felt there was so much untapped potential to the brain. For so many years, and decades, really, we've been trying to modulate the monoamines, serotonin, dopamine, and norepinephrine in various different combinations, like a roulette wheel. That's all we've been doing over and over again, different combinations, and our outcomes have really stalled. The benefits that patients are getting from medications don't seem to be improving very rapidly, if at all. There may be better tolerability in some cases, but the efficacy has really flatlined, and it's flatlined way below what patients need. So many patients are not getting the type of response, remission, and most importantly, functional outcomes that they need and they deserve.
So, I'm hopeful that new mechanisms of action could fill the gap for patients who aren't getting those kinds of benefits from their current treatments. So, some of the new mechanisms I'm excited about, in schizophrenia, we have TAAR1 agonism. TAAR1 is an intercellular molecule that can modulate and shape dopamine by having the ability to combine with dopamine receptors in the cell membrane, and without directly binding to dopamine, influence the effects that dopamine has. So, the road might lead to dopamine, but it doesn't directly block it, and it therefore can avoid a lot of the adverse reactions that are associated with those medications.
Another one in schizophrenia is muscarinic cholinergic agonism. So, we're used to acetylcholine talking about antagonism anticholinergics, but procholinergics have been shown in previous studies to have potential for cognitive benefits and some antipsychotic benefits as well. There [are] medications now in both phase 2 and in phase 3 for schizophrenia, and we're very hopeful that this could also possibly pan out by not directly interfacing with dopamine to have a better risk benefit profile for patients.
In major depressive disorder, once again, it's been serotonin, dopamine, or norepinephrine. But now, we're starting to tap into a much greater part of the brain, which are GABA and glutamate. So, when you look at the number of neurons in the brain, the number of synapses that those neurons make, the monoamines altogether combined only are responsible for 5% of it. Another 5% are many other neurotransmitters put together, and then the rest of the 90% is either GABA or glutamate, with glutamate making up about 50%, GABA about 40%. So, it's no wonder that we're not getting the kind of outcomes we want, so we're looking at medications in phase 3 trials, and we have 1 approved agent currently, esketamine, that interacts with the glutamate system, and then there's other medications coming down the pipeline that work on the glutamate system as well, as well as GABA. The GABA agent that's being studied can actually show rapid benefit with improvements starting within 2 days and full benefit by 2 weeks. So, a lot of these GABA and glutamate medications are rapid-acting antidepressants compared to the typical 4 to 6 weeks we're used to.
And then, finally, one last new mechanism that's being studied in MDD in phase 3 is actually in the orexin system. Now for the past 7 or 8 years, we've been looking at orexin antagonists for the treatment of insomnia disorder. There are 3 of those on the market, but this new investigational compound has the potential to be treating MDD. It's being looked at as adjunct to a current typical antidepressant, and more specifically, in patients with prominent symptoms of insomnia. So, it's kind of the start of the realm of precision psychiatry, that rather than just assuming all patients with MDD are the same, which when you only have to meet 5 out of 9 criteria, that adds up to hundreds of combinations of ways to have MDD. We have to figure out a way to subtype it. And so, this could be the first step in that process if it yields fruitful results when the phase 3 studies are complete.
So, even if 1 of these new mechanisms pans out for any of these diseases, I would be thrilled, and hopefully we'll get more than 1, because again, our patients have so many unmet needs that we need to start filling, and hopefully these new medications might be able to do that.