Will New Antipsychotics for Schizophrenia Be Game Changers?

Nick Youngson / Pix4free

In a previous article, I made the case that little has changed within the antipsychotic drug landscape over the past 70 years since the only effective medications for the treatment of schizophrenia have been “5-HT2, D2, me too” drugs whose mechanism of action seems to primarily involve modulation of dopamine and/or serotonin. In this follow-up, I’ll take a look at two new antipsychotic medications—ulotaront and xanomeline/trospium—that seem to have genuinely novel mechanisms of action and try to answer whether, as a result, they might be “game changers” for the treatment of people with psychotic disorders.

Before I go on, I’ll make a few introductory points. The first is that this article isn’t intended to be a promotion of the two new drugs on the horizon. I have no relationship with the pharmaceutical companies that are developing them and don’t have any stake in their success, other than a hope that we’ll one day have safer and more effective options to treat psychosis.

The second is that while existing antipsychotics all seem to exert their therapeutic effects through dopaminergic and serotonergic mechanisms, they also have a variety of other pharmacologic actions. Indeed, one of the brand names for the first antipsychotic medication, chlorpromazine, was “Largactyl” in recognition of its large number of actions on various neurotransmitters including histamine, acetylcholine, and epinephrine.

Furthermore, it may be that antipsychotic medications act through as-of-yet-unknown mechanisms. Recent findings about the anti-inflammatory and antimicrobial effects of antidepressants and their potential efficacy in treating COVID-19 remind us that we still have a long way to go in understanding exactly how psychotropic medications work.¹

So, it’s possible that there are relevant mechanistic differences between existing “5-HT2, D2, me too” drugs that we don’t really understand. That said, there isn’t good evidence that any one existing antipsychotic, aside from clozapine, is any more effective than another, suggesting that their mechanisms of action are more similar than different.

Ulotaront and TAAR1 Agonism

Ulotaront, studied under the investigational name SEP-363856, is believed to exert an antipsychotic effect through agonism (i.e., stimulation) of the trace amine-associated receptor 1 (TAAR1) as well as serotonin 1A (5-HT1A) receptors. While it doesn’t affect dopamine D2 or serotonin 5-HT2 receptors the way that the existing “5-HT2, D2, me too” antipsychotics do, activation of TAAR1 receptors has been found to inhibit dopaminergic neurons in certain areas of the brain that are relevant to psychosis by dampening presynaptic dopamine release or synthesis rather than blocking postsynaptic dopamine receptors.

An initial Phase 2 clinical trial of ulotaront demonstrated superiority to placebo in the treatment of schizophrenia in a four-week multicenter randomized controlled trial (RCT) involving 120 subjects with evidence of continued improvements in a six-week open-label follow-up study.^2,3 Side effects were minimal with no significant motoric symptoms, weight gain, or changes in blood sugar or cholesterol that are common side effects with “5-HT2, D2, me too” drugs. As a result of these and other encouraging findings,⁴ the FDA awarded ulotaront “Breakthrough Therapy Designation” in 2019.

Unfortunately, as often ends up being the case, the enthusiasm surrounding these initial results was recently dampened by the results of two additional Phase 3 trials called the Developing Innovative Approaches for Mental Disorders (DIAMOND) 1 and 2 studies. Although the results of these RCTs involving more than 900 patients have not yet been published, it has been reported that ulotaront failed to demonstrate any benefit over placebo in either study.⁵ It should be noted that the placebo response, especially in DIAMOND 1, was quite high.

In any case, since two “positive” Phase 3 RCTs are needed to obtain FDA approval and there have only been two “negative” studies to date, ulotaront’s future as an FDA-approved drug for schizophrenia seems tenuous.

Xanomeline/Trospium and Muscarinic Agonism

A potential therapeutic role of muscarinic agonists that increase acetylcholine neurotransmission for the treatment of schizophrenia has been discussed for many years, in part due to observational reports that arecoline, a chemical contained in betel nut, is used to treat psychosis in some cultures.^6,7 This is an interesting observation since many “5-HT2, D2, me too” are muscarinic antagonists that block acetylcholine and cause side effects like dry mouth, constipation, and cognitive impairment.

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However, while clozapine itself is also strongly anticholinergic, one of its major metabolites is an M1 muscarinic agonist, so it’s possible that clozapine’s superior efficacy could be related to cholinergic stimulation.

In 2008, a four-week RCT of the muscarinic agonist xanomeline (a derivative of arecoline) which preferentially stimulates M1 and M4 cholinergic receptors demonstrated superior effectiveness in the treatment of schizophrenia compared to placebo with reductions in “positive” symptoms like delusions and hallucinations as well as cognitive symptoms that are a common feature of schizophrenia independent of antipsychotic side effects.⁸ Unfortunately, cholinergic side effects like nausea, vomiting, diarrhea, and hypersalivation made xanomeline so difficult to tolerate that further drug development was abandoned.

More recently, xanomeline has been combined with trospium, a peripheral muscarinic antagonist with minimal activity in the brain, to minimize those cholinergic side effects. A Phase 2 placebo-controlled trial of xanomeline-trospium (branded as KarXT) demonstrated significant positive and negative symptom reduction compared to placebo in schizophrenia.^9,10

While some cholinergic and anticholinergic side effects like constipation and nausea were observed, the rate of common antipsychotic adverse events like weight gain and motor side effects was no different than placebo.¹¹ Post-hoc analyses of this RCT also found significant improvements in cognitive impairment.¹²

Although still unpublished, the results of two Phase 3 trials involving over 500 subjects have been reported which—unlike the Phase 3 trials of ulotaront—demonstrated KarXT's robust efficacy over placebo for schizophrenia at the end of 5 weeks.^13,14 These two positive RCTs have been submitted to the FDA for drug approval, which is expected sometime in 2024 if not earlier.

A Game Changer?

With ulotaront “stalled in the water” at the moment, it’s anticipated that KarXT will be the first antipsychotic medication approved by the FDA that finally breaks the “5-HT2, D2, me too” mold. It’s impossible to predict just how much of a game changer KarXT will be, but its novel mechanism of action and its demonstrated efficacy across all symptom domains of schizophrenia (positive, negative, and cognitive) is certainly reason for at least cautious enthusiasm.

It should be noted that ulotaront’s poor showing thus far doesn’t necessarily mean it will never see the light of day. For one thing, it may perform better in other Phase 3 trials—if it does, it would hardly be the first time that a medication gained FDA approval with two positive trials on the heels of initial negative trials.

But more importantly, if we consider that schizophrenia is not one disorder, but an umbrella term that encompasses a number of distinct pathophysiologies, then it may be that what's really needed is several different medications with distinct mechanisms of action that only help a subset of patients with that diagnosis (just like hypertension, as I mentioned in my previous article).

Years ago, when I was doing clinical research, I witnessed one patient in a clinical trial for a new antipsychotic medication who had never done well on previous medications improve significantly. Unfortunately for him, the study medication was never approved because the overall study results were negative.

Just so, if 10 percent of patients with schizophrenia benefit from stimulation of TAAR-1 receptors, but 90 percent do not, a medication like ulotaront will fail in clinical trials. And yet it could be exactly what that 10 percent needs.

Future clinical research will hopefully begin to disentangle the heterogeneity of schizophrenia and its response to different antipsychotic medications. Continued drug development of medications with novel mechanisms of action is sorely needed to get us there.