Vive la révolution! a paradigm shift in the pharmacological treatment of schizophrenia

All currently available medications for the treatment of schizophrenia, as approved by the US Food and Drug Administration (FDA), have affinity to the post-synaptic dopamine D2 receptor and are antagonists or partial agonists at that site¹. They are referred to as “antipsychotics” and some are also approved for other indications such as mood disorders, irritability associated with autistic disorder, and for the control of tics and vocal utterances of Tourette’s Disorder, and many have been studied and used for unapproved purposes^2,3. The first agent to become widely available was chlorpromazine in the 1950s⁴, with haloperidol emerging later in the 1960s^5,6. It was not until 1989 that clozapine, the first “atypical” antipsychotic was approved – atypical because there are fewer motoric adverse effects that are otherwise commonly encountered with the older agents⁷. However, clozapine’s use was restricted to those with treatment-refractory schizophrenia because of the risk of drug-induced agranulocytosis⁷. From 1993 to date there have been 12 additional atypical antipsychotics approved by the FDA for the treatment of schizophrenia and, in contrast to clozapine, can be used as a first-line treatment. All carry similar warnings and precautions regarding potential adverse effects⁸, reflecting a common mechanism of action – post-synaptic dopamine receptor blockade. Although this mechanism is logical given that it is believed that psychotic symptoms are the result of increased dopaminergic signaling to the striatum^9,10, is there another way to address this? Perhaps, better efficacy could be achieved through a mechanism that does not involve direct antagonism or partial agonism of dopamine D2 receptors. One can also expect different (and perhaps improved) tolerability and safety profiles. Moreover, having different mechanisms of action in play opens the door to rational polypharmacy, with the possibility for better outcomes when medications are used in combination, akin to the current state of the art for the management of hypertension and diabetes mellitus, where several different therapeutic approaches are available.

In this issue of Current Medical Research & Opinion, Hopkins and colleagues outline some of the challenges in the clinical development of “non-D2 compounds” for schizophrenia¹¹. The four authors are employed by Sunovion Pharmaceuticals, Inc. who together with Otsuka Pharmaceutical Development & Commercialization, Inc., are studying ulotaront as a potential treatment for schizophrenia¹². Ulotaront is a trace amine-associated receptor agonist, and by targeting this receptor this mechanism modulates dopaminergic activity without direct blockade of the post-synaptic dopamine D2 receptor^12,13. This is not the first attempt at developing a medication for schizophrenia that does not have any affinity for the dopamine D2 receptor. It is of historical interest to note that in the 1950s reserpine, a non-D2 compound, was introduced to the US market, and among other indications reserpine was also used to treat psychosis¹⁴. Unfortunately, reserpine is not well tolerated as it is a non-specific irreversible inhibitor of the Vesicular Monoamine Transporter centrally and peripherally¹⁵ and thus quite challenging to use¹⁶; reserpine is no longer available for human use in the US.

In their review, Hopkins and colleagues duly recognize that for more than a half-century, available FDA-approved treatments have shared blockade of dopamine D2 receptors as their primary mechanism of action, with shortcomings in both efficacy and tolerability. It is encouraging to hear that there are over 50 Phase 2/3 studies, identified in ClinicalTrials.gov for studies of non-D2-based compounds for the treatment of schizophrenia. As noted, ulotaront is one candidate and is currently in phase 3 of development as a first-line treatment for schizophrenia¹² after a successful phase 2 trial evidenced efficacy and good tolerability¹⁷.

Another novel agent in phase 3 of clinical development is a combination of xanomeline and trospium from Karuna Therapeutics, Inc.¹⁸. Xanomeline is a muscarinic M1 and M4 receptor agonist and is thought to reduce aberrantly high dopamine signaling to the striatum but is not well tolerated because of peripheral pro-cholinergic adverse effects^19,20. These adverse effects can be attenuated with the use of trospium, a muscarinic receptor antagonist that does not cross the blood brain barrier. Prior attempts in the 1950s at using this strategy of combining muscarinic/antimuscarinic medications were limited by the choice of agents available at that time²¹. This newer approach of combining xanomeline and trospium has been more successful. Xanomeline-trospium combination appears reasonably well-tolerated and demonstrated efficacy for the treatment of schizophrenia in a phase 2 trial of which the results were published in 2021²². A recently reported phase 3 trial demonstrated similar results²³.

Both ulotaront and xanomeline-trospium combination offer an opportunity to treat schizophrenia without direct blockade of post-synaptic dopamine D2 receptors^13,20. Their tolerability profiles appear promising and differ starkly from that of the currently available medications used to treat psychotic symptoms, although longer-term data is needed. By avoiding D2 blockade, motoric adverse events such as drug-induced parkinsonism, acute dystonia, akathisia, and perhaps tardive dyskinesia, can be relegated to the past. Gone too would be concerns about abnormal elevations in prolactin. So far, these novel agents appear to have no or limited effects on weight and metabolic outcomes. All this a quantum leap ahead. Vive la Révolution!

Transparency

Declaration of financial/other relationships

In the past 5 years Leslie Citrome has served as consultant to AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Cerevel, Clinilabs, COMPASS, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Lyndra, Medavante-ProPhase, Marvin, Merck, Mitsubishi-Tanabe Pharma, Neurocrine, Neurelis, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sunovion, Supernus, Teva, University of Arizona, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research; speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, Teva, and CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and Universities and Professional Organizations/Societies; owns stock (small number of shares of common stock) in Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased > 10 years ago, and stock options in Reviva; earns royalties/publishing income from Taylor & Francis (Editor-in-Chief, Current Medical Research & Opinion, 2022-date), Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics).

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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