Introduction
Betel is the fourth-most consumed psychoactive substance in the world after caffeine, nicotine, and alcohol.Reference Warnakulasuriya, Chaturvedi and Gupta 1 , Reference Gupta and Warnakulasuriya 2 Like Cobenfy—the novel schizophrenia medication derived, in part, from betel and composed of 2 agents: xanomeline and trospium—betel is a mixture of compounds rather than a single agent. The constituent parts that comprise betel are the nut of the areca palm (Areca catechu), the leaf of the betel pepper (Piper betle), and slaked lime (calcium hydroxide).Reference Norton 3 Each component contributes to the experience of chewing betel, with parasympathomimetic arecoline from the areca nut acting as the primary psychoactive agent. As we will see, unchecked parasympathetic activation gives rise to side effects (eg, nausea, vomiting, diarrhea, cramps, high blood pressure) that decrease user satisfaction and limit therapeutic potential. For betel users, the parasympathetic effects of the areca nut may be modulated through the addition of calcium hydroxide and betel leaf. Chewing areca nut with calcium hydroxide hydrolyzes arecoline into arecaidine, which is a strong uptake inhibitor of gamma-aminobutyric acid (GABA), one of the primary inhibitory neurotransmitters in the human brainReference Chu 4 , Reference Stahl 5; chewing it with betel leaf may further increase sympathetic nervous system activityReference Chu 4 to curb arecoline’s parasympathetic effects and minimize unpleasant adverse reactions. However, betel is a complicated topic. The term “betel” itself is ambiguous, with enormous variability in ingredients and preparations across cultural and geographic contexts. While the 3 ingredients described above—areca nut, calcium hydroxide, and betel leaf—represent the most common formulation of betel, the degree to which this particular combination actually allows users to minimize parasympathetic side effects remains unclear. We will therefore focus, for now, on the primary psychoactive component—the areca nut itself. Later, we will revisit these parasympathetic elements in the setting of emerging schizophrenia drug development strategies as we outline the events and innovations that brought us from a simple seed to an emerging class of psychiatric medication.
Areca nut
Areca catechu can be found in Southeast Asia.Reference Peng, Liu and Wu 6 Archeologists have evidence of A. catechu cultivation sites in Thailand as early as 10,000 BCE.Reference Wang, Guo and Luo 7 Its seed (commonly referred to as areca nut) has since spread throughout Asia, East Africa, and the Pacific.Reference Salehi, Konovalov and Fru 8 An Indian poem from 900 BCE describes soldiers chewing areca nut,Reference Wang, Guo and Luo 7 and writings from 504 BCE recount a Ceylonian (Sri Lankan) princess gifting one of her nurses an areca nut to chew.Reference Chu 4 , Reference Burton-Bradley 9 Around the first century CE, we see the areca nut described as an antidepressant in Chinese literature,Reference Liu and Chang 10 with additional descriptions of areca nut as an antiparasitic agent, a digestive aid, and an aphrodisiac, appearing across a wide array of cultures and traditions.Reference Chu 4 , Reference Liu and Chang 10 To date, more than 59 compounds have been isolated from A. catecha, with at least 50 isolated from the seed itself.Reference Peng, Liu and Wu 6 The medicinal applications of A. catechu relate to these compounds’ reported ability to exert a wide range of effects on the immune, digestive, nervous, and cardiovascular systems.Reference Peng, Liu and Wu 6 The chemical component arecoline, specifically, has also demonstrated antiatherosclerotic and antidiabetic properties.Reference Wang, Guo and Luo 7 For our purposes, the most interesting pharmacologic effect of arecoline may be its ability to influence cognition and psychosis, discussed below. In addition to these therapeutic effects, areca nut also demonstrates pronounced deleterious effects. Beyond the adverse parasympathetic reactions previously discussed, chemical components of A. catecha demonstrate neurotoxic, addictive, and carcinogenic properties that may have further hampered translational efforts to develop areca-derived clinical interventions.Reference Salehi, Konovalov and Fru 8 , Reference Stokes, Pino and Hagan 11
Arecoline
Arecoline, an alkaloid derived from areca nut, crosses the blood–brain barrier and induces a variety of subjective effects, including increased cognition, euphoria, and arousal, as well as decreased anxiety.Reference Volgin, Bashirzade and Amstislavskaya 12 In 1957, researchers suggested that arecoline may have utility as a treatment for patients diagnosed with schizophrenia. When patients were treated with 10 mg of subcutaneous arecoline, a small subset reported increased lucidity. When the dose was increased to 20 mg, a higher percentage of patients exhibited increasingly lucid intervals; nonverbal or catatonic patients demonstrated increased interest in their surroundings; other patients became more emotive and engaged in the psychiatric interview process.Reference Pfeiffer and Jenney 13 This is consistent with stimulant characteristics frequently described by betel users throughout Southeast Asia.Reference Stokes, Pino and Hagan 11 Unfortunately, the side effects were significant and included tachycardia, increased systolic and diastolic blood pressures, tremors, and vomiting. Investigators theorized that some combination of arecoline plus the muscarinic antagonist atropine might minimize parasympathetic side effects and improve tolerance. They reasoned that methylated atropine might block the peripheral effects of arecoline, while the central muscarinic action of arecoline on the brain would remain intact and therapeutic. But it would be over 50 years before this strategy would translate to a U.S. Food and Drug Administration (FDA)-approved intervention.
Distracted by dopamine
One reason for the delay in the establishment of arecoline and its cholinergic mechanism of action as a viable drug target might be the success of dopaminergic approaches during the first and second eras of modern psychopharmacology. Most psychiatric drugs have been “discovered” by accident, and therefore, are empiric in their origins. Our field discovers something that works, and then investigators endeavor to understand how and why. Early in the treatment of schizophrenia, medications that demonstrated the greatest efficacy were those with antidopaminergic mechanisms of action, thereby increasing pharmaceutical interest in the development of these medications. The muscarinic agonists, with their stubborn and intrusive side-effect profiles, perhaps fell out of favor as investigators and drug developers explored dopamine modulation as a potential treatment mechanism for psychiatric disorders. This conceptualization of dopamine as a major actor in psychiatric pathophysiology is sometimes referred to as “the dopamine hypothesis” or “the dopamine hypothesis of schizophrenia.”Reference Stahl 5 , Reference Meltzer and Stahl 14 In brief, the dopamine hypothesis associates the positive symptoms of schizophrenia (e.g., psychosis) with an abundance of dopamine in the mesolimbic pathway. A simplified circuit (Figure 1) illustrates this relationship. To a lesser extent, the dopamine hypothesis also associates negative and cognitive symptoms of schizophrenia (e.g., asociality, impaired executive functioning) with a scarcity of dopamine in the mesocortical pathway. This allows us to understand why direct dopamine blockade is associated with worsened nonpositive symptoms of schizophrenia. Furthermore, when dopamine is directly blocked in the nigrostriatal pathway, patients may also experience significant motor side effects that mirror movement abnormalities observed in Parkinson’s disease. For a time, the therapeutic effects of dopamine-blocking agents overshadowed their side effects.
Figure 1. Xanomeline modulation of dopamine. (A) In psychosis, increased dopamine release in the nucleus accumbens (NA) is associated with the positive symptoms of psychosis. This is regulated by dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain, which is modulated by cholinergic inputs from the laterodorsal tegmentum (LDT) as well as a combination of inhibitory and excitatory neuronal inputs from the cortex. Dopaminergic neurons from the VTA also project to the prefrontal cortex. These are regulated by a combination of inhibitory and excitatory neurons from the cortex, resulting in a low dopaminergic state that is often associated with negative symptoms in schizophrenia. (B) An M1 and M4 muscarinic acetylcholine receptor agonist (e.g., xamomeline) activates GABAergic interneurons in the prefrontal cortex via the M1 receptor. It also activates presynaptic M4 receptors in the VTA and NA. This results in synergistic reduction of dopamine release in the NA and increased dopamine release in the prefrontal cortex. Notably, the dopaminergic neurons in the substantia nigra (SN) and connections in the dorsal striatum (DS) are not affected because presynaptic receptors projecting from pedunculopontine nucleus (PPN) cholinergic neurons possess M2, not M4, muscarinic acetylcholine receptors, thereby preventing motor side effects observed in traditional antidopaminergic antipsychotics.
A cholinergic balance to dopamine
The dopamine hypothesis remained center stage for decades. However, behind the scenes, evidence for acetylcholine’s role in schizophrenia continued to accumulate. In the late 1940s, organophosphates—chemicals that increase acetylcholine levels—entered the market as a new and affordable form of insecticides for crop protection. These chemicals, acetylcholine-esterase inhibitors that inhibit the breakdown of acetylcholine, were toxic to a wide range of insect species. But their selectivity was imprecise and affected humans as well. As their use became commonplace, agricultural workers exposed to these agents demonstrated signs and symptoms of cholinergic toxicity,Reference Gershon and Shaw 15 , Reference Rowntree, Nevin and Wilson 16 the same parasympathetic effects caused by arecoline, discussed earlier. As we would expect, farmers and field workers developed muscle cramps, diarrhea, and vomiting.Reference Gershon and Shaw 15 Moreover, they also reported puzzling psychiatric symptoms. Some even found themselves in emergency departments with acute-onset psychosis. These presentations mirrored the positive symptoms of schizophrenia so closely that many were formally diagnosed with schizoaffective disorder before the organophosphate exposure was discovered.Reference Gershon and Shaw 15
Similarities between organophosphate and cholinergic medicament exposure led investigators to posit a relationship between acetylcholine and psychosis.Reference Yohn, Weiden, Felder and Stahl 17 Indeed, as more cases of organophosphate poisoning were reported, increased acetylcholine levels were linked to both positive and negative symptoms of schizophrenia, with individuals exposed to organophosphates also reporting significant difficulties in concentration. However, for reasons we are only just beginning to understand, the relationships between acetylcholine, positive symptoms, and negative symptoms were far from clear-cut. Other studies demonstrated that a decrease in acetylcholine elicited psychotic symptoms.Reference Yohn, Weiden, Felder and Stahl 17 , Reference Friedhoff and Alpert 18 Indeed, the effects of cholinergic agonists and antagonists continued to produce opposing effects in patients. Although linked, positive and negative symptoms of schizophrenia varied at different stages of the illness,Reference Lindenmayer, Kay and Friedman 19 with no unifying hypothesis at the time to explain a separation of the two phenomenologies. Treatments with anticholinergics to relieve motor side effects from first-generation antipsychotics were also sometimes reported to improve negative symptoms related to cognition but worsen positive symptoms.Reference Singh, Kay and Opler 20 –Reference Johnstone, Crow and Ferrier 22 Additionally, second-generation antipsychotics with the greatest anticholinergic activity (particularly clozapine) seemed to have greater efficacy than their first-generation counterparts. Due to these observations, our field developed a renewed interest in acetylcholine as a central driver of schizophrenia.Reference Tandon and Greden 23 But these conflicting observations led to a big question: are schizophrenia symptoms improved by enhancing acetylcholine signaling, or are they improved by blocking acetylcholine signaling? It is no wonder that further development of cholinergic treatments for schizophrenia languished for years while this issue remained unresolved. Only later would a rational treatment development strategy emerge after investigators discovered acetylcholine’s ability to regulate dopamine release via muscarinic 1 (M1) and muscarinic 4 (M4) receptors (Figure 1A). For an in-depth pharmacological discussion, we refer readers to the excellent review by Yohn and colleagues.Reference Yohn, Weiden, Felder and Stahl 17
Xanomeline
Based largely on the structure and pharmacology of betel’s arecoline,Reference Coppola and Mondola 24 xanomeline was synthesized in the early 1990s as part of a drug development effort by Eli Lily and Company aimed at finding novel treatments for cognitive deficits associated with conditions like Alzheimer’s disease.Reference Sauerberg, Olesen and Nielsen 25 In this way, xanomeline is a direct arecoline derivative.Reference Bender, Jones and Lindsley 26 In addition to improving cognition, initial studies found that xanomeline also reduced dementia-related psychotic symptoms, which was not initially anticipatedReference Bodick, Offen and Levey 27 given the field’s relative lack of understanding of acetylcholine and dopamine signaling interactions at the time. Investigators wondered how and why this was occurring. After all, the drug did not directly affect dopamine. According to the widely accepted version of the dopamine hypothesis, acetylcholine would not have influenced the positive symptoms caused by high levels of dopamine in the mesolimbic pathway. Furthermore, evidence continued to mount that anticholinergic burden could be worsening cognitive and negative symptoms.Reference Minzenberg, Poole, Benton and Vinogradov 28 , Reference Tandon and Dequardo 29
Here, muscarinic acetylcholine receptors took center stage in driving the idea that this system could be a key therapeutic target. It had long been noted that administration of nonselective muscarinic antagonists could induce schizophrenia-like symptoms, implying that stimulation of these receptors might stabilize neurotransmission in affected individuals.Reference Raedler, Bymaster, Tandon, Copolov and Dean 30 Clinical and neuropathological studies of subjects with schizophrenia showed a reduction of M1 and M4 receptor density in key frontocortical areas involved in both the positive and cognitive symptoms, including the caudate and putamen.Reference Dean, Crook, Opeskin, Hill, Keks and Copolov 31 , Reference Crook, Dean, Pavey and Copolov 32 This reduction was also later found in the prefrontal cortex, an area associated generally with cognitive and executive function.Reference Crook, Tomaskovic-Crook, Copolov and Dean 33 , Reference Dean, McLeod, Keriakous, McKenzie and Scarr 34 Further, researchers began targeting the cognitive symptoms of schizophrenia with cholinesterase inhibitors, most commonly donepezil, which found success in improving working memory and executive function in multiple smaller studies.Reference Buchanan, Summerfelt, Tek and Gold 35 –Reference Erickson, Schwarzkopf, Palumbo, Badgley-Fleeman, Smirnow and Light 38
Thus, drug developers began to pivot toward models of psychosis structured around muscarinic receptor activity once it was discovered that M1 and M4 receptors regulated downstream dopamine activity (Figure 1A) and that M1 and M4 agonists reduced relevant behavioral measurements in animal models of psychosis.Reference Yohn, Weiden, Felder and Stahl 17 Thus, xanomeline, now known to be a central M1 and M4 agonist, became an increasingly attractive agent for the potential treatment of schizophrenia. However, the side effect profile remained a major challenge because xanomeline is also a muscarinic 2 (M2) and muscarinic 3 (M3) agonist. Stimulating these receptors outside of the brain creates undesirable peripheral parasympathetic side effects, specifically gastrointestinal (nausea, vomiting, diarrhea) and musculoskeletal (weakness and cramping) side effects. Notably, many patients participating in xanomeline trials dropped out due to parasympathetic overactivation.Reference Yohn, Weiden, Felder and Stahl 17 Their side effects mirrored those experienced by agricultural workers suffering from organophosphate poisoning, with both groups experiencing significant gastrointestinal and motor symptoms due to their exposure to cholinergic agents.
Cobenfy (xanomeline + trospium)
Despite its procognitive and antipsychotic effects both in animal models and as a monotherapy in patients with Alzheimer’s diseaseReference Raffaele, Berardi, Asthana, Morris, Haxby and Soncrant 39 –Reference Asthana, Greig and Holloway 41 and schizophrenia,Reference Yohn, Weiden, Felder and Stahl 17 researchers found that xanomeline as a monotherapy resulted in unacceptable peripheral cholinergic side effects,Reference Dowd, Dowd, Johnson and Mariotti 42 contributing to a poor tolerability profileReference Bodick, Offen and Levey 27 , Reference Shekhar, Potter and Lightfoot 43 that limited dosage options. To counteract these adverse effects, Karuna Therapeutics developed KarXT, branded as Cobenfy.Reference Kingwell 44 –Reference Brannan, Sawchak, Miller, Lieberman, Paul and Breier 46 Cobenfy is a combination drug comprised of xanomeline and trospium chloride (Sanctura), the latter of which is an FDA-approved antimuscarinic agent used to treat overactive bladder. Not only does trospium counteract xanomeline’s peripheral activation—especially of M2 and M3 muscarinic receptors—but it also fails to cross the blood–brain barrier, thereby mitigating anticholinergic central effects (e.g., confusion, memory impairment) while facilitating the desired procognitive and antipsychotic effects of xanomelineReference Brannan, Sawchak, Miller, Lieberman, Paul and Breier 46 without blocking central M1 and M4 receptors. Tolerability of Cobenfy is best captured in multiple Phase 3 trial data, which not only replicated robust clinical efficacy in the treatment of schizophrenia but also revealed a low dropout rate secondary to adverse effects, primarily gastrointestinal, comparable to that of placebo.Reference Smith, Augustine and Dorrough 47 Although a direct head-to-head Phase 3 trial comparing the efficacy and tolerability of Cobenfy and other established antipsychotic agents has yet to occur, cross-trial data suggest that Cobenfy’s unique mechanism confers a reduced side effect burden compared to its counterparts and an effect size for clinical efficacy comparable to known D2 antagonists.Reference Smith, Augustine and Dorrough 47 , Reference Kaul, Sawchak and Walling 48
The antipsychotic effects of Cobenfy can be explained by dopamine modulation achieved through distinct muscarinic receptor pathways involving complex neurocircuitry of the frontal cortex, ventral tegmental area, and nucleus accumbensReference Yohn, Weiden, Felder and Stahl 17 , Reference Foster, Bryant and Conn 49 (Figure 1A). The details of this neurocircuitry are discussed elsewhere,Reference Yohn, Weiden, Felder and Stahl 17 but it is worth highlighting 3 important observations. First, stimulation of postsynaptic M1 receptors in the prefrontal cortex leads to decreased downstream dopamine release in the nucleus accumbens (Figure 1B). This is perhaps the mechanism by which Cobenfy may improve positive symptoms in schizophrenia and Alzheimer’s disease. Second, stimulation of these same postsynaptic M1 receptors in the prefrontal cortex leads to increased downstream dopamine release in the prefrontal cortex (Figure 1B), a proposed mechanism by which Cobenfy may improve negative and cognitive symptoms in schizophrenia and Alzheimer’s disease. Third, simultaneous stimulation of presynaptic M4 autoreceptors in the nucleus accumbens and the ventral tegmental area leads to decreased dopamine release in the nucleus accumbens (Figure 1B), which explains why Cobenfy may improve positive symptoms in schizophrenia and Alzheimer’s disease.
Evidence for differential muscarinic receptor–mediated modulation of dopamine, while supported primarily by preclinical models, remains largely inferential in human subjects, given limited neuroimaging and biomarker data.Reference Dean and Scarr 50 , Reference McKinzie, Bymaster, Geyer and Gross 51 However, support for these concepts is underscored by the clinical efficacy of Cobenfy demonstrated in Phase 2 and Phase 3 clinical trials. The results of these investigations support the conjecture that stimulation of central M1 and M4 receptors, while blocking peripheral M2 and M3 receptors, results in statistically significant improvements in positive and negative symptoms, while also achieving acceptable tolerability profiles compared to placebo.Reference Brannan, Sawchak, Miller, Lieberman, Paul and Breier 46 , Reference Correll, Miller, Sawchak, Kaul, Paul and Brannan 52 , Reference Kaul, Sawchak and Claxton 53 Furthermore, the absence of motor side effects—commonly known as extrapyramidal symptoms (e.g., dystonia, parkinsonism) associated with D2-blocking agents—further supports the notion that Cobenfy acts by cholinergic control of dopaminergic pathways as opposed to brute-force D2 blockade.Reference Bolbecker, Shekhar, Fryer, Christopoulos and Nathanson 54 , Reference Jones and Harvey 55
As of September 26, 2024, Cobenfy is approved as a monotherapy to treat the positive symptoms of psychosis in schizophrenia. One intriguing prospect for Cobenfy is its aforementioned potential to target negative symptoms,Reference Horan, Targum and Claxton 56 which have largely been unaddressed by mainstream antipsychotic agents, and cognitive impairments in schizophrenia patients.Reference Horan, Sauder and Harvey 57 Phase 3 trial data showed a statistically significant improvement in negative symptoms of schizophrenia with Cobenfy compared to placebo,Reference Smith, Augustine and Dorrough 58 , Reference Kurczoba, Skonieczna and Badziąg 59 though the evidence for its effects on cognitive symptoms is more nuanced. A post hoc data analysis suggests that the most pronounced improvement in cognitive function was observed in patients with greater baseline cognitive impairments as opposed to those with milder deficits.Reference Smith, Augustine and Dorrough 58 While the clinical efficacy of Cobenfy on negative symptoms is clear in replicated prospective randomized trials, both targeted studies assessing cognitive symptoms prospectively and the use of validated tools are necessary to determine the role of Cobenfy on cognition. It is possible that Cobenfy may also have utility in the treatment of psychotic and cognitive symptoms for Alzheimer’s disease—perhaps as an augmentation agent for inadequate response to traditional D2-blocking antipsychotic medications that lack concomitant central muscarinic antagonism. At the time of this writing, ongoing clinical trials are exploring these possibilities.
Cobenfy’s highly anticipated debut as an alternative to antidopaminergic agents has generated significant curiosity and excitement as psychiatry stands poised to enter a new era of schizophrenia treatment. Cobenfy has ignited a veritable “cholinergic gold rush” with more and more pro-cholinergic agents entering clinical trials. New pro-cholinergic agents under active investigation include selective M4 agonists (eg, NBI-1117568; NBI-1117569), selective M4 positive allosteric modulators (eg, emraclidine, NMRA-266), selective M1 receptor allosteric agonists (eg, NBI-1117567, ANAVEX3-71), and, like Cobenfy, additional selective M1/M4 agonists (ML-007/PAC, sebcomeline/PAC, NBI-1117570) as well as nicotinic agonists (eg, DMXB-A), and nicotinic positive allosteric modulators (eg, AVL-3288).Reference Yohn, Weiden, Felder and Stahl 17 , Reference Kingwell 60 Even familiar acetylcholinesterase inhibitors (eg, galantamine, donepezil) are under exploration as adjunctive therapy with atypical antipsychotics.Reference Koola, Looney, Hong, Pillai and Hou 61 , Reference Thakurathi, Brenda and Henderson 62 It seems increasingly likely that we will soon have an entire portfolio of pro-cholinergic agents in the future.Reference Yohn, Weiden, Felder and Stahl 17 All this is due, at least in part, to that ancient betel nut.
Conclusion
As in the case of betel, arecoline, and Cobenfy, psychiatric medications are often derived from repurposed or repositioned agents after observing—sometimes quite accidentally—therapeutic utility in other domains. While the first-generation antipsychotics of the 1950s had a profound effect on psychiatric care and marked the beginning of the psychopharmacological revolution, many of these drugs followed a similar discovery pipeline. The phenothiazines (from which the prototypic first-generation antipsychotic chlorpromazine would later be derived) were themselves derived from dyes used in the German textile industry and were first administered because of their antihistaminic actions.Reference López-Muñoz, Alamo, Cuenca, Shen, Clervoy and Rubio 63 Monoamine oxidase inhibitors (MAOIs), the first medications specifically targeting depression, trace their origins to failed tuberculosis trials in which investigators noted remarkable mood improvements in patients treated with the prototypical MAOI isoniazid.Reference López-Muñoz and Alamo 64 Some aspects of lithium’s journey from a gout medication to a mood stabilizer may be attributed to anecdotal observations that drinking from lithium-containing mineral springs (such as those found in Texas’ “crazy waters”) improved psychiatric presentationsReference Shorter 65; certainly, valproate’s expanded indication from anticonvulsant to mood stabilizer represent another example of drug repurposing following clinical observations of psychiatric utility.Reference Guay 66 , Reference Fava 67 Currently, there is significant interest in repurposing hallucinogenic botanicals (eg, psilocybin mushrooms) for psychiatric indications, with other plant-based medicines (“phytoceuticals”) also representing an active area of psychopharmaceutical research.Reference Sarris, Marx and Ashton 68 While drug repurposing is not unique to the field of psychiatry, it may be disproportionately represented and inordinately reliant upon preliminary anecdotal observations and happy accidents due to logistical and ethical challenges inherent to research in this field. Limited biomarkers for psychiatric disease, difficult-to-translate preclinical models, and complex moral issues related to consenting psychiatrically unwell patients into clinical research trials are just a few examples of investigatory challenges that may contribute to the field’s exploitation of—if not reliance upon—drug repositioning pipelines. Now, it is betel’s turn to step into the (slaked) limelight as yet another drug being repositioned for psychiatric indications. Indeed, the journey from arecoline to xanomeline highlights an enduring pattern in psychopharmacology where initial serendipitous observations give rise to clinically useful translational outcomes.
As clinicians, how do we operationalize such a burgeoning schizophrenia treatment? Our opinion is that Cobenfy is positioned distinctly from its third-generation antipsychotic counterparts—such as aripiprazole and lumateperone, as well as earlier generation antipsychotics, all of which modulate dopamine activity directly—due to its novel mechanism of action directly upon the cholinergic system that underpins both its clinical benefit and tolerability profile. It is a new generation antipsychotic in a pharmacologic class by itself. The most striking difference from earlier antipsychotics is Cobenfy’s tolerability profile compared to D2 antagonists, which will potentially appeal to those patients who poorly tolerate those other agents. In terms of efficacy, it is not yet clear who might respond better to a D2 antagonist versus Cobenfy as no head-to-head trials have been conducted. Nor is it clear to what extent augmenting D2 antagonists with Cobenfy would enhance efficacy and have adequate tolerability. So far, the data suggest that effect sizes of Cobenfy in all three of its Phase 3 studies are the same magnitude as known D2 antagonists compared to placebo. With respect to cognitive symptoms, a host of current D2 antagonist antipsychotics inadvertently worsen executive function and memory due to their anticholinergic effects, as well as due to very high degrees of D2 antagonism. Whether employed as a monotherapy or as augmentation with another agent, the pro-cholinergic Cobenfy has the potential of limiting cognitive impairment while bolstering cognitive function. Further clinical trials of cognition in schizophrenia with Cobenfy will be required to determine its theoretically promising role as a procognitive agent in patients with schizophrenia.
Recent developments surrounding Cobenfy and other muscarinic agents currently under investigation may represent the beginning of what some are calling the third generation of antipsychotic pharmacology, or—to embrace more neuroscientifically grounded nomenclature, which moves away from indication-based naming conventions in favor of language that references a drug’s mechanism of actionReference Zohar, Nutt and Kupfer 69—we may be at the beginning of the third era of modern psychopharmacology: the era of muscarinic agonism. At the time of this writing, xanomeline-trospium (Cobenfy) has just recently been approved by the FDA for the treatment of schizophrenia, with many more muscarinic agonists in active clinical trials (as discussed above). It has been over 70 years since the last FDA-approved psychiatric medication with a novel mechanism of action,Reference Kingwell 44 and the field is abuzz with anticipation and hope. This new class of medications seems to sidestep many of the problematic side effects that limited the utility of previous agents while simultaneously offering distinct advantages in its potential ability to address negative symptoms. There are even indications that this new class may have procognitive effects and potential applications for Alzheimer’s disease. While still early in its life cycle, the data up to this point are compelling. By all currently available accounts, the 10,000-year journey from betel nut to a new class of psychiatric medication represents one of the most astounding drug development stories in the history of medicine.
Author contribution
Conceptualization: S.M.S., J.B.A., S.M.M., J.F.C.
Financial support
JBA is supported by MH101072.
Disclosures
JFC: no disclosures. SNM: no disclosures. JBA: no disclosures. SMS: Grant/Research: Acadia, Alkermes, Allergan/AbbVie, AssureX, Astra Zeneca, Arbor Pharmaceuticals, Avanir, Axovant, Biogen, Boehringer Ingelheim, Braeburn Pharmaceuticals, BristolMyer Squibb, Celgene, CeNeRx, Cephalon, Daiichi Sankyo Brazil, Dey, Eisai, Eli Lilly, Forest, GenOmind, Glaxo Smith Kline, Harmony Biosciences, Indivior, Intra-Cellular Therapies, Ironshore, ISSWSH, Janssen, JayMac, Jazz, Lundbeck, Merck, Neurocrine, Neuronetics, Novartis, Otsuka, Pear Therapeutics, Pfizer, Reviva, Roche, Sage, Servier, Shire, Sprout, Sunovion, Supernus, TMS NeuroHealth Centers, Takeda, Teva, Tonix, Torrent, Vanda Consultant/Advisor: Acadia, AbbVie/Allergan, Alkermes, Altus, AstraZeneca, Avanir, Axsome, Biogen, Biomarin, Biopharma, Cerevel, Clearview, Clexio, Done, Eisai Pharmaceuticals, EMD Serono, Enveric Biosciences, Eurolink, Faber Kramer, Gedeon Richter, Genetica, Genomind, Impel, Innovative Science Solutions, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen, Jazz, Karuna Therapeutics, Libbs, Lilly, Lipidio, Longboard, Lundbeck, Merck, Neurawell, Neurocrine Biosciences, NeuroPharma, Noveida, Otsuka, Pfizer, Pierre Fabre, Proxymm, Recordati, Relmada Therapeutics, Sage Therapeutics, Saniona, Servier, Sprout, Sunovion, Supernus, Takeda, Taliaz, Teva, TMS NeuroHealth, Tonix, Tris Pharma, Trius, Vanda, Vertex, Viforpharma Speakers Bureau: Abbvie/Allergan, Acadia, Genentech, Janssen, Lundbeck, Neurocrine, Otsuka, Servier, Sunovion, Takeda, Teva. Options Holdings: Delix, Genomind, Lipidio, NeuraWell.
Open access
