Rationale for Adjunctive Treatment Targeting Multiple Mechanisms in Schizophrenia

Bruce J. Kinon; Stefan Leucht; Carol Tamminga; Alan Breier; Ronald Marcus; Steven M. Paul

doi:10.4088/JCP.23nr15240

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Narrative Review

Rationale for Adjunctive Treatment Targeting Multiple Mechanisms in Schizophrenia

Bruce J. Kinon, MD; Stefan Leucht, MD; Carol Tamminga, MD; Alan Breier, MD; Ronald Marcus, MD; and Steven M. Paul, MD

Published: August 19, 2024

Abstract

Importance: Schizophrenia is a complex syndrome with taxing symptoms and for which treatment challenges remain. Current dopamine D₂receptor–blocking antipsychotics have well-known limitations, including ineffectively treating across all symptom domains and generating common side effects such as motor disturbances, weight gain, and metabolic dysfunction. New approaches are sorely needed to address the continued unmet treatment needs for individuals living with schizophrenia.

Observations: Although current antipsychotic drugs indicated for the treatment of schizophrenia interact with various neurotransmitter receptors, they all commonly act as dopamine D₂receptor antagonists or partial agonists. While antipsychotics primarily relieve positive symptoms, residual positive symptoms are still common, and management of negative symptoms and cognitive impairment remains an unmet need. Problematic side effects are common with current agents and can contribute to nonadherence. In addition to alterations in dopaminergic pathways, increasing evidence indicates that the pathophysiology of schizophrenia also includes dysfunction in other neurotransmitter systems including glutamate, acetylcholine, serotonin, and γ-aminobutyric acid. While the pathophysiology of schizophrenia is complex, treatments with novel pharmacologic actions that target these systems are of interest as adjunctive treatment for individuals with schizophrenia.

Conclusion and Relevance: An unmet need exists for effective treatment of all the core symptoms of schizophrenia. Novel antipsychotics with a nondopaminergic mechanism of action may be useful candidates for antipsychotic adjunctive treatment in people with schizophrenia who are showing inadequate responses, treatment resistance, or low tolerance to dopamine D₂receptor–blocking antipsychotics.

J Clin Psychiatry 2024;85(3):23nr15240

Author affiliations are listed at the end of this article.

Schizophrenia is a complex and chronic syndrome that affects approximately 24 million people worldwide¹and remains associated with considerable disability,¹premature mortality,²and significant economic burden.³The primary symptom domains of schizophrenia include positive symptoms such as hallucinations and delusions, negative symptoms such as social withdrawal, and cognitive dysfunction. Approved treatments for schizophrenia are limited in their efficacy across symptom domains and are associated with side effects including motor symptoms, somnolence/sedation, weight gain, hormonal abnormalities, and metabolic dysregulation.⁴When an individual living with schizophrenia does not have an adequate response to treatment, alternative strategies are often employed, including dose increases, switching to another antipsychotic drug, or combination with a second psychotropic medication, such as antipsychotics, antidepressants, anxiolytics, stimulants, and mood stabilizers.^5–7There are currently no approved pharmacologic combinations for the treatment of schizophrenia.

While the classical dopamine hypothesis of psychosis has been an enduring theory in schizophrenia, this hypothesis has been refined, with additional neurotransmitter systems implicated in the pathophysiology of schizophrenia.⁸In addition to dopaminergic dysfunction, alterations in glutamate, γ-aminobutyric acid (GABA), serotonin, and acetylcholine neurotransmitter systems have been reported.^9–13All currently approved antipsychotics are dopamine D₂receptor antagonists or partial agonists, and many bind with varying affinities to other receptors, contributing to both their efficacy and side effect profiles.^9,14To date, strong evidence is lacking to support the combination of an antipsychotic drug with a second psychotropic medication for improved symptom reduction.⁷Novel pharmacologic approaches are profoundly needed.

This article reviews existing pharmacologic treatments for schizophrenia and investigational antipsychotic and psychotropic agents with novel, non-D₂receptor mechanisms of action, with a focus on adjunctive or cotreatments for schizophrenia. In this article, the term “adjunctive treatment” is used to describe a therapy given to enhance the main or current treatment to maximize its effectiveness. This term is used interchangeably with similar terms such as “augmentation,” “add-on,” “combination treatment,” or “cotreatment” to reflect the term used in the cited literature. It is acknowledged that these terms are not necessarily synonymous in meaning and may, in some instances, denote 2 cotreatments given together to enhance the effectiveness of either given alone.

LIMITATIONS OF CURRENT ANTIPSYCHOTIC MEDICATIONS

Current antipsychotic medications address positive symptoms of schizophrenia without clear evidence of efficacy in controlling primary negative or cognitive symptoms, except for cariprazine and amisulpride in low doses.¹⁵No or partial responses to antipsychotics are common. An analysis of 16 randomized, controlled trials showed that 67% of individuals with acute exacerbation of schizophrenia had ≤50% reduction in overall symptoms, and 20% had no reduction at all.¹⁶Approximately 24%–30% of people with schizophrenia have treatment-resistant schizophrenia,^17–19defined as failure to respond to ≥2 trials of adequate dose and duration of antipsychotic medications.²⁰Further, up to 60% of people with treatment-resistant schizophrenia do not respond to clozapine,²¹the only antipsychotic agent specifically indicated for this condition.²²Even when psychosis responds to the antipsychotic used and positive symptoms are reduced extensively, the overall therapeutic effect is usually not a cure or complete remission. Manifestations of the illness are persistent, especially those related to negative symptoms and cognitive impairments. Residual symptoms are also associated with higher relapse rates.^23,24

Antipsychotics are associated with increased risks of extrapyramidal symptoms (EPS) including antipsychotic drug–induced parkinsonism, akathisia, and rescue use of antiparkinson medications, as well as weight gain, metabolic side effects, and elevated serum prolactin levels.^25–29Among these side effects, EPS and increased prolactin are attributable to D₂receptor blockade.³⁰In general, antipsychotics with relatively lower D₂antagonism and higher 5-hydroxytryptamine 2A (5-HT_2A) receptor antagonism tend to carry a lower risk of EPS and prolactin elevation, but a greater risk of weight gain.³¹Studies in individuals taking typical and atypical antipsychotics reported prevalence rates ranging from approximately 20%–35% for antipsychotic-induced parkinsonism and tardive dyskinesia.³²A systematic review and meta-analysis of 15 studies that included users of typical and/or atypical antipsychotics found overall pooled prevalence of approximately 20%, 11%, and 7% for antipsychotic drug-induced parkinsonism, akathisia, and tardive dyskinesia, respectively.³³Unfavorable side effects of antipsychotics also contribute to treatment discontinuation, poor compliance, and subsequent relapse.^34,35A systematic review of 39 studies found an estimated nonadherence rate of 40%–50% in individuals with schizophrenia.³⁶Approximately 75% of people with schizophrenia stopped the first antipsychotic prescribed during the first 18 months of treatment.³⁷

Both negative and cognitive symptoms are common in most individuals with schizophrenia and are associated with functional impairment.^38–40Primary negative symptoms are intrinsic to the underlying pathophysiology and present throughout the course of the disease, while secondary negative symptoms are thought to be related to other factors such as positive symptoms, side effects of medications including certain antipsychotics, other comorbidities, social deprivation, and substance abuse; the 2 types can be clinically indistinguishable.⁴¹While antipsychotics can reduce negative symptoms in individuals with schizophrenia and exacerbations of psychosis, it is unclear whether their effects are on primary or secondary negative symptoms.⁴¹A meta-analysis revealed that amisulpride was the only antipsychotic drug to improve primary negative symptoms with evidence from placebo controlled trials, while drugs like olanzapine and zotepine did not outperform placebo, and cariprazine was the only antipsychotic that was clearly better than another antipsychotic (risperidone) in this regard.¹⁵Commonly prescribed antipsychotic medications for schizophrenia have limited cognitive benefits.⁴²Meta analyses found only mild neurocognitive improvements for certain atypical antipsychotics, mainly compared to haloperidol, and the effect sizes were generally small.^43–46Moreover, neurocognitive improvements may be the result of improvements in secondary factors such as EPS.^47,48

ADJUNCTIVE AND COMBINATION TREATMENT STRATEGIES

Combining multiple antipsychotic medications or adding a nonantipsychotic agent to an antipsychotic agent is a common practice for addressing inadequate responses to antipsychotic monotherapy. The goal is to improve general or selective symptoms, functional outcome, and/or tolerability.^6,49

Inherent challenges exist to demonstrate the superiority of combinations vs monotherapy. A comprehensive, systematic overview of 29 meta analyses for 42 combinations (mostly antipsychotic/nonantipsychotic combinations) showed significantly more benefit with some strategies versus their antipsychotic monotherapy controls in positive or negative symptoms.⁷Fourteen agents, including certain antidepressants, antioxidants, and mood stabilizers, combined with antipsychotics were found superior to controls for total symptom reductions, while all clozapine augmentation strategies did not outperform controls.⁷However, the effect sizes of the pooled interventions were inversely correlated with the quality of the studies included in the meta-analyses, lowering the confidence in recommending any of the combination strategies.⁷

Results from a meta-analysis showed that augmentation of a current antipsychotic with a different antipsychotic appeared to be more effective than monotherapy in overall symptom reduction in open label or low-quality studies, but not in double-blind, high quality studies.⁵⁰In a meta-analysis of clozapine augmentation studies, only aripiprazole among the 10 add-on antipsychotics analyzed exhibited a greater effect vs placebo in reducing total psychosis,⁵¹consistent with the real-world data that clozapine augmented with aripiprazole reduces rehospitalization risks compared with clozapine alone.⁵²However, the effect of the clozapine/aripiprazole combination on total psychosis was not statistically different when poor-quality studies were excluded from the meta-analysis.⁵¹It was speculated that the treatment response resulting from D₂receptor blockade may already be maximized with clozapine, and therefore, adding a second dopamine blocker would provide limited benefit,⁵³although clozapine at clinical doses was shown to only transiently occupy 47%–72% of D₂receptors without saturating the receptors.^54–56Preliminary data from a small pilot study suggest that clozapine augmentation with cariprazine, which has partial D₂/D₃receptor agonism, may improve overall, negative, and cognition symptoms.⁵⁷The positive effects of cariprazine were hypothesized to be related to its unique pharmacodynamic profile of partial agonism at D₃/D₂receptors and 5-HT_1Areceptors along with antagonism of 5-HT_2Aand 5-HT_2Breceptors.^57,58Further evaluations in large, randomized controlled studies are needed to confirm these effects. A meta-analysis of 2 randomized controlled trials with head-to-head comparisons of augmentation with another antipsychotic versus switching to a new antipsychotic found no significant differences between the 2 strategies in controlling total, positive, or negative symptoms.⁵⁹Overall, current evidence remains inconclusive to show the superior efficacy of antipsychotic combinations compared with monotherapies. This is especially notable considering that most studies included in these meta analyses had small sample sizes, which can cause potential biases in meta-analysis as smaller studies tend to overestimate treatment effects.⁶⁰

Antidepressants, anxiolytics, mood stabilizers, and antioxidants have been studied as adjunctive therapies with antipsychotics.^5,61Results from meta-analyses suggest the beneficial effects of adjunctive antidepressants (eg, selective serotonin reuptake inhibitors) on reducing negative or depressive symptoms are small,^62,63particularly for people with chronic schizophrenia.⁶⁴A comparative, real-world effectiveness study showed that adjunctive antidepressants were associated with lower risks of psychiatric hospitalization and emergency department visits compared with alternative antipsychotic therapy, while poorer outcomes were observed for adjunctive benzodiazepines and mood stabilizers.⁶⁵However, data from 2 earlier meta-analyses did not provide support for the effectiveness of adjunctive antidepressants.^66,67Despite mixed findings, these combination strategies are common in clinical practice. Real-world data from Europe showed that in outpatient treatment, 8%–23%, 7%–19%, and 22%–37% of individuals with schizophrenia who took antipsychotics received adjunctive antidepressants, mood stabilizers, and anxiolytics, respectively.⁶⁸A nationwide register based study among individuals with schizophrenia in inpatient or specialized outpatient care in Finland and Sweden found a rate of 25%–30% for adjunctive antidepressants, 17%–18% for adjunctive mood stabilizers, and 22–33% for adjunctive benzodiazepines and related drugs.⁶⁹

Positive effects with adjunctive anti-inflammatory agents or azapirones have been reported.^70,71A systematic review and meta-analysis of 7 randomized, controlled studies showed that adjunctive N-acetylcysteine versus placebo reduced total and negative schizophrenia symptoms after 24 weeks of treatment and improved the cognitive domain of working memory.⁷²However, the absolute changes may be too small to be clinically meaningful.⁷³In a more recent, randomized, placebo controlled study in people with treatment-resistant schizophrenia who were taking clozapine, no significant benefits were observed in negative symptoms or cognition function at any time point over 1 year of treatment with adjunctive N-acetylcysteine.⁷⁴

Augmenting cognitive remediation therapy with novel medications has also been studied in individuals with schizophrenia. Amphetamine^75,76and memantine⁷⁷were found to enhance auditory discrimination and learning in cognitive training for schizophrenia. When combined with auditory cognitive remediation, D-serine improved plasticity compared with placebo.⁷⁸However, no significant effects on cognitive performance were observed for D-serine,⁷⁹PF-03463275,⁸⁰and iclepertin,⁸¹when these agents were combined with computerized cognitive training compared with training alone.

Concerns exist regarding the potential exacerbation of D₂receptor blocking–related adverse effects with concurrent use of multiple antipsychotics. Combinations of multiple antipsychotics have been reported to cause more side effects than monotherapies, particularly antipsychotic drug-induced parkinsonism, rescue anticholinergic use, and hyperprolactinemia.⁸²An overall greater total dose of antipsychotics can contribute to the increased risk of side effects.^82,83Antipsychotic combinations may also have detrimental effects on cognition,⁸²although a causal relationship has not been definitively established.⁸⁴However, less insomnia was seen when combining 2 D₂receptor antagonists compared with monotherapy.⁵⁰Adjunctive aripiprazole, a D₂receptor partial agonist, was also found to lower prolactin levels and reduce body weight.^50,85

While augmentation of clozapine with other agents has been recommended for clozapine-refractory schizophrenia by the Treatment Response and Resistance in Psychosis Working Group,⁸⁶current treatment guidelines lack direction for other augmentation strategies. The National Institute for Health and Care Excellence guideline recommends against the regular combined use of antipsychotic medications except for short periods of time such as when changing medication.⁸⁷The American Psychiatric Association practice guidelines suggest augmentation approaches for individuals showing no or partial response to antipsychotics, although a trial of clozapine should not be delayed.⁸⁸Combining multiple antipsychotics for refractory schizophrenia is possible by the Royal Australian and New Zealand College of Psychiatrists guidelines, but careful monitoring is required due to potentially increased side effects, hospitalization, and mortality.⁸⁹

RATIONALE FOR TARGETING MULTIPLE NEUROTRANSMITTER SYSTEMS

Increasing evidence suggests that the pharmacologic actions of current antipsychotics, all of which share the ability to block the D₂receptor, are insufficient to adequately control all symptoms of schizophrenia for all individuals. Postmortem and neuroimaging studies revealed differences in dopamine neurotransmission between treatment-responsive and treatment-resistant schizophrenia.^90–93Based on these findings, 2 subtypes of schizophrenia were hypothesized, one with increased dopamine synthesis and release capacity in the striatum (hyperdopaminergic) and the other with unaltered dopaminergic function (normodopaminergic), with the latter type likely involving nondopaminergic mechanisms.⁹⁴Given that all current antipsychotics are D₂receptor blockers, a sizable subgroup of people with schizophrenia with little dopaminergic pathophysiology would not be expected to respond well to current antipsychotic treatments.^94,95Moreover, positive symptoms of schizophrenia are associated with dopamine hyperactivity in the striatum, and negative and cognitive symptoms have been hypothesized to be associated with reduced cortical dopamine signaling.^10,96,97Current antipsychotic drugs acting as D₂receptor functional antagonists could therefore actually impair cognition and secondarily increase negative symptoms. This is supported by evidence that administration of antipsychotics can induce negative symptoms and cognitive dysfunction in healthy volunteers^98,99and increase or cause secondary negative symptoms in people with schizophrenia.³⁰

Therapies combining complementary mechanisms have been shown to provide more clinical benefits than monotherapy when treating diseases with diverse mechanisms, such as diabetes, hypertension, and cancer.^100–102Similarly, targeting multiple mechanisms in schizophrenia may improve treatment effects. Perturbations in acetylcholine, glutamate, GABA, and serotonin neurotransmitter systems have been implicated in schizophrenia and may contribute to negative and cognitive symptoms.^38,97Treatments targeting these nondopaminergic pathways may produce beneficial effects on these symptom domains. The rationale for adjunctive therapy with multiple antipsychotics targeting different mechanisms also stems from the observation that high-efficacy antipsychotic drugs, particularly clozapine, have complex actions with pleiotropic effects on multiple neurotransmitter systems. Compared with other antipsychotics, clozapine is more effective in controlling overall and secondary negative symptoms,^27,103although no clear difference was found between olanzapine and clozapine.^104,105Clozapine is also associated with lower risks of EPS, hospitalization, and all-cause discontinuation.¹⁰⁶While not the first-line drug of choice due to its safety profile, clozapine is the only antipsychotic drug approved by the US Food and Drug Administration (FDA) for treatment-resistant schizophrenia.²²The superior efficacy of clozapine has been postulated to be attributable to its low D₂receptor occupancy, rapid dissociation from D₂receptors, a higher affinity ratio for 5-HT_2Aversus D₂receptors, and high D₄receptor affinity.¹⁰⁷The ability of clozapine to interact with other receptors, including the muscarinic (M₁, M₂, M₃, and M₅), histamine, and α₁-adrenergic receptors may also contribute to its superior efficacy.¹⁰⁷Additionally, clozapine’s effects on glycine transport inhibition¹⁰⁸and glutamatergic modulation,^109,110as well as the M₁and M₄agonism attributable to norclozapine,¹⁰⁹may be involved in its unique efficacy.

Advantages of combining traditional antipsychotic agents with a nondopaminergic agent have been reported. For example, adjunctive sodium benzoate, a D-amino acid oxidase (DAAO) inhibitor that indirectly enhances N-methyl-D-aspartate (NMDA) receptor functions, was shown to improve a variety of symptom domains and cognitive function when added to an ongoing antipsychotic medication.^111,112Improvements in several domains of cognition were also observed for combinations of antipsychotics with acetylcholinesterase inhibitors.¹¹³Taken together, these data suggest that individuals suffering from schizophrenia very likely have complex and heterogeneous pathophysiology. There is hope that they may demonstrate more favorable outcomes when treated with pharmacologic approaches that go beyond D₂receptor blockade.

NOVEL PSYCHOTROPIC AGENTS THAT DO NOT BLOCK DOPAMINE RECEPTORS

Considerable efforts have been dedicated to the research and development of non-D₂agents for schizophrenia over the past 20 years,¹¹⁴although none of these new agents has received FDA approval, with some being unsuccessful in phase 3 programs. For instance, encenicline, a selective partial α7 nicotinic receptor agonist, demonstrated only limited cognitive effects when added to stable antipsychotics in 2 large phase 3 trials.¹¹⁵Three phase 3 studies evaluating adjunctive bitopertin, a glycine transporter 1 (GlyT1) inhibitor, missed their primary efficacy end point of significant improvement in negative symptoms.¹¹⁶Pomaglumetad methionil, a mGlu2/3 receptor agonist, failed to show greater improvement in psychotic symptoms compared with placebo in its pivotal, phase 2 study,¹¹⁷nor did it demonstrate superiority over aripiprazole in a phase 3 study.¹¹⁸However, there is continued interest in the development of novel, nondopaminergic psychotropics for people with schizophrenia who do not respond to approved antipsychotics properly. Several new agents are currently at their later stage of clinical development (Table 1).¹¹⁹

Targeting the Glutamate Receptors

Glutamatergic dysfunction is implicated in the pathophysiology of schizophrenia,^10,11so there is great interest in investigating the therapeutic potential of glutamatergic compounds. However, most of these compounds (eg, mGlu2/3 receptor agonists, riluzole, and memantine) have failed to demonstrate definitive efficacy on positive, negative, or cognitive symptoms.^38,117Results from meta-analyses suggest that NMDA receptor–enhancing agents have little to negligible effect on improving overall cognition when added to antipsychotics.^120,121However, adjunctive NMDA receptor modulators as a group exhibited a small effect on negative symptoms,¹²²and adjunctive NMDA receptor coagonists, such as glycine, D-serine, and D-alanine, have been reported to improve both positive and negative symptoms in some but not in all studies.^123–127In addition, a review of current findings suggests that indirect modulators of the NMDA receptor glycine modulatory site, such as GlyT1 inhibitors or DAAO inhibitors, may offer more benefits, at least on cognition, than direct modulators.¹²⁸

Iclepertin (BI 425809) is a GlyT1 inhibitor that indirectly potentiates glutamate acting on the NMDA receptor, resulting in normalization of the NMDA receptor–mediated cortical excitatory-inhibitory imbalance.¹²⁹A phase 2, randomized controlled study showed significantly greater improvement in cognition with oral, adjunctive iclepertin vs placebo.¹³⁰The treatment was well tolerated, with similar incidence of adverse events (AEs) across treatment groups and low frequencies of serious AEs and AE-related study discontinuations.¹³⁰Several phase 3 trials are ongoing to further investigate the efficacy and safety of adjunctive iclepertin in treating impaired cognition and daily functioning associated with schizophrenia (Table 1).¹²⁹

Luvadaxistat (TAK-831 or NBI-1065844) is a DAAO inhibitor that increases the synaptic levels of the glutamate coagonist D-serine, thereby indirectly modulating the NMDA receptor activity.¹³¹A small, phase 2a, randomized controlled, crossover study did not demonstrate any effect of adjunctive luvadaxistat at an oral, daily dose of 50-mg or 500-mg on learning as assessed with eyeblink conditioning (primary end point). However, the 50-mg dose improved or showed a trend toward improving mismatch negativity (MMN) and auditory steady-state responses, which are the neurocircuitry biomarkers implicated in NMDA receptor function and schizophrenia.¹³¹Luvadaxistat was well tolerated in the study with mild, nontreatment-related AEs.¹³¹The phase 2, randomized controlled, INTERACT study showed that 12 weeks of treatment with luvadaxistat added to current antipsychotics did not improve negative symptoms of schizophrenia (primary end point) in adults with schizophrenia.¹³²However, INTERACT met its secondary end points of improving cognitive function,¹³²and luvadaxistat is being further investigated for the treatment of cognitive impairment in schizophrenia (Table 1).

Evenamide is a highly selective, voltage-gated sodium channel blocker that normalizes excessive glutamate release due to NMDA receptor hypofunction.¹³³In a pilot, phase 2, open-label trial, evenamide added to an ongoing antipsychotic was shown to improve the overall symptoms of schizophrenia from baseline to 6 weeks, 6 months, and 1 year, with favorable tolerability, in people with treatment-resistant schizophrenia.¹³³Evenamide also demonstrated progressively increasing efficacy as assessed with the Clinical Global Impression (CGI)- Severity and CGI-Change scales.¹³³No clinically important weight gains, metabolic syndrome, or EPS were noted in the study.¹³³A phase 3, randomized controlled study has been planned to further evaluate evenamide in treatment resistant schizophrenia (Table 1).¹³⁴

Targeting the Muscarinic Acetylcholine Receptors

KarXT (xanomeline and trospium chloride) is an oral, investigational treatment that combines xanomeline, a dual M₁and M₄preferring muscarinic acetylcholine receptor agonist, with trospium chloride, a peripherally restricted pan-muscarinic acetylcholine receptor antagonist.¹³⁵Xanomeline was initially developed to treat the cognitive symptoms of Alzheimer disease but unexpectedly demonstrated efficacy in reducing and preventing psychosis symptoms (eg, delusions and hallucinations) in people with Alzheimer disease.¹³⁶A later, proof-of-concept, phase 2 trial demonstrated antipsychotic-like effects of xanomeline in people with schizophrenia or schizoaffective disorder.¹³⁷However, further clinical development of xanomeline was hampered by its significant peripheral cholinergic side effects.¹³⁸The addition of trospium chloride to xanomeline reduces the incidence of these cholinergic AEs in healthy volunteers, making the development of the combination, KarXT, for schizophrenia possible.¹³⁹In the phase 2, randomized controlled, EMERGENT-1 trial, KarXT significantly improved overall, positive, and negative symptoms vs placebo in people with acute exacerbations of schizophrenia.¹³⁵Post hoc analyses from EMERGENT 1 also revealed cognitive improvement with KarXT that was independent of the improvement in positive symptoms in participants with baseline clinical cognitive impairment.¹⁴⁰Procholinergic (nausea or vomiting) or anticholinergic (dry mouth or constipation) AEs occurred early in treatment and were transient in nature.¹⁴¹Incidence of weight gain and EPS was similar with KarXT and placebo, and no clinically meaningful changes in metabolic parameters were observed.^135,141The randomized, placebo-controlled, phase 3, EMERGENT-2 trial further demonstrated the efficacy of KarXT, which significantly reduced the Positive and Negative Syndrome Scale (PANSS) total score versus placebo in acutely psychotic hospitalized adults with schizophrenia after 5 weeks of treatment (primary end point).¹⁴²Frequencies of treatment-emergent EPS, akathisia, weight gain, and somnolence were similar across treatment groups.¹⁴²KarXT is being further investigated as a monotherapy and as an adjunctive therapy for schizophrenia in several other ongoing phase 3 studies (Table 1).

Emraclidine (CVL-231) is an oral, brain-penetrant, highly selective positive allosteric modulator of the muscarinic M₄receptor.¹⁴³A two-part, phase 1b trial evaluated the safety, tolerability, and pharmacology of multiple ascending doses of emraclidine monotherapy in people with schizophrenia.¹⁴³The study demonstrated a favorable safety profile and potential antipsychotic activities of emraclidine without need for dose titration.¹⁴³Both the 30-mg (daily) and 20-mg (twice daily) doses significantly improved overall symptoms, and the 30-mg dose also significantly improved the CGI-Severity score.¹⁴³No treatment effects on EPS were noted, gastrointestinal AEs were infrequent, and emraclidine-associated increases in heart rate and blood pressure were modest and transient.¹⁴³Emraclidine is currently in phase 2 of clinical development as monotherapy (Table 1).

Different from KarXT, emraclidine selectively stimulates the M₄receptor and therefore may reduce peripheral side effects, such as increased gastrointestinal motility and increased secretions associated with peripheral M₁receptor stimulation.¹⁴⁴Dosing schedules are different for the 2 agents. Flexible dosing (twice daily) is used for KarXT and could complicate efficacy evaluation and affect patient adherence compared with the constant dosing (daily) used for emraclidine.

Targeting the Serotonin and Other Neurotransmitter Receptors

Pimavanserin is an oral, selective inverse agonist and antagonist of 5-HT_2A¹⁴⁵approved for the treatment of hallucinations and delusions associated with Parkinson disease.¹⁴⁶The activity of pimavanserin for the treatment of schizophrenia was tested in 2 randomized controlled trials.^147–149In the phase 2, ADVANCE study, adjunctive pimavanserin significantly improved negative symptoms compared with placebo in people with predominant negative symptoms of schizophrenia who were receiving a background antipsychotic medication; the treatment was well tolerated, with no clinically significant differences in vital signs, body weight, and EPS between the 2 treatment groups.¹⁴⁸Higher pimavanserin exposure was associated with improved response, without increasing the incidence of key AEs, such as anxiety, headache, insomnia, and somnolence.¹⁴⁷In the phase 3, ENHANCE study in adult outpatients with schizophrenia and an inadequate response to their ongoing antipsychotics, adjunctive pimavanserin failed to demonstrate an improvement in the PANSS total score (primary end point) but did show a trend toward improvement in negative symptoms.¹⁴⁹Pimavanserin was well tolerated in the study, with a low rate of serious AEs and AE-related discontinuations.¹⁴⁹However, adjunctive pimavanserin did not demonstrate significant improvement in negative symptoms of schizophrenia (primary end point) compared with adjunctive placebo in the phase 3, randomized controlled ADVANCE-2 study¹⁵⁰(Table 1), and further development of pimavanserin has been stopped.

Roluperidone (MIN-101) is an oral antagonist of σ₂and 5-HT_2Areceptors; it also binds to α₁-adrenergic receptors but has no or low binding affinity for dopaminergic, muscarinic, cholinergic, and histaminergic receptors.¹⁵¹Improvements in negative symptoms, cognitive performance, and social functioning with roluperidone monotherapy were observed in individuals with stable positive and concurrent negative symptoms of schizophrenia in a phase 2b, randomized controlled trial.^151–154No changes in vital signs, laboratory values, and EPS ratings were observed in the study and changes in body weight were small.¹⁵¹A larger, phase 3 trial failed to demonstrate statistical significance on the primary outcome of negative symptom improvement of the low (32-mg/day) and high (64-mg/day) roluperidone doses as planned, although the higher dose did demonstrate nominally statistically significant improvement vs placebo in the modified intent-to-treat population.¹⁵⁵Similarly as in the phase 2b trial, roluperidone was not associated with notable changes in weight, plasma prolactin, and EPS ratings.¹⁵⁵Open-label extension studies of the 2 trials demonstrated sustained effects of roluperidone up to 40 weeks on negative symptoms and social functioning.¹⁵⁶The new drug application for roluperidone for the treatment of negative symptoms in schizophrenia was filed last year but was recently rejected by the FDA.¹⁵⁷

Ulotaront (SEP-363856) is an oral agonist of trace amine–associated receptor 1 (TAAR1) and 5-HT_1Areceptors that has no binding affinity for D₂or 5-HT_2Areceptor.¹⁵⁸Ulotaront monotherapy was shown to improve total symptoms of schizophrenia compared with placebo in people with an acute exacerbation of schizophrenia in a 4-week, phase 2, randomized controlled trial,¹⁵⁹and the improvement persisted during the subsequent 26-week, open-label extension study.¹⁶⁰Ulotaront was generally well tolerated; the incidence rates of AEs related to EPS, metabolic syndrome, and serum prolactin levels were similar across treatment groups during the placebo-controlled phase¹⁵⁹and remained minimal during the extension phase.¹⁶⁰A relatively high completion rate (67%) was observed in the extension study.¹⁶⁰Moreover, preclinical evidence suggests that ulotaront can reduce weight gain associated with common antipsychotics, such as olanzapine.¹⁶¹Further investigations on the efficacy and safety of ulotaront for the treatment of schizophrenia are ongoing (Table 1). However, recent results from the phase 3, randomized controlled, DIAMOND 1 and DIAMOND 2 trials showed no significant improvement in overall symptoms with ulotaront versus placebo in acutely psychotic adults with schizophrenia, although the high response to placebo in the 2 trials may possibly obscure a significant drug effect.¹⁶²

PERSONALIZED TREATMENT

Schizophrenia is a highly heterogeneous disease, and significant interindividual differences likely exist in clinical characteristics and underlying pathophysiology.^{90,93,163–165}Response to antipsychotic medications varies considerably across individuals with schizophrenia.^17,21,166By tailoring the treatment to the clinical, or ideally biological, characteristics of each individual, a personalized approach could optimize the treatment response. As part of the approach, identifying biomarkers that are predictive of antipsychotic drug outcomes could markedly facilitate informed selection of treatment for individuals with schizophrenia.^167,168

Pharmacogenetic studies have identified a number of genetic variants that are associated with antipsychotic efficacy and side effects, such as antipsychotic-induced weight gain, metabolic syndrome, risk of tardive dyskinesia, antipsychotic related prolactin levels, and clozapine-induced agranulocytosis.^167,169,170In particular, dose reductions for aripiprazole and clozapine are recommended by the FDA for the CYP2D6 poor metabolizers who carry nonfunctioning variants of the cytochrome P450 2D6 enzyme to prevent potential drug-associated AEs caused by increasing drug exposure.^22,171However, the clinical relevance of these identified genetic markers may be limited due to their small effect sizes and the need for them to be validated in large, well-designed studies.^167,169

Electroencephalography (EEG) features have been linked to antipsychotic treatment responses¹⁷²and can serve as a useful research tool for studying the treatment effect of an antipsychotic agent. One of the EEG-based biomarkers is MMN. In the recent phase 2a study of luvadaxistat, MMN responses to treatment aligned with the cognitive improvement produced by luvadaxistat at the same dose in the parallel, INTERACT study, suggesting the potential of MMN as a predictive biomarker for antipsychotic effects.¹³¹With the potential establishment of procholinergic antipsychotics for schizophrenia treatment, markers that can predict response to procholinergic vs dopaminergic agents will be useful when choosing effective treatment. Possible muscarinic deficit markers include resistance to antidopaminergic agents, visual hallucinations, severe cognitive deficits, reduced MMN, presence of antimuscarinic antibodies, and reduced M₁receptor availability on radionucleotide imaging.¹⁷³Additional neuroimaging, proteomic, and metabolic biomarkers have also been identified for schizophrenia.^168,174

It is believed that biomarker testing may help stratify individuals with heterogeneous characteristics of schizophrenia into relatively more homogeneous subgroups and aid in the selection of optimal antipsychotic treatment.¹⁷⁵This may also ultimately provide a framework for a rational approach to combination treatment strategies.

CONCLUSIONS

Current antipsychotic medications are all D₂receptor antagonists or partial agonists and are associated with suboptimal efficacy and intolerable side effects in many individuals with schizophrenia. While combinations of currently prescribed antipsychotics are commonly used to improve inadequate treatment response, evidence supporting their superior efficacy over antipsychotic monotherapies is inconclusive. It is highly likely that the etiology and pathophysiology of schizophrenia is quite heterogeneous, and thus, subsets of people with schizophrenia are likely unable to achieve optimal treatment response to the dopamine receptor–blocking agents, highlighting the need for targeting other, non-D₂receptors. Clinical findings on investigational antipsychotic agents and innovative psychotropics that act via novel, nondopaminergic mechanisms are encouraging. If the results with these novel agents can be corroborated, they may serve as useful adjunctive or cotreatments in people with schizophrenia who do not derive sufficient benefits from current treatment strategies.

Article Information

Published Online: August 19, 2024. https://doi.org/10.4088/JCP.23nr15240
© 2024 Physicians Postgraduate Press, Inc.
Submitted: December 29, 2023; accepted May 23, 2024.
To Cite: Kinon BJ, Leucht S, Tamminga C, et al. Rationale for adjunctive treatment targeting multiple mechanisms in schizophrenia. J Clin Psychiatry. 2024;85(3):23nr15240.
Author Affiliations: Karuna Therapeutics, Boston, Massachusetts (Kinon and Paul (former employees), Bristol Myers Squibb, Princeton, New Jersey (Marcus); Department of Psychiatry and Psychotherapy, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany (Leucht); Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, Texas (Tamminga); Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana (Breier).
Corresponding Author: Bruce J. Kinon, MD ([email protected]), c/o Alicia Meli, MS, Bristol Myers Squibb Corporate Headquarters, Route 206 & Province Line Road, Princeton, NJ 08543
Relevant Financial Relationships: Drs Kinon and Paul are former employees of Karuna Therapeutics. Dr Marcus is an employee of Bristol Myers Squibb. Dr Leucht has received honoraria as an advisor/consultant and/or for lectures and/or for educational material from Alkermes, Angelini, Apsen, Eisai, Gedeon Richter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Merck Sharp and Dome, Mitsubishi, Neurotorium, Novo Nordisk, Otsuka, Recordati, Roche, Rovi, Sanofi Aventis, and Teva. Dr Tamminga has received honoraria as a consultant from Karuna and Kynexis and is a founding partner of Kynexis. Dr Breier is a consultant for Karuna, BioXcel, and Neumarker.
Funding/Support: Karuna Therapeutics, a Bristol Myers Squibb company, provided support for the medical writing assistance.
Role of the Sponsor: The Sponsor had the opportunity to review during manuscript development, but the authors had final control of the content included in the manuscript.
Acknowledgment: We thank Hui Zhang, PhD (Precise Publications); Alicia Meli, MS (Bristol Myers Squibb); and Nichole Neugebauer, PhD (Bristol Myers Squibb) for their medical writing and editorial assistance. Hui Zhang declares no conflicts of interest. Alicia Meli and Nichole Neugebauer are employees of Bristol Myers Squibb.

Clinical Points

Currently available antipsychotics act as D₂receptor antagonists/partial agonists, which may lack effectiveness for some individuals with schizophrenia.
Treatments combining multiple mechanisms of action hold promise in addressing some of the unmet treatment needs in schizophrenia.
Novel agents without direct D₂receptor blocking may be useful to augment current antipsychotics’ effects in individuals with inadequate response/intolerance to current schizophrenia treatment.

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Rationale for Adjunctive Treatment Targeting Multiple Mechanisms in Schizophrenia

Abstract

LIMITATIONS OF CURRENT ANTIPSYCHOTIC MEDICATIONS

ADJUNCTIVE AND COMBINATION TREATMENT STRATEGIES

RATIONALE FOR TARGETING MULTIPLE NEUROTRANSMITTER SYSTEMS

NOVEL PSYCHOTROPIC AGENTS THAT DO NOT BLOCK DOPAMINE RECEPTORS

Targeting the Glutamate Receptors

Targeting the Muscarinic Acetylcholine Receptors

Targeting the Serotonin and Other Neurotransmitter Receptors

PERSONALIZED TREATMENT

CONCLUSIONS

Article Information

Clinical Points

References

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