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. 2021 Jun 29;12(9):1459–1475. doi: 10.1039/d1md00096a

Progress in mechanistically novel treatments for schizophrenia

James Neef 1, Daniel S Palacios 1,✉
PMCID: PMC8459322  PMID: 34671731

Abstract

Currently available pharmacological treatments for schizophrenia derive their activity mainly by directly modulating the D2 receptor. This mode of action can alleviate the positive symptoms of schizophrenia but do not address the negative or cognitive symptoms of the disease and carry a heavy side effect burden that leads to high levels of patient non-compliance. Novel mechanisms to treat the positive symptoms of schizophrenia with improved tolerability, as well as medicines to treat negative and cognitive symptoms are urgently required. Recent efforts to identify small molecules for schizophrenia with non-D2 mechanisms will be highlighted, with a focus on those that have reached clinical development. Finally, the potential for disease modifying treatments for schizophrenia will also be discussed.

Recent efforts to identify small molecules for schizophrenia with non-D2 mechanisms will be highlighted. The potential for disease modifying treatments for schizophrenia will also be discussed.graphic file with name d1md00096a-ga.jpg

Introduction

Schizophrenia is a devastating psychiatric illness that affects approximately 1% of the global population and is a leading cause of disability worldwide.1 The presentation of schizophrenia is complex and varied, but there are three core features that characterize this disease: positive symptoms, negative symptoms and cognitive impairment. The positive symptoms of schizophrenia are those most often associated with this disease and present as an inability to correctly perceive reality through frequent hallucinations and delusions, clinical signs otherwise known as psychosis. Conversely, the negative symptoms of schizophrenia include social withdrawal, reduction in speech, apathy and lack of motivation. Finally, cognitive impairment in schizophrenia often manifests as disorganized speech and/or thoughts, executive function deficits and impaired attention. Combined, these symptoms can be debilitating and prevent individuals with schizophrenia from leading full, independent lives. The positive symptoms of schizophrenia can be symptomatically managed through the use of antipsychotics, but, as will be discussed further below, these treatments are associated with significant adverse events that are poorly tolerated. Furthermore, while meta-analyses suggest that antipsychotics may also treat negative2 and cognitive symptoms3 no agents have been approved specifically to treat these facets of the disease and so there is clearly an urgent need for new treatments for schizophrenia.

Antipsychotics are a relatively old class of pharmaceuticals, with the first example, chlorpromazine (1, Fig. 1), being developed in the 1950s. Since that time, additional antipsychotics have been developed, which are generally termed first-generation (typical), second-generation and third generation antipsychotics (atypical).4 While second generation antipsychotics interact with multiple GPCRs, notably the serotonin receptors, and third generation antipsychotics function as D2 partial agonists,5 all currently approved medications for schizophrenia derive their efficacy at least in part by interacting with the dopamine receptors, mainly D2. Thus, even though a number of antipsychotics have been developed since the advent of chlorpromazine, there has been relatively little target innovation in this field. While effective in some instances, D2 antipsychotics come with significant adverse events, both on and off target, that lead to overall poor tolerability. Because these medications directly impact striatal dopamine signaling, an undesirable aspect of this pharmacology are the development of a series of motor disturbances, known as extrapyramidal side effects (EPS).6 The most common of these extrapyramidal side effects are akathisia, exemplified by an unpleasant feeling of restlessness accompanied by restless movement, and drug induced Parkinsonism. While akathisia and Parkinsonism are acute and typically disappear when D2 antipsychotics are discontinued, long term motor disturbances, such as uncontrolled mouth moving or grimacing, known as tardive dyskinesias (TD) can arise in individuals that have taken these medications chronically. TD may continue for months or even years after discontinuing treatment and while TD is more prevalent in individuals taking older antipsychotics such as haloperidol (3, Fig. 1) or chlorpromazine, this side effect remains a significant risk in more recently approved medications.7

Fig. 1. Structures of representative antipsychotics. On the left are depicted common first generation antipsychotics while the middle shows typical second generation molecules and the right hand panel shows third generation antipsychotics.

Fig. 1

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In addition to the on-target extrapyramidal side effects, most antipsychotics also cause off-target metabolic side effects including weight gain, increases in lipid levels and insulin resistance.8 These metabolic effects significantly increase the risk of cardiovascular disease in patients taking antipsychotics and contribute to the overall higher risk of mortality in the schizophrenic population.9 Collectively, the extensive and serious adverse events associated with antipsychotics are poorly tolerated and overall lead to poor patient compliance. In the seminal CATIE antipsychotic trial,10 the investigators found that between 64 and 82% of patients stopped taking their medication within 18 months, with the severity of the side effects being a major reason for discontinuation of therapy. Similar rates of discontinuation for oral antipsychotics have been observed by other investigators11 and in surveys of individuals taking antipsychotics, adverse effects are cited by patients as giving a negative overall experience with treatment.12

With all medications currently available for schizophrenia operating through the D2 and 5-HT receptors, there are limited alternatives for treatment resistant schizophrenia.13 Up to 30% of schizophrenic patients do not respond to commonly prescribed antipsychotics and for this population, the sole option is clozapine (4, Fig. 1).14,15 Clozapine also functions mainly through the D2 receptor, but for reasons that are incompletely understood, it has some efficacy in patients that have failed to respond to other D2 antipsychotics.16 Among antipsychotics, clozapine is known as a treatment of last resort due to its serious, life-threatening adverse events including agranulocytosis, myocarditis and gastrointestinal hypomotility.17 Even with these extremely severe side effects, patients still take clozapine, though, which shows how desperate individuals are to control their symptoms and highlights that novel mechanisms to treat even just the positive symptoms of schizophrenia would transform lives.

The search for new targets is challenged, however, by the poorly understood pathogenesis and pathophysiology of schizophrenia. Genetic analyses have implicated genes involved in inflammation18 and synaptic development19 in the pathogenesis of schizophrenia but environmental factors such as maternal infection20 and parental age appear to play a role as well.21 In addition, current neurochemical models of schizophrenia do not point to obvious therapeutic targets. The observation that functional D2 antagonism can alleviate the positive symptoms of schizophrenia has led to the hypothesis that excessive dopamine signaling in the striatum is the basis for the disease.22 However, as mentioned above, D2 antipsychotics do not address negative or cognitive symptoms and so the dopamine hypothesis fails to explain the full spectrum of schizophrenia symptoms. Despite the poor understanding of this complex disease, multiple non-D2 mechanisms have been identified as potential targets for schizophrenia and a selection of these will be reviewed below. To sharpen the focus of discussion, we have chosen to highlight mechanisms with small molecules that have entered or will soon enter clinical development and have not been reviewed recently (i.e. the TAAR1 ligands) or to provide updates on mechanisms with ongoing trials (e.g. the PDE ligands). This review, however, will not discuss recent developments in targeting the mGlu receptors, GABAA receptors or α7 nACh receptors because these topics have been extensively reviewed recently.23 Finally, we will summarize emerging genetic and functional data that may point towards possible disease modifying treatments for schizophrenia, which remains the ultimate goal of the field.

M4 receptor

The muscarinic receptors M1–M5 are G-protein coupled receptors (GPCRs) that modulate the parasympathetic nervous system through activation by acetylcholine.24 The genesis of M4 as a target for schizophrenia arose from clinical studies of the M1/M4 preferring agonist xanomeline (10, Fig. 2) that was originally developed by Eli Lilly and Company as a M1 agonist for cognitive improvement in Alzheimer's disease. In addition to cognitive decline, Alzheimer's patients also frequently suffer from dementia related psychosis25 and xanomeline was found to dose dependently decrease hallucinations, delusions and agitation in this population.26 Furthermore, the antipsychotic efficacy of xanomeline was also confirmed in a small pilot study in schizophrenic patients, where improvements in negative and cognitive symptoms were also noted,27 suggesting the generality of this mechanism for treating psychosis in both neurodegenerative and psychiatric diseases. The clinical potential of xanomeline is tantalizing, but it was not fully developed as a single agent because it required thrice daily dosing for efficacy and non-selective muscarinic agonism led to significant, poorly tolerated gastrointestinal side effects. At the time of the initial clinical trial, it was not clear which muscarinic receptor(s) was responsible for the antipsychotic activity of xanomeline. Later studies with xanomeline in M1 and M4 knockout mice using the amphetamine induced locomotor activity (LMA) experiment as a model of acute psychosis subsequently demonstrated M4 to be the primary antipsychotic efficacy target.28,29 This genetic evidence was further validated pharmacologically by selective positive allosteric modulators (PAMs) of M4 identified by Eli Lilly and Vanderbilt University that were active in the rodent LMA experiment (see below).30,31 While the antipsychotic mechanism of M4 agonists remains unclear, it has been suggested that activation of this receptor suppresses striatal dopamine release in concert with the CB2 cannabinoid receptor, consistent with the dopamine hypothesis of schizophrenia.32

Fig. 2. Structures of xanomeline and compounds from the Merck M4 PAM research program.

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Since these preclinical validation experiments, multiple groups have attempted to capitalize on the M4 receptor as a novel antipsychotic target with several of these efforts leading to small molecules currently in clinical development. First, given that most of the AE for xanomeline result from activation of the peripheral muscarinic system, Karuna Therapeutics is currently developing KarXT, a combination of xanomeline and the peripherally restricted muscarinic antagonist trospium chloride, which is currently approved for overactive bladder, to block the peripheral side effects of xanomeline. A phase II trial of KarXT in schizophrenia validated this concept with KarXT showing reduced peripheral side effects relative to xanomeline monotherapy, and an improvement in the positive symptoms of schizophrenia (NCT03697252).33,34

In contrast to the peripheral blocking strategy, an alternative approach would be to develop a highly selective M4 agonist to achieve the efficacy of xanomeline without the intolerable GI side effects mediated by M1, M2 and M3. The high degree of homology in the orthosteric binding site of the muscarinic receptors has made this a long-standing challenge in the field, and so some groups instead decided to investigate the potential of PAMs for M4. Through the binding of an allosteric site, PAMs can directly activate GPCRs as well as increase the efficacy and/or potency of native ligands,35 such as acetylcholine in the case of M4. The reader is referred to more in-depth reviews on this topic36,37 while this discussion will focus on two molecules, MK-4710 (14, Fig. 2) and CVL-231 (structure not yet disclosed) that are approaching or are in active clinical development.

For the identification of the Merck M4 PAM, Schubert and coworkers set out to identify a tool molecule that was active against both human and rat M4 to better understand the in vivo pharmacology of M4 potentiation.38 Beginning with a bi-substituted pyridine (11, Fig. 2) from a HTS screen, an optimization campaign centered on M4 potency, selectivity and ADME properties to enable high CNS exposure was undertaken that ultimately led to the discovery of a cinnoline tool compound (12, Fig. 2). As desired, 12 was active on both human (IC50: 17 nM) and rat (IC50: 29 nM) M4, was >100× selective against M1–M3 and M5 and was highly permeable to facilitate good brain penetration. After confirming the in vivo efficacy of 12 in the rat LMA model, rats were given increasing doses of 12 to determine if M4 selectivity leads to fewer side effects in comparison to xanomeline. When dosed at 10 and 100 mg kg−1i.p., 12 had 3.2 fold and 7.9 fold higher exposures, respectively, than the efficacious exposure for the LMA experiment (25 nM). At the 100 mg kg−1 dose, only mild sedation and pupil constriction was noted, in contrast to xanomeline, which led to significant salivation and pupil constriction. These key results suggest that M4 selectivity does indeed have the potential to reduce muscarinic side effects in the clinic compared to what was observed for xanomeline. Presumably, these efforts led to the development of clinical candidate MK-4710, which was disclosed at the Fall 2020 ACS meeting39 but neither the optimization campaign nor clinical development plan for this molecule have been disclosed.

In addition to providing key preclinical data, 12 also informed the development of a M4 PAM PET ligand to map the M4 receptors within the brain and determine target engagement in vivo.40 Using 12 as an entry point, Tong and coworkers optimized the scaffold specifically for PET applications which require high affinity, high permeability and low non-specific binding to provide a high specific signal as well as a means to install a radionuclide in the setting of a clinical PET center. These design criteria led to the identification of [11C]MK-6884, (13, Fig. 2). To demonstrate utility of this imaging agent, monkeys were pre-dosed with 12 which significantly reduced the striatal binding of [11C]MK-6884, suggesting that it could be used to clinically determine M4 receptor occupancy/plasma exposure relationships. [11C]MK-6884 has subsequently been tested in a small pilot study to map M4 receptors in Alzheimer's disease and showed initial promise in this application.41

The other advanced M4 PAM, CVL-231, originated from the Pfizer neuroscience unit and is currently being developed by Cerevel Therapeutics. The structure and development of CVL-231 have not yet been disclosed, but Cerevel corporate presentations give some insight into the pharmacology of this molecule.42 While CVL-231 evidently lacks the GI side effects of xanomeline in preclinical species, it may affect the cardiovascular system. For example, CVL-231 increases the systolic blood pressure of mice but this increase dissipates with repeat dosing of CVL-231 and, importantly, efficacy as judged by an LMA experiment is not affected by this repeat dosing. A heart rate increase was also observed in dogs upon the initial dose but again this effect is attenuated over multiple days of dosing. To evaluate the safety and tolerability of CVL-231 in schizophrenic patients, a multiple ascending dose phase 1b study is currently underway with an estimated completion in June 2021 (NCT04136873).

Since the M4 activation mechanism of an M4 PAM is slightly different than xanomeline, some groups alternatively tried to solve the difficult challenge of achieving sub-type selectivity with an orthosteric agonist. Progress has been made in this area, despite the significant selectivity hurdles and representative dual M1/M4 and M4 preferring agonists have been identified as shown in Fig. 3. These molecules typically rely on an ethyl carbamate for M4 activity and as reviewed by Takai and coworkers in their discussion of the 4-methyl piperidine (15) and bridged piperidine (16),43 alterations both proximate and distal to the carbamate can significantly influence muscarinic selectivity. An ethyl carbamate also features prominently in dual M1/M4 and M4 selective agonists from Sosei Heptares. Representative structures from this group such as a spirocyclic cyclohexane (17)44 and a spirocyclic pyrrolidine (18)45 are shown in Fig. 3. The work on this target at Sosei Heptares led to HTL0016878 (structure not disclosed) that was advanced to phase I clinical trials. HTL0016878 was tested in healthy adult and elderly individuals (NCT03244228) and the trial was concluded in November 2019, but the results have not been published and the current development status of HTL0016878 is unknown.

Fig. 3. Structures of representative dual M1/M4 or selective M4 orthosteric agonists mentioned in the text.

Fig. 3

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As discussed in this section, the clinical data for xanomeline is encouraging and preclinical data suggests that selective M4 agonists and PAMs may achieve the efficacy of xanomeline without the intolerable peripheral muscarinic side effects. In the context of schizophrenia, the initial pilot study with xanomeline showed improvements in the positive, negative and cognitive aspects of the disease and if a selective M4 agonist or PAM could reproduce this efficacy it would be a transformational medicine for schizophrenia. Furthermore, since xanomeline improved psychotic symptoms in Alzheimer's patients, a selective M4 agonist could be broadly useful as a symptomatic treatment for psychosis across neuropsychiatric and neurodegenerative diseases and would undoubtedly become a core treatment option in the field.

5-HT2A receptor

The 5-HT2A receptor is part of the serotonin receptor family of GPCRs that is expressed widely in the CNS and there are a couple lines of evidence suggesting a role for this receptor in schizophrenia. One is that hallucinogens such as LSD and psilocybin are agonists of 5-HT2A, and can cause temporary effects similar to the positive symptoms of schizophrenia in healthy individuals.46 The second is the observation that clinically efficacious second-generation antipsychotics such as melperone and clozapine are potent antagonists of this receptor, in addition to their D2 activity.47 While these two pieces of evidence are correlative, to date, strong mechanistic and/or genetic data has not emerged to further support the role of 5-HT2A in schizophrenia. However, based on the associations mentioned above, scientists at Acadia Pharmaceuticals screened a collection of compounds to identify selective 5-HT2A inverse agonists and developed an initial hit into tool compound AC90179 (19, Fig. 4). This compound was profiled against a broad range of receptors and was found to have no D2 affinity, as desired, and was also tested in a rat amphetamine LMA model and found to be active in vivo.48 AC90179 is not orally bioavailable, though, and so additional optimization efforts were undertaken that led to identification of ACP-103 (20, aka pimavanserin, Fig. 4).49 ACP-103 is potent on 5-HT2A (pIC50: 8.73), lacks appreciable D2 activity and is active in the rat LMA model when dosed orally.

Fig. 4. Structures of the 5-HT2A ligands being investigated as treatments for schizophrenia.

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The potential of pimavanserin in schizophrenia was first suggested in preclinical experiments demonstrating that the efficacy of haloperidol and risperidone in the MK-801 induced rat LMA model of acute psychosis can be enhanced by pimavanserin.50 Building on this work Meltzer and coworkers tested pimavanserin as an adjunct to sub-therapeutic doses of haloperidol and risperidone in a small phase II study and the authors found that while pimavanserin did enhance the efficacy of risperidone it did not alter the effect of sub-efficacious haloperidol.51 The phase III ENHANCE trial (NCT02970292) tested adjunct pimavanserin in a larger population, but pimavanserin failed to improve upon the primary endpoint (improvement in the Positive and Negative Syndrome Scale, aka PANSS, commonly utilized for evaluating symptom severity) beyond the placebo arm.52 In addition to being investigated as an adjunctive therapy, pimavanserin has also been investigated as a single agent in schizophrenia, initially in a pilot study of clozapine resistant schizophrenia.53 Treatment with pimavanserin did demonstrate a reduction in hallucinations and delusions, but there was no control arm in this study and only one dose of pimavanserin was tested, making the generality of this response difficult to predict. To clarify these results and identify patients which will be most likely to respond to pimavanserin monotherapy in schizophrenia, the Sub-Zero trial has recently been initiated (NCT03994965).54 This trial will administer pimavanserin to antipsychotic naive schizophrenic patients and use PET imaging to determine the density of 5-HT2A receptors in the frontal cortex of these individuals. The mechanistic hypothesis is that patients with the lowest levels of 5-HT2A binding potential will be the greatest responders to pimavanserin treatment and the goal of this study is to facilitate patient selection for pimavanserin treatment in the future.

In addition to the studies summarized above, pimavanserin is also being investigated as a supplemental therapy to improve the negative symptoms of schizophrenia. In the phase II ADVANCE trial (NCT02970305) pimavanserin was given to schizophrenic patients with predominately negative symptoms in addition to maintaining the antipsychotic therapy that controlled their positive symptoms. This was a 26 week randomized trial with three doses of pimavanserin, 10, 20 and 34 mg and the topline results demonstrated a statistically significant improvement in the primary endpoint, the Negative Symptom Assessment-16 (NAS-16) scale, though no improvement was found in the secondary endpoint, the Personal and Social Performance scale (PSP).55 For improvements in the NAS-16 score, the investigators found the greatest effect in patients taking the top 34 mg dose and based on this result, the ADVANCE-2 trial using only the 34 mg dose has been initiated to investigate the potential of pimavanserin to alleviate the negative symptoms of schizophrenia (NCT04531982).

The discussion to this point has focused on psychosis in the context of schizophrenia, but psychosis is a common facet of many neuropsychiatric and neurodegenerative diseases including Alzheimer's disease, Huntington's disease, unipolar depression, bipolar disorder and Parkinson's disease. D2 antipsychotics are often used outside the context of schizophrenia to treat psychosis56 but the adverse effects of these therapies significantly limit their utility, particularly in the elderly population, which have a higher risk of mortality when taking D2 antipsychotics for dementia related psychosis.57 Despite this risk, D2 antipsychotics are often prescribed off-label for this indication, demonstrating the critical need for safe and effective therapies not only in the context of dementia related psychosis but also more generally for psychosis in different disease contexts. To address this gap, pimavanserin was developed specifically in Parkinson's disease psychosis, for which it was approved in 2016.58 More recently, pimavanserin was also evaluated more generally in dementia related psychosis, but the results were mixed.59,60 Despite the unclear outcome, however, pimavanserin was given breakthrough status by the FDA in dementia related psychosis, evidence of the clear need for antipsychotics that can be used safely outside the context of schizophrenia.

A second 5-HT2A ligand that is being evaluated for schizophrenia is the mixed 5-HT2A σ2 receptor antagonist MIN-101 (21, aka roluperidone, Fig. 4). The discovery and molecular pharmacology of this molecule have not been disclosed but it has been investigated as a treatment for the negative symptoms of schizophrenia. The initial phase II results for MIN-101 were promising, with statistically significant improvement in the PANSS negative score observed for MIN-101 compared to placebo.61 However, the efficacy observed in this phase II study did not reproduce in a phase III study (NCT03397134) where MIN-101 failed to meet its primary and secondary endpoints. Confounding these results was a large placebo effect at week 12, and since there was some early signs of functional improvement, as measured by PSP at the top dose of 64 mg, the company has suggested MIN-101 merits continued investigation for the treatment of primary negative symptoms and is consulting with the FDA regarding next steps for MIN-101 development in this larger study.62

Trace-amine associated receptor 1

Trace amine associated receptor 1 (TAAR1) is an intracellular GPCR that is widely expressed throughout the body and binds trace amines such as p-tyramine and beta-phenylethylamine. Abnormal concentrations of these trace amines have been implicated in psychiatric diseases, including schizophrenia, suggesting the relevance of this target.63 In addition, investigations with TAAR1 knockout mice demonstrated that TAAR1 mediates dopaminergic neurotransmission, further supporting a role for this receptor in schizophrenia. Finally, while there is no direct evidence linking TAAR1 to schizophrenia, this gene is located in an area of the chromosome that have been implicated in the disease.64 As will be discussed below as well, the identification of tool compounds by researchers at Roche also supports TAAR1 as a target for schizophrenia.

The dihydrooxazole RO5166017 (22, Fig. 5) was identified as a potent agonist of TAAR1 with activity in HEK293 cells expressing mouse, rat, human and monkey TAAR1.65 To test the antipsychotic potential of this mechanism, Revel and coworkers tested RO5166017 in the cocaine stimulated LMA model and found that it dose-dependently reduces cocaine induced hyperlocomotion, similar to olanzapine. Furthermore, the authors demonstrated this activity to be TAAR1 dependent with RO5166017 having no effect in the cocaine LMA experiment conducted using TAAR1−/− mice. The structurally related tool molecules66 RO5256390 (23, Fig. 5) and RO5263397 (24, Fig. 5) further characterized the potential of TAAR1 in schizophrenia.67 First, both compounds were confirmed to be active in the cocaine and phencyclidine (PCP) LMA models, similar to the initial tool compound RO5166017. In addition, these tool molecules also demonstrated the possibility of TAAR1 agonism to improve the currently unaddressed cognitive and negative symptoms of schizophrenia. For example, both RO5256390 and RO5263397 showed pro-cognitive effects when given to monkeys in an object retrieval paradigm of cognitive function. Furthermore, the partial TAAR1 agonist RO5263397, but not the full agonist RO5256390, demonstrated anti-depressant like properties in rats in the forced swim test, suggesting that the extent of receptor activation will be critical to obtaining clinical efficacy. Importantly, the authors found that that unlike haloperidol, neither compound induced catalepsy in rats, a preclinical model of EPS, nor did either compound cause weight gain in rats, unlike olanzapine. Collectively, these preclinical data suggest that TAAR1 agonists may be able to treat the full spectrum of symptoms in schizophrenia, without the side effects of currently available antipsychotics. To this end, investigators at Roche have identified ralmitaront (25, aka RO6889450 Fig. 5)68 as a TAAR1 agonist that is currently being tested in phase II trials for the positive (NCT04512066) and negative (NCT03669640) symptoms of schizophrenia. Both of these trials are expected to be completed in 2022 which may greatly illuminate our understanding of TAAR1 agonism for the treatment of schizophrenia.

Fig. 5. Structures of the TAAR1 agonists from the Roche research program mentioned in the text.

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TAAR1 was also identified from a target agonistic approach by scientists at Dainippon Sunitomo and PsychoGenics through a phenotypic drug discovery strategy. Using PsychoGenics's proprietary mouse based SmartCube® system69 a 1000 compound library was screened with the aim of identifying an antipsychotic compound that did not have a D2 related mechanism.70 From this in vivo screen a thiophene (26, Fig. 6) was identified as a promising hit with activity at 30 mg kg−1i.p. and an optimization campaign was undertaken to improve the activity of this scaffold using the SmartCube® system. These efforts led to the identification of a benzothiophene (27, Fig. 6), which was inactive against D2 in vitro and displayed superior activity at 10 mg kg−1i.p. in the SmartCube® system. Furthermore, 27 was also found to reverse PCP induced locomotor activity in mice, when dosed at 5 mg p.o. These results were very promising, but since this molecule was identified from an in vivo phenotypic screen, the efficacy target was unknown.

Fig. 6. Structures of the mixed TAAR1–5-HT1A ligands originating from an in vivo phenotypic screen aimed at identifying non-D2 antipsychotic mechanisms.

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Building on the identification of this series of molecules, the Dainippon Sunitomo/PsychoGenics team took a more advanced compound, SEP-856 (28, Fig. 6) to study its mechanism of action.71 First, SEP-856 was confirmed to be active at 1 mg kg−1p.o. in the mouse PCP LMA model and it was profiled in vitro against a broad range of neurologically relevant receptors. This receptor profiling identified significant activity for trace amine associated receptor 1 (TAAR1, agonist EC50: 140 nM, 101% Emax) and 5-HT1A (agonist EC50: 2300 nM, 75% Emax) but very weak activity against D2 (EC50: 10 μM, 24% Emax, IC50: 24 μM), consistent with the overall goal of the program to identify non-D2 mechanisms. Therefore, the authors further investigated the role of these receptors in the mechanism of SEP-856 and obtained in vivo and ex vivo data indicating that SEP-856 is a functional ligand of both TAAR1 and 5-HT1A. The authors therefore suggest that that a combination of TAAR1 and 5-HT1A activity may be responsible for the observed preclinical activity of SEP-856, though this hypothesis requires further validation.

With preliminary preclinical validation of the non-D2 mechanism of SEP-856 established, this compound (now called SEP-363856) was advanced to the clinic to evaluate its potential as a mechanistically novel antipsychotic.72 Using PANSS as the primary endpoint in schizophrenic patients, SEP-363856 was found to significantly improve the score for positive symptoms relative to placebo after 4 weeks of treatment. Promisingly, because SEP-363856 does not significantly interact with D2, the extrapyramidal side effects associated with SEP-363856 were not significantly greater than the placebo treated arm. The results of this trial are very encouraging, but it was relatively small (120 total patients) and short (4 weeks) and so longer and larger trials will be necessary to determine if SEP-363856 will be a useful alternative treatment to D2 antipsychotics to treat the positive symptoms of schizophrenia.

Excitatory glutamatergic signaling and schizophrenia

Over the past several decades both pre-clinical and clinical evidence has suggested glutamatergic dysfunction in the etiology and pathophysiology of schizophrenia.73 This has been termed the ‘glutamate hypothesis’ and several models suggest specifically that hypo-function of the N-methyl-d-aspartate receptor (NMDAR) could be a key contributor to the pathophysiology of schizophrenia.74,75 For example, NMDA antagonists, such as PCP and ketamine, have shown to model not only the psychotic symptoms, but also the negative symptoms and cognitive deficits in both animals and humans. NMDAR requires simultaneous binding of the agonist glutamate to the GluN2 subunit and a glycine co-agonist to GluN1. In addition, it has been shown that the amino acid d-serine has a much higher affinity to the GluN1 co-agonist site and also has high regional distribution to NMDAR expressing neurons.76 These observations have led to human clinical trials with NMDA agonists, such as glycine, d-serine, d-cycloserine and sarcosine, and these studies have demonstrated symptomatic benefit for both negative symptoms and cognition.77 Although these studies provided proof of concept that NMDA activation could provide therapeutic benefit, the poor brain penetration, high metabolism and modest intrinsic potency of these substrates make them unlikely to be developed into marketed therapies.

To address the limitations of d-serine treatment, Concert pharmaceuticals has developed a deuterated version of d-serine (CTP-692, the exact deuteration sites are not disclosed) in an attempt to attenuate the metabolism of d-serine by d-amino acid oxidase (DAAO),78 to improve the low bioavailability and reduce the high doses and potential peripheral nephrotoxicity which has been associated with d-serine treatment.79 Concert is developing CTP-692 as an adjunctive treatment for schizophrenia that will be administered in addition to standard antipsychotic medicines. In a phase I study in healthy volunteers (NCT03778320) CTP-692 was well tolerated over all the dose ranges tested, with no indication of renal impairment from blood or urine biomarkers of kidney function. A phase II study was initiated to evaluate the safety and efficacy of CTP-692 at 1, 2 and 4 gram doses as an adjunctive in schizophrenia (NCT04158687). In February 2021, Concert announced they failed to meet their primary endpoint of statistically significant improvement over placebo in the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks compared to baseline. Additionally, no significant improvements were observed in either the positive or negative symptoms subscales of the PANSS scale at any of the CTP-692 doses evaluated.80

A complimentary approach to increase d-serine concentration in the CNS can be achieved by inhibiting the flavoenzyme DAAO that degrades d-amino acids via a process of oxidative deamination.81 SyneuRx has taken this therapeutic approach by developing sodium benzoate (29, NaBen, Fig. 7), a simple DAAO inhibitor. A phase II trial of fifty-two patients receiving six weeks of add-on treatment to antipsychotic medication with 1 g daily of NaBen was associated with a 21% improvement in the PANSS total score compared with placebo. Significant improvements were also observed in Scales for the Assessment of Negative Symptoms, the Global Assessment of Function, the Quality of Life Scale, and the Clinical Global Impression in patients receiving add-on NaBen treatment compared with placebo.82 NaBen was granted breakthrough therapy designation as an add-on therapy of refractory schizophrenia by the FDA, but despite initiation of a phase IIb/III study designed to evaluate the safety and efficacy of NaBen as an add-on therapy in schizophrenia in 2014, recruitment is still ongoing. Currently a completion date December 31, 2021 is stated on ClinicalTrials.gov (NCT02261519).

Fig. 7. Chemical structures of DAAO inhibitors TAK831 and NaBen.

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TAK-831 (30, Fig. 7) is a highly potent and selective DAAO inhibitor under clinical development by Takeda in collaboration with Neurocrine Biosciences. TAK-831 is capable of dose dependently increasing d-serine across CSF, cerebellum and plasma and demonstrated efficacy within multiple rodent models of negative symptoms and cognitive impairment associated with schizophrenia.83 Phase I trials of TAK-831 showed that it was safe and well tolerated and, promisingly, a PK/PD relationship with increases in d-serine in CSF was also observed, reaching maximum effect with daily doses of 400 mg and 600 mg.84 An ongoing phase 2 study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of 3 dose levels of TAK-831 as an adjunctive treatment of adult participants with primarily negative symptoms of schizophrenia is now underway (NCT03382639).

An alternative strategy to indirectly activate NMDA receptors is to inhibit glycine transporter 1 (GlyT1), which regulates synaptic glycine levels and would consequently increase co-agonist concentration at the synapse available to activate NMDAR, theoretically enhancing its function. Several decades of research has been devoted to developing GlyT1 inhibitors, with a diverse range of chemical structures entering clinical studies. Unfortunately, despite early encouraging proof of concept clinical data for negative and cognitive symptoms in schizophrenia, GlyT1 inhibition has shown mixed results in larger studies, with several failing to meet their primary outcomes. The development of GlyT1 inhibitors has been extensively reviewed elsewhere85 and highlights some of the challenges observed with several advanced candidates, including bitopertin (31), PF-3463275 (32), AMG 747 (33), Org25935 (34), and GSK1018921 (35), all of which have been discontinued after various phases of clinical development (Fig. 8). One of the major challenges in developing GlyT1 inhibitors appears to be the narrow window of therapeutic exposure, with efficacious doses correlating to sub-maximal occupancies and a U-shaped dose response associated with diminished or no efficacy occurring at higher occupancy levels. The lack of efficacy at higher occupancies could be attributed to excess glycine inducing NMDA receptor internalization or activation of glycine receptor (GlyR) mediated inhibitory activity that could negate the beneficial effects of enhanced NMDA receptor function. Although yet to be validated with clinical evidence, binding studies have suggested that competitive inhibitors might offer therapeutic advantages over non-competitive inhibitors, improving the narrow therapeutic window by achieving selective synaptic blockade in relation to local endogenous glycine levels.86 Boehringer Ingelheim's BI 425809 (36, Fig. 8), now the most advanced GlyT1 inhibitor remaining in development for schizophrenia, has recently completed a phase II study in which patients that were randomized to oral BI 425809 (2, 5, 10, and 25 mg) once daily or placebo for 12 weeks (NCT02832037).87 The results were presented at the 33rd European College of Neuropsychopharmacology (ECNP) Congress and showed that BI 425809 was well tolerated and met its primary endpoint, assessed by the change from baseline in cognitive function as measured by the total score of the composite Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Consensus Cognitive Battery (MCCB) score.88 BI 425809 is also in an ongoing phase II study to determine the role of increased cognitive stimulation in the form of adjunctive computerized cognitive training to aid the efficacy of BI 425809 (NCT03859973).89

Fig. 8. Structures of GlyT1 inhibitors studies in clinical trials.

Fig. 8

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Related to these efforts is the hypothesis that the kynurenine pathway is involved in the pathophysiology of schizophrenia. The amino acid tryptophan can be degraded through the kynurenine pathway into several neuroactive compounds including kynurenic acid, which is an antagonist of the NMDA and α7 nAch receptors and elevated levels of kynurenic acid have been linked to schizophrenia.90 The synthesis of kynurenic acid in the brain is predominantly controlled by kynurenine aminotransferase91 which has emerged as another potential target in schizophrenia.92

AMPA receptor

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptors have gained interest in cognition due to their role in glutamatergic excitatory neurotransmission93,94 and several AMPA PAMs have entered clinical evaluation in multiple CNS disorders including Alzheimer's disease, anxiety, major depression, attention deficient hyperactivity disorder (ADHD), and schizophrenia.95–97 Opening of AMPA receptors leads to depolarization of the neuronal membrane and release of the magnesium ion that blocks N-methyl-d-aspartate receptors (NMDAR). NMDAR activation has been shown to enhance synaptic function and long-term potentiation98,99 that underlines learning and memory.100 Many AMPA PAMs have shown nootropic effects on memory and learning in pre-clinical rodent models with optimization efforts focused on balancing therapeutic effects over the CNS adverse effects (tremors and convulsions) that result from over stimulation of AMPA.101 AMPA PAMs broadly fall into two types of MoA to increase and prolong synaptic currents; ‘low-impact’ compounds that act to slow deactivation and ‘high-impact’ that slow both the deactivation and desensitization of the channel.102 Although AMPA PAMs have failed to meet their primary clinical endpoints for numerous CNS conditions, including cognitive impairment associated with schizophrenia (CIAS),103 many of these were conducted with low-impact PAMs. Work conducted by Ranganathan and co-workers at Pfizer suggested that high-impact PAMs might provide a better opportunity to show clinical efficacy in CIAS. To demonstrate this, they investigated two high impact PAMs LY451646 (37, Fig. 9) and PF-4778574 (38, Fig. 9) in a non-human primate (NHP) model that used ketamine to induce NMDA hypo-function cognitive impairments, a pathophysiology thought to be associated with CIAS. Their work demonstrated both compounds could protect against ketamine-induced working memory impairments but not the behavioral effects induced by ketamine in NHPs.104 From their positive NHP efficacy studies, Pfizer carried out further optimization of this series focused on identifying high-impact PAMs with a suitable therapeutic index (TI) over CNS AEs. A concerted effort to constrain the sulphonamide region into the active conformation led to dramatic increases in affinity relative to the linear sulphonamide of LY451646 and LY451395 (39, aka mibamptor, Fig. 9). Further structure based drug design to optimize the 2-cyanophenyl to a 5-cyanothiophene led to the identification PF-04958242 (40, Fig. 9), which showed significantly improved metabolic stability in human liver microsomes and no efflux in the MDR-1 assay.105 Preclinical work demonstrated that PF-04958242 was able to protect against ketamine-induced deficits on spatial working memory in rats.96 This model was used in a translational approach as the effect that was later recapitulated in NHPs and humans, where PF-04958242 was shown to attenuate ketamine-induced deficits in verbal learning and memory in a small study of healthy volunteers (n = 29 subjects)106 and in subjects with stable schizophrenia.107 Based upon these promising data, PF-04958242 (now known as BIIB104 following an acquisition by Biogen) is currently in a phase II study of CIAS with an expected completion in early 2022 (TALLY trial, NCT03745820).

Fig. 9. Examples of AMPAR PAMs.

Fig. 9

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Modulators of phosphodiesterase (PDEs)

Cyclic nucleotide phosphodiesterases are a group of intracellular enzymes that catalyze the hydrolysis of the phosphodiester bond with the monophosphate in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDEs belong to 11 families, with 21 PDE isoforms and numerous splice variants that differ in structure, expression, substrate specificity, and physiological function.108 Depending on the PDE isoform they can specifically hydrolyze cAMP, cGMP or both. PDE isoforms can also be localized to specific brain regions, offering the potential to selectively target a region within the brain with a highly selective ligand.109 As PDEs can directly influence the duration and amplitude of the intracellular signal transduction pathways downstream of GPCRs and ionotropic receptors, they have gathered considerable attention for their potential to treat the dopaminergic and glutamatergic dysfunction associated with schizophrenia.110

PDE10A inhibitors are capable of activating indirect D2-type pathways in medium spiny neurons (MSNs) in the striatum similar to dopamine D2 receptor antagonists and so have gathered interest for their potential anti-psychotic properties. PDE10A inhibitors can also activate the D1-type direct pathway in MSNs that is suggested to be associated with cognitive functions.111 Numerous PDE10A inhibitors have entered clinical studies and the reader is pointed towards a 2019 two part review by Jankowska and Świerczek for a comprehensive summary in this area108,112 and a short summary will be given here. Candidates that have been investigated in phase II trials include MP-10 (41, aka PF-02545920, Fig. 10) (NCT01939548, NCT00570063, NCT01175135), OMS-824 (42, Fig. 10) (NCT01952132) Lu AF11167 (structure undisclosed) (NCT03929497 and NCT03793712) and TAK-063 (43, Fig. 10) (NCT02477020). Despite the promising preclinical activity of these compounds, the clinical trial outcomes have so far been disappointing. For example, the highly selective PDE10A inhibitor (>1000× over other PDEs) PF-02545920 showed dose dependent increases in cGMP in rodent striatum and demonstrated efficacy in a conditioned avoidance response assay (CAR, a preclinical model of psychosis), with an ED50 of 1 mg kg−1.113 One of the first PDE10A inhibitors to enter clinical development, PF-02545920 failed to meet its primary endpoint of improving PANSS, unlike the positive control haloperidol.114 Similarly, TAK-063, a selective PDE10A inhibitor (>15 000× over other PDEs) produced elevations in both cAMP and cGMP after oral administration in mice and showed potent suppression of PCP induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg kg−1.115 Both TAK-063 and PF-02545920 activate the indirect pathway in MSN to a similar extent, which is believed to drive the anti-psychotic effects. However, TAK-063 activates the direct pathway to a lesser extent than PF-02545920, potentially due to a faster off-rate, and as these pathways have competing effects on antipsychotic-like activities and extrapyramidal symptoms in rodent, it was hypothesized that TAK-063 could reduce some of the potential side effects of other PDE10A inhibitors.116,117 TAK-063 was shown to be safe and well tolerated at single doses up to 1000 mg in healthy volunteers and multiple dose up to 100 mg once daily in schizophrenic patients (NCT01879722). Despite the balanced activation, good safety profile and extensive pre-clinical and clinical efforts, including pharmacologic MRI, EEG and PET imaging studies118,119 to support phase II dose selection, TAK-063 failed to meet is primary endpoint of change from baseline in PANSS. TAK-063 did meet some secondary endpoints that were generally supportive of antipsychotic efficacy and the overall negative result is confounded by a relatively high placebo effect, lack of dose-ranging (only a single dose of 20 mg tested) and lack of active reference.120

Fig. 10. Structures of PDE inhibitors.

Fig. 10

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In the same vein, the PDE10A inhibitor MK-8189 (structure not disclosed) did not improve PANSS score unlike active control risperidone (NCT03055338). Despite this negative data, however, MK-8189 is still being investigated and is undergoing a phase 1 trial evaluating the safety, tolerability, and pharmacokinetics of alternate MK-8189 titration regimens in participants with schizophrenia (NCT04506905). PDE10A inhibitors have also been investigated as treatments for the negative symptoms of schizophrenia, but the results here are also disappointing. For example, Lu AF11167, a PDE10A inhibitor under development by Lundbeck for the negative symptoms of schizophrenia, was discontinued in August 2020 after a futility interim analysis concluded that the trial is unlikely to achieve statistical significance on its primary endpoint, mean change from baseline to week 12 on the Brief Negative Symptom Scale (BNSS).121

Although PDE10 has been the most extensively studied family member in the context of schizophrenia, other isoforms have also investigated. For example, PDE1B isoforms are the only PDEs to regulate neuronal cAMP and cGMP levels in a Ca2+/calmodulin (CaM) dependent manner and like PDE10, inhibition of PDE1B increases cAMP levels in the striatum. Unlike PDE10, Nishi and coworkers have proposed PDE1B couples with the direct pathway via D1 signaling and, as a result, a PDE1B inhibitor may be well suited to treat cognitive and motor deficits associated with deficient D1 dopaminergic signaling.122,123 Consistent with this proposal, knock-down of PDE1B in the hippocampus of adult mice enhances contextual and spatial memory without effects on non-cognitive behaviors.124 A pre-clinical tool molecule DNS-0056 (45, Fig. 10) showed efficacy in a rat novel object recognition (NOR) task at 0.3 mg kg−1 (PO), but significant efflux of this compound from the brain prevented the development of this molecule.125 Despite this, Lundbeck is testing the hypothesis that PDE1B inhibition can improve cognitive function, by developing the PDE1B inhibitor Lu AF88434 (structure not disclosed) for CIAS. This compound is currently in two phase 1 trials; one to assess its safety and tolerability in healthy volunteers (NCT04082325) and another is a positron emission tomography (PET) study with [11C]-Lu AF88434, investigating the blood–brain barrier penetration of Lu AF88434 (NCT04538014).

Another PDE target of interest for schizophrenia is PDE9, inhibition of which can inhibit the hydrolysis of cGMP to theoretically enhance NMDA receptor signaling.126 Researchers at Boehringer Ingelheim developed BI 409306 (44, Fig. 10), a potent and selective PDE9 inhibitor, which has a human IC50 of 65 nM against PDE9 and showed micromolar or greater activities against the other PDE isoforms.127 BI 409306 was shown to increase cGMP levels in rat prefrontal cortex and cerebrospinal fluid and attenuated a reduction in mouse striatum cGMP induced by the NMDA-receptor antagonist MK-801. Treatment of mice with BI 409306 reversed MK-801-induced working memory deficits in a T-maze spontaneous-alternation task and improved long-term memory in an object recognition task.118 With preclinical evidence of synaptic plasticity, as demonstrated by improvements in episodic and working memory function in rodents, BI 409306 was progressed into two clinical studies for Alzheimer's disease and although BI 409306 was well tolerated, both trials failed to demonstrate efficacy in improving cognition in patients with prodromal or mild AD.128 These trials were followed with a negative phase II trial in CIAS studying BI 409306 in 518 patients randomized into groups of placebo or BI 409306 (10, 25, 50, or 100 mg) for 12 weeks. BI 409306 also failed to meet it primary endpoints of improving cognition in CIAS in patients who were clinically stable and receiving antipsychotic treatment.129 Despite these setbacks, BI 409306 is currently undergoing in two additional phase II trials in schizophrenia. One is a 6-month trial to determine if BI 409306 can prevent relapse of symptoms in schizophrenic patients taking antipsychotics (NCT03351244) and a second is investigating the efficacy of BI 409306 in attenuated psychosis syndrome, a psychiatric illness potentially related to schizophrenia (NCT03230097).

Conclusions and future directions in schizophrenia therapeutic targets

In addition to the challenge in identifying new targets for schizophrenia mentioned in the introduction, the mechanisms discussed have highlighted the difficulty in translating promising preclinical data into clinical efficacy. While this is true for all therapeutic areas, it is particularly challenging in schizophrenia due to the small number of robust animal models for the disease.130 Because of this, the development of translatable PK/PD or PK–efficacy relationships to predict what level of target modulation is required for human efficacy is challenging. For example, even the classic D2 antipsychotics required iterative optimization, with clinical data being essential to this process. The initial first generation antipsychotics such as haloperidol (3) are full D2 antagonists which have poorer tolerability relative to second generation or third generation antipsychotics such as quetiapine (5) or brexpiprazole (9).131 Brexpiprazole (9) is a partial D2 agonist which functionally acts as a mixed agonist/antagonist depending on the local concentration of dopamine in the synapse.132 This mixed molecular pharmacology, combined with activity at 5-HT1A, widen the therapeutic index of brexpiprazole relative to first generation antipsychotics, which would have been difficult to predict a priori. As demonstrated by this example, the extent of target engagement to balance efficacy versus potential on-target adverse events is a central challenge in developing novel medicines for schizophrenia.

While the mechanisms and molecules detailed in this review present a real, transformative opportunity to identify new therapies in schizophrenia these are likely to be symptomatic treatments, while the ultimate goal in the field would be to slow or prevent the disease altogether.133 As noted in the introduction, the multifactorial nature of schizophrenia makes it difficult to uncover genetically validated targets for this disease. However, continued progress and innovations in human genetics have shed light on heritable risk factors for schizophrenia to aid target selection and two such targets with the potential for disease modification will be highlighted below.

Consistent with previous literature suggesting an immune involvement in the development of schizophrenia,134 a publication in 2016 suggested that there is a genetic link between schizophrenia and the classical complement pathway.135 Specifically, using a variety of genetic techniques, Sekar and coworkers found that elevated levels of the key complement protein C4 are associated with schizophrenia. Peripherally, the complement cascade helps to clear microbial infections and damaged cells, but in the CNS, the complement system has also been suggested to play an integral role in synaptic pruning.136 Based on this connection, the authors performed mechanistic studies in mice and found that C4 RNA is present in retinal ganglion cells during developmental periods with high levels of synaptic pruning. Furthermore, the authors also demonstrated that C4−/− mice showed areas of less synaptic pruning than wild type littermates and heterozygous C4+/− mice possessed a phenotype in between the wildtype and homozygous null mice, suggesting that C4 is indeed playing a functional role in developmental pruning.

From the genetic and functional data, the authors then proposed a model of complement over activation in schizophrenia. The pruning of synapses by microglia is a normal aspect of human development, a process that begins in adolescence and lasts well into adulthood.137 The authors hypothesize that in individuals with schizophrenia, higher levels of C4 lead to excessive complement mediated synaptic pruning and that this is the pathological basis of schizophrenia. This disease hypothesis is supported by the timing of schizophrenia which typically appears in late adolescence and early adulthood, concurrent with an active period of synapse pruning in human CNS development. Consistent with this observation, post-mortem studies reveal that individuals with schizophrenia had reduced synaptic density relative to healthy controls, suggestive of lower synapse numbers, in the frontal cortex.138,139 To investigate this hypothesis in vitro, Sellgren and coworkers140 used induced pluripotent stem cell (iPSC) technology to create a model of microglia mediated synapse engulfment. Using cells derived from schizophrenic patients and healthy controls, the authors found increased levels of synapse elimination in the schizophrenic patient cell lines, relative to the control lines, further supporting the synapse over-reduction hypothesis. Together, these data suggest that partially inhibiting complement mediated synapse pruning could delay or prevent the progression of schizophrenia. Promisingly, therapeutic modulation of the peripheral complement pathways has been utilized to treat multiple complement mediated diseases,141 implying that this may be achievable in the CNS as well.

Another compelling target highlighted from genome wide association studies (GWAS) is the L-type voltage gated calcium channel CaV1.2. Single nucleotide polymorphisms (SNPs) in both CACNA1C, which encodes for the pore forming α1C subunit, and CACNB2, which encodes for the regulatory β subunit have shown associations with the disease.142 Furthermore, SNPs in CACNA1C and CACNB2 have also been identified in a cross-GWAS meta-analysis of 5 psychiatric disorders including schizophrenia, bipolar disorder, major depression, attention deficit hyperactivity disorder (ADHD) and autism.143 These studies suggest CaV1.2 may be involved in the pathophysiology of multiple psychiatric disorders. The function of CaV1.2 within the CNS and its potential role in the pathophysiology and etiology of schizophrenia has been extensively reviewed elsewhere.144–146 In short, neuronal excitation via CaV1.2 mediates Ca2+ signaling through Ca2+/calmodulin-dependent protein kinase II (CaMKII), which modulates gene transcription via cAMP response element-binding protein (CREB).147 This pathway is thought to play a role in numerous synaptic functions such as, neuronal survival, dendritic development, synaptic plasticity, learning, memory, and behavior. As synaptic dysfunction is a core pathological feature of many psychiatric disorders such as bipolar disorder, schizophrenia and depression, CaV1.2 is an attractive target to attempt to treat the core pathological deficit. Many CaV1.2 antagonists are available and used clinically to treat cardiac arrhythmia and hypertension but clinical investigations using calcium antagonist drugs, such as isradipine, nimodipine, nifedipine and verapamil in both schizophrenia and bipolar disorder have failed to show consistent, robust effects.148 These failures complement the evidence that associated SNPs lead to a reduction of function or expression of the CaV1.2 channel. Many of the risk SNPs lie within intronic regions of the allele and fall into predicted enhancer/promotor regions and therefore likely determine gene expression.149,150 Although there has been some conflicting reports, quantitative trait loci (eQTL) and allelic skewing of patient SNPs have been found to be associated with decreased expression.151 Exome sequencing has also identified rare mutations in both schizophrenia and bipolar disorder leading to truncating mutations predicted to cause loss of function.152 Finally, many animal models exploring the impact of reduced gene dosage of CaV1.2 have identified phenotypes consistent with psychiatric disorders including changes in mood, anxiety, cognition, motor function, sociability and neurogenesis.153,154 Therefore, a small molecule that could enhance the function of CaV1.2 may provide a broad therapeutic benefit by restoring deficits associated with decreased CaV1.2 function in psychiatric disease.

Given that many generic medicines are available to treat the positive symptoms of schizophrenia there can be a perception that novel pharmacological therapies are not required for this disease. However, as outlined in this review, research into new treatments for schizophrenia remains a very active area of investigation, with multiple candidates and mechanisms reaching clinical development. While D2 antipsychotics are available to treat the positive symptoms of schizophrenia, the two other core facets of this mental illness, negative and cognitive symptoms, are incompletely addressed. Furthermore, the medicines at hand to alleviate positive symptoms come with significant, burdensome adverse events that are not well tolerated and lead to poor patient compliance. The poor tolerability of antipsychotics also impacts the mental health field more broadly because psychosis is a common component of many psychiatric and neurological diseases and therefore antipsychotics are used extensively outside of their application in schizophrenia. Clearly, new medicines are urgently required to meet this significant unmet medical need. Novel symptomatic therapies to address the negative and/or cognitive aspects of the disease as well as safer, better tolerated antipsychotics would be transformative medicines with a worldwide impact. In addition, recent advances in understanding the genetic basis of schizophrenia have given the field a hint that the disease course of schizophrenia may be slowed or prevented, which would be truly revolutionary.

Conflicts of interest

Both authors are employees of Novartis Institutes for Biomedical Research and are involved in neuroscience drug discovery projects.

Supplementary Material

Acknowledgments

We thank our colleagues Kevin Gardinier, Mark Healy, Brent Kuzmiski, Gopi Shanker and Yishan Sun for helpful comments and feedback during the writing of this review.

Biographies

Biography

James Neef.

James Neef

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James Neef Joined the Global Discovery Chemistry organization at the Novartis Institute for Biomedical Research in the UK in 2002 as an undergraduate apprentice and obtained his B.S. from the University of Greenwich in 2007. Throughout his time with Novartis James has supported drug discovery projects covering a wide range of biological targets including kinases, ion channels and GPCRs in various disease areas including respiratory, gastrointestinal and cardiovascular. James transitioned to Cambridge in the USA in 2014, since then he has been a project team leader investigating novel drug targets for neurological diseases.

Biography

Daniel Palacios.

Daniel Palacios

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Daniel Palacios obtained his B.S. from the University of California at San Diego (2005) and his Ph.D. from the University of Illinois at Urbana Champaign with Prof. Marty Burke (2011). Subsequently he joined the Global Discovery Chemistry organization at the Novartis Institute for Biomedical Research where he has led projects from hit and target identification through to clinical candidate selection. He is currently a Senior Principal Scientist investigating novel therapeutic modalities for neurological diseases.

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