The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review

Girgis, Ragy R.; Zoghbi, Anthony W.; Javitt, Daniel C.; Lieberman, Jeffrey A.

doi:10.1016/j.jpsychires.2018.07.006

Cited by 61 publications

(63 citation statements)

References 339 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Numerous advances have been made in understanding the potential role of receptors other than D 2 in contributing to drug efficacy and specific side effects in schizophrenia. Recent antipsychotic drug development has focused on non-D 2 targets, including D 1 , D 4 , D 3 , NMDA, 5-HT 2A , 5-HT 2C , M 1 , M 4 , H 3 , NK 3 , and s receptors (Miyamoto et al, 2005;Karam et al, 2010;Girgis et al, 2019). However, to date, no compound lacking D 2 receptor blockade has proven effective for any symptom dimension of schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

“…It is characterized by positive symptoms (e.g., hallucinations, delusions, and thought disorders), negative symptoms (e.g., flat affect, anhedonia, alogia, and avolition), and cognitive deficits (e.g., impaired memory, attention, and executive functioning). Despite advances in our understanding of the pathophysiology, schizophrenia remains one of the most challenging diseases to treat due to the diversity of clinical symptoms, the heterogeneity of clinical response, the side effects of current treatments, and its association with high morbidity and mortality (Insel, 2010;Meyer-Lindenberg, 2010;Girgis et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Since then, numerous new antipsychotics have been launched, but they have essentially the same mechanism of action, mediating their efficacy against the positive symptoms through antagonism of dopamine D 2 and/or serotonin 5-HT 2A receptors. Although improvements in drug safety have been made, a focus on the same molecular targets has not led to improved efficacy (Lieberman et al, 2005;Girgis et al, 2019). In fact, the negative and cognitive symptoms remain largely untreated by currently available antipsychotics.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, drug development efforts have focused on molecular targets other than D 2 and 5-HT 2A receptors, including GlyT1, D 1 , D 4 , D 3 , N-methyl-D-aspartate (NMDA), mGluR2/3, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 5-HT 2C , nicotinic a7, muscarinic M 1 /M 4 , H 3 , NK-3, and s receptors (Miyamoto et al, 2000;Karam et al, 2010;Girgis et al, 2019). However, despite promising efficacy in preclinical models for many of these targets, most novel, non-D 2 /5-HT 2A mechanisms have shown limited or no success in clinical trials (Girgis et al, 2019). Thus, it is crucial to pursue alternative strategies for novel drug development for schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂Receptor Mechanism of Action

Dedic

Jones

Hopkins

et al. 2019

J Pharmacol Exp Ther

138

178

View full text Add to dashboard Cite

For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D 2 receptors. Drug development of non-D 2 compounds, seeking to avoid the limiting side effects of dopamine receptor blockade, has failed to date to yield new medicines for patients. In this work, we report the discovery of SEP-363856 (SEP-856), a novel psychotropic agent with a unique mechanism of action. SEP-856 was discovered in a medicinal chemistry effort utilizing a high throughput, high content, mouse-behavior phenotyping platform, in combination with in vitro screening, aimed at developing non-D 2 (anti-target) compounds that could nevertheless retain efficacy across multiple animal models sensitive to D 2-based pharmacological mechanisms. SEP-856 demonstrated broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition, and PCP-induced deficits in social interaction. In addition to its favorable pharmacokinetic properties, lack of D 2 receptor occupancy, and the absence of catalepsy, SEP-856's broad profile was further highlighted by its robust suppression of rapid eye movement sleep in rats. Although the mechanism of action has not been fully elucidated, in vitro and in vivo pharmacology data as well as slice and in vivo electrophysiology recordings suggest that agonism at both trace amine-associated receptor 1 and 5-HT 1A receptors is integral to its efficacy. Based on the preclinical data and its unique mechanism of action, SEP-856 is a promising new agent for the treatment of schizophrenia and represents a new pharmacological class expected to lack the side effects stemming from blockade of D 2 signaling. SIGNIFICANCE STATEMENT Since the discovery of chlorpromazine in the 1950s, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D 2 receptors, which is associated with substantial side effects and little to no efficacy in treating the negative and cognitive symptoms of schizophrenia. In this study, we describe the discovery and pharmacology of SEP-363856, a novel psychotropic agent that does not exert its antipsychotic-like effects through direct interaction with D 2 receptors. Although the mechanism of action has not been fully elucidated, our data suggest that agonism at both trace amine-associated receptor 1 and 5-HT 1A receptors is integral to its efficacy. Based on its unique profile in preclinical species, SEP-363856 represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders. At the time these studies were conducted, all authors were employees of either Sunovion Pharmaceuticals or PsychoGenics. Some authors are inventors on patents related to the subject matter. 1 N.D. and P.G.J. contributed equally to the work.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂Receptor Mechanism of Action

Dedic

Jones

Hopkins

et al. 2019

J Pharmacol Exp Ther

138

178

View full text Add to dashboard Cite

show abstract

“…Nicotinic receptors are also important for the pathomechanism of SZ [40] as most of the schizophrenic patients smoke [41]. In particular, positive allosteric modulators of some subtypes (e.g.…”

Section: Disturbances In Neurotransmission In Szmentioning

confidence: 99%

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

et al. 2020

View full text Add to dashboard Cite

Schizophrenia (SZ) is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms, and is not satisfactorily treated by current antipsychotics. Progress in understanding the basic pathomechanism of the disease has been hampered by the lack of appropriate models. In order to develop modern drugs against SZ, efficient methods to study them in in vitro and in vivo models of this disease are required. In this review a short presentation of current hypotheses and concepts of SZ is followed by a description of current progress in the field of SZ experimental models. A critical discussion of advantages and limitations of in vitro models and pharmacological, genetic, and neurodevelopmental in vivo models for positive, negative, and cognitive symptoms of the disease is provided. In particular, this review concerns the important issue of how cellular and animal systems can help to meet the challenges of modeling the disease, which fully manifests only in humans, as experimental studies of SZ in humans are limited. Next, it is emphasized that novel clinical candidates should be evaluated in animal models for treatment-resistant SZ. In conclusion, the plurality of available in vitro and in vivo models is a consequence of the complex nature of SZ, and there are extensive possibilities for their integration. Future development of more efficient antipsychotics reflecting the pleiotropy of symptoms in SZ requires the incorporation of various models into one uniting model of the multifactorial disorder and use of this model for the evaluation of new drugs.

show abstract

A schizophrenia risk factor induces marked anatomical deficits at GABAergic‐dopaminergic synapses in the rat ventral tegmental area: Essential evidence for new targeted therapies

Seo

Sizemore

Reader

et al. 2021

J of Comparative Neurology

View full text Add to dashboard Cite

To develop new therapies for schizophrenia, evidence accumulated over decades highlights the essential need to investigate the GABAergic synapses that presynaptically influence midbrain dopaminergic neurons. Since current technology restricts these studies to animals, and evidence accumulated in recent decades indicates a developmental origin of schizophrenia, we investigated synaptic changes in male rat offspring exposed to maternal immune activation (MIA), a schizophrenia risk factor. Using a novel combination of lentiviruses, peroxidase‐immunogold double labeling, three‐dimensional serial section transmission electron microscopy and stereology, we observed clear anatomical alterations in synaptic inputs on dopaminergic neurons in the midbrain posterior ventral tegmental area (pVTA). These changes relate directly to a characteristic feature of schizophrenia: increased dopamine release. In 3‐month‐old and 14‐month‐old MIA rats, we found a marked decrease in the volume of presynaptic GABAergic terminals from the rostromedial tegmental nucleus (RMTg) and in the length of the synapses they made, when innervating pVTA dopaminergic neurons. In MIA rats in the long‐term, we also discovered a decrease in the volume of the postsynaptic density (PSD) and in the maximum thickness of the PSD at the same synapses. These marked deficits were evident in conventional GABA‐dopamine synapses and in synaptic triads that we discovered involving asymmetric synapses that innervated RMTg GABAergic presynaptic terminals, which in turn innervated pVTA dopaminergic neurons. In triads, the PSD thickness of asymmetric synapses was significantly decreased in MIA rats in the long‐term cohort. The extensive anatomical deficits provide a potential basis for new therapies targeted at synaptic inputs on midbrain pVTA dopaminergic neurons, in contrast to current striatum‐targeted antipsychotic drugs.

show abstract

The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review

Cited by 61 publications

References 339 publications

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂Receptor Mechanism of Action

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂Receptor Mechanism of Action

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

A schizophrenia risk factor induces marked anatomical deficits at GABAergic‐dopaminergic synapses in the rat ventral tegmental area: Essential evidence for new targeted therapies

Contact Info

Product

Resources

About

The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review

Cited by 61 publications

References 339 publications

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2Receptor Mechanism of Action

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2Receptor Mechanism of Action

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

A schizophrenia risk factor induces marked anatomical deficits at GABAergic‐dopaminergic synapses in the rat ventral tegmental area: Essential evidence for new targeted therapies

Contact Info

Product

Resources

About

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂Receptor Mechanism of Action

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂Receptor Mechanism of Action