Potential serotonergic agents for the treatment of schizophrenia

ABSTRACT

Introduction: For the last 30 years, drugs targeting serotonin receptors (5-HTR) have been intensively investigated in schizophrenia. New drugs targeting 5-HTRs are under development in patients with schizophrenia.

Areas covered: In this review, the authors describe the recent clinical trials for schizophrenia with selective serotonergic agents and provide an opinion on how the investigated drugs can help to fulfil current treatment needs. Clinical trials were found in US and EU clinical trial registries and in the medical literature. Relevant 5-HTR antagonists active in animal models of schizophrenia were also analysed.

Expert opinion: Antipsychotics reduce positive symptoms of schizophrenia (delusions, hallucinations and disordered thought), but have undesirable side effects. Moreover, satisfactory treatment of negative symptoms (apathy, poverty of speech, lack of interest in social interactions) and cognitive dysfunction is currently not available. The selective 5-HT2CR full agonist vabicaserin showed antipsychotic efficacy with fewer side effects than olanzapine. Adjunctive pimavanserin (a selective 5-HT2AR inverse agonist) facilitated antipsychotic dose and side-effect reductions. Selective 5-HT3R antagonists (ondansetron, tropisetron and granisetron) showed positive results on negative symptoms and/or cognitive impairments in phase II trials. Adjunctive ondansetron has now entered a phase III trial for such indications. Finally, 5-HTA5R and 5-HT7R antagonists have shown procognitive actions in animal models of schizophrenia. These novel serotonergic drugs seem promising for improving the current treatment of schizophrenia.

KEYWORDS:

• Serotonin
• serotonin receptor antagonists
• 5-HT receptor antagonists
• schizophrenia
• clinical trials

Declaration of interest

RP Garay, E De Paillette and A Hameg are members of the non-profit association for therapeutic innovation – Craven, Villemoisson-sur-Orge, France. L Samalin has received honoraria for conferences and consulting from AstraZeneca, Bristol-Myers Squibb, Janssen-Cilag, Lundbeck A/S, Otsuka and Takeda. M Bourin is appointed as a World Health Organization (WHO) expert in drug dependence. PM Llorca declares grant support in addition to support for consultancy, expertise and honoraria for conferences from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen-Cilag, Lundbeck A/S, Otsuka, Roche, and Sanofi Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Article highlights

• Schizophrenia is a chronic, severe mental disorder which was among the top 20 causes of disability worldwide

• Drug treatment for schizophrenia is based on antipsychotics, which antagonize dopamine D2 receptors and mostly reduce positive symptoms (delusions, hallucinations and disordered thought)

• Antipsychotics have undesirable side effects and a satisfactory treatment of negative symptoms (apathy, poverty of speech and lack of interest in social interactions) and cognitive dysfunction is currently not available. Seven selective 5-HTR agents are on clinical development to fulfill these unmet treatment needs.

• The selective 5-HT2CR full agonist vabicaserin showed antipsychotic efficacy with fewer side effects than olanzapine and adjunctive pimavanserin (a selective 5-HT2AR inverse agonist) facilitated antipsychotic dose and side-effect reductions.

• Some 5-HT3R antagonists showed positive results on negative symptoms and/or cognitive impairments in phase II trials, and ondansetron entered phase III clinical development. 5-HTA5R and 5-HT7R antagonists showed procognitive actions in animal models of schizophrenia.

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ORCID

Ricardo P. Garay http://orcid.org/0000-0001-6209-926X

Michel Bourin http://orcid.org/0000-0002-7268-4590

Pierre-Michel Llorca http://orcid.org/0000-0001-7438-8990