Investigational dopamine antagonists for the treatment of schizophrenia

ABSTRACT

Introduction: Schizophrenia is a debilitating illness with a chronic impact on social function and daily living. Although various antipsychotics are available, there are still many challenges and unmet needs. Thus, many compounds with diverse mechanisms have been investigated, but all approved antipsychotics still require interactions with dopamine D₂ receptors.

Areas covered: We searched for investigational drugs using the key words ‘dopamine’ and ‘schizophrenia’ in American and European clinical trial registers (clinicaltrials.gov; clinicaltrialsregister.eu). Published articles were searched in PubMed, Embase, Medline, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Web of Science and the Cochrane Central Register of Controlled Trials Library.

Expert opinion: The prospect of developing a dopamine antagonist is hopeful. Brexpiprazole and cariprazine, which were agents listed as ‘investigational dopamine antagonists,’ just received FDA approval. Novel agents such as BL 1020, ITI-007, and JNJ-37822681 have solid published data available, and agents such as L-THP, Lu AF35700, S33138, and SB-773812 are under vigorous investigation. However, the expected benefits of the newly developed antagonists may not be great because they offer little enhanced efficacy for negative symptoms, cognition and functional outcomes.

KEYWORDS:

• Schizophrenia
• Investigational antipsychotics
• Phase II
• agonist
• antagonist
• dopamine

Article Highlights

• Schizophrenia is a debilitating illness with a chronic impact on social, vocational, and daily living functioning. Numerous potential agents having diverse mechanism of action were investigated. However, dopamine D₂ blocking agents still remained the only approved and effective drug class for schizophrenia and related psychotic disorders.

• The prospect of developing a clinically useful novel agent that generates a dopamine blockade is promising. Although ABT-925 failed to show its superior efficacy over placebo, BL-1020, ITI-007, and JNJ-37822681, have solid published data showing their efficacy and the potential to provide enhanced safety than the currently available atypical antipsychotics. Other agents such as L-THP, Lu AF35700, S33138, and SB-773812 are currently under vigorous investigation.

• These potential agents may broaden pharmacological options for clinicians in the future. Unfortunately, expected benefits from these agents are likely to be small because they may offer little enhanced efficacy for negative symptoms, cognition, and functional outcomes.

• More in-depth exploration of extra-dopaminergic mechanisms is necessary. Paradoxically, deeper understanding about atypical antipsychotics, such as clozapine, and better insight regarding dopamine theory will be required to develop a more efficacious and safe antipsychotics.

• Agents with diverse mechanisms of action beyond dopamine are being investigated, with positive prospects. However, much as ‘all roads lead to Rome,’ all the studied agents to date lead to alteration of dopamine receptors. Thus, the development of agents with dopamine antagonist properties will continue, unless a drug having a truly extra-dopaminergic mechanism, with its mechanism of action fully explained, is developed.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare (HI12C0003); however, the funding source had no further role in preparation, data collection, or writing of the paper.