Emerging therapeutic targets for schizophrenia: a framework for novel treatment strategies for psychosis

ABSTRACT

Introduction: Antipsychotic drugs are central to the treatment of schizophrenia, but their limitations necessitate improved treatment strategies. Multiple lines of research have implicated glutamatergic dysfunction in the hippocampus as an early source of pathophysiology in schizophrenia. Novel compounds have been designed to treat glutamatergic dysfunction, but they have produced inconsistent results in clinical trials.

Areas covered: This review discusses how the hippocampus is thought to drive psychotic symptoms through its influence on the dopamine system. It offers the reader an evaluation of proposed treatment strategies including direct modulation of GABA or glutamate neurotransmission or reducing the deleterious impact of stress on circuit development. Finally, we offer a perspective on aspects of future research that will advance our knowledge and may create new therapeutic opportunities. PubMed was searched for relevant literature between 2010 and 2020 and related studies.

Expert opinion: Targeting aberrant excitatory-inhibitory neurotransmission in the hippocampus and its related circuits has the potential to alleviate symptoms and reduce the risk of transition to psychosis if implemented as an early intervention. Longitudinal multimodal brain imaging combined with mechanistic theories generated from animal models can be used to better understand the progression of hippocampal-dopamine circuit dysfunction and heterogeneity in treatment response.

KEYWORDS:

• Schizophrenia
• antipsychotic
• dopamine
• glutamate
• gaba
• hippocampus
• d2
• early intervention

Article Highlights

• Developmental animal models relevant to schizophrenia are an effective approach to examine how neurotransmitter systems interact and change over time, which can provide valuable information about potential targets for early intervention and treatment.

• Animal models have demonstrated that stress during puberty can impair perineuronal nets around interneurons and have long-lasting impacts on dopamine neuron activity.

• Modulating excitatory-inhibitory dysregulation is promising as an alternative therapeutic strategy to D₂-targeting antipsychotic drugs, and merits further research as a potential early intervention.

• Targeting hippocampal pathophysiology upstream of dopamine neuron dysfunction has the potential to both normalize dopamine neuron activity and alleviate other symptoms of schizophrenia.

• Future research must focus on categorizing subtypes to determine which patients may benefit most from a treatment, adapting clinical trial design for non-dopaminergic agents, and employing animal models to study changes that may not be apparent in normal rodents.

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Declaration of interest

AA Grace has received consulting fees from Alkermes, Lundbeck, Takeda, Roche, Lyra, Concert, and research funding from Lundbeck. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer reports serving on the Aristada Schizophrenia Advisory Board for Alkermes and the MedinCell Psychiatry Advisory Board. They have conducted clinical research supported by the NIMH, Sunovion, the Stanley Foundation, Takeda, Taisho, Lundbeck, Boehringer Ingelheim, NeuroRX, Teva and Lilly within the last 24 months and were a co-investigator on a study that receives lumeteperone and reimbursement for safety testing for an investigator-initiated research from Intra-Cellular Therapies Inc. He owns a small number of shares of common stock from GSK. One reviewer has received manuscript or speaker’s fees from Astellas, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Elsevier Japan, Janssen Pharmaceuticals, Kyowa Yakuhin, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Novartis, Otsuka Pharmaceutical, Shionogi, Shire, Tsumura, Wiley Japan, and Yoshitomi Yakuhin, and research grants from Eisai, Mochida Pharmaceutical, Meiji Seika Pharma and Shionogi. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

The research of the authors is supported by grants from the US National Institutes of Mental Health (MH057440 to AAG).