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Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents

Molecular Psychiatry volume 17, pages 1206–1227 (2012)Cite this article

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Abstract

Since the introduction of chlorpromazine and throughout the development of the new-generation antipsychotic drugs (APDs) beginning with clozapine, the D2 receptor has been the target for the development of APDs. Pharmacologic actions to reduce neurotransmission through the D2 receptor have been the only proven therapeutic mechanism for psychoses. A number of novel non-D2 mechanisms of action of APDs have been explored over the past 40 years but none has definitively been proven effective. At the same time, the effectiveness of treatments and range of outcomes for patients are far from satisfactory. The relative success of antipsychotics in treating positive symptoms is limited by the fact that a substantial number of patients are refractory to current medications and by their lack of efficacy for negative and cognitive symptoms, which often determine the level of functional impairment. In addition, while the newer antipsychotics produce fewer motor side effects, safety and tolerability concerns about weight gain and endocrinopathies have emerged. Consequently, there is an urgent need for more effective and better-tolerated antipsychotic agents, and to identify new molecular targets and develop mechanistically novel compounds that can address the various symptom dimensions of schizophrenia. In recent years, a variety of new experimental pharmacological approaches have emerged, including compounds acting on targets other than the dopamine D2 receptor. However, there is still an ongoing debate as to whether drugs selective for singe molecular targets (that is, ‘magic bullets’) or drugs selectively non-selective for several molecular targets (that is, ‘magic shotguns’, ‘multifunctional drugs’ or ‘intramolecular polypharmacy’) will lead to more effective new medications for schizophrenia. In this context, current and future drug development strategies can be seen to fall into three categories: (1) refinement of precedented mechanisms of action to provide drugs of comparable or superior efficacy and side-effect profiles to existing APDs; (2) development of novel (and presumably non-D2) mechanism APDs; (3) development of compounds to be used as adjuncts to APDs to augment efficacy by targeting specific symptom dimensions of schizophrenia and particularly those not responsive to traditional APD treatment. In addition, efforts are being made to determine if the products of susceptibility genes in schizophrenia, identified by genetic linkage and association studies, may be viable targets for drug development. Finally, a focus on early detection and early intervention aimed at halting or reversing progressive pathophysiological processes in schizophrenia has gained great influence. This has encouraged future drug development and therapeutic strategies that are neuroprotective. This article provides an update and critical review of the pharmacology and clinical profiles of current APDs and drugs acting on novel targets with potential to be therapeutic agents in the future.

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Authors and Affiliations

  1. Department of Neuropsychiatry, St Marianna University School of Medicine, Kawasaki, Japan

    S Miyamoto & N Miyake

  2. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    L F Jarskog

  3. Department of Psychiatry, North Carolina Psychiatric Research Center, Central Regional Hospital—Raleigh Campus, Raleigh, NC, USA

    L F Jarskog

  4. Department of Psychiatry and Psychotherapy, Medical University Innsbruck, Innsbruck, Austria

    W W Fleischhacker

  5. Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, NY, USA

    J A Lieberman

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  1. S Miyamoto
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Correspondence to J A Lieberman.

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Competing interests

Dr Miyamoto is a consultant for Dainippon Sumitomo Pharmaceutical. He has received advisory board honoraria from Chugai Pharmaceutical. Dr Jarskog has received grant support from Genentech, GlaxoSmithKline, Novartis and Sunovion. Dr Fleischhacker has received research grants from Alkermes, Janssen Cilag, Eli Lilly, BMS/Otsuka and Pfizer. He has received honoraria for educational programs from Janssen, Pfizer and AstraZeneca, speaking fees from AstraZeneca, Pfizer, Janssen Cilag, Roche, Lundbeck, BMS/Otsuka and advisory board honoraria from BMS/Otsuka, Wyeth, Janssen Cilag Neurosearch, Amgen, Lundbeck, Endo, United Biosource, Targacept, MedAvante and AstraZeneca. Dr Lieberman has received grant/research funding from Allon, GlaxoSmithKline, Merck, Novartis, Pfizer, Sepracor and Targacept and also served on advisory boards for Bioline, Eli Lilly, GlaxoSmithKline, Intracellular Therapies, Pierre Fabre and Psychogenics.

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Miyamoto, S., Miyake, N., Jarskog, L. et al. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 17, 1206–1227 (2012). https://doi.org/10.1038/mp.2012.47

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