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Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Psychiatry | doi: 10.3389/fpsyt.2019.00601

Neurobiology, Clinical Course, and Therapeutic Approaches of Treatment Resistant Schizophrenia: Toward an Integrated View.

  • 1King's College London, United Kingdom
  • 2South London and Maudsley NHS Foundation Trust, United Kingdom
  • 3Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, United Kingdom

Despite considerable psychotherapeutic advancement since the discovery of chlorpromazine, almost one third of patients with schizophrenia remain resistant to dopamine-blocking antipsychotics, and continue to be exposed to unwanted and often disabling side effects, but little if any clinical benefit. Even clozapine, the superior antipsychotic treatment, is ineffective in approximately half of these patients. Thus treatment resistant schizophrenia (TRS), continues to present a major therapeutic challenge to psychiatry. The main impediment to finding novel treatments is the lack of understanding of precise molecular mechanisms leading to TRS. Not only has the neurobiology been enigmatic for decades, but accurate and early detection of patients who are at risk of not responding to dopaminergic blockade remains elusive.

Fortunately, recent work in the field has started to unravel some of the neurobiological mechanisms underlying treatment resistance, providing long awaited answers, at least to some extent. Here we focus on the scientific advances in the field, from the clinical course of TRS to neurobiology and available treatment options. We specifically emphasize emerging evidence from TRS imaging and genetic literature that implicates dysregulation in several neurotransmitters, particularly dopamine and glutamate, and in addition genetic and neural alterations that concertedly may lead to the formation of TRS. Finally, we integrate available findings into a putative model of TRS, which may provide a platform for future studies in a bid to open the avenues for subsequent development of effective therapeutics.





Keywords: Schizophrenia, Treatment-resistant, Neurobiology, Neuroimaging, Genetics, Clozapine, Dopamine, Glutamate, GABA, ECT, rTMS, tDCS

Received: 15 Oct 2018; Accepted: 29 Jul 2019.

Copyright: © 2019 Leung, Gadelrab, Ntephe, Mcguire and Demjaha. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Cheryl C. Leung, King's College London, London, United Kingdom, cheryl.leung@kcl.ac.uk
Dr. Arsime Demjaha, King's College London, London, United Kingdom, arsime.demjaha@kcl.ac.uk