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

Front. Psychiatry | doi: 10.3389/fpsyt.2019.00870

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

  • 1Department of Neuroscience, University of Naples Federico II, Italy
  • 2Molecular Brain Science Department, Centre for Addiction and Mental Health (CAMH), Canada
  • 3The Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, United States

Treatment resistant schizophrenia (TRS) is a disease entity whose tracts are yet to be fully deciphered. The characterization of effective therapeutic strategies for this severe condition represents one of the more relevant unmet need of contemporary psychiatry. Nonetheless, researches on therapeutic strategies are strictly intermingled with the characterization of clinical determinants and boundaries of the disease, and with the elucidation of its biological underpinnings. These elements cannot be separated from each other and their combined evaluation has been the objective of this Research Topic. As an ideal starting point for the Topic, Cheryl Cheuk-Yan Leung and colleagues provide a thorough summarization of the current knowledge on TRS. These Authors make an excellent overview of the current challenges with the definition and neurobiology of TRS, the heterogeneity of clinical course, the difficulty with an optimal characterization of predictors, the standard-of-care and criticism of TRS therapy. The idea that schizophrenia and TRS may be categorically distinct is tackled in the contribution by Bruce Kinon, as the Author critically discusses the issue of TRS heterogeneity. Recalling the classical definition of Bleuler for schizophrenia, Kinon proposes to refer to TRS as The Group of Treatment Resistant Schizophrenias, due to the patent heterogeneity in the trajectory of nonresponse to antipsychotics. This heterogeneity depends on multiple factors and mostly on inconsistency in defining TRS, preventing the possibility to understand whether TRS may be a distinct disease category or on a continuum with schizophrenia. Parsing patient segments to achieve more homogenous ones sharing common pathophysiology may allow moving from more broadly to more targeted segments, paving the way to data or at least hypothesis-driven novel drug strategies for TRS. In agreement with these reports, our study group has attempted to delineate the distinctive features and determinants of disease severity in TRS vs. non-TRS patients. We find that disease severity is higher in TRS patients and mostly associated with negative symptoms. In turn, negative symptoms mediate the effects of cognitive dysfunctions and possibly neurodevelopmental alterations in TRS patients. Despite this contribution appears to support the idea of a categorical distinction between TRS and non-TRS patients, it also enlightens one of the limitations of current operational criteria: the most relevant factor driving disease severity in TRS patients is the extent of negative symptoms, that are notoriously not targeted by current antipsychotics. A dog chasing its own tail. These challenges and uncertainties strongly illustrate the urge to achieve pathophysiological models and neurobiological markers of TRS to develop targeted therapies. As reported in Cheryl Cheuk-Yan Leung article, the traditional model of dopamine dysfunction for the pathogenesis of schizophrenia seems not to be applicable to explain TRS, and other neurochemical dysfunctions (e.g. cortical hyper-glutamatergy) may play a role in the disease. In partial agreement with this consideration, the contribution of Davide Amato and colleagues depicts an intriguing novel theoretical model to explain some forms of TRS. Based on previous experimental studies [1], Amato et al. suggest that response to antipsychotics may stem from an imbalance between D2 receptor blockade and Dopamine Transporter (DAT) blockade to achieve adequate extracellular dopamine levels to trigger presynaptic dopaminergic neuron autoinhibition. Presynaptic autoinhibition alleviates psychotic symptoms by reducing dopamine release and post-synaptic neuron activation. A failure of this mechanism, due to multiple factors (e.g. reduced DAT expression as a consequence of genetic factors, prior exposure to psychostimulants, or aging), may lead to treatment resistance.Another remarkable contribution, by Md Shaki Mostaid and colleagues, describes an overall upregulation of transcripts within the Neuregulin-ErbB signaling pathway among individuals with schizophrenia. Indeed, Authors investigated Neuregulin signaling pathway mRNA transcripts in whole blood of 71 TRS patients and 57 healthy controls and found upregulated levels in TRS patients for five transcripts, although only one surviving correction for multiple testing. Still on neurobiological markers of TRS, the excellent review by Mary-Anne Bellwood MacKay and colleagues summarizes current findings on system and circuit-level brain dysconnectivity in treatment-resistant schizophrenia based on neuroimaging studies. As described in this report, a clear-cut separation at multiple levels of connectivity emerges between TRS and non-TRS patients, opening the way to circuit-based interventions. The issue of therapeutic strategies has been addressed in multiple articles. An intriguing contribution is given by Tsuyoshi Miyaoka and colleagues. These Authors describe the case of a schizophrenia patient with predominant severe hallucinations and delusions non-responsive to antipsychotics, who showed a reduction of psychotic symptoms and improvement in social functioning after receiving bone marrow transplantation for acute myeloid leukemia. This case report has a place into the current debate on immune pathogenesis of schizophrenia [2]. Unfortunately, TRS patients are exposed to high doses of antipsychotics, causing severe undesirable effects. The contribution by Robert Eriksson and colleagues deals with a less debated but still relevant antipsychotic side effect, i.e. impaired bone mineral status, which is investigated in obese non-diabetic antipsychotic-treated patients, showing a reduction of bone mineral density in 23% of the included patients. The search for strategies beyond mere pharmacological interventions is the object of the metaanalysis conducted by Daniela Polese and colleagues. These Authors focused on psychological interventions in TRS patients, either in augmentation or in substitution of antipsychotics. Psychological interventions showed a therapeutic effect in 40 out of 42 selected studies. The most improvement was found in positive symptoms for Cognitive Behavioral Therapy, as well as for other psychological interventions (albeit with different degrees). This contribution strongly encourages psychological interventions in TRS. The contribution of Yolanda Marono Souto and colleagues illustrates the results of a randomized controlled trial for an online emotional training devoted to social cognition rehabilitation in schizophrenia patients. The Authors find significant improvement in emotion recognition and multiple Theory-of-Mind tasks. Although to date impairment of social cognition has been only limitedly studied in TRS, it is presumable that social cognition-oriented interventions may soon become indicated in these patients. However, literature on severe mental illness should face relevant methodological limitations, as illustrated in the contribution by John Lally and colleagues. Authors find that psychotic participants in a large trial of psychosocial interventions to improve physical health in severe mental illness had a lower degree of overall illness severity and functional impairment than eligible non-participant psychotic individuals, therefore challenging representativeness of participants to the trial and concluding that more severe patients may tendentially be not predisposed to be enrolled. Although a generalization of these results to other kinds of trials (e.g. pharmacological or psychological) is beyond Authors' scope, more focused recruitment efforts should be considered when carrying out trials on severely ill patients. This recommendation should be specifically applied to TRS patients since they exhibit more severe psychopathology and more impaired social functioning even when compared to responder patients [3].

Keywords: psychosis, antipsychotic, Clozapine, Schizophrenia, Treatment refractory

Received: 14 Sep 2019; Accepted: 04 Nov 2019.

Copyright: © 2019 Iasevoli, De Luca and Nucifora Jr.. 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: Prof. Felice Iasevoli, University of Naples Federico II, Department of Neuroscience, Naples, Italy,