Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review

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Abstract

Background

Schizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant. The only evidence-based treatment for these patients is clozapine, an atypical antipsychotic with relatively weak dopamine antagonism. It is plausible that varying degrees of response to antipsychotics reflect categorically distinct illness subtypes, which would have significant implications for research and clinical practice. If these subtypes could be distinguished at illness onset, this could represent a first step towards personalised medicine in psychiatry. This systematic review investigates whether current evidence supports conceptualising treatment-resistant and treatment-responsive schizophrenoa as categorically distinct subtypes.

Method

A systematic literature search was conducted, using PubMed, EMBASE, PsycInfo, CINAHL and OpenGrey databases, to identify all studies which compared treatment-resistant schizophrenia (defined as either a lack of response to two antipsychotic trials or clozapine prescription) to treatment-responsive schizophrenia (defined as known response to non-clozapine antipsychotics).

Results

Nineteen studies of moderate quality met inclusion criteria. The most robust findings indicate that treatment-resistant patients show glutamatergic abnormalities, a lack of dopaminergic abnormalities, and significant decreases in grey matter compared to treatment-responsive patients. Treatment-resistant patients were also reported to have higher familial loading; however, no individual gene-association study reported their findings surviving correction for multiple comparisons.

Conclusions

Tentative evidence supports conceptualising treatment-resistant schizophrenia as a categorically different illness subtype to treatment-responsive schizophrenia. However, research is limited and confirmation will require replication and rigorously controlled studies with large sample sizes and prospective study designs.

Electronic supplementary material

The online version of this article (doi:10.1186/s12888-016-1177-y) contains supplementary material, which is available to authorized users.

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Most cited references 89

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Age of onset of mental disorders: a review of recent literature

Ronald C Kessler, G Amminger, Sergio Aguilar-Gaxiola … (2007)

The aim of this article is to review recent epidemiological research on age-of-onset of mental disorders, focusing on the WHO World Mental Health surveys. Median and inter-quartile range (IQR; 25th-75th percentiles) of age-of-onset is much earlier for phobias (7-14, IQR 4-20) and impulse-control disorders (7-15; IQR 4-35) than other anxiety disorders (25-53, IQR 15-75), mood disorders (25-45, IQR 17-65), and substance disorders (18-29, IQR 16-43). Although less data exist for nonaffective psychosis, available evidence suggests that median age-of-onset is in the range late teens through early 20s. Roughly half of all lifetime mental disorders in most studies start by the mid-teens and three quarters by the mid-20s. Later onsets are mostly secondary conditions. Severe disorders are typically preceded by less severe disorders that are seldom brought to clinical attention. First onset of mental disorders usually occur in childhood or adolescence, although treatment typically does not occur until a number of years later. Although interventions with early incipient disorders might help reduce severity-persistence of primary disorders and prevent secondary disorders, additional research is needed on appropriate treatments for early incipient cases and on long-term evaluation of the effects of early intervention on secondary prevention.

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Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology.

Oliver Howes, Rob McCutcheon, Ofer Agid … (2017)

Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines.

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The dopamine hypothesis of schizophrenia: version III--the final common pathway.

O. Howes, S Kapur (2009)

The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia-version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.

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Author and article information

Contributors

Amy L. Gillespie: amy.gillespie@kcl.ac.uk

Ruta Samanaite: samanaite@gmail.com

Jonathan Mill: j.mill@exeter.ac.uk

Alice Egerton: alice.egerton@kcl.ac.uk

James H. MacCabe: james.maccabe@kcl.ac.uk

Journal

Journal ID (nlm-ta): BMC Psychiatry

Journal ID (iso-abbrev): BMC Psychiatry

Title: BMC Psychiatry

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-244X

Publication date (Electronic): 13 January 2017

Publication date PMC-release: 13 January 2017

Publication date Collection: 2017

Volume: 17

Electronic Location Identifier: 12

Affiliations

[1 ]Psychosis Studies Department, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, Denmark Hill, London, SE5 8AF UK

[2 ]Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

[3 ]University of Exeter Medical School, Exeter University, St Luke’s Campus, Exeter, UK

Article

Publisher ID: 1177

DOI: 10.1186/s12888-016-1177-y

PMC ID: 5237235

PubMed ID: 28086761

SO-VID: 4d3efe23-f026-466a-a84e-28a86c607e9a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 10 June 2016

Date accepted : 23 December 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000272, National Institute for Health Research;

Award ID: PCS9212

Funded by: FundRef http://dx.doi.org/10.13039/501100004963, Seventh Framework Programme;

Award ID: 279227

Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;

Award ID: MR/L003988/1

Award Recipient : Alice Egerton

Custom metadata

ScienceOpen disciplines: Clinical Psychology & Psychiatry

Keywords: schizophrenia,treatment resistance,treatment refractory,treatment response,clozapine,classification

Data availability:

ScienceOpen disciplines: Clinical Psychology & Psychiatry

Keywords: schizophrenia, treatment resistance, treatment refractory, treatment response, clozapine, classification

Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review

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Conclusions

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Most cited references 89

Age of onset of mental disorders: a review of recent literature

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology.

The dopamine hypothesis of schizophrenia: version III--the final common pathway.

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