Schizophrenia Research 242 (2022) 94–95
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Schizophrenia Research
journal homepage: www.elsevier.com/locate/schres
Reinventing schizophrenia: The rules of the game
Robert A. McCutcheon *, Philip McGuire
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, De Crespigny Park, London SE5 8AF, UK
The concept of a ‘language game’ was developed in Wittgenstein's
Philosophical Investigations, to illustrate how the meaning of words de­
pends on the rules of the setting, or ‘game’, in which they are employed
(Wittgenstein, 1953). Wittgenstein's aim is to demonstrate how the use
of a word determines its meaning. Who uses the word ‘Schizophrenia’?
Psychiatrists more than most, their patients at times, researchers too.
These users of ‘schizophrenia’ are not always playing the same game,
and this complicates attempts to reimagine psychiatric nosology.
If we restrict the players to clinicians and researchers, both may use
the word similarly, for example to categorise patients or aid communi­
cation. There are also, however, differences in the role the construct
plays for each group. The clinician's aim is to provide optimal care for
the patient in front of them. The researcher may have this goal in mind,
but lacks urgency to provide an immediate clinical decision, and broader
goals such as advancing understanding of disease pathophysiology are
understood as necessary steps along the way. As a result, while the
clinician requires a construct to guide treatment decisions, the
researcher may prefer one that better maps to a purported underlying
reality, even if immediate clinical utility is limited.
For a change to be more than simple rebranding, any replacement for
schizophrenia cannot be shaped in isolation. Psychiatric taxonomies are
complex systems of intertwined parts, and any significant evolution
needs to encompass psychiatric classification as a whole. Perhaps the
best known initiative aimed at moving away from current classification
systems in research was the National Institute of Mental Health Research
Domain Criteria (RDoC) initiative (Insel et al., 2010). This is a research
focused framework, intended to free scientists from the constraints of
diagnostic systems, and thereby allow a mapping to more fundamental
processes. This was not intended as a replacement for clinical classifi­
cation systems, and in the decade since its launch optimism remains as
to its potential (Sanislow, 2020). It is difficult, however, to point to any
RDoC related findings that have had a direct clinical impact, and recent
advances in pharmacological treatments continue to be framed in terms
of DSM defined categories (Brannan et al., 2021; Koblan et al., 2020).
A more recent initiative from the Hierarchical Taxonomy of Psy­
chopathology (HiTOP) is more clinically focused, and explicitly aims to
* Corresponding author.
E-mail address: robert.mccutcheon@kcl.ac.uk (R.A. McCutcheon).
https://doi.org/10.1016/j.schres.2021.12.009
Received 18 October 2021; Accepted 9 December 2021
Available online 6 January 2022
0920-9964/© 2022 Elsevier B.V. All rights reserved.
improve upon existing classifications (Kotov et al., 2020). Its dimen­
sional approach may more accurately capture the covariance of psy­
chiatric symptoms than traditional diagnoses. With HiTOP, however,
the clinical presentation remains the criterion by which individuals are
assessed. This makes for relatively straightforward clinical imple­
mentation but retains some drawbacks of existing approaches, particu­
larly the inability to distinguish between patients who have similar
symptoms but distinct underlying pathophysiologies (Haeffel et al.,
2021).
Despite a frequent focus on paradigm shifts, much of clinical progress
occurs by gradual improvement. A common frame of reference that al­
lows regular cross-pollination between clinicians and researchers is
central to this more incremental form of progress. There is a danger that
systems distinct from current clinical classifications, such as RDoC, may
become increasingly divorced from clinical reality, and as a result be
unlikely to address the relevant clinical questions. For iterative
advancement to succeed, a language that enables close communication
between research and the reality of clinical practice is required.
A key question is how to find a common language that doesn't
obscure nature on the one hand, or stymie research by locking science to
manmade categories on the other. The impetus to reinvent the schizo­
phrenia concept is partly borne from a fear that persisting with the
current concept may lead to stagnation, allowing minor refinements but
not fundamental progress. Approaches such as HiTOP may be a step in
the right direction, but still remain bound to external signs and
symptoms.
One approach to classification that can maintain communication
between clinic and laboratory, yet move beyond purely symptomatic
descriptions is a focus on clinically meaningful outcomes, such as
treatment response or course of illness. Employing a ‘precision psychi­
atry’ strategy has several potential advantages over solely symptom-
based approaches. First, it is highly relevant to clinical practice, with
research findings having clear implications for subsequent patient
management. Second, compared to symptomatic description alone, it is
more likely to map onto underlying pathophysiological processes
(Mouchlianitis et al., 2016). Finally, treatment response or clinical
R.A. McCutcheon and P. McGuire
course specifiers can be integrated into existing classification systems
without significant disruption, thereby allowing for a gradual evolution
rather than a sudden shift in practice. For example, a patient with
schizophrenia might be further characterised according to the likely
illness trajectory and their response to antipsychotic medications.
The success of this approach will depend on whether robust patho­
physiological differences between patients with similar clinical pheno­
types can be identified. Recent research suggests that the response to
antipsychotic treatment may be related to differences in polygenic risk,
brain chemistry and connectivity, and the levels of inflammatory
markers (Egerton et al., 2018; Jauhar et al., 2018; McCutcheon et al.,
2020; Mondelli et al., 2015; Sarpal et al., 2016; Yu et al., 2018; Zhang
et al., 2019). Less is known about differences related to clinical course in
schizophrenia, but in people at clinical high risk for the disorder, the
subgroup who go on to develop schizophrenia differ from those that do
not in measures of brain morphometry and chemistry, and in plasma
levels of proteomic and lipidomic markers (Bossong et al., 2019; Cannon
et al., 2015; Howes et al., 2011; Mechelli et al., 2011; Morgan et al.,
2020). Classifying patients in terms of outcomes like treatment response
or clinical course will appeal to clinicians who are not bound to diag­
nostic labels and tend to treat symptomatically (Waszczuk et al., 2017).
If treatment response and clinical course better reflect biology than
symptomatic measures, this approach may help biomarker development
avoid the impasse resulting from diagnoses unreflective of pathophysi­
ology (Keshavan and Ongur, 2014).
There are of course weaknesses to this approach. For example,
unpicking placebo and treatment specific responses is not trivial, and it
is the latter that is of primary interest, yet many studies focus on mea­
sures of overall response. Furthermore treatment response is normally
distributed, raising questions about where to draw the classification line
(McCutcheon et al., 2021). More generally, although patient subgroups
with similar outcomes may be more biologically homegenous than the
group of all patients with schizophrenia, even subgroups may not share
the same pathophyshiological process. Nevertheless, we believe this
approach charts a cautious path, keeping what is beneficial in current
approaches, while allowing progress to be made. A new taxonomy
guided by clinically meaningful outcomes may thereby evolve, allowing
the concept of schizophrenia to remain in play until we are ready to
move onto the next game.
Role of funding
Dr. McCutcheons funding pays his salary, funder played no other
role.
CRediT authorship contribution statement
Robert McCutcheon and Philip McGuire wrote the perspective.
Declaration of competing interest
Dr. McCutcheon has received honoraria from Otsuka for educational
talks. Prof McGuire reports receiving personal fees from Sunovion and
Takeda.
Acknowledgement
RA McCutcheon's work is funded by the National Institute for Health
Research.
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