CanJPsychiatry 2015;60(3 Suppl 2):S14–S18

Chapter 2

What Does Schizophrenia Teach Us About Antipsychotics?

Gary Remington, MD, PhD, FRCPC1; Ofer Agid, MD2; George Foussias, MD, PhD, FRCPC3;
Gagan Fervaha, BSc (PhD Candidate)4; Hiroyoshi Takeuchi, MD, PhD5;
Jimmy Lee, MBBS, MMed6; Margaret Hahn, MD, PhD, FRCPC3
1
Professor, Department of Psychiatry, University of Toronto, Toronto, Ontario; Lead, Subspecialty Clinics, Schizophrenia Program, Centre for Addiction and
Mental Health, Toronto, Ontario; Senior Scientist, Campbell Family Mental Health Research Institute, Toronto, Ontario; Faculty, Institute of Medical Science,
Toronto, Ontario.
Correspondence: Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8; gary.remington@camh.ca.
2
Associate Professor, Department of Psychiatry, University of Toronto, Toronto, Ontario; Medical Leader, Home Intervention Program, Schizophrenia Program,
Centre for Addiction and Mental Health, Toronto, Ontario; Faculty, Institute of Medical Science, Toronto, Ontario.
3
Assistant Professor, Department of Psychiatry, University of Toronto, Toronto, Ontario; Staff Psychiatrist, Schizophrenia Program, Centre for Addiction and
Mental Health, Toronto, Ontario; Scientist, Campbell Family Mental Health Research Institute, Toronto, Ontario.
4
Student, Institute of Medical Science, Toronto, Ontario.
5
Post-doctoral Fellow, Department of Psychiatry, University of Toronto, Toronto, Ontario; Assistant Professor, Department of Neuropsychiatry, Keio University,
Tokyo, Japan.
6
Post-doctoral Fellow, Department of Psychiatry, University of Toronto, Toronto, Ontario; Psychiatrist and Consultant, Department of General Psychiatry,
Institute of Mental Health, Singapore, Singapore; Assistant Professor, Office of Clinical Sciences, Duke-National University of Singapore Graduate Medical
School, Singapore, Singapore.

Objective: To examine how advances in our understanding of schizophrenia have shaped

Key Words: schizophrenia,
first-episode psychosis,
prodrome, treatment
resistance, pharmacotherapy,
antipsychotics, polypharmacy,
classification, outcome
Received, revised, and
accepted June 2014.
open
access
thinking about antipsychotics (APs) and their role in treatment.
Method: Three specific developments in the field of schizophrenia are highlighted: advances
in knowledge related to the earliest stages of schizophrenia, specifically the prodrome;
reconceptualization of schizophrenia as an illness of multiple symptom domains; and greater
clarification regarding the efficacy of clozapine and a new generation of APs.
Results: Evidence indicating that negative and cognitive symptoms are present during the
prodrome suggests that intervention at the time of first-episode psychosis constitutes late
intervention. The limited efficacy of APs beyond psychosis argues against a magic bullet
approach to schizophrenia and for polypharmacy that is symptom domain–specific. Clozapine’s
unique, but limited, efficacy in treatment resistance supports subtyping schizophrenia based on
treatment response.
Conclusions: Advances in our understanding of schizophrenia have important implications
regarding the current use of APs, expectations regarding response, and future drug
development.
WWW

Que nous enseigne la schizophrénie sur les antipsychotiques?

Objectif : Examiner comment les progrès de notre compréhension de la schizophrénie ont
formé notre idée sur les antipsychotiques (AP) et leur rôle dans le traitement.
Méthode : Trois développements spécifiques du domaine de la schizophrénie sont présentés :
le progrès des connaissances relatives aux stades précoces de la schizophrénie, spécialement
le prodrome; la reconceptualisation de la schizophrénie comme étant une maladie de multiples
domaines de symptômes; et une clarification accrue concernant l’efficacité de la clozapine et
d’une nouvelle génération d’AP.
Résultats : Les données probantes indiquant que des symptômes négatifs et cognitifs
sont présents durant le prodrome suggèrent que l’intervention au moment du premier
épisode psychotique constitue une intervention tardive. L’efficacité limitée des AP au-delà
de la psychose est un argument défavorable à une approche de solution magique pour la
schizophrénie, et en faveur de la polypharmacie qui est propre au domaine de symptômes.
L’efficacité unique mais limitée de la clozapine dans la résistance au traitement soutient le sous-
typage de la schizophrénie selon la réponse au traitement.
Conclusions : Les progrès de notre compréhension de la schizophrénie ont d’importantes
implications pour l’utilisation actuelle des AP, les attentes quant à la réponse, et le
développement pharmaceutique futur.

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D rug development in the field of schizophrenia has
flourished since the 1990s, beginning with clozapine’s
reintroduction and paralleled by technological advances in
areas (for example, neuroimaging and electrophysiology)
that have markedly impacted thinking regarding the illness’
underlying neurobiology.
Shifts in how we conceptualize the illness clinically, combined
with a greater understanding regarding how medications work
within these newer frameworks, offer yet another opportunity
to advance pharmacotherapy and form the basis of the present
discussion. Here we comment on 3 developments that have
evolved out of these advances, developments we argue hold
important ramifications regarding expectations about APs, and
the search for new agents.
Antipsychotic Treatment, by Definition,
Constitutes Late Intervention in
First-Episode Schizophrenia
The 1990s also witnessed a growing interest in the early
stages of schizophrenia, specifically FEP. Driving this
line of thinking was evidence that considerable delays in
implementing treatment often occur, and, further, delayed
treatment (that is, DUP) compromises outcome. While a
body of evidence has supported this hypothesis, findings
have been inconsistent, and debate regarding the benefits
of early intervention continues.1–5 Notably, there appears
to be a disparity between clinical and functional outcome
in as much as remission in psychosis does not guarantee
functional recovery.6,7
As this work unfolded, schizophrenia was being
reconceptualized, no longer positioned as an illness of only
positive symptoms. Through the 1980s, negative or deficit
symptoms garnered attention,8–11 and their importance was
reflected in the development of clinical scales that clearly
differentiated, while capturing, both positive and negative
symptoms.12–14 Through the 1990s, increased focus was
given to neurocognition, and by the turn of the century, the
notion of schizophrenia as an illness of multiple symptom
domains was firmly established.15–17
Shedding further light on these other symptoms was
an evolving line of investigation also focused on the
early stages of schizophrenia, but in this case the illness’
prodrome. This stage precedes the first psychotic break,
can span a period of years, and is characterized by various
nonpsychotic symptoms and behavioural changes often
Abbreviations
AP antipsychotic
DA dopamine
DUP duration of untreated psychosis
FEP first-episode psychosis
TRS treatment-resistant schizophrenia
URS ultra-resistant schizophrenia
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What Does Schizophrenia Teach Us About Antipsychotics?
Clinical Implications
• Positive symptoms represent the end stage in
schizophrenia, with evidence that other key symptom
domains are in place by the time of FEP.
• The idea that a single agent will prove useful across
these different symptom domains (the magic bullet
approach) is naïve and has not been substantiated,
endorsing a new form of polypharmacy that is presently
being pursued.
• From the standpoint of psychosis, evidence based on
treatment response defines 3 subgroups that should
be treated as such as we seek to understand the
underlying neurobiology.
Limitations
• Efforts to intervene earlier than FEP remain hampered
by the absence of clearly established clinical and (or)
biomarkers that accurately delineate those who will
convert.
• Acknowledging schizophrenia’s heterogeneity
represents an important advance that also highlights
major gaps in treatment (for example, negative and
cognitive symptoms; clozapine-resistant schizophrenia).
associated with functional deterioration. Evidence gathered
suggests that cognitive deficits (both neurocognition and
social cognition), as well as negative symptoms, are in
place during the prodrome.18–21
Why are these details important? A closer examination of
functional outcome and its determinants has established that
domains other than psychotic or positive symptoms may be
more relevant. While such a statement may be skewed, in
that people are generally being treated for their positive
symptoms, it remains that both cognitive and negative
symptoms have been posited to play a more important role
in functional recovery.22–24
The implications of these different lines of investigation
are considerable. First, from a clinical standpoint, the
onset of positive symptoms really represents a late stage
of schizophrenia regarding its evolution; by the time a first
psychotic break occurs, the other key symptom domains are
already established. Second, it is these domains that seem to
play a critical role in functional recovery. Finally, evidence
indicates that APs are not particularly effective in treating
these other symptoms.25–27 That early intervention with
APs has not dramatically impacted measures of functional
outcome is consistent with this, and highlights the current
limitations facing FEP programs and the concept of early
intervention, as well as the potential impact of APs, even
used in the earliest stages of psychosis, on functional
outcome.
Embracing Polypharmacy:
the Myth of Magic Bullets
The magic bullet era surrounding APs may be drawing
to a close. In retrospect, it was relatively short lived, and
our embracing of this model seems a complex interplay of
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Chapter 2
science, hope, and marketing. The era was short lived in
that APs were seen as just that (that is, anti-psychosis drugs)
almost exclusively prior to clozapine’s reintroduction in the
early 1990s. As noted, interest in the negative symptoms
really only took a foothold in the 1980s (and largely argued
against the potential use of APs, or pharmacotherapy
generally, in effectively treating primary negative-deficit
symptoms).9–11 Similarly, interest in neurocognition did not
gain momentum until the 1990s.15–17
The finding that clozapine also appeared to impact negative
symptoms in the work involving TRS28 seems an important
catalyst in setting the stage for expectations that APs could
be more than that. It is likely that time further contributed
to this shift; almost immediately on the heels of clozapine
came the advent of the newer atypical APs, drugs that were
to mirror clozapine and, ideally, circumvent its burdensome
side effect profile. The next decade saw claims regarding the
benefits of these new medications expand considerably,29
perhaps fuelled by aggressive marketing. In fairness, it was
likely driven as well by the hope that we could set behind
us the therapeutic nihilism accompanying the evolution
of the conventional APs and the growing recognition that
even highly selective DA D2 antagonists (for example,
haloperidol and pimozide), which theoretically should
represent the ideal AP, fell woefully short.30–32 Be that as
it may, claims of broader, as well as greater, efficacy grew,
but the science to firmly establish these could simply not
keep pace. As a result, we have, more recently, witnessed
a series of investigations that temper, if not dismiss, these
claims.33–35
As the dust settles, we face a very different landscape. For
example, evidence that these drugs meaningfully impact
cognitive deficits and negative symptoms has not been
forthcoming.25–27 Remembering what resurrected clozapine
(that is, efficacy in TRS), it is now also clear that these other
new drugs are not comparable.36,37 That said, enthusiasm
generated by the introduction of a new class of APs
generated renewed interest in research that fundamentally
changed how we conceptualize the illness. It is now
patently evident that schizophrenia represents much more
than psychosis.38 Further, the apparent disconnect between
clinical and functional outcome might better be understood
in the context of these other symptom domains.22–24
It is here we pick up the polypharmacy story, which had,
to a considerable extent, been built around the practice of
using multiple APs to manage TRS. Evidence has been
equivocal, at best, particularly when other factors, such as
cost and side effect burden, are taken into consideration.39–41
However, the field of schizophrenia is now courting
polypharmacy through another door. It has become
increasingly apparent that our expectations of a magic
bullet approach to schizophrenia were overly optimistic at
best, or simply misguided at worst. In abandoning such an
approach, we are still left to deal with an illness that has
multiple domains, and the more recent shift in focus from
clinical to functional recovery only reinforces this.
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Our new definition of polypharmacy is no longer about
combining APs. It is now about the possibility of accessing
other drugs that can be used in conjunction with anti-
psychosis agents to improve these other symptoms. Indeed,
it may well provide indirect support for some of the other
forms of polypharmacy identified as prevalent (that is,
use of multiple psychotropics for treatment of anxiety or
depression).40 Only now we will be looking to add anti-
negative symptom drugs, anti-cognitive deficit drugs, and
perhaps others as our understanding of schizophrenia’s
complexity evolves.
Interestingly, this approach very much aligns with the
growing interest in personalized or individualized medicine.
Clinical practice tells us that people with schizophrenia
differ markedly across these different symptom clusters,
a point captured in the multi-domains now detailed for
clinical assessment in the Diagnostic and Statistical Manual
of Mental Disorders, Fifth Edition.42 By having different
drugs for each, we can individualize treatment in a fashion
that best suits a particular individual. What is less clear
at present, though, is whether the foreseeable future will
provide us agents that can effectively treat these other
symptoms in a clinically meaningful way.
Subtyping Schizophrenia by
Antipsychotic Response
With the exception of clozapine in TRS,36,37 APs are
generally considered to be similar in terms of clinical
response. Moreover, all APs share in common DA D2
antagonism, considered critical to their AP effects.43
Clinicians routinely initiate AP treatment with the goal
of symptom remission, switching agents in the case of
suboptimal response to achieve this. Evidence suggests
that, as a group, people with first-episode schizophrenia
demonstrate a high response rate to the first AP, in the range
of 70%, regardless of drug choice. Thereafter, the response
rate drops precipitously, findings indicating that subsequent
trials are associated with a response in the range of 20%
or less.44 Operational criteria have been established to
define TRS, and for this group about 30% to 60% of people
will demonstrate a favourable response.28,45,46 For those
who prove ultra-resistant (that is, suboptimal response to
clozapine), no treatment or combination of treatments has
proven to demonstrably capture a substantial number of this
population.47
This implies at least 3 types of schizophrenia based on
treatment response.48 The first group, the largest, responds
to one of the currently available APs (other than clozapine
as it cannot be used at this point), and can be designated AP
responsive. There is no compelling evidence that atypical
agents are superior in this group, although findings do
suggest there is a modest chance (<20%) that one agent may
work when another has failed. The second group represents
people who respond to clozapine (that is, TRS) and falls
under the category of clozapine responsive, while the third
group constitutes a clozapine nonresponsive sample (that
is, URS).
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These findings have important implications, both clinically
and theoretically. Clinically, undertaking multiple trials of
APs in nonresponsive people before moving to clozapine
is simply not supported by the evidence, which highlights
clozapine as the single agent with proven efficacy, at least
for a subgroup of those designated TRS.36,37 Unfortunately,
for the URS population, there is no empiric evidence
presently that can be used to guide clinical decision-making
in prioritizing interventions.47
Theoretically, this same information can be used to guide
research in drug development. For one subgroup, again
the largest it seems, response can be achieved with DA
D2 antagonism, common to all APs. That it is purely DA
D2-related may be an overstatement, given evidence that
a small number of people will respond to another non-
clozapine AP44; however, DA D2 antagonism appears
central.43 For a second subgroup, TRS, response is tied to
clozapine, which has in common with other APs DA D2
binding.49 However, its unique response in this population
implicates other mechanisms are critical as well, although,
to date, these have not been clearly delineated. Finally,
there is this third subgroup of people who fail to respond
to all APs currently available, including clozapine. Other
mechanisms must define this group, and, in fact, it may
be that more than one subsample constitutes this URS
population.
Summarizing, treatment response defines at least 3 forms
of schizophrenia. Such an approach aligns with the current
notion that schizophrenia is heterogeneous in nature, and
may better serve efforts aimed at improving treatment. As
an example, mixing TRS and URS people clearly obfuscates
efforts to find clozapine-like agents that are superior from
a side effect profile, as a disproportionate number of URS
subjects in a study sample would leave a putative agent
appearing ineffective.
Conclusions
Looking back, it now seems naive that APs were once
viewed as a panacea for the treatment of schizophrenia.
Even as anti-psychosis drugs, these agents have marked
limitations. The importance of DA D2 occupancy remains,
but from an efficacy standpoint captures only a subgroup of
people. Better delineating the poorly responsive population
(for example, clozapine responders, compared with
nonresponders) seems a useful starting point to advance
future treatments, while highlighting that we still do not
understand the underlying pharmacological mechanisms
that make clozapine unique. The notion that early treatment
with APs is going to substantially improve measures of
functional outcome seems misguided, at least based on
current knowledge regarding how the illness unfolds, the
importance of other symptom domains, and the limited
impact of current drugs. Polypharmacy represents a next
logical step, combining and individualizing symptom
domain–specific agents, although, at present, the evidence
involving investigational compounds has yet to match the
proven efficacy of APs for psychosis.
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What Does Schizophrenia Teach Us About Antipsychotics?
Acknowledgements
Dr Remington has received research support from the
Canadian Diabetes Association, the Canadian Institutes
of Health Research (CIHR), Medicure, Neurocrine
Biosciences, Novartis Canada, Research Hospital Fund–
Canada Foundation for Innovation, Ontario Mental Health
Foundation, and the Schizophrenia Society of Ontario,
and has served as a consultant or speaker for Novartis,
Laboratorios Farmacéuticos Rovi, Synchroneuron, and
Roche. Dr Agid has received research support from
Pfizer and Janssen-Ortho, and served as a consultant or
speaker for Janssen-Ortho, Eli Lilly, Novartis, Sepracor,
and Sunovion. Dr Foussias has received research support
from a Centre for Addiction and Mental Health (CAMH)
Post-doctoral Research Award, a CIHR Clinician-Scientist
Training Award, an American Psychiatric Association–
AstraZeneca Young Minds in Psychiatry Award, and
a National Alliance of Research on Schizophrenia and
Depression Young Investigator Award, and served as
a consultant or speaker for Roche. Gagan Fervaha has
received academic support through Ontario graduate
studies and a Vanier CIHR award. Dr Takeuchi has received
fellowship awards from CAMH, the Japanese Society of
Clinical Neuropsychopharmacology, Astellas Foundation
for Research on Metabolic Disorders, and has served
as a consultant or speaker for Dainippon Sumitomo, Eli
Lilly, GlaxoSmithKline, Janssen, Meiji Seika Pharma, and
Otsuka. Dr Lee has served as a consultant for Roche and is
currently supported by the Singapore Ministry of Health’s
National Medical Research Council under its Transition
Award (grant NMRC/TA/002/2012). Dr Hahn has received
research support through CAMH and the Banting and Best
Diabetes Centre (Reuben and Helene Dennis Scholar in
Diabetes Research).
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