Whither the Attenuated Psychosis Syndrome?

Abstract

After 4 years of debate, a decision has been made. The attenuated psychosis syndrome (APS) will not be a coded diagnosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Formerly known as the psychosis risk syndrome, the proposed diagnosis was based on criteria developed in the mid-1990s that were informed by a comprehensive review of retrospective studies on the prodromal phase of nonaffective psychosis.1 These criteria aimed to identify prospectively people in the prodrome of schizophrenia and other psychotic disorders and have been variously titled “ultra high risk (UHR),” “clinical high risk (CHR),” “at risk mental state (ARMS),” and the “prodromal stage,” and included a group with attenuated (subthreshold) positive psychotic symptoms.2 The criteria are associated with rates of onset of psychotic disorder substantially higher than in the general population3 and other clinical populations.4 A recent meta-analysis reported the rate of onset of a psychotic disorder to be 36% after 3 years.5 About 73% of those developing a psychotic disorder fulfill criteria for schizophrenia spectrum psychoses.6 It should be noted that these data are from treated samples consisting of patients referred to specialist clinical services.

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Schizophrenia Bulletin vol. 38 no. 6 pp. 1130–1134, 2012
doi:10.1093/schbul/sbs108
© The Author 2012. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
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Whither the Attenuated Psychosis Syndrome?
Alison R.Yung*,1, Scott W.Woods2, StephanRuhrmann3, JeanAddington4, FraukeSchultze-Lutter5, Barbara
A.Cornblatt6,7,8, G. PaulAmminger1,9, AndreasBechdolf1,3, MaxBirchwood10, StefanBorgwardt11, Tyrone D.Cannon12,
Lieuwede Haan13, PaulFrench14,15, PaoloFusar-Poli16, MatcheriKeshavan17, JoachimKlosterkötter3, Jun SooKwon18,
Patrick D.McGorry1, PhilipMcGuire16, MasafumiMizuno19, Anthony P.Morrison14, AnitaRiecher-Rössler20, Raimo
K.R.Salokangas21, Larry J.Seidman17, MichioSuzuki22, LuciaValmaggia16, Markvan der Gaag23, Stephen J.Wood10,
and Thomas H.McGlashan2
1Orygen Youth Health Research Centre, Centre for Youth Mental Health, University of Melbourne, Australia; 2Department of
Psychiatry, PRIME Research Clinic for the Psychosis Risk Syndrome, Yale University, New Haven, CT; 3Department of Psychiatry
and Psychotherapy, University Hospital of Cologne, Germany; 4Department of Psychiatry, University of Toronto, Canada; 5University
Hospital of Child and Adolescent Psychiatry, University of Bern, Switzerland; 6Division of Psychiatry Research, The Zucker Hillside
Hospital, North Shore—Long Island Jewish Health System, Glen Oaks, NY; 7Center for Psychiatric Neuroscience, The Feinstein
Institute for Medical Research, North Shore, Long Island Jewish Health System, Manhasset, NY; 8Hofstra North Shore-LIJ School of
Medicine, Hemptead, NY; 9 Department of Child & Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria; 10School
of Psychology, University of Birmingham; 11Department of Psychiatry, University of Basel, Basel, Switzerland; 12Department of
Psychology, Yale University, New Haven, CT; 13AMC, Academic Psychiatric Centre, Department Early Psychosis, Amsterdam, the
Netherlands; 14School of Psychological Sciences, University of Manchester; 15Greater Manchester West Mental Health NHS Trust,
Manchester; 16Department of Psychology, King’s College London, Institute of Psychiatry, London; 17Beth Israel Deaconess Medical
Center and Massachusetts Mental Health Center, Harvard Medical School, Boston, MA; 18Department of Psychiatry, Seoul National
University College of Medicine, Seoul, Korea; 19Department of Neuropsychiatry, Toho University School of Medicine, Tokyo, Japan;
20University Psychiatric Clinics, Center for Gender Research and Early Detection, c/o Universitätsspital Basel, Switzerland; 21Department
of Psychiatry, University of Turku; Psychiatric Clinic, Turku University Hospital, Finland; 22Department of Neuropsychiatry, University
of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan; 23VU University and EMGO Institute,
Amsterdam and Parnassia Psychiatric Institute, The Hague, the Netherlands
*To whom correspondence should be addressed; Orygen Youth Health Research Centre, Centre for Youth Mental Health, The University of
Melbourne, 35 Poplar Rd Parkville 3052, Victoria, Australia; tel:+61 3 9342 2800, fax: +61 3 9342 2921, e-mail: aryung@unimelb.edu.au
After 4 years of debate, a decision has been made. The
attenuated psychosis syndrome (APS) will not be a coded
diagnosis in the Diagnostic and Statistical Manual of
Mental Disorders (DSM-5). Formerly known as the
psychosis risk syndrome, the proposed diagnosis was based
on criteria developed in the mid-1990s that were informed
by a comprehensive review of retrospective studies on the
prodromal phase of nonaffective psychosis.1 These criteria
aimed to identify prospectively people in the prodrome
of schizophrenia and other psychotic disorders and have
been variously titled “ultra high risk (UHR),” “clinical
high risk (CHR),” “at risk mental state (ARMS),” and the
“prodromal stage,” and included a group with attenuated
(subthreshold) positive psychotic symptoms.2 The criteria
are associated with rates of onset of psychotic disorder
substantially higher than in the general population3
and other clinical populations.4 A recent meta-analysis
reported the rate of onset of a psychotic disorder to
be 36% after 3 years.5 About 73% of those developing
a psychotic disorder fulll criteria for schizophrenia
spectrum psychoses.6 It should be noted that these data
are from treated samples consisting of patients referred to
specialist clinical services.
Despite the consistent nding that there is a high risk of
developing a psychotic disorder associated with the APS
group,5 there has been considerable controversy around
the idea of formally codifying it into a DSM5 diagnosis.
Indeed, we, the authors of this communication, all active
researchers in the area, have had differences in opinion
about the merits of including APS as a new diagnosis in
the DSM.7–12
One issue debated was the tension between the possi-
bility of early intervention to prevent progression of dis-
order vs potential unnecessary diagnosis and treatment
of what might be a self-limiting phase. The possibility
of stigma and discrimination was also raised.10,11 Some
speculated that a formal diagnosis would be assumed
to equate to an indication for antipsychotic medication
and so increase the likelihood of antipsychotic prescrip-
tion.11 Others argued that the absence of an APS diag-
nosis has led to some clinicians using the term psychosis
NOS (not otherwise specied), which may lead to anti-
psychotic prescription. The APS as an alternative to this
diagnosis could then actually reduce antipsychotic pre-
scribing.9,12 Importantly, an APS diagnosis will enable
evidence-based treatments to be developed, including
AT ISSUE
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Whither the Attenuated Psychosis Syndrome?
psychological therapies, and could therefore decrease
antipsychotic use.12
Ultimately, the decision to exclude APS as a coded
diagnosis was made not in response to any of the above
issues or in the light of data addressing the principal dis-
putes but because data on the diagnostic reliability of
APS in clinical practice were limited and inconclusive.
Following this decision, some critics have been quick
to denounce the whole APS/ultra high-risk/clinical high-
risk/prodromal concept.13–15 We, therefore, feel it is timely,
as a group involved in high-risk (prodromal) research,
to document some points of consensus between us and
highlight areas for future research.
Points of Consensus
Attempts to recognize the prodrome of schizophre-
nia prospectively have been active for nearly 20years.2
Many samples of persons meeting high-risk criteria
have been seen and evaluated. Astrong consensus exists
that individuals meeting APS criteria (which includes a
criterion for help-seeking) are symptomatic and in need
of clinical care.16–18 People meeting the criteria do in fact
fulll the broad denition of mental disorder: “a clini-
cally signicant behavioral and psychological syndrome
or pattern … that is associated with present distress …
or disability … or with a signicantly increased risk of
suffering death, pain, disability, or an important loss of
freedom,”19 (p. xxi). Thus, treatment is clearly justied,
regardless of the justication of reduction of risk or
prevention. We agree that this treatment should include
monitoring of mental state, supportive therapy, and
attention to current practical needs. Cognitive therapy
and omega-3 fatty acids may also be helpful. On current
evidence, antipsychotic medication is no more effective
than other more benign treatments and so is typically
not recommended.20
A second point of consensus is that people meeting
APS criteria have a greatly increased risk of develop-
ing a psychotic disorder within a brief time frame.3,5,21,22
Despite evidence that the transition rate (conversion from
high-risk state to rst-episode psychosis) may be declin-
ing in the short term23 and the nding of low rate of psy-
chosis in recent intervention trials,24,25 its magnitude is
similar to other risk syndromes,26,27 and still in the order
of hundreds fold above the risk of the general popula-
tion. Given this, we agree that regular assessment of men-
tal state to detect rst episode of psychosis is indicated.
The monitoring of mental state and early detection of
psychosis allow prompt treatment and the minimization
of the duration of untreated psychosis, which, if pro-
longed, is harmful to both patients and their families and
is known to be associated with a poor outcome.28,29
Finally, we agree that more research into the APS is
needed. We support the Psychotic Disorders Workgroup
in its recommendation to include the APS as a category
in the appendix (Section 3)of DSM-5 as a condition for
furtherstudy.
Collectively, we have devoted many hours into thinking
about this condition. Through our research and clinical
experience with these patients, we have evolved our
thinking and our conceptualization of APS. Initially, the
high-risk criteria were developed, as the name suggests,
to detect individuals at high risk of psychotic disorder.
However, the use of the criteria should not be thought of
as identifying and treating an asymptomatic group at risk
of a poor outcome, analogous to detecting and treating
hyperlipidemia to prevent myocardial infarction (MI).
APS patients are symptomatic and distressed. Thus, angina
may be a more apt analogy. However, better still is to think
of the criteria as detecting chest pain. The condition is
distressing, symptomatic, and leads to help seeking. It
may indicate the early signs or risk for a serious cardiac
disease such as MI, a serious but noncardiac disease, such
as pneumonia or a benign self-limiting condition such
as esophageal spasm or costochondritis. Likewise, APS
may indicate the early signs or risk for illnesses such as
nonaffective and affective psychotic disorder, presence or
risk for a serious but nonpsychotic illness such as severe
unipolar depression, or it may indicate something that
is not serious and which may resolve, with or without
treatments such as psychological support, stress reduction
family interventions, and practicalhelp.
This way of conceptualizing APS leads to many differ-
ent paths for research. Suggestions for the future research
agenda follow.
Expanding the Range of Outcomes to Be Studied
Investigation of different outcomes in both the short and
long term including psychotic disorders, nonpsychotic dis-
orders, persistence or remission of APS, and social and
cognitive functioning is needed. Rening risk factors for
these different outcomes is another avenue of research. It
may be that added criteria are necessary to enrich the sam-
ple for schizophrenia, such as basic and negative symptoms
and decline in cognitive and social skills.30,31 Other meth-
ods of enrichment for other outcomes can also be studied,
including multiple subclinical symptoms plus depression,32
presence of personality disorder, family history of mental
disorder, and childhood trauma and adversity.33
Examining recovery and remission of the high-risk state
as outcomes is another area that is currently understud-
ied. Searching for predictors of these positive outcomes
can then lead to adding such factors to ascertainment cri-
teria as exclusions, which would result in a reduced false
positive rate and increased positive predictive power.
Searching for Markers of Different Trajectories
Examining associated neurobiological,34–36 cognitive,37
physiological,38 metabolic,39 and genetic40,41 associations
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A. R.Yung etal.
with the APS and its different outcomes is needed so that
subgroups can be more sharply delineated. Longitudinal
follow-up is needed to elucidate whether the biological
markers that are observed in the APS group are indicative
of a trait vulnerability to psychotic disorder or whether
they are state markers. Comparison with other psychiat-
ric groups without APS will determine whether biological
ndings are specic to APS and represent a continuum
with psychotic disorders such as schizophrenia or whether
they are associated with general psychiatric distress.
Stigma and the Effect of Symptoms and Diagnosis
Research is also needed as to what harms and benets are
associated with an APS diagnosis. This should include
assessing any perceived stigma, and comparison made
with the stigma, stereotypes, and wish for social dis-
tance associated with overt psychiatric symptoms that
may occur prior to help seeking and diagnosis. Whether
clinical care that provides information, treatment, and
hope of a good outcome can minimize stigma should
also be studied. The effects of creating a new diagnosis,
on patients, their families, and the wider health system,
needs to be better understood.
Reliability and Clinical Utility
While reliability of assessment has been demonstrated in
previous studies using structured interviews,42,43 the clini-
cal utility and reliability of assessment in routine practice
needs to be assessed and improved and the impact of the
proposed diagnosis on prescribing practice examined.
Investigation of factors that lead APS patients to seek
help will also be useful. Currently, it is unclear how much
of the distress that leads to seeking help is related to the
psychotic-like symptoms or to associated nonpsychotic
mental disorders, such as depression and anxiety.44 Little
is known about the prevalence of APS in adolescent and
adult clinical populations and in the general community
and this also needs further study.
TreatmentTrials
Further intervention research is also needed. Omega-3
fatty acids have shown promise in reducing symptoms
as well as decreasing the risk of transition to psychotic
disorder in one study.45 This requires replication. Other
novel treatments such as psychological treatments, vita-
min D, glycine, and other neuroprotective agents are also
worth testing.
Possibility of a Pluripotent Risk Syndrome
Finally, with increasing the knowledge of risk factors for
different outcomes (see above), the APS model could also be
extended to a more general a strategy for early intervention
in a range of mental disorders. It may be that many disor-
ders develop from initial nonspecic symptoms and syn-
dromes, from a background of specic and nonspecic risk
factors (such as genes and early environment). Worsening
of symptoms and acquisition of new symptoms may occur,
together with progressive neurobiological abnormalities,
and related neurobehavioral decits, until clear-cut recog-
nizable mental disorders appear.46 Progression of symp-
toms and neurobiological abnormalities could continue
after “threshold” diagnosis, with development of chronic
symptoms, relapses, and ongoing functional deterioration.
Transition from one stage to the next is not inevitable, either
due to different risk and resilience factors or due to nonspe-
cic or specic intervention. Thus, preventive possibilities
exist across this spectrum of evolving illness.
This concept of a pluripotent risk syndrome opens up
a range of research possibilities. Studying genetic and
environmental risk factors and gene and environment
interactions for different outcomes, further work on
resilience and protective factors, and examination of
different trajectories are all future avenues of research.
Whether any specic markers for particular course and
outcome can be detected early is another area and leads
to the possibility of early specic treatments. Novel
methods such as multimodal imaging and neurocognitive
analysis, single subject methods to predict individual
disease course are also possible.
Conclusion
APS concept remains a useful one. It identies people
with signicant mental health problems that justify
treatment in their own right, as well as having a higher
likelihood of developing a psychotic disorder (mostly
schizophrenia) within a few years. Research into this
group will increase our understanding of psychotic-like
symptoms and their trajectories and the emerging phase
of psychotic disorders. The APS concept is consistent
with the continuum view of psychosis and is probably
a reection of biologic reality. Outcomes other than
psychotic disorder are also clearly worthy of study. The
placement of APS in the DSM-5 appendix should be
a clarion call to the eld to focus attention on these
patients and families inneed.
Acknowledgments
A.B. and J.K. have received investigator-initiated grant
support from Bristol Myers Squibb. A.B. has received
speaker fees and travel support from Bristol Myers
Squibb, Eli Lilly, Janssen Cilag, and Servier. P.D.M. has
received unrestricted research grant support from Janssen
Cilag, honoraria for educational events and consultancies
from Janssen-Cilag and Roche, and unrestricted Research
Grant Support from Astra Zeneca. As these sources of
funding have not inuenced the content of this article, all
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1133
Whither the Attenuated Psychosis Syndrome?
authors have declared that there are no conicts of inter-
est in relation to the subject of this article.
Funding
National Health and Medical Research Council (Australia)
Senior Research Fellowship (#566593), and the Colonial
Foundation (to A.R.Y.); National Institute for Mental
Health (NIMH) grants (#5U01MH081857 and #5R01
MH061523 to B.A.C.); German Research Foundation,
NARSAD, the German Ministry of Education and
Research, the Faculty of Medicine of the University
of Cologne (to A.B.); the National Institute for Health
Research (NIHR) Birmingham and Black Country
Collaboration for Leadership in Applied Health
Research and Care (to M.B.); NIHR Biomedical
Research Centre for Mental Health at the South London
and Maudsley NHS Foundation Trust and Institute of
Psychiatry King’s College London (to P.F.-P., P.M., and
L.V.); the German Research Foundation, the European
Commission, the German Ministry of Education and
Research, and the Faculty of Medicine of the University
of Cologne (to J.K.); the University of Basel (to S.B.
and A.R.-R.), Swiss National Foundation, Stanley
Foundation, European Union FP7, Österreichische
Forschungsförderungsgesellschaft, Foundation Alamaya
(to A.R.-R.); NIMH (U01 MH081928, P50 MH080272),
Massachusetts Department of Mental Health, R21
MH093294, R01 MH096027 (to L.S.); and NIMH and
the Norwegian Research Council (to T.H.M.).
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