Short Report Psychopathology 2014;47:287–291 DOI: 10.1159/000365221
Received: January 22, 2014 Accepted after revision: June 13, 2014 Published online: July 23, 2014
Attenuated Psychosis Syndrome: Need for Debate on a New Disorder William T. Carpenter
Key Words Prodrome · Psychosis · Schizophrenia · Early intervention · Prevention
Abstract This ‘pro’ statement of the controversial issue, defending the need for a new disorder classification of attenuated psychosis syndrome (APS), provides data supporting the clinical validity of this category and responds to the most frequently asserted criticisms. It provides arguments why APS is not pathologizing non-ill behaviors and is not stigmatizing for those affected but rather they merit clinical attention for what is already manifest. It also argues against the view that establishing the diagnostic category of APS results in an unreasoned excessive use of antipsychotic medications but rather encourages prevention and early intervention programs. Finally, bodies of research are presented which could contribute to further validating APS and provide the preconditions for moving this category from Section 3 to Section 2 © 2014 S. Karger AG, Basel of DSM-5.1.
The DSM-5 Psychosis Work Group considered a proposal put forward by McGlashan et al. [1] for a new disorder termed attenuated psychosis syndrome (APS). The proposed criteria were based on prodromal psychopathology of schizophrenia and pioneered in Melbourne, © 2014 S. Karger AG, Basel 0254–4962/14/0475–0287$39.50/0 E-Mail [email protected] www.karger.com/psp
Australia, and were adopted and further developed in New Haven, Conn., USA. Original work was conducted in many centers using overlapping constructs including ultra-high risk, clinical high risk, at-risk mental state, prodromal stage, brief intermittent psychosis syndrome, familial high risk, basic symptom high risk, and attenuated positive psychotic symptoms. These overlapping constructs can be considered together under the term APS [2]. DSM-5 consideration of this proposal has been described [3] and moved from an initial view of a risk syndrome concept [4, 5] to a disorder concept [3]. While validation for mental disorder captured by the APS concept was not in doubt [6], the need for a new disorder class for research or clinical purposes was debated [3, 7]. The Psychosis Work Group agreed that diagnostic reliability demonstrated in ordinary clinical settings without special expertise and structured interviews was essential for the new disorder proposal to be recommended for DSM-5. The relevant DSM-5 field trial resulted in an acceptable kappa value, but in a wide confidence interval resulting in an inadequate trial with too few cases to be informative [8]. The Work Group recommended APS for Section 3 for further study, and a unique diagnostic code is not available for clinical use. During the DSM-5 process, this issue was hotly debated among experts, other professionals, other stakeholders, and within the Work Group. Asserted criticisms included the following: (1) pathologizing of non-ill beWilliam T. Carpenter, MD Department of Psychiatry, University of Maryland School of Medicine Maryland Psychiatric Research Center, PO Box 21247 Baltimore, MD 21228 (USA) E-Mail wcarpent @ mprc.umaryland.edu
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Department of Psychiatry, University of Maryland School of Medicine, Maryland Psychiatric Research Center, and VA Capitol Health Care Network (VISN 5) MIRECC, Baltimore, Md., USA
My View
There is much room for informed debate and alternative viewpoints. In presenting one side of the argument, I will characterize the criticisms of a proposed APS for clarity and then provide a response. Why APS? It is based on symptoms common in the non-ill population, it will include false positives regarding risk for schizophrenia, will stigmatize young people and create negative expectations for their future. Treatment is not known, but excessive use of antipsychotic drugs will create harm. Validity is questionable, reliability in clinical settings is not known, and current available disorder diagnoses can be used without creating a new disorder category. (1) APS, by definition, is not pathologizing non-ill behaviors. Of course the psychotic-like symptoms observed in APS can be found in non-ill populations. But the criteria for an APS diagnosis require help-seeking and distress, disability and/or dysfunction related to the symptoms. These are the criteria that distinguish most mental disorders from similar experiences in non-ill 288
Psychopathology 2014;47:287–291 DOI: 10.1159/000365221
persons. Just as major depression disorder does not pathologize normal sadness, APS does not pathologize normal perceptual distortions, magical ideation, or aberrant thought processes. (2) The false-positive concept relates to a definition of a risk syndrome. Hypercholesterolemia is a risk factor for myocardial infarction leading to primary prevention with a very high false-positive rate. But APS is a disorder affecting a person who merits clinical attention for what is already manifest. One goal is prevention of full psychosis in the subgroup vulnerable to this outcome, but treatment of current symptoms and functional disability is applicable to all cases. This parallels angina or chest pain rather than hypercholesterolemia. As in all disorders, there can be a misdiagnosis, but there is, by definition, no false-positive issue. (3) Stigma is an important issue associated with mental disorders. The impact of the psychopathology associated with APS will challenge self-esteem, self-autonomy and the sense of self-agency, and the associated behaviors will induce reactions from peers, family and others. Some critics contend that labeling a person with APS is harmful. But doctors do not label; their role is to diagnose, treat, and care. Here the question is whether APS as a new disorder category will enhance or diminish the clinician’s ability to address stigma. To the extent that knowledge and understanding inform the clinician’s approach to each patient, organizing knowledge related to APS provides a net benefit (see below as to why alternative diagnoses are not satisfactory for this purpose). Some critics would favor simply not having a diagnosis when working with a troubled young person. There are two prime reasons to reject this proposal. First, many health care systems require diagnosis for reimbursement and statistical purposes, so some diagnosis is essential for the provision of care. Second, absence of an overarching construct with the ability to identify cases will preclude systematic accumulation of knowledge. Finally, some have been concerned that an expectation of becoming psychotic and having a diagnosis of schizophrenia will be stigmatizing. However, much depends on how the clinician relates relevant knowledge in individualized clinical care. Withholding salient information deprives a patient of partnership in decision-making and may reduce motivation to participate in treatments that could reduce vulnerability. The wise clinician will stress positive expectations as well as noting issues of concern. Parenthetically, I often wonder if the ‘doctors will cause stigma’ critics apply this concern to their own Carpenter
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haviors; (2) high false-positive ascertainment rates; (3) increasing stigma; (4) no need for a disorder class without established treatment; (5) excessive drug treatment with more harm than benefit; (6) lack of validating data; (7) unjustified placement of cases in the schizophrenia spectrum, and (8) no need for a disorder class without established treatment. In this article I will defend the need for a new disorder classification and address the above-listed issues. As a semidebate format, brevity is critical and the reader can anticipate a presentation of a different view in a companion article. DSM-5 is intended as a living document with potential for changes based on evidence without waiting for DSM6. One intent of this debate format is to clarify issues that need to be resolved for APS to be considered for DSM-5.1 or 5.2. There are three important implications of the term APS: first, it captures the range of research conducted under various terms as mentioned above. Second, syndrome in the name makes clear that this is not a single disease entity with uniform expectation of disorder outcome. Third, unlike most DSM/ICD disorders, it is not intended as a final diagnosis, but rather is a placeholder awaiting clarification over time as each case advances over time to recovery or another diagnostic class.
fore, reduce unwarranted use of antipsychotic medications. This view is speculative, but so is the concern that introducing APS as a new disorder will increase unwarranted prescribing of medication. With or without APS, the field is challenged to provide effective clinical care without introducing therapies with adverse benefit/risk profiles. The issue is whether APS will increase or decrease a problem that already exists. (6) Clinical validity is not much in question. A substantial body of work now documents that persons with APS differ from non-ill volunteers on a range of structure, function and chemistry indices in neuroimaging studies, have impaired cognition, increased likelihood of negative symptoms, a range of functional impairments, and a very robust excess in developing a full psychotic illness within a year (about 22%) or 2 years (about 30%) [10]. The issue is not validity, but how to classify the clinical and associated pathology associated with APS. The studies to date provide validation for the ill/non-ill distinction, but do not assess the respective validity of alternative classification approaches. (7)It is not necessary to conceptualize APS within the schizophrenia spectrum, but the concept developed from the schizophrenia prodrome, the observed pathology is a conceptual fit, the validating evidence is comparable with the schizophrenia spectrum, and the majority of cases progressing to full psychosis receive a diagnosis of schizophrenia. (8) Psychotic symptoms, especially hallucinations and delusions, are common in a number of mental disorders. So too is anxiety and depression. Instead of a new category, why not use existing categories such as anxiety with a psychosis-like specifier for some cases, depression with the same specifier for other cases, bipolar II for others, psychosis NOS for some, schizotypal personality for others, obsessive-compulsive for still others, etc. The first point here is that the presence of APS as a diagnostic option does not eliminate any of these diagnoses from differential diagnoses. A DSM-5 APS definition in Section 3 has the exclusion criteria that the case does not better fit another, already existing category. That being said, the main argument is validity on the one hand, and heuristics on the other. For validity, the other disorders already available for clinical use are meant to be stable disorders, not a place-holding status awaiting recovery or progression to some established disorder. It is conceptually incompatible to associate anxiety disorders with primary negative symptoms or high conversion rates to schizophrenia. Cognition impairments associated with APS are not part of
Attenuated Psychosis Syndrome
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clinical work, or just mean that others would cause harm. (4) The question of why specify a disorder in the absence of proven effective treatment strikes me as silly. The function of a diagnostic manual is the classification of disorders, not therapeutics. Furthermore, regarding APS, rather a good deal is already known about treatment. Clinical care is currently oriented around issues such as establishing a supportive relationship, developing an understanding with the patient and significant others regarding current problems, reducing stressful circumstances, enhancing strengths and resiliency, and addressing specific issues such as school or work challenges, sleep disturbance, anxiety, suicidal thoughts, etc. These are competencies that we expect in clinicians and may be at the core of ‘treatment as usual’ (TAU) in the experimental studies to date. We do not know how effective these interventions may be since no study has defined the course of APS in untreated cohorts. Clinical trials around APS or related constructs are still early in development, but Stafford et al. [9] reviewed 11 trials of various experimental treatments usually added to TAU and compared with TAU (or a placebo comparison if a compound was tested). Small sample sizes and few replication studies limit knowledge from random assignment clinical trials to date, but each study suggests that current symptoms are reduced more in the experimental treatment and that secondary prevention of full psychosis is more robust with experimental treatment. The effects are not trivial, and across these studies the experimental treatment was associated with progression to full psychosis in about 7% of cases compared to about 20% transition to psychosis in the TAU control groups. (5) The issue of excessive use of antipsychotic medications is important, but speculative. In the United States, second-generation antipsychotic drugs have been commonly prescribed to young people with a wide range of disorders, mostly not psychotic. Excessive use of these drugs is already a reality. Experts in the APS field and professional societies offering guidelines agree that antipsychotic drugs should not be used routinely or early in APS [6]. As such, education on this issue and identification of the most effective interventions may minimize the inappropriate use of antipsychotic drugs. If primary care doctors are more likely to prescribe second-generation antipsychotic drugs, then education about APS may increase referrals to specialists more able to consider a range of interventions. Organizing clinical care around APS may, there-
Color version available online
Start of life
Environment-related factors
Gene related factors
Gene × enviroment ŝŶƚĞƌĂĐƟŽŶ Vulnerability ĂŶdžŝĞƚLJ͕ĚĞƉƌĞƐƐŝŽŶ͕ŝĚĞŶƟƚLJ
Fig. 1. Concepts of disorder development.
SSD = Schizophrenia spectrum disorders; BP = bipolar.
Generalized anxiety disorder
A DSM-5 Footnote
The recommendation of the Psychosis Work Group to include APS in Section 3 for further study was accepted, and APS was not intended for a main text diagnosis. However, late editorial action decided that all Section 3 putative disorders could be listed as ‘Other Specified Disorders’. I was surprised later to learn that ‘Other Specified Schizophrenia Spectrum and Other Psychotic Disorders’ included APS along with three other examples of psychosis-like features that do not meet criteria for an established disorder. This category is on page 122; the clinician is expected to state clinical features and why criteria for a Psychopathology 2014;47:287–291 DOI: 10.1159/000365221
Depression Attenuated psychosis disorder
SSD
End of life
the early presenting picture of a number of these other disorders. Defining schizotypal personality as a trait disorder is not compatible with the recent onset or rapid change associated with APS. In this sense the data available now are not compatible with the diagnoses that are alternatives to APS. As to the heuristics, none of these alternative disorders has led to a body of knowledge on detection and intervention. Our best hope for evidence-based treatment and prevention is to organize the study of the APS phenomena in a cohesive framework rather than scatter it across DSM and ICD categories. Providing a diagnostic placeholder status has the advantage of reflecting the pleiotropic nature of the syndrome and the full range of outcomes from recovery without impairment to psychotic illness.
290
Substance abuse
BP with psychosis
Mood with psychosis
formal diagnosis are not met, and use 298.8 as the code. APS does not have a unique code and is not an established disorder in DSM-5.
Final Comments
I am a proponent of early detection/intervention. From a career perspective based on the care and study of persons with schizophrenia and mindful of minimal progress since chlorpromazine was introduced 62 years ago, the opportunity to delay or prevent psychotic illness is incredibly important. Accomplishing this in some cases with APS while offering a therapeutic advantage to other cases less vulnerable to full psychosis is a substantial advance for our field without equal during my career. It is not yet known whether a critical time for intervention ameliorates, delays or prevents psychotic illness. A delay may have long-lasting benefits even if underlying pathophysiology progresses. Enabling young people to accomplish milestones such as completing education, establishing occupation, and developing a social niche offers benefits for life for all of us and provides a stronger base to meet challenges associated with psychosis. If long-lasting prevention occurs in some cases, this is a profound accomplishment exceeding any therapeutic achievement in our field since antibiotics prevented the development of tertiary syphilis. The developmental interactive model for schizophrenia proposed by John Strauss and me in our 1981 book [11] provides a framework in which critical time points Carpenter
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Phobia
for primary and secondary prevention can be defined and where vulnerability shifts to disorder and therapeutic intervention are warranted. A current version related to APS is presented in figure 1. One can imagine early intervention aimed at preventing the development of vulnerability. Vulnerable status is seen as pleiotropic with many possible outcomes if progression to illness occurs. Among the illness categories illustrated, APS is viewed as a category with high vulnerability to further progression towards full psychosis. When a psychotic disorder emerges, it need not be schizophrenia. The nature of the studies to date bias in that direction, naturally so, since the schizophrenia prodrome was the springboard for these developments. Further work with early emerging signs of other psychotic disorders will broaden the vulnerability platform and APS will probably become more heterogeneous, at least in terms of psychosis outcomes. The staging of clinical care advocated by McGorry et al. [12] and McGorry [13] can be mapped onto the developmental interactive model. This results in a compelling construct for clinicians to engage vulnerable persons at different stages. Controversy here will likely only relate to how different societies can establish the staging of care. This will be very challenging in the United States given the limited commitment to financing mental illness care, the low priority for prevention, and failure to provide integrated care with a trained workforce. If APS is to be proposed for movement from Section 3 to Section 2 of DSM-5.1, what new data are required? This has been discussed elsewhere [5]. Briefly stated:
• Determining the training required for reliable application of the diagnosis in ordinary clinical settings. • Establishing an acceptable level of reliability in these settings without relying on structured interviews. In my view the above should be sufficient, but more is likely to be needed. A short wish list includes: • A body of research supporting efficacy and effectiveness of treatment for functional outcomes, symptom reduction, and secondary delay or prevention of psychosis. Replication of the omega-3 free fatty acid study [14] in the eight-center study now being conducted would be very influential. It is difficult to believe that many would oppose diagnostic identification of persons who may receive profound benefits from a treatment with no apparent downside. • A body of research clarifying how broadly the APS construct relates to various psychosis outcomes. The evidence to date places APS clearly in the schizophrenia spectrum based on the range of findings associated with APS and the high rate of a schizophrenia diagnosis in cases that transition [6, 10]. But the APS platform may be wider and new data based on transition to other psychotic disorders will be informative. • Biomarkers would be welcome. • Health services research demonstrating the feasibility of establishing programs addressing APS. A response from Professor Barnaby Nelson will provide the reader with an alternative viewpoint and increase the level of discourse and debate as the field struggles forward.
1 McGlashan TH, Walsh BC, Woods SW: The Psychosis-Risk Syndrome: Handbook for Diagnosis and Follow-Up. Oxford, Oxford University Press, 2010. 2 Yung AR, Woods SW, Ruhrmann S, Addington J, Schultze-Lutter F, Cornblatt BA, Amminger GP, Bechdolf A, Birchwood M, Borgwardt S, Cannon TD, de Haan L, French P, Fusar-Poli P, Keshavan M, Klosterkötter J, Kwon JS, McGorry PD, McGuire P, Mizuno M, Morrison AP, Riecher-Rössler A, Salokangas RKR, Seidman LJ, Suzuki M, Valmaggia L, van der Gaag M, Wood SJ, McGlashan TH: Whither the attenuated psychosis syndrome? Schizophr Bull 2012;38:1130–1134. 3 Tsuang MT, Van Os J, Tandon R, Barch DM, Bustillo J, Gaebel W, Gur RE, Heckers S, et al: Attenuated psychosis syndrome in DSM-5. Schizophr Res 2013;150:31–35. 4 Heckers S: Who is at risk for a psychotic disorder? Schizophr Bull 2009;35:847–850.
Attenuated Psychosis Syndrome
5 Carpenter WT: Anticipating DSM-V: should psychosis risk become a diagnostic class? Schizophr Bull 2009;35:841–843. 6 Fusar-Poli P, Carpenter WT, Woods SW, McGlashan TH: Attenuated psychosis syndrome: ready for DSM-5.1? Annu Rev Clin Psychol 2014;10:155–192. 7 Carpenter WT, van Os J: Should attenuated psychosis syndrome be a DSM-V diagnosis? Am J Psychiatry 2011;168:460–463. 8 Regier DA, Narrow WE, Clarke DE, Kraemer HC, Kuramoto SJ, et al: DSM-5 field trials in the United States and Canada. Part II: Testretest reliability of selected categorical diagnoses. Am J Psychiatry 2013;170:59–70. 9 Stafford MR, Jackson H, Mayo-Wilson E, Morrison AP, Kendall T: Early interventions to prevent psychosis: systematic review and meta-analysis. BMJ 2013;346:f185. 10 Fusar-Poli P, Borgwardt S, Bechdolf A, Addington J, Riecher-Rossler R, et al: The psy-
11 12
13
14
chosis high-risk state: a comprehensive stateof-the-art review. JAMA Psychiatry 2013; 70: 107–120. Strauss JS, Carpenter WT: Schizophrenia. New York, Plenum Press, 1981. McGorry PD, Hickie IB, Yung AR, Pantelis C, Jackson HJ: Clinical staging of psychiatric disorders: a heuristic framework for choosing earlier, safer and more effective interventions. Aust NZ J Psychiatry 2006;40:616–622. McGorry PD: Early clinical phenotypes, clinical staging and strategic biomarker research: building blocks for personalized psychiatry. Biol Psychiatry 2013;74:394–395. Amminger P, Schäfer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, Berger GE: Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomised, placebo-controlled trial. Arch Gen Psychiatry 2010;67:146–154.
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References
Received: January 22, 2014 Accepted after revision: June 13, 2014 Published online: July 23, 2014
Attenuated Psychosis Syndrome: Need for Debate on a New Disorder William T. Carpenter
Key Words Prodrome · Psychosis · Schizophrenia · Early intervention · Prevention
Abstract This ‘pro’ statement of the controversial issue, defending the need for a new disorder classification of attenuated psychosis syndrome (APS), provides data supporting the clinical validity of this category and responds to the most frequently asserted criticisms. It provides arguments why APS is not pathologizing non-ill behaviors and is not stigmatizing for those affected but rather they merit clinical attention for what is already manifest. It also argues against the view that establishing the diagnostic category of APS results in an unreasoned excessive use of antipsychotic medications but rather encourages prevention and early intervention programs. Finally, bodies of research are presented which could contribute to further validating APS and provide the preconditions for moving this category from Section 3 to Section 2 © 2014 S. Karger AG, Basel of DSM-5.1.
The DSM-5 Psychosis Work Group considered a proposal put forward by McGlashan et al. [1] for a new disorder termed attenuated psychosis syndrome (APS). The proposed criteria were based on prodromal psychopathology of schizophrenia and pioneered in Melbourne, © 2014 S. Karger AG, Basel 0254–4962/14/0475–0287$39.50/0 E-Mail [email protected] www.karger.com/psp
Australia, and were adopted and further developed in New Haven, Conn., USA. Original work was conducted in many centers using overlapping constructs including ultra-high risk, clinical high risk, at-risk mental state, prodromal stage, brief intermittent psychosis syndrome, familial high risk, basic symptom high risk, and attenuated positive psychotic symptoms. These overlapping constructs can be considered together under the term APS [2]. DSM-5 consideration of this proposal has been described [3] and moved from an initial view of a risk syndrome concept [4, 5] to a disorder concept [3]. While validation for mental disorder captured by the APS concept was not in doubt [6], the need for a new disorder class for research or clinical purposes was debated [3, 7]. The Psychosis Work Group agreed that diagnostic reliability demonstrated in ordinary clinical settings without special expertise and structured interviews was essential for the new disorder proposal to be recommended for DSM-5. The relevant DSM-5 field trial resulted in an acceptable kappa value, but in a wide confidence interval resulting in an inadequate trial with too few cases to be informative [8]. The Work Group recommended APS for Section 3 for further study, and a unique diagnostic code is not available for clinical use. During the DSM-5 process, this issue was hotly debated among experts, other professionals, other stakeholders, and within the Work Group. Asserted criticisms included the following: (1) pathologizing of non-ill beWilliam T. Carpenter, MD Department of Psychiatry, University of Maryland School of Medicine Maryland Psychiatric Research Center, PO Box 21247 Baltimore, MD 21228 (USA) E-Mail wcarpent @ mprc.umaryland.edu
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Department of Psychiatry, University of Maryland School of Medicine, Maryland Psychiatric Research Center, and VA Capitol Health Care Network (VISN 5) MIRECC, Baltimore, Md., USA
My View
There is much room for informed debate and alternative viewpoints. In presenting one side of the argument, I will characterize the criticisms of a proposed APS for clarity and then provide a response. Why APS? It is based on symptoms common in the non-ill population, it will include false positives regarding risk for schizophrenia, will stigmatize young people and create negative expectations for their future. Treatment is not known, but excessive use of antipsychotic drugs will create harm. Validity is questionable, reliability in clinical settings is not known, and current available disorder diagnoses can be used without creating a new disorder category. (1) APS, by definition, is not pathologizing non-ill behaviors. Of course the psychotic-like symptoms observed in APS can be found in non-ill populations. But the criteria for an APS diagnosis require help-seeking and distress, disability and/or dysfunction related to the symptoms. These are the criteria that distinguish most mental disorders from similar experiences in non-ill 288
Psychopathology 2014;47:287–291 DOI: 10.1159/000365221
persons. Just as major depression disorder does not pathologize normal sadness, APS does not pathologize normal perceptual distortions, magical ideation, or aberrant thought processes. (2) The false-positive concept relates to a definition of a risk syndrome. Hypercholesterolemia is a risk factor for myocardial infarction leading to primary prevention with a very high false-positive rate. But APS is a disorder affecting a person who merits clinical attention for what is already manifest. One goal is prevention of full psychosis in the subgroup vulnerable to this outcome, but treatment of current symptoms and functional disability is applicable to all cases. This parallels angina or chest pain rather than hypercholesterolemia. As in all disorders, there can be a misdiagnosis, but there is, by definition, no false-positive issue. (3) Stigma is an important issue associated with mental disorders. The impact of the psychopathology associated with APS will challenge self-esteem, self-autonomy and the sense of self-agency, and the associated behaviors will induce reactions from peers, family and others. Some critics contend that labeling a person with APS is harmful. But doctors do not label; their role is to diagnose, treat, and care. Here the question is whether APS as a new disorder category will enhance or diminish the clinician’s ability to address stigma. To the extent that knowledge and understanding inform the clinician’s approach to each patient, organizing knowledge related to APS provides a net benefit (see below as to why alternative diagnoses are not satisfactory for this purpose). Some critics would favor simply not having a diagnosis when working with a troubled young person. There are two prime reasons to reject this proposal. First, many health care systems require diagnosis for reimbursement and statistical purposes, so some diagnosis is essential for the provision of care. Second, absence of an overarching construct with the ability to identify cases will preclude systematic accumulation of knowledge. Finally, some have been concerned that an expectation of becoming psychotic and having a diagnosis of schizophrenia will be stigmatizing. However, much depends on how the clinician relates relevant knowledge in individualized clinical care. Withholding salient information deprives a patient of partnership in decision-making and may reduce motivation to participate in treatments that could reduce vulnerability. The wise clinician will stress positive expectations as well as noting issues of concern. Parenthetically, I often wonder if the ‘doctors will cause stigma’ critics apply this concern to their own Carpenter
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haviors; (2) high false-positive ascertainment rates; (3) increasing stigma; (4) no need for a disorder class without established treatment; (5) excessive drug treatment with more harm than benefit; (6) lack of validating data; (7) unjustified placement of cases in the schizophrenia spectrum, and (8) no need for a disorder class without established treatment. In this article I will defend the need for a new disorder classification and address the above-listed issues. As a semidebate format, brevity is critical and the reader can anticipate a presentation of a different view in a companion article. DSM-5 is intended as a living document with potential for changes based on evidence without waiting for DSM6. One intent of this debate format is to clarify issues that need to be resolved for APS to be considered for DSM-5.1 or 5.2. There are three important implications of the term APS: first, it captures the range of research conducted under various terms as mentioned above. Second, syndrome in the name makes clear that this is not a single disease entity with uniform expectation of disorder outcome. Third, unlike most DSM/ICD disorders, it is not intended as a final diagnosis, but rather is a placeholder awaiting clarification over time as each case advances over time to recovery or another diagnostic class.
fore, reduce unwarranted use of antipsychotic medications. This view is speculative, but so is the concern that introducing APS as a new disorder will increase unwarranted prescribing of medication. With or without APS, the field is challenged to provide effective clinical care without introducing therapies with adverse benefit/risk profiles. The issue is whether APS will increase or decrease a problem that already exists. (6) Clinical validity is not much in question. A substantial body of work now documents that persons with APS differ from non-ill volunteers on a range of structure, function and chemistry indices in neuroimaging studies, have impaired cognition, increased likelihood of negative symptoms, a range of functional impairments, and a very robust excess in developing a full psychotic illness within a year (about 22%) or 2 years (about 30%) [10]. The issue is not validity, but how to classify the clinical and associated pathology associated with APS. The studies to date provide validation for the ill/non-ill distinction, but do not assess the respective validity of alternative classification approaches. (7)It is not necessary to conceptualize APS within the schizophrenia spectrum, but the concept developed from the schizophrenia prodrome, the observed pathology is a conceptual fit, the validating evidence is comparable with the schizophrenia spectrum, and the majority of cases progressing to full psychosis receive a diagnosis of schizophrenia. (8) Psychotic symptoms, especially hallucinations and delusions, are common in a number of mental disorders. So too is anxiety and depression. Instead of a new category, why not use existing categories such as anxiety with a psychosis-like specifier for some cases, depression with the same specifier for other cases, bipolar II for others, psychosis NOS for some, schizotypal personality for others, obsessive-compulsive for still others, etc. The first point here is that the presence of APS as a diagnostic option does not eliminate any of these diagnoses from differential diagnoses. A DSM-5 APS definition in Section 3 has the exclusion criteria that the case does not better fit another, already existing category. That being said, the main argument is validity on the one hand, and heuristics on the other. For validity, the other disorders already available for clinical use are meant to be stable disorders, not a place-holding status awaiting recovery or progression to some established disorder. It is conceptually incompatible to associate anxiety disorders with primary negative symptoms or high conversion rates to schizophrenia. Cognition impairments associated with APS are not part of
Attenuated Psychosis Syndrome
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clinical work, or just mean that others would cause harm. (4) The question of why specify a disorder in the absence of proven effective treatment strikes me as silly. The function of a diagnostic manual is the classification of disorders, not therapeutics. Furthermore, regarding APS, rather a good deal is already known about treatment. Clinical care is currently oriented around issues such as establishing a supportive relationship, developing an understanding with the patient and significant others regarding current problems, reducing stressful circumstances, enhancing strengths and resiliency, and addressing specific issues such as school or work challenges, sleep disturbance, anxiety, suicidal thoughts, etc. These are competencies that we expect in clinicians and may be at the core of ‘treatment as usual’ (TAU) in the experimental studies to date. We do not know how effective these interventions may be since no study has defined the course of APS in untreated cohorts. Clinical trials around APS or related constructs are still early in development, but Stafford et al. [9] reviewed 11 trials of various experimental treatments usually added to TAU and compared with TAU (or a placebo comparison if a compound was tested). Small sample sizes and few replication studies limit knowledge from random assignment clinical trials to date, but each study suggests that current symptoms are reduced more in the experimental treatment and that secondary prevention of full psychosis is more robust with experimental treatment. The effects are not trivial, and across these studies the experimental treatment was associated with progression to full psychosis in about 7% of cases compared to about 20% transition to psychosis in the TAU control groups. (5) The issue of excessive use of antipsychotic medications is important, but speculative. In the United States, second-generation antipsychotic drugs have been commonly prescribed to young people with a wide range of disorders, mostly not psychotic. Excessive use of these drugs is already a reality. Experts in the APS field and professional societies offering guidelines agree that antipsychotic drugs should not be used routinely or early in APS [6]. As such, education on this issue and identification of the most effective interventions may minimize the inappropriate use of antipsychotic drugs. If primary care doctors are more likely to prescribe second-generation antipsychotic drugs, then education about APS may increase referrals to specialists more able to consider a range of interventions. Organizing clinical care around APS may, there-
Color version available online
Start of life
Environment-related factors
Gene related factors
Gene × enviroment ŝŶƚĞƌĂĐƟŽŶ Vulnerability ĂŶdžŝĞƚLJ͕ĚĞƉƌĞƐƐŝŽŶ͕ŝĚĞŶƟƚLJ
Fig. 1. Concepts of disorder development.
SSD = Schizophrenia spectrum disorders; BP = bipolar.
Generalized anxiety disorder
A DSM-5 Footnote
The recommendation of the Psychosis Work Group to include APS in Section 3 for further study was accepted, and APS was not intended for a main text diagnosis. However, late editorial action decided that all Section 3 putative disorders could be listed as ‘Other Specified Disorders’. I was surprised later to learn that ‘Other Specified Schizophrenia Spectrum and Other Psychotic Disorders’ included APS along with three other examples of psychosis-like features that do not meet criteria for an established disorder. This category is on page 122; the clinician is expected to state clinical features and why criteria for a Psychopathology 2014;47:287–291 DOI: 10.1159/000365221
Depression Attenuated psychosis disorder
SSD
End of life
the early presenting picture of a number of these other disorders. Defining schizotypal personality as a trait disorder is not compatible with the recent onset or rapid change associated with APS. In this sense the data available now are not compatible with the diagnoses that are alternatives to APS. As to the heuristics, none of these alternative disorders has led to a body of knowledge on detection and intervention. Our best hope for evidence-based treatment and prevention is to organize the study of the APS phenomena in a cohesive framework rather than scatter it across DSM and ICD categories. Providing a diagnostic placeholder status has the advantage of reflecting the pleiotropic nature of the syndrome and the full range of outcomes from recovery without impairment to psychotic illness.
290
Substance abuse
BP with psychosis
Mood with psychosis
formal diagnosis are not met, and use 298.8 as the code. APS does not have a unique code and is not an established disorder in DSM-5.
Final Comments
I am a proponent of early detection/intervention. From a career perspective based on the care and study of persons with schizophrenia and mindful of minimal progress since chlorpromazine was introduced 62 years ago, the opportunity to delay or prevent psychotic illness is incredibly important. Accomplishing this in some cases with APS while offering a therapeutic advantage to other cases less vulnerable to full psychosis is a substantial advance for our field without equal during my career. It is not yet known whether a critical time for intervention ameliorates, delays or prevents psychotic illness. A delay may have long-lasting benefits even if underlying pathophysiology progresses. Enabling young people to accomplish milestones such as completing education, establishing occupation, and developing a social niche offers benefits for life for all of us and provides a stronger base to meet challenges associated with psychosis. If long-lasting prevention occurs in some cases, this is a profound accomplishment exceeding any therapeutic achievement in our field since antibiotics prevented the development of tertiary syphilis. The developmental interactive model for schizophrenia proposed by John Strauss and me in our 1981 book [11] provides a framework in which critical time points Carpenter
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Phobia
for primary and secondary prevention can be defined and where vulnerability shifts to disorder and therapeutic intervention are warranted. A current version related to APS is presented in figure 1. One can imagine early intervention aimed at preventing the development of vulnerability. Vulnerable status is seen as pleiotropic with many possible outcomes if progression to illness occurs. Among the illness categories illustrated, APS is viewed as a category with high vulnerability to further progression towards full psychosis. When a psychotic disorder emerges, it need not be schizophrenia. The nature of the studies to date bias in that direction, naturally so, since the schizophrenia prodrome was the springboard for these developments. Further work with early emerging signs of other psychotic disorders will broaden the vulnerability platform and APS will probably become more heterogeneous, at least in terms of psychosis outcomes. The staging of clinical care advocated by McGorry et al. [12] and McGorry [13] can be mapped onto the developmental interactive model. This results in a compelling construct for clinicians to engage vulnerable persons at different stages. Controversy here will likely only relate to how different societies can establish the staging of care. This will be very challenging in the United States given the limited commitment to financing mental illness care, the low priority for prevention, and failure to provide integrated care with a trained workforce. If APS is to be proposed for movement from Section 3 to Section 2 of DSM-5.1, what new data are required? This has been discussed elsewhere [5]. Briefly stated:
• Determining the training required for reliable application of the diagnosis in ordinary clinical settings. • Establishing an acceptable level of reliability in these settings without relying on structured interviews. In my view the above should be sufficient, but more is likely to be needed. A short wish list includes: • A body of research supporting efficacy and effectiveness of treatment for functional outcomes, symptom reduction, and secondary delay or prevention of psychosis. Replication of the omega-3 free fatty acid study [14] in the eight-center study now being conducted would be very influential. It is difficult to believe that many would oppose diagnostic identification of persons who may receive profound benefits from a treatment with no apparent downside. • A body of research clarifying how broadly the APS construct relates to various psychosis outcomes. The evidence to date places APS clearly in the schizophrenia spectrum based on the range of findings associated with APS and the high rate of a schizophrenia diagnosis in cases that transition [6, 10]. But the APS platform may be wider and new data based on transition to other psychotic disorders will be informative. • Biomarkers would be welcome. • Health services research demonstrating the feasibility of establishing programs addressing APS. A response from Professor Barnaby Nelson will provide the reader with an alternative viewpoint and increase the level of discourse and debate as the field struggles forward.
1 McGlashan TH, Walsh BC, Woods SW: The Psychosis-Risk Syndrome: Handbook for Diagnosis and Follow-Up. Oxford, Oxford University Press, 2010. 2 Yung AR, Woods SW, Ruhrmann S, Addington J, Schultze-Lutter F, Cornblatt BA, Amminger GP, Bechdolf A, Birchwood M, Borgwardt S, Cannon TD, de Haan L, French P, Fusar-Poli P, Keshavan M, Klosterkötter J, Kwon JS, McGorry PD, McGuire P, Mizuno M, Morrison AP, Riecher-Rössler A, Salokangas RKR, Seidman LJ, Suzuki M, Valmaggia L, van der Gaag M, Wood SJ, McGlashan TH: Whither the attenuated psychosis syndrome? Schizophr Bull 2012;38:1130–1134. 3 Tsuang MT, Van Os J, Tandon R, Barch DM, Bustillo J, Gaebel W, Gur RE, Heckers S, et al: Attenuated psychosis syndrome in DSM-5. Schizophr Res 2013;150:31–35. 4 Heckers S: Who is at risk for a psychotic disorder? Schizophr Bull 2009;35:847–850.
Attenuated Psychosis Syndrome
5 Carpenter WT: Anticipating DSM-V: should psychosis risk become a diagnostic class? Schizophr Bull 2009;35:841–843. 6 Fusar-Poli P, Carpenter WT, Woods SW, McGlashan TH: Attenuated psychosis syndrome: ready for DSM-5.1? Annu Rev Clin Psychol 2014;10:155–192. 7 Carpenter WT, van Os J: Should attenuated psychosis syndrome be a DSM-V diagnosis? Am J Psychiatry 2011;168:460–463. 8 Regier DA, Narrow WE, Clarke DE, Kraemer HC, Kuramoto SJ, et al: DSM-5 field trials in the United States and Canada. Part II: Testretest reliability of selected categorical diagnoses. Am J Psychiatry 2013;170:59–70. 9 Stafford MR, Jackson H, Mayo-Wilson E, Morrison AP, Kendall T: Early interventions to prevent psychosis: systematic review and meta-analysis. BMJ 2013;346:f185. 10 Fusar-Poli P, Borgwardt S, Bechdolf A, Addington J, Riecher-Rossler R, et al: The psy-
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chosis high-risk state: a comprehensive stateof-the-art review. JAMA Psychiatry 2013; 70: 107–120. Strauss JS, Carpenter WT: Schizophrenia. New York, Plenum Press, 1981. McGorry PD, Hickie IB, Yung AR, Pantelis C, Jackson HJ: Clinical staging of psychiatric disorders: a heuristic framework for choosing earlier, safer and more effective interventions. Aust NZ J Psychiatry 2006;40:616–622. McGorry PD: Early clinical phenotypes, clinical staging and strategic biomarker research: building blocks for personalized psychiatry. Biol Psychiatry 2013;74:394–395. Amminger P, Schäfer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, Berger GE: Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomised, placebo-controlled trial. Arch Gen Psychiatry 2010;67:146–154.
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References
