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Attenuated Psychotic Symptoms: Risky, But Not Predictive of Psychosis

17 February 2012. A new study published online January 2 in the Archives of General Psychiatry, led by Mark Weiser of Sheba Medical Center in Tel Hashomer, Israel, finds that, in the general population, self-reported attenuated psychotic symptoms (APSs) confer risk for later psychosis, but aren’t useful to predict who will subsequently convert to a full-blown psychotic illness.

A diagnosis of schizophrenia or a related psychotic disorder is often preceded by a lengthy prodrome, during which the patient exhibits milder, though still distressing, symptoms. Although these attenuated symptoms are thought to confer a high risk for clinical psychotic illness, not all patients with these symptoms eventually develop a major psychotic disorder. There is a strong link between APSs (such as suspicious beliefs, magical thinking, or unusual perceptual experiences) and later development of psychotic illness in the literature (Poulton et al., 2000; Dominguez et al., 2011); however, these studies are limited by the use of non-clinician interviewer evaluations for diagnosis. In the current study, Weiser’s group utilized a more reliable and more conservative outcome measure—subsequent psychiatric hospitalization—to assess the link between APSs and psychotic illness.

Weiser’s study bears attention from the research community, according to Barbara Cornblatt, director of the Recognition and Prevention Program of Zucker Hillside Hospital in Glen Oak, New York. Cornblatt, who was not associated with the study, told SRF that its significance lies in its sample: “a population resource that is totally unique and can provide information you can’t get anyplace else.”

First author Nomi Werbeloff and colleagues utilized data from an epidemiological study performed in Israel in the 1980s using 4,914 individuals aged 25 to 34 years at the time of baseline assessment. All subjects with a diagnosis of psychotic illness at baseline were subsequently excluded. APSs were self-reported using the false beliefs and perceptions subscale of the Psychiatric Epidemiology Research Interview, with approximately 15 percent of the sample population reporting at least one strong APS within the last year, and over half (57 percent) reporting at least one weak APS within the same timeframe.

The researchers then merged the epidemiological data set with a list of all psychiatric hospitalizations in the country as of 2007, using the National Psychiatric Case Registry, to assess whether the APSs were associated with later risk of hospitalization for nonaffective psychosis (including schizophrenia and schizoaffective disorder, but excluding bipolar disorder). Subjects were followed for an average of 24 years.

Increased risk, but no predictive power
Werbeloff and colleagues report that a higher average APS score was associated with a greater risk of later hospitalization for a nonaffective psychotic disorder, with an odds ratio of 3.6 (indicating that for every unit increase in mean APS score, a greater than threefold increase in risk of hospitalization occurred). With each additional weak and strong APS reported, the risk for later nonaffective psychosis increased by 30 percent and 41 percent, respectively. Additionally, similar findings were observed using hospitalization for pure schizophrenia as the outcome measure, with an odds ratio of 4.1.

Self-reported APSs also increased the risk of hospitalization for other non-psychotic psychiatric illnesses, though to a lesser extent than for nonaffective psychosis. A Kaplan-Meier survival curve demonstrated that, following strong APSs, nearly all hospitalizations for nonaffective psychosis occurred within a much narrower time window following baseline than those for a non-psychotic psychiatric illness (five years vs. 12 years, respectively), which suggests that, to some degree, APSs may be specific for nonaffective psychoses.

Although over half the subjects reported some form of APS at baseline, only 0.5 percent were later hospitalized for a nonaffective psychotic illness, consistent with previous reports using other outcome measures (e.g., van Os et al., 2000; Kendler et al., 1996). Thus, not surprisingly, APSs are substantially more common in the general population than psychotic disorders, but unfortunately can’t be used reliably to forecast subsequent psychiatric illness. The 12-month conversion rate among high-risk individuals, who often have a family history of psychosis and decline in cognitive function in addition to experiencing APSs, is around 10 percent (Cannon et al., 2008; Ruhrmann et al., 2010). The substantially lower conversion rate in the general population observed by Werbeloff and colleagues suggests that variables such as APSs that are used to predict conversion in high-risk clinics may not be relevant for predicting psychosis in the general population.

Interestingly, poor social functioning and anxiety disorders at baseline emerged as variables that significantly interacted with APSs in increasing the risk of hospitalization for nonaffective psychosis, consistent with recent data implicating these variables in risk for psychotic illness (Cornblatt et al., 2011; Freeman, 2007). Although the current study was not able to determine the nature of these interactions (e.g., does poor social functioning increase the conversion from APSs to psychosis, or does it increase the rate of APSs?), future studies may shed light on the role of these variables in transition to psychotic disorders.

One potential limitation of this study, as noted by the authors, is the relatively advanced age of the population sampled. The onset of psychosis typically occurs during late adolescence or early adulthood—well before the average baseline age of 29 years in this sample. Given that subjects who converted to psychosis prior to the baseline assessment were excluded, an earlier baseline time point would provide a more complete picture of the relationship between APSs and psychotic disorders. An additional factor that requires clarification in future studies concerns the risk of APSs for subsequent affective psychoses, such as bipolar disorder and depression with psychosis, that were not examined in the present study.

To classify or not to classify?
Identification of patients at high risk for developing psychotic illness has been the focus of a substantial amount of research (see SRF related news story), as well as controversy. The current study may inform a question that is currently on the minds of clinicians and researchers alike: should the new Diagnostic and Statistical Manual of Mental Disorders (DSM-5), slated for publication in 2013, include an "attenuated psychosis syndrome" diagnostic class (Carpenter and Van Os, 2011)? This very question was the subject of a 2009 SRF Online Discussion).

On one side of the debate are those who argue that a separate diagnostic class is warranted since it would serve a patient population that is, by definition, distressed and, in many cases, help seeking. A new diagnostic category, proponents say, would facilitate early treatment, thereby improving outcome. On the other hand, opponents contend that low rates of conversion to psychotic illness, risk of stigma resulting from diagnosis, and the potential administration of unnecessary medication outweigh the benefits of a separate diagnostic class.

So, how does the current study inform this debate? According to Cornblatt, the data support both sides of the argument: “This paper illustrates the difficulties inherent in adapting risk factors from a selected, enriched, high-risk population for use with the general clinical populations [that the DSM is intended for]," she said. "At the same time, it suggests that APS symptoms are meaningful in increasing the risk for nonaffective psychosis.”—Allison A. Curley.

Werbeloff N, Drukker M, Dohrenwend BP, Levav I, Yoffe R, van Os J, Davidson M, Weiser M. Self-reported Attenuated Psychotic Symptoms as Forerunners of Severe Mental Disorders Later in Life. Arch Gen Psychiatry. 2012 Feb 10. Abstract

Comments on News and Primary Papers
Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 8 March 2012
Posted 8 March 2012

Werbeloff et al. make a valuable contribution with an epidemiological cohort that permits estimates of self-reported attenuated psychosis-like experiences as a risk factor for a future psychotic disorder in the non-ill population. The possibility that attenuated psychosis syndrome would be included in DSM-5 has created an intense and interesting debate. Jim van Os and I, both members of the responsible DSM-5 Work Group, provided an update on the controversy last year (Carpenter and van Os, 2011), and I have offered a rebuttal to some of the objections elsewhere (Carpenter, 2011). As this is a work in progress, I will briefly state where we are, at the moment, in the DSM-5 process.


Carpenter WT and van Os J. Should Attenuated Psychosis Syndrome Be a DSM-5 Diagnosis? Am J Psychiatry 2011 168: 460-463. Abstract

Carpenter Jr. WT. Criticism of the DSM-V risk syndrome: A rebuttal. Cognitive Neuropsychiatry, 16(2):101-106, 2011. Abstract

Fusar-Poli P, Bonoldi I, Yung AR, Borgwardt S, Kempton MJ, Valmaggia L, Barale F, Caverzasi E, McGuire P. Predicting Psychosis: Meta-analysis of Transition Outcomes in Individuals at High Clinical Risk. Arch Gen Psychiatry. 2012; 69(3);220-229. Abstract

View all comments by William CarpenterComment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 9 March 2012
Posted 9 March 2012

Editor's note: This is an addendum to Will Carpenter's previous comment above.

Jim van Os and colleagues now report on transition to psychosis from a non-clinical population sample. Transition rates are elevated for those with psychotic-like experiences, and persistence of these experiences increases risk for transition. Rates are substantially higher than the representative population without psychotic experiences, but much lower than clinical referral populations reported in studies to date.


Kaymaz N, Drukker M, Lieb R, Wittchen HU, Werbeloff N, Weiser M, Lataster T, van Os J. Do subthreshold psychotic experiences predict clinical outcomes in unselected non-help-seeking population-based samples? A systematic review and meta-analysis, enriched with new results. Psychol Med. 2012 Jan 20;1-15. Abstract

View all comments by William Carpenter

Comments on Related News

Related News: Signs of Things to Come? Seeking Biomarkers for the Schizophrenia Prodrome

Comment by:  Thomas McGlashan
Submitted 21 January 2012
Posted 21 January 2012

Three very recent publications have detailed that biomarkers can identify and quantify high-risk or prodromally symptomatic subjects who subsequently undergo conversion to psychosis. McGuire and his group (Howes et al., 2011) used fluoro-dopa positron emission tomography scanning to measure dopamine synthesis. Koutsouleris et al. (Koutsouleris et al., 2011) used structural MRI data to develop a neuroanatomical classification system for predicting psychosis conversion, and Amminger et al. (Amminger et al., 2011) used capillary gas chromatography of erythrocyte membrane fatty acid levels to provide information about brain phospholipids. All measures were significantly successful in identifying high-risk or prodromally symptomatic subjects who went on to develop a first episode of psychosis.

These papers point to an exciting future in our efforts to elaborate easily identifiable risk factors that can pinpoint among clinically identified "prodromal" subjects those who are most likely to become psychotic. That such diverse measures proved to be successful in identifying "true positives" can be regarded as a milestone in this line of investigation. It represents a quantitative leap forward in our ability to reduce the uncertainty of predicting psychosis, and hints at the day when tragedies such as the one occurring in Tucson, Arizona, become a thing of the past.


Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR, Murray RM, McGuire P. Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study. Am J Psychiatry. 2011 Dec 1; 168: 1311-1317. Abstract

Koutsouleris N, Borgwardt S, Meisenzahl EM, Bottlender R, Möller HJ, Riecher-Rössler A. Disease Prediction in the At-Risk Mental State for Psychosis Using Neuroanatomical Biomarkers: Results From the FePsy Study. Schizophr Bull. 2011 Nov 10. Abstract

Amminger GP, Schäfer MR, Klier CM, Slavik JM, Holzer I, Holub M, Goldstone S, Whitford TJ, McGorry PD, Berk M. Decreased nervonic acid levels in erythrocyte membranes predict psychosis in help-seeking ultra-high-risk individuals. Mol Psychiatry. 2011 Dec 20. Abstract

View all comments by Thomas McGlashan

Related News: News Brief: Attenuated Psychosis Syndrome Left Out of DSM-5 Main Text

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 27 June 2012
Posted 27 June 2012

Debating APS is interesting, and reasonable people will disagree on key issues. Clarity on a couple of points would reduce confusion and help make the debate more substantive:

1. Attenuated psychotic symptoms and attenuated psychosis syndrome are not at all the same. The latter is under consideration by DSM-5; the former is not. APS, if referring to the syndrome, is a putative disorder class with criteria requiring distress, disability, dysfunction, and help seeking. It encompasses a clinical cohort where, by definition, another DSM-5 disorder class is not a better fit. When low-level psychotic-like phenomena are observed in non-ill populations, it is interesting, but by definition these are not disease symptoms, and they have no known relationship to the disorder concept captured by APS as defined in the DSM-5 considerations.

2. Anxiety and depression are ubiquitous in persons developing a number of disorders. This is clearly the case in persons developing psychotic disorders. The diagnostic significance of anxiety and depression experiences is often clear in hindsight when the full pattern of illness is clarified. If a person with low-level psychotic-like experiences and anxiety and depression affect/mood disturbance progress to schizophrenia, for example, we do not conceptualize this as comorbid affective disorder and psychotic disorder, but rather the natural progression into schizophrenia. The admixture of symptoms at early stages is challenging for clinical diagnosis—hence, the general view that persons who meet APS criteria should be provided clinical care for the actual symptoms present, and have stressful circumstances addressed while being monitored over time to determine illness course trajectory. APS is not an endstage diagnostic category.

3. The DSM-5 field trials were for reliability only, and a far more stringent test than used in the DSM-IV field trials. There was no evidence for poor reliability with non-expert clinicians undertaking separate assessments, unstructured, of the same case at different times. In fact, the kappa was far better than, for example, a major mood disorder. The problem was that the very small sample and wide confidence interval simply meant the study was not adequately informative. This was very important in the DSM-5 Psychosis Work Group consideration. We viewed it as unlikely that we would propose including APS in the main text unless we demonstrated reliability among clinicians who were not experts in the "at risk" research field. Had reliability been adequately demonstrated, our Work Group would have had a vigorous debate with uncertain outcome regarding text versus Section 3 (appendix).

4. In other comments, I have pointed out two sides to the debate about stigma and whether antipsychotic drug use would increase or decrease, and will not repeat them here (Carpenter and van Os, 2011; Carpenter, 2009). Also, if the robust effect on symptoms and transition to psychosis as reported by Amminger et al. (Amminger et al., 2010) is replicated, I suspect that opposition to forming a diagnostic class relevant for omega-3 fatty acid therapy will rapidly disappear. If true, this is an interesting dilemma from a DSM or ICD vantage, since these are diagnostic manuals, not therapeutic manuals.

Disclosure: William Carpenter is Chair of the DSM-5 Psychotic Disorders Work Group.


Amminger GP, 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 randomized, placebo-controlled trial. Arch Gen Psychiatry . 2010 Feb 1 ; 67(2):146-54. Abstract

Carpenter WT, van Os J. Should attenuated psychosis syndrome be a DSM-5 diagnosis? Am J Psychiatry. 2011 May ;168(5):460-3. Abstract

Carpenter WT. Anticipating DSM-V: should psychosis risk become a diagnostic class? Schizophr Bull. 2009 Sep 1;35(5):841-3. Abstract

View all comments by William Carpenter

Related News: News Brief: Attenuated Psychosis Syndrome Left Out of DSM-5 Main Text

Comment by:  Allen Frances
Submitted 28 June 2012
Posted 28 June 2012

Among all the problematic DSM-5 suggestions, this was the most premature and the riskiest. The three strikes against it are: 1) an unacceptably high false positive rate (over 90 percent in the most recent study; Morrison et al., 2012); 2) no intervention has been proven effective; and 3) the likelihood it would result in inappropriate use of harmful antipsychotic medication.


Morrison AP, French P, Stewart SL, Birchwood M, Fowler D, Gumley AI, Jones PB, Bentall RP, Lewis SW, Murray GK, Patterson P, Brunet K, Conroy J, Parker S, Reilly T, Byrne R, Davies LM, Dunn G. Early detection and intervention evaluation for people at risk of psychosis: multisite randomised controlled trial. BMJ . 2012 ; 344():e2233. Abstract

View all comments by Allen Frances

Related News: News Brief: Attenuated Psychosis Syndrome Left Out of DSM-5 Main Text

Comment by:  Frauke Schultze-LutterStephan RuhrmannJoachim Klosterkötter
Submitted 6 July 2012
Posted 6 July 2012

Inclusion of the attenuated psychosis syndrome in Section III of DSM-5—Chance or Defeat?
The heated, often assuming scientific and public debate of the past three years over the introduction of an attenuated psychosis syndrome in DSM-5 has recently come to a conclusion for the time being, with the DSM committee deciding not to include it in the main section but rather the appendix, i.e., Section III. With this, attenuated psychotic symptoms (APS), one of the five main single criteria developed and examined within the context of preventive efforts to psychosis (Fusar-Poli et al., 2012), will continue to be the subject of further research for some time. However, in comparison to other at-risk criteria such as the remaining two ultra-high-risk criteria (Yung and McGorry, 1996) or the basic symptoms criteria (Schultze-Lutter et al., 2007), it will be considered not mainly as a predictor or risk syndrome of psychosis, but as a syndrome or diagnostic class in its own right.

Public perception of the departure from the psychosis risk syndrome
One of the reasons for the negative decision on including the attenuated psychosis syndrome in the main text right now was the frequent, persistent (mis)perception of it as a risk syndrome and, consequently, the critique of the low transition risks to psychosis (e.g., see a Nature News article). Indeed, the first proposal version had intended the introduction of a prognostic category, a "Risk Syndrome for First Psychosis" (Woods et al., 2009). This proposal was based on results of the first 15 years of early detection of psychosis research, which found transition risks that, even at their lowest estimates, are still several 100-fold higher than the risk in the general population (Fusar-Poli et al., 2012). The probabilistic nature of these criteria, however, yielded subsamples of persons classified as "at-risk," yet who did not develop psychosis. The proportions varied across different operationalized criteria (Schultze-Lutter et al., in press), sampling procedures, centers, and lengths of observation period (Fusar-Poli et al., 2012). Furthermore, a considerable proportion showed (at least transient) remissions of at-risk symptoms (Addington et al., 2011), not least as a result of support and treatment. While these results had already provoked a debate about the ethical and medical justification of preventive measures (International Early Psychosis Association Writing Group, 2005; Klosterkötter and Schultze-Lutter, 2010; Schimmelmann et al., 2012, in press; Schultze-Lutter et al., 2008; Ruhrmann et al., 2010a), it was further fueled by the first DSM-5 proposal of a risk syndrome.

Another problem related to this first proposal that soon became obvious was of a methodological nature: as the structure of DSM—different from several somatic areas in the ICD-10—does not include prognostic entities, a risk syndrome would have also caused systematic difficulties such as: 1) likelihood of treating persons not in need of treatment; 2) inability to develop and evaluate treatment strategies related to a definite and not only probable outcome; 3) focus on not a current but a future mental state; 4) current and future dependence on the concepts of psychoses; 5) inability of cross-sectional falsification of psychopathological significance; and 6) limited access to current health care generally not meant for risk syndromes but rather for current disorders (Ruhrmann et al., 2010b). However, regardless of the prognostic aspects, a large number of studies ranging from psychosocial functioning and quality of life to neurobiology (Ruhrmann et al., 2010b; Fusar-Poli et al., in press) demonstrated that help-seeking patients fulfilling at-risk criteria, mainly APS, also fulfilled general DSM criteria of a mental disorder in terms of a “clinically significant behavioral and psychological syndrome or pattern … that is associated with present distress … or disability … or with a significantly increased risk of suffering death, pain, disability, or an important loss of freedom” (DSM-IV-TR, p. xxi). Thus, following a debate at the 2010 SIRS Conference organized by B. Cornblatt and S. Ruhrmann, a conceptual change from a "Risk Syndrome for First Psychosis" to an “Attenuated Psychosis Syndrome” (in terms of a diagnostic class in its own right) was made (Carpenter and van Os, 2011; Carpenter, 2011).

Like ICD-10’s Schizotypal Disorder—a diagnostic class in itself
A similar diagnostic class, the Schizotypal Disorder (F21) including all but grandiose APS, has long been part of the psychosis section (F2) of the ICD-10 (Ruhrmann et al., 2010a). Such a diagnostic category has so far been missing in DSM, where APS is only considered as clinical features and part of the schizotypal personality disorder if formed by early adulthood, persists throughout life, and affects every aspect of day-to-day behavior. Thus, according to DSM, the many patients who suffer from and report APS according to at-risk criteria, i.e., with a more or less recent onset and a potentially non-continuous but only repeated occurrence (Schultze-Lutter et al., in press), are currently not being considered ill and not entitled to mental health care. An introduction of the attenuated psychosis syndrome in DSM-5 would have closed a gap between ICD and DSM. Unfortunately, however, the communication and visibility of this major conceptual change were not successful—and the debate continued to mainly circle around the same issues as with the risk syndrome: 1) allegedly low short-term transition risks; 2) emergence of spontaneous remissions and, as a consequence, unnecessary interventions, particularly with antipsychotic drugs (recommended only as the last resort when, despite other benign treatments, symptoms clearly progress towards frank psychotic symptoms [International Early Psychosis Writing Group, 2005]); 3) potential early stigmatization; and 4) overdiagnosis, based on studies of psychotic-like experiences that are frequently mistaken as measures of APS in the general population (Schultze-Lutter et al., 2011). However, none of these are reported to have occurred with the ICD-10’s Schizotypal Disorder.

Consequences of the conceptual shift from prevention to treatment
The implications of a shift from prevention to treatment—targeting present complaints and not only (uncertain) future outcomes—were particularly not generally seized. Furthermore, concerns focused on the noncritical use of antipsychotics. Yet, as in major depression—another mental disorder with impairing symptoms, spontaneous remissions, and an uncertain future course, but a much better established consensus about indication for treatment—medication is only one option and its prescription has to be tailored to the patient's needs. Consequently, the following advantages of the revised proposal as a distinct diagnostic entity were generally overlooked (Ruhrmann et al., 2010b):

However, despite these impressive advantages, some concerns were also voiced with respect to the proposed diagnosis, such as the unclear prevalence and psychopathological significance in the general population (Schimmelmann et al., 2011), developmental aspects (Schimmelmann et al., in press), and, in light of the different operationalized APS criteria (Schultze-Lutter et al., in press), uncertainty about the most reliable and valid definition. Yet it was not such concerns that finally guided the decision to include attenuated psychosis syndrome not in the main text of DSM-5 but in its appendix, but rather the inconclusive results of an insufficient reliability study in just two centers and on just seven subjects.

Looking forward
So, while in the aftermath of the past three years debates over this decision are continuing, hopefully the decision will soon be regarded as a chance to better communicate the current proposal, overcome its outdated perception as a risk syndrome, and to examine open questions. Furthermore, the inclusion of an attenuated psychosis syndrome in DSM-5—even if only in Section III—will hopefully encourage more research in this area, including a refinement of criteria (Ruhrmann et al., 2010a; Ruhrmann et al., 2010b; Klosterkötter et al., 2011) and increased attention to these patients (in need of help for current symptoms) and their families.


Addington J., Cornblatt B.A., Cadenhead K.S., et al. At Clinical High Risk for Psychosis: Outcome for Nonconverters. Am J Psychiatry, 2011. 168(8): p. 800-5. Abstract

American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 4th edition, text revision ed. 2000, Washington, DC: American Psychiatric Association.

Carpenter W.T. and van Os J. Should attenuated psychosis syndrome be a DSM-5 diagnosis? Am J Psychiatry, 2011. 168(5): p. 460-3. Abstract

Carpenter W.T. Criticism of the DSM-V risk syndrome: a rebuttal. Cognit Neuropsychiatry, 2011. 16(2): p. 101-6. Abstract

Fusar-Poli P., Bonoldi I., Yung A.R., et al. Predicting psychosis: meta-analysis of transition outcomes in individuals at high clinical risk. Arch Gen Psychiatry, 2012. 69(3): p. 220-9. Abstract

Fusar Poli P., Borgwardt S., Bechdolf A., et al. The psychosis high-risk state—a comprehensive state-of-the-art review. Arch Gen Psychiatry, in press.

Gaebel W., Zaske H. and Baumann A.E. The relationship between mental illness severity and stigma. Acta Psychiatr Scand, 2006. 429 Suppl: p. 41-5. Abstract

International Early Psychosis Association Writing Group. International clinical practice guidelines for early psychosis. Br J Psychiatry, 2005. 48 Suppl: p. s120-4. Abstract

Klosterkötter J. and Schultze-Lutter F. Prevention and early treatment, in Ethics in Psychiatry—European contributions. In: H. Helmchen and Sartorius N., Editors. 2010. Springer Science+Business Media B.V.: Heidelberg. p. 235-62.

Klosterkötter J., Schultze-Lutter F., Bechdolf A., et al. Prediction and prevention of schizophrenia: what has been achieved and where to go next? World Psychiatry, 2011. 10: p. 165-74. Abstract

Penn D.L., Kohlmaier J.R. and Corrigan P.W. Interpersonal factors contributing to the stigma of schizophrenia: social skills, perceived attractiveness, and symptoms. Schizophr Res, 2000. 45(1-2): p. 37-45. Abstract

Ruhrmann S., Schultze-Lutter F. and Klosterkötter J. Probably at-risk, but certainly ill—Advocating the introduction of a psychosis spectrum disorder in DSM-V. Schizophr Res, 2010a. 120(1-3): p. 23-37. Abstract

Ruhrmann S., Schultze-Lutter F. and Klosterkötter J. Sub-threshold states of psychosis—a challenge to diagnosis and treatment. Clin Neuropsychiatry, 2010b. 7(2): p. 72-87. Abstract

Schimmelmann B.G., Michel C., Schaffner N., et al. What percentage of people in the general population satisfies the current clinical at-risk criteria of psychosis? Schizophr Res, 2011. 125(1): p. 99-100. Abstract

Schimmelmann B.G., Walger P. and Schultze-Lutter F. Significance of prodromal symptoms of schizophrenia in childhood and adolescence. Can J Psychiatry, in press.

Schultze-Lutter F., Klosterkötter J., Picker H., et al. Predicting first-episode psychosis by basic symptom criteria. Clin Neuropsychiatry, 2007. 4(1): p. 11-22. Abstract

Schultze-Lutter F., Ruhrmann S. and Klosterkötter J. Early detection and early intervention in psychosis in Western Europe. Clin Neuropsychiatry, 2008. 5(6): p. 303-15. Abstract

Schultze-Lutter F., Schimmelmann B.G. and Ruhrmann S. The Near Babylonian Speech Confusion in Early Detection of Psychosis. Schizophr Bull, 2011. 37(4): p. 653-5. Abstract

Schultze-Lutter F., Ruhrmann S., Schimmelmann B.G., et al. A rose is a rose is a rose“, but at-risk criteria differ. Psychopathology, in press.

Woods S.W., Addington J., Cadenhead K.S., et al. Validity of the prodromal risk syndrome for first psychosis: findings from the North American Prodrome Longitudinal Study. Schizophr Bull, 2009. 35(5): p. 894-908. Abstract

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Related News: News Brief: Attenuated Psychosis Syndrome Left Out of DSM-5 Main Text

Comment by:  Patrick McGorry, SRF Advisor
Submitted 17 July 2012
Posted 17 July 2012

Diagnosis in psychiatry is struggling to deliver. Its main function should be to guide clinicians to select the right treatment approaches. However, we have too many categories that overlap and have low utility for treatment planning and prediction of outcome.

Diagnostic inflation (more “splitting” with micro-categories) is not the answer. We need a simpler but more practical approach. This will involve “lumping,” with categories only included if they are justified by differential treatment needs.

I have argued that we need to import the clinical staging idea from general medicine (McGorry et al., 2006). The purpose would be to help with more accurate treatment selection and to allow early diagnosis of potentially serious illness in a safe and non-stigmatizing way, ensuring that benefits always outweigh risks. Of course, this means breaking the nexus in the U.S. that drug treatment is the main or only form of intervention for patients—a nexus reinforced by the hard neurobiological reductionism that took over American psychiatry from the 1980s, and by direct marketing of medicines to the public. Obviously, however, we must not throw the baby out with the bathwater; neuroscience is a vital element of research, and medicines have a key place in healthcare. Contrasting with the overreaching of medication-based care, the apparent retreat of the pharmaceutical industry from discovery in the mental health field is of concern. Restoring the balance is the key.

In diabetes, breast cancer, lymphoma, asthma, and arthritis, a bald or global diagnosis is an insufficient basis for treatment. We need to know what stage the illness has reached so we can avoid overtreatment (with more risks than benefits), but also ensure that the earliest clinical stages can be recognized and much secondary damage prevented or delayed.

Clinical staging in medicine has the advantage at present over psychiatry in being able to be validated and refined through biomarkers and other investigations (hence, it becomes clinicopathological staging). This may turn out to be possible in many (but probably not all) psychiatric disorders if we study these by stage as well as syndrome.

In psychiatry, our nineteenth-century diagnostic framework, buttressed by the DSM process, is poorly formulated for these purposes. The main diagnostic categories are derived from tertiary settings and samples of middle-aged patients. Yet these disorders do not develop overnight. Their onset is usually slow, and most patients experience prolonged delays in accessing care. The onset phase for 75 percent of disorders is in young people up to 25 years, and our diagnostic system is not very useful for them or, indeed, for primary care settings generally, where mild to moderate mental ill health dominates.

Some would say that we should retreat to the severe end of the spectrum of illness where our conventional diagnoses fit better and drug therapies have a sound evidence base. I believe this would be a real failure of vision and practice for psychiatry as a branch of medicine. Our first duty is to relieve suffering and to do no harm. Psychiatry is not just drug therapy and serious mental illness. Psychotherapy, psychosocial interventions, and social psychiatry are central aspects of our field and are effective on their own and in combination with medicines. Rather than overtreatment, inappropriate treatment (too early and sole use of medication), and delayed treatment (for most) are what typically occurs in the real world. I think we can tackle the issues in a much better way if we broaden our minds, create an integrative psychiatry, and embrace the challenges.

We need more research on the onset phase of mental ill health and mental disorder, and this is one of the arguments for deferring the inclusion of an early clinical phenotype, such as APS, for potentially serious mental illness in the DSM-5. The Ultra-High Risk concept that we developed in Melbourne in the early 1990s, which is the basis for the proposed APS concept, has been a prototype of this type of research. It has transformed the field of schizophrenia research by allowing the onset stage to be mapped and studied prospectively for the first time. Drawing on the indicated prevention concept reformulated for psychiatry by Mrazek and Haggerty (1994) in their influential Institute of Medicine report on Reducing Risks for Mental Disorders, the early and sub-threshold clinical phenotype of psychosis has been better defined in a prospective way. The large wave of research in this domain over the past 15 years has allowed the neurobiology and clinical epidemiology to be uncovered, and has led to the reformulation of the earlier neurodevelopmental theory of schizophrenia. It is now clear that critical changes in brain structure and function are occurring during the peri-onset stage. Several treatment strategies have been studied in randomized clinical trials. This is also a key life stage of transition to adulthood, the challenges of which create risk for a wide range of mental ill health, not just psychosis (McGorry, 2011a; McGorry, 2011b).

The current criteria are certainly not the final word, and the variable transition rate shows that their deployment in routine clinical settings also needs more study. They perform well when the level of enrichment (of true positives) in the sample presenting for care reaches around 20-30 percent. They do not work so well, purely on a mathematical basis (as David Sackett [1991] showed for all diagnostic tests), in the general population and primary care, where the true base rate is much lower and where non-pathological psychotic-like features are also not uncommon. In such settings the false positive rate for persistent psychosis can rise to 90 percent, while in enriched settings it drops to around 65 percent (though most of the remainder have other psychiatric disorders and/or persistence of sub-threshold psychosis). So enrichment in help-seeking people via screening tools as shown by recent Dutch research (Rietdijk et al., 2012) is the key.

For these reasons, and because there is a broader diagnostic reform envisioned using the ultra-high risk (UHR) concept as the prototype, arguably the best DSM-5 outcome now for the UHR/APS definition is for it to be included as a concept for further study in the research section of the manual. This has strong support from the UHR/prodromal research field. If this occurs, the intense debate, which has also been mirrored within the research field of UHR/prodromal research, will have led to a reasonable outcome. In any case, this very valuable clinical and neurobiological research paradigm will continue to develop and, I hope, evolve into a cross-diagnostic reform front in conceptual thinking, research, and clinical practice.

The clinical staging model suggests that a pluripotential initial stage of need for care without a specific diagnostic term may be a useful “provisional” or semi-permeable step. This would allow people with persistent distress, life problems, and functional impairment to access support, assessment, and monitoring in a primary care environment. This is how mental ill health, transient or persistent, is experienced and manifests in an experiential and social matrix. There should be no early pressure to force such people into a specific category. More specificity in diagnostic terminology should follow a “minimalistic” or “utilitarian” approach such that it is only useful or necessary to guide a change in treatment (e.g., from cross-diagnostic interventions such as supportive psychotherapy, CBT, or case management support) to more specific types of psychosocial intervention (e.g., DBT or cognitive remediation, or specific drug therapies).

To advance this agenda, we do need safe environments, with “soft entry,” no stigma, and a welcoming and optimistic primary care culture. We need to ensure that a listening ear, social support, and expert assessment are the front line response to develop engagement and trust, and to refer elsewhere or simply reassure if this is the best option. The assumption that medication is the cornerstone of all intervention, so prevalent in the U.S. healthcare system, has no place in this new approach. In Australia, our health financing system and the creation of a new system of primary care for young people and families is allowing a psychosocial envelope of care to be typically offered as a first line (except when severity, stage of illness, or acute risk require immediate commencement of medication), and also to be always available to wrap around those young people with a genuine need for medication.

This is a major reform challenge for the mental health. The international research conducted by people from many different countries in the early stages of psychosis and schizophrenia has been vital in setting the scene for future progress. The concerns raised by critics have been extremely useful in promoting deep reflection across the field and highlighting distortions in the traditional diagnostic approach and in the mindset and financing of many health systems. There is an integrative opportunity to move the mental health field to a level of sophistication on a par with the rest of healthcare and within the context of the twenty-first century.


McGorry PD, Hickie IB, Yung AR, Pantelis C, Jackson HJ. 2006. Clinical staging of psychiatric disorders: a heuristic framework for choosing earlier, safer and more effective interventions. Aust N Z J Psychiatry 40(8):616-622. Abstract

McGorry P. 2011a. Transition to adulthood: the critical period for pre-emptive, disease-modifying care for schizophrenia and related disorders. Schizophr Bull 37(3):524-530. Abstract

McGorry PD, Purcell R, Goldstone S, Amminger GP. 2011b. Age of onset and timing of treatment for mental and substance use disorders: implication for preventive intervention strategies and models of care. Curr Opin Psychiatry 24(4):301-306. Abstract

Mrazek PJ and Hagerty R. 1994. Reducing Risks for Mental Disorders. Institute of Medicine. Washington DC.

Sackett DL, Haynes RB, Guyatt GH, Tugwell P. 1991. Clinical epidemiology: a basic science for clinical medicine. London: Little Brown & Company.

Rietdijk J, Klaassen R, Ising H, Dragt S, Nieman DH, van de Kamp J, Cuijpers P, Linszen D, van der Gaag M. 2012. Detection of people at risk of developing a first psychosis: comparison of two recruitment strategies Acta Psychiatr Scand 126(1):21-30. Abstract

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