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IPRN 2013—Identifying and Treating the Psychosis Prodrome

26 April 2013. More than 100 researchers gathered to discuss the early stages of oncoming psychosis at the meeting of the International Prodromal Research Network (IPRN) on 21 April 2013 in Orlando, Florida. Like the rain outside, ideas poured forth in the meeting, organized by Tyrone Cannon of Yale University, New Haven, Connecticut, and Barbara Cornblatt of the Zucker Hillside Hospital, Glen Oaks, New York, as a satellite to the International Congress on Schizophrenia Research. For 11 years, the group has been meeting to share research about the prodrome, early signs of oncoming psychosis. Although the matter of whether to include a prodromal category in the new version of the DSM-5 has been settled for now (in the negative; see SRF related news story), the researchers made clear that work remains to refine ideas about the prodrome, how best to detect it, and how to intervene.

Paths to psychosis
The first two talks explored different ways to detect people destined to develop psychosis among those who show early signs. Describing two such patients, Diana Perkins of the University of North Carolina, Chapel Hill, challenged the audience to predict which actually developed psychosis. Noting the need for other evidence to help evaluate this question, she referred to existing diabetes or heart disease algorithms that take into account different variables about people to predict the chances of their developing these disorders. “My fantasy is that maybe in five years we can do this for psychosis,” she said.

Perkins then presented new data on the development of a blood test, based on samples taken from 72 people at “clinical high risk” (CHR) before they developed psychosis. Measuring 141 components in blood, many inflammation-related, the researchers eventually culled 16 that differed between those who eventually developed psychosis (n = 32) and those who did not. When values for these 16 components were put into an algorithm, it correctly identified 91 percent of those who became psychotic and 78 percent of those who did not. It also distinguished between those who developed psychosis from healthy controls. Future studies will have to see if this algorithm could work in other samples, and Perkins noted that such a blood test would be only one piece of a panel of items that could help evaluate psychosis risk among people already showing early signs, rather than being a screening test for the general population.

In the audience, Sabine Bahn of the University of Cambridge, U.K., noted the difficulties of discerning whether such blood tests index general risk rather than something specific to the process of becoming psychotic. She suggested that repeated blood tests may be more capable of picking up key changes on the way to psychosis than would a single baseline measurement.

Turning to the brain, Daniel Mathalon of the University of California, San Francisco (UCSF), presented his data on using composite measures of brain activity, as measured by electroencephalography (EEG), to distinguish those destined to develop psychosis. While listening to a train of auditory stimuli, human brain waves vary depending on whether the stimulus was expected or not. When it does not match expectations, a negative signal develops, termed “mismatch negativity” (MMN). Measuring MMN in 212 people at CHR for psychosis, he reported that MMN was reduced in those who eventually developed psychosis two years later. This reduction is also found in schizophrenia patients, whereas those who do not “convert” to psychosis and healthy controls maintain robust MMN responses. Because MMN is thought to reflect a form of plasticity at synapses in the brain, Mathalon proposed that the run-up to psychosis may be marked by impaired synaptic plasticity, which would lead to an overabundance of weak synapses. Excessive pruning away of these synapses could then drive conversion to psychosis.

Stressful burden
Noting that stress may push someone toward psychosis, Rachel Loewy of UCSF talked about ways to get a readout of a person’s stress levels. First, Loewy found an increased incidence of trauma in 69 people at CHR for psychosis, compared to 56 healthy controls matched for age and socioeconomic status. To get a biological index of stress, Loewy found that the 34 people from the CHR group had higher levels of cortisol, a stress hormone present in saliva, than 32 controls while enduring a stressful task involving public speaking or math problem solving. The at-risk group tended to rate this experience as more threatening (as opposed to challenging) than controls, and this rating correlated with cortisol levels. Loewy suggested that people at risk may be sensitized to stress, responding more strongly to stressful situations than controls, and that something like cognitive behavioral therapy (CBT) might help people manage stress by learning to reappraise aversive situations. An audience member suggested that certain interventions such as school programs against bullying could limit stressful experiences in a way that could have a real impact in preventing psychosis. Another member raised the possibility that the subjective burden of stress may be more important than the actual number of stressful events a person experiences.

Early intervention
Citing the benefits of cognitive remediation therapies for people who have already developed schizophrenia, Matcheri Keshavan of Harvard Medical School, Cambridge, Massachusetts, explored whether such a strategy would be useful to a small at-risk group (n = 14). A “Cognitive Enhancement Therapy” consisting of computerized training as well as group and individual therapy (Hogarty et al., 2004) was delivered for 40 hours over eight weeks and consisted of cognitive training and social cognitive training (i.e., emotion recognition). This significantly improved performance in the training categories, including processing speed and visual learning. These gains correlated with functional improvements measured after training, as well as with a decrease in brain activation measured by fMRI—something that might reflect increased brain efficiency. Although it is not clear yet whether this could forestall psychosis, Keshavan and others suggested that the emphasis on whether interventions bring down rates of conversion to psychosis overlooks other informative outcomes, such as depression symptoms, negative symptoms, and other functional deficits. While an intervention may not prevent conversion, it could still mitigate the severity of someone’s illness.

Kristin Cadenhead of the University of California, San Diego, followed with a review of some of the 11 randomized, controlled trials of interventions for CHR done so far, including CBT, antipsychotics, and omega 3 fatty acids. These interventions had moderate effects, meaning they seemed to reduce the number of people who went on to develop full-blown psychosis. Cadenhead reviewed other avenues worth trying, including treating biomarkers of illness such as gray matter loss or suppression of μ brain waves. Because only a subset of at-risk people go on to convert to psychosis, she emphasized that finding approaches that combined both pharmacological and non-pharmacological treatments may make more sense.

Whatever the treatment route chosen, it should be taken early, was the message from Thomas McGlashan of Yale University, who spoke on behalf of Tor Ketil Larsen. He went on to describe the TIPS (Treatment and Intervention in Psychosis) early-detection study published last year, which found that treatment-as-usual given in the early stages of psychosis produces durable reductions in negative and cognitive symptoms, lasting up to 10 years (Hegelstad et al., 2012), compared to giving the same treatment later. “Early timing appears to have a lasting difference,” he said.—Michele Solis.

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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

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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

World Health Organization. Prevention of mental disorders: effective interventions and policy options, ed. W.H. Organization. 2004, Geneva: World Health Organization.

Yung A.R. and McGorry P.D. The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull, 1996. 22(2): p. 353-70. 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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