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March 11, 2020

Clinical High Risk for Psychosis—Not Seeing the Trees for the Wood

Author Affiliations
  • 1Orygen, Parkville, Victoria, Australia
  • 2Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia
JAMA Psychiatry. 2020;77(7):559-560. doi:10.1001/jamapsychiatry.2019.4635

“It's not the tools that you have faith in: tools are just tools. They work, or they don't work. It's people you have faith in or not.”

Steve Jobs

Three decades ago, the schizophrenia field finally began to challenge the intrinsic pessimism that had inhibited preventive approaches for a century. Early detection and specialized early treatment models for first-episode psychosis have since become the global standard of care, producing better outcomes that “bend the curve” of the early course of illness1 and have opened the door to the prevention or delay of the first episode of psychosis. The development of operational criteria (the “ultra” or “clinical” high risk [CHR] criteria) for identifying what we originally termed the at-risk mental state meant that an even earlier stage of illness could be identified prospectively and studied for its heuristic and therapeutic potential.

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    1 Comment for this article
    Preventive treatments for prodromal stage of psychosis: the need for further evidence
    Dina Bosnjak Kuharic, MD | University Psychiatric Hospital Vrapce, Zagreb, Croatia
    In their editorial, McGorry and Nelson1 address treatment models used for clinical high risk for psychosis, arguing that the field needs serious scrutiny, but doubt that this can be achieved with “Cochrane reviews and various species of meta-analysis”; they consider that these tools “can be subject to error and bias, are increasingly subject to inexpert use and overuse”. However, this generic criticism of meta-analysis as a tool1 is in contrast with their endorsement of “meta-analyses of the first wave of studies” that showed “positive” results.2
    In the editorial, authors address our Cochrane review3 about interventions for prodromal stage of
    psychosis, and repeatedly4 reinforce misleading messages.
    McGorry and Nelson1 consider that our review3 reinforced the impression that there is no evidence that interventions for prodromal stage of psychosis are effective and that we are sending a misleading headline message that patients do not benefit at all from intervention. This interpretation is discrepant with our Cochrane review, as there is not a single sentence in our review that sends message about “no benefit”. Instead, we concluded that evidence was uncertain, of low quality and that more research is needed. The main conclusion of our Cochrane review was not that the analyzed interventions for treating prodromes of psychosis do not work.5 Instead, we concluded that we would benefit from more studies that are adequately powered. We are glad that McGorry and Nelson1 agree with us on that point, as they also consider that among 20 clinical trials that we have included in our review, “a number of studies were underpowered”.
    We classified evidence as low or very low quality, based on risk of bias and imprecision and uncertainty3, McGorry and Nelson consider1 that the included studies “used the best possible methodology”, and that we have classified them as low quality without fully accessing the relevant materials essential to make an accurate judgment regarding quality. We will welcome specific information about available information that could help us improve our assessments.
    We are personally optimistic about prospects of treatment for prodromal stage of psychosis, and we support the need for conducting new studies in this field. We share the view of McGorry and Nelson that there is no need for disappointment, and that search for further knowledge will ultimately help us all to get to the conclusive message about benefits and harms of these interventions.


    1. McGorry PD, Nelson B. Clinical High Risk for Psychosis-Not Seeing the Trees for the Wood. JAMA psychiatry. Mar 11 2020.
    2. van der Gaag M, Smit F, Bechdolf A, et al. Preventing a first episode of psychosis: meta-analysis of randomized controlled prevention trials of 12 month and longer-term follow-ups. Schizophrenia research. Sep 2013;149(1-3):56-62.
    3. Bosnjak Kuharic D, Kekin I, Hew J, Rojnic Kuzman M, Puljak L. Interventions for prodromal stage of psychosis. The Cochrane database of systematic reviews. Nov 1 2019;2019(11).
    4. Nelson B, Amminger GP, Bechdolf A, et al. Evidence for preventive treatments in young patients at clinical high risk of psychosis: the need for context. The lancet. Psychiatry. Dec 19 2019.
    5. Bosnjak Kuharic D, Kekin I, Hew J, Rojnic Kuzman M, Puljak L. Preventive treatments in patients at high risk of psychosis. The lancet. Psychiatry. 2020;In press.

    Dina Bosnjak Kuharic, Ivana Kekin, Joanne Hew, Martina Rojnic Kuzman, Livia Puljak