Many symptoms and a great deal of disability develop during the prodromal phase of schizophrenia and other psychotic disorders 1–3
. It is also possible that neurobiological and neurocognitive changes occur during this period.4,5
This underlines the importance of recognizing emerging psychotic disorder. If the prodrome can be detected prospectively and treatment provided at this stage, then disability could be minimized, some recovery may occur before symptoms and poor functioning become entrenched, and the possibility of preventing, delaying, or ameliorating the onset of diagnosable psychotic disorder arises.
However, prodromal symptoms are nonspecific. Common prodromal symptoms include depression, anxiety, and social withdrawal.2
Even psychotic-like experiences (attenuated or subthreshold psychotic symptoms) have been found to occur commonly in the general population, especially among adolescents and young adults.6–10
Because of this lack of specificity, there are problems with using prodromal symptoms and signs alone to identify people thought to be at incipient risk of onset of psychotic disorder as this would result in a high false positive rate, ie, many people not actually at risk of psychosis would be falsely labeled as such. Thus, some added criteria are needed to identify those most likely to be at highest risk.
In order to address this issue, we used a “close-in strategy”11
which requires multiple risk factors to be combined to define a group at ultra high risk (UHR) of psychosis, that is putatively prodromal. Age in the period of highest risk of first onset of psychotic disorder is one intake criterion. In addition, 3 criteria are currently used to identify the UHR group.12,13
These are (1) Attenuated Psychotic Symptoms (APS) Group: have experienced subthreshold, attenuated positive psychotic symptoms during the past year; (2) Brief Limited Intermittent Psychotic Symptoms (BLIPS) Group: have experienced episodes of frank psychotic symptoms that have not lasted longer than a week and have been spontaneously abated; or (3) Trait plus State Risk Factor Group: have a first-degree relative with a psychotic disorder or the identified client has a schizotypal personality disorder and they have experienced a significant decrease in functioning during the previous year. Additionally, a perceived need for psychiatric help is also required as the person needs to have been referred to a specialized psychiatric service for management, the Personal Assessment and Crisis Evaluation (PACE) Clinic.14
Using these UHR criteria, we found a rate of transition to psychosis of over 34% within 6 months of referral to the PACE service and between 35% and 40% within 12 months.12,13
These rates are several thousand fold over the expected incidence rate for first-episode psychosis in the general population. This occurred despite the provision of supportive counseling, case management, and antidepressant medication if required.
The PACE UHR criteria have since been adopted and adapted by a number of other settings around the world.15,16
For example, the Prevention through Risk Identification, Management and Education Clinic at Yale University, USA, reported a 54% transition rate (7 of 13 subjects) within 12 months.17
The Psychological Assistance Service in Newcastle, Australia, described a 50% transition rate over 12 months,18
the TOPP Clinic in Norway reported a 12-month transition rate of 43%,19
the Early Identification and Intervention Evaluation Clinic in Manchester, UK, described a 22% transition rate,20
and the Cognitive Assessment and Risk Evaluation (CARE) Clinic in San Diego reported a 15% transition rate at 12 months.15
(For a more detailed review, see Haroun et al15
, Olsen and Rosenbaum16
, and McGorry et al.21
However, a reduction in the rate of transition to psychosis has been suspected over the last few years. Recent data from the PACE Clinic found a 6-month transition rate of only 9.2%.22
Although a young person meeting UHR criteria still has significantly greater odds of becoming psychotic within a brief time period than someone not meeting the criteria,22
the apparently decreasing transition rate needs examination. It has implications for the use of interventions in this population. If a high proportion of those treated to prevent or delay psychosis are in fact “false positives” and were not actually at risk of developing psychotic disorder, at least in the short term, then intervention may not be justified. This would be particularly the case with biological treatments such as antipsychotics, which have potentially harmful side effects. Psychosocial treatment may be harmful too, if it involves educating individuals about psychosis and informing them that they are at risk, if they are not actually at risk. Treatment may needlessly alarm them, result in possible curtailment of activities, and cause stigma including self-stigmatization (eg, they may decide to cease attending university or work to avoid stress).23–25
The seeming reduction in transition rate is also relevant for research. Investigators have assumed that those meeting the UHR criteria are in the prodromal phase of either psychotic disorders in general and/or of schizophrenia in particular. Some even refer to “the prodrome” or “prodromals,” an attitude that reifies the syndrome.26
However, if the risk in this cohort has truly fallen to rates around 10%–15%, then the assumption that a high proportion of the UHR population are in the prodromal phase may no longer be valid. True positives (those making the transition) will be outnumbered by false positives. However, the possibility of “false false positives,” that is those who would have made the transition to psychotic disorder had it not been for some intervention or change in circumstances, needs to be remembered.12
At follow-up points, these false false positives are impossible to distinguish phenotypically from false positives: they have both failed to make the transition to full blown psychotic disorder (see ). False false positives may differ from false positives genotypically or endophenotypically.
Fig. 1. Theoretical Distinction Between False Positives and False False Positives. (A) True positive: psychosis threshold is crossed. (B) False positive: psychosis threshold is not crossed. (C) False false positive: psychosis threshold is not crossed but would (more ...)
Given the relatively low transition rate and our inability to distinguish between false positives and false false positives, the findings about a range of proposed endophenotypes in the UHR population, including neurocognitive, neurophysiological, and biological, cannot be assumed to be tenable for the “prodrome” or early stage of schizophrenia. Presumed endophenotypes for psychotic disorder in general, or schizophrenia in particular, may actually just be indicative of psychiatric distress, a feature of all young people seeking help at UHR or prodromal clinics.
Because of the importance of the issue, we set out to examine the transition rate over time in more detail. We aimed to explore possible clinical and demographic factors which may be contributing to a seeming reduction in the rate.