Is the Clinical High-Risk State a Valid Concept? Retrospective Examination in a First-Episode Psychosis Sample

There was considerable agreement among experts in the field as to what constitutes APSPS. Using a semistructured interview-based instrument (CORS) with FEP patients and their caregivers and aided by detailed chart reviews, we found that at least half of all consenting patients in this catchment area–based clinical sample, and two-thirds (68%) of those who completed all assessments, recalled experiencing one or more APSPS prior to their FEP. Although each of the nine APSPS identified by the experts were individually present in a minority of patients, the most common early signs and symptoms reported in the overall assessments of the FEP patients were, in fact, depression, anxiety, and impaired role functioning. Overall, those with and without APSPS were similar in social, demographic, and clinical features at baseline.

With the exception of inappropriate affect, the nine early signs and symptoms identified by the experts readily map onto the various subscales of the Comprehensive Assessment of At-Risk Mental States (CAARMS) (10) and the Structured Interview for Psychosis-Risk Syndrome (SIPS) (11), both widely accepted instruments documenting the CHR construct (25). Odd or bizarre ideas, passivity experiences, subthreshold delusions, and suspiciousness (included in the TOPE) are accounted for by the unusual thought content, delusional ideas, suspiciousness or persecutory ideas, and grandiose ideas of the SIPS and the unusual thought content and nonbizarre ideas of the CAARMS. Unusual perceptions (not clearly psychotic) and subthreshold hallucinations (TOPE) reflect perceptual abnormalities or hallucinations of the SIPS and perceptual abnormalities of the CAARMS. Disorganized or odd speech (TOPE) is represented by disorganized communication (SIPS) and disorganized speech (CAARMS). Finally, the TOPE’s odd or unusual behavior is described in both the unusual thought content and the perceptual abnormalities scales of the SIPS and CAARMS.

Despite excitement about the CHR stage, it has been unclear whether most individuals with a FEP pass through an identifiable CHR phase. This knowledge gap has emerged in part because interventions for the high-risk state are largely organized around CHR research clinics, where patients are assertively recruited and followed on the basis of defined CHR criteria. In contrast to those prospective longitudinal studies of CHR youths, this study is the first to provide evidence that at least half of FEP patients, and 68% of those who completed all assessments, recalled experiencing early APSPS consistent with the CHR state. A key advantage of our analysis is its catchment area–based sample, which included both inpatients and outpatients with any form or severity of FEP. It supports Schultze-Lutter and colleagues’ speculation that their own report may have underestimated the prevalence of CHR symptoms prior to an FEP (19).

This work also has important consequences from a population health and service-planning perspective. Because only a minority of persons in a CHR state transition to FEP (17), arguments for the feasibility and relevance of targeting the CHR state (via early identification, prevention, or other intervention efforts) presume that this state is in fact a frequent pathway en route to the FEP. In other words, if most patients with a psychosis had not actually experienced APSPS and had only nonspecific (non-CHR) early signs and symptoms prior to their FEP, then case identification or other interventions targeting the CHR phase would have limited relevance or utility for delaying or preventing FEP. In contrast, our conclusion that a majority of consenting FEP patients (68% of those who completed all assessments) reported experiencing early APSPS provides an important validation of the CHR state’s relevance for mental health service planning and strengthens the clinical utility of CHR for case identification and indicated prevention initiatives.

Such arguments must bear in mind potential risks, such as the labeling of individuals as being at risk of psychosis when most of them will not in fact develop a FEP. Furthermore, the finding that many individuals with FEP did not pass through a CHR phase underscores the fact that multiple forms of psychopathology occur en route to an FEP and that a sole focus on interventions for CHR may ignore other pathways to FEP.

It is perhaps surprising that there were no significant sociodemographic or clinical differences (including both baseline symptoms and functioning [Table 1]) between the groups with and without APSPS at the point of help seeking for an FEP. This finding suggests that the form of symptoms can change substantially between the prepsychotic period and emergence of an FEP. APSPS are not required in a prodrome but can occur prior to the prodrome (9); there was a trend toward earlier age at onset of the prodrome in the group that had experienced APSPS compared with the group without APSPS. However, no difference was found in the age at onset of psychosis between the two patient groups. Furthermore, our results indicate that even though the prodrome is a concept linked to schizophrenia, individuals with a history of APSPS did not differ in their rate of development of affective versus nonaffective (schizophrenia spectrum) FEP (Table 1). Intriguingly, recent work supports the view that early APSPS may be of limited consequence; the presence of subthreshold positive symptoms among CHR youths followed prospectively is not related to functioning either initially or over time (26).

Strengths of our study included the agreement across multiple continents by internationally recognized experts in the early psychosis field and the use of semistructured interviews followed by consensus decision making about symptom onset and key time points. Our methodology also enabled us to capture distress, help-seeking behavior, and APSPS that emerged prior to the prodrome (for example, APSPS that were followed by a period of full symptom resolution, then by either more APSPS or nonspecific symptoms that evolved into an FEP). Potential explanations for the higher rates of APSPS seen in our sample are the inclusion of younger patients and those from both inpatient and outpatient settings, in many cases capturing psychosis onset in the community prior to initiation of psychosocial or pharmacological treatment. Also, because our sample was derived from a catchment-based FEP program with no competing services, our data likely reflect real-world diversity in intensity and severity of illness onset.

Limitations included the fact that some individuals receiving FEP care did not consent to their data being used for research purposes, meaning that they could not be included in this sample. In addition, many who consented did not complete all assessments required for the analysis. There were significant differences in symptoms and functioning between the 351 study completers and the 131 noncompleters (Table 1). As a result, the 68% of study completers who experienced at least one APSPS could be an over- or underestimate of APSPS in the total FEP population.

Furthermore, our list of 27 early signs and symptoms was shorter and less detailed than the more than 100 symptoms included in other instruments, such as the Interview for the Retrospective Assessment of the Onset of Schizophrenia (24). Two of the nine identified features (inappropriate affect and passivity experiences) were endorsed by only slightly more than the 60% threshold of experts (Table 2), and inappropriate affect does not readily map onto elements screened for in prospective CHR diagnostic instruments. A more rigorous survey of experts could have used higher thresholds; more intensive approaches, including feedback; or a push toward convergence, as is typically done in studies using Delphi methods. Recall bias is a limitation of any instrument that is based on recollection of symptoms and behaviors, and such bias may have persisted even when data from family members and other caregivers were integrated and despite multiple probes and anchors provided in the CORS and TOPE (birthdays, milestones, and major events). Further investigation of the psychometric properties of both the CORS and the TOPE is required. Finally, although the baseline sample represented patients with relatively untreated FEP, the ≥30-day exclusion criterion regarding use of antipsychotic medications may have excluded those who received such medications for more than one month before referral to PEPP-Montréal.

This report provides the first evidence that in a catchment area–based sample, at least half of consenting youths with an FEP, and over two-thirds of all study completers, had experienced a prior phase of APSPS resembling the operationalized CHR state. Even though patients with and without APSPS had similar baseline sociodemographic and clinical characteristics, our finding that APSPS preceded development of an FEP in a substantial proportion of patients is an important validation of the population-level feasibility and relevance of the CHR construct for FEP. It also supports the CHR state’s viability as a target for early intervention, such as through case identification or indicated prevention approaches. Finally, it lends credence to a clinical staging model (27) in which later and more differentiated forms of illness are sometimes—but not always—preceded by subthreshold syndromes.