The principal finding of the present study is that the SIPS structured interview identifies a prodromal risk syndrome that is generally distinct from NC, HSC, and FHR groups across symptom, functioning, comorbidity, family history, and course of illness domains ().
Summary of Differences From Prodromal Patients
Clear and compelling differences between a prodrome sample and NC subjects are certainly necessary to establish the validity of a prodromal diagnosis. Relatively few prior studies of prodromal patients in the past decade have taken this necessary step in any domain.12,16,24
Historically, attempts to identify prodromal patients using the Diagnostic and Statistical Manual of Mental Disorders
(Third Edition Revised) checklist foundered on the inability of the checklist to distinguish patients from nonpatients.53
Our findings based on current methods of prodromal diagnosis establish the distinction from NC subjects convincingly.
Although distinction from a NC group is necessary, this demonstration is by no means sufficient. A more rigorous test of syndromal validity would be provided by a comparison group from the same referral pool: those who were clinically referred for prodrome evaluation but who did not meet prodrome criteria on interview. We identify such patients here as “HSC subjects.” Few previous studies have compared prodromal patients with HSC subjects,4,16–18,21,26
and these either limited themselves to 1 or 2 measurement domains4,17,18,21,26
or had a small prodromal sample.16
The multiple differences from HSC subjects on most cross-sectional variables, as well as the profound differences in conversion outcomes, provide very strong evidence of validity of the prodromal risk syndrome.
FHR subjects had historically offered the available research paradigm with the highest risk of psychosis, prior to the advent of prospective prodromal research. Prodromal patients were robustly distinguished from FHR subjects on all measures of current functioning and on risk of transition to psychosis over the near term. Although prodromal patients and FHR subjects are quite distinct on theoretical grounds, this is the first study to our knowledge to make empirical comparisons between these groups.
The symptoms of the psychosis prodrome and the symptoms of SPD are similar on a cross-sectional basis.54
The 2 syndromes are, however, clearly delineated by definition: Prodromal patients must show progression of illness in the past year while SPD patients may have been stably ill; SPD patients must exhibit symptoms in at least 5/9 areas while prodromal patients may exhibit fewer symptoms. Clear delineation of the 2 syndromes also permits them to co-occur. In our sample, 26% of prodromal patients met SPD criteria, and 67% of schizotypally diagnosed patients met prodrome criteria.
Because the 2 syndromes share membership in the psychosis-spectrum group of conditions, however, the interpretation of comparisons between the 2 groups does not speak as straightforwardly as the previous comparisons to issues of discriminant (or convergent) validity. These comparisons are nevertheless of interest. The final rate of transition to psychosis in patients with SPD alone was similar to that in the prodromal group ( 2). Thus, our results suggest that SPD in adolescents and young adults may be like the prodrome in that it may also constitute an identifiable risk syndrome for psychosis.
The conclusion that SPD can constitute a risk syndrome for psychosis does have some precedents. While SPD has often been conceptualized as a stable condition, this stability may primarily apply to older samples. Others have also reported that adolescents and young adults with SPD are at substantial risk of developing psychosis,55,56
although neither of these studies removed comorbid prodromal patients from the SPD analysis group as in the current analyses.
SPD in adolescents and young adults may capture individuals with a more gradual progression of illness than the prodrome criteria. Evidences in the current study consistent with such speculation are the greater impairment of premorbid adjustment in the SPD-alone group than the prodromal group, the lack of dramatic progression in the year before baseline in the SPD-alone subjects (by virtue of their not meeting prodrome criteria), and the suggestion in that conversions occurred somewhat later in the patients with SPD alone than in prodromals. A factor that may contribute to the possibly later conversion in the SPD group is their younger age at ascertainment because more time would be required to enter the age of maximum risk.
Strengths and Limitations
The primary strength of the study is the large sample size of well-characterized patients meeting prodrome criteria: Three hundred seventy-seven is 2–3 times as large as the next largest reported samples.8,21,25,26
An additional strength is the use of the SIPS for evaluating subjects. Psychometric properties for this instrument have been favorable,4,5,20,33,34
and reliability in its use was established cross-site.
An important potential limitation is that comparisons involving symptom severity, family history, and functional decline could be viewed as tautological because these domains contribute to making a prodromal diagnosis. However, several considerations suggest that these comparisons reflect discriminant validity largely independently from definitional issues. First, only 1.7% of the prodromal sample qualified for a prodromal diagnosis based solely on family history and functional decline.30
Removal of this small number of subjects would have little impact on the family history findings in or the functional findings in . Second, only positive symptoms contribute to the prodrome definition, and the pattern of the data for the nonpositive symptoms is similar to that for the positive symptoms (). Lastly, the contribution of severity of positive symptoms to a prodromal diagnosis is not a deterministic one, as the prodromal syndromes defined by positive symptoms require symptom frequency and recent symptom change criteria in addition to symptom severity. Thus, prodromal patients are not required by definition to have more severe positive symptoms than HSC subjects.
Other limitations stem from the study data having been originally collected through independent protocols. Such limitations include the variability of statistical power across pairwise comparisons, the absence of symptom data other than those from the SOPS, methods of recruitment and evaluation that varied somewhat, the need to estimate SOPS data for most FHR subjects, the uncertain agreement between the Axis II interviews employed, and our inability to subdivide family history of nonpsychotic illness into finer-grained categories.
Because the large majority () of the prodromal patients met only 1 of the 3 sets of prodrome criteria, those for attenuated positive symptoms, another limitation is that the current evidence of syndromal validity applies almost exclusively to this common prodromal syndrome. The current data do not provide an adequate test of the validity of the other 2 less common prodromal syndromes (brief intermittent frank psychosis and genetic risk with functional decline).
A further limitation is that the current data do not address the probability of diagnostic changes after baseline other than conversion. For example, initial HSC subjects or schizotypal patients may meet prodrome criteria during follow-up, and FHR subjects or prodromal patients may develop schizotypal personality during follow-up.
Lastly, the aim of the current prodromal definition focused on positive symptoms was to identify patients relatively late in an ongoing prodrome. Retrospective work suggests that identifiable negative, anxiety, and depressive symptoms may precede the onset of attenuated positive symptoms during the prodrome,57
but the specificity of such early symptoms in prospectively identifying patients who will transit to psychosis remains an area that requires further investigation. Some self-perceived mental functioning deficits, known as “basic symptoms,”58
may also provide a means to identify patients as prodromal before the onset of attenuated positive symptoms.
Specific Psychotic Outcomes of the Prodromal Risk Syndrome
Following usual practice among prodromal research clinics, this article reports on conversion to psychosis, including cases of affective psychosis, rather than conversion more narrowly to schizophrenia. Conversions to affective psychosis from the prodrome represented a substantial, albeit a minority, proportion (10%, ). This proportion is in general agreement with previous reports.8–10,19
The initial reason that prodromal clinics reported conversion to the broader psychosis construct related to the perceived relative instability of specific diagnoses in early first-episode psychosis.3
Recent studies have confirmed that the initial DSM-IV
diagnosis is somewhat unstable in the first episode.59–65
The large majority of first-episode affective psychosis diagnoses in these studies were stable, however, with 82% of the 488 patients again receiving affective psychosis diagnoses at 12- to 36-month follow-up. Based on these previous findings, many of our affective psychosis converters might remain cases of affective psychosis if further follow-up were available.
Thus, the preliminary conclusion is that affective psychoses may share with schizophrenia-spectrum psychosis a prodrome characterized by attenuated positive symptoms. Similarly, recent work describing prodromal symptoms for mania found attenuated positive symptoms more predictive of psychotic mania than nonpsychotic mania.66
This preliminary conclusion of a similar prodrome in schizophrenic and affective psychosis is consistent with genetic epidemiology and molecular genetic data suggesting a similarity between schizophrenic and affective psychoses.67–72
Additional emerging data from the NAPLS collaboration suggest that the converse may be true as well: The prodromal risk syndrome for psychosis may not confer high specific risk for nonpsychotic affective disorder. Nonpsychotic mania at follow-up was more common in the HSC subjects than in the prodromal group.73
Comorbidity in the Prodromal Risk Syndrome
The common comorbidity of established DSM-IV
diagnoses in prodromal patients, reported previously,17
is not dissimilar to the range of comorbidity reported for schizophrenia itself, when no diagnostic hierarchy is imposed as in the current study.74–82
The presence of the comorbid diagnoses should not rule out consideration of a prodrome diagnosis if the comorbid diagnoses do not account for the symptoms, distress, and functional impairment that the patient experiences.
Next Steps for the Prodromal Risk Syndrome
The current construct validity findings comprise part of the work necessary to establish a fully valid diagnosis; however, several other questions remain which will require additional studies.
One of the most important questions is whether the prodromal diagnosis can be refined so as to increase the proportion of cases that convert to psychotic illness. Our group has focused on this question elsewhere.52
We found that the addition of 3 clinical severity criteria to the current prodromal diagnostic criteria can increase the proportion of converting patients to 80%. Unfortunately, imposing 3 additional severity criteria also leads to a substantial loss of sensitivity, such that 70% of converting cases are now falsely predicted not to convert. Thus, further studies are needed to refine the prodromal diagnosis, both to replicate that more stringent criteria continue to predict conversion in a high proportion of individuals and to determine whether other revisions to the criteria could substantially restore sensitivity.
Because only 89% of the converters in our clinically referred sample had met prodrome criteria at baseline, another question is whether to revise prodrome criteria to try to capture the 11% of converting cases that were not diagnosed as prodromal at baseline. Most of these subjects met schizotypal criteria, but a few did not. Some cases may have met prodrome or SPD criteria at an intervening time point, as discussed earlier.
An additional challenge for this field is to characterize the outcomes of a prodromal diagnosis more rigorously. Fully formed psychosis is likely not to be the only psychosis-spectrum outcome. Developing psychosis captured as an initial diagnosis of prodrome may stabilize at a subsyndromal or “schizotypal” level. Such outcomes are worthy of increased attention. Similarly, we need to know more about how often and how completely apparently “prodromal” symptoms remit spontaneously and how often nonpsychotic diagnoses such as depression newly emerge or persist.
Another important question centers on the effect of the patient pool from which evaluations for the prodrome are drawn. Recent reports of a declining rate of conversions to psychosis (16% at 2 y26
compared with 30% in the present sample, 12% at 12 mo25
compared with 22% in the present sample) have emphasized the possible role of referral of subjects whose “prodromal” symptoms are not associated with distress, help seeking, or reduced functioning but are only incidental to help-seeking behavior associated with other psychiatric syndromes.25,26
This interpretation is consistent with a well-documented literature on the frequency of nonpathologic and asymptomatic self-reported psychotic symptoms in the general population.83–88
Future studies on subsequent course should address the impact of imposing additional phenomenological requirements such as distress, help seeking, and/or loss of functioning associated with the psychotic-like symptoms. Inclusion of indices of disturbance of the basic sense of self could potentially increase conversion rates as well.89
In the meantime, the apparent recent attraction of higher proportions of low-risk patients to prodromal diagnostic evaluation stresses the importance of investigating low-risk treatment options, such as cognitive therapy9
and medications other than antipsychotics.
Future studies should also address what proportion of the general population
actually receive prodromal diagnoses on specialized structured interviews like the SIPS and what are the psychosis conversion rates in this group. The current normative data suggest that the proportion will be quite low, but NC subjects are prescreened for health and thus cannot estimate prevalence in the general population. Previous epidemiologic studies83–88,90
unfortunately cannot address these questions directly. In the meantime, use of prodromal diagnostic assessments should be reserved for patients clinically referred specifically because of concerns about psychosis.