Brief Limited Intermittent Psychotic Symptoms (BLIPS), are 1 of the 3 operational definitions for individuals at ultra high risk for psychosis (UHR¹), that were incorporated into the Comprehensive Assessment of At Risk Mental State (CAARMS),² along with Attenuated Psychosis Symptoms (APS) and Genetic Risk and Deterioration Syndrome (GRD). BLIPS identify a group of “young people with a history of fleeting psychotic experiences that spontaneously resolved within one week” (page 8 in Yung et al³), without the use of antipsychotic. Under the UHR paradigm, BLIPS are not considered psychotic and do not receive a diagnosis of full-blown psychosis. This makes the psychosis threshold of the UHR paradigm different from that of current psychiatric classifications such as ICD and DSM.⁴

The actual diagnostic significance of the BLIPS subgroup is unknown. Although it has been recommended that BLIPS should be contrasted against operationally based ICD/DSM psychotic disorders (page 706 Miller et al⁵), no comparative studies have yet been conducted, and hence their relationship deserve clarification. The prognostic significance of BLIPS is also unclear. A first recent meta-analysis from our group has compared the risk of psychosis onset across different UHR subgroups, indicating that the BLIPS have a distinct profile, with higher risk of psychosis than the APS and GRD subgroups.⁶ Another meta-analysis from our group compared the BLIPS against standard ICD-10 and DSM-5 categories of brief psychotic episodes. BLIPS were found to have the same risk of psychotic recurrence as the ICD-10 category of Acute and Transient Psychotic Disorder (ATPD) and DSM-5 “Brief psychotic disorder,”⁷ while they have a lower risk than remitted cases of first-episode schizophrenia.⁷ However, this meta-analysis did not test whether the diagnoses overlapped at baseline or if the same patient could actually be diagnosed with both competing constructs. Furthermore, the exact longitudinal course of the BLIPS is still not completely clear. Little is known about clinical and sociodemographic factors predicting BLIPS outcome. This is probably because case identification is difficult owing to the fleeting features and the small number of BLIPS, accounting only for about 10% of UHR samples.⁶ For example, although BLIPS cases are by definition “intermittent,” the actual proportion and the longitudinal course of recurrent vs mono-episodic BLIPS is unknown. More to the point, the Structured Interview for Prodromal Symptoms (SIPS) and its companion Scale of Prodromal Symptoms (SOPS),⁸ that also address UHR symptoms, have introduced a close variant of the BLIPS, ie, “Brief Intermittent Psychotic Symptoms” (BIPS). The SIPS considers “seriously disorganizing or dangerous” features as fully psychotic and not as at risk BIPS symptoms. Conversely, these features are not routinely assessed with the CAARMS and therefore do not constitute exclusion criteria for BLIPS cases (for details on the differences between BLIPS and BIPS see table 1 in Fusar-Poli et al⁹). Yet, the rationale for considering seriously disorganizing or dangerous features fully psychotic and beyond the UHR state (under the BIPS construct) rather than as UHR symptoms (under the BLIPS construct) was not clarified by the SIPS/SOPS authors. Since these differences constitute an important source of disagreement between the CAARMS and the SIPS¹⁰ it is important to explore the actual prognostic significance of seriously disorganizing or dangerous features within the BLIPS framework.

We present here the first long-term prospective study in the largest sample of BLIPS individuals to date, assessed and treated by a clinical service for UHR individuals.¹¹ The first aim of this study is to address the diagnostic significance of the BLIPS, by investigating their relationship with competing ICD-10 diagnoses. The second aim of this study is to address the prognostic significance of BLIPS by exploring the impact of sociodemographic and clinical predictors of psychosis onset.

To our knowledge this is the first original study of CAARMS-defined BLIPS ever conducted. Since it is based on a large sample and long-term follow-up, it makes clear advances from earlier observations in several ways. First, it enhances the understanding of the diagnostic significance of BLIPS by investigating their relationship with competing ICD-10 diagnoses. We found that most BLIPS met ICD-10 criteria for ATPD (68%) followed by unspecified nonorganic psychosis (15%), mental and behavioral disorders due to use of cannabinoids (11%) and mania with psychotic symptoms (6%). Second, it examines a number of clinical and sociodemographic factors and makes it possible to point out specific predictors for BLIPS, while at the same time highlighting some conceptual limitations. We found that about 1 in 2 BLIPS individuals developed a psychotic disorder over time (5-year failure 0.54). Recurrent BLIPS episodes were relatively infrequent (11%) but associated with higher risk of psychosis onset at the univariate analysis (HR = 3.98). The best predictor of psychosis onset at the multivariate analysis was the presence of seriously disorganizing or dangerous features, which was associated with an extreme high risk (HR = 4.39, 5-year failure 0.89) of transitioning to psychosis.

The first aim of the current study was to address the diagnostic significance of the BLIPS compared to competing ICD-10 diagnoses. Our study’s findings suggest that about two-third of BLIPS cases met the diagnostic criteria for ATPDs, further corroborating our recent meta-analytical findings of comparable risk of psychosis between BLIPS and ATPD constructs.⁷ Conceptually, the BLIPS definition has more coherence with the ATPD construct as compared to other first-episode diagnoses. Because of this conceptual overlay, depending on the local availability of high-risk services, young adults presenting with brief psychotic episodes may equally receive a diagnosis of established psychosis and start an antipsychotic treatment (as ATPD/BPD), or an at-risk diagnosis (as BLIPS/BIPS) and undergo psychological interventions.²⁷ To overcome these inconsistencies these categories should be further compared, rather than abandoned, as suggested by other publications in this special issue.^28,29 Comparative analyses may specifically benefit the UHR research, because there is more knowledge into the epidemiology, course and outcomes of ATPD (eg, large follow-up studies with up to 5426 individuals³⁰) than in the BLIPS construct (only the current study available). For example, it may be argued that the BLIPS is diagnostically pluripotent and that it is not specific for schizophrenia spectrum psychoses. However, the meta-analytical risk of developing affective psychoses is actually higher in ATPD than in BLIPS (eFigure 4 from Fusar-Poli et al⁹). Thus, there is more evidence for pluripotential outcomes in ATPD than in BLIPS,³¹ with up to one-third of initial ATPD cases transitioning to affective psychoses.³² In fact, we found that BLIPS tend to overlap (78% of baseline BLIPS meeting ATPD criteria) with the ATPD subtypes characterized by schizophrenic symptoms: acute polymorphic psychotic disorder with symptoms of schizophrenia (F23.1) and acute schizophrenia-like psychotic disorder (F23.2). This is probably because BLIPS encompass Schneider’s first-rank symptoms, which have been incorporated into the ICD-10 criteria for schizophrenia. Conversely, ATPD constitutes a heterogeneous category including subtypes with polymorphic, schizophrenic and prevalently delusional symptoms, which are likely to herald longer lasting psychotic and affective disorders.²⁸ While acute polymorphic psychotic disorder lasts less than 3 months and refers to the earlier concepts of “bouffée délirante and cycloid psychosis,” featuring varied delusions, hallucinations, perceptual changes, perplexity, and emotional turmoil shifting daily or even faster, the ATPD subtypes with schizophrenic symptoms are set apart from schizophrenia only by temporal criteria of less than 1 month. The available evidence suggests that these subtypes have a high risk to evolve into schizophrenia over the short and longer terms.³⁰ The overlap between BLIPS and ATPD schizophrenic subtypes is also consistent with meta-analytical evidence indicating the UHR state specifically predicts schizophrenia spectrum psychoses (73% of transitions) rather than affective psychotic outcomes (11% of transitions only).³³ Recent original studies in UHR individuals (n = 271) as contrasted to comparison individuals (n = 171) further confirmed no evidence of diagnostic pluripotentiality with respect to new or incident anxiety, bipolar, or non-bipolar mood disorders.³⁴

The second aim of the current study was to address the prognostic significance of the BLIPS under the CAARMS framework and to address the impact of sociodemographic and clinical predictors of psychosis onset. The overall risk of psychosis in the long term (5-year) was 0.54 and it is in line with recent meta-analytical estimates in brief psychotic episodes.⁷ This value is also very similar to the 0.56 meta-analytical proportion of diagnostic instability observed from an initial ATPD.³⁵ The univariate analysis revealed that recurrent BLIPS, although not frequent, had a 4-fold increase in this risk (HR = 3.89) compared to mono-episodic BLIPS. Recurrent BLIPS may have a significant prognostic relevance because repeated episodes of BLIPS would not qualify as transition to psychosis under the CAARMS 12/2006 but rather still as UHR state. However, we found that the vast majority (6/8) of individuals presenting with recurrent BLIPS eventually developed a psychotic disorder (lasting more than 7 d). As the 2 individuals who did not develop psychosis had used cannabis during their index episode, it is possible to speculate that recurrent BLIPS not associated with drug abuse may almost inevitably transit to psychosis. This result, if validated by future studies, would question the clinical utility of a 7-day observation window and watchful and waiting strategies for recurrent BLIPS, advocating more assertive monitoring and focused treatments.

However, BLIPS recurrence did not survive the multivariate analysis, which selected only the presence of seriously disorganizing or dangerous BLIPS features as core predictive factor for BLIPS outcomes, with a 4-fold increase in risk (HR = 4.39). It is possible to hypothesize that the SIPS/SOPS authors had introduced this exclusion criterion on the assumption that this BLIPS subgroup would present with symptoms and behavior that were too extreme to qualify for a state of risk. Such an assumption remained untested for about 2 decades, until our bootstrapping analysis confirmed the robustness of their poor prognostic significance in the CAARMS framework. The BLIPS without seriously disorganizing or dangerous features showed a 5-year 0.37 risk of developing psychosis, as compared with the 5-year 0.89 for the seriously disorganizing or dangerous BLIPS. This was also reflected by an acceptable apparent test performance as observed with the AUC. The high-transition risk in seriously disorganizing or dangerous BLIPS may truly reflect the presence of extreme state factors that are close to the psychosis threshold,³⁶ as hypothesized by the SIPS/SOPS authors (see clinical implications below). They may have elaborated the seriously disorganizing or dangerous exclusion criterion on the basis of their earlier work on psychopathological subtypes of schizophrenia indicating that a drift toward disorganization (hebephrenia, see supplementary eDiscussion for details) was associated with “deterioration” and poorer functional outcome.³⁷

BLIPS were most likely to meet the criteria for ICD-10 diagnosis of ATPD at intake, mainly the subtypes with schizophrenic symptoms. About half of BLIPS cases developed a psychotic disorder over follow-up. Recurrent BLIPS were relatively infrequent but tended to transit to psychosis. Seriously disorganizing or dangerous features were associated with an extreme risk of psychosis.

Supplementary material is available at http://schizophreniabulletin.oxfordjournals.org.

This study was supported in part by a 2014 NARSAD Young Investigator Award to P.F-P.