Validity of the Prodromal Risk Syndrome for First Psychosis: Findings From the North American Prodrome Longitudinal Study

Treatment and prevention studies over the past decade have enrolled patients believed to be at risk for future psychosis. These patients were considered at risk for psychosis by virtue of meeting research criteria derived from retrospective accounts of the psychosis prodrome. This study evaluated the diagnostic validity of the prospective “prodromal risk syndrome” construct. Patients assessed by the Structured Interview for Prodromal Syndromes as meeting criteria of prodromal syndromes (n = 377) from the North American Prodrome Longitudinal Study were compared with normal comparison (NC, n = 196), help-seeking comparison (HSC, n = 198), familial high-risk (FHR, n = 40), and schizotypal personality disorder (SPD, n = 49) groups. Comparisons were made on variables from cross-sectional demographic, symptom, functional, comorbid diagnostic, and family history domains of assessment as well as on follow-up outcome. Prodromal risk syndrome patients as a group were robustly distinguished from NC subjects across all domains and distinguished from HSC subjects and from FHR subjects on most measures in many of these domains. Adolescent and young adult SPD patients, while distinct from prodromal patients on definitional grounds, were similar to prodromals on multiple measures, consistent with SPD in young patients possibly being an independent risk syndrome for psychosis. The strong evidence of diagnostic validity for the prodromal risk syndrome for first psychosis raises the question of its evaluation for inclusion in Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition).     

Prospective diagnosis of the initial prodrome for schizophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity

OBJECTIVE: This study was conducted to determine the interrater reliability and predictive validity of a set of diagnostic criteria for the prodrome of the first episode of schizophrenic psychosis when based on the Structured Interview for Prodromal Syndromes. METHOD: The subjects were patients referred for evaluation because of a suspected schizophrenia prodromal syndrome. For the reliability study, two to four raters independently diagnosed 18 patients on the basis of face-to-face or videotaped interviews. For the validity study, 6- and 12-month outcome data were collected for 29 patients. RESULTS: Agreement in differentiating prodromal from nonprodromal patients was 93%. The prodromal features had converted to schizophrenic psychosis for 46% of the prodromal patients at 6 months and for 54% at 12 months. CONCLUSIONS: In small groups of subjects, these diagnostic criteria for the schizophrenic prodrome and the Structured Interview for Prodromal Syndromes showed promising interrater reliability and predictive validity.     

Young people at risk for psychosis: case finding and sample characteristics of the Oulu Brain and Mind Study

Aim: Set within the general population‐based Northern Finland Birth Cohort 1986, the Oulu Brain and Mind Study aims to explore the causes and pathogenesis of psychotic illness by following young people at risk for psychosis due to having a first‐degree relative with psychotic illness or due to having experienced psychotic‐like symptoms themselves. We report the study methods and explore the relationship between these definitions of high risk for psychosis and operational criteria for a prodromal psychosis syndrome based on interview. Methods: Prospectively collected data from earlier follow‐ups of this cohort were combined with health register data to categorize subjects as those with familial risk (n = 272), symptomatic risk (n = 117), psychosis (n = 78), attention deficit hyperactivity disorder (ADHD) (n = 103) and a sample of controls (n = 193) drawn randomly from the remaining cohort. The Structured Interview for Prodromal Syndromes (SIPS) was applied to all, 295 participants together with questionnaires measuring psychosis vulnerability and schizotypal traits. Results: There were 29 (10%) current prodromal cases. Criteria for the current prodromal syndrome were fulfilled by 12% of the familial risk group and 19% of the symptomatic risk group, compared with 5% of the ADHD group and 4% of controls. Conclusion: We successfully detected young people with a prodromal psychosis syndrome although relatively few subjects deemed to be at high risk met the full operational criteria according to the SIPS interview. Combining methods from familial, clinical and psychometric high‐risk approaches provides a tractable method for studying risk of psychosis in the general population.     

A longitudinal study of neurocognitive function in individuals at-risk for psychosis

INTRODUCTION: Clinically defined prodromal diagnostic criteria identify at-risk individuals with a 35-40% likelihood of developing a psychotic disorder within a year. The time course and predictive value of cognitive deficits in the development of psychosis has not been established. METHODS: A comprehensive neurocognitive battery and clinical assessments were administered to 37 subjects meeting Criteria of Prodromal States (COPS) criteria for being at risk for psychosis, and two comparison groups: 59 first episode and 47 healthy subjects. Subjects were also evaluated at 6-month and 1-year follow-up periods. Primary analyses used a neurocognitive composite score derived from individual neurocognitive measures, including measures of vigilance, verbal memory, working memory, and processing speed. RESULTS: At-risk subjects performed more poorly than healthy subjects (t=2.93, P=0.01), but better than first episode subjects (t=4.72, p<0.0001). At-risk subjects were particularly impaired on measures of vigilance and processing speed. Cognitive composite scores were significantly lower in at-risk subjects who progressed to psychosis (N=11; z=-1.2), while those at-risk subjects who did not progress to psychosis (N=17) performed better (z=-0.5), and not significantly different from controls. Poor CPT performance combined with better WAIS-R digit symbol performance predicted progression to psychosis. Severity of neurocognitive deficits was not related to duration of prodrome or to time to development of psychosis and neurocognitive function improved in all subjects except those who progressed to psychosis. CONCLUSION: Neurocognitive impairment emerges early in the course of psychotic illness. Performance on tests of neurocognition may prove to be an early risk predictor for subsequent development of psychotic disorders.     

The assessment of "prodromal schizophrenia": unresolved issues and future directions

Because of the novelty of research with clinical high risk ("prodromal") patients, many unresolved issues exist concerning how the prodromal state is defined and measured. Data are presented from the Recognition and Prevention (RAP) program at the Zucker Hillside Hospital to address several outstanding questions. Baseline attenuated positive symptoms were rated in 42 putatively prodromal patients in the RAP program using the Scale of Prodromal Symptoms (SOPS). Followup data of 6 months or more were available on 34 of these subjects; 9 of these (26.5%) developed psychotic disorders. Patients who developed psychosis had significantly higher SOPS positive symptom scores at baseline than those who did not. Various thresholds, using both total SOPS positive symptom scores and highest single item score, significantly predicted transition to psychosis, which calls into question appropriate cutoffs for the distinction between health, prodromal status, and psychosis. The SOPS positive symptom "conceptual disorganization" was found to be significantly related to disorganized behavior but not to other positive symptoms or to psychotic outcome, suggesting the importance of examining dimensions of psychopathology. The dimensional quantification of prodromal symptom severity may be an important direction for future studies of the assessment of at-risk states.     

Subjective quality of life in subjects at risk for a first episode of psychosis: a comparison with first episode schizophrenia patients and healthy controls

The concept of quality of life (QoL) is of growing relevance in schizophrenia research. However, there is to date no information on subjective QoL in subjects at risk for a first episode of psychosis in comparison to first episode schizophrenia patients (FE) or healthy controls (HC). Therefore 45 subjects in a putatively early initial prodromal state (EIPS), 40 FE and 45 HC were assessed on demographics, symptoms and subjective QoL as measured by the Modular System for Quality of Life. Results indicated that in most areas HC experienced the highest QoL scores followed in hierarchical order by EIPS and FE. EIPS and FE experienced significantly lower QoL than HC in 5 and 6 of 7 QoL domains. EIPS experienced the lowest ratings in affective QoL. Thus the data demonstrates that subjective QoL in subjects at risk for a first episode of psychosis is substantially reduced when compared with HC and suggests that subjective QoL is already compromised prior to the onset of first positive schizophrenia symptoms. These findings support the notion that subjects at risk for a first episode of psychosis constitute a clinical population for which further service and intervention research is indicated.     

Rapid response to antipsychotic treatment on psychotic prodrome: Implications from a case series

The feasible intervention strategy at the prodromal state of psychosis is under debate. We report nine subjects clinically in a putative prodromal state of psychosis who responded to low‐dose aripiprazole within the first week of medication. We conjecture that the pathophysiological processes might be easier to modify by antipsychotics in the prodromal state and we believe a short‐term low‐dose trial of antipsychotic agents is a convenient option for subjects at ultra high risk of psychosis. We urge specific attention to monitor the dissolution of psychotic‐like symptoms carefully in order to have a better understanding of the pathogenesis and pharmacotherapy in the inception of psychosis.     

Evaluating and treating the prodromal stage of schizophrenia

Identification of a person in the prodromal stage of schizophrenia, before the onset of the first episode of psychosis, provides an opportunity for early, potentially preventative, interventions. Recent attempts to develop at risk or prodromal syndrome diagnostic criteria have proved to be successful at identifying individuals at high risk for psychosis. Preliminary investigations find that pharmacologic and psychotherapeutic interventions may reduce the risk of psychosis in at risk individuals, but until more is known, current treatment guidelines recommend close monitoring, therapeutic interventions that address identified problems, including supportive or cognitive therapies to reduce the functional consequences of the presenting symptoms, family interventions to reduce family distress and improve coping, and intervention with schools to decrease likelihood of school failure. Pharmacologic intervention targeting the prodromal symptoms is not recommended, given the uncertain risk to benefit ratio.     

Detection of people at risk of developing a first psychosis: comparison of two recruitment strategies

Rietdijk J, Klaassen R, Ising H, Dragt S, Nieman DH, van de Kamp J, Cuijpers P, Linszen D, van der Gaag M. Detection of people at risk of developing a first psychosis: comparison of two recruitment strategies. Objective: Better recruitment strategies are needed to improve the identification of people at ultra‐high risk of developing psychosis. This study explores the effectiveness of two recruitment strategies: a screening method in a consecutive help‐seeking population entering secondary mental health services for non‐psychotic problems vs. a population referred to the diagnostic center of an early‐psychosis clinic. Method: From February 2008 to February 2010, all general practitioner and self‐referrals (aged 18–35 years) to the secondary mental healthcare service in The Hague and Zoetermeer were screened with the Prodromal Questionnaire; patients who scored above the cutoff of 18 and had a decline in social functioning were assessed using the Comprehensive Assessment of At‐Risk Mental States (CAARMS). All referrals (aged 14–35 years) to the diagnostic center in Amsterdam were also assessed with the CAARMS. Results: The screening detected a three‐fold higher prevalence of at‐risk mental states: these subjects were older and more often female. manova showed significantly higher scores for the screened population on depression, social anxiety, distress with positive symptoms, and a higher rate of transition to psychosis within 12 months. Conclusion: The screening method detects more patients with at‐risk mental states than the referral method. The latter method is biased to young male patients in an earlier prodromal stage and a lower transition rate.     

Psychosis prediction: 12-month follow up of a high-risk ("prodromal") group

Intervention in the prodromal phase of schizophrenia and related psychoses may result in attenuation, delay or even prevention of the onset of psychosis in some individuals. However, a "prodrome" is difficult to recognise prospectively because of its nonspecific symptoms.This study set out to recruit and follow up subjects at high risk of transition to psychosis with the aim of examining the predictive power for psychosis onset of certain mental state and illness variables.Symptomatic individuals with either a family history of psychotic disorder, schizotypal personality disorder, subthreshold psychotic symptoms or brief transient psychotic symptoms were assessed and followed up monthly for 12 months or until psychosis onset.Twenty of 49 subjects (40.8%) developed a psychotic disorder within 12 months. Some highly significant predictors of psychosis were found: long duration of prodromal symptoms, poor functioning at intake, low-grade psychotic symptoms, depression and disorganization. Combining some predictive variables yielded a strategy for psychosis prediction with good sensitivity (86%), specificity (91%) positive predictive value (80%) and negative predictive value (94%) within 6 months.This study illustrates that it is possible to recruit and follow up individuals at ultra high risk of developing psychosis within a relatively brief follow-up period. Despite low numbers some highly significant predictors of psychosis were found. The findings support the development of more specific preventive strategies targeting the prodromal phase for some individuals at ultra high risk of schizophrenia.     

Commentary: Progress, issues, and implications of prodromal research: an inside view

This issue of the Schizophrenia Bulletin focuses around research in the prodromal phase of severe mental illness, largely schizophrenia. The years since the last Bulletin issue on early detection and intervention have witnessed success at identifying the prodrome prospectively, positive initial data about treating prodromal symptoms and delaying psychosis onset, and hopeful data about elucidating the pathophysiology of psychosis through the prodrome. In this overview I will comment on some of the opportunities and challenges generated by this new line of research. Themes include the recruitment of prodromal subjects, characteristics of prodromal samples thus far collected, the process of conversion to psychosis in these samples, minimizing false positive prodromal subjects, dosing of drug treatments in prodromal clinical trials, treatment practice implications of prodromal research, defining conversion to psychosis prospectively, and screening, assessing, and naming the prodrome. It is concluded that prodromal research holds much promise but will require the formal collaboration of many investigators and the availability of resources for sustained efforts to recruit what amounts to an incidence sample.     

Neurocognitive functioning in subjects at risk for a first episode of psychosis compared with first- and multiple-episode schizophrenia

Evidence from neurobiological studies suggests that schizophrenia arises from an early abnormality in brain development and possibly further progressive developmental mechanisms. Despite a delay between the acquisition of neuropathology and the triggering of psychosis, neurobiological susceptibility is likely to be expressed subclinically by biobehavioral markers in the premorbid stage. The exploratory study aims at identifying potential neurocognitive risk factors and investigating the unfolding of the illness within a cross-sectional design by comparing neurocognitive profiles in 179 healthy controls, 38 clinically identified subjects in an early initial prodromal state (EIPS) for psychosis, 90 subjects in a late initial prodromal state (LIPS), 86 first-episode patients with schizophrenia, and 88 multiple-episode patients. Subjects at risk were substantially impaired in verbal executive and verbal memory functions. Compared to EIPS subjects, LIPS subjects demonstrated additional attentional deficits. Both EIPS and LIPS subjects were superior to first-episode patients who presented a generalized neuropsychological deficit profile, and to multiple-episode patients who showed evidence for further decline. Although results were influenced by general intellectual abilities and demographic and clinical characteristics, they could not account for total group differences. Results support a neurodevelopmental model of psychosis with further progressive mechanisms and are consistent with a primary involvement of left frontotemporal networks in the prodromal phase.     

Comorbid Depressive and Anxiety Disorders in 509 Individuals With an At-Risk Mental State: Impact on Psychopathology and Transition to Psychosis

Background: The current diagnostic system for subjects at enhanced clinical risk of psychosis allows concurrent comorbid diagnoses of anxiety and depressive disorders. Their impact on the presenting high-risk psychopathology, functioning, and transition outcomes has not been widely researched. Methods: In a large sample of subjects with an At-Risk Mental State (ARMS, n = 509), we estimated the prevalence of DSM/SCID anxiety or depressive disorders and their impact on psychopathology, functioning, and psychosis transition. A meta-analytical review of the literature complemented the analysis. Results: About 73% of ARMS subjects had a comorbid axis I diagnosis in addition to the “at-risk” signs and symptoms. About 40% of ARMS subjects had a comorbid diagnosis of depressive disorder while anxiety disorders were less frequent (8%). The meta-analysis conducted in 1683 high-risk subjects confirmed that baseline prevalence of comorbid depressive and anxiety disorders is respectively 41% and 15%. At a psychopathological level, comorbid diagnoses of anxiety or depression were associated with higher suicidality or self-harm behaviors, disorganized/odd/stigmatizing behavior, and avolition/apathy. Comorbid anxiety and depressive diagnoses were also associated with impaired global functioning but had no effect on risk of transition to frank psychosis. Meta-regression analyses confirmed no effect of baseline anxiety and/or depressive comorbid diagnoses on transition to psychosis. Conclusions: The ARMS patients are characterized by high prevalence of anxiety and depressive disorders in addition to their attenuated psychotic symptoms. These symptoms may reflect core emotional dysregulation processes and delusional mood in prodromal psychosis. Anxiety and depressive symptoms are likely to impact the ongoing psychopathology, the global functioning, and the overall longitudinal outcome of these patients.Key words: psychosis, schizophrenia, ultra high risk, ARMS, prodromal, attenuated psychosis, psychosis risk, depression, anxiety     

Prospective outcome of early intervention for individuals at ultra-high-risk for psychosis

Aim: Based on previous reports of second‐generation antipsychotic agents having a beneficial effect on prodromal symptoms, we investigated the effectiveness and tolerability of atypical antipsychotic therapies in individuals at high risk for developing psychosis. Methods: We examined prodromal symptoms and functioning in individuals at ultra‐high‐risk for psychosis using an uncontrolled prospective design with pre‐ and post‐treatment measures. Results: Of the 27 subjects taking antipsychotics during the study period, 15 took part in at least one follow‐up assessment. Overall Com prehensive Assessment of At‐Risk Mental States scores significantly improved at the last evaluation point, with a medium‐size effect of Cohen's d = 0.54 (95% confidence interval, ?0.02 to 1.08) (mean follow‐up period = 8.8; SD = 8.3 months). Depression and anxiety symptoms were markedly reduced, and global and social functioning also significantly improved. Of the 27 subjects, two (7.4%) converted to psychosis and 16 (59.3%) experienced at least one treatment‐emergent adverse event, but no subjects exhibited serious adverse events. Conclusions: The results of this study support treating high‐risk individuals with antipsychotics to reduce prodromal symptoms with adequate safety.     

The relation of antipsychotic and antidepressant medication with baseline symptoms and symptom progression: A naturalistic study of the North American Prodrome Longitudinal Sample

A substantial number of patients who meet criteria for a prodromal syndrome for first psychosis are treated with antipsychotic and/or antidepressant medications. There is suggestive evidence that both classes of medication may reduce prodromal symptoms. This longitudinal study examined the relation of antipsychotic and antidepressant medication with prodromal symptom severity at baseline and 6-month follow-up. Participants met Structured Interview for Prodromal Syndromes (SIPS) criteria for the prodrome, and were evaluated at eight centers as part of the North American Prodrome Longitudinal Study (NAPLS). Symptom ratings (positive, negative, disorganized and general) and data on antipsychotics, SSRIs, and other antidepressant medications were obtained at baseline and 6-month follow-up. Analyses revealed that all symptom dimensions declined in severity over time, but there were differences in the magnitude of the decline as a function of antipsychotic medication. Those never on antipsychotics showed less reduction in positive and disorganized symptoms over time. SSRIs and other antidepressants were not linked with declines in symptom severity. Consistent with findings from small-sample, clinical trials, the present results suggest that atypical antipsychotics may be effective in reducing the severity of attenuated positive symptoms associated with the prodrome to psychotic disorders. Limitations of the present study are noted, including the fact that it is not a randomized trial, and data on duration and dosage of medication and 2-year follow-up were not available for most participants. The results are discussed in light of the relative risks and benefits of preventive interventions, both medication and cognitive therapies, and the importance of future clinical trials.     

Suicidality in the "prodromal" phase of schizophrenia

Objectives

Patients with schizophrenia are at high risk for suicide ideation, attempts, and completed suicide. However, suicidal behavior during the prodromal phase of schizophrenia and a possible association between prodromal suicidal behavior and suicidality after the onset of overt psychosis are not studied.

Methods

One hundred six consecutively admitted schizophrenia patients with recent onset were evaluated retrospectively for prodromal symptoms and suicidality during the prodromal phase and after the onset of frank psychosis. In addition, 106 matched control subjects from the general population were evaluated for suicidality during the same age period of the prodromal phase of the corresponding patient.

Results

Suicide ideation and attempt during the prodromal period were reported in 25.5% and 7.5% of the patients, which are 3.8- and 8-fold greater than in the controls, respectively. Patients with suicidal behavior experienced a greater number of prodromal symptoms than those without. Prodromal depressive mood, marked impairment in role functioning, and tobacco smoking exerted an independent effect on suicide ideation, whereas depressive mood was the symptom significantly more frequent in patients with suicide attempt. Suicide attempts were associated with an earlier onset of prodromal symptoms and frank psychosis. All patients with prodromal suicide attempts were cigarette smokers. Suicide ideation during the prodromal phase was strongly associated with lifetime suicidality after the onset of frank psychosis.

Conclusions

Suicidal behavior is quite common during the prodromal period. The association of smoking, depressive mood, impaired functioning, and a large number of prodromal symptoms, particularly in patients with an early onset of symptomatology, carries a substantially increased risk for suicide ideation. Particular care is needed in patients with prodromal suicide ideation after the onset of frank psychosis because the risk to attempt suicide is high.     

Does a parent-report measure of behavioral problems enhance prediction of conversion to psychosis in clinical high-risk adolescents?

Recent research on risk for psychosis has focused on youth who manifest subclinical signs that are often associated with the prodrome to psychosis. Standardized measures of prodromal symptoms have been shown to significantly enhance prediction of risk for conversion to an Axis I psychotic disorder. In the present study, a widely used parent-report measure of behavioral problems, the Child Behavior Checklist (CBCL) was administered to examine the clinical and diagnostic utility of the measure as an adjunctive screening instrument in the identification of at-risk youth. The CBCL, the Structured Interview for Prodromal Syndromes (SIPS), and other diagnostic measures were administered at baseline and at one year follow-up assessments to adolescents (n=41) at clinical high-risk for the development of a psychotic disorder. Analyses were conducted to compare the 14 at-risk adolescents who subsequently converted to psychosis to the 27 who did not. Conversion to psychosis was defined as conversion to an Axis I psychotic disorder or affective disorder with psychotic features. Consistent with expectations, at one year follow-up, compared to the Non-Converted participants, the Converted participants manifested significantly higher scores on the prodromal symptom scales of the SIPS. There were, however, no differences in CBCL social and behavioral ratings as a function of conversion status. It is concluded that the CBCL does not show promise as an alternative or adjunctive predictor of conversion to psychosis in at-risk adolescents.     

Pharmacological intervention in the initial prodromal phase of psychosis.

Early identification and treatment of schizophrenia may alleviate the symptoms, delay the onset and improve the outcome of psychosis. Thus, detection of individuals at risk during the prodromal phase is an important task. Universal approaches to screen the general population or healthy subjects at risk have not proven possible to-date. However, clinical criteria for detecting ultra-high risk individuals have been developed for specialized settings, with their implementation in interventional studies. This article examines the rationale for early detection and intervention of psychosis, along with a review of some of the current studies. These target prevention using psychological and/or pharmacological intervention strategies have demonstrated promising results in high risk individuals. The German Research Network on Schizophrenia (GRNS) is conducting two multicenter early intervention studies; one with early psychological intervention in subjects who manifest early prodromal symptoms; with the second trial applying clinical management and pharmacological early intervention in subjects experiencing late prodromal symptoms (high risk subjects). Despite the promising results, many of the current studies have small sample sizes with study durations of a short period. The full benefits of early detection and intervention should be revealed once larger and longer studies are conducted.     

Evaluating and treating the prodromal stage of schizophrenia

Identification of a person in the prodromal stage of schizophrenia, before the onset of the first episode of psychosis, provides an opportunity for early, potentially preventative, interventions. Recent attempts to develop “at risk#x201D; or #x201C;prodromal syndrome#x201D; diagnostic criteria have proved to be successful at identifying individuals at high risk for psychosis. Preliminary investigations find that pharmacologic and psychotherapeutic interventions may reduce the risk of psychosis in #x201C;at risk#x201D; individuals, but until more is known, current treatment guidelines recommend close monitoring, therapeutic interventions that address identified problems, including supportive or cognitive therapies to reduce the functional consequences of the presenting symptoms, family interventions to reduce family distress and improve coping, and intervention with schools to decrease likelihood of school failure. Pharmacologic intervention targeting the prodromal symptoms is not recommended, given the uncertain riskbenefit ratio.     

Recruitment and treatment practices for help-seeking "prodromal" patients

The prodrome of psychosis has become a target for early identification and for treatments that address both symptoms and risk for future psychosis. Interest and activity in this realm is now worldwide. Clinical trials with rigorous methodology have only just begun, making treatment guidelines premature. Despite the sparse evidence base, treatments are currently applied to patients in the new prodromal clinics, usually treatments developed for established psychosis and modified for the prodromal phase. This communication will describe representative samplings of how treatment-seeking prodromal patients are currently recruited and treated in prodromal clinics worldwide. Recruitment includes how prodromal patients are sought, initially evaluated, apprised of their high-risk status, and informed of the risks and benefits of prodromal treatments and how their mental state is monitored over time. The treatment modalities offered (and described) include engagement, supportive therapy, case management, stress management, cognitive behavioral treatment, family-based treatment, antipsychotic pharmacotherapy, and non-antipsychotic pharmacotherapy. References for details are noted.