Abstract The early psychosis movement was fuelled by the concept that early recognition and treatment of patients with psychosis could prevent long-term chronic impairment. Indeed, duration of untreated psychosis (DUP) predicts treatment response and early intervention services have since shown added value. However, considerable chronic impairment remains, with about 20%–30% of the patients with schizophrenia not responding to 2 different conventional antipsychotics in adequate doses and duration. In contrast to the research on DUP and early intervention in schizophrenia in general, far less research has systemically assessed the benefits of shortening the time between treatment onset and adequate treatment response. Yet timely recognition of treatment-resistant schizophrenia (TRS) could be vital since studies have indicated that a critical time window in which clozapine is most effective for TRS patients could exist. We believe that introducing the concept of Duration of Treatment Resistance (DTR) may help to investigate whether shortening of DTR by optimizing medication schedules can further prevent or mitigate long-term disability in patients with schizophrenia. In this editorial, we propose a definition of DTR and encourage the field to investigate the potential merits of this concept in future studies.

BACKGROUND The period preceding the first psychotic episode is regarded as a promising period for intervention. We aimed to develop an optimized prediction model of a first psychosis, considering different sources of information. The outcome of this model may be used for individualized risk estimation. METHODS Sixty-one subjects clinically at high risk (CHR), participating in the Dutch Prediction of Psychosis Study, were assessed at baseline with instruments yielding data on neuropsychology, symptomatology, environmental factors, premorbid adjustment, and neurophysiology. The follow-up period was 36 months. RESULTS At 36 months, 18 participants (29.5%) had made a transition to psychosis. Premorbid adjustment (P = .001, hazard ratio [HR] = 2.13, 95% CI = 1.39/3.28) and parietal P300 amplitude (P = .004, HR = 1.27, 95% CI = 1.08/1.45) remained as predictors in the Cox proportional hazard model. The resulting prognostic score (PS) showed a sensitivity of 88.9% and a specificity of 82.5%. The area under the curve of the PS was 0.91 (95% CI = 0.83-0.98, cross-validation: 0.86), indicating an outstanding ability of the model to discriminate between transition and nontransition. The PS was further stratified into 3 risk classes establishing a prognostic index. In the class with the worst social-personal adjustment and lowest P300 amplitudes, 74% of the subjects made a transition to psychosis. Furthermore, transition emerged on average more than 17 months earlier than in the lowest risk class. CONCLUSIONS Our results suggest that predicting a first psychotic episode in CHR subjects could be improved with a model including premorbid adjustment and information-processing variables in a multistep algorithm combining risk detection and stratification.

Patients at Ultra-High Risk (UHR) for developing a first psychosis vary widely in their symptom presentation and illness course. An important aim in UHR research concerns the characterization of the clinical heterogeneity in this population. We aimed to identify qualitatively and quantitatively different clinical symptom profiles at baseline and at 2-year follow-up in a group of UHR subjects and healthy controls. We employed a Latent Class Factor Analysis (LCFA) to the 19 items of the Structured Interview for Prodromal Syndromes (SIPS) ratings at baseline and at 2-year follow-up in a sample of 147 UHR subjects and 141 controls from the Dutch Prediction of Psychosis Study (DUPS) in the Netherlands. Additionally, a stepwise logistic regression analysis was performed with transition to psychosis as a dependent variable and baseline latent variable scores as predictors. Variation in symptomatology at baseline was explained by both quantitative and qualitative differences; at 2-year follow-up qualitative differences between individuals were no longer observed. Quantitative differences showed moderate stability over time (range=0.109–0.42). Within the UHR sample, transition to psychosis was significantly associated with quantitative differences in baseline SIPS scores. The results of our study suggest a ‘quasi’-continuous extended psychosis phenotype, a finding that merits replication in other samples.

A growing number of research papers focus on the identification of young individuals meeting 'ultra-high risk criteria' for developing a first episode of psychosis. Intervention in this early phase might possibly prevent or postpone the development of a full-blown psychosis. Different detection and treatment strategies within this target group are being discussed. This is illustrated using three cases. The first is a 20-year-old female with subclinical psychotic symptoms and recent functional decline; however, as her symptoms only presented following drug abuse, she was not considered to be at ultra-high risk for developing a first episode of psychosis. The second case involves a 17-year-old student who did meet at-risk criteria; after seeking help for subclinical psychotic symptoms and increasing social withdrawal behaviour his symptoms decreased with help of CBT. The third case, an 18-year-old male, illustrates that specialized investigation into high-risk symptoms of psychosis are sometimes needed to reveal frank psychotic symptoms.

A growing number of research papers focus on the identification of young individuals meeting 'ultra-high risk criteria' for developing a first episode of psychosis. Intervention in this early phase might possibly prevent or postpone the development of a full-blown psychosis. Different detection and treatment strategies within this target group are being discussed. This is illustrated using three cases. The first is a 20-year-old female with subclinical psychotic symptoms and recent functional decline; however, as her symptoms only presented following drug abuse, she was not considered to be at ultra-high risk for developing a first episode of psychosis. The second case involves a 17-year-old student who did meet at-risk criteria; after seeking help for subclinical psychotic symptoms and increasing social withdrawal behaviour his symptoms decreased with help of CBT. The third case, an 18-year-old male, illustrates that specialized investigation into high-risk symptoms of psychosis are sometimes needed to reveal frank psychotic symptoms

OBJECTIVE:To investigate the predictive value of the Strauss and Carpenter Prognostic Scale (SCPS) for transition to a first psychotic episode in subjects clinically at high risk (CHR) of psychosis.METHOD:Two hundred and forty-four CHR subjects participating in the European Prediction of Psychosis Study were assessed with the SCPS, an instrument that has been shown to predict outcome in patients with schizophrenia reliably.RESULTS:At 18-month follow-up, 37 participants had made the transition to psychosis. The SCPS total score was predictive of a first psychotic episode (P < 0.0001). SCPS items that remained as independent predictors in the Cox proportional hazard model were as follows: most usual quality of useful work in the past year (P = 0.006), quality of social relations (P = 0.006), presence of thought disorder, delusions or hallucinations in the past year (P = 0.001) and reported severity of subjective distress in past month (P = 0.003).CONCLUSION:The SCPS could make a valuable contribution to a more accurate prediction of psychosis in CHR subjects as a second-step tool. SCPS items assessing quality of useful work and social relations, positive symptoms and subjective distress have predictive value for transition. Further research should focus on investigating whether targeted early interventions directed at the predictive domains may improve outcomes.

Although transition rates in ‘ultra-high risk’ (UHR) for psychosis samples are declining, many young individuals at UHR still experience attenuated positive symptoms and impaired functioning at follow-up. The present study examined the association between a history of childhood trauma and transition to psychosis, and symptomatic and functional outcome, in UHR patients.Data on childhood trauma were available for 125 UHR individuals. Cox regression and linear regression analyses were used to determine the association between childhood trauma, and clinical and functional outcome, during the 24-month follow-up.Of the 125 UHR subjects 26 individuals (20.8%) transitioned to psychosis within 24 months. Childhood trauma did not predict transition to psychosis. However, at 24-month follow-up, UHR patients with higher levels of childhood trauma had higher levels of attenuated positive symptoms (b = 0.34, t = 2.925, p < 0.01), general symptoms (b = 0.29, t = 2.707, p < 0.01) and depression (b = 0.32, t = 2.929, p < 0.01) and lower levels of global functioning (b = − 0.33, t = − 2.853, p = 0.01). Childhood trauma was not significantly associated with a differential course of symptoms over time, although in those with higher levels of childhood trauma, attenuated positive symptoms were more persistent at a trend level.Our results suggest that childhood trauma may contribute to a shared vulnerability for several psychopathological domains.

BACKGROUND:The onset of schizophrenia is associated with genetic, symptomatic, social and environmental risk factors. The aim of the present study was to determine which environmental factors may contribute to a prediction of a first psychotic episode in subjects at Ultra High Risk (UHR) for developing psychosis. METHOD:We included 72 UHR subjects and followed them over a period of 36 months, of whom nineteen (26.4%) made a transition to psychosis. We applied survival analyses to determine associations between a transition to psychosis and environmental factors and social adjustment. To determine which items are the best predictors of transition to a first psychotic episode, Cox Regression analyses were applied. RESULTS:Urbanicity, receiving state benefits and poor premorbid adjustment (PMA) significantly influenced the transition to psychosis. Urbanicity (Wald=10.096, p=.001, HR=30.97), social-sexual aspects (Wald=8.795, p=.003, HR=1.91) and social-personal adjustment (Wald=10.794, p=.001, HR=4.26) appeared to be predictors for developing psychosis in our UHR group. CONCLUSIONS:Environmental characteristics and social adjustment are predictive of transition to a psychosis in subjects at UHR. These characteristics should be implemented in a model for prediction of psychosis. Such a model would be more specific than current models and may lead to patient-specific preventive interventions.

BACKGROUND:This study examines the ability of the Scale of Prodromal Symptoms (SOPS) to differentiate between negative and depression symptoms in a young help-seeking ultrahigh risk (UHR) group.METHODS:SOPS data of 77 help-seeking patients at UHR for psychosis were analyzed with an exploratory factor analysis. The extracted Depression factor was validated with the Beck Depression Inventory (BDI). The extracted SOPS Negative symptoms factor was validated with the Negative symptoms subscale of the Positive and Negative Syndrome Scale (PANSS).RESULTS:Four factors were extracted from the SOPS: a negative, depression, disorganized and positive factor. The Negative symptom factor consisted of three items (N1: social anhedonia and withdrawal, N3: decreased expression of emotion; N4: decreased experience of emotions and self), and could be validated with the PANSS Negative symptoms subscale. The Depression factor was also made up of three items (G2: dysphoric mood, G4: impaired tolerance to normal stress, and D4: personal hygiene/social attentiveness), and could be validated with the BDI.CONCLUSIONS:Our results suggest that 3 items of the Negative symptoms subscale of the SOPS, 2 items of the General and 1 item of the Disorganization subscale differentiate validly between negative and depression symptoms in an UHR population.

Objective: The relationship between cannabis use and psychosis has been studied intensively. Few data, however, are available on the relationship between cannabis use, ultra-high risk for developing psychosis and neurocognition. The aim of the present cross-sectional study was therefore to investigate the relationship between cannabis use, ultra-high-risk (UHR) symptoms and cognitive functioning in UHR patients and healthy controls.Methods: A total of 63 ultra-high-risk patients (34 cannabis users) and 58 control subjects (28 cannabis users) were assessed with clinical measures and a neuropsychological test battery. Patients were eligible for the study if they were between the ages of 12 and 35 years and if they fell into one or more of the following inclusion groups: familial risk and reduced functioning, attenuated psychotic symptoms, brief limited intermittent psychotic symptoms and basic symptoms. Control subjects were eligible for the study if they were between the ages 12 and 35, had no present or past psychiatric illness, no family history of psychiatric illness, no drug use in the non-cannabis-using group, and use of at least four joints per week in the cannabis-using control group.Results: In the UHR and the control group, cannabis users experienced more basic symptoms and UHR symptoms than the non-cannabis users. Moreover, cannabis users in the control group performed at the level of the UHR subjects on a test of verbal memory and verbal fluency. Frequency of cannabis use correlated with severity of several UHR symptoms.Conclusions: Cannabis-using UHR patients have more basic symptoms than non-using patients. In addition, healthy cannabis users have more subclinical UHR and basic symptoms and more neuropsychological dysfunctions than non-cannabis users. More frequent cannabis use was related to increased severity of certain UHR symptoms.

Background: The chance of transition to psychosis in patients at Ultra High Risk for developing psychosis (UHR) is 10-15%. The aim of present study was to investigate differences in baseline clinical symptomatology, general level of functioning (GAF-score) and genetic risk between UHR patients who did (UHR+T) or did not (UHR+NT) make a transition to psychosis. Sharpening UHR inclusion criteria may aid in improving prediction of transition to psychosis.Method: The study sample was taken from 285 patients who were examined within the Dutch Prediction of Psychosis Study (DUPS) at the Academic Medical Center of the University of Amsterdam, the Netherlands. Out of 73 included UHR subjects, 18 made a transition to psychosis. Psychopathology was investigated with the Structured Interview for Prodromal Syndromes, Bonn Scale for the Assessment of Basic Symptoms and GAF-score. The follow-up period of the study was three years.Results: The UHR+T group showed more social anhedonia and withdrawal, more bizarre thinking and a lower GAT score at baseline than the UHR + NT group.Conclusions: In agreement with the results of Cannon et at. [Cannon,T.D., Cadenhead, K., Cornblatt, B., Woods, S.W., Addington, J., Walker, E., Seidman, L.J., Perkins, D., Tsuang, M., McGlashan, T., Heinssen, R., 2008. Prediction of Psychosis in Youth at High Clinical Risk: A Multisite Longitudinal Study in North America. Arch. Gen. Psychiat. 65 (1) 28-37.], our study indicates that severity of specific symptoms at baseline is related to transition to psychosis in UHR subjects. These findings may contribute to a more accurate prediction of a first psychotic episode. Furthermore, symptoms that are increased at baseline in the UHR + T group could be a focus of cognitive behavioural therapy in the UHR period. (C) 2009 Elsevier B.V. All rights reserved.

Providers of mental health services need tools to screen for acute psychosis and ultrahigh risk (UHR) for transition to psychosis in help-seeking individuals. In this study, the Eppendorf Schizophrenia Inventory (ESI) was examined as a screening tool and for its ability to correctly predict diagnostic group membership (e.g., help seeking, mild psychiatric complaints, highly symptomatic mood or anxiety disorder, UHR, acute psychosis). Diagnostic evaluation with established instruments was used for diagnosis in 3 research samples. UHR status was assessed with the Structured Interview for Prodromal Symptoms/Scale of Prodromal Symptoms (Miller et al., 1999) and the Bonn Scale for the Assessment of Basic Symptoms Prediction list (Gross, Huber, Klosterkötter, & Linz, 1987; Klosterkötter, Hellmich, Steinmeyer, & Schulze-Lutter, 2001). This study showed that members of different diagnostic groups rate themselves significantly differently on the ESI and its subscales. A new subscale was constructed, the UHR-Psychosis scale, that showed good utility in detecting individuals with interview-diagnosed UHR status and acute psychosis. The scale is also sensitive to the threshold between UHR and acute psychosis. Practical applications of the ESI include use as a diagnostic tool within various settings.

Background Decline in social functioning occurs in individuals who later develop psychosis. Aims To investigate whether baseline differences in disability are present in those who do and those who do not make a transition to psychosis in a group clinically at high risk and whether disability is a risk factor for transition. Method Prospective multicentre, naturalistic field study with an 18-month follow-up period on 245 help-seeking individuals clinically at high risk. Disability was assessed with the Disability Assessment Schedule of the World Health Organization (WHODAS–II). Results At baseline, the transition group displayed significantly greater difficulties in making new friends ( z =−3.40, P = 0.001), maintaining a friendship ( z =−3.00, P = 0.003), dealing with people they do not know ( z =−2.28, P = 0.023) and joining community activities ( z =−2.0, P = 0.05) compared with the non-transition group. In Cox regression, difficulties in getting along with people significantly contributed to the prediction of transition to psychosis in our sample (β = 0.569, s.e. = 0.184, Wald = 9.548, P = 0.002, hazard ratio (HR) = 1.767, 95% CI 1.238–2.550). Conclusions Certain domains of social disability might contribute to the prediction of psychosis in a sample clinically at high risk.

Early identification of subjects with an increased risk of psychosis is necessary to develop interventions to delay or prevent disease onset. We recently reported that decreased semantic verbal fluency performance in ultra high risk (UHR) subjects predicts the development of psychosis (Becker et al., 2010). The present study investigated whether semantic and verbal fluency scores correlate with grey matter density in UHR subjects. Thirty-seven UHR subjects underwent structural MRI scanning and verbal fluency assessment after which they were followed up for 2 years. Using voxel-based morphometry, we investigated whether grey matter density correlated with verbal fluency scores in 10 UHR subjects who developed psychosis during follow-up and 27 UHR subjects who did not develop psychosis. In UHR subjects developing psychosis, lower semantic fluency scores correlated significantly with reduced grey matter density in the right superior and middle temporal gyrus, the right insula, and the left anterior cingulate cortex. This study shows that a correlation between semantic fluency performance and grey matter density in task-related areas can differentiate between UHR subjects who subsequently will develop psychosis and those who will not. Combining these two measures could improve psychosis prediction in UHR subjects.

Objective: The aim of the present study was to gain more insight into the positive and negative effects of cannabis in the prodromal phase of schizophrenia and in the ultra-high-risk (UHR) state for psychosis. Method: A theory-driven questionnaire was used to examine subjective effects in the prodromal phase in male subjects with a recent onset of schizophrenia or related disorder (n = 52) and in the UHR state in help-seeking male subjects screened for being at UHR for psychosis (n = 17); both groups were compared to cannabis-using controls from the general population (n=52). Results: Recent-onset patients and UHR subjects reported feeling more anxious, depressed and suspicious immediately after cannabis use. Some patients also reported feeling less depressed after cannabis use. Recent-onset patients reported increased visual and acoustic hallucinations, and confusion after cannabis use. Of the recent-onset patients 37% reported that their very first psychotic symptoms occurred during cannabis intoxication. Long-term effects of cannabis reported more often by both patient groups were depression, less control over thoughts and social problems. Conclusions: These results suggest that schizophrenia patients in the prodromal phase and subjects at UHR for psychosis are more sensitive to some negative effects of cannabis, in particular psychotic effects, compared to cannabis users from the general population. Although limited by the retrospective design in the recent-onset patients, the present study adds qualitative evidence to longitudinal studies that suggest that cannabis is a component cause in the onset of the first psychotic episode. Further studies are needed on the objective and subjective effects of cannabis in UHR subjects.

Background Subjects at ‘ultra high risk’ (UHR) for developing psychosis have differences in white matter (WM) compared with healthy controls. WM integrity has not yet been investigated in UHR subjects in relation to the development of subsequent psychosis. Hence, we investigated a prospective cohort of UHR subjects comparing whole brain fractional anisotropy (FA) of those later developing psychosis (UHR-P) to those who did not (UHR-NP). Method We recruited 37 subjects fulfilling UHR criteria and 10 healthy controls. Baseline 3 Tesla magnetic resonance imaging (MRI) scans and Positive and Negative Syndrome Scale (PANSS) ratings were obtained. UHR subjects were assessed at 9, 18 and 24 months for development of frank psychosis. We compared baseline FA of UHR-P to controls and UHR-NP subjects. Furthermore, we related clinical data to MRI outcome in the patient population. Results Of the 37 UHR subjects, 10 had transition to psychosis. UHR-P subjects showed significantly lower FA values than control subjects in medial frontal lobes bilaterally. UHR-P subjects had lower FA values than UHR-NP subjects, lateral to the right putamen and in the left superior temporal lobe. UHR-P subjects showed higher FA values, compared with UHR-NP, in the left medial temporal lobe. In UHR-P, positive PANSS negatively correlated to FA in the left middle temporal lobe. In the total UHR group positive PANSS negatively correlated to FA in the right superior temporal lobe. Conclusions UHR subjects who later develop psychosis have differences in WM integrity, compared with UHR subjects who do not develop psychosis and to healthy controls, in brain areas associated with schizophrenia.