Abstract Background The long-term outcome of first-episode schizophrenia needs improvement. Here, we evaluate the effectiveness of 5 years sustained specialist treatment (ST), ST including Parent groups (ST + P) or treatment as usual (TAU) on psychotic relapse and social functioning. Methods A three condition randomized, parallel assigned, single-blind efficacy trial, in which 198 first-episode psychosis (FEP) patients aged 15–28 years were included. The effect on time to first relapse, first relapse rates, mean number of relapses per patient, and time to the improvement of social functioning were analyzed using Cox regression or ANOVA. Results We found no significant differences between treatment conditions in the ITT analysis concerning time to first relapse, nor first relapse rate. Mean number of relapses per patient differed at a trend level between ST, ST + P or TAU conditions, respectively: 0.72; 0.62 or 1.02 (p = 0.069). No evidence was found for differential effect of treatment conditions on social functioning. Conclusion Five years sustained ST of FEP nor addition of parent groups increased time to first relapse or reduced first relapse rate, compared to sustained TAU. Indications for favorable effects of parent groups were found on relapses per patient.

AIM:Depression and suicidal ideation (SUI) and behaviour are more prevalent in females than males, and common in clinical high-risk (CHR) patients. Childhood adversities and trauma (CAT) are associated with adult depression and SUI. The role of gender as a moderator and depression as a mediator for the effect of CAT on SUI has not been explored in CHR patients.METHODS:In all, 245 young help-seeking CHR patients were assessed for SUI (thoughts of killing themselves) with the Beck Depression Inventory at baseline, 9-month and 18-month follow-ups. At baseline, clinical depression was assessed by the Structured Clinical Interview for DSM-IV (SCID-I), and CAT by the Trauma and Distress Scale (TADS) which includes the five domains of emotional, physical and sexual abuse, emotional and physical neglect.RESULTS:CAT total and all domains except physical neglect predicted SUI over the study period. The effect of CAT on SUI was mediated via clinical depression and concurrent depression symptoms differently for females and males. In females, the effect of emotional abuse and neglect on SUI was mediated via baseline depression. In males, emotional and physical abuse had a direct effect on SUI, and the effect of sexual abuse and emotional neglect was partly mediated via concurrent depression symptoms.CONCLUSIONS:For CHR females, the effect of CAT on adult SUI is mediated via depression, while for males, CAT and its domains have mainly direct effects in maintaining SUI. These gender differences should be taken into account when treating CHR patients with SUI.

OBJECTIVE:To investigate the impact of expressed emotion (EE) on the risk of developing the first psychotic episode (FEP).METHOD:The European Prediction of Psychosis Study (EPOS) investigated 245 patients who were at clinical high risk (CHR) of psychosis. The predictive value of EE alone and as a part of the multivariate EPOS model was evaluated.RESULTS:"Perceived irritability", a domain of the Level of Expressed Emotion Scale (LEE), was found to be predictive for the First Psychotic Episode (FEP), even as an individual variable. Furthermore, it was selected in the multivariate EPOS prediction model, thereby replacing two of the original predictor variables. This led to an improved revised version that enabled the identification of three significantly different risk classes with a hazard rate of up to 0.911.CONCLUSIONS:CHR subjects who perceive the most important person in their individual social environment to be limited in their stress coping skills had a higher risk of conversion to the first psychotic episode. The importance of this risk factor was further demonstrated by an improvement of risk estimation in the original EPOS predictor model. Perceiving a reference person as stress-prone and thus potentially unreliable might amplify self-experienced uncertainty and anxiety, which are often associated with the prodromal phase. Such an enforcement of stress-related processes could promote a conversion to psychosis.

Background: High levels of expressed emotion (EE) increase the risk for relapse in manifest psychosis. Yet, the value of EE for predicting a first psychotic episode has not previously been investigated. Methods: The European Prediction of Psychosis Study (EPOS) investigated the course of patients clinically at high risk for psychosis (CHR) during 18 months. Perceived EE was assessed in 235 patients by the Level of Expressed Emotion Scale (LEE), a 38-item self-rating instrument including four subscales (“perceived lack of emotional support,” “perceived intrusiveness,” “perceived irritability,” and “perceived criticism”). Predictive value of EE alone as well as its impact on the EPOS prediction model (Ruhrmann et al., JAMA Psychiatry 2010) was investigated. Results: The score of the LEE subscale ‘Perceived irritability’, characterizing the perceived stress management of the most influential person in a CHR subject’s social environment, was found to be predictive for a transition to psychosis within 18 months postbaseline. Furthermore, this variable was selected into a bootstrap tested prediction model when entering it together with the 6 variables of the original model (stepwise Cox regression); 2 of the original variables were removed. The resulting prognostic score was stratified into 3 significantly different risk classes with hazard rates from .032 to .911. Conclusion: To the authors’ awareness, this study demonstrated for the first time that EE is predictive for a transition to psychosis in individuals at CHR with ‘perceived irritability’ proving to be the most relevant sub-scale for this phase of the illness. This may indicate that the experience of inconsistent social support from a significant other may influence a further destabilization of CHR subjects. As such an experience will presumably increase the level of stress experienced by a CHR subject, stress induction rather than actual communication style may be a crucial factor for increased risk of transition.

Background:This study aims to evaluate the long-term cost-effectiveness of add-on cognitive behavior therapy (CBT) for the prevention of psychosis for individuals at ultrahigh risk (UHR) of psychosis.Method:The Dutch Early Detection and Intervention randomized controlled trial was used, comparing routine care (RC; n = 101) with routine care plus CBT for UHR (here called CBTuhr; n = 95). A cost-effectiveness analysis was conducted with treatment response (defined as proportion of averted transitions to psychosis) as an outcome and a cost-utility analysis with quality-adjusted life years (QALYs) gained as a secondary outcome.Results:The proportion of averted transitions to psychosis was significantly higher in the CBTuhr condition (with a risk difference of 0.122; b = 1.324, SEb = 0.017, z = 7.99, P < 0.001). CBTuhr showed an 83% probability of being more effective and less costly than RC by -US$ 5777 (savings) per participant. In addition, over the 4-year follow-up period, cumulative QALY health gains were marginally (but not significantly) higher in CBTuhr than for RC (2.63 vs. 2.46) and the CBTuhr intervention had a 75% probability of being the superior treatment (more QALY gains at lower costs) and a 92% probability of being cost-effective compared with RC at the Dutch threshold value (US$ 24 560; €20 000 per QALY).Conclusions:Add-on preventive CBTuhr had a high likelihood (83%) of resulting in more averted transitions to psychosis and lower costs as compared with RC. In addition, the intervention had a high likelihood (75%) of resulting in more QALY gains and lower costs as compared to RC.

Childhood adversity is associated with a range of mental disorders, functional impairment and higher health care costs in adulthood. In this study we evaluated if childhood adversity was predictive of adverse clinical and functional outcomes and health care costs in a sample of patients at ultra-high risk (UHR) for developing a psychosis. Structural Equation Modeling was used to examine the effect of childhood adversity on depression, anxiety, transition to psychosis and overall functioning at 4-year follow-up. In addition, we evaluated economic costs of childhood adversity in terms of health care use and productivity loss. Data pertain to 105 UHR participants of the Dutch Early Detection and Intervention Evaluation (EDIE-NL). Physical abuse was associated with higher depression rates (b=0.381, p=0.012) and lower social functional outcome (b=-0.219, p=0.017) at 4-year follow-up. In addition, emotional neglect was negatively associated with social functioning (b=-0.313, p=0.018). We did not find evidence that childhood adversity was associated with transition to psychosis, but the experience of childhood adversity was associated with excess health care costs at follow-up. The data indicate long-term negative effects of childhood adversity on depression, social functioning and health care costs at follow-up in a sample of UHR patients.

Aims: The first aim was to determine the cost-effectiveness of CBTuhr to prevent first-episode psychosis in ultra-high risk (UHR) at 18 and 48 months. The second aim was to develop an optimized prediction model of a first-episode psychosis. Methods: 196 help-seeking UHR patients participated in the Early Detection Intervention (EDIE) study in the Netherlands. All individuals were treated with routine care (RC) for non-psychotic disorders. The experimental group received add-on CBTuhr to prevent psychosis. Results: The CBTuhr intervention was cost saving at 18 and 48 months follow-up. This was achieved by less hospital admissions and a reduction in other service costs. Societal costs were reduced because more treated patients were employed. Prognostic modelling identified 3 UHR risk classes with 4%, 13% and 70% risk for transition within 18 months. In the highest risk class, transition to psychosis emerged on average ≥ 8 months earlier than in the lowest risk class. Conclusions: Using prognostic modelling and proactive care can accomplish health gain at lower costs.

The link between depression and paranoia has long been discussed in psychiatric literature. Because the causality of this association is difficult to study in patients with full-blown psychosis, we aimed to investigate how clinical depression relates to the presence and occurrence of paranoid symptoms in clinical high-risk (CHR) patients.

BackgroundCurrent ultra-high-risk (UHR) criteria appear insufficient to predict imminent onset of first-episode psychosis, as a meta-analysis showed that about 20% of patients have a psychotic outcome after 2 years. Therefore, we aimed to develop a stage-dependent predictive model in UHR individuals who were seeking help for co-morbid disorders.MethodBaseline data on symptomatology, and environmental and psychological factors of 185 UHR patients (aged 14–35 years) participating in the Dutch Early Detection and Intervention Evaluation study were analysed with Cox proportional hazard analyses.ResultsAt 18 months, the overall transition rate was 17.3%. The final predictor model included five variables: observed blunted affect [hazard ratio (HR) 3.39, 95% confidence interval (CI) 1.56–7.35, p < 0.001], subjective complaints of impaired motor function (HR 5.88, 95% CI 1.21–6.10, p = 0.02), beliefs about social marginalization (HR 2.76, 95% CI 1.14–6.72, p = 0.03), decline in social functioning (HR 1.10, 95% CI 1.01–1.17, p = 0.03), and distress associated with suspiciousness (HR 1.02, 95% CI 1.00–1.03, p = 0.01). The positive predictive value of the model was 80.0%. The resulting prognostic index stratified the general risk into three risk classes with significantly different survival curves. In the highest risk class, transition to psychosis emerged on average ⩾8 months earlier than in the lowest risk class.ConclusionsPredicting a first-episode psychosis in help-seeking UHR patients was improved using a stage-dependent prognostic model including negative psychotic symptoms (observed flattened affect, subjective impaired motor functioning), impaired social functioning and distress associated with suspiciousness. Treatment intensity may be stratified and personalized using the risk stratification.

Computerized adaptive tests (CATs) for positive and negative psychotic experiences were developed and tested in N = 5705 help-seeking, non-psychotic young individuals. Instead of presenting all items, CATs choose a varying number of different items during test administration depending on respondents' previous answers, reducing the average number of items while still obtaining accurate person estimates. We assessed the appropriateness of two-parameter logistic models to positive and negative symptoms of the Prodromal Questionnaire (PQ), computed measurement precision of all items and resulting adaptive tests along psychotic dimensions by Real Data Simulations (RDS), and computed indices for criterion and predictive validities of the CATs. For all items, mean absolute differences between observed and expected response probabilities were smaller than 0.02. CAT-POS predicted transition to psychosis and duration of hospitalization in individuals at-risk for psychosis, and CAT-NEG was suggestively related to later functioning. Regarding psychosis risk classifications of help-seeking individuals, CAT-POS performed less than the PQ-16. Adaptive testing based on self-reported positive and negative symptoms in individuals at-risk for psychosis is a feasible method to select patients for further risk classification. These promising findings need to be replicated prospectively in a non-selective sample that also includes non-at-risk individuals. Copyright © 2016 John Wiley & Sons, Ltd.

Background: Epidemiological and retrospective studies suggest a cannabis x catechol-O-methyltransferase (COMT) Val(158)Met interaction effect on development of psychosis. The aim of this study was to examine this interaction and its association with severity of subclinical symptoms in people with an At Risk Mental State (ARMS) for psychosis.Methods: Severity of symptoms, cannabis use and genotype were assessed at baseline in 147 help-seeking young adults who met the ARMS criteria and agreed to participate in the Dutch Early Detection and Intervention (EDIE-NL) trial.Results: Cannabis use and COMT Val-allele showed an interaction effect in ARMS subjects. Subjects who were weekly cannabis users at some point prior to entering the study showed more severe positive symptoms. This effect increased if they were carriers of the COMT Val-allele and even more so if they were homozygous for the Val-allele.Conclusions: Our results suggest that the COMT Val(158)Met polymorphism moderates the effect of regular cannabis use on severity of subclinical psychotic symptoms. (C) 2016 Elsevier B.V. All rights reserved.

BACKGROUNDPreviously, we demonstrated that cognitive behavior therapy for ultra-high risk (called CBTuhr) halved the incidence of psychosis over an 18-month period. Follow-up data from the same study are used to evaluate the longer-term effects at 4 years post-baseline.METHODThe Dutch Early Detection and Intervention Evaluation study was a randomized controlled trial of 196 UHR patients comparing CBTuhr with treatment-as-usual (TAU) for comorbid disorders with TAU only. Of the original 196 patients, 113 consented to a 4-year follow-up (57.7%; CBTuhr = 56 vs TAU = 57). Over the study period, psychosis incidence, remission from UHR status, and the effects of transition to psychosis were evaluated.RESULTSThe number of participants in the CBTuhr group making the transition to psychosis increased from 10 at 18-month follow-up to 12 at 4-year follow-up whereas it did not change in the TAU group (n = 22); this still represents a clinically important (incidence rate ratio [IRR] = 12/22 = 0.55) and significant effect (F(1,5) = 8.09, P = .03), favoring CBTuhr. The odds ratio of CBTuhr compared to TAU was 0.44 (95% CI: 0.24-0.82) and the number needed to treat was 8. Moreover, significantly more patients remitted from their UHR status in the CBTuhr group (76.3%) compared with the TAU group (58.7%) [t(120) = 2.08, P = .04]. Importantly, transition to psychosis was associated with more severe psychopathology and social functioning at 4-year follow-up.CONCLUSIONSCBTuhr to prevent a first episode of psychosis in persons at UHR of developing psychosis is still effective at 4-year follow-up. Our data also show that individuals meeting the formal criteria of a psychotic disorder have worse functional and social outcomes compared with non-transitioned cases.TRIAL REGISTRATIONThe trial is registered at Current Controlled Trials as trial number ISRCTN21353122 (http://controlled-trials.com/ISRCTN21353122/gaag).

Background There is a clear need for effective interventions to reduce cannabis use in patients with first-episode psychosis. This follow-up of a randomized trial examined whether an intervention for parents, based on motivational interviewing and interaction skills (Family Motivational Intervention, FMI), was more effective than routine family support (RFS) in reducing cannabis use in patients with recent-onset schizophrenia. Method In a single-blind trial with 75 patients in treatment for recent-onset schizophrenia, 97 parents were randomly assigned to either FMI or RFS. Assessments were conducted at baseline and at 3 and 15 months after the interventions had been ended. Analyses were performed on an intention-to-treat basis using mixed-effect regression models. Results From baseline to the 15-month follow-up, there was a significantly greater reduction in FMI compared to RFS in patients’ quantity (p = 0.01) and frequency (p < 0.01) of cannabis use. Patients’ craving for cannabis use was also significantly lower in FMI at 15 months follow-up (p < 0.01). Both groups improved in parental distress and sense of burden; however, only FMI parents’ appraisal of patients’ symptoms showed further improvement at the 15-month follow-up (p < 0.05). Conclusions The results support the sustained effectiveness of FMI in reducing cannabis use in patients with recent-onset schizophrenia at 15 months follow-up. Findings were not consistent with regard to the long-term superiority of FMI over RFS in reducing parents’ distress and sense of burden.

The link between depression and paranoia has long been discussed in the psychiatric literature. Because this association is difficult to study in patients with full-blown psychosis, we investigated clinical high-risk (CHR) patients. To clarify the causal connection between depression and paranoia. To investigate how clinical depression relates to presence and new occurrence of paranoid symptoms in CHR patients. Altogether, 245 young help-seeking CHR patients were assessed for suspiciousness/paranoid symptoms with the Structured Interview for Prodromal Syndromes at baseline, 9-month and 18-month follow-up. At baseline, clinical diagnoses were assessed by the Structured Clinical Interview for DSM-IV, childhood stressful experiences by the Trauma and Distress Scale, trait of suspiciousness by the Schizotypal Personality Questionnaire, and anxiety and depressive symptoms by the Positive and Negative Syndrome Scale. At baseline, 54.3 % of CHR patients reported at least moderate paranoid symptoms. At 9- and 18-month follow-ups, the corresponding figures were 28.3 % and 24.4 %. Depressive disorder, sexual abuse and anxiety symptoms associated with paranoid symptoms. Depressive, obsessive-compulsive and somatoform disorders, sexual abuse, and anxiety predicted occurrence of paranoid symptoms. Depressive disorder is one of the major clinical factors associating with and predicting paranoid symptoms in CHR patients; also childhood sexual abuse and anxiety symptoms associate with paranoia. In addition, obsessive-compulsive and somatoform disorders seem to predict paranoid symptoms. Low self-esteem may be a common mediator between affective disorders and paranoia. Effective treatment of these disorders may alleviate paranoid symptoms and improve interpersonal functioning in CHR patients.

Background Although there is evidence for the effectiveness of interventions for psychosis among ultra-high-risk (UHR) groups, health economic evaluations are lacking. This study aimed to determine the cost effectiveness and cost–utility of cognitive–behavioural therapy (CBT) to prevent first-episode psychosis. Method The Dutch Early Detection and Intervention Evaluation study was a randomized controlled trial of 196 UHR patients with an 18-month follow-up. All participants were treated with routine care (RC) for non-psychotic disorders. The experimental group ( n = 95) received add-on CBT to prevent first-episode psychosis. We report the intervention, medical and travel costs, as well as costs arising from loss of productivity. Treatment response was defined as psychosis-free survival and quality-adjusted life years (QALYs) gained. Results In the cost-effectiveness analysis, the proportion of averted psychoses was significantly higher in the CBT condition (89.5% v. 76.2%). CBT showed a 63.7% probability of being more cost effective, because it was less costly than RC by US$844 (£551) per prevented psychosis. In the cost–utility analysis, QALY health gains were slightly higher for CBT than for RC (0.60 v. 0.57) and the CBT intervention had a 52.3% probability of being the superior treatment because, for equal or better QALY gains, the costs of CBT were lower than those of RC. Conclusions Add-on preventive CBT for UHR resulted in a significant reduction in the incidence of first psychosis. QALY gains show little difference between the two conditions. The CBT intervention proved to be cost saving.