Development of a stage-dependent prognostic model to predict psychosis in ultra-high-risk patients seeking treatment for co-morbid psychiatric disorders.

BACKGROUND: Current 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. METHOD: Baseline 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. RESULTS: At 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. CONCLUSIONS: Predicting 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.

Motivational interviewing and interaction skills training for parents of young adults with recent-onset schizophrenia and co-occurring cannabis use: 15-month follow-up.

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.

Cost-effectiveness of preventing first-episode psychosis in ultra-high-risk subjects: multi-centre randomized controlled trial.

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.

Short-term functional outcome and premorbid adjustment in clinical high-risk patients. Results of the EPOS project.

PURPOSE: In patients with schizophrenia, premorbid psychosocial adjustment is an important predictor of functional outcome. We studied functional outcome in young clinical high-risk (CHR) patients and how this was predicted by their childhood to adolescence premorbid adjustment. METHODS: In all, 245 young help-seeking CHR patients were assessed with the Premorbid Adjustment Scale, the Structured Interview for Prodromal Syndromes (SIPS) and the Schizophrenia Proneness Instrument (SPI-A). The SIPS assesses positive, negative, disorganised, general symptoms, and the Global Assessment of Functioning (GAF), the SPI-A self-experienced basic symptoms; they were carried out at baseline, at 9-month and 18-month follow-up. Transitions to psychosis were identified. In the hierarchical linear model, associations between premorbid adjustment, background data, symptoms, transitions to psychosis and GAF scores were analysed. RESULTS: During the 18-month follow-up, GAF scores improved significantly, and the proportion of patients with poor functioning decreased from 74% to 37%. Poor premorbid adjustment, single marital status, poor work status, and symptoms were associated with low baseline GAF scores. Low GAF scores were predicted by poor premorbid adjustment, negative, positive and basic symptoms, and poor baseline work status. The association between premorbid adjustment and follow-up GAF scores remained significant, even when baseline GAF and transition to psychosis were included in the model. CONCLUSION: A great majority of help-seeking CHR patients suffer from deficits in their functioning. In CHR patients, premorbid psychosocial adjustment, baseline positive, negative, basic symptoms and poor working/schooling situation predict poor short-term functional outcome. These aspects should be taken into account when acute intervention and long-term rehabilitation for improving outcome in CHR patients are carried out.

Prediction of psychosis in clinical high-risk patients by the Schizotypal Personality Questionnaire. Results of the EPOS project.

OBJECTIVE: Schizotypal features indicate proneness to psychosis in the general population. It is also possible that they increase transition to psychosis (TTP) among clinical high-risk patients (CHR). Our aim was to investigate whether schizotypal features predict TTP in CHR patients. METHODS: In the EPOS (European Prediction of Psychosis Study) project, 245 young help-seeking CHR patients were prospectively followed for 18 months and their TTP was identified. At baseline, subjects were assessed with the Schizotypal Personality Questionnaire (SPQ). Associations between SPQ items and its subscales with the TTP were analysed in Cox regression analysis. RESULTS: The SPQ subscales and items describing ideas of reference and lack of close interpersonal relationships were found to correlate significantly with TTP. The co-occurrence of these features doubled the risk of TTP. CONCLUSIONS: Presence of ideas of reference and lack of close interpersonal relations increase the risk of full-blown psychosis among CHR patients. This co-occurrence makes the risk of psychosis very high.

The Strauss and Carpenter Prognostic Scale in subjects clinically at high risk of psychosis.

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.

Physical illnesses, developmental risk factors and psychiatric diagnoses among subjects at risk of psychosis.

BACKGROUND: Subjects with psychoses have significantly increased rates of physical illnesses, but the nature of the relationship remains largely unknown. MATERIAL AND METHODS: The present study is part of the European Prediction of Psychosis Study (EPOS). Data were collected from 245 help-seeking individuals from six European centers (age 16-35) who met criteria for ultra-high risk of psychosis criteria. This paper seeks to investigate self-reported physical ill health and its associations with psychiatric symptoms and disorders, risk factors, and onset of psychosis during 48 months of follow-up. RESULTS: In multivariate analysis, lifetime panic disorder (OR=2.43, 95%CI: 1.03-5.73), known complications during pregnancy and delivery (OR=2.81, 95%CI: 1.10-7.15), female gender (OR=2.88, 95%CI: 1.16-7.17), family history of psychosis (OR=3.08, 95%CI: 1.18-8.07), and having a relationship (OR=3.44, 95%CI: 1.33-8.94) were significantly associated with self-reported physician-diagnosed illness. In the Cox proportional hazard model we found no significant differences between those who had undergone a transition to psychosis and those who had not. CONCLUSIONS: The physical health of patients defined to be at ultra-high risk of psychosis seems to be commonly impaired and associated with female gender, marital status, complications during pregnancy and birth, lifetime panic disorder, and genetic risk of psychosis.

Age at onset of non-affective psychosis in relation to cannabis use, other drug use and gender.

BACKGROUND: Cannabis use is associated with an earlier age at onset of psychotic illness. The aim of the present study was to examine whether this association is confounded by gender or other substance use in a large cohort of patients with a non-affective psychotic disorder. METHOD: In 785 patients with a non-affective psychotic disorder, regression analysis was used to investigate the independent effects of gender, cannabis use and other drug use on age at onset of first psychosis. RESULTS: Age at onset was 1.8 years earlier in cannabis users compared to non-users, controlling for gender and other possible confounders. Use of other drugs did not have an additional effect on age at onset when cannabis use was taken into account. In 63.5% of cannabis-using patients, age at most intense cannabis use preceded the age at onset of first psychosis. In males, the mean age at onset was 1.3 years lower than in females, controlling for cannabis use and other confounders. CONCLUSIONS: Cannabis use and gender are independently associated with an earlier onset of psychotic illness. Our findings also suggest that cannabis use may precipitate psychosis. More research is needed to clarify the neurobiological factors that make people vulnerable to this precipitating effect of cannabis.

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.

Interventions to improve adherence to antipsychotic medication in patients with schizophrenia--a review of the past decade.

OBJECTIVE: Nonadherence to antipsychotic medication is highly prevalent in patients with schizophrenia and has a deleterious impact on the course of the illness. This review seeks to determine the interventions that were examined in the past decade to improve adherence rates. METHOD: The literature between 2000 and 2009 was searched for randomized controlled trials which compared a psychosocial intervention with another intervention or with treatment as usual in patients with schizophrenia. RESULTS: Fifteen studies were identified, with a large heterogeneity in design, adherence measures and outcome variables. Interventions that offered more sessions during a longer period of time, and especially those with a continuous focus on adherence, seem most likely to be successful, as well as pragmatic interventions that focus on attention and memory problems. The positive effects of adapted forms of Motivational Interviewing found in earlier studies, such as compliance therapy, have not been confirmed. CONCLUSION: Nonadherence remains a challenging problem in schizophrenia. The heterogeneity of factors related to nonadherence calls for individually tailored approaches to promote adherence. More evidence is required to determine the effects of specific interventions.

Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis.

OBJECTIVE: Numerous studies have found a robust association between cannabis use and the onset of psychosis. Nevertheless, the relationship between cannabis use and the onset of early (or, in retrospect, prodromal) symptoms of psychosis remains unclear. The study focused on investigating the relationship between cannabis use and early and high-risk symptoms in subjects at clinical high risk for psychosis. METHOD: Prospective multicenter, naturalistic field study with an 18-month follow-up period in 245 help-seeking individuals clinically at high risk. The Composite International Diagnostic Interview was used to assess their cannabis use. Age at onset of high risk or certain early symptoms was assessed retrospectively with the Interview for the Retrospective Assessment of the Onset of Schizophrenia. RESULTS: Younger age at onset of cannabis use or a cannabis use disorder was significantly related to younger age at onset of six symptoms (0.33 < r(s) < 0.83, 0.004 < P < 0.001). Onset of cannabis use preceded symptoms in most participants. CONCLUSION: Our results provide support that cannabis use plays an important role in the development of psychosis in vulnerable individuals. Cannabis use in early adolescence should be discouraged.

Ethnicity and baseline symptomatology in patients with an At Risk Mental State for psychosis.

BACKGROUND: Ethnicity has been associated with different incidence rates and different symptom profiles in young patients with psychotic-like disorders. No studies so far have examined the effect of ethnicity on symptoms in people with an At Risk Mental State (ARMS). METHOD: In this cross-sectional study, we analysed the relationship between ethnicity and baseline data on the severity of psychopathology scores in 201 help-seeking patients who met the ARMS criteria and agreed to participate in the Dutch Early Detection and Intervention (EDIE-NL) trial. Eighty-seven of these patients had a non-Dutch ethnicity. We explored the possible mediating role of ethnic identity. RESULTS: Higher rates of negative symptoms, and of anhedonia in particular, were found in the ethnic minority group. This result could be attributed mainly to the Moroccan-Dutch and Turkish-Dutch subgroups, who also presented with more depression symptoms when the groups were examined separately. The ethnic minority group displayed a lower level of ethnic group identity compared to the immigrants of the International Comparative Study of Ethnocultural Youth (ICSEY). Ethnic identity was inversely related to symptoms in the Moroccan-Dutch patient group. CONCLUSIONS: The prevalence of more severe negative symptoms and depression symptoms in ethnic minority groups deserves more attention, as the experience of attenuated positive symptoms when accompanied by negative symptoms or distress has proven to be predictive for transition to a first psychotic episode.

Perceived negative attitude of others predicts transition to psychosis in patients at risk of psychosis.

AIM: Our previous study (Salokangas et al., 2009) suggested that the subjective experience of negative attitude of others (NAO) towards oneself is an early indicator of psychotic development. The aim of this prospective follow-up study was to test this hypothesis. METHODS: A total of 55 young psychiatric outpatients assessed as being at current risk of psychosis (CROP) were followed for up to 60 months and rates of transition to psychosis (TTP) identified. CROP was assessed employing the Bonn Scale for assessment of basic symptoms (Schultze-Lutter and Klosterkötter, 2002) and the Structured Interview for prodromal symptoms (Miller et al., 2002). TTP was defined by a psychotic episode lasting for more than one week. Associations between NAO at baseline and TTP were analyzed by a Cox regression survival analysis. RESULTS: Eight (14.5%) TTP were identified: four (57.1%) within seven NAO patients and four (8.7%) within forty-six non-NAO patients. In the multivariate Cox regression analysis, NAO at baseline significantly (P=0.007) predicted TTP. CONCLUSION: The prospective follow-up results support our hypothesis that subjective experience of NAO is an early indicator of psychotic in development.

Motivational interviewing and interaction skills training for parents to change cannabis use in young adults with recent-onset schizophrenia: a randomized controlled trial.

BACKGROUND: Cannabis use by people with schizophrenia has been found to be associated with family distress and poor clinical outcomes. Interventions to reduce drug use in this patient group have had limited efficacy. This study evaluated the effectiveness of a novel intervention for parents of young adults with recent-onset schizophrenia consisting of family-based motivational interviewing and interaction skills (Family Motivational Intervention, FMI) in comparison with routine family support (RFS). METHOD: In a trial with 75 patients who used cannabis and received treatment for recent-onset schizophrenia, 97 parents were randomly assigned to either FMI (n=53) or RFS (n=44). Assessments were conducted at baseline and 3 months after completion of the family intervention by an investigator who remained blind throughout the study about the assignment of the parents. RESULTS: At follow-up, patients' frequency and quantity of cannabis use was significantly more reduced in FMI than in RFS (p<0.05 and p<0.04 respectively). Patients' craving for cannabis was also significantly reduced in FMI whereas there was a small increase in RFS (p=0.01). There was no difference between FMI and RFS with regard to patients' other substance use and general level of functioning. Both groups showed significant improvements in parental distress and sense of burden. CONCLUSIONS: Training parents in motivational interviewing and interaction skills is feasible and effective in reducing cannabis use among young adults with recent-onset schizophrenia. However, FMI was not more effective than RFS in increasing patients' general level of functioning and in reducing parents' stress and sense of burden.

Three-year course of clinical symptomatology in young people at ultra high risk for transition to psychosis.

OBJECTIVE: The investigation into the course of ultra high risk (UHR) symptomatology of those patients who eventually do not meet the psychosis-threshold criteria within the 3-year timeframe of the study. METHOD: The course of UHR symptoms, GAF score and employment status was investigated in 57 patients who did not make a transition to psychosis and who were examined within the Dutch Prediction of Psychosis Study in Amsterdam, the Netherlands. RESULTS: At the 3-year follow-up, 75% of the patients who did not make a transition to psychosis had remitted from UHR status. With a Generalized Estimation Equation Model it was shown that this group recovered from positive (F = 52.7, P < 0.0001), negative (F = 24.3, P < 0.0001), disorganization (F = 14.4, P < 0.0001) and general symptoms (F = 25.0, P < 0.0001) within the timeframe of the study. In addition, the level of global functioning and likelihood of having a job and/or education significantly improved. The largest improvements occurred within the first year. UHR symptoms did not re-occur after improvement. CONCLUSION: With the current UHR criteria, a large percentage of the included subjects appear to have transitory complaints and dysfunctioning. A refinement of the UHR criteria may diminish the chance of including 'false positives' in future UHR studies.

Increased saccadic rate during smooth pursuit eye movements in patients at Ultra High Risk for developing a psychosis.

Abnormalities in eye tracking are consistently observed in schizophrenia patients and their relatives and have been proposed as an endophenotype of the disease. The aim of this study was to investigate the performance of patients at Ultra High Risk (UHR) for developing psychosis on a task of smooth pursuit eye movement (SPEM). Forty-six UHR patients and twenty-eight age and education matched controls were assessed with a task of SPEM and psychiatric questionnaires. Our results showed that both the corrective and non-corrective saccadic rates during pursuit were higher in the UHR group. There were however no differences in smooth pursuit gain between the two groups. The saccadic rate was related to positive UHR symptoms. Our findings indicate that abnormalities in SPEM are already present in UHR patients, prior to a first psychotic episode. These abnormalities occur only in the saccadic system.

[Women, schizophrenia and oestrogen; neurobiological hypotheses and hormonetherapy studies]. / Vrouwen, schizofrenie en oestrogeen; neurobiologische hypothesen en interventiestudies.

BACKGROUND: Gender differences play a role in the origin and course of schizophrenia. It has been hypothesised that the gonadal hormone, oestrogen, may possibly perform a protective function in the development of certain forms of schizophrenia. AIM: To review neurobiological hypotheses concerning the role of oestrogen in the development and course of schizophrenia. METHOD: The relevant literature was consulted with the help of PubMed, textbooks and bibliographic references; the search terms used were 'oestrogen', 'schizophrenia', 'gender', 'epigenetics', 'psychosis', 'women' and 'brain'. There were no restrictions with regards to the time-period. RESULTS: Neuro-imaging, animal experiments and hormone-therapy studies showed several effects of oestrogen in the field of epigenetics, morphology of the brain, interaction with neurotransmitters and neuroprotection. CONCLUSION: Oestrogen is an important link in a complex of factors that clearly play a role in the varying development of schizophrenia in men and women. So far, however, there is insufficient evidence to support the existence of a specific mechanism that would explain why oestrogen may perform a protective function in schizophrenia.

Neurocognitive functioning before and after the first psychotic episode: does psychosis result in cognitive deterioration?

BACKGROUND: Cognitive impairment is considered to be a core characteristic of schizophrenia. The relationship between psychosis and cognitive deterioration, however, remains unclear. This longitudinal study investigated the neuropsychological functioning of patients before and after their first psychotic episode. Cognitive functioning of participants who later developed a psychosis was compared to that of people at ultra-high risk (UHR) for psychosis who did not develop psychosis at follow-up and healthy controls.MethodParticipants were 41 persons at UHR for psychosis (the UHR group), of whom 17 developed psychosis between the first and second assessment. Seventeen healthy controls were included in the study. Cognitive performance was assessed at intake (T0) and again after 18 months (T1). The areas of cognitive functioning assessed include verbal memory and learning, visuospatial working memory, executive function, sustained attention and motor speed. RESULTS: The transition group did not perform significantly worse at the second assessment than at the first on any of the outcome measures. The UHR group performed better on a verbal learning and memory test at T1 compared to T0. At T0, the control group scored significantly better than the UHR group and the transition group on the verbal learning and memory test and the verbal fluency test. CONCLUSIONS: The results indicate that no cognitive deterioration occurs during the first psychotic episode. Problems in verbal memory may be present before the first episode of psychosis.

Implicit and explicit affective associations towards cannabis use in patients with recent-onset schizophrenia and healthy controls.

BACKGROUND: Cannabis use is common in patients with recent-onset schizophrenia and this is associated with poor disease outcome. More insight in the cognitive-motivational processes related to cannabis use in schizophrenia may inform treatment strategies. The present study is the first known to compare implicit and explicit cannabis associations in individuals with and without psychotic disorder. METHOD: Participants consisted of 70 patients with recent-onset psychotic disorder and 61 healthy controls with various levels of cannabis use. Three Single-Category Implicit Association Tests (SC-IAT) were used to assess 'relaxed', 'active' and 'negative' implicit associations towards cannabis use. Explicit expectancies of cannabis use were assessed with a questionnaire using the same words as the SC-IAT. RESULTS: There were no differences in implicit associations between patients and controls; however, patients scored significantly higher on explicit negative affect expectancies than controls. Both groups demonstrated strong negative implicit associations towards cannabis use. Explicit relaxed expectancies were the strongest predictors of cannabis use and craving. There was a trend for implicit active associations to predict craving. CONCLUSIONS: The findings indicate that patients suffering from schizophrenia have associations towards cannabis similar to controls, but they have stronger negative explicit cannabis associations. The strong negative implicit associations towards cannabis could imply that users of cannabis engage in a behaviour they do not implicitly like. Explicit relaxing expectancies of cannabis might be an important mediator in the continuation of cannabis use in patients and controls.