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In the European Prediction of Psychosis Study (EPOS) a large sample of young patients at high risk of psychosis (HR) were examined and their conversion rate to psychosis during 18 months follow-up was estimated. This presentation describes quality of life (QoL) and its changes in patients at risk of psychosis who did or did not convert to psychosis.
In all, 245 young HR patients were recruited and followed for 9 and 18 months. Risk of psychosis was defined by occurrence of basic symptoms (BS), attenuated psychotic symptoms (ATP), brief, limited or intermittent psychotic symptoms (BLIPS) or familial risk plus reduced functioning (FR-RF). QoL was assessed at baseline and at 9 and 18 months’ follow-ups, and analysed in the HR-patients who converted (HR-P; n = 40) or did not converted to psychosis (HR-NP; n = 205).
There were no differences in the course of QoL between the HR-P and HR-NP patients. Of the inclusion criteria, only BS associated with poor QoL at baseline. Among HR-NP subjects, depressive symptoms associated with QoL at baseline and predicted poor QoL at 9 and 18 month follow-ups.
QoL of the HR-NP patients is as poor as that of the HR-P. From the QoL point of view, all HR patients require intensive treatment intervention from the first contact on. Especially, depressive disorders need to be treated vigorously.
Early detection and indicated early intervention in the initial prodromal phase should considerably improve the course of psychoses. Yet, the benefits of such programmes still require an evidence-based evaluation on the basis of a sufficient sample-size.
This report presents an overview on the concept and design of the European Prediction of Psychosis Study (EPOS) an European 4-country naturalistic field-study of the initial Prodrome.
Materials and Methods
Across six participating centres (Germany: Cologne, Berlin; Finland: Turku; The Netherlands: Amsterdam; United Kingdom: Birmingham, Manchester), 16 to 40 year old putatively prodromal persons attending specialized services or general psychiatric services underwent multi-level baseline, 9-months follow-up, and 18-months follow-up examinations. Inclusion criteria were the presence of APS, BLIPS, at least 2 of 9 Basic Symptoms (BS), and Familial Risk or Schizotypal Personality Disorder plus Reduced Functioning (FR+RF). In addition, psychopathological, neurocognitive, neurobiological, psychosocial, and service and treatment-related assessments were carried out.
A substantial part of more than 250 subjects included into the study participated in their respective baseline, 1st follow-up, and 2nd follow-up examinations. A high percentage presented themselves with BS and/or APS, a smaller percentage with BLIPS or FR+RF. The rates of transition into psychosis and the levels of psychopathology, distress and functional decline found among this patient group underline the need for indicated early recognition and intervention.
EPOS provides for the first time a sound data base allowing an evaluation of the applicability and cost-benefit ratio of early detection and intervention programmes in Europe.
The main aim of the European Prediction of Psychosis Study (EPOS) is to study a large sample of young patients who are at risk of psychosis and to estimate their conversion rate to psychosis during 18 months follow-up. The present presentation aims to describe premorbid adjustment in the patients at risk of psychosis.
In six European centres (Cologne, Berlin, Turku, Amsterdam, Birmingham, Manchester), 246 psychiatric patients at risk of psychosis were examined. Risk of psychosis was defined by occurrence of basic symptoms, attenuated psychotic symptoms, brief, limited or intermittent psychotic symptoms or familial risk plus reduced functioning during the past three months. Premorbid adjustment was measures by the Premorbid Adjustment Scale (PAS) and correlated with patient's baseline and outcome measures. Psychiatric patients without prodromal symptoms (not at risk) and healthy subjects, studied in one centre, acted as comparison groups.
PAS scores were poorer in the patients at risk of psychosis than in patients without prodromal symptoms or in healthy controls. In adolescence, differences in PAS scores were greater than in childhood or in adulthood. Within patients at risk of psychosis, men had poorer PAS scores than women. Childhood, adolescent and adulthood PAS scores associated extensively with patient's clinical and functional state at baseline examination. Adolescent and adulthood PAS scores correlated also with conversion to psychosis.
Disturbed premorbid psychosocial development, especially from adolescence on, may indicate vulnerability to and onset of psychosis.
To determine predictors of transition from ultrahigh risk into psychosis.
The Dutch EDIE trial has included 201 people with an ultrahigh risk for psychosis. These were included with both a referral based strategy and a screening all help-seeking people strategy. The study had a 24 month inclusion period and an 18 mont follow-up period with each patient. The preliminary results are presented.
A loogistic regression was performed over 164 cases. 29 patients developed a psychosis.
Predictor variables were depression, social intercation anxiety, positive symptoms on the CAARMS, negative symptoms on the CAARMS, quality of life, social functioning, genetic risk, and the personal beliefs about illness.
The backward logistice regression (likelyhood ratio) discarded four variables. Predictors of psychosis were depression, positive symptoms, genetic liability and beliefs about illness at basline.
People with hihd scores on depression and positive symptoms are likely to develop a psychosis. Also those who have a psychotic parent and positive symptoms a more lekly to make a transition. Interestingly people that consider their condition as hopeless, feel entrapped by their condition, excluded by other pople and not in control of symptoms also have a heightened chance for developing psychosis in this sample.
One aim of the European prediction of psychosis study (EPOS) has been to evaluate the clinical course of putatively prodromal patients in terms of psychopathology.
245 patients at risk for psychosis defined by attenuated positive symptoms, brief limited psychotic symptoms, a state/ trait combination or cognitive-perceptive basic symptoms was recruited in six centres in four countries. The Structured Interview for Prodromal Syndromes (SIPS) and the Bonn Scale for the Assessment of Basic Symptoms – Prediction List (BSABS-P) were employed. Follow-up was scheduled after 9 months (t1) and 18 months.
In total, 40 patients developed a psychosis (P). Compared to those without a transition (NP), P showed significantly higher SIPS scores at baseline. The same applied to the BSABS-P sub-scores 'cognitive perception disturbances' and 'cognitive motor disturbances'. The P sub-group developing psychosis after t1 showed no significant change of the SIPS positive (SIPS-P) sub-score or of any BSABS-P score from baseline to t1, whereas all scores improved in the NP group. At t1, SIPS-P and BSABS-P sub-score 'cognitive thought disturbances' were significantly lower in those later becoming psychotic.
Patients at risk showing a transition to psychosis during exhibited a pronounced psychopathology at baseline. Also, the positive symptom scores did not significantly improve during 1st follow-up, whereas those patients with no transition during the complete follow-up showed an improvement of all scores. As EPOS is a naturalistic study, different treatments have been performed in a considerable portion of the patients and association with course awaits further analysis.
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.
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.
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.
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.
A considerable number of patients at clinical high risk of psychosis (CHR) are found to meet criteria for co-morbid clinical psychiatric disorders.
It is not known how clinical diagnoses correspond to transitions to psychosis (TTP).
We aimed to examine distributions of life-time and current Axis I diagnoses, and their association with TTP in CHR patients.
In the European Prediction of Psychosis Study project, 245 young help-seeking CHR patients were examined, and their baseline and life-time diagnoses were assessed by the Structured Clinical Interview for DSM-IV (SCID-I). TTP was defined by continuation of BLIPS for more than seven days.
Altogether, 71 % of the CHR patients had one or more life-time and 62 % one or more current SCID-I diagnosis; about a half in each category received a diagnosis of life-time depressive and anxiety disorder. Currently, 34 % suffered from depressive, 39 % from anxiety disorder, 4 % from bipolar and 6.5 % from somatoform disorder. During follow-up, 37 (15.1 %) TTPs were identified. In multivariate Cox regression analyses, current bipolar disorder, somatoform and unipolar depressive disorders associated positively, and anxiety disorders negatively, with TTP.
Both life-time and current mood and anxiety disorders are highly prevalent among help-seeking CHR patients and need to be carefully evaluated. Among them, occurrence of bipolar, somatoform and depressive disorders seem to predict TTP, while anxiety disorder may predict non-transition to psychosis. Treatment of bipolar, somatoform and depressive disorders may prevent CHR patients from developing full-blown psychotic disorders.
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.
Depressive and anxiety disorders are the most common clinical diagnoses in patients at clinical high-risk (CHR) of psychosis (1).
Clinical disorders and functioning in CHR patients.
To study how depressive and anxiety disorders associate with patients’ functioning at baseline and follow-ups in CHR patients.
In the EPOS project, 245 young help-seeking CHR patients were examined, and their baseline diagnoses were assessed by the SCID-I. The patients were interviewed with the SIPS/SOPS, including assessments of positive and negative symptoms and the Global Assessment of Function (GAF), at baseline and at 9 and 18 months follow-ups.
At baseline and follow-ups, the patients without depressive or anxiety disorders had highest GAF scores. At baseline, the patients with depressive disorders had lower GAF scores than the patients with anxiety disorders. At follow-ups, there were no differences in GAF scores between the patients with depressive or anxiety disorders. In modelling, negative symptoms associated with low GAF scores at baseline and follow-ups, positive symptoms only at baseline and anxiety disorders at 18 months follow-up.
Depressive and anxiety disorders associate with poor functional outcome, and require thus special attention when intervention for the CHR patients is carried out. Positive symptoms predict transition to psychosis (2), but their role in predicting functional outcome is not as great. Instead, negative symptoms associate with poor functional outcome and require intensive intervention.
(1) Salokangas RKR et al. Schizophr Res 2012, doi:10.1016/j.schres.2012.03.008.
(2) Ruhrmann S et al. Arch Gen Psychiatry 2010;67:241-251.
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 premorbid adjustment.
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, disorganized, 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 analyzed.
During the 18-month follow-up, GAF scores improved significantly, and the proportion of patients with poor functioning decreased from 45% to 25%. 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.
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 executed.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
Participants 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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
Velo-cardio-facial syndrome (VCFS) is associated with deletions at chromosome 22q11, abnormalities in brain anatomy and function, and schizophrenia-like psychosis. Thus it is assumed that one or more genes within the deleted region are crucial to brain development. However, relatively little is known about how genetic variation at 22q11 affects brain structure and function. One gene on 22q11 is catechol-O-methyltransferase (COMT): an enzyme that degrades dopamine and contains a functional polymorphism (Val158Met) affecting enzyme activity. Here, we investigated the effect of COMT Val158Met polymorphism on brain anatomy and cognition in adults with VCFS.
The COMT Val158Met polymorphism was genotyped for 26 adults with VCFS on whom DNA was available. We explored its effects on regional brain volumes using hand tracing approaches; on regional grey- and white-matter density using computerized voxel-based analyses; and measures of attention, IQ, memory, executive and visuospatial function using a comprehensive neuropsychological test battery.
After corrections for multiple comparisons Val-hemizygous subjects, compared with Met-hemizygotes, had a significantly larger volume of frontal lobes. Also, Val-hemizygotes had significantly increased grey matter density in cerebellum, brainstem, and parahippocampal gyrus, and decreased white matter density in the cerebellum. No significant effects of COMT genotype on neurocognitive performance were found.
COMT genotype effects on brain anatomy in VCFS are not limited to frontal regions but also involve other structures previously implicated in VCFS. This suggests variation in COMT activity is implicated in brain development in VCFS.