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.

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.

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.

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.

The relation between dimensions of normal and pathological personality and childhood maltreatment in incarcerated boys.

The relation between subtypes of maltreatment and dimensions of personality and personality pathology was investigated in a representative sample of 142 incarcerated Dutch male juveniles. Normal personality dimensions were assessed with the Big Five Inventory, the Dimensional Assessment of Personality Pathology-Basic Questionnaire for Adolescents was used to measure pathological personality dimensions, and the Childhood Trauma Questionnaire was used to assess childhood maltreatment. The five maltreatment subtypes were found to be differentially and uniquely related to the normal and pathological personality dimensions in juvenile delinquents. The association between the abusive subtypes and Emotional Dysregulation depended on the co-occurrence of neglect. It was concluded that subtypes of maltreatment are distinctively related to dimensions of personality and personality pathology, possibly due to specific gene-environment interactions. Further research on this interplay is needed to be able to recognize genetic vulnerability. Early identification of children at risk could aid to limit the long-term consequences of maltreatment.

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.

Verbal fluency as a possible predictor for psychosis.

BACKGROUND: Neurocognitive abnormalities are prevalent in both first episode schizophrenia patients and in ultra high risk (UHR) patients. AIM: To compare verbal fluency performance at baseline in UHR in patients that did and did not make the transition to psychosis. METHOD: Baseline verbal fluency performance in UHR-patients (n=47) was compared to match first episode patients (n=69) and normal controls (n=42). RESULTS: Verbal fluency (semantic category) scores in UHR-patients did not differ significantly from the score in first episode schizophrenia patients. Both the UHR group (p<0.003) and the patient group (p<0.0001) performed significantly worse than controls. Compared to the non-transition group, the transition group performed worse on verbal fluency, semantic category (p<0.006) at baseline. CONCLUSIONS: Verbal fluency (semantic category) is disturbed in UHR-patients that make the transition to psychosis and could contribute to an improved prediction of transition to psychosis in UHR-patients.

White-matter markers for psychosis in a prospective ultra-high-risk cohort.

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.

P300 deficits are present in young first-episode patients with schizophrenia and not in their healthy young siblings.

OBJECTIVE: To evaluated P300 (P3b) abnormalities in young first episode patients with schizophrenia and their healthy young siblings. METHODS: An auditory oddball paradigm was used to assess P300 in 53 patients, 27 unaffected siblings and 28 healthy controls. Amplitude and latency of the three midline sites (Fz, Cz, and Pz) were compared between patients, siblings, and controls by a mixed-effects regression model. RESULTS: P300 amplitude was significantly reduced in patients with schizophrenia but not in healthy siblings, when compared to healthy controls. P300 latency did not significantly differ between the three groups. CONCLUSIONS: P300 amplitude but not latency was found to be affected in young patients with recent onset schizophrenia. However, P300 amplitude and latency were found not to be affected in healthy unaffected young siblings and, therefore, did not qualify as an endophenotype for schizophrenia. SIGNIFICANCE: The failure to find the P300 (P3b) abnormality in healthy siblings of patients with schizophrenia is an important finding and should be added to P300 literature.

Improvement of subjective well-being and enduring symptomatic remission, a 5-year follow-up of first episode schizophrenia.

INTRODUCTION: The aim of this prospective study was to compare the predictive validity of early improvement of subjective experience and early improvement of rater assessed symptoms on enduring symptomatic remission (ESR) status during 5 years follow. METHODS: 110 consecutively admitted patients suffering from a first episode of schizophrenia or related disorders were investigated. We defined early improvement of subjective well-being as a delta-score of the total Subjective Well-being under Neuroleptics scale-20 item version (SWN-K) at admission and after 6 weeks treatment. The severity of psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) at admission, 6 weeks, 6 months, 3 and 5 years after admission. Enduring symptomatic remission (ESR) was defined as complying to the symptomatic remission criteria at PANSS assessment at 6 months and 5 years and continuing this state between 6 months and 5 years follow-up. Paired-samples and independent t-test were used to compare means. RESULTS: Patients with ESR (n=30) had a higher mean improvement of subjective well-being during early treatment as assessed with the SWN-K than those without ESR (n=74) (p=0.004). Early symptomatic improvement as assessed with the PANSS was not related to ESR (p=0.95). DISCUSSION: Early improvement of subjective well-being is related to ESR in first episode schizophrenia or related disorders.

Antisaccade deficit is present in young first-episode patients with schizophrenia but not in their healthy young siblings.

BACKGROUND: Results of studies on antisaccade (AS) deficit in relatives of patients with schizophrenia are inconclusive. We hypothesized that AS performance in siblings of patients with schizophrenia is worse than in healthy controls and better than in patients with schizophrenia. METHOD: We included 55 first-episode patients with schizophrenia, 28 healthy siblings and 36 healthy controls to evaluate AS performance. Eye movements were measured electromagnetically by the double magnetic induction (DMI) method. RESULTS: Patients with schizophrenia had a significantly higher error rate than siblings (d=0.86, p<0.0001) and controls (d=1.35, p<0.0001). Siblings had a higher mean error rate than healthy controls but this did not reach significance (d=0.56, p=0.29). The intra-class correlation (ICC) was 0.33 for the error rate. Mean AS gain was higher in siblings than in patients (d=0.75, p=0.004) and controls (d=0.6, p=0.05). The ICC was 0.08. CONCLUSION: As parameters in strictly screened healthy young siblings of young first-episode patients with schizophrenia are comparable to results found in studies investigating older relatives. However, the statistical results (i.e. the ICCs) suggest that there is little evidence of shared environmental or genetic factors on error rate variation.

Pathways to psychosis: a comparison of the pervasive developmental disorder subtype Multiple Complex Developmental Disorder and the "At Risk Mental State".

BACKGROUND: The comparison of high-risk populations with different developmental pathways to psychosis may lend more insight into the heterogeneity of the manifestation of the psychotic syndrome, and possible differing etiological pathways. AIM: To compare high-risk traits and symptoms in two populations at risk for psychosis, i.e. (1) help-seeking adolescents presenting with prodromal symptoms meeting the criteria for At Risk Mental State (ARMS), and (2) adolescents with Multiple Complex Developmental Disorder (MCDD), a PDD-NOS subtype characterized by severe, early childhood-onset deficits in affect regulation, anxieties, disturbed social relationships, and thought disorder. METHOD: 80 ARMS- and 32 MCDD-adolescents (12-18 years) were compared on prodromal symptoms (Structured Interview of Prodromal Symptoms, and Bonn Scale for the Assessment of Basic Symptoms-Prediction list), and autism traits (Social Communication Questionnaire). In addition, both high-risk groups were compared with 82 healthy controls on schizotypal traits (Schizotypal Personality Questionnaire-Revised). RESULTS: Although the high-risk groups clearly differed in early developmental and treatment histories as well as autism traits, they did not differ with regard to schizotypal traits and basic symptoms, as well as disorganized and general prodromal symptoms. There were, however, group differences in positive and negative prodromal symptoms. Interestingly, 78% of the adolescents with MCDD met criteria for ARMS. CONCLUSION: These findings suggest that children diagnosed with MCDD are at high risk for developing psychosis later in life, and support the notion that there are different developmental pathways to psychosis. Follow-up research is needed to compare the rates of transition to psychosis in both high-risk groups.

Risk factors for medication non-adherence in patients with first episode schizophrenia and related disorders; a prospective five year follow-up.

INTRODUCTION: The goal of this study is to assess, prospectively, the relative contribution of baseline variables to long-term medication adherence in patients with a first episode of schizophrenia. METHODS: Consecutively admitted patients suffering from a first episode of schizophrenia or related disorders were investigated. Subjective experience, attitudes towards treatment, insight, interaction with members of staff, involuntary admission, substance abuse, and severity of psychopathology were independently assessed at first admission and related to medication adherence during five year follow up. RESULTS: Standard multiple regression analysis revealed that hostility and uncooperativeness (p=0.007) and involuntary admission (p=0.02) were associated with the level of adherence during 5 year follow-up after admission. DISCUSSION: In first episode schizophrenia and related disorders, the initial interaction with staff and involuntary admission partly predicts long-term adherence to antipsychotic medication. Ameliorating these initial interactions might have long-term consequences on medication adherence. Involuntary admitted patients need intensive outpatient care.

A meta-analysis of P50 studies in patients with schizophrenia and relatives: differences in methodology between research groups.

OBJECTIVE: To determine whether patients with schizophrenia as well as their relatives show deficits in sensory gating reflected by an abnormal P50 ratio and to quantify the differences from controls. METHODS: A systematic search on articles published between 1982 and 2006 was conducted. 28 patient studies that were suitable for analysis including 891 patients and 686 controls were retrieved. Six studies on P50 of relatives of schizophrenic patients were identified, including 317 relatives and 294 controls. RESULTS: In the patient studies we found an P50 effect size of 1.28 (SD=0.72). We confirmed high variability in outcomes across studies. Almost half of the studies included where published by one laboratory of the University of Colorado and these results differed significantly from the results found in studies performed in other laboratories. We found correlations between effect size outcome and sound intensity, filter settings and subjects' position which could be explained by differences between the Colorado laboratory and the other groups. In the relative studies we found a mean P50 effect size of 0.85 (+/-0.42). CONCLUSIONS: The differences in methodology and lack of reported demographics and methodology including raters blinding in some studies makes it hard to compare results across studies and to evaluate the validity and reliability of P50 as a candidate endophenotype for schizophrenia. There are large differences in outcomes from Colorado studies and non-Colorado studies. In contrast to the Colorado studies in the non-Colorado studies P50 suppression would not qualify as an endophenotype for schizophrenia. These differences might be explained by the differences in methodology e.g. lower levels of sound intensity, differences in filter settings and subjects' position. Finally we make some recommendations for future research based on the outcomes of this meta-analysis.

Failure to find P50 suppression deficits in young first-episode patients with schizophrenia and clinically unaffected siblings.

OBJECTIVE: To evaluate whether the P50 gating deficit is present in young first-episode patients with schizophrenia and their healthy young siblings. METHODS: An auditory paired-click paradigm was used to assess P50 gating in 53 patients, 27 unaffected siblings, and 28 healthy controls. P50 parameters were compared between patients, sibs, and unrelated controls by a mixed-effects regression model. RESULTS: P50 gating was not significantly impaired in patients with schizophrenia and healthy siblings as compared with controls. CONCLUSIONS: P50 gating was not found to be significantly impaired in young first-episode schizophrenia patients and in healthy young siblings. These results are in contrast with the existing literature. We suggest that P50 gating impairment may be developmentally or age dependent.

Psychometric properties of the Subjective Well-Being Under Neuroleptics scale and the Subjective Deficit Syndrome Scale.

RATIONALE: Subjective experience of antipsychotic drugs is relevant for medication compliance and quality of life. There is, however, sparse knowledge about the assessment of subjective experience. OBJECTIVES: To examine the internal consistency, test-retest reliability, sensitivity to medication change and concurrent validity of two test instruments: the Subjective Well-Being Under Neuroleptics (SWN) and the Subjective Deficit Syndrome Scale (SDSS). METHODS: Both instruments were used at admission and after 6 weeks of medication stabilization in 105 consecutively admitted patients diagnosed with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edn) diagnoses of recent-onset schizophrenia, schizophreniform disorder or schizoaffective disorder. RESULTS: Almost all patients were capable of reproducing their subjective experience in a consistent way both before and after medication stabilization. The internal consistency of both instruments was high. The test-retest reliability was high if medication was not changed, especially for the SWN. The SWN was sensitive for changes in medication and dosage. The short form of the SWN (SWN-20 items) had comparable psychometric qualities to the original instrument (SWN-38 items). The concurrent validity of the SWN and the SDSS was good, indicating that both tests measure the same concept. CONCLUSIONS: The assessment of subjective experience with the SWN (both versions) may be used in evaluating differential effects of anti-psychotics and dose on subjective well-being.

Clinical and neuropsychological correlates of the P300 in schizophrenia.

We investigated the relationship between the P300, neuropsychological test performance and symptomatology in recent-onset schizophrenic patients (n = 45) to gain insight into underlying mechanisms of abnormal P300 in schizophrenia. The P300 was recorded in two sessions with an intermission of five minutes, at the midline frontal, central and parietal electrode site. P300 amplitude and latency were compared with those obtained in 25 controls. Twenty patients were treated with olanzapine and 19 patients with risperidone. P300 amplitude was smaller and latency longer in patients than in controls. In the patient group, parietal P300 amplitude reduction was related to poorer performance on neuropsychological tests of memory. Frontal P300 amplitude reduction was related to impaired selective attention. In patients with negative symptomatology, P300 amplitude was reduced in the second P300 session compared with the first. Patients on risperidone demonstrated a smaller parietal P300 amplitude than patients using olanzapine. Reduced parietal P300 amplitude could signify a dysfunction in the continuous memory updating of current events. Negative symptomatology may be associated with a time dependent decrease in neuronal firing, as indicated by reduced P300 amplitude in the second P300 session.