Mette Bertelsen

Five-Year Follow-up of a Randomized Multicenter Trial of Intensive Early Intervention vs Standard Treatment for Patients With a First Episode of Psychotic Illness : The OPUS Trial

CONTEXT Intensive early treatment for first-episode psychosis has been shown to be effective. It is unknown if the positive effects are sustained for 5 years. OBJECTIVE To determine the long-term effects of an intensive early-intervention program (OPUS) for first-episode psychotic patients. DESIGN Single-blinded, randomized, controlled clinical trial of 2 years of an intensive early-intervention program vs standard treatment. Follow-up periods were 2 and 5 years. SETTING Copenhagen Hospital Corporation and Psychiatric Hospital, Aarhus, Denmark. Patients A total of 547 patients with a first episode of psychosis. Of these, 369 patients were participating in a 2-year follow-up, and 301 were participating in a 5-year follow-up. A total of 547 patients were followed for 5 years. INTERVENTIONS Two years of an intensive early-intervention program vs standard treatment. The intensive early-intervention treatment consisted of assertive community treatment, family involvement, and social skills training. Standard treatment offered contact with a community mental health center. MAIN OUTCOME MEASURES Psychotic and negative symptoms were recorded. Secondary outcome measures were use of services and social functioning. RESULTS Analysis was based on the principles of intention-to-treat. Assessment was blinded for previous treatment allocation. At the 5-year follow-up, the effect of treatment seen after 2 years (psychotic dimension odds ratio [OR], -0.32; 95% confidence interval [CI], -0.58 to -0.06; P = .02; negative dimension OR, -0.45; 95% CI, -0.67 to -0.22; P = .001) had equalized between the treatment groups. A significantly smaller percentage of patients from the experimental group were living in supported housing (4% vs 10%, respectively; OR, 2.3; 95% CI, 1.1-4.8; P = .02) and were hospitalized fewer days (mean, 149 vs 193 days; mean difference, 44 days; 95% CI, 0.15-88.12; P = .05) during the 5-year period. CONCLUSIONS The intensive early-intervention program improved clinical outcome after 2 years, but the effects were not sustainable up to 5 years later. Secondary outcome measures showed differences in the proportion of patients living in supported housing and days in hospital at the 5-year follow-up in favor of the intensive early-intervention program.

Suicidal behaviour and mortality in first-episode psychosis: the OPUS trial

BACKGROUND Those with first-episode psychosis are at high-risk of suicide. AIMS To identify predictive factors for suicidal thoughts, plans and attempts, and to investigate the rate of suicides and other deaths during the 5 years after first diagnosis and initiation of treatment. METHOD A longitudinal, prospective, 5-year follow-up study of 547 individuals with first-episode schizophrenia spectrum psychosis. Individuals presenting for their first treatment in mental health services in two circumscribed urban areas in Denmark were included in a randomised controlled trial of integrated v. standard treatment. All participants were followed in the Danish Cause of Death Register for 5 years. Suicidal behaviour and clinical and social status were assessed using validated interviews and rating scales at entry, and at 1- and 2-year follow-ups. RESULTS Sixteen participants died during the follow-up. We found a strong association between suicidal thoughts, plans and previous attempts, depressive and psychotic symptoms and young age, and with suicidal plans and attempts at 1- and 2-year follow-up. CONCLUSIONS In this first-episode cohort depressive and psychotic symptoms, especially hallucinations, predicted suicidal plans and attempts, and persistent suicidal behaviour and ideation were associated with high risk of attempted suicide.

Predictors of recovery from psychosis Analyses of clinical and social factors associated with recovery among patients with first-episode psychosis after 5 years

INTRODUCTION This paper aims to investigate the predictors of good outcome after first-episode non-affective psychosis and the clinical and social trajectories of those that recover. METHODS A cohort of 255 patients with first-episode non-affective psychosis was interviewed 5 years after first diagnosis and treatment. Recovery was defined as working or studying, having a GAF-function score of 60 or above, having remission of negative and psychotic symptoms, and not living in a supported housing facility or being hospitalized during the last 2 years before the five-year follow-up interview. RESULTS A total of 40 (15.7%) were found to be recovered, and 76 (29.8%) had a job or were studying after 5 years. Of those working, as many as 20 still had psychotic symptoms. Also notable is that out of the 40 recovered, less than half were recovered after 2 years. Recovery after 5 years was predicted by female sex (OR 2.4, 95% CI 1.0-5.8), higher age (OR 0.91, 95% CI 0.83-0.99), pre-morbid social adaptation (OR 0.72, 95% CI 0.56-0.93), growing up with both parents (OR 2.6, 95% CI 1.0-6.8) and low level of negative symptoms (OR 0.51, 95% CI 0.33 to 0.77) at baseline. DISCUSSION Our findings suggest that a stable social life with normal social functioning has a predictive value for good outcome. These measures might be influenced by negative symptoms, but in the multivariate analysis with negative symptoms included they have an independent effect. Also our findings suggest that, after first-episode psychosis, some patients can still experience psychotic symptoms, but have a job and a fairly stable life.

Predictors of recovery in first episode psychosis: The OPUS cohort at 10 year follow-up

BACKGROUND Recovery, the optimal goal in treatment, is the attainment of both symptomatic and functional remission over a sustained period of time. Identification of factors that promote recovery can help develop interventions that facilitate good outcomes for people with first episode psychosis. AIM To examine long-term outcomes within a cohort of people with first episode psychosis in relation to symptom remission, functioning and recovery, 10 years after diagnosis. METHOD The study had a prospective design. Participants from the OPUS trial (1998-2000) (n=496) completed a series of interviews and questionnaires to measure current levels of psychopathology and social/vocational functioning, ten years after diagnosis. Predictors of recovery were identified using socio-demographic and clinical characteristics collected at baseline. RESULTS A total of 304 participants were interviewed, giving a follow-up rate of 61%. A total of 42 people (14%) met the criteria for symptomatic and psychosocial recovery at 10 years. A multivariable binary logistic regression analysis indicated that baseline predictors accounted for 22% of the variance of full recovery. Lower severity of negative symptoms at baseline (Odds Ratio (OR) 0.53, 95% confidence interval CI 0.36-0.78, p<0.001) and earlier age of diagnosis (OR 0.92, 95% CI 0.86-0.99, p<0.05) predicted better rates of recovery at 10 years. CONCLUSION Results of this study indicated that negative symptoms could play a central role in the process of recovery from schizophrenia. A challenge for clinicians and researchers is to understand the mechanisms behind negative symptoms and develop interventions that can prevent or ameliorate these symptoms in order to promote recovery.

Cost-effectiveness of early intervention in first-episode psychosis: economic evaluation of a randomised controlled trial (the OPUS study)

BACKGROUND Information about the cost-effectiveness of early intervention programmes for first-episode psychosis is limited. AIMS To evaluate the cost-effectiveness of an intensive early-intervention programme (called OPUS) (trial registration NCT00157313) consisting of enriched assertive community treatment, psychoeducational family treatment and social skills training for individuals with first-episode psychosis compared with standard treatment. METHOD An incremental cost-effectiveness analysis of a randomised controlled trial, adopting a public sector perspective was undertaken. RESULTS The mean total costs of OPUS over 5 years (€123,683, s.e. = 8970) were not significantly different from that of standard treatment (€148,751, s.e. = 13073). At 2-year follow-up the mean Global Assessment of Functioning (GAF) score in the OPUS group (55.16, s.d. = 15.15) was significantly higher than in standard treatment group (51.13, s.d. = 15.92). However, the mean GAF did not differ significantly between the groups at 5-year follow-up (55.35 (s.d. = 18.28) and 54.16 (s.d. = 18.41), respectively). Cost-effectiveness planes based on non-parametric bootstrapping showed that OPUS was less costly and more effective in 70% of the replications. For a willingness-to-pay up to €50,000 the probability that OPUS was cost-effective was more than 80%. CONCLUSIONS The incremental cost-effectiveness analysis showed that there was a high probability of OPUS being cost-effective compared with standard treatment.

Gender differences in first-episode psychosis at 5-year follow-up--two different courses of disease? Results from the OPUS study at 5-year follow-up.

OBJECTIVE Gender differences in psychosis have been investigated, and the results have contributed to a better understanding of the disease, but many questions are unanswered. In clinical terms, women and men with psychosis differ in terms of access to social support, tendency of substance abuse, level of functioning and symptom patterns. We aimed to investigate how gender differences at onset of psychosis develop during the first 5years of treatment. METHOD A total of 578 patients with a first-episode psychosis in the schizophrenia spectrum were included in the Danish OPUS trial--a randomized clinical trial comparing 2 years of intensive early-intervention programme with standard treatment. All patients were assessed with validated instruments at inclusion, and after 2 and 5 years. Data were analysed for significant gender differences. RESULTS Males have significantly higher levels of negative symptoms at all times, and are more likely to live alone and suffer from substance abuse. Females reach higher levels of social functioning at follow-up, and show a greater tendency to be employed or in education than males. Markedly more women than men live with children. More women than men reach a state of recovery and are more compliant with medication. CONCLUSION There are significant gender differences at 2- and 5-year follow-up in this large cohort of first-episode psychotic patients. Males and females show different symptomatology and different levels of social functioning.

Comorbidity in patients with branch retinal vein occlusion: case-control study

Objectives To evaluate comorbidity before and after the diagnosis of branch retinal vein occlusion to determine whether it is a consequence of arterial thickening and therefore could serve as a diagnostic marker for other comorbidities and to evaluate the risk factors for the development of such occlusion. Design Case-control study with prospective follow-up data from Danish national registries. Setting Four secondary referral centres covering about 80% of the Danish population (4.4 million). Participants 1168 patients with photographically verified branch retinal vein occlusion and 116 800 controls alive and aged ≥40 when the occlusion was diagnosed in the corresponding case. Main outcome measures The risk of comorbidity 10 years and 1 year before the diagnosis of branch retinal vein occlusion and the incident comorbidity in a mean period of seven years after the diagnosis, with odds ratios and incidence rate ratios adjusted for age, sex, and year of diagnosis. Results Risk factors present 10 years and 1 year before the diagnosis of branch retinal vein occlusion included peripheral artery disease (odds ratio 1.83, 95% confidence interval 1.14 to 2.95), diabetes (1.74, 1.40 to 2.17) and arterial hypertension (2.16, 1.86 to 2.51). After the diagnosis, patients had an increased risk of developing arterial hypertension (incidence rate ratio 1.37, 95% confidence interval 1.15 to 1.57), diabetes (1.51, 1.17 to 2.04), congestive heart failure (1.41, 1.12 to 1.68), and cerebrovascular disease (1.49, 1.27 to 1.76). Conclusion Diabetes, hypertension, and peripheral artery disease are associated with an increased risk of developing branch retinal vein occlusion up to a decade later. Branch retinal vein occlusion was associated with an increased risk of subsequently developing hypertension, diabetes, congestive heart failure, and cerebrovascular disease, emphasising the importance of preventive initiatives. These results fit the assumption that branch retinal vein occlusion is a consequence of arterial thickening and that the arteriovenous crossing signs that precede it are hallmarks of arterial disease.

Long-term trajectories of positive and negative symptoms in first episode psychosis: A 10year follow-up study in the OPUS cohort.

OBJECTIVE Knowledge about course of illness can help clinicians to develop effective interventions and improve treatment outcomes. The goal of this study was to construct positive and negative symptom trajectories based on structured clinical assessments collected over 10years within a cohort of people with first episode psychosis. METHOD A cohort of 496 people with first episode psychosis (ICD-10, F20-28) originally recruited for the OPUS study (1998-2000) and treated in community psychiatric services were rated on clinical symptoms at 5 different occasions across ten years. Psychopathology was assessed using the Scales for Assessment of Positive and Negative Symptoms. Symptom trajectories were constructed using Latent Class Analysis. RESULTS Five distinct trajectories were identified for positive symptoms (response - 47%, delayed response - 12%, relapse - 15%, non-response - 13% and episodic response - 13%). Four distinct trajectories were identified for negative symptoms (response - 28%, delayed response - 19%, relapse - 26% and non-response - 27%). Multivariable regression analysis of baseline characteristics identified that longer duration of untreated psychosis (OR 1.27-1.47, p<0.05) and substance abuse (OR 3.47-5.90, p<0.01) were associated with poorer positive symptom trajectories (higher levels of psychotic symptoms) while poor social functioning (OR 1.34-5.55, p<0.05), disorganized symptoms (OR 2.01-2.38, p<0.05) and schizophrenia diagnosis (OR 5.70-8.86, p<0.05) were associated with poorer negative symptom trajectories (higher levels of negative symptoms). A proportion of people displayed significant changes in symptoms several years after diagnosis. CONCLUSIONS Trajectories of illness for positive and negative symptoms were heterogeneous among people with first episode psychosis. Positive symptoms showed a general pattern of reduction and stabilization over time while negative symptoms typically showed less variation over the ten years. Results have implications for the focus, timing and length of interventions in first episode psychosis.

Change in cannabis use, clinical symptoms and social functioning among patients with first-episode psychosis: a 5-year follow-up study of patients in the OPUS trial.

BACKGROUND Several studies indicate that cannabis use among patients with psychotic disorders is associated with worse outcome, but only a few studies have controlled for baseline condition and medication. METHOD At 5-year follow-up, interviews were carried out with 314 first-episode psychosis patients included in the OPUS trial. The patients included were in the age range of 18 to 45 years old and 59% were male. Cannabis use was extracted from the Schedule for Clinical Assessment in Neuropsychiatry. At follow-up, the patients were divided into different groups according to the variable cannabis use: abstainers, stoppers, starters and continuers. Psychotic, negative and disorganized dimensions (ranging from zero to five) were calculated for each of the four groups based on the Schedule for the Assessment of Positive and Negative Symptoms in Schizophrenia. RESULTS Cannabis users were younger (24.6 years v. 27.4 years, p < 0.001) and had a lower level of education. At the 5-year follow-up, users of cannabis had higher scores on the psychotic dimension [difference 0.97, 95% confidence interval (CI) 0.41-1.53, p = 0.001] and lower levels of the Global Assessment of Functioning (difference 8.26, 95% CI 2.13-14.39, p = 0.01). Those who stopped using cannabis between entry and 5-year follow-up had a significantly lower level of psychotic symptoms at 5-year follow-up even after controlling for baseline level of psychotic symptoms and for insufficient antipsychotic medication (adjusted difference in psychotic dimension -1.04, 95% CI -1.77 to -0.31, p = 0.006). CONCLUSIONS Continuous cannabis use was associated with higher levels of psychotic symptoms after 5 years, and this association was only partly explained by insufficient antipsychotic medication.

The effect of five years versus two years of specialised assertive intervention for first episode psychosis - OPUS II: study protocol for a randomized controlled trial

BackgroundThe Danish OPUS I trial randomized 547 patients with first-episode psychosis to a two-year early-specialised assertive treatment programme (OPUS) versus standard treatment. The two years OPUS treatment had significant positive effects on psychotic and negative symptoms, secondary substance abuse, treatment adherence, lower dosage of antipsychotic medication, and a higher treatment satisfaction. However, three years after end of the OPUS treatment, the positive clinical effects were not sustained, except that OPUS-treated patients were significantly less likely to be institutionalised compared with standard-treated patients. The major objective of the OPUS II trial is to evaluate the effects of five years of OPUS treatment versus two years of OPUS treatment.MethodsThe OPUS II trial is designed as a randomized, open label, parallel group trial with blinded outcome assessment. Based on our sample size estimation, 400 patients treated in OPUS for two years will be randomized to further three years of OPUS treatment versus standard treatment. The specialized assertive OPUS treatment consists of three core elements: assertive community treatment, psycho-educational family treatment, and social skills training.DiscussionIt has been hypothesized that there is a critical period from onset up to five years, which represents a window of opportunity where a long-term course can be influenced. Extending the specialized assertive OPUS treatment up to five years may allow the beneficial effects to continue beyond the high-risk period, through consolidation of improved social and functional outcome.Trial registrationClinical Trial.gov NCT00914238