Nikolai Albert

Five years of specialised early intervention versus two years of specialised early intervention followed by three years of standard treatment for patients with a first episode psychosis: randomised, superiority, parallel group trial in Denmark (OPUS II)

Objective To compare the effects of five years of specialised early intervention (SEI) treatment for first episode schizophrenia spectrum disorder with the standard two years of SEI plus three years of treatment as usual. Design Randomised, superiority, parallel group trial with blinded outcome assessment. Randomisation was centralised and computerised with concealed randomisation sequence carried out at an external site. Setting Participants were recruited from six OPUS teams in Denmark between 2009 and 2012. OPUS teams provide SEI treatment to all patients diagnosed with a schizophrenia spectrum disorder in Denmark. Participants 400 participants (51% women) with a mean age of 25.6 (standard deviation 4.3) were randomised to five years of SEI (experimental intervention; n=197) or to two years of SEI plus three years of treatment as usual (control; n=203). Interventions OPUS treatment consists of three core elements—modified assertive community treatment, family involvement, and social skill training—with a patient-case manager ratio of no more than 12:1. For participants randomised to five years of OPUS treatment, the treatment was largely unchanged. Participants randomised to the control group were mostly referred to community health centres after two years of SEI treatment. Main outcomes Follow-up assessments were conducted five years after start of OPUS treatment. Primary outcome was negative symptoms measured on the scale for assessment of negative symptoms (avolition-apathy, anhedonia, alogia, and affective blunting). Secondary outcomes were remission of both negative and psychotic symptoms, psychotic symptoms, suicidal ideation, substance abuse, compliance with medical treatment, adherence with treatment, client satisfaction, days in hospital care, and labour market affiliation. Results Levels of negative symptoms did not differ between the intervention group and control group (1.72 v 1.81 points; estimated mean difference −0.10 (95% confidence interval 0.33 to 0.13), P=0.39). Participants receiving five years of OPUS treatment were more likely to remain in contact with specialised mental health services (90.4% v 55.6%, P<0.001), had higher client satisfaction (estimated mean difference 2.57 points (95% confidence interval 1.36 to 3.79), P<0.001), and had a stronger working alliance (estimated mean difference 5.56 points (95% confidence interval 2.30 to 8.82), P=0.001) than the control group. Conclusions This trial tests SEI treatment for up to five years for patients with first episode schizophrenia spectrum disorder; previous trials have found treatment effects for programmes lasting from one to three years. The prolonged SEI treatment had few effects, which could be due to the high level of treatment provided to control participants and the late start of specialised treatment. Trial registration Clinicaltrial.gov NCT00914238.

Antipsychotic medication and remission of psychotic symptoms 10 years after a first-episode psychosis

BACKGROUND Several national guidelines recommend continuous use of antipsychotic medication after a psychotic episode in order to minimize the risk of relapse. However some studies have identified a subgroup of patients who obtain remission of psychotic symptoms while not being on antipsychotic medication for a period of time. This study investigated the long-term outcome and characteristics of patients in remission of psychotic symptoms with no use of antipsychotic medication at the 10-year follow-up. METHODS The study was a cohort study including 496 patients diagnosed with schizophrenia spectrum disorders (ICD 10: F20 and F22-29). Patients were included in the Danish OPUS Trial and followed up 10years after inclusion, where patient data was collected on socio-demographic factors, psychopathology, level of functioning and medication. FINDINGS 61% of the patients from the original cohort attended the 10-year follow up and 30% of these had remission of psychotic symptoms at the time of the 10-year follow up with no current use of antipsychotic medication. This outcome was associated with female gender, high GAF-F score, participation in the labour market and absence of substance abuse. CONCLUSION Our results describe a subgroup of patients who obtained remission while not being on antipsychotic medication at the 10-year follow-up. The finding calls for further investigation on a more individualized approach to long-term treatment with antipsychotic medication.

Stability and development of psychotic symptoms and the use of antipsychotic medication - long-term follow-up.

BACKGROUND Few studies have evaluated the development in the use of antipsychotic medication and psychotic symptoms in patients with first-episode psychosis on a long-term basis. Our objective was to investigate how psychotic symptoms and the use of antipsychotic medication changed over a 10-year period in a cohort of patients with first-episode psychosis. METHOD The study is a longitudinal prospective cohort study over 10 years with follow-ups at years 1, 2, 5 and 10. A total of 496 patients with first-episode psychosis were included in a multi-centre study initiated between 1998 and 2000 in Copenhagen and Aarhus, Denmark. RESULTS At all follow-ups, a large proportion (20-30%) of patients had remission of psychotic symptoms without use of antipsychotic medication at the time of the follow-up. Patients who were in this group at the 5-year follow-up had an 87% [95% confidence interval (CI) 77-96%] chance of being in the same group at the 10-year follow-up. This stability was also the case for patients who had psychotic symptoms and were treated with antipsychotic medication at year 5, where there was a 67% (95% CI 56-78%) probability of being in this group at the consecutive follow-up. CONCLUSIONS A large group of patients with psychotic illness were in remission without the use of antipsychotic medication, peaking at year 10. Overall there was a large degree of stability in disease courses over the 10-year period. These results suggest that the long-term outcome of psychotic illness is heterogeneous and further investigation on a more individualized approach to long-term treatment is needed.

Association of Substance Use Disorders With Conversion From Schizotypal Disorder to Schizophrenia

Importance Understanding the role of substance use disorders in conversion from schizotypal disorder to schizophrenia may provide physicians and psychiatrists with important tools for prevention or early detection of schizophrenia. Objective To investigate whether substance use disorders, in particular cannabis use disorder, are associated with conversion to schizophrenia in individuals with schizotypal disorder. Design, Setting, and Participants This prospective cohort study included a population-based sample of all individuals born in Denmark from January 1, 1981, through August 10, 2014, with an incident diagnosis of schizotypal disorder and without a previous diagnosis of schizophrenia. Follow-up was completed on August 10, 2014, and data were analyzed from March 10, 2017, through February 15, 2018. Exposures Information on substance use disorders combined from 5 different registers. Main Outcomes and Measures Cox proportional hazards regression using time-varying information on substance use disorders and receipt of antipsychotics and adjusted for parental history of mental disorders, sex, birth year, and calendar year were used to estimate hazard ratios (HRs) and 95% CIs for conversion to schizophrenia. Results A total of 2539 participants with incident schizotypal disorder were identified (1448 men [57.0%] and 1091 women [43.0%]; mean [SD] age, 20.9 [4.4] years). After 2 years, 16.3% (95% CI, 14.8%-17.8%) experienced conversion to schizophrenia. After 20 years, the conversion rate was 33.1% (95% CI, 29.3%-37.3%) overall and 58.2% (95% CI, 44.8%-72.2%) among those with cannabis use disorders. In fully adjusted models, any substance use disorder was associated with conversion to schizophrenia (HR, 1.34; 95% CI, 1.11-1.63). When data were stratified by substance, cannabis use disorders (HR, 1.30; 95% CI, 1.01-1.68), amphetamine use disorders (HR, 1.90; 95% CI, 1.14-3.17), and opioid use disorders (HR, 2.74; 95% CI, 1.38-5.45) were associated with conversion to schizophrenia. These associations were not explained by concurrent use of antipsychotics, functional level before incident schizotypal disorder, or parental history of mental disorders. Conclusions and Relevance Substance use disorders, in particular cannabis, amphetamines, and opioids, may be associated with conversion from schizotypal disorder to schizophrenia. However, conversion rates are high even in those without substance use disorders, indicating a need for universal and substance-targeted prevention in individuals with schizotypal disorder.

Early intervention services are effective and must be defended

tems. However, as they point out, the current evidence does not suggest that primary prevention strategies have any reliable impact on attenuating the longerterm course of the illness, even though they positively impact some important treatment-related outcomes. What is even more concerning is the limited uptake of screening, detection and referral to specialist services of people with emergent psychosis (stage 1c) in existing secondary services, where such strategies might be the most effective. On the other hand, the evidence base around the effectiveness of early engagement and treatment with people with an overt psychotic episode (stage 2) through multi-component interventions is more robust in terms of reducing the duration of untreated psychosis and improving treatment-related variables and functional outcome for both the person and caregivers. However, these interventions again do not seem to reduce the chance of relapse and thus a progression into stage 3. While strategies like early initiation of long-acting injectable antipsychotics, reduction of illicit substance abuse and a longer duration of engagement with specialist services can potentially improve outcomes, their impact on the longer-term course of the illness continues to be limited. Any disease staging process is based on the assumption that the defining variable(s) chosen to measure progression of the illness are closely linked to the underlying pathophysiology and strongly predictive of outcomes. As the authors point out, neither of these conditions is satisfied in the case of first-episode psychosis, where heterogeneity between and within the stages is common. The absence of reliable neurobiological measures of psychosis is a critical gap in developing targeted stage-specific interventions and, till these are available, the staging outlined in Fusar-Poli et al’s paper should be considered as provisional in nature. In the short term, the staging process can be progressively refined by future research that specifically examines potential neurobiological mechanisms underlying the functional outcomes, an explicit focus on the elucidation of more robust moderating and mediating variables, and efforts to include population-based cohorts to reduce selection bias that limit the generalizability of findings. It needs to be emphasized that the evidence presented in support of the staging process and matched interventions is derived from selected cohorts receiving dedicated treatments in high-income settings, where substantial investments have been made to make specialist first-episode psychosis services available. Thus, the essential precondition in making comprehensive, stage-specific, matched interventions more widely available is the presence of a well-functioning health system that can provide accessible, affordable, comprehensive and continued care. Globally, the overwhelming majority of people who experience a first episode of psychosis live in lowand middleincome countries and, in many of them, community-based mental health systems are either non-existent or rudimentary. Thus, the majority of such persons are unlikely to receive any treatments; for example, the recent national mental health survey in India has estimated that the treatment gap for people with a current diagnosis of psychosis is more than 75%. In such situations, it is extremely unlikely that rolling out resource intensive and specialist driven interventions for people at clinical high risk for psychosis will be feasible or become a national health priority in the face of scarce human and financial resources. A more realistic option might be to develop locally feasible and culturally appropriate methods for the early identification and treatment of people with a first episode of psychosis (stage 2 onwards) through a combination of wide community engagement methods and task sharing with other trained and supervised non-specialist health workers and community volunteers. There is no doubt that, given the enormous unmet need and therapeutic potential of services for people with a first episode of psychosis, there is an urgent need to develop and evaluate adaptations and innovations that are feasible, acceptable and cost-effective in lowand middleincome country settings. The ongoing Jan Man Swasth (People’s Mental Health) program in India shows that early intervention is feasible in rural Indian settings by adopting a three pronged approach: firstly, through intensive community engagement using culturally adapted methods; secondly, through the availability of trained accredited social health activists who are embedded in the local community as the first point of contact; and third, through effective linkages with community-based treatment teams which provide needbased comprehensive treatments. Making services for first-episode psychosis more widely available beyond highincome country settings is necessary but challenging, and an area where dedicated research attention is warranted as a matter of priority.

Development of a fidelity scale for Danish specialized early interventions service

BACKGROUND The efficacy of the Specialized Early Intervention (SEI) treatment in Denmark, the OPUS treatment, has in a randomized clinical trial proved to be very effective compared to treatment as usual, and the dissemination of SEI services is increasing in Denmark. A prerequisite for upholding positive effects along with creating new teams and preserving critical components is to ensure fidelity to the model. Currently there is no Danish fidelity scale for SEI services. AIM To establish a fidelity scale for SEI teams, in a brief and easily manageable form, for the use of evaluating and assessing the critical components in Danish SEI services. METHOD We identified essential evidence-based components of SEI services internationally and interviewed experts from five Danish SEI teams, using an adapted version of the Delphi Consensus method. RESULTS An 18-point fidelity scale was constructed. The scale was divided into two dimensions: one relating to the structure of the SEI team and one relating to the character and content of the SEI treatment. Each component can be rated either 1 or 0 (1 point = fulfilling the requirements for the components; and 0 point = the requirements were not met). The maximum score was a total of 18 points with 5 of the components being mandatory. CONCLUSION The development of the fidelity scale is an important tool for securing the quality of SEI treatment in Denmark.

O7.7. COGNITIVE FUNCTIONING FOLLOWING DISCONTINUATION OF ANTIPSYCHOTIC MEDICATION: A SUB-GROUP ANALYSIS FROM THE OPUS II TRIAL

Abstract Background The presence of cognitive defects in patients suffering from schizophrenia is well established. While the earlier “Kraepelinian” view was one of deteriorating cognitive functioning, more recent studies have found that cognitive deficits tend to be stable or improving over time. Cognitive impairments are associated with poorer functional outcomes and understanding the factors that influence cognitive functioning is critical for understanding how to improve cognitive and functional outcomes in patients. The effect of antipsychotics medication on cognitive functioning in patients diagnosed with schizophrenia is poorly understood. Some studies of second-generation antipsychotics indicated that they improved cognitive functioning while other studies have found that they decrease the level of cognitive functioning. Methods We included patients with schizophrenia who were in treatment with antipsychotics 1.5 years (baseline) after initiation of treatment and followed them up 3.5 years later (n=189). At follow-up 60 (32%) had discontinued their antipsychotic treatment and 129 (68%) were still taking antipsychotics. Using the Brief Assessment of Cognition in Schizophrenia (BACS) we assessed cognition at baseline and follow-up. Results The patients who had discontinued their medication had a higher level of cognitive functioning in all domains at baseline, as well as Global cognitive function (mean z-score -1.50 (SD 1.24) vs. -2.27 (SD 1.30), p<.001). After controlling for relevant confounders (age, sex, baseline functioning and negative symptoms) those who discontinued antipsychotic medication improved significantly more than those who remained on antipsychotic medication during the course of the follow-up on the Token Motor Task (estimated mean change difference -0.46, 95% CI(-0.89; -0.04), p=0.031), the Speed of Processing Domain (estimated mean change difference -0.38, 95% CI(-0.68; -0.08), p=0.012), and Global cognition (estimated mean change difference -0.36, 95% CI(-0.66; -0.07), p=0.016). Discussion Due to the naturalistic design we cannot conclude on the direction of the relationship between antipsychotic medication and cognition. There is no evidence that discontinuation of medication had a negative effect on cognitive functioning. Rather, we find that that discontinuation of medication was associated with better cognitive functioning.

O11.2. CHANGES IN PSYCHOPATHOLOGY PREDICT CHANGES IN WORKING ALLIANCE IN FIRST EPISODE PSYCHOSIS

Abstract Background The cooperative and dynamic relationship between patients and therapist known as Working Alliance, has in two meta-analysis shown to be an important factor for positive outcome in psychotherapy regardless the modality of therapy. Studies investigating the association between working alliance and outcome conducted in cohorts of patients with mental illness treated in a case manager setting has reported an association between a strong working alliance and reduced symptom severity, better social function, adherence to psycho-social treatment. For this study, we used data from a trial testing the effect of five years of specialized early intervention (SEI) compared to two years of SEI for patients diagnosed with first episode of schizophrenia spectrum disorder. We aimed to study the effect of the intervention on the working alliance and the change in working alliance as a dynamic factor in the two treatment conditions from baseline to follow-up. When extending specialized early intervention from two to five years’ vs transferring to treatment as usual, we hypothesized a change in working alliance and psychopathology favoring the patient in the extended SEI group. Methods Participants were recruited from SEI teams (OPUS) in Denmark. All newly diagnosed within the schizophrenia spectrum (ICD-10, F2), age between 18 and 35. Participants were included 1 ½ year after initiation of SEI treatment (baseline) and followed up 5 years after initiation of treatment. At both assessments participants were examined with a comprehensive assessment battery including working alliance, psychopathology, social function, cognitive function, adherence to medication and client satisfaction. Assessors were blind to treatment allocation. The primary outcome, working alliance inventory (WAI), was assessed by self-assessment. A change score was calculated by subtracting the baseline score from the follow-up score. Multivariable linear regression analyses were conducted, corrected for the baseline value of the independent and dependent variable. Results Of the 289 participants who attended the follow-up interview 258 (89%) had completed the WAI at baseline and follow-up. Participants who were randomized to prolonged SEI had a stable WA from baseline to follow-up, while participants who were randomized to TAU had a mean drop in WA over the same period. Change in WA was associated with change in negative-, psychotic-, and disorganized symptoms dimension, and social function in the extended OPUS group. In the TAU group, we found that change in WA were negatively associated with change in cognitive function measured with BACS. In both groups, there were an association between the change in WA and change in client satisfaction. Discussion This indicates that those participants’ who continued the extended SEI treatment maintained their experiences of a strong WA with their case manager, while those participants who were transferred to TAU experiences a lower degree of WA with their case manager compared to their time in SEI treatment. Furthermore, the participants who increased on their cognitive functioning were less likely to assess WA positively if they were transferred to TAU.

T54. TAILOR – TAPERED DISCONTINUATION VERSUS MAINTENANCE THERAPY OF ANTIPSYCHOTIC MEDICATION IN PATIENTS WITH NEWLY DIAGNOSED SCHIZOPHRENIA SPECTRUM DISORDERS IN REMISSION OF PSYCHOTIC SYMPTOMS

Abstract Background Schizophrenia spectrum disorders have major implications for the individuals, their families and society. Antipsychotic medication is the cornerstone in the treatment of psychotic symptoms and is effective in the reduction of psychotic symptoms and of relapse after remission of psychotic symptoms. This is the reason for recommending maintenance treatment with antipsychotic medication in national and international guidelines for the treatment of schizophrenia, one year after remission of psychotic symptoms in first episode psychosis. The aim of the study is to investigate the effect of tapered discontinuation versus maintenance therapy with antipsychotic medication in patients with newly diagnosed schizophrenia or persistent delusional disorder and with minimum three months remission of psychotic symptoms, and to find minimal effective dose of antipsychotic medication. Negative symptoms, cognitive impairments and the side effects of antipsychotic medication can cause a serious and long-term burden for patients and can reduce their quality of life. The TAILOR study will investigate these important aspects. Methods The study is a randomized multicenter single blinded clinical trial. The aim is to include 250 patients from the outpatient early intervention program, OPUS, a 2 years manualized psychiatric treatment programme. At baseline patients must have 3 months remission of psychotic symptoms as documented by the SAPS (Schedule for Assessment of Positive Symptoms in Schizophrenia). The patients will be randomized to either tapered discontinuation or dose reduction of antipsychotic medication or treatment as usual stratified according to substance abuse. The intervention will last for 1 year, and follow up interviews will be made after 1,2 and 5 years. The patients will receive a user-developed mobile phone application to make daily registrations. Results The study has been including patients since May 2017. The first data is expected in 2019. Discussion The TAILOR trial will contribute to knowledge about the effect of tapering/discontinuation of antipsychotic medication in early phases of schizophrenia spectrum disorders and hopefully the results may guide future clinical treatment regimens of antipsychotic medication. The trial is a complex medical intervention, and it raises ethical, practical and organizational challenges. When designing the TAILOR trial ethical questions were raised regarding blinding and the design of the intervention. In the trial only the researchers are blinded, neither clinicians nor patients, because they should be attentive of the high risk of relapse in the discontinuation group. The design gives the clinicians the possibility to adjust the dose of the antipsychotic medication to ensure sufficient treatment. Therefore, the trial only includes assessor blinding and the groups might end up being more similar than intended. In general, it is of ethical consideration that the trial participants in the tapering/discontinuation group will be subjected to a higher risk of relapse. On the other hand, it seems unethical if research were not to discover the group of patients who can discontinue antipsychotic medication without relapsing. Practical challenges will be sufficient recruitment or patient motivation and dropout.

Programme fidelity of specialized early intervention in Denmark

AIM Specialized early intervention (SEI) treatment in meta-analysis has proven to be effective, compared to usual treatment, in treating first-episode psychosis, and the dissemination of SEI services is increasing. A prerequisite for upholding positive effects is to ensure fidelity to the treatment concept once tested. The aim of this study was to map programme fidelity of SEI teams in Denmark by testing a newly developed fidelity scale. METHODS The 18-item SEI fidelity scale was assessed by visiting SEI teams in person. The scale is divided into 2 dimensions: one concerning the structure and the other concerning the character and content of the treatment. Interviews were conducted with team leaders, patients and members of the staff, and team conferences were observed. Satisfactory fidelity can be obtained at 2 levels: an elite level and an adequate level. RESULTS In total, 96% (n = 22) of the Danish SEI teams participated in the fidelity study. An elite fidelity score was achieved by 32% of the teams, scoring 15 or 16 on the 18-point scale; 27% reached adequate level. With regard to the structural domain of the scale, we found variation among the teams. CONCLUSIONS The multimodal approach was found to be very efficient in evaluating elements critical to SEI teams in Denmark. A low score on the structural domain could, in the long term, lead to an inability to maintain a well-functioning team and provide high-quality treatment.