20-year neurocognitive development following a schizophrenia spectrum disorder and associations with symptom severity and functional outcomes.

BACKGROUND: Cognitive deficits are a core feature of schizophrenia and are closely associated with poor functional outcomes. It remains unclear if cognitive deficits progress over time or remain stable. Determining patients at increased risk of progressive worsening might help targeted neurocognitive remediation approaches. METHODS: This 20-year follow-up study examined neurocognitive outcomes of 156 participants from the OPUS I trial. Neurocognition was assessed using the brief assessment of cognition in schizophrenia at the 10- and 20-year follow-up, allowing us to examine changes in neurocognition over ten years. RESULTS: We found that 30.5% of patients had a declining course of neurocognition, 49.2% had a stable course of neurocognition and 20.3% experienced improvements in neurocognition. Good cognitive functioning at the 20-year follow-up was significantly associated with higher levels of social functioning (B 6.86, CI 4.71-9.02, p < 0.001) while increasing experiential negative symptoms were significantly correlated to cognitive worsening (PC-0.231, p = 0.029). Younger age at inclusion (B: 0.23 per 10-years, CI 0.00-0.045, p = 0.047) and low level of education (below ten years) (mean difference: -0.346, CI -0.616 to -0.076, p = 0.012) predicted declining neurocognition. CONCLUSION: Our findings support the notion of different schizophrenia subtypes with varying trajectories. Neurocognitive impairment at the 20-year follow-up was associated with other poor outcomes, highlighting the importance of treatments aimed at improving neurocognition in patients with schizophrenia spectrum disorders.

Clinical illness course and family-related outcomes among parents with a first episode of schizophrenia spectrum disorder: a 20-year follow-up of the OPUS trial.

BACKGROUND: Studies investigating parenthood and how it affects long-term outcomes are lacking among individuals with schizophrenia spectrum disorders. This study aimed to examine the life of participants 20 years after their first diagnosis with a special focus on parenthood, clinical illness course, and family-related outcomes. METHODS: Among 578 individuals diagnosed with first-episode schizophrenia spectrum disorder between 1998 and 2000, a sample of 174 participants was reassessed at the 20-year follow-up. We compared symptom severity, remission, clinical recovery, and global functioning between 75 parents and 99 non-parents. Also, family functioning scored on the family assessment device, and the children's mental health was reported. We collected longitudinal data on psychiatric admission, supported housing, and work status via the Danish registers. RESULTS: Participants with offspring had significantly lower psychotic (mean (s.d.) of 0.89 (1.46) v. 1.37 (1.44), p = 0.031) negative (mean [s.d.] of 1.13 [1.16] v. 1.91 [1.07], p < 0.001) and disorganized symptom scores (mean [s.d.] of 0.46 [0.80] v. 0.85 [0.95], p = 0.005) and more were in remission (59.5% v. 22.4%, p < 0.001) and in clinical recovery (29.7% v. 11.1%, p = 0.002) compared to non-parents. When investigating global functioning over 20 years, individuals becoming parents after their first diagnosis scored higher than individuals becoming parents before their first diagnosis and non-parents. Regarding family-related outcomes, 28.6% reported unhealthy family functioning, and 10% of the children experienced daily life difficulties. CONCLUSIONS: Overall, parents have more favorable long-term outcomes than non-parents. Still, parents experience possible challenges regarding family functioning, and a minority of their children face difficulties in daily life.

Discontinuation of antipsychotics in individuals with first-episode schizophrenia and its association to functional outcomes, hospitalization and death: a register-based nationwide follow-up study.

BACKGROUND: Discontinuation of antipsychotic medication may be linked to high risk of relapse, hospitalization and mortality. This study investigated the use and discontinuation of antipsychotics in individuals with first-episode schizophrenia in relation to cohabitation, living with children, employment, hospital admission and death. METHODS: Danish registers were used to establish a nationwide cohort of individuals ⩾18 years with schizophrenia included at the time of diagnosis in1995-2013. Exposure was antipsychotic medication calculated using defined daily dose and redeemed prescriptions year 2-5. Outcomes year 5-6 were analysed using binary logistic, negative binomial and Cox proportional hazard regression. RESULTS: Among 21 351, 9.3% took antipsychotics continuously year 2-5, 38.6% took no antipsychotics, 3.4% sustained discontinuation and 48.7% discontinued and resumed treatment. At follow-up year 6, living with children or employment was significantly higher in individuals with sustained discontinuation (OR 1.98, 95% CI 1.53-2.56 and OR 2.60, 95% CI 1.91-3.54), non-sustained discontinuation (OR 1.25, 95% CI 1.05-1.48 and 2.04, 95% CI 1.64-2.53) and no antipsychotics (OR 2.00, 95% CI 1.69-2.38 and 5.64, 95% CI 4.56-6.97) compared to continuous users. Individuals with non-sustained discontinuation had more psychiatric hospital admissions (IRR 1.27, 95% CI 1.10-1.47) and longer admissions (IRR 1.68, 95% CI 1.30-2.16) year 5-6 compared to continuous users. Mortality during year 5-6 did not differ between groups. CONCLUSION: Most individuals with first-episode schizophrenia discontinued or took no antipsychotics the first years after diagnosis and had better functional outcomes. Non-sustained discontinuers had more, and longer admissions compared to continuous users. However, associations found could be either cause or effect.

Cognitive functioning following discontinuation of antipsychotic medication. A naturalistic sub-group analysis from the OPUS II trial.

BACKGROUND: 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. METHOD: 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 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 (s.d. 1.24) v. -2.27 (s.d. 1.30), p = 0.00015]. After controlling for relevant confounders 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 to -0.04)], the Speed of Processing Domain [estimated mean change difference -0.38 (95% CI -0.68 to -0.08)] and global cognition [estimated mean change difference -0.36 (95% CI -0.66 to -0.07)]. CONCLUSION: Due to the naturalistic design, we cannot conclude on the direction of the relationship between antipsychotics and cognition. There is no evidence that discontinuation of medication had a negative effect on cognitive functioning. Rather, we found that that discontinuation of medication was associated with better cognitive functioning.

The outcome of early intervention in first episode psychosis.

The last 20 years have seen an increased focus on early intervention in psychotic disorders in research and clinical practice. Interventions have typically aimed at either reducing the duration of untreated psychosis (DUP), or developing specialized treatment facilities for patients with first episode psychosis (FEP). This review presents an overview of the most important trials and meta-analytic evidence within this field. The possibilities for reducing DUP and elements included in specialized early intervention treatment are discussed. Further, it examines long-term outcomes of early interventions and results from prolonged early intervention trials. Lastly, it analyses possible interactions between DUP and specialized early intervention treatment. In conclusion, both elements appear necessary in order to develop an integrated service that can provide the optimal treatment for patients with FEP. The aim of this article is to provide an overview over the most important trials and evidence regarding the outcome of early intervention in first episode psychosis.

The prognosis of schizophrenia.

Psychotic and negative symptoms are core features of schizophrenia but knowledge on the long-term course of these symptoms is lacking. While antipsychotics improve psychotic symptoms, they have limited effect on negative symptoms. Specialized early interventions like OPUS show great effects while ongoing but long-term follow-up indicates no lasting disease-modifying effects. 18% of patients achieved clinical recovery, and 40% obtained symptom remission after 20 years, but high mortality rates and continuous negative symptoms constitute an unmet treatment need, as argued in this review.

Long-term quality of life and social disconnection 20 years after a first episode psychosis, results from the 20-year follow-up of the OPUS trial.

OBJECTIVE: Schizophrenia disorders severely impact social and occupational function and reduce quality of life, furthermore patients often suffer from social withdrawal and isolation. The aim of this study was to investigate long-term quality of life and social disconnection and determine 10-year changes in quality of life and social disconnection later in life in association with changes in symptom severity, cognition, and global function. METHODS: We used assessments of quality of life and assessor rated social disconnection from the 10- and 20-year follow-up of the OPUS trial to examined 10-year changes in self-rated quality of life and social disconnection in the later stage of illness following a first episode psychosis. Self-rated social disconnection was only assessed in the 174 participants of the 20-year follow-up. RESULTS: Twenty years after a first episode psychosis only half of the participants reported having face-to-face contact with someone in their network more than once a week, while 90 % reported often or always being able to get emotional support when needed. Quality of life ratings were lower in our study population compared to the general population. On average physical and environmental quality of life worsened from the 10- to the 20-year follow-up while psychological and social quality of life remained stable. All quality-of-life domains were associated with negative symptoms (physical QoL: b = -6.6, p < 0.001, psychological QoL: b = -8, p < 0.001, social QoL: b = -5.7, p < 0.001 and environmental QoL: b = -6.5, p < 0.001) and global function (physical QoL: b = -0. 47, p < 0.001, psychological QoL: b = 0.52, p < 0.001, social QoL: b = 0.31, p < 0.001 and environmental QoL: b = 0.49, p < 0.001). CONCLUSION: Social disconnection seems to persist over time. Social disconnection and quality of life were associated with negative symptoms and poor functioning, therefore interventions aimed at improving global and social function might likely also improve quality of life.

Functioning pre- and post-treatment in schizophrenia; further investigations into lead time bias and duration of untreated psychosis.

OBJECTIVE: The association between duration of untreated psychosis (DUP) and later outcome is not fully understood. Jonas et al. in their 20-year follow-up found that the association could be explained by lead-time bias. In this study we aimed to analyze the relationship between DUP, time since onset of psychosis and functional outcome using a similar statistical approach as the Jonas study. METHOD: Using data from 496 participants with first-episode schizophrenia, DUP was assessed using the IRAOS and functioning at the baseline assessment and the subsequent follow-ups (1, 2, 5 and 10 years) was assessed using the GAF-F. For premorbid functioning, the Premorbid Assessment of Functioning Scale was used and rescaled to correspond to the GAF. RESULTS: The model with the best fit of data included both a slope and a level change. This model of level of function over time had the inflection point at the time of first treatment. This model indicated a slow decline per year until first treatment, at which point there was a sharp decrease in functioning, and after which functioning gradually improved again. Both in this model and in models accounting for potential lead-time bias, however, longer DUP was associated with a decrease in function for each additional week of DUP. This is in contrast with the Jonas et al. study. CONCLUSION: In this study, we did not find evidence of a lead-time bias, but rather found that onset of treatment occurs at the time when participants level of functioning was most impaired, and consequently was not at random.

Predictors of Mortality Following a Schizophrenia Spectrum Diagnosis: Evidence From the 20-Year Follow-up of the OPUS Randomized Controlled Trial.

BACKGROUND AND HYPOTHESIS: The life expectancy of patients diagnosed with schizophrenia is 10-12 years lower than in the general population and the mortality gap seems to be worsening. Many of these deaths might be avoidable. We aimed to determine mortality rates and causes of death after a first-episode psychosis, and to examine if clinical characteristics at baseline or during illness could predict mortality. STUDY DESIGN: The OPUS study was a randomized controlled trial of 578 patients first diagnosed with schizophrenia spectrum disorders. Patients were clinically assessed after 2, 5, 10, and 20 years. Information about time and cause of death was obtained from the Danish Cause of Death Register. Hazard ratios were used to assess predictors of death. STUDY RESULTS: In total, 82 (14.4%) participants died during 20 years of follow-up. The most common cause of death was suicide (27%). At baseline employment (HR 0.47 P = .049), psychotic disorder other than schizophrenia (HR 0.36, P = .017), and longer duration of untreated psychosis (HR 0.57 P = .042) predicted lower mortality while substance use predicted higher mortality (HR 2.56, P < .001). During follow-up, symptom remission without antipsychotic medication and recovery predicted lower mortality (HR 0.08 P = .013 and HR 0.21, P = .028) while substance use (HR 3.64 P < .001), and all chronic illnesses predicted increased risk. CONCLUSIONS: There is an increased risk of early mortality in schizophrenia compared to the background population, and there is an urgent need for new efforts to improve the disparities in health that lead to this increased mortality.

Clinical Recovery and Long-Term Association of Specialized Early Intervention Services vs Treatment as Usual Among Individuals With First-Episode Schizophrenia Spectrum Disorder: 20-Year Follow-up of the OPUS Trial.

Importance: The OPUS 20-year follow-up is the longest follow-up of a randomized clinical trial testing early intervention services (EIS) among individuals with first-episode schizophrenia spectrum disorder. Objective: To report on long-term associations of EIS compared with treatment as usual (TAU) for first-episode schizophrenia spectrum disorder. Design, Setting, and Participants: A total of 547 individuals were included in this Danish multicenter randomized clinical trial between January 1998 and December 2000 and allocated to early intervention program group (OPUS) or TAU. Raters who were blinded to the original treatment performed the 20-year follow-up. A population-based sample aged 18 to 45 years with first-episode schizophrenia spectrum disorder were included. Individuals were excluded if they were treated with antipsychotics (>12 weeks prior to randomization), had substance-induced psychosis, had mental disability, or had organic mental disorders. Analysis took place between December 2021 and August 2022. Interventions: EIS (OPUS) consisted of 2 years of assertive community treatment including social skill training, psychoeducation, and family involvement by a multidisciplinary team. TAU consisted of the available community mental health treatment. Main Outcomes and Measures: Psychopathological and functional outcomes, mortality, days of psychiatric hospitalizations, number of psychiatric outpatient contacts, use of supported housing/homeless shelters, symptom remission, and clinical recovery. Results: Of 547 participants, 164 (30%) were interviewed at 20-year follow-up (mean [SD] age, 45.9 [5.6] years; 85 [51.8%] female). No significant differences were found between the OPUS group compared with the TAU group on global functional levels (estimated mean difference, -3.72 [95% CI, -7.67 to 0.22]; P = .06), psychotic symptom dimensions (estimated mean difference, 0.14 [95% CI, -0.25 to 0.52]; P = .48), and negative symptom dimensions (estimated mean difference, 0.13 [95% CI, -0.18 to 0.44]; P = .41). The mortality rate was 13.1% (n = 36) in the OPUS group and 15.1% (n = 41) in the TAU group. Likewise, no differences were found 10 to 20 years after randomization between the OPUS and TAU groups on days of psychiatric hospitalizations (incidence rate ratio, 1.20 [95% CI, 0.73-1.20]; P = .46) or number of outpatient contacts (incidence rate ratio, 1.20 [95% CI, 0.89-1.61]; P = .24). Of the entire sample, 53 participants (40%) were in symptom remission and 23 (18%) were in clinical recovery. Conclusions and Relevance: In this follow-up study of a randomized clinical trial, no differences between 2 years of EIS vs TAU among individuals with diagnosed schizophrenia spectrum disorders at 20 years were found. New initiatives are needed to maintain the positive outcomes achieved after 2 years of EIS and furthermore improve very long-term outcomes. While registry data was without attrition, interpretation of clinical assessments are limited by high attrition rate. However, this attrition bias most likely confirms the lack of an observed long-term association of OPUS with outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT00157313.

20-year trajectories of positive and negative symptoms after the first psychotic episode in patients with schizophrenia spectrum disorder: results from the OPUS study.

This study aimed to identify the 20-year trajectories of positive and negative symptoms after the first psychotic episode in a sample of patients with an ICD-10 diagnosis of schizophrenia spectrum disorder, and to investigate the baseline characteristics and long-term outcomes associated with these trajectories. A total of 373 participants in the OPUS trial were included in the study. Symptoms were assessed at baseline and after 1, 2, 5, 10 and 20 years using the Scales for the Assessment of Positive and Negative Symptoms. We used latent class growth mixture modelling to identify trajectories, and multinominal regression analyses to investigate predictors of membership to identified trajectories. Five trajectories of positive symptoms were identified: early continuous remission (50.9% of the sample), stable improvement (18.0%), intermittent symptoms (10.2%), relapse with moderate symptoms (11.9%), and continuous severe symptoms (9.1%). Substance use disorder (odds ratio, OR: 2.83, 95% CI: 1.09-7.38, p=0.033), longer duration of untreated psychosis (OR: 1.02, 95% CI: 1.00-1.03, p=0.007) and higher level of negative symptoms (OR: 1.60, 95% CI: 1.07-2.39, p=0.021) were predictors of the relapse with moderate symptoms trajectory, while only longer duration of untreated psychosis (OR: 1.01, 95% CI: 1.00-1.02, p=0.030) predicted membership to the continuous severe symptoms trajectory. Two trajectories of negative symptoms were identified: symptom remission (51.0%) and continuous symptoms (49.0%). Predictors of the continuous symptoms trajectory were male sex (OR: 3.03, 95% CI: 1.48-6.02, p=0.002) and longer duration of untreated psychosis (OR: 1.01, 95% CI: 1.00-1.02, p=0.034). Trajectories displaying continuous positive and negative symptoms were linked to lower neurocognition, as measured by the Brief Assessment of Cognition in Schizophrenia (BACS) (z-score: -0.78, CI: -1.39 to -0.17, for continuous positive symptoms; z-score: -0.33, CI: -0.53 to -0.13, for continuous negative symptoms). The same trajectories were also linked to higher use of antipsychotic medication at 20-year follow-up (continuous positive symptoms: 78%; continuous negative symptoms: 67%). These findings suggest that the majority of patients with first-episode schizophrenia spectrum disorder have a trajectory with early stable remission of positive symptoms. Long duration of untreated psychosis and comorbid substance abuse are modifiable predictors of poor trajectories for positive symptoms in these patients. In about half of patients, negative symptoms do not improve over time. These symptoms, in addition to being associated with poor social and neurocognitive functioning, may prevent patients from seeking help.

Clinical Recovery Among Individuals With a First-Episode Schizophrenia an Updated Systematic Review and Meta-Analysis.

BACKGROUND AND HYPOTHESIS: Through decades the clinical recovery outcomes among individuals diagnosed with schizophrenia have been highly inconsistent ranging from 13.5% to 57%. The primary objective of this updated examination was to report the pooled estimate and explore various moderators to improve the understanding of the course of schizophrenia. STUDY DESIGN: A systematic literature search was set up on PubMed, PsycInfo, and EMBASE until January 13th, 2022. Both observational and interventional studies among cohorts of individuals with the first episode of schizophrenia reporting on clinical recovery were included. The PRISMA 2020 statement was used and data was extracted for a random-effects meta-analysis, meta-regression, and sensitivity analyses. Risk of bias was assessed using The Newcastle-Ottawa Scale. STUDY RESULTS: A 20.8% (95% CI = 17.3 to 24.8) recovery rate was found among 26 unique study samples (mean trial duration, 9.5 years) including 3877 individuals (mean age, 26.4 years). In meta-regression none of the following study characteristics could uncover the diverse reported recovery rates; age at inclusion (P = .84), year of inclusion (P = .93), follow-up time (P = .99), drop-out rate (P = .07), or strictness of the recovery criteria (P = .35). Furthermore, no differences in recovery were found between early intervention services (EIS; 19.5%; 95% CI = 15.0 to 24.8) compared to other interventions (21%; 95% CI = 16.9 to 25.8), P = .65. CONCLUSIONS: A clinical recovery rate of approximately 21% was found with minimum impact from various moderators. The rate was not different comparing EIS with other interventions implying that new initiatives are needed to improve the rate of recovery.

Self-reported reasons for discontinuation or continuation of antipsychotic medication in individuals with first-episode schizophrenia.

AIM: Many individuals with schizophrenia discontinue initially prescribed antipsychotics. Knowledge on reasons for discontinuation among individuals with first-episode schizophrenia is sparse. We aimed to describe reasons for discontinuation and continuation, differences between individuals discontinuing and continuing, and factors predicting reasons for discontinuation or continuation. METHODS: This was a prospective cohort study with a post hoc design. Individuals with first-episode schizophrenia were included from early intervention teams in Denmark from 2009-2012. Sociodemographic and clinical variables were collected at baseline and reasons for discontinuation and continuation of antipsychotics were assessed at 3.5-year follow-up. RESULTS: Among 215 patients, 76 reported reasons for discontinuation and 139 for continuation. The most frequent reasons for discontinuation were "side effects" and "patient believed he/she no longer needed the medication because he/she was now better". The most frequent reasons for continuation were "benefits for positive symptoms" and "another person told them to". Individuals who discontinued antipsychotics were at baseline younger, had longer DUP, less negative symptoms, better social function, lower compliance, higher self-belief of coping, and fewer used antipsychotics compared to those continuing antipsychotics. CONCLUSIONS: The effect of antipsychotics is the main reason to continue, whereas side effects were the main reason to discontinue. Knowledge of reasons to discontinue or continue is helpful in shared decision-making, identifying individuals with high odds of discontinuation, improving adherence, and helping with safe discontinuation.

Treatment of schizotypal disorder: a protocol for a systematic review of the evidence and recommendations for clinical practice.

INTRODUCTION: Schizotypal disorder is associated with a high level of disability at an individual level and high societal costs. However, clinical recommendations for the treatment of schizotypal disorder are scarce and based on limited evidence. This review aims to synthesise the current evidence on treatment for schizotypal disorder making recommendations for clinical practice. METHODS AND ANALYSIS: This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic literature search will be performed in PsychArticles, Embase, Medline and Cochrane Central Register of Controlled Trials. Additionally, we will search for relevant articles manually. Inclusion criteria are published studies including individuals diagnosed with schizotypal personality disorder according to Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, or schizotypal disorder according to International Classification of Diseases (ICD) criteria. We will include interventional studies comprising any pharmacological and non-pharmacological treatment trials for patients with schizotypal disorder, and all relevant outcome measures will be reported. Risk of bias will be assessed by Cochrane risk-of-bias tools. Data will be synthesised using narrative or thematic analysis and, if suitable, through meta-analysis. ETHICS AND DISSEMINATION: No original data will be collected as part of this study and ethics approval is, therefore, not applicable. The results will be disseminated through peer-reviewed publication and presented at international scientific meetings. We will aim at submitting the final paper for publication within 4 months of completion of analyses. Furthermore, this systematic review will inform clinicians and researchers on the current state of evidence on treatment for schizotypal disorder. Findings may guide proposals for further research and potentially guide recommendations for clinical practice using the Grading of Recommendations Assessment, Development and Evaluation. PROSPERO REGISTRATION NUMBER: CRD42022375001.

Tapered discontinuation vs. maintenance therapy of antipsychotic medication in patients with first-episode schizophrenia: Obstacles, findings, and lessons learned in the terminated randomized clinical trial TAILOR.

Aim: Evidence is insufficient regarding the consequences of discontinuing vs. maintaining antipsychotic medication in patients with first-episode schizophrenia. Our aim was to examine tapered discontinuation vs. maintenance treatment regarding remission of psychotic symptoms and impact on other areas. Methods: Patients included had a diagnosis of schizophrenia, were treated with antipsychotic medication, and were in remission of psychotic symptoms. Participants were randomized to tapered discontinuation or maintenance treatment with antipsychotic medication. Assessments were undertaken at baseline and after 1-year. The primary outcome was remission of psychotic symptoms without antipsychotic medication. Results: The trial was terminated due to insufficient recruitment. In total, 29 participants were included: 14 in the tapering/discontinuation group and 15 in the maintenance group. Adherence to maintenance treatment was poor. At 1-year follow-up, remission of psychotic symptoms without antipsychotic medication for 3 months was observed in five participants in the tapering/discontinuation group and two in the maintenance group. Conclusion: Due to insufficient recruitment this study does not provide a conclusion on whether unfavorable outcomes or advantages follow tapering of antipsychotic medication. Recruitment and adherence to maintenance treatment encountered obstacles. Based on experiences from this trial, we discussed alternative study designs as consistent evidence is still needed on whether to continue or discontinue antipsychotic medication in remitted patients with first-episode schizophrenia. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-000565-23/DK, EU Clinical Trials Register-EudraCT no. 2016-000565-23.

The Danish OPUS Early Intervention Services for First-Episode Psychosis: A Phase 4 Prospective Cohort Study With Comparison of Randomized Trial and Real-World Data.

OBJECTIVE: The Danish OPUS trial showed significant efficacy of early intervention services for first-episode schizophrenia spectrum disorders compared with standard treatment, leading to implementation of the OPUS intervention in clinical practice. The authors sought to determine whether the effectiveness of OPUS treatment in real-world clinical practice is comparable to the efficacy seen in the trial. METHODS: The study compared patients who received OPUS treatment as part of the original randomized trial to those who received standard treatment in the trial (the control group) and those who received OPUS treatment after it was implemented in Denmark. The authors investigated whether the three groups differed on register-based outcomes, such as use of secondary health care, functional outcomes, and death. Analyses were adjusted for relevant confounders. RESULTS: Compared with trial study participants, patients who received OPUS treatment after implementation (N=3,328) had a tendency toward lower mortality (hazard ratio=0.60, 95% CI=0.33, 1.09), fewer and shorter psychiatric admissions, and possibly fewer filled prescriptions of antipsychotics and other psycholeptics after 4 or 5 years. While at first less likely to be working or studying, patients who received postimplementation OPUS treatment eventually had higher odds of working than did those in the OPUS trial (after 5 years, odds ratio=1.49, 95% CI=1.07, 2.09). The odds of being in a couple relationship were also higher among patients in the postimplementation group than those in the trial. Other outcomes showed less clear associations with treatment group. Generally, the control group in the trial fared worse than both of the OPUS treatment groups. CONCLUSIONS: Not only did OPUS treatment maintain its efficacy after it was implemented as a standard treatment, it paralleled or surpassed many of the effects observed when the OPUS intervention was delivered in a randomized trial. The study results provide further evidence in support of implementation and funding of early intervention services worldwide.

Repetitive transcranial magnetic stimulation and transcranial direct current stimulation for auditory hallucinations in schizophrenia: Systematic review and meta-analysis.

Through imaging studies, a significant increase in cerebral activity has been detected in fronto-temporal areas in patients experiencing auditory verbal hallucinations. Therefore, non-invasive neuromodulation, in particular transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), has been considered as a therapeutic intervention for medication-resistant auditory verbal hallucinations in schizophrenia. We aimed to synthesize results from randomized trials on either rTMS or tDCS versus placebo in patients with schizophrenia by including five recently published trials in the field. A systematic review and meta-analysis of relevant literature was conducted. Studies were included on the basis of pre-defined selection criteria. The quality of the studies was assessed by the Cochrane Risk of Bias Tool for Randomized Controlled Trials. RevMan 5.3 was used to conduct the statistical analysis. Including 465 and 960 patients, respectively, 12 tDCS and 27 rTMS studies were included. Regarding treatment of medication refractory auditory verbal hallucinations, no significant effect of tDCS (-0.23 [-0.49, 0.02], p = 0.08) or rTMS (-0.19 [-0.50, 0,11], p = 0.21) was found compared to sham in this meta-analysis. The current study found that it cannot be concluded that rTMS and tDCS are efficacious in treating medication-resistant auditory verbal hallucinations. Larger randomized controlled tDCS trials of a higher quality should be conducted in the future to establish substantial evidence of tDCS. The interventions appear safe and may have beneficial effects on other outcomes.

Reversibility of Antipsychotic-Induced Weight Gain: A Systematic Review and Meta-Analysis.

Background and Aims: Weight gain is a major adverse effect of antipsychotic medication, negatively affecting physical and mental well-being. The objective of this study was to explore if dose reduction, discontinuation, switch to a partial agonist, or switch from polypharmacy to monotherapy will lead to weight loss. Methods: Controlled and uncontrolled studies reporting the effects of discontinuation, dose reduction, switch to a partial agonist, or switch from polypharmacy to monotherapy on weight were included. Primary outcome was difference in weight compared to maintenance groups based on controlled studies. Secondary outcome was change in weight from initiation of one of the included interventions until follow-up in a pre-post analysis. Results: We identified 40 randomized controlled trials and 15 uncontrolled studies including 12,279 individuals. The effect of the interventions, i.e. dose reduction, drug discontinuation, or switch to a partial agonis, reduced the weight with 1.5 kg (95% CI -2.03 to -0.98; P < 0.001) compared to maintenance treatment. The weight change from pre to post was a reduction of 1.13 kg (95% CI -1.36 to -0.90; P < 0.001). Conclusion: We found a significant but small reduction in weight, suggesting that antipsychotic-induced weight gain can be reversed to some degree. Only a few studies were designed to address the question as primary outcome, which limits the generalizability of our findings.

Associations between duration of untreated psychosis and domains of positive and negative symptoms persist after 10 years of follow-up: A secondary analysis from the OPUS trial.

BACKGROUND: Long duration of untreated psychosis (DUP) has been linked with more severe psychotic and negative symptoms. However, it is uncertain which specific psychotic and negative domains that are affected over time and if these are stable over the course of illness. OBJECTIVE: To examine whether DUP is associated with psychotic and negative symptoms measured longitudinally up to 10 years after initial assessment. METHOD: Psychopathology of participants from the OPUS I trial, aged 18-45 years with a baseline ICD-10 schizophrenia spectrum diagnosis, excluding schizotypal disorder (468 participants left), was assessed at baseline and 2, 5 and 10 years after initial assessment. The associations between DUP and domains of positive and negative symptoms were calculated using linear regression analysis. RESULTS: Longer DUP was significantly associated with the severity of hallucinations, delusions and anhedonia-asociality at baseline. Longer DUP remained significantly associated with hallucinations, delusions and anhedonia-asociality after 2 years. DUP was significantly associated with hallucinations, delusions, avolition-apathy and anhedonia-asociality after 5 years. Longer DUP was still significantly associated with hallucinations and delusions but not with any of the negative symptom subdomains after 10 years. Results were not substantially changed after adjusting for treatment with antipsychotic medication at each point in time. CONCLUSION: We demonstrated associations between DUP and the severity of hallucinations and delusions which persist after at least 10 years of follow-up and an association between longer DUP and anhedonia-asociality which persist until 5 years of follow-up. Further, DUP was associated with avolition-apathy after 5 years.

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.