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.

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.

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.

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.

Association between cannabis use disorder and schizophrenia stronger in young males than in females.

BACKGROUND: Previous research suggests an increase in schizophrenia population attributable risk fraction (PARF) for cannabis use disorder (CUD). However, sex and age variations in CUD and schizophrenia suggest the importance of examining differences in PARFs in sex and age subgroups. METHODS: We conducted a nationwide Danish register-based cohort study including all individuals aged 16-49 at some point during 1972-2021. CUD and schizophrenia status was obtained from the registers. Hazard ratios (HR), incidence risk ratios (IRR), and PARFs were estimated. Joinpoint analyses were applied to sex-specific PARFs. RESULTS: We examined 6 907 859 individuals with 45 327 cases of incident schizophrenia during follow-up across 129 521 260 person-years. The overall adjusted HR (aHR) for CUD on schizophrenia was slightly higher among males (aHR = 2.42, 95% CI 2.33-2.52) than females (aHR = 2.02, 95% CI 1.89-2.17); however, among 16-20-year-olds, the adjusted IRR (aIRR) for males was more than twice that for females (males: aIRR = 3.84, 95% CI 3.43-4.29; females: aIRR = 1.81, 95% CI 1.53-2.15). During 1972-2021, the annual average percentage change in PARFs for CUD in schizophrenia incidence was 4.8 among males (95% CI 4.3-5.3; p < 0.0001) and 3.2 among females (95% CI 2.5-3.8; p < 0.0001). In 2021, among males, PARF was 15%; among females, it was around 4%. CONCLUSIONS: Young males might be particularly susceptible to the effects of cannabis on schizophrenia. At a population level, assuming causality, one-fifth of cases of schizophrenia among young males might be prevented by averting CUD. Results highlight the importance of early detection and treatment of CUD and policy decisions regarding cannabis use and access, particularly for 16-25-year-olds.

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.

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.

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.

[Non-pharmacological therapies show effect in the treatment of schizophrenia].

Treating schizophrenia requires both antipsychotic medication and psychosocial interventions. This review summarises the current knowledge in this area. A mixed treatment meta-analysis has recently concluded that family interventions, psychoeducation and cognitive behavioural therapy show the greatest effect in preventing relapse and reducing symptoms. These are included in the Danish OPUS treatment, but far from all patients receive these treatment options. This needs to be prioritised, if we want to ensure the best treatment for all patients suffering from schizophrenia.

Mortality in substance-induced psychosis: a register-based national cohort study.

AIMS: We aimed to analyze whether people with substance-induced psychosis (SIP), both those who convert and do not convert to schizophrenia, have higher all-cause and cause-specific mortality when compared to the general population. DESIGN: Prospective cohort study. SETTING: Nationwide Danish registers. PARTICIPANTS/CASES: We included all people born in Denmark, living in Denmark on their 15th birthday, and age 15 or more during the study period from January 1, 1994, and August 10, 2017. MEASUREMENTS: Exposure was categorized as: (i) neither SIP nor schizophrenia; (ii) SIP without preceding schizophrenia; (iii) SIP converted to schizophrenia; and (iv) schizophrenia without preceding SIP. Any SIP and substance-specific SIPS were examined regarding all-cause and cause-specific mortality. FINDINGS: The study included a total of 5 619 691 individuals. Compared to people with neither schizophrenia nor SIP, people with SIP without preceding schizophrenia had an increased risk of dying (hazard ratio [HR] = 6.23, 95% CI = 5.96-6.50), as had those with SIP converting to schizophrenia (HR = 9.77, 95% CI = 8.84-10.79) and those with only schizophrenia (HR = 3.07, 95% CI = 3.03-3.13). A similar pattern, albeit with higher HRs, was observed for suicides and accidental deaths. Other cause-specific-mortality groups also generally showed the same pattern, as did types of individual substances. CONCLUSIONS: Substance-induced psychosis was strongly associated with an increased risk of both all-cause and cause-specific mortality, even among cases who did not convert to schizophrenia. This provides a strong rationale for monitoring people with previous diagnosis of substance-induced psychosis and developing and implementing interventions to reduce this excess mortality.

Annual incidence of cannabis-induced psychosis, other substance-induced psychoses and dually diagnosed schizophrenia and cannabis use disorder in Denmark from 1994 to 2016.

BACKGROUND: Worldwide, cannabis is the most used illegal substance, and the use of cannabis has increased over the years. An increase in the level of tetrahydrocannabinol (THC) in cannabis has also been seen. It is currently unclear whether this has led to an increase in the incidence of cannabis-induced psychosis. We aimed to investigate (1) the development of incidence of cannabis-induced psychosis over time compared with other substance-induced psychoses and (2) the development of incident cases of cannabis-induced psychosis over time compared with dual diagnosis defined as schizophrenia and a cannabis use disorder. METHOD: Data on psychiatric diagnoses were extracted from the Danish Psychiatric Central Research Register and summarized per year as both absolute incidence (number of cases) and incidence rates per 100 000 person years. RESULTS: The incidence rate of cannabis-induced psychosis increased steadily from 2.8 per 100 000 person years in 2006 to 6.1 per 100 000 person years in 2016. There was a corresponding increase in dual diagnosis with schizophrenia and cannabis use disorder, but a decrease in alcohol-induced psychosis. The data showed no trend in the other substance-induced psychosis investigated in this thesis. CONCLUSION: The increase in cannabis-induced psychosis follows both the increase in the level of THC in cannabis, and the increase in cannabis use. The change in diagnostic practice does not appear to explain the increase in incidence of cannabis-induced psychosis.

Infections as a Risk Factor for and Prognostic Factor After Substance-Induced Psychoses.

OBJECTIVE: Previous studies have suggested that infections increase the risk of schizophrenia. In this study, the authors aimed to investigate 1) whether infections increase the risk of substance-induced psychosis, and 2) whether infections increase the risk of converting from substance-induced psychosis to schizophrenia. METHODS: The study data were drawn from the combined nationwide Danish registers and included all people born in Denmark since 1981. The authors used Cox proportional hazards regression with infections as time-varying covariates, estimating hazard ratios and 95% confidence intervals. Infections were operationalized both as any infection and by the site of infection. RESULTS: The study included 2,256,779 individuals, for whom 3,618 cases of incident substance-induced psychosis were recorded. Any infection increased the risk of substance-induced psychosis (hazard ratio=1.30, 95% CI=1.22-1.39). For the first 2 years, the risk was doubled. Hepatitis was the infection most strongly associated with substance-induced psychosis (hazard ratio=3.42, 95% CI=2.47-4.74). Different types of infections were linked with different types of substance-induced psychosis. Most associations remained significant after controlling for potential confounders, such as substance use disorders. Only hepatitis predicted conversion to schizophrenia after substance-induced psychosis (hazard ratio=1.87, 95% CI=1.07- 3.26). CONCLUSIONS: The study results support the hypothesis of an immunological component to psychosis.

Rates and Predictors of Conversion to Schizophrenia or Bipolar Disorder Following Substance-Induced Psychosis.

OBJECTIVE: The authors investigated the rates of conversion to schizophrenia and bipolar disorder after a substance-induced psychosis, as well as risk factors for conversion. METHOD: All patient information was extracted from the Danish Civil Registration System and the Psychiatric Central Research Register. The study population included all persons who received a diagnosis of substance-induced psychosis between 1994 and 2014 (N=6,788); patients were followed until first occurrence of schizophrenia or bipolar disorder or until death, emigration, or August 2014. The Kaplan-Meier method was used to obtain cumulative probabilities for the conversion from a substance-induced psychosis to schizophrenia or bipolar disorder. Cox proportional hazards regression models were used to calculate hazard ratios for all covariates. RESULTS: Overall, 32.2% (95% CI=29.7-34.9) of patients with a substance-induced psychosis converted to either bipolar or schizophrenia-spectrum disorders. The highest conversion rate was found for cannabis-induced psychosis, with 47.4% (95% CI=42.7-52.3) converting to either schizophrenia or bipolar disorder. Young age was associated with a higher risk of converting to schizophrenia. Self-harm after a substance-induced psychosis was significantly linked to a higher risk of converting to both schizophrenia and bipolar disorder. Half the cases of conversion to schizophrenia occurred within 3.1 years after a substance-induced psychosis, and half the cases of conversion to bipolar disorder occurred within 4.4 years. CONCLUSIONS: Substance-induced psychosis is strongly associated with the development of severe mental illness, and a long follow-up period is needed to identify the majority of cases.