Effectiveness and optimal duration of early intervention treatment in adult-onset psychosis: a randomized clinical trial.

BACKGROUND: Contrasting the well-described effects of early intervention (EI) services for youth-onset psychosis, the potential benefits of the intervention for adult-onset psychosis are uncertain. This paper aims to examine the effectiveness of EI on functioning and symptomatic improvement in adult-onset psychosis, and the optimal duration of the intervention. METHODS: 360 psychosis patients aged 26-55 years were randomized to receive either standard care (SC, n = 120), or case management for two (2-year EI, n = 120) or 4 years (4-year EI, n = 120) in a 4-year rater-masked, parallel-group, superiority, randomized controlled trial of treatment effectiveness (Clinicaltrials.gov: NCT00919620). Primary (i.e. social and occupational functioning) and secondary outcomes (i.e. positive and negative symptoms, and quality of life) were assessed at baseline, 6-month, and yearly for 4 years. RESULTS: Compared with SC, patients with 4-year EI had better Role Functioning Scale (RFS) immediate [interaction estimate = 0.008, 95% confidence interval (CI) = 0.001-0.014, p = 0.02] and extended social network (interaction estimate = 0.011, 95% CI = 0.004-0.018, p = 0.003) scores. Specifically, these improvements were observed in the first 2 years. Compared with the 2-year EI group, the 4-year EI group had better RFS total (p = 0.01), immediate (p = 0.01), and extended social network (p = 0.05) scores at the fourth year. Meanwhile, the 4-year (p = 0.02) and 2-year EI (p = 0.004) group had less severe symptoms than the SC group at the first year. CONCLUSIONS: Specialized EI treatment for psychosis patients aged 26-55 should be provided for at least the initial 2 years of illness. Further treatment up to 4 years confers little benefits in this age range over the course of the study.

Sex differences in symptom severity, cognition and psychosocial functioning among individuals with at-risk mental state for psychosis.

AIM: Sex differences are well documented in schizophrenia, but have been much less studied in at-risk mental state (ARMS) for psychosis. We aimed to examine sex differences in symptomatology, cognition, social and role functioning in individuals with ARMS, with specific focus on clarifying relationships between sex, negative symptoms and functioning. METHODS: One hundred and seventy-seven Chinese participants aged 15-40 years with ARMS were recruited from a specialized early intervention service in Hong Kong. ARMS status was verified by Comprehensive Assessment of At-Risk Mental State. Assessments encompassing symptom profiles, a brief battery of cognitive tests and social and role functioning were conducted. Brief Negative Symptom Scale was adapted to measure negative symptoms at the level of five core domains. RESULTS: Males with ARMS exhibited significantly poorer social functioning and more severe asociality of negative symptoms than female counterparts. Mediation analysis revealed that sex difference in social functioning became statistically insignificant when asocality was included in the model, indicating that asociality mediated the relationship between sex and social functioning. No sex differences were observed in other core domains of negative symptoms, other symptom dimensions, cognitive measures and role functioning. CONCLUSIONS: This study suggests that sex differences in ARMS may be less pronounced that those observed in established psychotic disorders. Our findings of differential pattern of asociality between sexes and its mediating role on sex difference in social functioning underscore the importance in investigating negative symptoms at a separable domain-level. Further research is required to identify sex-specific predictors of longitudinal outcomes in at-risk populations.

Predictors of Treatment-Resistant and Clozapine-Resistant Schizophrenia: A 12-Year Follow-up Study of First-Episode Schizophrenia-Spectrum Disorders.

Studies on the long-term development and early predictors of treatment-resistant schizophrenia (TRS) and clozapine-resistant TRS (CR-TRS) in patients with first-episode schizophrenia-spectrum disorders (FES) are limited and have not considered the impact of early intervention services (EIS). This study aimed to explore the development of TRS and CR-TRS among patients with FES over 12 years of follow-up. Of the 1234 patients with FES, 15% developed TRS. A total of 450 patients with schizophrenia or schizoaffective disorder were included in a nested case-control study (157 TRS and 293 non-TRS). Younger age of onset, poorer premorbid social adjustment during adulthood, longer duration of first episode, a greater number of relapses, and a higher antipsychotic dose in the first 24 months were associated with earlier TRS. CR-TRS patients, constituting 25% of TRS patients, had a poorer premorbid social adjustment in late adolescence and longer delay before clozapine initiation compared with non-CR-TRS. CR-TRS had poorer clinical and functional outcomes at 12-year follow-up. However, TRS patients on clozapine had a lower mortality rate compared with non-TRS patients. EIS did not have a significant impact on the development of TRS, but patients in the EIS group had a shorter delay of clozapine initiation. Results suggested that neurodevelopmental factors, early clinical characteristics, and requirement for higher antipsychotic dose may be associated with TRS development, highlighting multiple pathways leading to this form of illness. Specific interventions including relapse prevention and early initiation of clozapine during the early course of illness may reduce the rate of TRS and improve patient outcomes.

Psychiatric comorbidity in individuals at-risk for psychosis: Relationships with symptoms, cognition and psychosocial functioning.

AIM: Psychiatric comorbidity frequently occurs with at-risk mental state (ARMS) for psychosis. Its relationships with psychopathology, cognition and functioning, however, remain to be further clarified. We aimed to examine prevalence and correlates of psychiatric comorbidity, and its associations with psychosocial functioning and subjective quality-of-life (QoL) in a representative sample of Chinese ARMS individuals. METHODS: One hundred ten help-seeking participants aged 15 to 40 years with ARMS were recruited from a specialized early psychosis service in Hong Kong. ARMS status was verified by comprehensive assessment of at-risk mental state (CAARMS). Comorbid Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition non-psychotic psychiatric disorders at baseline were ascertained using diagnostic interview and medical record review. Assessments encompassing symptom profiles, psychosocial functioning, subjective QoL and a brief cognitive battery were conducted. RESULTS: Forty-nine (44.5%) ARMS participants were diagnosed as having comorbid non-psychotic psychiatric disorders at baseline, primarily depressive and anxiety disorders. Binary multiple logistic regression analysis revealed that female gender, more severe depressive symptoms, higher suicidality and poorer global cognitive functioning were independently associated with comorbid diagnosis status. ARMS participants with psychiatric comorbidity displayed significantly more limited extended social networks and poorer subjective QoL than those without psychiatric comorbidity. CONCLUSION: Comorbid disorders were frequently observed in Chinese ARMS individuals, and were linked to poorer cognition and higher suicide risk. Our findings underscore a potential critical role of psychiatric comorbidity in determining social functioning and subjective QoL in at-risk individuals. Further longitudinal research is required to clarify trajectories of comorbid disorder status and its prospective impact on clinical and functional outcomes in ARMS populations.

The role of symptoms and insight in mediating cognition and functioning in first episode psychosis.

INTRODUCTION: Achieving functional recovery in patients with psychosis is a challenge in clinical practice. Investigating the complex interplay between cognition, symptoms, insight and functional outcome in first episode psychosis will be crucial to understanding the factors leading to better functioning. METHODS: In this 12-month prospective follow-up study, we investigated how cognition, clinical symptoms, and insight into illness affected overall functioning in 160 patients with first episode psychosis recruited from the Early Assessment Service for Young People with Psychosis (EASY) in Hong Kong from July 1, 2014 to June 30, 2016. Cognition was assessed at baseline while symptoms, insight, and functioning were assessed at 12-month follow-up. Structural equation modelling was used to examine the direct and indirect relationships between functioning and other latent constructs. RESULTS: Symptoms (negative symptoms and general psychopathology) and insight were shown to be significant mediators between cognition and functioning. The significant direct relationship between cognition and functioning (ß = 0.387; p < 0.001) became insignificant (ß = 0.079; p = 0.578) after including symptoms and insight in the model. Symptoms and insight were significantly associated with cognition (symptoms, ß = -0.469; p < 0.001; insight, ß = -0.372; p < 0.001) and predicted functioning (symptoms, ß = -0.558; p < 0.001; insight, ß = -0.264; p < 0.01). CONCLUSION: Symptoms and insight mediated the effects of cognition on functioning. Interventions for improving functioning in patients with first episode psychosis should target not only cognition but also symptoms and insight.

Long-term effects of discontinuation from antipsychotic maintenance following first-episode schizophrenia and related disorders: a 10 year follow-up of a randomised, double-blind trial.

BACKGROUND: The long-term consequences of discontinuing antipsychotic medication after successful treatment of first-episode psychosis are not well studied. We assess the relation between early maintenance therapy decisions in first-episode psychosis and the subsequent clinical outcome at 10 years. METHODS: This is a 10 year follow-up study, spanning Sept 5, 2003, to Dec 30, 2014, of a randomised, double-blind trial in seven centres in Hong Kong in which 178 patients with first-episode psychosis with full positive symptom resolution after at least 1 year of antipsychotic treatment were given maintenance treatment (n=89; oral quetiapine 400 mg daily) or early treatment discontinuation (n=89; placebo) for 12 months. After the trial, patients received naturalistic treatment. Overall this cohort of patients will have received about 3 years of treatment before entering the follow-up phase of the study: about 2 years of maintenance treatment before study entry and 1 year of treatment in the trial. The primary outcome of this follow-up was the proportion of patients in each group (including those for whom direct follow-up was not available) with good or poor long-term clinical outcomes at 10 years, with poor outcome defined as a composite of persistent psychotic symptoms, a requirement for clozapine treatment, or death by suicide. The randomised trial was registered with ClinicalTrials.gov, number NCT00334035, and the follow-up study was registered with ClinicalTrials.gov, number NCT01926340. FINDINGS: Poor 10 year clinical outcome occurred in 35 (39%) of 89 patients in the discontinuation group and 19 (21%) of 89 patients in the maintenance treatment group (risk ratio 1·84, 95% CI 1·15-2·96; p=0·012). Suicide was the only serious adverse event that occurred in the follow-up phase (four [4%] patients in the early discontinuation group vs two [2%] in the maintenance group). INTERPRETATION: In patients with first-episode psychosis with a full initial response to treatment, medication continuation for at least the first 3 years after starting treatment decreases the risk of relapse and poor long-term clinical outcome. FUNDING: Food and Health Bureau, Research Grants Council of Hong Kong, and AstraZeneca.

A 3-year prospective study of neurological soft signs in first-episode schizophrenia.

Neurological soft signs are biological traits that underlie schizophrenia and are found to occur at higher levels in at-risk individuals. The expression of neurological soft signs may be modifiable during the onset of the first psychotic episode and the subsequent evolution of the illness and its treatment. This study investigates neurological soft signs in 138 patients with first-episode schizophrenia and tracks the expression of motor soft signs in the following 3 years. For the 93 patients who have completed the 3-year follow-up, we find that neurological soft signs are stable in the 3 years that follow the first psychotic episode, and that neurological soft signs are already elevated at the presentation of first-episode psychosis in medication-naive subjects. The level of neurological soft signs at clinical stabilization is lower for patients with a shorter duration of untreated psychosis. Although the quantity of neurological soft signs does not significantly change in the 3 years that follow the first episode, the relationship between neurological soft signs and negative symptoms does not become apparent until 1 year after the initial episode. A higher level of neurological soft signs is related to a lower educational level and an older age at onset, but the level of neurological soft signs does not predict the outcome in terms of relapse or occupational functioning.

A prospective 3-year longitudinal study of cognitive predictors of relapse in first-episode schizophrenic patients.

BACKGROUND: Cognitive predictors of relapse have been extensively explored only in few long term longitudinal studies of first-episode schizophrenia. METHOD: This study prospectively followed 93 patients with first-episode schizophrenia, schizophreniform disorder, and schizoaffective disorder for 3 years after their first-episode illness. Cognitive domains including verbal intelligence, verbal and visual memory, verbal fluency, and Wisconsin Card Sorting Test performance were investigated as potential predictors of relapse. RESULTS: We found that by the first year 21% patients had relapsed, by the second year 33% had relapsed, and by the third year 40% had relapsed. There was a significant difference in the relapse rate between patients with good adherence and patients with poor adherence to medication regimes. A multiple logistic regression analysis revealed that after controlling for medication adherence, perseverative error in the Wisconsin Card Sorting Test was the only cognitive function that significantly predict relapse with an odds ratio of 2.4. CONCLUSIONS: Cognitive flexibility in set shifting is related to tendency towards relapse in first-episode schizophrenic patients. Other cognitive factors appear not to be related to relapse. Possible mechanisms included the link between prefrontal dysfunction and sub-cortical dopamine system stability, as well as the effects of executive dysfunction on insight impairment and adherence behavior.

Prospective relationship between duration of untreated psychosis and 13-year clinical outcome: a first-episode psychosis study.

BACKGROUND: The adverse effects of a long duration of untreated psychosis (DUP) have been explored in numerous short-term studies. These studies support the development of early interventions that reduce treatment delay and promote recovery. However, the enduring impact of DUP is largely unknown, partly due to the paucity of prospective long-term studies. Although the DUP-outcome relationship is commonly assumed to be linear, the threshold effect has not been adequately examined. OBJECTIVE: To explore the relationship between DUP and long-term symptomatic remission. METHODS: This was a prospective study of a cohort of 153 first-episode psychosis patients in Hong Kong at the 13-year follow-up. The patients were categorized into short (≤30days), medium (31-180days) and long (>180days) DUP groups. RESULTS: The long-term outcome was ascertained in 73% of the patients. Nearly half of the patients (47%) fulfilled the criteria for symptomatic remission. The short DUP group experienced a significantly higher remission rate over the course of the illness. The odds of long-term symptomatic remission was significantly reduced in the medium DUP (by 89%) and long DUP (by 85%) groups compared with the short DUP group. Further analysis showed that DUP had a specific impact on negative symptom remission. CONCLUSION: The findings support the threshold theory that DUP longer than 30days adversely impacts the long-term outcome. The present study is one of the few studies that confirmed the enduring impact of DUP on long-term outcomes based on well-defined criteria and adequate statistical adjustment.

Longitudinal changes in semantic categorization performance after symptomatic remission from first-episode psychosis: a 3-year follow-up study.

Semantic categorization abnormalities have been observed in schizophrenia, but studies have rarely focused on the longitudinal trajectory. In this study, we consider semantic performance and the relationship with symptomatic changes during recovery from a first-episode of schizophrenia over a period of 3 years. Thirty-seven first-episode patients with schizophrenia were compared to thirty-seven matched controls in a categorization task. Patients were assessed at first episode, after clinical stabilization, and annually for the subsequent 3 years. In the task, participants indicated whether a word belonged to a given category. Each category contained words of varying degrees of semantic relatedness: typical, atypical, borderline, related-but-outside, and unrelated. Reaction times and proportion of 'yes' responses were analyzed. At first assessment, semantic categorization abnormalities were observed in first-episode patients. Patients assigned more semantically-dissimilar words to the categories than controls. As patients stabilized from acute states, their semantic categorization performance improved and then remained stable throughout the entire follow up period of 3 years. Interestingly, semantic performance deficits, particularly a diminished typicality effect, correlated with negative symptoms in the initial episode, but not at stabilization when symptoms subsided. No significant associations between positive and negative symptoms, or pre-defined categorization measures were identified. The data demonstrated semantic memory abnormalities in first-episode schizophrenia. However, an improvement of semantic categorization performance was observed in stabilized schizophrenia patients. Overall, the data are suggestive of a state effect in semantic abnormalities rather than a trait effect. The correlation between degree of impairment and symptoms may explain previous inconsistent findings.

The impact of family experience on the duration of untreated psychosis (DUP) in Hong Kong.

BACKGROUND: Previous family experience of psychotic illness may play an important role in whether and when a patient seeks help in first-episode psychosis. This study investigated the relationship between family experience of psychosis and the duration of untreated psychosis in a prospective sample of first-episode psychosis patients in Hong Kong. We also studied the effects of pre-morbid adjustment, educational level, living alone, and mode of onset as potential determinants of the duration of untreated psychosis (DUP). METHODS: A total of 131 first-episode psychosis patients in Hong Kong were recruited in a study of the DUP and related factors. The Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS) was used to measure the DUP and to provide a structured assessment of family history, educational level, household arrangement, and mode of onset. RESULTS: Previous family experience of psychiatric illness (the presence of another family member who has been receiving psychiatric treatment) and an acute mode of onset were significant predictors of a shorter DUP. Educational level had a modest effect on its own, but was not significant in the binary logistic regression model. Living alone had a moderate effect size, but was non-significant, possibly because of the small proportion of single-person households in the sample. The symptom profile, pre-morbid adjustment, and other demographic factors were not significantly related to the DUP. CONCLUSION: In addition to the mode of onset, previous family experience plays an important role in the presentation of early psychosis. Educational efforts that target the family should be an important part of any strategy for the early detection of psychosis.