Niall Crumlish

Early insight predicts depression and attempted suicide after 4 years in first‐episode schizophrenia and schizophreniform disorder

Objective:  To map the development of insight in the 4 years after presentation with first‐episode schizophrenia and schizophreniform disorder and to determine the effects of evolving insight on depression and the likelihood of attempted suicide.

Beyond the critical period: longitudinal study of 8-year outcome in first-episode non-affective psychosis

BACKGROUND The critical period hypothesis proposes that deterioration occurs aggressively during the early years of psychosis, with relative stability subsequently. Thus, interventions that shorten the duration of untreated psychosis (DUP) and arrest early deterioration may have long-term benefits. AIMS To test the critical period hypothesis by determining whether outcome in non-affective psychosis stabilises beyond the critical period and whether DUP correlates with 8-year outcome; to determine whether duration of untreated illness (DUI) has any independent effect on outcome. METHOD We recruited 118 people consecutively referred with first-episode psychosis to a prospective, naturalistic cohort study. RESULTS Negative and disorganised symptoms improved between 4 and 8 years. Duration of untreated psychosis predicted remission, positive symptoms and social functioning at 8 years. Continuing functional recovery between 4 and 8 years was predicted by DUI. CONCLUSIONS These results provide qualified support for the critical period hypothesis. The critical period could be extended to include the prodrome as well as early psychosis.

Prospective relationship of duration of untreated psychosis to psychopathology and functional outcome over 12 years.

BACKGROUND The duration of untreated psychosis is well recognised as an independent predictor of symptomatic and functional outcome in the short term and has facilitated the development of worldwide early intervention programmes. However, the extent and mechanisms by which it might influence prognosis beyond a decade remain poorly understood. METHODS The authors examined the relationship between duration of untreated psychosis and outcome 12years after a first episode of psychosis and assessed whether its relationship with function is affected by symptoms in a prospective, 12-year follow-up of an epidemiologically-based inception cohort. RESULTS Longer duration of untreated psychosis predicted poorer remission status, more severe positive and negative symptoms, and greater impairment in general functioning, social functioning and quality of life at 12years on standardised measures, independent of other factors at baseline. It was not associated with gainful employment, for which education was the only predictor, or independent living, for which age was the only predictor. The relationship between duration of untreated psychosis and functional outcome was mediated by concurrent psychopathology, particularly negative symptoms. CONCLUSIONS These results provide qualified support for the potential long-term benefit of reduction in the duration of untreated psychosis in terms of improvement in symptoms and functional outcome. Its failure to predict real-life outcomes such as independent living and gainful employment could reflect the importance of pre-existing socio-cultural factors such as individual opportunity. The relationship between duration of untreated psychosis and negative symptoms was largely responsible for its effect on function, suggesting a possible long-term protective mechanism against disability.

Dysbindin (DTNBP1) and the Biogenesis of Lysosome-Related Organelles Complex 1 (BLOC-1): Main and Epistatic Gene Effects Are Potential Contributors to Schizophrenia Susceptibility

BACKGROUND The DTNBP1 gene, encoding dysbindin, has been strongly implicated in schizophrenia (SZ) susceptibility by a series of independent genetic association and gene expression studies. Among its known functions, dysbindin is part of a protein complex, termed the biogenesis of lysosome-related organelles complex 1 (BLOC-1), the molecular components of which might be involved in the regulation of vesicular trafficking and dendrite branching. METHODS A systematic investigation of the other seven BLOC-1 genes (MUTED, PLDN, CNO, SNAPAP, BLOC1S1, BLOC1S2, and BLOC1S3) for evidence of association with SZ was undertaken in a sample of 373 SZ cases and 812 control subjects. Possible epistasis between combinations of BLOC-1 genes, including DTNBP1, was tested with a novel method of investigating for gene-gene interaction. Quality control measures were incorporated into genotyping strategy, and all results were corrected for multiple testing to prevent false positive results. RESULTS We identified significant evidence of association between BLOC1S3 and SZ (odds ratio = 1.45, confidence interval = 1.13-1.86, p = .0028, corrected p = .0389). We also report evidence for epistatic interaction between DTNBP1 and MUTED contributing to SZ in the absence of a significant main effect at MUTED (p = .0009, corrected p = .0252). Single marker and epistasis results remained significant after correction for multiple testing. CONCLUSIONS Together these data provide evidence for the involvement of the BLOC-1 protein complex in SZ pathogenesis.

Nonadherence to Medication Four Years After a First Episode of Psychosis and Associated Risk Factors

OBJECTIVES This study examined concurrent associations and predictors at first indication of nonadherence to antipsychotic medication four years after a first episode of psychosis. METHODS A prospective cohort of 171 patients in urban Ireland with a first episode of psychosis was followed up four years after inception (follow-up primary analysis, N=84; secondary analysis, N=104). RESULTS At the four-year follow-up 76% were adherent and 24% were not. Nonadherence was concurrently associated with substance misuse (p<.01), increased symptomatology (p<.01), less insight (p=.01), lower global functioning (p<.01), and negative attitudes toward medication (p<.01). Compared with other patients, those who were nonadherent had more readmissions (p=.01). Predictors of future nonadherence were substance misuse (p=.02) and duration of untreated psychosis (p=.04). CONCLUSIONS This prospective investigation confirms previous cross-sectional studies. The association between longer duration of untreated psychosis and nonadherence warrants further research because it could be interpreted as further evidence of the importance of early intervention.

Chitinase-3-Like 1 (CHI3L1) Gene and Schizophrenia: Genetic Association and a Potential Functional Mechanism

BACKGROUND Gene expression data and association analyses in two Chinese samples implicate chitinase 3-like 1 (CHI3L1), a cellular survival gene, in schizophrenia susceptibility. METHODS We tested whether the association data are robust to replication in a Caucasian schizophrenia sample and performed a comprehensive investigation of common genetic variation at the locus. RESULTS In a sample of 375 case and 812 control subjects we identified significant association with the same risk allele at the promoter single nucleotide polymorphism (SNP) associated in the original study (rs10399805; p = .018) and with another SNP at intron 7 of CHI3L1 (rs2275351; p = .008). The rs10399805 SNP is located at position -247 and disrupts the C/EBP-AML-1 binding site in the gene promoter; the risk allele is predicted to increase CHI3L1 expression, as has been reported in several postmortem schizophrenia studies. Carriers of the risk variant presented with fewer positive symptoms and relatively spared cognitive performance compared with other schizophrenia patients. CONCLUSIONS These findings support a functional mechanism for involvement of CHI3L1 in schizophrenia susceptibility, possibly contributing to a less severe illness. The associated variants in this study are not well tagged by all Whole-Genome Association (WGA) platforms, suggesting additional genotyping may be necessary despite the imminent availability of WGA data from large SZ samples. Because CHI3L1 may be involved in transmission of stress-induced cellular responses, studies of interaction with known environmental risk factors may also be warranted.

Mental health and the asylum process

A refugee, according to the United Nations and Irish law, is: “a person who owing to a well-founded fear of being persecuted for reasons of race, religion, nationality, membership of a particular social group or political opinion, is outside the country of his nationality and is unable or, owing to such fear, is unwilling to avail himself of the protection of that country”.1,2 An asylum-seeker is a person who has left his or her country of origin, has applied for refugee status in another jurisdiction and is awaiting a decision on that application.3 The majority of asylum-seekers are from countries that are in conflict.4 Because asylum-seekers lack refugee status under the UN Convention Relating to the Status of Refugees, they do not have the rights to which a refugee is entitled under international law. The prevalence of mental disorder among all forcibly displaced people is high, because of pre-migration traumas, difficulties encountered during migration, and post-migration stressors.5,6 From a mental health perspective, the situation that asylum-seekers find themselves in after arriving in their destination country differs in key respects to the situation of a refugee. Asylum-seekers experience post-migration stressors that refugees do not.7 They have insecure residency status and live in constant fear of repatriation.8 Asylum applications may take years to process and during this time people seeking asylum in Ireland do not have the right to work or to private accommodation.9 The asylum process is adversarial, with the burden of proof placed on the asylum-seeker.10 Detention, a stressor that refugees do not endure once they achieve refugee status, has repeatedly been shown adversely to affect mental health.7,11