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First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes.
We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS.
In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group.
The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder.
There is limited evidence of the safety and impact of task-shared care for people with severe mental illnesses (SMI; psychotic disorders and bipolar disorder) in low-income countries. The aim of this study was to evaluate the safety and impact of a district-level plan for task-shared mental health care on 6 and 12-month clinical and social outcomes of people with SMI in rural southern Ethiopia.
In the Programme for Improving Mental health carE, we conducted an intervention cohort study. Trained primary healthcare (PHC) workers assessed community referrals, diagnosed SMI and initiated treatment, with independent research diagnostic assessments by psychiatric nurses. Primary outcomes were symptom severity and disability. Secondary outcomes included discrimination and restraint.
Almost all (94.5%) PHC worker diagnoses of SMI were verified by psychiatric nurses. All prescribing was within recommended dose limits. A total of 245 (81.7%) people with SMI were re-assessed at 12 months. Minimally adequate treatment was received by 29.8%. All clinical and social outcomes improved significantly. The impact on disability (standardised mean difference 0.50; 95% confidence interval (CI) 0.35–0.65) was greater than impact on symptom severity (standardised mean difference 0.28; 95% CI 0.13–0.44). Being restrained in the previous 12 months reduced from 25.3 to 10.6%, and discrimination scores reduced significantly.
An integrated district level mental health care plan employing task-sharing safely addressed the large treatment gap for people with SMI in a rural, low-income country setting. Randomised controlled trials of differing models of task-shared care for people with SMI are warranted.
The development of effective preventions for psychosis is hindered by conceptual challenges underlying diagnosis and the fact that few of the many biological risk factors identified to date are sufficiently well understood to form the basis of a targeted intervention. On the other hand, a great deal is known of the psychosocial conditions that increase the lifetime risk of most mental illnesses: surely enough to justify better resourcing of interventions focused on antenatal care and the emotional well-being of children from the early years through adolescence, where as much as a half of all mental ill health has its roots.
Although antipsychotic medication remains the mainstay of treatment for schizophrenia, medications alone are not always successful. Cognitive–behavioural therapy (CBT) is recommended as an adjunct to pharmacological treatment. The Cochrane review under consideration evaluates the effects of offering CBT as an add-on to standard care compared with standard care alone, and this commentary puts those findings into their clinical context.
Oxidative stress is implicated in the etiology of schizophrenia, and the antioxidant defense system may be protective in this illness. We examined the major antioxidant glutathione (GSH) in prefrontal brain, and its correlates with clinical and demographic variables, in schizophrenia.
GSH levels were measured in the dorsolateral prefrontal region of 28 patients with chronic schizophrenia using a magnetic resonance spectroscopy sequence specifically adapted for GSH. We examined correlations of GSH levels with age, age at onset of illness, duration of illness, and clinical symptoms.
We found a negative correlation between GSH levels and age at onset (r=-.46, p=.015), and a trend-level positive relationship between GSH and duration of illness (r=.34, p=.076).
Our findings are consistent with a possible compensatory upregulation of the antioxidant defense system with longer duration of illness, and suggests the antioxidant defense system may play a role in schizophrenia.
The aggregation of neurocognitive deficits among the non-psychotic first-degree relatives of adult- and childhood-onset schizophrenia patients suggests that there may be a common etiology for these deficits in childhood- and adult-onset illness. However, there is considerable heterogeneity in the presentation of neurobiological abnormalities, and whether there are differences in the extent of familial transmission for specific domains of cognitive function has not been systematically addressed.
We employed variance components analysis, as implemented in SOLAR-Eclipse, to evaluate the evidence of familial transmission for empirically derived composite scores representing attention, working memory, verbal learning, verbal retention, and memory for faces. We contrast estimates for adult- and childhood-onset schizophrenia families and matched community control pedigrees, and compare our findings to previous reports based on analogous neurocognitive assessments.
We observed varying degrees of familial transmission; attention and working memory yielded comparable, significant estimates for adult-onset and community control pedigrees; verbal learning was significant for childhood-onset and community control pedigrees; and facial memory demonstrated significant familial transmission only for childhood-onset schizophrenia. Model-fitting analyses indicated significant differences in familiality between adult- and childhood-onset schizophrenia for attention, working memory, and verbal learning.
By comprehensively assessing a wide range of neurocognitive domains in adult- and childhood-onset schizophrenia families, we provide additional support for specific neurocognitive domains as schizophrenia endophenotypes. Whereas comparable estimates of familial transmission for certain dimensions of cognitive functioning support a shared etiology of adult- and childhood-onset neurocognitive function, observed differences may be taken as preliminary evidence of partially divergent multifactorial architectures.
Previous models suggest biological and behavioral continua among healthy individuals (HC), at-risk condition, and full-blown schizophrenia (SCZ). Part of these continua may be captured by schizotypy, which shares subclinical traits and biological phenotypes with SCZ, including thalamic structural abnormalities. In this regard, previous findings have suggested that multivariate volumetric patterns of individual thalamic nuclei discriminate HC from SCZ. These results were obtained using machine learning, which allows case–control classification at the single-subject level. However, machine learning accuracy is usually unsatisfactory possibly due to phenotype heterogeneity. Indeed, a source of misclassification may be related to thalamic structural characteristics of those HC with high schizotypy, which may resemble structural abnormalities of SCZ. We hypothesized that thalamic structural heterogeneity is related to schizotypy, such that high schizotypal burden would implicate misclassification of those HC whose thalamic patterns resemble SCZ abnormalities.
Following a previous report, we used Random Forests to predict diagnosis in a case–control sample (SCZ = 131, HC = 255) based on thalamic nuclei gray matter volumes estimates. Then, we investigated whether the likelihood to be classified as SCZ (π-SCZ) was associated with schizotypy in 174 HC, evaluated with the Schizotypal Personality Questionnaire.
Prediction accuracy was 72.5%. Misclassified HC had higher positive schizotypy scores, which were correlated with π-SCZ. Results were specific to thalamic rather than whole-brain structural features.
These findings strengthen the relevance of thalamic structural abnormalities to SCZ and suggest that multivariate thalamic patterns are correlates of the continuum between schizotypy in HC and the full-blown disease.
To determine the baseline individual characteristics that predicted symptom recovery and functional recovery at 10-years following the first episode of psychosis.
AESOP-10 is a 10-year follow up of an epidemiological, naturalistic population-based cohort of individuals recruited at the time of their first episode of psychosis in two areas in the UK (South East London and Nottingham). Detailed information on demographic, clinical, and social factors was examined to identify which factors predicted symptom and functional remission and recovery over 10-year follow-up. The study included 557 individuals with a first episode psychosis. The main study outcomes were symptom recovery and functional recovery at 10-year follow-up.
At 10 years, 46.2% (n = 140 of 303) of patients achieved symptom recovery and 40.9% (n = 117) achieved functional recovery. The strongest predictor of symptom recovery at 10 years was symptom remission at 12 weeks (adj OR 4.47; CI 2.60–7.67); followed by a diagnosis of depression with psychotic symptoms (adj OR 2.68; CI 1.02–7.05). Symptom remission at 12 weeks was also a strong predictor of functional recovery at 10 years (adj OR 2.75; CI 1.23–6.11), together with being from Nottingham study centre (adj OR 3.23; CI 1.25–8.30) and having a diagnosis of mania (adj OR 8.17; CI 1.61–41.42).
Symptom remission at 12 weeks is an important predictor of both symptom and functional recovery at 10 years, with implications for illness management. The concepts of clinical and functional recovery overlap but should be considered separately.
Mounting evidence shows genetic overlap between multiple psychiatric disorders. However, the biological underpinnings of shared risk for psychiatric disorders are not yet fully uncovered. The identification of underlying biological mechanisms is crucial for the progress in the treatment of these disorders.
We applied gene-set analysis including 7372 gene sets, and 53 tissue-type specific gene-expression profiles to identify sets of genes that are involved in the etiology of multiple psychiatric disorders. We included genome-wide meta-association data of the five psychiatric disorders schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. The total dataset contained 159 219 cases and 262 481 controls.
We identified 19 gene sets that were significantly associated with the five psychiatric disorders combined, of which we excluded five sets because their associations were likely driven by schizophrenia only. Conditional analyses showed independent effects of several gene sets that in particular relate to the synapse. In addition, we found independent effects of gene expression levels in the cerebellum and frontal cortex.
We obtained novel evidence for shared biological mechanisms that act across psychiatric disorders and we showed that several gene sets that have been related to individual disorders play a role in a broader range of psychiatric disorders.
The association between schizophrenia and decreased vitamin D levels is well documented. Low maternal and postnatal vitamin D levels suggest a possible etiological mechanism. Alternatively, vitamin D deficiency in patients with schizophrenia is presumably (also) the result of disease-related factors or demographic risk factors such as urbanicity.
In a study population of 347 patients with psychotic disorder and 282 controls, group differences in vitamin D concentration were examined. Within the patient group, associations between vitamin D, symptom levels and clinical variables were analyzed. Group × urbanicity interactions in the model of vitamin D concentration were examined. Both current urbanicity and urbanicity at birth were assessed.
Vitamin D concentrations were significantly lower in patients (B = −8.05; 95% confidence interval (CI) −13.68 to −2.42; p = 0.005). In patients, higher vitamin D concentration was associated with lower positive (B = −0.02; 95% CI −0.04 to 0.00; p = 0.049) and negative symptom levels (B = −0.03; 95% CI −0.05 to −0.01; p = 0.008). Group differences were moderated by urbanicity at birth (χ2 = 6.76 and p = 0.001), but not by current urbanicity (χ2 = 1.50 and p = 0.224). Urbanicity at birth was negatively associated with vitamin D concentration in patients (B = −5.11; 95% CI −9.41 to −0.81; p = 0.020), but not in controls (B = 0.72; 95% CI −4.02 to 5.46; p = 0.765).
Lower vitamin D levels in patients with psychotic disorder may in part reflect the effect of psychosis risk mediated by early environmental adversity. The data also suggest that lower vitamin D and psychopathology may be related through direct or indirect mechanisms.
This review aims to assess the cost-effectiveness of psychological interventions for schizophrenia/bipolar disorder (BD), to determine the robustness of current evidence and identify gaps in the available evidence.
Electronic searches (PsycINFO, MEDLINE, Embase) identified economic evaluations relating incremental cost to outcomes in the form of an incremental cost-effectiveness ratio published in English since 2000. Searches were concluded in November 2018. Inclusion criteria were: adults with schizophrenia/BD; any psychological/psychosocial intervention (e.g., psychological therapy and integrated/collaborative care); probability of cost-effectiveness at explicitly defined thresholds reported. Comparators could be routine practice, no intervention, or alternative psychological therapies. Screening, data extraction, and critical appraisal were performed using pre-specified criteria and forms. Results were summarized qualitatively. The protocol was registered on the PROSPERO database (CRD42017056579).
Of 3,864 studies identified, 12 met the criteria for data extraction. All were integrated clinical and economic randomized controlled trials. The most common intervention was cognitive behavioral therapy (CBT, 6/12 studies). The most common measure of health benefit was the quality-adjusted life-year (6/12). Follow-up ranged from 6 months to 5 years. Interventions were found to be cost-effective in most studies (9/12): the probability of cost-effectiveness ranged from 35-99.5 percent. All studies had limitations and demonstrated uncertainty (particularly related to incremental costs).
Most studies concluded psychological interventions for schizophrenia/BD are cost-effective, including CBT, although there was notable uncertainty. Heterogeneity across studies makes it difficult to reach strong conclusions. There is a particular need for more evidence in the population with BD and for longer-term evidence across both populations.
We review studies of whether cortisol levels following psychosocial stress exposure differ between patients with psychosis and healthy control subjects.
Original research published between 1993 and February 2019 was included in the literature search. Studies that used experimentally induced psychosocial stress and reported stress response measures of plasma or saliva cortisol levels in patients at any stage of illness (i.e. high risk, first episode and chronic phase) were included.
A total of 17 studies were included. Although there was evidence of inconsistencies in measures, we observed moderate evidence of an association with stress-induced cortisol blunting response across studies.
This review highlights recent evidence of blunting of cortisol response following experimentally induced psychosocial stress. While there was some evidence of this blunted response across illness types and stages, the strongest evidence was observed for those with chronic schizophrenia. Due to the low number of studies, in particular in bipolar disorder, much work is still needed to accurately characterise the biological effects of stress in psychosis.
Substantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ.
The present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2370 male and 2574 female UK Biobank participants.
There was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (β = 0.191, q = 0.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (β = 0.098, p = 0.026), compared to a negative association among controls (β = −0.087, p = 0.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons.
Our significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general.
Cognitive behavioural therapy (CBT) is a first-line strategy in reducing or delaying risk of transition to psychosis among young individuals with at-risk mental states (ARMS). However, there is little knowledge about its effects on other outcomes associated with ARMS. No study on CBT for ARMS has assessed worry, an important process associated with this condition. The present study investigated changes in worry at immediate post-treatment and 14-month follow-up after CBT for young individuals with ARMS seeking psychiatric care in mental health services. Thirty-seven young individuals (mean age = 26 years, SD = 6.07; 22.20% female) seeking psychiatric care in mental health services and classified as reporting ARMS through the Comprehensive Assessment of At-Risk Mental States were included. The Positive And Negative Syndrome Scales (PANSS) and Penn State Worry Questionnaire (PSWQ) were administered at baseline, post-treatment, and follow-up. CBT consisted of 30 weekly individual 1-hour sessions based on a validated CBT for ARMS manual enriched with components targeting worry [psychoeducation, problem-solving, (meta)cognitive restructuring, behavioural experiments]. Seven participants (18.91%) at follow-up had cumulatively made transition to psychosis. Repeated measures ANOVA with post-hoc pairwise comparisons showed significant changes in PSWQ scores from baseline to post-treatment and from baseline to follow-up; PSWQ scores remained stable from post-treatment to follow-up. This is the first study investigating changes in worry after CBT for ARMS, which appears to be a promising strategy also for this outcome. Future research with a larger sample size and control group may determine whether changes in worry are also associated with reduced transition risk.
Key learning aims
(1)To understand CBT evidence and procedures for young individuals with ARMS.
(2)To reflect on the current limitations in the literature on CBT for ARMS.
(3)To understand the importance and clinical implications of assessing worry in ARMS.
(4)To focus on changes in worry as an outcome after CBT for ARMS.
(5)To reflect on future research directions on the role of worry in CBT for ARMS.
Computerized cognitive remediation therapy (CCRT) is generally effective for the cognitive deficits of schizophrenia. However, there is much uncertainty about what factors mediate or moderate effectiveness and are therefore important to personalize treatment and boost its effects.
In total, 311 Chinese inpatients with Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia were randomized to receive CCRT or Active control for 12 weeks with four to five sessions per week. All participants were assessed at baseline, post-treatment and 3-month follow-up. The outcomes were cognition, clinical symptoms and functional outcomes.
There was a significant benefit in the MATRICS Consensus Cognitive Battery (MCCB) total score for CCRT (F1,258 = 5.62; p = 0.02; effect size was 0.27, 95% confidence interval 0.04–0.49). There were no specific moderators of CCRT improvements. However, across both groups, Wisconsin Card Sort Test improvement mediated a positive effect on functional capacity and Digit Span benefit mediated decreases in positive symptoms. In exploratory analyses younger and older participants showed cognitive improvements but on different tests (younger on Symbol Coding Test, while older on the Spatial Span Test). Only the older age group showed MSCEIT benefits at post-treatment. In addition, cognition at baseline negatively correlated with cognitive improvement and those whose MCCB baseline total score was around 31 seem to derive the most benefit.
CCRT can improve the cognitive function of patients with schizophrenia. Changes in cognitive outcomes also contributed to improvements in functional outcomes either directly or solely in the context of CCRT. Age and the basic cognitive level of the participants seem to affect the cognitive benefits from CCRT.
Schizophrenia is associated with significant cognitive impairment. However, the pathophysiological mechanisms underlying cognitive dysfunction in schizophrenia remain unclear. Brain-derived neurotrophic factor (BDNF) and C-reactive protein (CRP) are among the most commonly investigated peripheral markers of cognition in schizophrenia.
A systematic review in PubMed and Scopus databases was performed until 31 January 2019 to assess the relationship between cognitive impairment, CRP and BDNF levels in schizophrenia. A random-effects meta-analysis was conducted.
Current meta-analysis included 21 studies including 2449 patients with schizophrenia-spectrum disorders. Overall, both BDNF [r = 0.12, confidence interval (CI) 0.04–0.19] and CRP (r = −0.13, CI 0.08–0.18) levels were very modestly but significantly related to cognitive functioning in schizophrenia (r = 0.12, CI 0.04–0.19). In meta-analyses of cognitive domains, BDNF levels were significantly associated with verbal memory (r = 0.16, CI 0.09–0.23), working memory (r = 0.14, CI 0.06–0.22), processing speed (r = 0.18, CI 0.10–0.26) and verbal fluency (r = 0.09, CI 0–0.18) performances. Elevated CRP levels were related to all cognitive domains (r = −0.09 to −0.13) except for fluency. Subgroup analyses suggested that the relationship between cognitive and BDNF levels were more pronounced in chronic samples.
Current findings suggest that cognitive impairment in schizophrenia is significantly related to elevated CRP and reduced BDNF levels in schizophrenia, particularly in chronic samples. However, small effect sizes of these correlations suggest that inflammation and decreased BDNF levels do not play a major role in cognitive dysfunction in most patients with schizophrenia. Further studies are needed to investigate the potential intermediating and confounding factors which can influence the level of relationship between inflammation, neurotrophic factors and cognition in schizophrenia.
Little is known about long-term employment outcomes for patients with first-episode schizophrenia-spectrum (FES) disorders who received early intervention services.
We compared the 10-year employment trajectory of patients with FES who received early intervention services with those who received standard care. Factors differentiating the employment trajectories were explored.
Patients with FES (N = 145) who received early intervention services in Hong Kong between 1 July 2001 and 30 June 2002 were matched with those who entered standard care 1 year previously. We used hierarchical clustering analysis to explore the 10-year employment clusters for both groups. We used the mixed model test to compare cluster memberships and piecewise regression analysis to compare the employment trajectories of the two groups.
There were significantly more patients who received the early intervention service in the good employment cluster (early intervention: N = 98 [67.6%]; standard care: N = 76 [52.4%]; P = 0.009). In the poor employment cluster, there was a significant difference in the longitudinal pattern between early intervention and standard care for years 1–5 (P < 0.0001). The number of relapses during the first 3 years, months of full-time employment during the first year and years of education were significant in differentiating the clusters of the early intervention group.
Results suggest there was an overall long-term benefit of early intervention services on employment. However, the benefit was not sustained for all patients. Personalisation of the duration of the early intervention service with a focus on relapse prevention and early vocational reintegration should be considered for service enhancement.
Declaration of interests
No relevant conflicts of interests reported by C.L.M.H., Y.N.S., P.S., H.H.P. and K.K.Y. S.K.W.C., W.C.C. and E.H.M.L. report that they are members of the working group of the Early Assessment Service for Young People with Psychosis (EASY) programme of the Hospital Authority in Hong Kong. E.Y.H.C. is the convener of the working group of the EASY programme of the Hospital Authority in Hong Kong.
Aggressive and violent behavior, including both verbal and physical aggression, have considerable adverse consequences for people with schizophrenia. There are several potential causes of violent behavior on the part of people with severe mental illness, which include intellectual impairments, cognitive and social-cognitive deficits, skills deficits, substance abuse, antisocial features, and specific psychotic features. This review explores the interventions that have been tested to this date. Computerized Cognitive Training (CCT) or Computerized Social-Cognitive Training (CSCT) have been associated with reductions in violence. Combined CCT and CSCT have been found to improve social cognition and neurocognition, as well as everyday functioning when combined with rehabilitation interventions. These interventions have been shown to reduce violence in schizophrenia patients across multiple environments, including forensic settings. The reductions in violence and aggression have manifested in various ways, including reduced violent thinking and behavior, reduced physical and violent assaults, and reduced disruptive and aggressive behaviors. Effects of cognitive training may be associated with improvements in problem-solving and the increased ability to deploy alternative strategies. The effect of social cognition training on violence reduction appears to be direct, with improvements in violence related to the extent of improvement in social cognition. There are still remaining issues to be addressed in the use of CCT and CSCT, and the benefits should not be overstated; however, the results of these interventions are very promising.
Genome-wide association studies (GWAS) have consistently revealed that a variant of microRNA 137 (MIR137) shows a quite significant association with schizophrenia. Identifying the network of genes regulated by MIR137 could provide insights into the biological processes underlying schizophrenia. In addition, DLPFC functional connectivity, a robust correlate of MIR137, may provide plausible endophenotypes. However, the regulatory role of the MIR137 gene network in the disrupted functional connectivity remains unclear. Here, we tested the effects of the MIR137 regulated genes on the risk for schizophrenia and DLPFC functional connectivity.
To evaluate the additive effects of the MIR137 regulated genes (N = 1274), we calculated a MIR137 polygenic risk score (PRS) for schizophrenia and tested its association with the risk for schizophrenia in the genomic data of a Han Chinese population that included schizophrenia patients (N = 589) and normal controls (N = 575). We then investigated the association between MIR137 PRS and DLPFC functional connectivity in two independent young healthy cohorts (N = 356 and N = 314).
We found that the MIR137 PRS successfully captured the differences in genetic structure between the patients and controls, but the single gene MIR137 did not. We then consistently found that a higher MIR137 PRS was correlated with lower functional connectivities between the DLPFC and both the superior parietal cortex and the inferior temporal cortex in two independent cohorts.
The findings suggested that these two functional connectivities of the DLPFC could be important endophenotypes linking the MIR137-regulated genetic structure to schizophrenia.