The latest medical research on Schizophrenia

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

Schizophrenia Bulletin

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.

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.

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.

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.

Aberrant Cerebello-Thalamo-Cortical Functional and Effective Connectivity in First-Episode Schizophrenia With Auditory Verbal Hallucinations.

Schizophrenia Bulletin

The thalamus is known to be impaired in schizophrenia patients with auditory verbal hallucinations (AVHs). Abnormal filtering function of the thala...

Heightened COVID-19 Mortality in People With Severe Mental Illness Persists After Vaccination: A Cohort Study of Greater Manchester Residents.

Schizophrenia Bulletin

Previous studies show that people with severe mental illness (SMI) are at higher risk of COVID-19 mortality, however limited evidence exists regarding risk postvaccination. We investigated COVID-19 mortality among people with schizophrenia and other SMIs before, during and after the UK vaccine roll-out.

Using the Greater Manchester (GM) Care Record to access routinely collected health data linked with death records, we plotted COVID-19 mortality rates over time in GM residents with schizophrenia/psychosis, bipolar disorder (BD), and/or recurrent major depressive disorder (MDD) from February 2020 to September 2021. Multivariable logistic regression was used to compare mortality risk (risk ratios; RRs) between people with SMI (N = 193 435) and age-sex matched controls (N = 773 734), adjusted for sociodemographic factors, preexisting comorbidities, and vaccination status.

Mortality risks were significantly higher among people with SMI compared with matched controls, particularly among people with schizophrenia/psychosis (RR 3.18, CI 2.94-3.44) and/or BD (RR 2.69, CI 2.16-3.34). In adjusted models, the relative risk of COVID-19 mortality decreased, though remained significantly higher than matched controls for people with schizophrenia (RR 1.61, CI 1.45-1.79) and BD (RR 1.92, CI 1.47-2.50), but not recurrent MDD (RR 1.08, CI 0.99-1.17). People with SMI continued to show higher mortality rate ratios relative to controls throughout 2021, during vaccination roll-out.

People with SMI, notably schizophrenia and BD, were at greater risk of COVID-19 mortality compared to matched controls. Despite population vaccination efforts that have prioritized people with SMI, disparities still remain in COVID-19 mortality for people with SMI.

A Randomized Controlled Trial of the Effects of Early Intervention Services On Insight in First Episode Psychosis.

Schizophrenia Bulletin

Impaired insight into one's illness is common in first episode psychosis (FEP), is associated with worse symptoms and functioning, and predicts a worse course of illness. Despite its importance, little research has examined the effects of early intervention services (EIS) on insight.

This paper evaluated the impact of EIS (NAVIGATE) on insight compared to usual community care (CC) in a large cluster randomized controlled trial. Assessments were conducted at baseline and every 6 months for 2 years.

A multilevel regression model including all time points showed a significant time by treatment group interaction (P < .001), reflecting greater improvement in insight for NAVIGATE than CC participants. Impaired insight was related to less severe depression but worse other symptoms and functioning at baseline for the total sample. At 6 months, the same pattern was found within each group except insight was no longer associated with depression among NAVIGATE participants. Impaired insight was more strongly associated with worse interpersonal relationships at 6 months in NAVIGATE than in CC, and changes in insight from baseline to 6 months were more strongly correlated with changes in relationships in NAVIGATE than CC.

The NAVIGATE program improved insight significantly more than CC. Although greater awareness of illness has frequently been found to be associated with higher depression in schizophrenia, these findings suggest EIS programs can improve insight without worsening depression in FEP. The increased association between insight and social relationships in NAVIGATE suggests these 2 outcomes may synergistically interact to improve each other in treatment.

Recovery After Stress-Autonomic and Subjective Arousal in Individuals With Psychosis Compared to Healthy Controls.

Schizophrenia Bulletin

Heightened stress levels in individuals with psychosis (PSY) are associated with psychotic symptom occurrence and may be partially attributed to well-established deficits in resting-state heart rate variability (HRV) and emotion regulation. In healthy participants, resting-state HRV and self-reported emotion regulation skills have been linked to recovery after a stressor; however, it is unclear whether stress recovery is altered in PSY. Thus, we compared the autonomic and subjective recovery of PSY to healthy controls (HC) and investigated the predictive value of resting-state HRV and emotion regulation skills.

We assessed resting-state HRV and self-reported emotion regulation one week prior to a combined physical and cognitive stress induction. After the stress exposure, we assessed the autonomic (decrease in heart rate [HR], increase in HRV) and subjective (decrease in subjective stress and negative affect) recovery in PSY (n = 50) and HC (n = 50) over 60 min.

Repeated-measures ANOVA revealed the expected interaction of time × group for subjective stress but not negative affect or autonomic stress. Resting-state HRV predicted recovery of HR, and emotion regulation skills predicted recovery of HRV but not of the other parameters.

Although subjective stress recovery was delayed in PSY, the absence of autonomic recovery deficits suggests that a prolonged stress response may not contribute to heightened stress levels to the expected extent. Improving resting-state HRV and emotion regulation may support autonomic recovery, but further investigation is required to test the impact of such improvements on psychotic symptoms.

Genome-Transcriptome-Functional Connectivity-Cognition Link Differentiates Schizophrenia From Bipolar Disorder.

Schizophrenia Bulletin

Schizophrenia (SZ) and bipolar disorder (BD) share genetic risk factors, yet patients display differential levels of cognitive impairment. We hypothesized a genome-transcriptome-functional connectivity (frontoparietal)-cognition pathway linked to SZ-versus-BD differences, and conducted a multiscale study to delineate this pathway.

Large genome-wide studies provided single nucleotide polymorphisms (SNPs) conferring more risk for SZ than BD, and we identified their regulated genes, namely SZ-biased SNPs and genes. We then (a) computed the polygenic risk score for SZ (PRSSZ) of SZ-biased SNPs and examined its associations with imaging-based frontoparietal functional connectivity (FC) and cognitive performances; (b) examined the spatial correlation between ex vivo postmortem expressions of SZ-biased genes and in vivo, SZ-related FC disruptions across frontoparietal regions; (c) investigated SZ-versus-BD differences in frontoparietal FC; and (d) assessed the associations of frontoparietal FC with cognitive performances.

PRSSZ of SZ-biased SNPs was significantly associated with frontoparietal FC and working memory test scores. SZ-biased genes' expressions significantly correlated with SZ-versus-BD differences in FC across frontoparietal regions. SZ patients showed more reductions in frontoparietal FC than BD patients compared to controls. Frontoparietal FC was significantly associated with test scores of multiple cognitive domains including working memory, and with the composite scores of all cognitive domains.

Collectively, these multiscale findings support the hypothesis that SZ-biased genetic risk, through transcriptome regulation, is linked to frontoparietal dysconnectivity, which in turn contributes to differential cognitive deficits in SZ-versus BD, suggesting that potential biomarkers for more precise patient stratification and treatment.

Levetiracetam Attenuates Adolescent Stress-induced Behavioral and Electrophysiological Changes Associated With Schizophrenia in Adult Rats.

Schizophrenia Bulletin

Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats.

Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31-40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded.

Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress.

These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence.

First-Episode Psychosis Patients Who Deteriorated in the Premorbid Period Do Not Have Higher Polygenic Risk Scores Than Others: A Cluster Analysis of EU-GEI Data.

Schizophrenia Bulletin

Cluster studies identified a subgroup of patients with psychosis whose premorbid adjustment deteriorates before the onset, which may reflect variat...

Listening to and Believing Derogatory and Threatening Voices.

Schizophrenia Bulletin

A plausible cause of distress for voice hearers is listening to and believing the threats and criticisms heard. Qualitative research indicates that patients have understandable reasons to listen. This study aimed to develop the understanding of distress using this listening and believing framework. Measures were developed of listening and believing voices and the reasons, and associations with distress tested.

A cross-sectional study of patients hearing derogatory and threatening voices (N = 591). Listening and Believing-Assessment and Listening and Believing-Reasons item pools were completed, and assessments of distress. Exploratory and confirmatory factor analyses and structural equation modeling (SEM) were conducted.

52% (n = 307) of participants believed their voices most or all the time. Listening and believing had 4 factors: active listening, passive listening, believing, and disregarding. Higher levels of believing, active listening, and particularly passive listening were associated with higher levels of anxiety, depression, and voice distress. Reasons for listening and believing formed 7 factors: to better understand the threat; being too worn down to resist; to learn something insightful; being alone with time to listen; voices trying to capture attention; voices sounding like real people; and voices sounding like known people. Each type of reason was associated with active listening, passive listening, and believing. SEM showed that feeling worn down in particular accounted for listening and believing. Test-retest reliability of measures was excellent.

A framework of listening and believing negative voices has the potential to inform the understanding and treatment of voice distress.

Cerebrospinal Fluid and Blood Biomarkers of Neuroinflammation and Blood-Brain Barrier in Psychotic Disorders and Individually Matched Healthy Controls.

Schizophrenia Bulletin

Neuroinflammation and blood-brain barrier (BBB) dysfunction have been observed in patients with psychotic disorders. However, previous studies have mainly focused on selected patients and broad screenings of cerebrospinal fluid (CSF) of patients with recent onset psychosis compared to healthy controls are lacking.

We included 104 patients with recent onset psychotic disorder and 104 individually matched healthy controls. CSF and blood were analyzed for readily available markers assessing neuroinflammation and BBB dysfunction. Primary outcomes were CSF white blood cell count (WBC), total protein, IgG Index, and CSF/serum albumin ratio. Secondary outcomes included additional markers of inflammation and BBB, and analyses of association with clinical variables.

CSF/serum albumin ratio (Relative Mean Difference (MD): 1.11; 95%CI: 1.00-1.23; P = .044) and CSF/serum IgG ratio (MD: 1.17; 95%CI: 1.01-1.36; P = .036) was increased in patients compared to controls. A higher number of patients than controls had CSF WBC >3 cells/µl (seven vs. one, OR: 7.73, 95%CI: 1.33-146.49, P = .020), while WBC>5 cells/µl was found in two patients (1.9%) and no controls. Inpatients had higher serum WBC and neutrophil/lymphocyte ratio (all p-values for effect heterogeneity < .011). Mean CSF WBC (MD: 1.10; 95%CI: 0.97-1.26), protein (MD: 1.06; 95%CI: 0.98-1.15) and IgG index (MD: 1.05; 95%CI: 0.96-1.15) were not significantly elevated.

When comparing a broad group of patients with psychotic disorders with healthy controls, patients had increased BBB permeability, more patients had high CSF WBC levels, and inpatients had increased peripheral inflammation, consistent with the hypothesis of a subgroup of patients with increased activation of the immune system.

Maternal Schizophrenia and the Risk of a Childhood Chronic Condition.

Schizophrenia Bulletin

Maternal schizophrenia heightens the risk for certain perinatal complications, yet it is not known to what degree future childhood chronic health conditions (Childhood-CC) might arise.

This population-based cohort study using health administrative data from Ontario, Canada (1995-2018) compared 5066 children of mothers with schizophrenia to 25 324 children of mothers without schizophrenia, propensity-matched on birth-year, maternal age, parity, immigrant status, income, region of residence, and maternal medical and psychiatric conditions other than schizophrenia. Cox proportional hazard models generated hazard ratios (HR) and 95% confidence intervals (CI) for incident Childhood-CCs, and all-cause mortality, up to age 19 years.

Six hundred and fifty-six children exposed to maternal schizophrenia developed a Childhood-CC (20.5/1000 person-years) vs. 2872 unexposed children (17.1/1000 person-years)-an HR of 1.18, 95% CI 1.08-1.28. Corresponding rates were 3.3 vs. 1.9/1000 person-years (1.77, 1.44-2.18) for mental health Childhood-CC, and 18.0 vs. 15.7/1000 person-years (1.13, 1.04-1.24) for non-mental health Childhood-CC. All-cause mortality rates were 1.2 vs. 0.8/1000 person-years (1.34, 0.96-1.89). Risk for children exposed to maternal schizophrenia was similar whether or not children were discharged to social service care. From age 1 year, risk was greater for children whose mothers were diagnosed with schizophrenia prior to pregnancy than for children whose mothers were diagnosed with schizophrenia postnatally.

A child exposed to maternal schizophrenia is at elevated risk of chronic health conditions including mental and physical subtypes. Future research should examine what explains the increased risk particularly for physical health conditions, and what preventive and treatment efforts are needed for these children.

Treatments for Social Interaction Impairment in Animal Models of Schizophrenia: A Critical Review and Meta-analysis.

Schizophrenia Bulletin

While pharmacological treatments for positive symptoms of schizophrenia are widely used, their beneficial effect on negative symptoms, particularly social impairment, is insufficiently studied. Therefore, there is an increasing interest in preclinical research of potentially beneficial treatments, with mixed results. The current review aims to evaluate the efficacy of available treatments for social deficits in different animal models of schizophrenia.

A systematic literature search generated 145 outcomes for the measures "total time" and "number" of social interactions. Standardized mean differences (SMD) and 95% confidence interval (CI) were calculated, and heterogeneity was tested using Q statistics in a random-effect meta-analytic model. Given the vast heterogeneity in effect sizes, the animal model, treatment group, and sample size were all examined as potential moderators.

The results showed that in almost all models, treatment significantly improved social deficit (total time: SMD = 1.24; number: SMD = 1.1). The moderator analyses discovered significant subgroup differences across models and treatment subgroups. Perinatal and adult pharmacological models showed the most substantial influence of treatments on social deficits, reflecting relative pharmacological validity. Furthermore, atypical antipsychotic drugs had the highest SMD within each model subgroup.

Our findings indicate that the improvement in social interaction behaviors is dependent on the animal model and treatment family used. Implications for the preclinical and clinical fields are discussed.