Mortality in people with schizophrenia: a systematic review and meta‐analysis of relative risk and aggravating or attenuating factors

People with schizophrenia die 15‐20 years prematurely. Understanding mortality risk and aggravating/attenuating factors is essential to reduce this gap. We conducted a systematic review and random‐effects meta‐analysis of prospective and retrospective, nationwide and targeted cohort studies assessing mortality risk in people with schizophrenia versus the general population or groups matched for physical comorbidities or groups with different psychiatric disorders, also assessing moderators. Primary outcome was all‐cause mortality risk ratio (RR); key secondary outcomes were mortality due to suicide and natural causes. Other secondary outcomes included any other specific‐cause mortality. Publication bias, subgroup and meta‐regression analyses, and quality assessment (Newcastle‐Ottawa Scale) were conducted. Across 135 studies spanning from 1957 to 2021 (schizophrenia: N=4,536,447; general population controls: N=1,115,600,059; other psychiatric illness controls: N=3,827,955), all‐cause mortality was increased in people with schizophrenia versus any non‐schizophrenia control group (RR=2.52, 95% CI: 2.38‐2.68, n=79), with the largest risk in first‐episode (RR=7.43, 95% CI: 4.02‐13.75, n=2) and incident (i.e., earlier‐phase) schizophrenia (RR=3.52, 95% CI: 3.09‐4.00, n=7) versus the general population. Specific‐cause mortality was highest for suicide or injury‐poisoning or undetermined non‐natural cause (RR=9.76‐8.42), followed by pneumonia among natural causes (RR=7.00, 95% CI: 6.79‐7.23), decreasing through infectious or endocrine or respiratory or urogenital or diabetes causes (RR=3 to 4), to alcohol or gastrointestinal or renal or nervous system or cardio‐cerebrovascular or all natural causes (RR=2 to 3), and liver or cerebrovascular, or breast or colon or pancreas or any cancer causes (RR=1.33 to 1.96). All‐cause mortality increased slightly but significantly with median study year (beta=0.0009, 95% CI: 0.001‐0.02, p=0.02). Individuals with schizophrenia <40 years of age had increased all‐cause and suicide‐related mortality compared to those ≥40 years old, and a higher percentage of females increased suicide‐related mortality risk in incident schizophrenia samples. All‐cause mortality was higher in incident than prevalent schizophrenia (RR=3.52 vs. 2.86, p=0.009). Comorbid substance use disorder increased all‐cause mortality (RR=1.62, 95% CI: 1.47‐1.80, n=3). Antipsychotics were protective against all‐cause mortality versus no antipsychotic use (RR=0.71, 95% CI: 0.59‐0.84, n=11), with largest effects for second‐generation long‐acting injectable anti­psychotics (SGA‐LAIs) (RR=0.39, 95% CI: 0.27‐0.56, n=3), clozapine (RR=0.43, 95% CI: 0.34‐0.55, n=3), any LAI (RR=0.47, 95% CI: 0.39‐0.58, n=2), and any SGA (RR=0.53, 95% CI: 0.44‐0.63, n=4). Antipsychotics were also protective against natural cause‐related mortality, yet first‐generation antipsychotics (FGAs) were associated with increased mortality due to suicide and natural cause in incident schizophrenia. Higher study quality and number of variables used to adjust the analyses moderated larger natural‐cause mortality risk, and more recent study year moderated larger protective effects of antipsychotics. These results indicate that the excess mortality in schizophrenia is associated with several modifiable factors. Targeting comorbid substance abuse, long‐term maintenance antipsychotic treatment and appropriate/earlier use of SGA‐LAIs and clozapine could reduce this mortality gap.     

Alterations of urinary perchlorate levels in euthyroid postpubertal children with autism spectrum disorder

BackgroundPerchlorates ClO₄(⁻) are known environmental and food contaminants that act as inhibitors of iodine uptake by the thyroid gland; however, information concerning their possible association with the development of autism spectrum disorder (ASD) is still missing. The current study is first presenting the alterations in perchlorate urine levels in euthyroid children with ASD.ObjectivesTo examine urinary perchlorates and iodides in euthyroid children diagnosed with ASD, compared to age-, and BMI-matched neurotypical controls, and to verify the association between these two ions in ASD.MethodsIons were determined in 24 h urine samples determined by ion chromatography–conductivity cell detection (IC-CD) and ion chromatography–pulsed amperometric detection (IC-PAD) techniques, respectively, in a total of 130 postpubertal euthyroid children with normal BMI (the mean age 14.46 years, SD = 1.32; the mean BMI 20.6, SD = 1.37), divided into age- and BMI-matched groups of ASD patients and neurotypical, healthy children (control).ResultsThe ASD group presented with significantly higher perchlorate urine levels than the controls (median = 1.05 μg/L, interquartile range(IQR) = 1.5 versus median = 0.09 μg/L, IQR = 0.097, respectively), as well as lower iodide urine levels (median = 100.2 μg/L, IQR = 37 versus median = 156.95 μg/L, IQR = 26.11, respectively). The ASD group presented significantly lower TSH and higher free thyroid hormone (fT4, fT3) levels than the controls. In regression analyses, perchlorate urine levels showed significant positive relationships with normal BMI values and serum TSH, and inverse relationships with serum fT4. Urinary iodide levels showed significant inverse relationships with BMI values. The absence of ASD was associated with decreased odds of perchlorate urine levels (OR = 0.012, 95 % confidence interval [CI] 0.0002−0.76), and increased odds of iodide urine levels (OR = 1.15, 95 %CI 1.05–1.27).ConclusionsASD may have an independent and significant impact on perchlorate as well as iodide levels in urine of euthyroid lean postpubertal children. Perchlorate levels do not appear to be directly associated with iodide levels in euthyroid children.     

The high‐energy transition state of the glutamate transporter homologue GltPh

Membrane transporters mediate cellular uptake of nutrients, signaling molecules, and drugs. Their overall mechanisms are often well understood, but the structural features setting their rates are mostly unknown. Earlier single‐molecule fluorescence imaging of the archaeal model glutamate transporter homologue Glt_Ph from Pyrococcus horikoshii suggested that the slow conformational transition from the outward‐ to the inward‐facing state, when the bound substrate is translocated from the extracellular to the cytoplasmic side of the membrane, is rate limiting to transport. Here, we provide insight into the structure of the high‐energy transition state of Glt_Ph that limits the rate of the substrate translocation process. Using bioinformatics, we identified Glt_Ph gain‐of‐function mutations in the flexible helical hairpin domain HP2 and applied linear free energy relationship analysis to infer that the transition state structurally resembles the inward‐facing conformation. Based on these analyses, we propose an approach to search for allosteric modulators for transporters.     

Identification of rare variants causing urea cycle disorders: A clinical,genetic, and biophysical study

Urea cycle disorders (UCDs) are a group of rare metabolic conditions characterized by hyperammonemia and a broad spectrum of phenotypic severity. They are caused by the congenital deficiency in the eight biomolecules involved in urea cycle. In the present study, five cases of UCD were recruited and submitted to a series of clinical, biochemical, and genetic analysis with a combination of high throughput techniques. Moreover, in silico analysis was conducted on the identified missense genetic variants. Various clinical and biochemical indications (including profiles of amino acids and urinary orotic acids) of UCD were manifested by the five probands. Sequence analysis revealed nine diagnostic variants, including three novel ones, which caused Argininosuccinic aciduria (ASA) in one case, Carbamoyl phosphate synthetase 1deficiency (CPS1D) in two cases, Ornithine transcarbamylase deficiency (OTCD) in one case, and Citrin deficiency in 1case. Results of in silico biophysical analysis strongly suggested the pathogenicity of each the five missense variants and provided insight into their intramolecular impacts. In conclusion, this study expanded the genetic variation spectrum of UCD, gave solid evidence for counselling to the affected families, and should facilitate the functional study on the proteins in urea cycle.     

Impaired instrumental learning in Spred1−/− mice,a model for a rare RASopathy

RASopathies are neuro-cardio-facio-cutaneous disorders stemming from mutations in genes regulating the RAS-MAPK pathway. Legius syndrome is a rare RASopathy disorder caused by mutations in the SPRED1 gene. SPRED1 protein negatively regulates activation of Ras by inhibiting RAS/RAF and by its interaction with neurofibromin, a Ras GTPase-activating protein (RAS-GAP). Cognitive impairments have been reported in Legius syndrome as well as in other RASopathy disorders. Modelling these cognitive deficits in a Spred1 mouse model for Legius syndrome has demonstrated spatial learning and memory deficits, but other cognitive domains remained unexplored. Here, we attempted to utilize a cognitive touchscreen battery to investigate if Spred1^−/− mice exhibit deficits in other cognitive domains. We show that Spred1^−/− mice had heterogeneous performance in instrumental operant learning, with a large subgroup (n = 9/20) failing to reach the standard criterion on touchscreen operant pretraining, precluding further cognitive testing. To examine whether targeting the RAS-MAPK signalling pathway could rescue these cognitive impairments, Spred1^−/− mice were acutely treated with the clinically relevant mitogen-activated protein kinase (MEK) inhibitor PD325901. However, MEK inhibition did not improve their instrumental learning. We conclude that Spred1^−/− mice can model severe cognitive impairments that cannot be reversed in adulthood.