Sex/gender differences in the brain and cognition in schizophrenia

Mendrek, Adrianna; Mancini-Marı̈e, Adham

doi:10.1016/j.neubiorev.2015.10.013

Cited by 209 publications

(188 citation statements)

References 229 publications

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“…For instance, the prevalence of autism spectrum disorders (ASD; (2) ) is increased 4-5 fold in males compared to females. Schizophrenia prevalence is also increased in males; age of onset and illness presentation also varies between males and females (3,4) .…”

Section: Introductionmentioning

confidence: 99%

Sex differences in Variability of Brain Structure Across the Lifespan

Forde

Jeyachandra

Joseph

et al. 2019

Preprint

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Several brain disorders exhibit sex differences in onset, presentation, and prevalence.Increased understanding of the neurobiology of sex-based differences across the lifespan can provide insight into potential disease risk and protective mechanisms. We focused on sex-related differences in variability, which may be indicative of both disease vulnerability and resilience. In n=3,069 participants, from 8-95 years of age, we first analyzed the variance ratio in females vs. males of cortical surface area and global and subcortical volumes for discrete brain regions, and found widespread greater variability in males. In contrast, variance in cortical thickness was similar for males and females. Multivariate analysis that accounts for structural covariance supported variance ratio findings. Findings were present from early life and stable with age. We then examined variability among brain regions by sex. We found significant age-by-sex interactions across neuroimaging metrics, whereby in very early life males had reduced among-region variability compared to females, while in very late life this was reversed. Overall, our findings of greater regional variability but less among-region variability in males in early life may aid our understanding of sex-based risk for neurodevelopmental disorders. In contrast, our findings in late life may provide a potential sex-based risk mechanism for dementia.

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Section: Introductionmentioning

confidence: 99%

Sex differences in Variability of Brain Structure Across the Lifespan

Forde

Jeyachandra

Joseph

et al. 2019

Preprint

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“…This protein is of special clinical interest given that variation in the DTNBP1 gene has been associated with risk for schizophrenia (Allen et al, 2008;Ayalew et al, 2012) and that DTNBP1 gene and/or protein expression are down regulated in multiple brain regions (ie, the hippocampal formation (HF: Talbot et al, 2004Talbot et al, , 2011Weickert et al, 2008), dorsolateral prefrontal cortex (PFC: Weickert et al, 2004;Tang et al, 2009), and auditory association cortices ) of schizophrenia cases. These regions are essential elements in a hippocampal-prefrontal cortical network that is implicated in the regulation not only of memory, emotion, and other selfreferential processes (Aggleton, 2012) but also of putative sexually dimorphic cognitive dysfunction in schizophrenia (Mendrek and Mancini-Marie, 2015). Indeed, the role of dysregulated dysbindin-1 gene and protein expression in schizophrenia appears most closely related to the prominent cognitive impairment in that disorder as DTNBP1 genotype influences cognition both in normal subjects and in schizophrenia (Burdick et al, 2007;Zinkstok et al, 2007;Zhang et al, 2010;Wolf et al, 2011;Baek et al, 2012;Varela-Gomez et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of Specialized Delay/Interference-Dependent Working Memory Following Loss of Dysbindin-1A in Schizophrenia-Related Phenotypes

Petit

Michalak

Cox

et al. 2016

Neuropsychopharmacol

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Dysbindin-1, a protein that regulates aspects of early and late brain development, has been implicated in the pathobiology of schizophrenia. As the functional roles of the three major isoforms of dysbindin-1, (A, B, and C) remain unknown, we generated a novel mutant mouse, dys-1A, with selective loss of dysbindin-1A and investigated schizophrenia-related phenotypes in both males and females. Loss of dysbindin-1A resulted in heightened initial exploration and disruption in subsequent habituation to a novel environment, together with heightened anxiety-related behavior in a stressful environment. Loss of dysbindin-1A was not associated with disruption of either long-term (olfactory) memory or spontaneous alternation behavior. However, dys-1A showed enhancement in delay-dependent working memory under high levels of interference relative to controls, ie, impairment in sensitivity to the disruptive effect of such interference. These findings in dys-1A provide the first evidence for differential functional roles for dysbindin-1A vs dysbindin-1C isoforms among phenotypes relevant to the pathobiology of schizophrenia. Future studies should investigate putative sex differences in these phenotypic effects.

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“…Generally, schizophrenia is characterized by three categories: positive symptoms, negative symptoms, and cognitive deficits. Schizophrenia also shows substantial sex differences in the incidence rate, age of onset, and symptom severity [2][3][4] . Schizophrenia appears to be a multifactorial disorder with a strong genetic predisposition.…”

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confidence: 99%

Lithium for schizophrenia: supporting evidence from a 12-year, nationwide health insurance database and from Akt1-deficient mouse and cellular models

Luo

Chang

Huang

et al. 2020

Sci Rep

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Accumulating evidence suggests AKT1 and DRD2-AKT-GSK3 signaling involvement in schizophrenia. AKT1 activity is also required for lithium, a GSK3 inhibitor, to modulate mood-related behaviors. Notably, GSK3 inhibitor significantly alleviates behavioral deficits in Akt1 −/− female mice, whereas typical/atypical antipsychotics have no effect. In agreement with adjunctive therapy with lithium in treating schizophrenia, our data mining indicated that the average utilization rates of lithium in the Taiwan National Health Insurance Research Database from 2002 to 2013 are 10.9% and 6.63% in inpatients and outpatients with schizophrenia, respectively. Given that lithium is commonly used in clinical practice, it is of great interest to evaluate the effect of lithium on alleviating Akt1-related deficits. Taking advantage of Akt1 +/− mice to mimic genetic deficiency in patients, behavioral impairments were replicated in female Akt1 +/− mice but were alleviated by subchronic lithium treatment for 13 days. Lithium also effectively alleviated the observed reduction in phosphorylated GSK3α/β expression in the brains of Akt1 +/− mice. Furthermore, inhibition of Akt expression using an Akt1/2 inhibitor significantly reduced neurite length in P19 cells and primary hippocampal cell cultures, which was also ameliorated by lithium. Collectively, our findings implied the therapeutic potential of lithium and the importance of the AKT1-GSK3 signaling pathway.

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Sex/gender differences in the brain and cognition in schizophrenia

Cited by 209 publications

References 229 publications

Sex differences in Variability of Brain Structure Across the Lifespan

Sex differences in Variability of Brain Structure Across the Lifespan

Dysregulation of Specialized Delay/Interference-Dependent Working Memory Following Loss of Dysbindin-1A in Schizophrenia-Related Phenotypes

Lithium for schizophrenia: supporting evidence from a 12-year, nationwide health insurance database and from Akt1-deficient mouse and cellular models

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