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Review
. 2023 Feb:252:231-241.
doi: 10.1016/j.schres.2022.12.011. Epub 2023 Jan 20.

Sex and pubertal influences on the neurodevelopmental underpinnings of schizophrenia: A case for longitudinal research on adolescents

M E A Barendse  1 , G A Lara  1 , A E Guyer  2 , J R Swartz  3 , S L Taylor  4 , E A Shirtcliff  5 , S T Lamb  1 , C Miller  1 , J Ng  1 , G Yu  1 , L M Tully  6
Affiliations
Review

Sex and pubertal influences on the neurodevelopmental underpinnings of schizophrenia: A case for longitudinal research on adolescents

M E A Barendse et al. Schizophr Res. 2023 Feb.

Abstract

Sex is a significant source of heterogeneity in schizophrenia, with more negative symptoms in males and more affective symptoms and internalizing comorbidity in females. In this narrative review, we argue that there are likely sex differences in the pathophysiological mechanisms of schizophrenia-spectrum disorders (SZ) that originate during puberty and relate to the sex-specific impacts of pubertal maturation on brain development. Pubertal maturation might also trigger underlying (genetic or other) vulnerabilities in at-risk individuals, influencing brain development trajectories that contribute to the emergence of SZ. This review is the first to integrate links between pubertal development and neural development with cognitive neuroscience research in SZ to form and evaluate these hypotheses, with a focus on the frontal-striatal and frontal-limbic networks and their hypothesized contribution to negative and mood symptoms respectively. To test these hypotheses, longitudinal research with human adolescents is needed that examines the role of sex and pubertal development using large cohorts or high risk samples. We provide recommendations for such studies, which will integrate the fields of psychiatry, developmental cognitive neuroscience, and developmental endocrinology towards a more nuanced understanding of the role of pubertal factors in the hypothesized sex-specific pathophysiological mechanisms of schizophrenia.

Keywords: Hormones; MRI; Pathophysiology; Psychosis; Sex-specific.

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Conflict of interest statement

Declaration of competing interest The authors have declared that there are no conflicts of interest in relation to the subject of this study.

Figures

Figure 1.
Figure 1.
Theoretical model of how sex and genetic and early-environmental risk factors for schizophrenia-spectrum disorders (SZ) are hypothesized to moderate the influence of pubertal maturation on the development of frontal-limbic & frontal-striatal brain networks, changing the risk for the emergence of psychotic, affective and negative symptoms. The hypothesized pathways are based on the literature discussed in sections 2 to 4 and can be tested using recommendations described in section 5.
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