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Sex-informed estrogen receptor modulation in schizophrenia: a male-focused ERβ/GPER1 framework for cognitive and
1Independent Researcher, Bozeman, MT, United States.
Frontiers in Psychiatry
|February 25, 2026
Summary
Selective estrogen receptor modulators, like raloxifene, show promise for treatment-resistant schizophrenia (TRS). Targeting estrogen pathways (ERβ, GPER1) may improve cognitive and negative symptoms in TRS patients.
Area of Science:
- Neuroscience
- Pharmacology
- Endocrinology
Background:
- Treatment-resistant schizophrenia (TRS) presents significant challenges, especially in males with severe negative and cognitive symptoms.
- Estrogenic signaling, via estrogen receptor beta (ERβ) and G-protein-coupled estrogen receptor 1 (GPER1), is a potential therapeutic target for TRS domains.
- Current dopamine-based therapies show limited efficacy in specific TRS patient populations.
Purpose of the Study:
- To review evidence for selective estrogen receptor modulators (SERMs) as adjunctive treatments for TRS.
- To explore the role of ERβ and GPER1 signaling in mitigating TRS pathophysiology.
- To discuss emerging strategies for optimizing central nervous system delivery of estrogenic agents.
Main Methods:
- Synthesis of preclinical, stem cell-derived, and clinical data on ERβ and GPER1 signaling in TRS.
- Review of findings related to aromatase activity, neurosteroidogenesis, and genetic variations (ESR2, CYP19A1).
- Examination of innovative therapeutic approaches, including biased ligands and novel delivery systems.
Main Results:
- ERβ and GPER1 signaling enhance synaptic plasticity, mitochondrial function, and anti-inflammatory glial states.
- Estrogenic modulation supports dopaminergic-glutamatergic balance, crucial for TRS.
- Biomarker-guided stratification opportunities exist based on genetic and molecular factors.
Conclusions:
- Receptor-selective estrogenic modulation offers a mechanistically grounded approach for TRS.
- SERMs, such as raloxifene, can target central estrogenic pathways without systemic feminizing effects.
- Optimized delivery systems and GPER1-biased ligands may improve efficacy and safety for TRS patients.
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