Abstract
Antipsychotic drugs (APDs) are effective in treating positive symptoms of schizophrenia (SCZ). However, they have a substantial impact on postmortem studies. As most cohorts lack samples from drug-naive patients, many studies, rather than understanding SCZ pathophysiology, are analyzing the drug effects. We hypothesized that comparing SCZ-altered and APD-influenced signatures derived from the same cohort can provide better insight into SCZ pathophysiology. For this, we performed LCMS-based proteomics on dorsolateral prefrontal cortex (DLPFC) samples from control and SCZ subjects and used statistical approaches to identify SCZ-altered and APD-influenced proteomes, validated experimentally using independent cohorts and published datasets. Functional analysis of both proteomes was contrasted at the biological-pathway, cell-type, subcellular-synaptic, and drug-target levels. In silico validation revealed that the SCZ-altered proteome was conserved across several studies from the DLPFC and other brain areas. At the pathway level, SCZ influenced changes in homeostasis, signal-transduction, cytoskeleton, and dendrites, whereas APD influenced changes in synaptic-signaling, neurotransmitter-regulation, and immune-system processes. At the cell-type level, the SCZ-altered and APD-influenced proteomes were associated with two distinct striatum-projecting layer-5 pyramidal neurons regulating dopaminergic-secretion. At the subcellular synaptic level, compensatory pre- and postsynaptic events were observed. At the drug-target level, dopaminergic processes influenced the SCZ-altered upregulated-proteome, whereas nondopaminergic and a diverse array of non-neuromodulatory mechanisms influenced the downregulated-proteome. Previous findings were not independent of the APD effect and thus require re-evaluation. We identified a hyperdopaminergic cortex and drugs targeting the cognitive SCZ-symptoms and discussed their influence on SCZ pathology in the context of the cortico-striatal pathway.
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All analyzed data are available in the main text or the supplementary materials. The raw data are available from the corresponding author upon reasonable request.
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RSA is supported by a predoctoral fellowship from the government of Saudi Arabia.
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RS and RSA conceptualized the study and wrote the manuscript. JR, MAE, JM, and REM participated with RSA in LCMS data generation and processing. SMO and AJF participated with RSA in western blot analysis. All authors participated in writing the manuscript.
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Alnafisah, R.S., Reigle, J., Eladawi, M.A. et al. Assessing the effects of antipsychotic medications on schizophrenia functional analysis: a postmortem proteome study. Neuropsychopharmacol. 47, 2033–2041 (2022). https://doi.org/10.1038/s41386-022-01310-8
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DOI: https://doi.org/10.1038/s41386-022-01310-8
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