Assessing the effects of antipsychotic medications on schizophrenia functional analysis: a postmortem proteome study

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2022-11, Vol.47 (12), p.2033-2041
• Main Authors: Alnafisah, Rawan S, Reigle, James, Eladawi, Mahmoud Ali, O'Donovan, Sinead M, Funk, Adam J, Meller, Jaroslaw, Mccullumsmith, Robert E, Shukla, Rammohan
• Format: Article
• Language: English
• Subjects: Antipsychotics; Cognitive ability; Cytoskeleton; Dendrites; Dopamine receptors; Drug delivery; Homeostasis; Immunosuppressive agents; Mental disorders; Neostriatum; Pathophysiology; Prefrontal cortex; Proteomes; Proteomics; Psychotropic drugs; Pyramidal cells; Schizophrenia; Signal transduction
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/s41386-022-01310-8

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.