The molecular pathophysiological mechanisms underlying
schizophrenia have remained unknown, and no treatment exists for primary prevention. We used Ingenuity Pathway Analysis to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for
glutamate receptor signaling, hepatic
fibrosis, and
glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic
fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. Results from a Finnish nation-wide database showed that the risk of
schizophrenia relapse was 41% lower among first-episode patients during the use of
losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA-related pathway, compared to those time periods when the same individual did not use the
drug. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA-related
purine, oxidative stress, and glutamatergic signaling pathways are among primary pathophysiological alterations in
schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as
losartan, and ADCYAP1/
PACAP -deficit alleviators, such as metabotropic
glutamate 2/3 agonist
MGS0028 and 5-HT7 antagonists - which have shown beneficial effects in an experimental Adcyap1-/- mouse model for
schizophrenia - could be potential treatments even before the full manifestation of illness involving dopaminergic abnormalities.