Connectivity analyses of bioenergetic changes in schizophrenia: Identification of novel treatments

Courtney R. Sullivan; Catharine A. Mielnik; Sinead M. O’Donovan; Adam J. Funk; Eduard Bentea; Erica A.K. DePasquale; Zhexing Wen; Vahram Haroutunian; Pavel Katsel; Amy J. Ramsey; Jarek Meller; Robert E. McCullumsmith

Using the connected signatures function in iLINCS, we identified chemical perturbagens that produce L1000 signatures that are highly discordant (anti-correlated) with our seed gene Next, we combined all discordant perturbagens from Table S4 and reported the top 20 overall discordant perturbagen signatures across all seed gene knockdown signatures (Table S5 ). After removing duplicate hits, 12 unique perturbagens remained (Table 4 ). Hits included PPARγ agonists (troglitazone and genistein), valproic acid (a voltage-gated sodium channel blocker and HDAC inhibitor), typical antipsychotic drugs (trifluoperazine, thioridazine, and fluphenazine), and two PI3K inhibitors (Wortmannin and LY-294002). We selected the FDA approved PPARγ agonist pioglitazone for preclinical trials due to its ability to regulate glycolytic pathways that are abnormal in schizophrenia, as well as evidence that pioglitazone treatment improves negative symptoms in patients (cognition has not been studied) (54, 66) .