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

The top unique perturbagen in our signature connectivity analysis (Table 4 ) was valproic acid, an HDAC inhibitor that modulates sodium channels and enhances gamma-aminobutyric acid (GABA)-mediated neurotransmission (traditionally used to treat epilepsy and bipolar disorder) (104) . Interestingly, sodium valproate (valproic acid) is commonly used as an adjunctive therapy for the treatment of schizophrenia, and a recent 4 week randomized clinical trial demonstrated improvement in psychopathology with a combination therapy of valproate and risperidone or olanzapine compared to antipsychotics alone (n=249) (105) . There is also some evidence for positive effects on aggression and tardive dyskinesia in schizophrenia, although sample sizes are small (106) . Valproic acid also affects ERK and Wnt pathways, which were . CC-BY-NC-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/338392 doi: bioRxiv preprint implicated in our pathway analyses and regulate cell survival and cytoskeletal modifications (107) . Stimulation of ERK1/2 has the ability to enhance the transcriptional activity of PPARs and increase glucose metabolism, indicating PPAR agonists might also be potential therapeutic targets (108) . Interestingly, two of our unique perturbagen hits included PPAR agonists (troglitazone and Genistein) (109) . Troglitazone, part of the TZD family, is an anti-inflammatory and antidiabetic drug developed to treat type 2 diabetes. Troglitazone is a ligand to both PPARα and (more strongly) PPARγ, promotes glucose uptake by increasing two transporters we previously found decreased in pyramidal neurons in schizophrenia (GLUT1 and GLUT3), and inhibits the pro-inflammatory factor NFKB (implicated in our Enrichr analyses) (18, 54, 110, 111) .