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Geerts H, Roberts P, Spiros A. A Quantitative System Pharmacology Computer Model for Cognitive Deficits in Schizophrenia. CPT: Pharmacometrics and Systems Pharmacology. 2013 April 3 ; 2(e36) Abstract

Comments on News and Primary Papers

Primary Papers: A Quantitative System Pharmacology Computer Model for Cognitive Deficits in Schizophrenia.

Comment by:  Bryan Roth, SRF Advisor
Submitted 6 May 2013
Posted 6 May 2013

At the furthest frontier of computational biology are computational approaches to mimic the actions of the human mind and cognition (O’Reilly, 2006). In a recent paper, Hugo Geerts and colleagues "boldly go where no one has gone before" by modeling cognitive deficits in schizophrenia and their amelioration by GABAergic and atypical antipsychotic drugs. Remarkably, predictions from their models accurately recapitulated legacy clinical data. They suggest that such an approach early in the drug discovery pipeline might enhance chances for success by focusing on those compounds predicted to have robust effects on enhancing cognition in schizophrenia. Going forward, it will be interesting for the authors to make similar predictions regarding the large number of drugs proposed for enhancing cognition in schizophrenia (e.g., GlyT1 inhibitors, α7 nicotinic agents, AMPAkines, and so on) (Javitt, 2012; Lieberman et al., 2013).

One of the innovative aspects of this particular effort is their attention to the robust polypharmacological profile of atypical antipsychotic drugs as well as their main active metabolites. Remarkably, they accurately predicted that the combination of clozapine and risperidone would diminish cognition (Akdede et al., 2006). I think this is an important observation, as polypharmacology—particularly the combination of various atypical and typical antipsychotic drugs—appears to be common practice without any supporting evidence that the combination is of any benefit (Correll et al., 2012). It would be interesting for the authors to enhance their study to include other potential atypical-atypical and typical-atypical antipsychotic drug combinations—especially those combinations that are common—to see what beneficial or detrimental effects might be predicted.


Akdede BB, Anil Yağcioğlu AE, Alptekin K, Turgut TI, Tümüklü M, Yazici MK, Jayathilake K, Tunca Z, Göğüş A, Meltzer HY. A double-blind study of combination of clozapine with risperidone in patients with schizophrenia: effects on cognition. J Clin Psychiatry. 2006 Dec;67(12):1912-9. Abstract

Correll CU, Gallego JA. Antipsychotic polypharmacy: a comprehensive evaluation of relevant correlates of a long-standing clinical practice. Psychiatr Clin North Am. 2012 Sep;35(3):661-81. Abstract

Javitt DC. Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp Pharmacol. 2012;(213):367-99. Abstract

Lieberman JA, Dunbar G, Segreti AC, Girgis RR, Seoane F, Beaver JS, Duan N, Hosford DA. A Randomized Exploratory Trial of an Alpha-7 Nicotinic Receptor Agonist (TC-5619) for Cognitive Enhancement in Schizophrenia. Neuropsychopharmacology. 2013 May;38(6):968-75. Abstract

O'Reilly RC. Biologically based computational models of high-level cognition. Science. 2006 Oct 6;314(5796):91-4. Abstract

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