• Amir Inamdar, Emilio Merlo-Pich, Michelle Gee, Clare Makumi, Prafull Mistry, Jon Robertson, Erik Steinberg, Stefano Zamuner, Susan Learned, Robert Alexander, and Emiliangelo Ratti.
• Neurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline R&D Ltd, Harlow, Essex, UK The first two authors equally contributed to the work here reported Present address: Takeda Development Centre Europe Ltd., London, UK amir.inamdar@takeda.com.
• J. Psychopharmacol. (Oxford). 2014 Jun 1; 28 (6): 570-81.

AbstractPro-inflammatory cytokines (PICs) may play important pathophysiological roles in some forms of Major Depressive Disorder (MDD). The p38 MAPK inhibitor losmapimod (GW856553) attenuates the pro-inflammatory response in humans by reducing PIC production. Losmapimod (7.5 mg BD) was administered for 6 weeks in two randomised, placebo-controlled trials in subjects with MDD enriched with symptoms of loss of energy/interest and psychomotor retardation (Studies 574 and 009). Primary efficacy endpoints were the Bech 6-item depression subscale of the HAMD-17 (the 'Bech,') for Study 009; and the Bech, Inventory of Depressive Symptomatology-Clinician Rated (IDS-C), HAMD-17, and Quick Inventory of Depressive Symptomatology (self-rated) (QIDS-SR) for Study 574. Key cytokine biomarker levels were also measured. Study 574 (n=24) was terminated prematurely in light of emerging data from an internal study in rheumatoid arthritis. Efficacy results available at termination favoured losmapimod (Bech, 6 weeks: endpoint drug vs. placebo difference = -4.10; 95% CI, -7.36, -0.83; p=0.017). A subsequent study, Study 009 (n=128), designed using a Bayesian approach based on a prior derived from Study 574, showed no advantage for losmapimod (Bech, 6 weeks: endpoint drug vs. placebo difference = 1.11; 95% credible interval, -0.22, 2.50). Biomarker data showed no significant changes. In conclusion 7.5 mg BID losmapimod was not effective in MDD. © The Author(s) 2014.

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