Circadian rhythms in cognitive functioning among patients with schizophrenia: Impact on signal detection in clinical trials of potential pro-cognitive therapies ☆ , ☆☆ Michael R. Hufford a, ⁎, Vicki G. Davis b , Dana Hilt c , Nancy Dgetluck c , Yona Geffen d , Anthony Loebel e , George Haig f , Luca Santarelli g , Richard S.E. Keefe b,h a e-Nicotine Technology, Chapel Hill, NC, United States b NeuroCog Trials, Inc., Durham, NC, United States c EnVivo Pharmaceuticals, Watertown, MA, United States d BioLineRx, Jerusalem, Israel e Sunovion Pharmaceuticals, Marlborough, MA, United States f Abbvie Pharmaceuticals, Chicago, IL, United States g Roche Pharmaceuticals, Nutley, NJ, United States h Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, United States abstract article info Article history: Received 10 April 2014 Received in revised form 8 July 2014 Accepted 9 July 2014 Available online xxxx Keywords: Cognition Psychopharmacology Signal detection Circadian rhythms Objective: Cognition is affected by circadian rhythms over the course of a day. Circadian rhythms in cognitive functioning are driven by a variety of both endogenous and exogenous factors. Patients with schizophrenia are known to have disturbed circadian rhythms that can affect their cognitive functioning. We examined the impact of time of day on cognitive test scores from subjects participating in clinical trials of potential pro-cognitive ther- apies for schizophrenia and then explored how this diurnal variation affected signal detection. Method: Baseline data from 8 separate schizophrenia clinical trials using the MATRICS Consensus Cognitive Bat- tery (MCCB) were aggregated (Total N = 2032). The MCCB assessments were divided into five 2-hour time in- tervals based on the start-time of the assessments (varying from 8:00 am to 5:59 pm) and then analyzed for differences by time interval. Next, data from two Phase 2 schizophrenia clinical trials of potential pro-cognitive therapies were analyzed to explore the impact of this diurnal variation on placebo separation. Results: Time of day exerted a significant effect on baseline composite MCCB scores (p = .002). Follow-up com- parisons revealed significant differences among multiple temporal epochs. In both Phase 2 clinical trials, subjects whose cognitive functioning was assessed at consistent times of day between their baseline and endpoint visits showed a more robust treatment response as compared to subjects assessed at inconsistent times of day. Conclusion: Cognitive functioning ebbs and flows over the course of the day. Maintaining consistency in the time of day of cognitive test administrations between visits can help to reduce the noise introduced by circadian rhythms, thereby enhancing signal detection in clinical trials of potential pro-cognitive therapies. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Over one hundred years ago, while performing groundbreaking research into human learning, memory, and forgetting, Hermann Ebbinghaus made the following observation about the impact of time of day on cognitive functioning: “In the later hours of the day mental vigor and receptivity are less. The series learned in the morning and then relearned at a later hour, aside from other influences, require more work for relearning than they would if the relearning were done at a time of mental vigor equal to that of the original learning.” [Ebbinghaus (1885)] From this simple observation regarding the impact of time of day on the learning of nonsense syllables, a wealth of studies has now established that circadian rhythms in cognitive functioning are perva- sive and affect a wide variety of cognitive processes, including attention Schizophrenia Research xxx (2014) xxx–xxx ☆ These results have previously been presented at the 2012 autumn conference of the International Society for CNS Clinical Trials and Methodology (Marina del Rey, CA). ☆☆ Clinical trials registrations: ClinicalTrials.gov identifiers NCT00567710, NCT00968851, NCT01077700, NCT01095562, NCT01192880, NCT01192906, NCT01192867, NCT00604760, NCT00641745. ⁎ Corresponding author at: 409 E. Winmore, Ave., Chapel Hill, NC 27516, United States. Tel.: +1 919 244 2514 (office); fax: +1 919 869 1496. E-mail address: michael.hufford@gmail.com (M.R. Hufford). SCHRES-05967; No of Pages 6 http://dx.doi.org/10.1016/j.schres.2014.07.018 0920-9964/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Please cite this article as: Hufford, M.R., et al., Circadian rhythms in cognitive functioning among patients with schizophrenia: Impact on signal detection in clinical trials of pot..., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.07.018