title: Circadian rhythms in cognitive functioning among patients with schizophrenia: impact on signal detection in clinical trials of potential pro-cognitive therapies.
abstract: 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 therapies for schizophrenia and then explored how this diurnal variation affected signal detection.
  
  
  METHODS
  Baseline data from 8 separate schizophrenia clinical trials using the MATRICS Consensus Cognitive Battery (MCCB) were aggregated (Total N=2032). The MCCB assessments were divided into five 2-hour time intervals 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 comparisons 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: e-Nicotine Technology, Chapel Hill, NC, United States. Electronic address: michael.hufford@gmail.com.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hufford
authors.affiliation: NeuroCog Trials, Inc., Durham, NC, United States.
authors.forename: Vicki G
authors.initials: VG
authors.lastname: Davis
authors.affiliation: EnVivo Pharmaceuticals, Watertown, MA, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Hilt
authors.affiliation: EnVivo Pharmaceuticals, Watertown, MA, United States.
authors.forename: Nancy
authors.initials: N
authors.lastname: Dgetluck
authors.affiliation: BioLineRx, Jerusalem, Israel.
authors.forename: Yona
authors.initials: Y
authors.lastname: Geffen
authors.affiliation: Sunovion Pharmaceuticals, Marlborough, MA, United States.
authors.forename: Antony
authors.initials: A
authors.lastname: Loebel
authors.affiliation: Abbvie Pharmaceuticals, Chicago, IL, United States.
authors.forename: George
authors.initials: G
authors.lastname: Haig
authors.affiliation: Roche Pharmaceuticals, Nutley, NJ, United States.
authors.forename: Luca
authors.initials: L
authors.lastname: Santarelli
authors.affiliation: NeuroCog Trials, Inc., Durham, NC, United States; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, United States.
authors.forename: Richard S E
authors.initials: RS
authors.lastname: Keefe
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D021081:Chronobiology Disorders / Q000175:diagnosis* / Q000209:etiology*; D017322:Clinical Trials, Phase II as Topic; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012559:Schizophrenia / Q000150:complications*; D012565:Schizophrenic Psychology; D018709:Statistics, Nonparametric; D014481:United States
keywords: Circadian rhythms; Cognition; Psychopharmacology; Signal detection