PMID- 31773211
OWN - NLM
STAT- MEDLINE
DCOM- 20200728
LR  - 20240328
IS  - 1432-2072 (Electronic)
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 237
IP  - 2
DP  - 2020 Feb
TI  - A randomized, placebo-controlled, phase 1 study to evaluate the effects of 
      TAK-063 on ketamine-induced changes in fMRI BOLD signal in healthy subjects.
PG  - 317-328
LID - 10.1007/s00213-019-05366-1 [doi]
AB  - RATIONALE: Phosphodiesterase 10A inhibitor TAK-063 has shown effects that suggest 
      efficacy in schizophrenia treatment. OBJECTIVE: This randomized, double-blind, 
      placebo-controlled, incomplete-crossover study investigated effects of single 
      oral administration of TAK-063 on ketamine-induced changes in blood oxygen 
      level-dependent (BOLD) signal in healthy males. METHODS: Healthy men aged 18 to 
      45 years with normal magnetic resonance imaging (MRI) scans and 
      electroencephalogram measurements at screening were eligible. Each subject was 
      randomized to one of nine treatment schedules: all subjects received placebo and 
      two of three doses of TAK-063 followed by ketamine. The primary endpoint was 
      ketamine-induced brain activity in select regions of the brain during resting 
      state. Secondary endpoints included pharmacokinetic parameters of TAK-063, 
      proportion of subjects with treatment-emergent adverse events (AEs), and 
      percentage of subjects meeting criteria for abnormal safety laboratory tests and 
      vital sign measurements. RESULTS: The study comprised 27 subjects. Prior to 
      ketamine infusion, TAK-063 exerted region-specific effects on resting state 
      functional MRI (fMRI) BOLD signal. After ketamine administration, TAK-063 reduced 
      the Cohen's effect size for resting-state fMRI BOLD signal in key brain regions 
      examined, and exerted similar effects on BOLD signal during the working memory 
      task across all doses. TAK-063 was safe and well tolerated. CONCLUSIONS: Our 
      results are consistent with non-clinical studies of ketamine and TAK-063 and 
      clinical studies of ketamine and risperidone. It is unknown whether these data 
      are predictive of potential antipsychotic efficacy, and further analyses are 
      required.
FAU - Yurgelun-Todd, Deborah A
AU  - Yurgelun-Todd DA
AUID- ORCID: 0000-0002-7242-4190
AD  - The Brain Institute, University of Utah, 383 Colorow Drive, Salt Lake City, UT, 
      84108, USA. Deborah.Yurgelun-Todd@hsc.utah.edu.
FAU - Renshaw, Perry F
AU  - Renshaw PF
AD  - The Brain Institute, University of Utah, 383 Colorow Drive, Salt Lake City, UT, 
      84108, USA.
FAU - Goldsmith, Paul
AU  - Goldsmith P
AD  - Takeda Development Center Europe, Ltd., 61 Aldwych, London, WC2B 4AE, UK.
FAU - Uz, Tolga
AU  - Uz T
AD  - Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 
      60015, USA.
FAU - Macek, Thomas A
AU  - Macek TA
AD  - Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 
      60015, USA.
LA  - eng
GR  - N/A/Takeda Development Center Americas/
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20191126
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 
      (1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyridazines)
RN  - 690G0D6V8H (Ketamine)
RN  - EC 3.1.4.- (PDE10A protein, human)
RN  - EC 3.1.4.- (Phosphoric Diester Hydrolases)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Brain/*diagnostic imaging/drug effects/metabolism
MH  - Cross-Over Studies
MH  - Double-Blind Method
MH  - Drug Interactions/physiology
MH  - Electroencephalography/drug effects/methods
MH  - Excitatory Amino Acid Antagonists/administration & dosage/blood
MH  - Healthy Volunteers
MH  - Humans
MH  - Ketamine/*administration & dosage/*blood
MH  - Magnetic Resonance Imaging/*methods
MH  - Male
MH  - Middle Aged
MH  - Phosphodiesterase Inhibitors/administration & dosage/blood
MH  - Phosphoric Diester Hydrolases/metabolism
MH  - Pyrazoles/*administration & dosage/*blood
MH  - Pyridazines/*administration & dosage/*blood
MH  - Young Adult
PMC - PMC7018803
OTO - NOTNLM
OT  - BOLD
OT  - Ketamine
OT  - PDE-10 inhibitor
OT  - TAK-063
OT  - fMRI
COIS- Thomas A. Macek and Tolga Uz were employees of Takeda Development Center 
      Americas, Inc., Deerfield, IL, at the time of this study, and Paul Goldsmith was 
      an employee of Takeda Development Centre Europe Ltd., London, UK, at the time of 
      this study. Deborah Yurgelun-Todd and Perry Renshaw have no conflicts of interest 
      to disclose.
EDAT- 2019/11/28 06:00
MHDA- 2020/07/29 06:00
PMCR- 2019/11/26
CRDT- 2019/11/28 06:00
PHST- 2019/03/15 00:00 [received]
PHST- 2019/09/22 00:00 [accepted]
PHST- 2019/11/28 06:00 [pubmed]
PHST- 2020/07/29 06:00 [medline]
PHST- 2019/11/28 06:00 [entrez]
PHST- 2019/11/26 00:00 [pmc-release]
AID - 10.1007/s00213-019-05366-1 [pii]
AID - 5366 [pii]
AID - 10.1007/s00213-019-05366-1 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2020 Feb;237(2):317-328. doi: 
      10.1007/s00213-019-05366-1. Epub 2019 Nov 26.