title: Early stage development of the glycine-1 re-uptake inhibitor SCH 900435: central nervous system effects compared with placebo in healthy men.
abstract: OBJECTIVE
  To report the first three studies with SCH 900435, a selective glycine-1 re-uptake inhibitor in development for treating schizophrenia, using systematic evaluations of pharmacodynamics to understand the observed effects.
  
  
  METHODS
  Three double-blind, placebo-controlled studies (single, visual effect and multiple dose) were performed. In the single and multiple dose study SCH 900435 (0.5-30 mg) was given to healthy males and frequent pharmacokinetic and pharmacodynamic measurements were performed. The visual effects study incorporated visual electrophysiological measures of macular, retinal and intracranial visual pathway function.
  
  
  RESULTS
  In the single dose study (highest difference, 95% CI, P) increases in smooth pursuit eye movements (8, 12 mg (-6.09, 10.14, -2.04, 0.013), 30 mg), pupil : iris ratio (20 and 30 mg (-0.065, 0.09, -0.04, <0.0001)), VAS colour perception (30 mg (-9.48, 13.05, -5.91, <0.0001)) and changes in spontaneous reports of visual disturbance were found, while FSH (8 mg (0.42, 0.18, 0.66, 0.0015), 12, 20 mg), LH (8-30 mg (1.35, 0.65, 2.05, 0.0003)) and EEG alpha2 activity decreased (12, 20, 30 mg (0.27, 0.14, 0.41, 0.0002)). A subsequent dedicated visual effects study demonstrated that visual effects were transient without underlying electrophysiological changes. This provided enough safety information for starting a multiple ascending dose study, showing less visual symptoms after twice daily dosing and titration, possibly due to tolerance.
  
  
  CONCLUSIONS
  Several central nervous system (CNS) effects and gonadotropic changes resulted from administration of 8 mg and higher, providing evidence for CNS penetration and pharmacological activity of SCH 900435. Antipsychotic activity in patients, specificity of the reported effects for this drug class and possible tolerance to visual symptoms remain to be established.
authors.affiliation: Centre for Human Drug Research, Zernikedreef 10, Leiden, The Netherlands. mariekemoolenaar@me.com
authors.forename: Marieke
authors.initials: M
authors.lastname: Liem-Moolenaar
authors.forename: Pierre
authors.initials: P
authors.lastname: Peeters
authors.forename: Ingrid M C
authors.initials: IM
authors.lastname: Kamerling
authors.forename: Chris
authors.initials: C
authors.lastname: Hogg
authors.forename: Graham
authors.initials: G
authors.lastname: Holder
authors.forename: Huub Jan
authors.initials: HJ
authors.lastname: Kleijn
authors.forename: Edwin
authors.initials: E
authors.lastname: Spaans
authors.forename: Joanna
authors.initials: J
authors.lastname: Udo De Haes
authors.forename: Marieke L
authors.initials: ML
authors.lastname: de Kam
authors.forename: Kari L
authors.initials: KL
authors.lastname: Franson
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cohen
authors.forename: Joop M A
authors.initials: JM
authors.lastname: van Gerven
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D003118:Color Perception / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D055808:Drug Discovery; D004569:Electroencephalography / Q000187:drug effects; D005133:Eye Movements / Q000187:drug effects*; D005998:Glycine / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; C520612:N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)aminomethylcarboxylic acid; D014179:Neurotransmitter Uptake Inhibitors; D013764:Tetrahydronaphthalenes; D005998:Glycine