Early stage development of the glycine-1 re-uptake inhibitor SCH 900435: central nervous system effects compared with placebo in healthy men

Authors


  • Financial support
  • The first study was executed at the Centre for Human Drug Research in Leiden, the Netherlands. The second study was performed at the Clinical Unit of Guy's Drug Research Unit, Quintiles Limited, London, UK for the in-clinic parts of the study and at the Moorfields Eye Hospital and Institute of Ophthalmology, London, UK for dose administration and electrophysiology measurements. The third study was performed at the Clinical Unit of Guy's Drug Research Unit, Quintiles Limited, London, UK.
  • All studies were executed with financial support of Merck Sharp & Dohme (MSD), Early Stage Development, Oss, The Netherlands of whom the authors
  • Huub Jan Kleijn, Edwin Spaans and Joanna Udo De Haes are (or were) employees.

Correspondence

Mrs Marieke Liem-Moolenaar, Centre for Human Drug Research, Zernikedreef 10, Leiden, the Netherlands.

Tel.: +31 71 5246 400

Fax: +31 71 5246 499

e-mail: mariekemoolenaar@me.com

Abstract

Aims

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.

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