Article date: June 2013
By: Marieke Liem‐Moolenaar, Pierre Peeters, Ingrid M. C. Kamerling, Chris Hogg, Graham Holder, Huub Jan Kleijn, Edwin Spaans, Joanna Udo De Haes, Marieke L. Kam, Kari L. Franson, Adam F. Cohen, Joop M. A. Gerven, in Volume 75, Issue 6, pages 1455-1467
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.
DOI: 10.1111/bcp.12015
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