The Selective Glycine Uptake Inhibitor Org 25935 as an Adjunctive Treatment to Atypical Antipsychotics in Predominant Persistent Negative Symptoms of Schizophrenia: Results From the GIANT Trial

Using a selective glycine uptake inhibitor as adjunctive to
second-generation antipsychotic (SGA) was hypothesized to ameliorate
negative and/or cognitive symptoms in subjects with schizophrenia.
Subjects with predominant persistent negative symptoms (previously
stabilized Q3 months on an SGA) were enrolled in a randomized,
placebo-controlled trial to investigate adjunctive treatment with Org
25935, a selective inhibitor of type 1 glycine transporter, over 12 weeks
in a flexible dose design. Org 25935 was tested at 4 to 8 mg twice daily
and 12 to 16 mg twice daily versus placebo. Primary efficacy outcome
was mean change from baseline in Scale for Assessment of Negative
Symptoms composite score. Secondary efficacy end points were Positive
and Negative Syndrome Scale total and subscale scores, depressive
symptoms (Calgary Depression Scale for Schizophrenia), global functioning
(Global Assessment of Functioning scale), and cognitive measures using
a computerized battery (Central Nervous System Vital Signs). Responder
rates were assessed post hoc. A total of 215 subjects were
randomized, of which 187 (87%) completed the trial. Both dose groups of Org 25935 did not differ significantly from placebo on Scale for Assessment of Negative Symptoms, Positive and Negative Syndrome Scale (total or subscale scores), Global Assessment of Functioning, or the majority of tested cognitive domains. Org 25935 was generally well tolerated within the tested dose range, with no meaningful effects on extrapyramidal symptoms and some reports of reversible visual adverse effects. Org 25935 did not differ significantly from placebo in reducing negative symptoms or improving cognitive functioning when administered as adjunctive treatment to SGA. In our study population, Org 25935 appeared to be well tolerated in the tested dose ranges.