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Org 25935 was Organon's (later Merck, after the 2009 Schering-Plough/Organon merger) entry into the glycine reuptake inhibitor race, arriving on the scene around the same time as Roche's bitopertin and chasing the identical NMDA-hypofunction rationale for schizophrenia's negative symptoms. It also had a second life as a candidate for relapse prevention in alcohol dependence, based on glycinergic modulation of mesolimbic reward circuitry. The schizophrenia program culminated in the GIANT trial, a 215-patient, multi-center, placebo-controlled study of Org 25935 as an add-on to second-generation antipsychotics in patients with persistent negative symptoms. The drug was well tolerated but did not separate from placebo on negative symptoms or cognition, and Merck did not pursue it further after the 2014 publication, leaving it one of several GlyT1 inhibitors that could not translate the mechanism into a working schizophrenia drug.
- generally well tolerated with no significant extrapyramidal side effects
- tested a mechanistically sound NMDA-enhancing strategy
- also explored for alcohol-dependence relapse prevention
- failed to significantly reduce negative symptoms versus placebo
- no meaningful cognitive improvement demonstrated
- some reversible visual adverse effects reported in trial participants
- Org 25935 and bitopertin were developed almost in parallel by two different pharma companies chasing the exact same glycine transporter target for the exact same indication.
Mechanism
Selective glycine transporter 1 (GlyT1) inhibitor; raises glycine to enhance co- signaling, the same target class as bitopertin and sarcosine.
Safetyrisks and cautions, not medical advice
Reversible visual disturbances are the signature effect, and they showed up in both programmes: the 215-patient schizophrenia trial reported them, and the alcohol dependence trial listed transient visual events alongside fatigue and dizziness as its commonest complaints. They resolved, and neither study found a safety problem serious enough to stop dosing; the schizophrenia trial also saw no meaningful movement side effects. Twelve weeks is the longest anyone has been on it, and both trials ended for lack of benefit rather than for harm.
History
Developed by Organon, continued under Merck after the 2009 merger; the GIANT trial (published 2014) tested it as an antipsychotic add-on for negative symptoms in 215 patients and found no significant benefit over placebo.
Subjective profileweighing the evidence above
A well-run trial of a reasonable mechanism that simply didn't move the needle; one more data point against glycine-transporter inhibition as a schizophrenia treatment strategy.
Resources
This entry is here for reference.
Research
- 1.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
- 2.Efficacy and safety of the glycine transporter-1 inhibitor org 25935 for the prevention of relapse in alcohol-dependent patients: a randomized, double-blind, placebo-controlled trial.
2 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
How is Org 25935 different from bitopertin?
Both are GlyT1 inhibitors with the same basic mechanism, developed by rival companies (Organon/Merck versus Roche) around the same era; Org 25935's pivotal GIANT trial for negative symptoms was negative, while bitopertin at least had a positive Phase II before failing in Phase III.
Was Org 25935 ever tested for anything besides schizophrenia?
Yes, it was also studied as a relapse-prevention treatment for alcohol dependence, on the theory that glycine transporter inhibition modulates the same reward circuitry involved in alcohol craving.
Adverse effects
- failed to significantly reduce negative symptoms versus placebo
- no meaningful cognitive improvement demonstrated
- some reversible visual adverse effects reported in trial participants