tuneTypical Dose
40 mg per day
Pharmaceutical
NSI-189
NSI-189 phosphate
Evidence TierCWADA NOT PROHIBITED
watchEffect Window
4–12 weeks for antidepressant and cognitive endpoints based on trial durations.
check_circleCompliance
WADA NOT PROHIBITED
Overview
Clinical Summary
NSI-189 is an investigational compound studied for depression and cognitive symptoms, with proposed neurogenesis-related mechanisms. It is discussed for mood and cognitive outcomes, but remains experimental.
Early trials reported signals for improved depressive symptoms and cognitive measures, with hypothesized effects on hippocampal plasticity. Larger confirmatory studies are limited, so clinical confidence remains low. Minority interest includes anxiety and PTSD-related symptoms, but evidence is sparse. Benefits remain uncertain without robust replication and longer-term safety data.
Stimulates hippocampal neurogenesis via unknown receptor target. Does not act through monoamine reuptake inhibition. Increases BDNF and GDNF.
Outcomes
What This Is Expected To Influence
Primary Outcomes
- Phase 1 showed dose-dependent antidepressant signal on MADRS
- Phase 2 failed primary MADRS endpoint but showed cognitive sub-score improvements
Secondary Outcomes
- Hippocampal neurogenesis hypothesis (unconfirmed in human MRI)
- Improvement on Symbol Digit Modalities Test in MDD patients
Safety
Contraindications and Interactions
Contraindications
- Pregnancy
- Lactation
- Concurrent antidepressant use without medical supervision
Side effects
- Headache
- Insomnia
- GI upset
- Dizziness
Interactions
- Antidepressants (SSRIs, SNRIs, MAOIs), unknown interaction profile
Avoid if
- Pregnancy
- Lactation
- Minors
- Active psychiatric conditions on existing pharmacotherapy
Evidence
Study-level References
nsi-189-SRC-001Phase 2 RCT
Sourceopen_in_newPapakostas GI, et al. "A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder." Mol Psychiatry. 2020.
Population: Adults with Major Depressive Disorder (MDD)
Key findings: NSI-189 failed to beat placebo on MADRS but showed significant cognitive improvements on SDMT-like tasks and was generally tolerated.
Paper content
NSI-189 failed to beat placebo on MADRS but showed significant cognitive improvements on SDMT-like tasks and was generally tolerated.
nsi-189-SRC-002Phase 2, double-blind, placebo-controlled trial using sequential-parallel comparison design.
Sourceopen_in_newPapakostas GI, Johe K, Hand H, et al. A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder. Mol Psychiatry. 2020;25(7):1569-1579. doi:10.1038/s41380-018-0334-8. PMID:30626911.
Population: Outpatients with major depressive disorder.
Dose protocol: 40 mg/day or 80 mg/day NSI-189 versus placebo for 12 weeks in 220 MDD outpatients.
Key findings: Failed primary MADRS endpoint. 40 mg dose showed advantages on secondary cognitive measures (SDMT). Both doses well tolerated.
Notes: The published Phase 2 trial. Most rigorous clinical test of NSI-189 available.
Paper content
This Phase 2 trial randomized 220 MDD outpatients to NSI-189 (40 or 80 mg/day) or placebo for 12 weeks. The primary endpoint (MADRS change) was not met, meaning NSI-189 did not significantly outperform placebo for depression severity. However, the 40 mg dose showed statistically significant improvements on secondary cognitive measures including the SDMT and patient-reported physical and cognitive functioning. Both doses were well tolerated. The study represents the most rigorous clinical test of NSI-189 to date. The failed primary endpoint limits enthusiasm, while the cognitive secondary signal remains hypothesis-generating rather than confirmatory.