Phase I

Phase II

Phase III

Depression, Bipolar Disorder, Alzheimer’s disease and Parkinson’s disease


TNX-4300* (estianeptine), the single (S)-isomer of tianeptine is in preclinical development as a potential new treatment for psychiatric disorders, including depression and bipolar disorder, as well as neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Racemic tianeptine is a 1:1 mixture of (S)– and (R)-tianeptine isomers. Tonix is developing racemic tianeptine as TNX-601 (tianeptine hemioxalate extended-release), which is in a Phase 2 study for major depressive disorder. Tianeptine as an immediate-release three-times-daily medicine has been approved and marketed as an antidepressant for more than 30 years in Europe, Asia and South America.

TNX-4300 is believed to have a distinct mechanism of action relative to traditional treatments for depression approved in the U.S. Tianeptine was known to be a plastogen and to restore neuronal connectivity, or neuroplasticity,1,2 as well as enable neurogenesis. Tonix scientists discovered that (S)-tianeptine acts on nuclear PPAR-β/δ and PPAR-γ in neurons and glia. We believe TNX-4300 has potential applicability in a number of psychiatric and neurodegenerative diseases in which neuronal connections are atrophying.3 The mechanistic findings of (S)-tianeptine challenge the status quo since the only known way to restore the connectivity of neurons damaged in the state of depression was to increase the synaptic levels or activity of neurotransmitters such as the monoamines serotonin, norepinephrine, and dopamine.

The PPAR-β/δ-activating mechanism for (S)-tianeptine may also explain why tianeptine does not cause sexual dysfunction, weight gain or several other treatment-limiting side effects associated with traditional antidepressants. Tianeptine is believed to treat depression by activating select nuclear PPAR isoforms.

Importantly, the (S)-isomer of tianeptine is also free of µ-opioid receptor activity. In contrast, the (R)-isomer of tianeptine is a weak agonist of the µ-opioid receptor and is believed to account for the weak agonist activity of racemic tianeptine.3

Key experiments were performed by scientists at Tonix’s Research and Development Center (RDC) in Frederick, Maryland.


*TNX-4300 (estianeptine) is an investigational new drug and has not been approved for any indication.
1 Sullivan, GM et al. June 1, 2023. Poster presentation at the American Society of Clinical Psychopharmacology, Miami, FL.
2 McEwen, B. S., et al. Mol. Psychiatry 2010, 15 (3), 237–249
3 Samuels et al., Neuropsychopharmacology. 2017, 42(10):2052-2063