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TAK-041 (NBI-1065846); the most advanced GPR139 agonist, a novel habenula-targeting probe for anhedonia and negative symptoms, with clear target engagement but a negative phase 2 anhedonia trial.
- novel mechanism: selective GPR139 agonism to modulate the habenula, a circuit central to motivation and anhedonia
- orally available with clear target engagement and biological signals (ventral-striatal reward activity, cerebral blood flow)
- generally well tolerated across phase 1 and phase 2
- the most clinically advanced test of a genuinely new, non-monoamine approach to reward and negative symptoms
Overview
the leading GPR139 agonist; a novel habenula-targeting approach to anhedonia and negative symptoms with real target engagement, but its phase 2 anhedonia trial (TERPSIS) missed. do not confuse NBI-1065846 (this) with NBI-1065845 (TAK-653).
- GPR139 is an 'orphan' receptor and is packed into the habenula, the brain's disappointment center.
- its half-life is enormous for a CNS drug, up to about 300 hours, so it clears very slowly.
- its Neurocrine code NBI-1065846 is just one digit off from TAK-653's NBI-1065845, and they are totally different drugs.
- it visibly increased reward-anticipation brain activity, yet still failed to beat placebo for anhedonia.
Mechanism
TAK-041 (NBI-1065846) is a potent, selective small-molecule of GPR139, an orphan G-protein-coupled receptor that is unusually concentrated in the habenula, a small epithalamic nucleus that has been linked to depression, schizophrenia and substance-use disorder. it emerged from a Takeda high-throughput-screen and medicinal-chemistry campaign on a benzotriazinone scaffold, and in preclinical work GPR139 agonism modulated habenula cell activity and rescued social-interaction deficits in the BALB/c mouse model (Reichard et al., 2021, J Med Chem, https://doi.org/10.1021/acs.jmedchem.1c00820). the therapeutic thesis is circuit-specific: because the lateral habenula encodes aversion and reward suppression and is thought to be hyperactive in depression and anhedonia, tuning it through GPR139 could improve motivation and reward processing that monoamine drugs miss. clinically, TAK-041 has good oral , nearly linear pharmacokinetics and a strikingly long of roughly 170 to 302 hours; a phase 1 program in healthy volunteers and stable schizophrenia patients was generally well tolerated and showed exploratory signals on an anxiety-depression subscale and a pleasure scale (not corrected for multiplicity) (Yin et al., 2022, Br J Clin Pharmacol, https://doi.org/10.1111/bcp.15305). imaging in schizophrenia patients found time-dependent effects on cerebral blood flow and, at day 14, increased reward-anticipation activity in the ventral striatum, though no improvement on a cognition battery (Hawkins et al., 2025, Psychopharmacology, https://doi.org/10.1007/s00213-025-06884-x). the definitive efficacy test, however, was negative: according to PubMed, the phase 2 TERPSIS trial in MDD patients with anhedonia did not meet its primary endpoint (Dimensional Anhedonia Rating Scale) or secondary depression endpoints, as both drug and placebo groups improved substantially with no significant separation (Benedetto et al., 2025, J Clin Psychopharmacol, https://doi.org/10.1097/JCP.0000000000002046). so TAK-041 stands as the most advanced clinical probe of the GPR139/habenula hypothesis: an intriguing, novel mechanism with target engagement and some biological signals, but without a positive controlled efficacy result to date.
receptor fingerprint
GPR139 (orphan G-protein-coupled receptor)potent, selective small-molecule agonist; highly expressed in the habenula
lateral habenula circuit (downstream)GPR139 agonism modulates habenular output implicated in anhedonia and negative/cognitive symptoms
Dosingtypical ranges, not medical advice
interested in protocols and clinical dosages? make an account to see them! ^_^
Safetyrisks and cautions, not medical advice
across phase 1 and phase 2, TAK-041/NBI-1065846 was generally well tolerated, with treatment-emergent adverse events reported as mild or moderate. its very long half-life (about 170-302 hours) means slow accumulation and washout, which matters for any exposure. it is an investigational drug whose lead efficacy trial was negative; it is not approved or available, and any grey-market claim to sell it is unverified.
History
TAK-041 was discovered by Takeda as a clinical GPR139 agonist tool compound aimed initially at negative symptoms of schizophrenia, then broadened toward anhedonia in depression as the habenula hypothesis gained traction. Neurocrine Biosciences licensed it as NBI-1065846 (not to be confused with its AMPA-PAM sibling NBI-1065845/TAK-653). despite target engagement and some exploratory signals, the phase 2 TERPSIS anhedonia trial reported in 2025 failed to separate from placebo, tempering enthusiasm for the approach.
Reputation
TAK-041 is regarded as a scientifically bold, mechanism-first compound; the flagship attempt to drug GPR139 and the habenula for mood and motivation. it is respected for opening a novel target, but its reputation is now shaded by the negative TERPSIS result, which left the whole GPR139-for-anhedonia idea unproven. the frequent point of confusion in write-ups is its Neurocrine code being one digit off from TAK-653's.
Subjective profileweighing the evidence above
Scientifically the most serious attempt yet at a non-monoamine route to anhedonia, with clear target engagement, and the phase 2 trial still came back negative. Well tolerated, but with a half-life measured in weeks, no approval and no legitimate supply, it is a research story rather than a product.
Resources
This entry is here for reference.
Research
- 2021first citedDiscovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negat…
- 2026most recentThe GPR139 agonist TAK-041 produces time-dependent alterations to cerebral blood flow and rewar…
- 1.A Phase 2 Randomized Trial of NBI-1065846 (TAK-041) in Patients With Anhedonia Associated With Major Depressive Disorder: Results of the TERPSIS Study
- 2.Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia
- 3.A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia
- 4.The GPR139 agonist TAK-041 produces time-dependent alterations to cerebral blood flow and reward system function in patients with schizophrenia: a randomised placebo-controlled trial.
4 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
what is TAK-041 (NBI-1065846)?
it is a potent, selective small-molecule agonist of GPR139, an orphan G-protein-coupled receptor concentrated in the habenula, a small brain nucleus tied to mood, motivation and reward. by activating GPR139 it modulates habenula activity, which is why it was pursued for negative and cognitive symptoms and for anhedonia (Reichard et al., 2021, J Med Chem, https://doi.org/10.1021/acs.jmedchem.1c00820).
one warning about the code numbers: is NBI-1065846 the same as NBI-1065845?
no; be careful. NBI-1065846 is TAK-041, the GPR139 agonist. NBI-1065845 is TAK-653, the AMPA potentiator. they are two entirely different Neurocrine-licensed Takeda compounds whose codes differ by a single digit.
what was it developed for?
two main directions: negative and cognitive symptoms of schizophrenia, and anhedonia (loss of pleasure) in major depressive disorder. the unifying idea was that dialing habenula activity via GPR139 could improve motivation and reward processing that current drugs leave untreated.
does it work for depression/anhedonia?
the key trial was negative. the phase 2 TERPSIS study in MDD patients with anhedonia did not meet its primary endpoint (Dimensional Anhedonia Rating Scale) or its secondary depression endpoints; both drug and placebo groups improved a lot, with no significant difference (Benedetto et al., 2025, J Clin Psychopharmacol, https://doi.org/10.1097/JCP.0000000000002046). it was generally well tolerated.
is there any positive human signal at all?
some mechanistic and exploratory hints, but nothing confirmed. in a phase 1 schizophrenia study, exploratory signals appeared on an anxiety-depression subscale and a pleasure scale (not corrected for multiplicity) (Yin et al., 2022, Br J Clin Pharmacol, https://doi.org/10.1111/bcp.15305). in a separate imaging study in schizophrenia, TAK-041 changed cerebral blood flow and, at day 14, increased reward-anticipation activity in the ventral striatum, but did not improve a cognition battery (Hawkins et al., 2025, Psychopharmacology, https://doi.org/10.1007/s00213-025-06884-x).
why the habenula?
the lateral habenula is a hub for encoding disappointment and suppressing reward; overactivity there is linked to depression and anhedonia. because GPR139 is unusually concentrated in the habenula, an agonist offered a way to modulate that specific circuit, which is a genuinely novel angle compared with monoamine antidepressants.
anything unusual about its pharmacology?
yes; it has a very long half-life, roughly 170 to 302 hours across doses in humans, with nearly linear pharmacokinetics and good oral bioavailability (Yin et al., 2022, Br J Clin Pharmacol, https://doi.org/10.1111/bcp.15305). that is an unusually slow washout for a CNS drug.
can i buy it?
no. it is an investigational drug whose lead depression trial failed; it is not approved and not a supplement. it is covered here as the most clinically advanced GPR139 agonist and a real-world test of the habenula-targeting hypothesis.