SLC6A4 solute carrier family 6 member 4
ENSG00000108576 · protein coding · Open Targets profile
Serotonin transporter that cotransports serotonin with one Na(+) ion in exchange for one K(+) ion and possibly one proton in an overall electroneutral transport cycle. Transports serotonin across the plasma membrane from the extracellular compartment to the cytosol thus limiting serotonin intercellular signaling (PubMed:10407194, PubMed:12869649, PubMed:21730057, PubMed:27049939, PubMed:27756841, PubMed:34851672). Essential for serotonin homeostasis in the central nervous system. In the developing somatosensory cortex, acts in glutamatergic neurons to control serotonin uptake and its trophic functions accounting for proper spatial organization of cortical neurons and elaboration of sensory circuits. In the mature cortex, acts primarily in brainstem raphe neurons to mediate serotonin uptake from the synaptic cleft back into the pre-synaptic terminal thus terminating serotonin signaling at the synapse (By similarity). Modulates mucosal serotonin levels in the gastrointestinal tract through uptake and clearance of serotonin in enterocytes. Required for enteric neurogenesis and gastrointestinal reflexes (By similarity). Regulates blood serotonin levels by ensuring rapid high affinity uptake of serotonin from plasma to platelets, where it is further stored in dense granules via vesicular monoamine transporters and then released upon stimulation (PubMed:17506858, PubMed:18317590). Mechanistically, the transport cycle starts with an outward-open conformation having Na1(+) and Cl(-) sites occupied. The binding of a second extracellular Na2(+) ion and serotonin substrate leads to structural changes to outward- occluded to inward-occluded to inward-open, where the Na2(+) ion and serotonin are released into the cytosol. Binding of intracellular K(+) ion induces conformational transitions to inward-occluded to outward- open and completes the cycle by releasing K(+) possibly together with a proton bound to Asp-98 into the extracellular compartment. Na1(+) and Cl(-) ions remain bound throughout the transport cycle (PubMed:10407194, PubMed:12869649, PubMed:21730057, PubMed:27049939, PubMed:27756841, PubMed:34851672). Additionally, displays serotonin- induced channel-like conductance for monovalent cations, mainly Na(+) ions. The channel activity is uncoupled from the transport cycle and may contribute to the membrane resting potential or excitability (By similarity). {ECO:0000250|UniProtKB:P31652, ECO:0000250|UniProtKB:Q60857, ECO:0000269|PubMed:10407194, ECO:0000269|PubMed:12869649, ECO:0000269|PubMed:17506858, ECO:0000269|PubMed:18317590, ECO:0000269|PubMed:21730057, ECO:0000269|PubMed:27049939, ECO:0000269|PubMed:27756841, ECO:0000269|PubMed:34851672}.
Each band is a group of drugs. It runs from the kind of drug on the left to the furthest stage that drug has reached in any disease on the right. Thicker bands mean more drugs.
Approved bands are highlighted. Withdrawn means the drug was pulled from the market or from development. A combined phase counts as the later one (Phase 1/2 is shown as Phase 2). Hover a band for the drug names. Source: Open Targets Platform, fetched live.
Each row is a cancer, strongest overall evidence first. The two dots show how strong the inherited (germline) and tumour-mutation (somatic) evidence is; the line between them is the gap.
Scores run from 0 (no evidence) to 1 (strongest). A missing dot at 0 means Open Targets holds no evidence of that kind. Source: Open Targets Platform, fetched live.
Tractability
- Small molecule
- Approved Drug, Structure with Ligand, High-Quality Ligand, Druggable Family
- Antibody
- UniProt loc high conf, GO CC high conf, UniProt SigP or TMHMM
- PROTAC
- Small Molecule Binder
- Other modalities
- Advanced Clinical
gnomAD loss of function constraint: o/e 0.2997100055217743 (upper bound 0.42796000838279724). Low values mean loss of function is poorly tolerated, a safety flag for inhibition.
Who runs trials of these drugs
Principal investigators and study chairs on 400 registry trials, updated in the last three years, of the most advanced drugs against SLC6A4 (desvenlafaxine, methamphetamine, fluoxetine, nortriptyline, trazodone, paroxetine, lumateperone, levomilnacipran, escitalopram oxalate, dasotraline, citalopram hydrobromide, mazindol), ranked by Phase 2+ trials. Live from ClinicalTrials.gov.
- Madhukar TrivediUniversity of Texas Southwestern Medical Center · 3 of 4 trials Phase 2+
- Jeffrey R StrawnUniversity of Cincinnati · 3 of 3 trials Phase 2+
- Manish JhaUniversity of Texas Southwestern Medical Center · 3 of 3 trials Phase 2+
- Rudolf UherNova Scotia Health Authority · 3 of 3 trials Phase 2+
- Heather WebberThe University of Texas Health Science Center, Houston · 2 of 3 trials Phase 2+
- Didier Jutras-AswadCHUM · 2 of 2 trials Phase 2+
- Kimberly VanoverIntra-Cellular Therapies, Inc. · 2 of 2 trials Phase 2+
- M Safwan BadrJohn D. Dingell VA Medical Center, Detroit, MI · 2 of 2 trials Phase 2+
- Susan KozauerIntra-Cellular Therapies, Inc. (ITI) · 2 of 2 trials Phase 2+
- Catherine J HarmerUniversity of Oxford · 1 of 2 trials Phase 2+
- Phillip CoffinSan Francisco Department of Public Health · 1 of 2 trials Phase 2+
- A. DaigneaultDouglas Mental Health University Institute, Montreal, Quebec · 1 of 1 trials Phase 2+
- A. RavindranCentre for Addictions and Mental Health, Toronto, Ont. · 1 of 1 trials Phase 2+
- A. SchafferSunnybrook Health Sciences Centre, Toronto, Ont. · 1 of 1 trials Phase 2+
- A.V. MysoreSt. John's hospital, Bangalore, India · 1 of 1 trials Phase 2+
Registry trials of desvenlafaxine, methamphetamine, fluoxetine, nortriptyline, trazodone, paroxetine, lumateperone, levomilnacipran, escitalopram oxalate, dasotraline, citalopram hydrobromide, mazindol updated in the last three years, counted by the country group of their listed sites. A trial with sites in several groups counts in each; 354 of 384 have all sites in one country.
Site counts are not patients per country, and trials registered only outside ClinicalTrials.gov are not covered. Where sites are is a fact about the record, not a judgement of its quality. Europe is the EU and EEA, the UK and Switzerland. 16 trials list no sites and are left out. Source: ClinicalTrials.gov, fetched live.
190 trials of drugs against SLC6A4 were stopped early; 24 give no reason
Terminated, withdrawn and suspended interventional trials of desvenlafaxine, methamphetamine, fluoxetine, nortriptyline, trazodone, paroxetine, lumateperone, levomilnacipran, escitalopram oxalate, dasotraline, citalopram hydrobromide, mazindol, newest update first, live from ClinicalTrials.gov. Each reason is quoted exactly as the registry gives it; we do not sort reasons into safety, efficacy or business. Dates are the last registry update. Showing the 25 most recent of 190.
- terminated · 2026-11-05 · Dr. Inge Winter · matched by the registry's drug synonyms“The site in Israel stopped recruitment due to logistic reasons. Other sites are recruiting for 2023-506602-39-00, 2023-506605-19-00, 2023-506617-21-00.”
- suspended · 2026-10-27 · University of California, Irvine · Nortriptyline, Paroxetine“Enrollment temporarily paused pending IRB continuing review; recruitment expected to resume.”
- withdrawn · 2026-09-18 · Queen's Medical Center · matched by the registry's drug synonyms“The study never commenced. The funding went through as year 2 for NCT06532370”
- terminated · 2026-08-25 · The Cleveland Clinic · Nortriptyline“Not enough participants - only 5 since the study started”
- suspended · 2026-07-14 · National Institute of Allergy and Infectious Diseases (NIAID) · matched by the registry's drug synonyms“Temporarily Closed (Paused) to Accrual”
- withdrawn · 2026-07-10 · University of Minnesota · Fluoxetine, Metformin+Fluoxetine“Study was not initiated because funding was not received.”
- suspended · 2026-06-30 · Global Coalition for Adaptive Research · Intervention A Fluoxetine Hydrochloride (HCl)“The trial has been temporarily suspended due to administrative issues”
- suspended · 2026-05-20 · Global Coalition for Adaptive Research · Intervention A Fluoxetine Hydrochloride (HCl)“Deferred at this time”
- terminated · 2026-05-12 · University of Wisconsin, Madison · matched by the registry's drug synonyms“due to sponsor financial constraints”
- withdrawn · 2026-05-04 · University of Southern California · Trazodone“PI left institution. Study never started.”
- terminated · 2026-01-21 · Shanghai Mental Health Center · matched by the registry's drug synonyms“Main trial terminated after pilot trial: full randomization proved infeasible for nonlocal participants; baseline symptom-based allocation added confounding variable; comparison with CBGT alone was deemed sufficient to assess SC-ICBT effectiveness”
- terminated · 2025-12-10 · Case Comprehensive Cancer Center · matched by the registry's drug synonyms“Slow accrual”
- terminated · 2025-09-10 · Lancaster General Hospital · Nortriptyline“The study was stopped prematurely due to a low enrollment rate.”
- terminated · 2025-08-06 · Weill Medical College of Cornell University · matched by the registry's drug synonyms“funding stopped”
- withdrawn · 2025-07-14 · Sadat City University · Paroxetine“Institutional and funding constrains”
- withdrawn · 2025-07-14 · Sadat City University · matched by the registry's drug synonyms“Institutional and funding constrains”
- withdrawn · 2025-07-14 · Sadat City University · matched by the registry's drug synonyms“Institutional and funding constrains”
- withdrawn · 2025-07-14 · Sadat City University · matched by the registry's drug synonyms“Institutional and funding constrains”
- terminated · 2025-07-03 · Maastricht University Medical Center · Nortriptyline“The inclusion of participants went more difficult than initially thought. Preliminary analysis showed that the difference between the groups was great enough to draw conclusions from it, so the trial is terminated prematurely.”
- terminated · 2025-05-20 · University of Calgary · matched by the registry's drug synonyms“Low recruitment”
- terminated · 2025-05-15 · University of British Columbia · matched by the registry's drug synonyms“Recruitment was stopped before the planned sample size was reached owing to the Covid-19 pandemic and expiration of funding.”
- suspended · 2025-05-13 · New York State Psychiatric Institute · matched by the registry's drug synonyms“NYSPI paused human subjects research (HSR) 6/23. The US Dept. of Health and Human Services Office of Human Research Protections issued an FWA restriction pausing such research 6/23/23. The IO and IRB paused HSR 6/12/23. Hence no current enrolling.”
- terminated · 2025-04-29 · The University of Texas Health Science Center, Houston · matched by the registry's drug synonyms“Lack of enrollment”
- terminated · 2025-04-27 · Janssen Research & Development, LLC · matched by the registry's drug synonyms“Following discussion on pediatric strategy with HAs, it was determined that we have sufficient data to inform next steps for the seltorexant pediatric program.”
- withdrawn · 2025-04-27 · Janssen-Cilag International NV · Trazodone Prolonged Release“New design was developed to better fit company strategy, a new study has replaced 5413541TRD3011 study”
Paediatric incentives and obligations for SLC6A4's drugs
For desvenlafaxine, methamphetamine, fluoxetine, nortriptyline, trazodone, paroxetine, lumateperone, levomilnacipran, escitalopram oxalate, dasotraline, citalopram hydrobromide, mazindol: what EMA and FDA publish about paediatric plans, orphan status and pediatric approvals, and how many registered studies take children. Each line is a yes, no or not published fact from the record linked under it; none of it is a forecast.
- FDA pediatric target list: no · SLC6A4 is not on the listRule: Target is on FDA's Pediatric Molecular Target List (relevant targets). Source: FDA Pediatric Molecular Target List (Listed as February 2026 on the FDA Pediatric Oncology page; the file served is 9.7.22_the_relevant_molecular_target_list.xlsx, whose Summary of Changes sheet is headed 'SEPTEMBER 2022 UPDATE' (footnote date 2022-09-01)), 2026-11-11
- EU paediatric investigation plan: yes · EMEA-002142-PIP01-17 (trazodone (hydrochloride), Treatment of insomnia): P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s), 19 Dec 2017; EMEA-002263-PIP01-17 (trazodone (hydrochloride);gabapentin, Treatment of painful diabetic neuropathy): W: decision granting a waiver in all age groups for all conditions or indications, 16 Mar 2018; EMEA-001724-PIP01-14 (levomilnacipran, Treatment of stroke): RW: decision refers to a refusal on a request for waiver in all age groups for the listed condition(s), 5 Jun 2015Rule: An EMA PIP decision (agreement, modification or waiver) lists the drug as its active substance, exact name. Source: EMA data download (dated snapshot), 2026-11-11
- EU orphan designation: yes · EU/3/22/2676 positive 10 Aug 2022: Treatment of idiopathic hypersomnia; EU/3/15/1547 positive 9 Oct 2015: Treatment of narcolepsy; EU/3/15/1444 withdrawn 12 Feb 2015: Treatment of narcolepsyRule: An EU orphan designation lists the drug as its active substance (exact name) or belongs to a medicine that does; withdrawn and expired designations are listed with their status. Source: EMA data download (dated snapshot), 2026-11-11
- Authorised in the EU: no · Pristiqs: application withdrawnRule: An EMA medicine record lists the drug as its active substance or INN, exact name; national-only authorisations are not in this file. Source: EMA EPAR Pristiqs, 2026-11-11
- FDA orphan designation: not published · FDA's orphan designation database turns away automated requests, so this app does not read it; search it by hand at the linkRule: Would be: an FDA orphan designation names the drug. Source: FDA orphan designations search
- FDA pediatric oncology approval: no · FDA's table lists no pediatric approval of desvenlafaxine, methamphetamine, fluoxetine, nortriptyline, trazodone, paroxetine, lumateperone, levomilnacipran, escitalopram oxalate, dasotraline, citalopram hydrobromide, mazindolRule: FDA's Pediatric Oncology Drug Approvals table names the drug. Source: FDA Pediatric Oncology Drug Approvals (content current as of 2026-03-03), 2026-11-12
- Registered studies open to children: yes · 169 interventional studies of desvenlafaxine, methamphetamine, fluoxetine, nortriptyline, trazodone, paroxetine, lumateperone, levomilnacipran, escitalopram oxalate, dasotraline, citalopram hydrobromide, mazindol include patients under 18; 25 are recruiting, not yet recruiting or activeRule: The registry's age group includes Child (birth to 17 years), which also counts studies that set no minimum age. Source: ClinicalTrials.gov search, 2026-11-12
Rare pediatric disease voucher. FDA, content current as of 29 Apr 2026: “As of February 3, 2026, enactment of the Consolidated Appropriations Act, 2026, the rare pediatric disease PRV program will sunset after September 30, 2029. FDA may not award any PRVs under this program after September 30, 2029.” Voucher sale prices are not shown here; they appear only as company-reported news. FDA: Rare Pediatric Disease Designation and Priority Review Voucher Programs
All 67 drugs and clinical candidates as a table
Each drug, stage and indication links to its Open Targets record, where the trials and approvals behind it are listed. Salt forms (for example a mesylate) are listed as Open Targets records them, as separate entries.