# Reboxetine
**Reboxetine**, sold as Edronax, is an antidepressant of the selective noradrenaline reuptake inhibitor (NRI, or norepinephrine reuptake inhibitor) class, developed in Italy in the mid-1980s and approved in Europe in 1997 for the acute treatment of depressive illness and major depression and for maintaining improvement in patients who initially respond.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC12059740/) • [2](https://www.medicines.org.uk/emc/product/1578/smpc) It was the first selective norepinephrine reuptake inhibitor used in the treatment of depression.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954275/) Its application for approval was rejected in the United States, and a 2010 meta-analysis including previously unpublished trial data concluded it was an ineffective and potentially harmful antidepressant, although a subsequent UK and European regulatory review that reinstated a pivotal trial found the benefit-risk balance positive in its authorized indication.[4](https://www.bmj.com/content/341/BMJ.c4737) • [5](https://www.gov.uk/drug-safety-update/reboxetine-benefit-risk-balance-reviewed)
| Key fact | Detail |
|---|---|
| Class and mechanism | Highly selective, potent inhibitor of noradrenaline reuptake; weak effect on serotonin reuptake and no effect on dopamine uptake[2](https://www.medicines.org.uk/emc/product/1578/smpc) |
| Dosing | 4 mg twice daily (8 mg/day) orally, increased to 10 mg/day after 3–4 weeks if response is incomplete; maximum 12 mg/day[2](https://www.medicines.org.uk/emc/product/1578/smpc) |
| Pharmacokinetics | Terminal half-life about 13 h allowing twice-daily dosing; absolute bioavailability at least 60%; 97% bound to plasma proteins in young adults; metabolised mainly by CYP3A4[2](https://www.medicines.org.uk/emc/product/1578/smpc) • [6](https://pubmed.ncbi.nlm.nih.gov/9169308/) |
| Regulatory status | Approved in many European countries and elsewhere (as Edronax, Pfizer); application rejected in the United States[4](https://www.bmj.com/content/341/BMJ.c4737) |
| Efficacy vs placebo (2010 meta-analysis) | No significant difference in remission rates (OR 1.17, 95% CI 0.91–1.51); inferior to SSRIs for remission (OR 0.80, 0.67–0.96) and response (OR 0.80, 0.67–0.95)[4](https://www.bmj.com/content/341/BMJ.c4737) |
| Publication bias | Published data overestimated benefit versus placebo by 99–115% and versus SSRIs by 19–23%; 74% of patient data in the meta-analysis was unpublished[4](https://www.bmj.com/content/341/BMJ.c4737) |
| Regulatory re-review (2011) | MHRA and European review concluded the benefit-risk balance remains positive in the authorized indication, with an updated meta-analysis showing response benefit over placebo (OR 1.47, 95% CI 1.10–1.97)[5](https://www.gov.uk/drug-safety-update/reboxetine-benefit-risk-balance-reviewed) |
## Pharmacology
Reboxetine acts mainly by binding to the norepinephrine transporter and blocking reuptake of extracellular norepinephrine, increasing noradrenaline availability in the synaptic cleft.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954275/) [In vitro](https://www.edgepedia.org/in-vitro) studies show no significant affinity for adrenergic (α1, α2, β) or muscarinic receptors, receptor activities associated with the cardiovascular, anticholinergic, and sedative side effects of older antidepressants.[2](https://www.medicines.org.uk/emc/product/1578/smpc)
The drug is a racemic mixture of (R,R) and (S,S) enantiomers, both active; the S,S enantiomer is more potent, with plasma levels about two times lower and urinary excretion two times higher than the other enantiomer.[2](https://www.medicines.org.uk/emc/product/1578/smpc) • [6](https://pubmed.ncbi.nlm.nih.gov/9169308/) After a single 4 mg oral dose, peak plasma levels of about 130 ng/ml are reached within 2 hours, and steady state occurs within 5 days.[2](https://www.medicines.org.uk/emc/product/1578/smpc) Elimination is governed by biotransformation, principally via CYP3A4, with only 10% of the dose excreted unchanged in urine; because of a narrow therapeutic margin, potent CYP3A4 inhibitors such as ketoconazole, erythromycin, and fluvoxamine should not be co-prescribed.[2](https://www.medicines.org.uk/emc/product/1578/smpc) Systemic exposure roughly doubles in patients with renal or hepatic insufficiency and rises about threefold in elderly patients.[2](https://www.medicines.org.uk/emc/product/1578/smpc)
## Clinical efficacy evidence
The central efficacy question was settled by a 2010 systematic review and meta-analysis (Eyding and colleagues, BMJ) that, for the first time, combined published and unpublished acute-treatment trials of reboxetine against placebo or selective serotonin reuptake inhibitors (SSRIs) in adults with major depressive disorder.[4](https://www.bmj.com/content/341/BMJ.c4737) It analyzed 13 double-blind randomised trials including 4098 patients, of whom 3033 (74%) came from unpublished trials; in the placebo comparison, 86% of participants (1946/2256) were from unpublished studies.[4](https://www.bmj.com/content/341/BMJ.c4737)
Against placebo, no significant difference in remission rates was found (odds ratio 1.17, 95% CI 0.91 to 1.51; P=0.216). Response rates showed substantial heterogeneity (I²=67.3%) across eight trials, driven by a small inpatient trial (trial 091, n=52) with an odds ratio of 11.43; after excluding it, the remaining seven trials showed no significant difference (OR 1.24, 95% CI 0.98 to 1.56; P=0.071). Meta-regression identified care setting as the most probable effect modifier: inpatient trials and trials in severe depression consistently showed better efficacy than outpatient trials, and the two outpatient-only trials showed no difference (OR 1.05, 0.73 to 1.50).[4](https://www.bmj.com/content/341/BMJ.c4737)
Reboxetine was inferior to the SSRIs fluoxetine, paroxetine, and citalopram for both remission (OR 0.80, 95% CI 0.67 to 0.96; P=0.015) and response rates (OR 0.80, 0.67 to 0.95; P=0.01), and inferior to placebo for both harm outcomes (P<0.001), with more withdrawals due to adverse events than fluoxetine (OR 1.79, 1.06 to 3.05).[4](https://www.bmj.com/content/341/BMJ.c4737) A later network meta-analysis of 21 antidepressants similarly found reboxetine the least effective drug in the comparison, with an odds ratio versus placebo of 1.37 (95% credible interval 1.16 to 1.63) against a range of 1.37 to 2.13 across the class, and the highest dropout rates.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC5889788/) • [4](https://www.bmj.com/content/341/BMJ.c4737)
## Publication bias
The 2010 meta-analysis provided a quantified example of publication bias in psychopharmacology. Adding unpublished data reversed the picture shown by published trials alone: a published-data advantage of reboxetine over placebo became a non-significant difference, and a non-significant difference versus SSRIs became inferiority of reboxetine. Published data overestimated the beneficial effect versus placebo by 99–115% and versus SSRIs by 19–23%, and also underestimated harm.[4](https://www.bmj.com/content/341/BMJ.c4737) Earlier favorable reviews had included only three of the eight placebo-controlled studies and only one unpublished trial, and two were co-written by a sponsor employee; the authors argued the case for mandatory publication of clinical trial data, including older agents.[4](https://www.bmj.com/content/341/BMJ.c4737)
## Regulatory re-review
Following the meta-analysis, the UK Commission on Human Medicines and the European Pharmacovigilance Working Party re-assessed the totality of the evidence, including the original license-application data.[5](https://www.gov.uk/drug-safety-update/reboxetine-benefit-risk-balance-reviewed) The MHRA noted limitations of the published meta-analysis: a pivotal efficacy study had been excluded from the efficacy analysis as a statistical outlier, which the regulator did not consider adequate justification for omitting a valid study. When that study and other pre-licensing studies were included in an updated meta-analysis, reboxetine showed a benefit in treatment response over placebo (OR 1.47, 95% CI 1.10 to 1.97; p=0.01). Differences in care setting and baseline disease severity were considered the most likely explanation for the divergent effect sizes, and a thorough safety review identified no previously unrecognised safety concerns. The review concluded that the balance of benefits and risks remains positive in the authorized indication.[5](https://www.gov.uk/drug-safety-update/reboxetine-benefit-risk-balance-reviewed) UK guidance nonetheless restricts reboxetine to patients in whom SSRIs are ineffective or not tolerated.[5](https://www.gov.uk/drug-safety-update/reboxetine-benefit-risk-balance-reviewed)
## Tolerability and safety
In placebo-controlled studies of 8 weeks or less, adverse events were reported in approximately 80% of reboxetine-treated patients versus approximately 70% on placebo, with discontinuation for adverse events in about 9% versus 5%.[2](https://www.medicines.org.uk/emc/product/1578/smpc) Very common reactions include insomnia, dizziness, dry mouth, constipation, and hyperhidrosis; common ones include tachycardia, palpitations, urinary retention, and erectile dysfunction.[2](https://www.medicines.org.uk/emc/product/1578/smpc) Urologic events showed a marked sex difference, reported in 31.4% of reboxetine-treated men (143/456) versus 7.0% of treated women (59/847), while frequencies were similar between sexes on placebo.[2](https://www.medicines.org.uk/emc/product/1578/smpc) Reboxetine raises mean heart rate by 6 to 12 beats per minute versus placebo in short-term studies.[2](https://www.medicines.org.uk/emc/product/1578/smpc) Warnings cover serotonin syndrome with serotonergic co-medication, seizures in patients with convulsive disorders, mydriasis and narrow-angle glaucoma, and avoidance in patients under 18 years.[2](https://www.medicines.org.uk/emc/product/1578/smpc)
## Other investigated uses
A meta-analysis of randomized double-blind placebo-controlled trials found adjunctive reboxetine added to antipsychotics improved negative symptoms of schizophrenia (9 RCTs, n=602; SMD −0.47, 95% CI −0.87 to −0.07; p=0.02, with high heterogeneity I²=82%), but not overall, positive, or general psychopathology scores.[8](https://pubmed.ncbi.nlm.nih.gov/31207653/)
## References
1. [Reintroduction of antidepressants and serendipity in drug discovery (historical analysis), PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC12059740/)
2. [Edronax 4 mg Tablets, Summary of Product Characteristics, electronic Medicines Compendium](https://www.medicines.org.uk/emc/product/1578/smpc)
3. [Eyding D, et al. Reboxetine for acute treatment of major depression (PMC version), BMJ 2010;341:c4737](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954275/)
4. [Eyding D, et al. Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and SSRI controlled trials. BMJ 2010;341:c4737](https://www.bmj.com/content/341/BMJ.c4737)
5. [Reboxetine: benefit-risk balance reviewed, Drug Safety Update, MHRA/GOV.UK, September 2011](https://www.gov.uk/drug-safety-update/reboxetine-benefit-risk-balance-reviewed)
6. [Dostert P, Benedetti MS, Poggesi I. Review of the pharmacokinetics and metabolism of reboxetine. Eur Neuropsychopharmacol 1997;7 Suppl 1:S23-35](https://pubmed.ncbi.nlm.nih.gov/9169308/)
7. [Cipriani A, et al. Comparative efficacy and acceptability of 21 antidepressant drugs: systematic review and network meta-analysis, The Lancet (PMC)](https://pmc.ncbi.nlm.nih.gov/articles/PMC5889788/)
8. [Adjunctive Reboxetine for Schizophrenia: Meta-analysis of Randomized Double-blind, Placebo-controlled Trials, PubMed](https://pubmed.ncbi.nlm.nih.gov/31207653/)
9. [FDA Orphan Drug Designations and Approvals: reboxetine, narcolepsy, Axsome Therapeutics](https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=656118)
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*Topic: Encyclopedia › Life and health › Human health and medicine › Medicines and therapeutics › Psychiatric and neurological medications › Sedatives, hypnotics, and anxiolytics*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license