Reboxetine

There has been much debate as to whether reboxetine is more efficacious than placebo in the treatment of depression. According to a 2009 meta-analysis of 12 second-generation antidepressants, reboxetine was no more effective than placebo, and was "significantly less" effective and less acceptable than the other drugs in treating the acute-phase of adults with unipolar major depression.{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C | title = Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis | journal = Lancet | volume = 373 | issue = 9665 | pages = 746–58 | date = February 2009 | pmid = 19185342 | doi = 10.1016/S0140-6736(09)60046-5 | s2cid = 35858125 | url = http://www.cipralex.co.il/sitecontent/ExternalFiles/213.pdf | archive-url = https://web.archive.org/web/20130929174834/http://www.cipralex.co.il/sitecontent/ExternalFiles/213.pdf | url-status = dead | archive-date = 2013-09-29 }}

The British MHRA said in September 2011 that the study had several limitations, and that "Overall the balance of benefits and risks for reboxetine remains positive in its authorised indication."{{cite web|title=Reboxetine: benefit-risk balance reviewed|date=September 2011|url=http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON128957|work=Drug Safety Update|publisher=Medicines and Healthcare products Regulatory Agency|access-date=10 November 2013}} A UK and Europe-wide review of available efficacy and safety data has confirmed that reboxetine has benefit over placebo in its authorised indication. Efficacy was clearly shown in patients with severe or very severe depression.

According to a systematic review and meta-analysis by IQWiG, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm, concluding that reboxetine was an ineffective and potentially harmful antidepressant. The study also showed that nearly three quarters of the data on patients who took part in trials of reboxetine had not been published by Pfizer.

A 2018 systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs concluded that reboxetine was more effective than placebo but significantly less efficacious than other antidepressants tested.{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR | display-authors = 6 | title = Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis | journal = Lancet | volume = 391 | issue = 10128 | pages = 1357–1366 | date = April 2018 | pmid = 29477251 | pmc = 5889788 | doi = 10.1016/S0140-6736(17)32802-7 }}

In a randomised double-blind placebo-controlled trial reboxetine significantly improved the symptoms of panic disorder.{{cite journal | vauthors = Versiani M, Cassano G, Perugi G, Benedetti A, Mastalli L, Nardi A, Savino M | title = Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder | journal = The Journal of Clinical Psychiatry | volume = 63 | issue = 1 | pages = 31–7 | date = January 2002 | pmid = 11838623 | doi = 10.4088/JCP.v63n0107 }} Another randomised controlled trial that compared paroxetine to reboxetine found that paroxetine significantly outperformed reboxetine as a treatment for panic disorder.{{cite journal | vauthors = Bertani A, Perna G, Migliarese G, Di Pasquale D, Cucchi M, Caldirola D, Bellodi L | title = Comparison of the treatment with paroxetine and reboxetine in panic disorder: a randomized, single-blind study | journal = Pharmacopsychiatry | volume = 37 | issue = 5 | pages = 206–10 | date = September 2004 | pmid = 15359375 | doi = 10.1055/s-2004-832593 | s2cid = 12495057 }} Despite this discouraging finding an open-label trial examining the efficacy of reboxetine in SSRI-resistant panic disorder demonstrated significant benefit from reboxetine treatment.{{cite journal | vauthors = Dannon PN, Iancu I, Grunhaus L | title = The efficacy of reboxetine in the treatment-refractory patients with panic disorder: an open label study | journal = Human Psychopharmacology | volume = 17 | issue = 7 | pages = 329–33 | date = October 2002 | pmid = 12415550 | doi = 10.1002/hup.421 | s2cid = 19996027 }}

Numerous clinical trials have provided support for the efficacy of reboxetine in the treatment of attention deficit hyperactivity disorder (ADHD) in both the short{{cite journal | vauthors = Hashemian F, Mohammadian S, Riahi F, Ghaeli P, Ghodsi D | title = A comparison of the effects of reboxetine and placebo on reaction time in adults with Attention Deficit-Hyperactivity Disorder (ADHD) | journal = Daru | volume = 19 | issue = 3 | pages = 231–5 | year = 2011 | pmid = 22615662 | pmc = 3232108 }}{{cite journal | vauthors = Tehrani-Doost M, Moallemi S, Shahrivar Z | title = An open-label trial of reboxetine in children and adolescents with attention-deficit/hyperactivity disorder | journal = Journal of Child and Adolescent Psychopharmacology | volume = 18 | issue = 2 | pages = 179–84 | date = April 2008 | pmid = 18439114 | doi = 10.1089/cap.2006.0034 }}{{cite journal | vauthors = Ratner S, Laor N, Bronstein Y, Weizman A, Toren P | title = Six-week open-label reboxetine treatment in children and adolescents with attention-deficit/hyperactivity disorder | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 44 | issue = 5 | pages = 428–33 | date = May 2005 | pmid = 15843764 | doi = 10.1097/01.chi.0000155327.30017.8c }}{{cite journal | vauthors = Riahi F, Tehrani-Doost M, Shahrivar Z, Alaghband-Rad J | title = Efficacy of reboxetine in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled clinical trial | journal = Human Psychopharmacology | volume = 25 | issue = 7–8 | pages = 570–6 | date = November 2010 | pmid = 21312292 | doi = 10.1002/hup.1158 | s2cid = 8634761 }} and long-term{{cite journal | vauthors = Toren P, Ratner S, Weizman A, Lask M, Ben-Amitay G, Laor N | title = Reboxetine maintenance treatment in children with attention-deficit/hyperactivity disorder: a long-term follow-up study | journal = Journal of Child and Adolescent Psychopharmacology | volume = 17 | issue = 6 | pages = 803–12 | date = December 2007 | pmid = 18315452 | doi = 10.1089/cap.2006.0145 }}{{cite journal | vauthors = Quintero J, López-Muñoz F, Alamo C, Loro M, García-Campos N | title = Reboxetine for ADHD in children non-responders or with poor tolerance to methylphenidate: a prospective long-term open-label study | journal = Attention Deficit and Hyperactivity Disorders | volume = 2 | issue = 3 | pages = 107–13 | date = November 2010 | pmid = 21432596 | doi = 10.1007/s12402-010-0027-x | s2cid = 41617072 }} and in both children/adolescents and adults.

A case series and open-label pilot study demonstrated the efficacy of reboxetine in treating bulimia nervosa.{{cite journal | vauthors = El-Giamal N, de Zwaan M, Bailer U, Lennkh C, Schüssler P, Strnad A, Kasper S | title = Reboxetine in the treatment of bulimia nervosa: a report of seven cases | journal = International Clinical Psychopharmacology | volume = 15 | issue = 6 | pages = 351–6 | date = November 2000 | pmid = 11110011 | doi = 10.1097/00004850-200015060-00006 | s2cid = 21260625 }}{{cite journal | vauthors = Fassino S, Daga GA, Boggio S, Garzaro L, Pierò A | title = Use of reboxetine in bulimia nervosa: a pilot study | journal = Journal of Psychopharmacology | volume = 18 | issue = 3 | pages = 423–8 | date = September 2004 | pmid = 15358988 | doi = 10.1177/026988110401800314 | s2cid = 24287884 }} Reboxetine may also have efficacy in treating therapy-resistant paediatric nocturnal enuresis.{{cite journal | vauthors = Nevéus T | title = Reboxetine in therapy-resistant enuresis: results and pathogenetic implications | journal = Scandinavian Journal of Urology and Nephrology | volume = 40 | issue = 1 | pages = 31–4 | year = 2006 | pmid = 16452053 | doi = 10.1080/00365590500407803 | s2cid = 41990481 }} A pilot study demonstrated the efficacy of reboxetine in the treatment of narcolepsy.{{cite journal | vauthors = Larrosa O, de la Llave Y, Bario S, Granizo JJ, Garcia-Borreguero D | title = Stimulant and anticataplectic effects of reboxetine in patients with narcolepsy: a pilot study | journal = Sleep | volume = 24 | issue = 3 | pages = 282–5 | date = May 2001 | pmid = 11322710 | url = http://www.journalsleep.org/ViewAbstract.aspx?pid=25527 | doi = 10.1093/sleep/24.3.282 | doi-access = free | archive-date = 2016-08-15 | access-date = 2013-11-10 | archive-url = https://web.archive.org/web/20160815165213/http://www.journalsleep.org/ViewAbstract.aspx?pid=25527 | url-status = dead }} Individual trials and meta-analysis suggest that reboxetine can attenuate antipsychotic-induced weight gain{{cite journal | vauthors = Poyurovsky M, Isaacs I, Fuchs C, Schneidman M, Faragian S, Weizman R, Weizman A | title = Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: a double-blind, placebo-controlled study | journal = The American Journal of Psychiatry | volume = 160 | issue = 2 | pages = 297–302 | date = February 2003 | pmid = 12562576 | doi = 10.1176/appi.ajp.160.2.297 | url = http://ajp.psychiatryonline.org/data/Journals/AJP/3745/297.pdf }}{{cite journal | vauthors = Matthews PR, Horder J, Pearce M | title = Selective noradrenaline reuptake inhibitors for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD010219 | date = January 2018 | issue = 1 | pmid = 29368813 | pmc = 6491172 | doi = 10.1002/14651858.CD010219.pub2 }} and there is some evidence of a benefit on depressive, and possibly other symptoms of schizophrenia when added to antipsychotic treatment.{{cite journal | vauthors = Kishi T, Mukai T, Matsuda Y, Moriwaki M, Iwata N | title = Efficacy and safety of noradrenalin reuptake inhibitor augmentation therapy for schizophrenia: a meta-analysis of double-blind randomized placebo-controlled trials | journal = Journal of Psychiatric Research | volume = 47 | issue = 11 | pages = 1557–63 | date = November 2013 | pmid = 23899496 | doi = 10.1016/j.jpsychires.2013.07.003 }}

Reboxetine is contraindicated in narrow-angle glaucoma, cardiovascular disease, epilepsy, bipolar disorder, urinary retention, prostatic hypertrophy, those hypersensitive to reboxetine or any of its excipients.{{cite book | isbn = 978-0-85711-084-8 | title = British National Formulary (BNF) | last1 = Joint Formulary Committee | year = 2013 | publisher = Pharmaceutical Press | location = London, UK | edition = 65 | pages = [https://archive.org/details/bnf65britishnati0000unse/page/254 254–255] | url = https://archive.org/details/bnf65britishnati0000unse/page/254 }}

There is conflicting information regarding use with MAOIs: one says the combination is possible with monitoring of side effects {{cite journal | vauthors = Van den Eynde V, Abdelmoemin WR, Abraham MM, Amsterdam JD, Anderson IM, Andrade C, et al. |title = The Prescriber's Guide to Classic MAO Inhibitors (Phenelzine, Tranylcypromine, Isocarboxazid) for Treatment-Resistant Depression | journal = CNS Spectrums | volume = 28 | issue = 4 | pages = 427–40 | date = 2023 | doi = 10.1017/S1092852922000906 |pmid = 35837681 | url = https://www.cambridge.org/core/journals/cns-spectrums/article/prescribers-guide-to-classic-mao-inhibitors-phenelzine-tranylcypromine-isocarboxazid-for-treatmentresistant-depression/29C70FD3DA65E23A024D5E05C4369983 | hdl = 2292/61637 | hdl-access = free }} but the product informations indicate them as contraindicated.

Very common (>10% incidence) adverse effects include insomnia, dizziness, dry mouth, constipation, nausea, and excessive sweating.{{cite web|title=Edronax 4mg Tablets|publisher=UK Electronic Medicines Compendium|date=October 2015|access-date=20 August 2017|url=http://www.medicines.org.uk/emc/medicine/8386/SPC/Edronax+4mg+Tablets/}}

Common (1–10%) adverse effects include loss of appetite, agitation, anxiety, headache, restlessness, tingling sensations, distorted sense of taste, difficulty with seeing near or far (problems with accommodation), fast heart beat, heart palpitations, relaxing of blood vessels leading to low blood pressure, high blood pressure, vomiting, rash, sensation of incomplete bladder emptying, urinary tract infection, painful or difficult urination, urinary retention, erectile dysfunction, ejaculatory pain or delay, and chills.

A 2009 meta-analysis found that reboxetine was significantly less well tolerated than the other 11 second-generation antidepressants compared in the analysis.

Reboxetine is considered a relatively low-risk antidepressant in overdose.{{cite book | isbn = 978-0-470-97948-8 | title = The Maudsley prescribing guidelines in psychiatry | vauthors = Taylor D, Paton C, Shitij K | year = 2012 | publisher = Wiley-Blackwell | location = West Sussex | page = 588 }} The symptoms are as follows:

• Sweating
• Tachycardia
• Changes in blood pressure

Because of its reliance on CYP3A4, reboxetine O-desethylation is markedly inhibited by papaverine and ketoconazole. It weakly inhibits CYP2D6 and CYP3A4. Reboxetine is an intermediate-level inhibitor of P-glycoprotein, which gives it the potential to interact with ciclosporin, tacrolimus, paroxetine, sertraline, quinidine, fluoxetine, fluvoxamine.{{cite journal | vauthors = Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE | title = Inhibition of P-glycoprotein by newer antidepressants | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 305 | issue = 1 | pages = 197–204 | date = April 2003 | pmid = 12649369 | doi = 10.1124/jpet.102.046532 | s2cid = 5897406 }}

Reboxetine is a fairly selective norepinephrine reuptake inhibitor (NRI), with approximately 20-fold selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Despite this selectivity, reboxetine does slightly inhibit the reuptake of serotonin at therapeutic doses.{{cite book | editor = Rossi, S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }} It does not interact with or inhibit the dopamine transporter (DAT).

Reboxetine has been found to inhibit both brain and cardiac GIRKs, a characteristic it shares with the NRI atomoxetine.{{cite journal | vauthors = Kobayashi T, Washiyama K, Ikeda K | title = Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine | journal = Neuropsychopharmacology | volume = 35 | issue = 7 | pages = 1560–9 | date = June 2010 | pmid = 20393461 | pmc = 3055469 | doi = 10.1038/npp.2010.27 }}

Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolized by the CYP3A4 isoenzyme.{{cite journal | vauthors = Wienkers LC, Allievi C, Hauer MJ, Wynalda MA | title = Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes | journal = Drug Metabolism and Disposition | volume = 27 | issue = 11 | pages = 1334–40 | date = November 1999 | doi = 10.1016/S0090-9556(24)14936-7 | pmid = 10534319 }}

The primary metabolite of reboxetine is O-desethylreboxetine, and there are also three minor metabolites—Phenol A, Phenol B, and UK1, Phenol B being the most minor.

Reboxetine has two chiral centers. Thus, four stereoisomers may exist, the (R,R)-, (S,S)-, (R,S)-, and (S,R)-isomers. The active ingredient of reboxetine is a racemic mixture of two enantiomers, the (R,R)-(–)- and (S,S)-(+)-isomer.{{cite journal |vauthors=Melloni P, Della Torre A, Lazzari E, Mazzini G, Meroni M | title=Configuration studies on 2-[alpha -(2-ethoxyphenoxy)benzyl]-morpholine FCE 20124|journal=Tetrahedron | volume=41 | issue=1 | year=1985 | pages=1393–1399 | doi=10.1016/S0040-4020(01)96541-X}}

Reboxetine was discovered at Farmitalia-Carlo Erba and was first published in 1984; Farmitalia did the first clinical studies.{{cite journal | vauthors = Cocchiara G, Battaglia R, Pevarello P, Strolin Benedetti M | title = Comparison of the disposition and of the metabolic pattern of Reboxetine, a new antidepressant, in the rat, dog, monkey and man | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 16 | issue = 3 | pages = 231–9 | year = 1991 | pmid = 1814741 | doi = 10.1007/bf03189965 | s2cid = 874781 }}First publication per prior citation: {{cite journal |author= Melloni M |year=1984 |title= Potential antidepressant agents. α-aryloxy-benzyl derivatives of ethanolamine and morpholine |journal= Eur J Med Chem |volume=3 |pages= 235–242 |display-authors=etal}} Farmitalia was acquired by Pharmacia in 1993,{{cite journal |title=Farmitalia bought by Kabi Pharmacia |journal=Annals of Oncology |date=May 1993 |volume=4 |issue=5 |pages=345 |doi=10.1093/oxfordjournals.annonc.a058508|doi-access=free }} and Pharmacia in turn was acquired by Pfizer in 2003.{{cite news |work=CNN/Money | date = 16 April 2003 | url = https://money.cnn.com/2003/04/16/news/companies/pfizer_pharma/ | title = It's official: Pfizer buys Pharmacia }}

It was first approved in Europe in 1997 and was provisionally approved by the FDA in 1999.{{cite web | first = Derek | last = Lowe | name-list-style = vanc | work = In the pipeline | date = 17 January 2011 | url = https://www.science.org/content/blog-post/reboxetine-doesn-t-work-s-not-real-problem | title = Reboxetine Doesn't Work. But That's Not the Real Problem }} In 2001 the FDA issued Pfizer a "not approvable" letter based on clinical trials the FDA had required when it issued the preliminary approval letter.{{cite web | work = Adis Insight | url = http://adisinsight.springer.com/drugs/800000662 | title = Reboxetine | access-date = 17 April 2016 }}{{cite journal | vauthors = Page ME | title = The promises and pitfalls of reboxetine | journal = CNS Drug Reviews | volume = 9 | issue = 4 | pages = 327–42 | year = 2003 | pmid = 14647527 | doi = 10.1111/j.1527-3458.2003.tb00258.x | pmc = 6741698 }}

In 2010, the German Institute for Quality and Efficiency in Health Care (IQEHC) published results of a meta-analysis of clinical trial data for reboxetine in acute depression, which included data on about 3,000 subjects that Pfizer had never published but had mentioned; IQEHC had combed through Pfizer's publications and reboxetine approvals and had determined this data was missing from the publication record. The analysis of the complete data set yielded a result that reboxetine was not more effective than placebo but had more side effects than placebo and more than fluoxetine; the paper led to widespread and sharp criticism of Pfizer, and stronger calls for publication of all clinical trial data.{{cite web | author = Staff | work = Genetic Engineering News | date = 14 October 2010 | url = http://www.genengnews.com/gen-news-highlights/did-sneaky-publication-tactics-help-pfizer-s-reboxetine-slip-through-to-market/81244066/ | title = Did Sneaky Publication Tactics Help Pfizer's Reboxetine Slip Through to Market? }}

Edronax is the brand name of reboxetine in every English-speaking country that has approved it for clinical use. Brand names include (where † denotes a product that is no longer marketed):

• Davedax (IT)
• Edronax (AU, AT, BE, CZ, DK, FI, DE, IE, IL, IT, MX, NZ, NO, PH, PL, PT, ZA, SE, CH, TH, TR, UK)
• Irenor (ES)
• Norebox (ES)
• Prolift (AR,^† BR, CL, VE^†)
• Solvex (DE)
• Yeluoshu (CN)
• Zuolexin (CN)

{{Reflist|2}}

• [http://www.jpgmonline.com/article.asp?issn=0022-3859;year=2003;volume=49;issue=4;spage=373;epage=375;aulast=Kadhe Reboxetine: A Novel Antidepressant]

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