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.[6]
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."[7] 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.[7]
According to a systematic review and meta-analysis by IQWiG, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also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.[5]
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.[8]
Panic disorder
In a randomised double-blind placebo-controlled trial reboxetine significantly improved the symptoms of panic disorder.[9] Another randomised controlled trial that compared paroxetine to reboxetine found that paroxetine significantly outperformed reboxetine as a treatment for panic disorder.[10] Despite this discouraging finding an open-label trial examining the efficacy of reboxetine in SSRI-resistant panic disorder demonstrated significant benefit from reboxetine treatment.[11]
Attention deficit hyperactivity disorder
Numerous clinical trials have provided support for the efficacy of reboxetine in the treatment of attention deficit hyperactivity disorder (ADHD) in both the short[12][13][14][15] and long-term[16][17] and in both children/adolescents[13][14][16][17] and adults.[12][15]
Other uses
A case series and open-label pilot study demonstrated the efficacy of reboxetine in treating bulimia nervosa.[18][19] Reboxetine may also have efficacy in treating therapy-resistant paediatric nocturnal enuresis.[20] A pilot study demonstrated the efficacy of reboxetine in the treatment of narcolepsy.[21] Individual trials and meta-analysis suggest that reboxetine can attenuate antipsychotic-induced weight gain[22][23] and there is some evidence of a benefit on depressive, and possibly other symptoms of schizophrenia when added to antipsychotic treatment.[24][23]
There is conflicting information regarding use with MAOIs: one says the combination is possible with monitoring of side effects [26] but the product informations indicate them as contraindicated.[2]
Adverse effects
Very common (>10% incidence) adverse effects include insomnia, dizziness, dry mouth, constipation, nausea, and excessive sweating.[27]
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.[27]
A 2009 meta-analysis found that reboxetine was significantly less well tolerated than the other 11 second-generation antidepressants compared in the analysis.[6]
Overdose
Reboxetine is considered a relatively low-risk antidepressant in overdose.[28] The symptoms are as follows:[28]
Reboxetine has been found to inhibit both brain and cardiac GIRKs, a characteristic it shares with the NRI atomoxetine.[34]
Pharmacokinetics
Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolized by the CYP3A4isoenzyme.[29]
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.[29]
Chemistry
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.[35]
History
Reboxetine was discovered at Farmitalia-Carlo Erba and was first published in 1984; Farmitalia did the first clinical studies.[36][37] Farmitalia was acquired by Pharmacia in 1993,[38] and Pharmacia in turn was acquired by Pfizer in 2003.[39]
It was first approved in Europe in 1997 and was provisionally approved by the FDA in 1999.[40] 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.[41][42]
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.[5][40][43]
Society and culture
Brand names
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):[4]
^ abReboxetine Mesilate. The Royal Pharmaceutical Society of Great Britain. 8 November 2011. Retrieved 10 November 2013. {{cite book}}: |work= ignored (help)
^Versiani M, Cassano G, Perugi G, Benedetti A, Mastalli L, Nardi A, Savino M (January 2002). "Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder". The Journal of Clinical Psychiatry. 63 (1): 31–7. doi:10.4088/JCP.v63n0107. PMID11838623.
^Bertani A, Perna G, Migliarese G, Di Pasquale D, Cucchi M, Caldirola D, Bellodi L (September 2004). "Comparison of the treatment with paroxetine and reboxetine in panic disorder: a randomized, single-blind study". Pharmacopsychiatry. 37 (5): 206–10. doi:10.1055/s-2004-832593. PMID15359375. S2CID12495057.
^Dannon PN, Iancu I, Grunhaus L (October 2002). "The efficacy of reboxetine in the treatment-refractory patients with panic disorder: an open label study". Human Psychopharmacology. 17 (7): 329–33. doi:10.1002/hup.421. PMID12415550. S2CID19996027.
^ abTehrani-Doost M, Moallemi S, Shahrivar Z (April 2008). "An open-label trial of reboxetine in children and adolescents with attention-deficit/hyperactivity disorder". Journal of Child and Adolescent Psychopharmacology. 18 (2): 179–84. doi:10.1089/cap.2006.0034. PMID18439114.
^ abRatner S, Laor N, Bronstein Y, Weizman A, Toren P (May 2005). "Six-week open-label reboxetine treatment in children and adolescents with attention-deficit/hyperactivity disorder". Journal of the American Academy of Child and Adolescent Psychiatry. 44 (5): 428–33. doi:10.1097/01.chi.0000155327.30017.8c. PMID15843764.
^ abRiahi F, Tehrani-Doost M, Shahrivar Z, Alaghband-Rad J (November 2010). "Efficacy of reboxetine in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled clinical trial". Human Psychopharmacology. 25 (7–8): 570–6. doi:10.1002/hup.1158. PMID21312292. S2CID8634761.
^ abToren P, Ratner S, Weizman A, Lask M, Ben-Amitay G, Laor N (December 2007). "Reboxetine maintenance treatment in children with attention-deficit/hyperactivity disorder: a long-term follow-up study". Journal of Child and Adolescent Psychopharmacology. 17 (6): 803–12. doi:10.1089/cap.2006.0145. PMID18315452.
^ abQuintero J, López-Muñoz F, Alamo C, Loro M, García-Campos N (November 2010). "Reboxetine for ADHD in children non-responders or with poor tolerance to methylphenidate: a prospective long-term open-label study". Attention Deficit and Hyperactivity Disorders. 2 (3): 107–13. doi:10.1007/s12402-010-0027-x. PMID21432596. S2CID41617072.
^El-Giamal N, de Zwaan M, Bailer U, Lennkh C, Schüssler P, Strnad A, Kasper S (November 2000). "Reboxetine in the treatment of bulimia nervosa: a report of seven cases". International Clinical Psychopharmacology. 15 (6): 351–6. doi:10.1097/00004850-200015060-00006. PMID11110011. S2CID21260625.
^Fassino S, Daga GA, Boggio S, Garzaro L, Pierò A (September 2004). "Use of reboxetine in bulimia nervosa: a pilot study". Journal of Psychopharmacology. 18 (3): 423–8. doi:10.1177/026988110401800314. PMID15358988. S2CID24287884.
^Nevéus T (2006). "Reboxetine in therapy-resistant enuresis: results and pathogenetic implications". Scandinavian Journal of Urology and Nephrology. 40 (1): 31–4. doi:10.1080/00365590500407803. PMID16452053. S2CID41990481.
^Kishi T, Mukai T, Matsuda Y, Moriwaki M, Iwata N (November 2013). "Efficacy and safety of noradrenalin reuptake inhibitor augmentation therapy for schizophrenia: a meta-analysis of double-blind randomized placebo-controlled trials". Journal of Psychiatric Research. 47 (11): 1557–63. doi:10.1016/j.jpsychires.2013.07.003. PMID23899496.
^ abc"Edronax 4mg Tablets". UK Electronic Medicines Compendium. October 2015. Retrieved 20 August 2017.
^ abTaylor D, Paton C, Shitij K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. p. 588. ISBN978-0-470-97948-8.
^ abcWienkers LC, Allievi C, Hauer MJ, Wynalda MA (November 1999). "Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes". Drug Metabolism and Disposition. 27 (11): 1334–40. doi:10.1016/S0090-9556(24)14936-7. PMID10534319.
^Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE (April 2003). "Inhibition of P-glycoprotein by newer antidepressants". The Journal of Pharmacology and Experimental Therapeutics. 305 (1): 197–204. doi:10.1124/jpet.102.046532. PMID12649369. S2CID5897406.
^ abcRoth BL, Driscol J. "PDSD Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 2013-11-08. Retrieved 2014-03-31.
^ abBrunton L, Chabner B, Knollman B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN978-0-07-162442-8.
^Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN978-0-9805790-9-3.
^Melloni P, Della Torre A, Lazzari E, Mazzini G, Meroni M (1985). "Configuration studies on 2-[alpha -(2-ethoxyphenoxy)benzyl]-morpholine FCE 20124". Tetrahedron. 41 (1): 1393–1399. doi:10.1016/S0040-4020(01)96541-X.
^Cocchiara G, Battaglia R, Pevarello P, Strolin Benedetti M (1991). "Comparison of the disposition and of the metabolic pattern of Reboxetine, a new antidepressant, in the rat, dog, monkey and man". European Journal of Drug Metabolism and Pharmacokinetics. 16 (3): 231–9. doi:10.1007/bf03189965. PMID1814741. S2CID874781.
^First publication per prior citation: Melloni M; et al. (1984). "Potential antidepressant agents. α-aryloxy-benzyl derivatives of ethanolamine and morpholine". Eur J Med Chem. 3: 235–242.
