Reboxetine (Edronax, Vestra) very selectively inhibits pre-synatic reuptake of norepinephrine.  It is more selective for increasing just the norepinephrine effects than any other anti-depressant.  It does induce adaptive changes in the alpha1-adrenergic receptors, especially it enhances their functional responsiveness. However, whether this functional responsiveness is important for the clinical antidepressant efficacy or not is unknown.  It is as good as other anti-depressants and will probably help a small percentage unaided by other anti-depressants.  While it is not yet available in the U.S., it is available from international sources at a very reasonable price.  It has been approved by the FDA for a physician and his or her patient to import a medication which is unavailable in the U.S. for needed treatment.

The half-life is 12 hours. The maximum blood level is 2-4 hours after taking the medicine. Food affects the rate of absorption but roughly 94% is absorbed whether taken with food or separately.  It is metabolized primarily by the liver, especially by CPY3A4.  Fluoxetine does not affect its blood levels.  The standard dose is 8-10 mg/d.  It is always given twice a day, although other psychotropics with even shorter half-lives do fine with once a day dosing.  Perhaps because insomnia is a common side-effect, taking all of the medicine in the morning would lessen this risk. Like almost every other medication, small dosages should be used for the elderly.  There is some evidence that SSRI medication, working on serotonin, is better for anxiety and young adults, while medicines increasing the norepinephrine effect are better for the more seriously ill and those with psychomotor retardation.

Although reboxetine may be approved as a new anti-depressant in the U.S., the first published study of its use in man in 1991 mentions it as an anti-depressant. Eur J Drug Metab Pharmacokinet. 1991 Jul-Sep;16(3):231-9. 

Reboxetine Better than Placebo in 3 of 4 DB; Especially for Psychomotor Retardation, Least with Insomnia: A review of four DB PC trials of patients with Major Depressive Disorder found 63% of reboxetine 8-10 mg/d patients had a 50% decrease in their depression vs. 36% of those on placebo and in three of the four studies the difference was significant. The antidepressant efficacy of reboxetine in patients with severe depression. Montgomery S, Ferguson JM, Schwartz GE. J Clin Psychopharmacol 2003 Feb;23(1):45-50; Compared between placebo (n = 353) and reboxetine (n = 350) treatment groups, reboxetine significantly improved psychomotor retardation in all four trials. Cognitive disturbance and anxiety were improved in three of four trials. Effects of reboxetine on Hamilton Depression Rating Scale factors from randomized, placebo-controlled trials in major depression. Ferguson JM, Mendels J, Schwart GE. Int Clin Psychopharmacol 2002 Mar;17(2):45-51

Reboxetine and the FDA Trials: In 2000, the manufacturers of reboxetine received two letters of approval from the FDA for the use of reboxetine for depression in adults.  It needed only one more successful trial. Ann Pharmacother 2000 Nov;34(11):1302-12.  A speaker, who works very closely with drug companies, was explaining at the May, 2003 APA convention how drug companies routinely fund eight trials when trying to get FDA approval since they need two trials where the drug is found more effective than placebo.  Because there is a large natural tendency towards improvement (a high "placebo" effect) in psychiatric illness, trials where the drug does not do better than placebo are fairly common.  The speaker used the example of a anti-depressant drug currently being researched for FDA approval in which only one of the eight double-blind trials turned out favorable, so the drug's introduction into the U.S. has been at least temporarily blocked.  Unless my memory fails me, the drug he mentioned was reboxetine.  Many of these "failed trials" are never published, although the results must be filed with the FDA.

Reboxetine = Fluoxetine in DB: A large 381 patient 8-week DB PC trial of reboxetine vs. fluoxetine vs. placebo found that both anti-depressants had significantly higher response rates than the placebo, but did not differ from each other despite the fact that their known mechanisms of action are exactly the opposite, i.e. reboxetine selectively increases the norepinephrine effect and fluoxetine selectively increases the serotonin effect. The comparative levels of side-effects were similar although the pattern of side-effects were different. Reboxetine, a new noradrenaline selective antidepressant, is at least as effective as fluoxetine in the treatment of depression. Andreoli V, Caillard V, Deo RS, Rybakowski JK, Versiani M. J Clin Psychopharmacol 2002 Aug;22(4):393-9

Reboxetine Hum Psychopharmacol Clin Exp 1998;13:S29-S39;

Reboxetine as Good as Imipramine: In a 6-week, 256-patient study of major depression comparing imipramine to reboxetine, the response was similar for both.  Side-effect dropouts were 10% for reboxetine and 14% for imipramine.  However, the researchers single out the dry mouth side-effect of imipramine.  This suggests that patients were not allowed to be given bethanechol in the study. Bethanechol is very effective at relieving the dry mouth side-effect of imipramine with virtually no side-effects of its own.  Berzewski H, Van Moffaert M, Gagiano CA. Efficacy and tolerability of reboxetine compared with imipramine in a double-blind study in patients suffering from major depressive offsodes. Eur Neuropsychopharmacol 1997;7(Suppl 1):S37-47

Reboxetine Not Quite as Effective as Imipramine in Elderly in DB: While this 8-week, 346-patient DB study of reboxetine 4-6 mg/d vs. imipramine 50-100 mg/d was promoted in a review of the literature by University of Toronto psychiatrists as showing reboxetine doing just as well as imipramine ( J Psychiatry Neurosci 2002 Nov;27(6):41), in fact dysthymic patients did better on imipramine by both HAM-D and CGI measures. The study authors strongly emphasize that reboxetine had fewer serious side-effects but actual numbers of side-effects were fairly similar and numerous for both medicines.  The definition of serious may be somewhat arbitrary and stacked in favor of reboxetine. The superiority of imipramine seemed downplayed. Middlesex Hospital, London. Reboxetine versus imipramine in the treatment of elderly patients with depressive disorders: a double-blind randomised trial. Katona C, Bercoff E, Chiu E, Tack P, Versiani M, Woelk H. J Affect Disord. 1999 Oct;55(2-3):203-13

Reboxetine Reduces Relapses Compared to Placebo: A Brazilian study of recurrent depression treated all patients for six weeks with reboxetine. The 283 responders were randomly assigned to placebo or reboxetine and followed an additional 46 weeks. Relapse was much higher for the placebo group.  It was also lower for patients who had remitted by the six week randomization. 61% of reboxetine vs. 40% of placebo patients were relapse free at six months. Reboxetine, a unique selective NRI, prevents relapse and recurrence in long-term treatment of major depressive disorder. Versiani M, Mehilane L, Gaszner P, Arnaud-Castiglioni R. J Clin Psychiatry 1999 Jun;60(6):400-6

Reboxetine Just as Good as Fluoxetine in DB: A 168-patient, 8-week DB study of reboxetine 8-10 mg/d vs. fluoxetine 20-40 mg/d found identical levels of improvement on all measures including MADRS, HAM-D, and percentages of response and of remission. Massana J, Moller HJ, Burrows GD, Montenegro RM. Reboxetine: a double-blind comparison with fluoxetine in major depressive disorder. Int Clin Psychopharmacol 1999;14:73-80.  Ed: The researchers teased out through a sub-analysis that the most severe patients did better with reboxetine.  This would seem to suggest that the less severe did better on fluoxetine. It is not clear whether the sub-analysis was preplanned or an after-thought.  Tricyclics are also better than SSRIs for the most severely depressed.

Reboxetine but not Paroxetine Improved Cognitive Functioning in Depressed in DB: In a small DB PC study of 74 MDD patients, University of Utah researchers documented that at the end of 8 weeks, the cognitive functioning of patients on reboxetine 8-10 mg/d improved but that the cognitive functioning on paroxetine patients did not. Reboxetine versus paroxetine versus placebo: effects on cognitive functioning in depressed patients. Ferguson JM, Wesnes KA, Schwartz GE. Int Clin Psychopharmacol 2003 Jan;18(1):9-14. (Ed: Paroxetine is the shortest acting SSRI and this presents a number of problems not present in other SSRIs.  Whether the findings of this small study are replicable and whether they apply to other SSRIs is unclear.)

Reboxetine Better than Placebo in Severely Depressed: In an inpatient study of 52 severely depressed were treated for 6 weeks. Dropout rates due to lack of improvement were 64% for placebo vs. 15% for reboxetine.  Depression scores decreased 74% for reboxetine vs. 20% for placebo. Federal University, Rio do Janeiro. Double-blind, placebo-controlled study with reboxetine in inpatients with severe major depressive disorder. Versiani M, Amin M, Chouinard G. J Clin Psychopharmacol. 2000 Feb;20(1):28-34

Panic Patients did Better while on SSRI Citalopram than Reboxetine in Inadequate Study: A single-blind cross-over study of just 19 panic disorder patients had all patients receive each medication for eight weeks with a two week washout in between the two treatments. In all 82% improved while on citalopram vs. 54% while on reboxetine.  Three did better while on citalopram while one did better while on reboxetine. The University of Stellenbosch researchers wrongly called these four individuals "responders" to each treatment.  With such an extremely small study and with spontaneous improvements not uncommon, no one individual can be called a responder.  Also, single-blind studies have a number of inherent shortcomings since both the physicians and patients know which medication they are on.  Reboxetine and citalopram in panic disorder: a single-blind, cross-over, flexible-dose pilot study. Seedat S, van Rheede van Oudtshoorn E, Muller JE, Mohr N, Stein DJ. Int Clin Psychopharmacol 2003 Sep;18(5):279-84

Reboxetine Better than Placebo for Panic in DB: A Brazilian DB PC study of 82 Panic Disorder patients with or without agoraphobia found that after 8 weeks both panic and phobic symptoms had decreased as well as depression and anxiety symptoms. Dry mouth symptoms occurred in 36% vs. 16% with placebo. Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder. Versiani M, Cassano G, Perugi G, Benedetti A, Mastalli L, Nardi A, Savino M. J Clin Psychiatry. 2002 Jan;63(1):31-7. Univ. Rio de Janiero.  (Ed: Since virtually every anti-depressant studied has been found to decrease panic symptoms somewhat, this study doesn't tell us much.  The question is whether reboxetine is any better than any other.)

Reboxetine Didn't Help Negative Symptoms of Schizophrenia with Haldol in DB: A small 30 patient DB PC study didn't find benefit. Reboxetine add on therapy to haloperidol in the treatment of schizophrenia: a preliminary double-blind randomized placebo-controlled study. Schutz G, Berk M. Int Clin Psychopharmacol. 2001 Sep;16(5):275-8

Reboxetine Given to Narcolepsy Patients: In an open trial with objective sleep measures, 12 narcolepsy patients were given reboxetine 10 mg/d.  They showed increased REM sleep, increased sleep latency by 55%, decreased sleepiness scores (subjective) by 48%, and decreased cataplexy. Univ. Madrid. Stimulant and anticataplectic effects of reboxetine in patients with narcolepsy: a pilot study. Larrosa O, de la Llave Y, Bario S, Granizo JJ, Garcia-Borreguero D. Sleep 2001 May 1;24(3):282-5

Reboxetine No Sexual Side-effects: In a DB PC study of 450 adults in MDD, patients on fluoxetine had less sexual satisfaction than those on reboxetine. Women on reboxetine and placebo both had increases in the frequency of orgasm, while those of fluoxetine had a decrease. Univ. Virginia. Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder. Clayton AH, Zajecka J, Ferguson JM, Filipiak-Reisner JK, Brown MT, Schwartz GE. Int Clin Psychopharmacol 2003 May;18(3):151-6.

Olanzapine Patients Gain Less Weight While on Reboxetine: A DB study in Israel of 26 patients treated with olanzapine found that those on olanzapine alone gained an average of 11 pounds over the four weeks of the study vs. a 5 pound weight gain for those on olanzapine plus reboxetine 8 mg/d. There was a trend toward less depression in the reboxetine group. Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: a double-blind, placebo-controlled study. Poyurovsky M, Isaacs I, Fuchs C, Schneidman M, Faragian S, Weizman R, Weizman A. Am J Psychiatry 2003 Feb;160(2):297-302

Two Cases of Painful Ejaculation on Reboxetine Improve After Tamulosin: Painful ejaculations are an uncommon side-effect occurring with many different anti-depressants including tricyclics, venlafaxine, SSRIs, and MAO inhibitors. In this report, two patients were given the alpha-1 receptor antagonist tamulosin and showed marked improvement. Painful ejaculation and urinary hesitancy in association with antidepressant therapy: relief with tamulosin. Demyttenaere K, Huygens R. Eur Neuropsychopharmacol 2002 Aug;12(4):337-41

Tamulosin Helps Urinary Hesitation: A study of 8 male patients on reboxetine 4-8 mg/d, four were given tamulosin for urinary hesitancy and four were given it prophylactically.  All improved within 20 minutes of a 0.4 mg/d dose. Univ. Vienna. Successful treatment of reboxetine-induced urinary hesitancy with tamsulosin. Kasper S, Wolf R. Eur Neuropsychopharmacol. 2002 Apr;12(2):119-22

Reboxetine May Have Anti-Cholinergic Heart Effects in Vivo: Although it has none in vitro, researchers in a study of 8 healthy adults taking single doses of reboxetine, amitriptyline, citalopram or placebo one week apart found amitriptyline decreased saliva but had no heart effect. Reboxetine increased heart rate and blood pressure and reduced the high frequency power of R-R interval variability, which reflects cardiac parasympathetic tone.  It also increased 3,4-dihydroxyphenylglycol (DHPG) plasma concentrations. Reboxetine by contrast to the effects of amitriptyline, citalopram and reboxetine on autonomic nervous system. A randomised placebo-controlled study on healthy volunteers. Penttila J, Syvalahti E, Hinkka S, Kuusela T, Scheinin H. Psychopharmacology (Berl). 2001 Apr;154(4):343-9. Univ Turku, Finland.

Reboxetine: Only specific presynaptic uptake inhib of NE. Buproprion has NE reuptake plus DA reup and venlafaxine has NE reup plus 5-HT reup. SSRIs only 5-HT reup. Nefazodone 5-HT reup and 5-HT-2A and alpha-1 while Mirtazapine has 5-HT-2A and 2C and 3 and alpha-2 and histamine. No cytochrome P450 inhib for Reboxetine, mirtazapine, bupropion, venlafaxine, or citalopram tho nefazodone effect 3A4, and all SSRIs effect 1 to 3 of 4 CYP enzymes. Only mirtazapine and venlafaxine have sleep effects. No effect on sleep from reboxetine. J Clin Psychiatry 59:suppl#20, ’98.  It was expected that reboxetine would be released in the U.S. in 2003 or 2004.  However, only one of eight DB PC FDA trials found reboxetine better than placebo and at least two are needed.  It appears that the manufacturer will stopping pursuing U.S. licensure.

Reboxetine as Good as Imipramine and Better than Fluoxetine (Prozac): In an 8-week DB PC study of 1144 patients with major depression, reboxetine 8-10 mg/day, fluoxetine 20-40 mg/day, and imipramine 150-200 mg/day were compared. There were more side-effects with imipramin. Massana, Barcelona, APA 5/30/98 Toronto

Reboxetine as Good as Imipramine: 256 pt 6 week DB. Equal efficacy. 10% reboxetine side-effect drop-out vs 14% with imipramine. Efficacy and tolerability of reboxetine compared with imipramine in a double-blind study in patients suffering from major depressive offsodes. dry mouth, hypotension and/or related symptoms and tremor was significantly higher on imipramine Berzewski H, Van Moffaert M, Gagiano CA. Eur Neuropsychopharmacol 1997 Apr;7 Suppl 1:S37-47; discussion S71-3

Reboxetine as Good as Imipramine in Elderly: DB 347 pt 4-6mg reboxetine vs 50-100 mg imipramine 6 weeks. Anti-depressant effect not mentioned much in abstract but,if anything, favored imipramine. Side-effects 68% vs 71%. Slightly fewer moderate to severe side-effects in reboxetine. Reboxetine-treated patients were less likely to develop hypotension and related symptoms (7% vs. imipramine 16%) or cardiovascular disorders (12.5% vs. imipramine 21.1%). Reboxetine versus imipramine in the treatment of elderly patients with depressive disorders: a double-blind randomised trial. Katona C, Bercoff E, Chiu E, Tack P, Versiani M, Woelk H. J Affect Disord 1999 Oct;55(2-3):203-13

Reboxetine Did Better with Retarded Depressed than Anxious Depressed Stroke Patients: In a 16-week DB PC study of 74 post-stroke depressed patients, citalopram was more effective in anxious depressed and reboxetine more effective in retarded depressed patients. Prediction of the response to citalopram and reboxetine in post-stroke depressed patients. Rampello L, Chiechio S, et al. University of Catania, Italy. Psychopharmacology (Berl). 2004 Apr;173(1-2):73-8.

Reboxetine Better than Placebo: 4 DB PC studies 8-10mg/d reboxetine 4-8 week MDD HAM-D>24. Response rate 63% vs. 36%. The antidepressant efficacy of reboxetine in patients with severe depression. Montgomery S, Ferguson JM, Schwartz GE. J Clin Psychopharmacol 2003 Feb;23(1):45-50

Reboxetine Has Muscarinic Side-Effects: DB PC crossover 12 healthy volunteers rx reboxetine 4mg bid x 2 weeks. Vasoconstrictory response of cutaneous vessels (VR) and skin conductance response (SCR) following sudden deep breath were employed as parameters for autonomic function. Tiredness (n=12), dry mouth (n=9), delayed urination (n=3) and constipation (n=1) were noted with reboxetine. Sustained peripheral and/or central sympathetic activation accounts for the prolongation of VR. The decrease of SCR and typical side effects suggest a relevant antimuscarinic drug action. Technical Univ, Dresden, The effects of reboxetine on autonomic and cognitive functions in healthy volunteers. Siepmann M, Muck-Weymann M, Joraschky P, Kirch W. Psychopharmacology (Berl) 2001 Sep;157(2):202-7

Reboxetine Reduces Heart Rate Variability: DB crossover 1 week each amitriptyline 75mg, reboxetine 4mg, and citalopram. 8 healthy volunteers. Reboxetine increased heart rate and blood pressure and reduced the HF (high frequency) power of RRI (R-R ECG interval) and 3,4-dihydroxyphenylglycol (DHPG) plasma concentrations. Amitriptyline diminished salivary secretion and had a prominent sedative action. Measurements after citalopram did not differ significantly from placebo. Reboxetine, despite its low antimuscarinic activity in vitro, had distinct effects on the HF power of RRI, consistent with anticholinergic activity in vivo. Amitriptyline had a measurable anticholinergic effect in the salivary glands, but, surprisingly, not in the heart. We suggest that the sedative effect of amitriptyline could alter cardiac sympathovagal balance and, therefore, counteract the anticholinergic drug effect. University of Turku, The effects of amitriptyline, citalopram and reboxetine on autonomic nervous system. A randomised placebo-controlled study on healthy volunteers. Penttila J, Syvalahti E, Hinkka S, Kuusela T, Scheinin H. Psychopharmacology (Berl) 2001 Apr;154(4):343-9

Reboxetine Not so Selective, Increases Dopamine Effect: Rat study. clinical treatment with reboxetine may result in facilitation of both prefrontal DA output and the excitability of Ventral Tegmental Area DA neurons, effects that may contribute to its antidepressant action, especially on drive and motivation. Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex. Linner L, Endersz H, Ohman D, Bengtsson F, Schalling M, Svensson TH. J Pharmacol Exp Ther 2001 May;297(2):540-6, Karolinska Inst

Halve Reboxetine Dose for Elderly: 12 healthy average age 81 and 12 young adults compared. Half-life 24 hr vs 12 hr. Cmax 270 vs 111. AUC four times that of younger adults. Recommends only 4mg/d for very elderly. Pharmacokinetics of reboxetine in healthy, elderly volunteers. Bergmann JF, Laneury JP, Duchene P, Fleishaker JC, Houin G, Segrestaa JM. Eur J Drug Metab Pharmacokinet 2000 Jul-Dec;25(3-4):195-8

Other Conditions Besides Depression

Reboxetine No Impact on Pain in Small Study: In an 8-week DB study of just 35 pain disorder patients, those treated with a standard dose of citalopram (40 mg/d) had a significant decrease in pain intensity (28%) but those given reboxetine (8 mg/d) did not (11%). The patients were not suffering from depression and there was no effect on symptoms of depression. Randomized double-blind comparison of serotonergic (Citalopram) versus noradrenergic (Reboxetine) reuptake inhibitors in outpatients with somatoform, DSM-IV-TR pain disorder. Aragona M, Bancheri L, et al. University of Rome, Italy. Eur J Pain. 2005 Feb;9(1):33-8. 

Reboxetine Less Effective than SSRI for Panic: In a single-blind randomized study of 68 Panic Disorder adults, over 90 days, paroxetine (Paxil) reduced panic attacks significantly more than reboxetine although both were equally effective at reducing anticipatory anxiety and avoidance. There was less weight gain and fewer sexual side-effects with reboxetine. Comparison of the treatment with paroxetine and reboxetine in panic disorder: a randomized, single-blind study. Bertani A, Perna G, Migliarese G, et al. Milan, Italy. Pharmacopsychiatry. 2004 Sep;37(5):206-10

Reboxetine No Benefit as Schizophrenia Adjunct: DB PC 30 pt 6 weeks on haldol 5mg/d. Witwatersrand. Reboxetine add on therapy to haloperidol in the treatment of schizophrenia: a preliminary double-blind randomized placebo-controlled study. Schutz G, Berk M. Int Clin Psychopharmacol 2001 Sep;16(5):275-8

Reboxetine in Narcolepsy: Open trial 12 patients 10mg/d. mean decrease of 48.6% on the Epworth Daytime Sleepiness Scale and a mean increase of 54.7% in sleep latency on the MSLT. Furthermore, a significant reduction in the cataplexy subscore of the Ullanlinna Narcolepsy Scale and in REM-sleep was found. Stimulant and anticataplectic effects of reboxetine in patients with narcolepsy: a pilot study. Larrosa O, de la Llave Y, Bario S, Granizo JJ, Garcia-Borreguero D. Sleep 2001 May 1;24(3):282-5

Reboxetine Helps Panic Disorder, Dry Mouth Side-Effect: In a DB PC of 8 weeks covering 82 patients ages 18-65 with Panic Disorder, 6-8 mg/day of reboxetine caused dry mouth in 36% vs. 16% with placebo, constipation 27% vs. 22%, and insomnia 26% vs. 22%. Reboxetine, a selective norepinephrine reuptake inhibitor, was claimed to be an effective and well-tolerated treatment for panic disorder. Versiani M, Cassano G, Perugi G, Benedetti A, Mastalli L, Nardi A, Savino M. J Clin Psychiatry 2002 Jan;63(1):31-; Article on tamsulosin claims reboxetine has no anti-cholinergic effect. Tamsulosin as an effective treatment for reboxetine-associated urinary hesitancy. Demyttenaere K, Huygens R, Van Buggenhout R. Int Clin Psychopharmacol 2001 Nov;16(6):353-5