Abstract
Objective: To describe the effectiveness and tolerability of reboxetine under Special Access Program conditions in Canada in a group of patients with refractory depressive disorders.
Design: Retrospective open-label study.
Setting: Six clinical academic settings in Canada, primarily tertiary institutional settings.
Patients: Twenty-six female and 19 male outpatients with depressive disorders, primarily unipolar depression. Most of the patients were treatment resistant.
Intervention: Reboxetine through the Special Access Program.
Outcome measure: Severity of depression before treatment with reboxetine was retrospectively assessed with the Clinical Global Impression (CGI) Global Severity Scale; change with treatment was evaluated with the CGI Global Improvement Scale.
Results: Before reboxetine treatment, 20 (44%) patients scored in the moderate CGI severity category, 11 (24%) in the marked category and 12 (27%) in the severe category. The dose range for reboxetine was 2–16 mg, with 40 (89%) patients in the 4–10 mg range. With reboxetine treatment, 25 (56%) patients were considered “very much improved” or “much improved”; 8 (18%) patients were “minimally improved”; 7 (16%) received ratings that reflected “no change” or minimal worsening, and 5 (11%) were rated as “much worse” or “very much worse.”
Conclusions: Reboxetine was effective at a clinically meaningful level in decreasing severity of depression in 56% of patients. Given the high rate of prior resistance to other antidepressant therapies, there is a definite role for this agent in the treatment of depressive disorders.
Introduction
During the past decade, clinicians have been presented with an increasing number of antidepressant options. Selective serotonin reuptake inhibitors (SSRI) and novel antidepressants have become established as first-line treatments for major depressive disorder (MDD).1 Novel agents in Canada include bupropion, mirtazapine, nefazodone and venlafaxine. Bupropion is thought to act through modulation of noradrenergic and dopaminergic activity.2 Mirtazapine is an α2-noradrenergic receptor antagonist which enhances both noradrenaline and serotonin release without reuptake inhibition.3 Nefazodone is primarily a 5-HT2 receptor antagonist with weak serotonin uptake-blocking effects,4 whereas venlafaxine blocks reuptake of both serotonin and, at higher doses, noradrenaline.5 Despite the number of treatment options, fewer than 50% of patients with MDD achieve full remission during acutephase treatment and 30% remain treatment resistant.6–8
Reboxetine represents the first of a new class of antidepressants that selectively inhibits noradrenergic reuptake.9 It has neither affinity for serotonin or dopamine uptake sites nor for muscarinic, histaminic or α-noradrenergic receptors.10,11 Reboxetine is rapidly absorbed, with peak plasma concentrations being reached within 2 hours. It has an elimination half-life of approximately 13 hours, which makes it suitable for twice-daily dosing.9 The usual dosage range is 4–12 mg daily.
Reboxetine is superior to placebo12–14 and has comparable efficacy to desipramine,13 fluoxetine15 and imipramine.14,16 Reboxetine was found to be more effective than fluoxetine in improving social functioning in depressed patients.15,17,18 Furthermore, reboxetine is reported to be well tolerated during both acute-phase12–15 and maintenance treatment.14 Dry mouth, insomnia, increased sweating and constipation are among the most commonly reported side effects.12,13,15,19 In both double-blind and open studies, reboxetine has been shown to be effective and well tolerated in the treatment of depression in elderly patients.14,20
Reboxetine is approved for use in Europe and is available in Canada through the Special Access Program of the Therapeutic Products Programme Branch of Health Canada. This access to a novel antidepressant prompted our group to systematically examine the role of reboxetine in previously nonresponsive or drug-intolerant patients who suffered from a major depression episode (MDE), either in the context of MDD or bipolar disorder. This report reflects data collected on 45 patients by 7 Canadian psychiatrists at 6 academic or private practice sites.
Methods
Twenty-six women (58%) and 19 men (42%) aged 20–72 (mean 43) years were evaluated. All subjects met criteria for a current MDE. In 4 (9%) cases, the MDE occurred in the context of a bipolar disorder; the remaining 41 patients (91%) had MDD. In addition, 1 patient had a diagnosis of borderline personality disorder and another was diagnosed with both chronic fatigue syndrome and fibromyalgia. Concurrent anxiety disorders were present in 14 (31%) patients. Diabetes and hypertension were comorbid physical conditions in the case of a 72-year-old woman.
In general, these patients represented a treatment-resistant population; all patients had been exposed to SSRI, venlafaxine or tricyclic antidepressant treatment. Monoamine oxidase inhibitor (MAOI) treatment had also been prescribed with varying degrees of effectiveness in 19 (42%) patients; many of these discontinued this therapy because of adverse effects.
A previous adequate antidepressant trial (in terms of dose and duration) was defined as a minimum of 6 weeks with at least 1 dose increment. These subjects had received, on average, 5.8 prior antidepressant treatments: 2 (4%) patients received 2 or fewer treatments, 24 (53%) received 3–6 and 19 (42%) had 7 or more prior treatments. Fourteen (31%) patients had received electroconvulsive therapy (ECT).
All subjects who received reboxetine through the Special Access Program at the study sites were retrospectively evaluated in an open-label trial using the Clinical Global Impression (CGI) Severity and Improvement scales.21 The information was collected under semi-structured conditions.
Results
The dose range for reboxetine was 2–16 mg, with 40 (89%) patients in the 4–10 mg range. Reboxetine was prescribed alone for 24 (53%) patients and in combination with other medications for the remaining 21 (47%). These other medications included SSRIs (14 patients), venlafaxine (1 patient), divalproex sodium (1 patient), lithium carbonate (1 patient), mirtazapine (1 patient), dextroamphetamine (5 patients), gabapentin (1 patient), buspirone (4 patients), triiodothyronine (1 patient) and thioridazine (1 patient). Some patients were taking more than 1 adjunctive medication.
Drug discontinuation due to adverse effects was reported in 4 (9%) cases. In all cases, insomnia and agitation were the main reasons for discontinuation, and in 1 case (a 51-year-old woman with a concomitant diagnosis of borderline personality disorder), worsening suicidal ideation was reported.
On the basis of the CGI Global Severity Scale, most patients were rated in the moderate (n = 20, 44%), marked (n = 11, 24%) or severe (n = 12, 27%) categories. Two (4%) patients were rated “among the most severely depressed.” After treatment with reboxetine, outcomes, based on the CGI Global Improvement Scale, were rated as follows: 25 (56%) patients were considered “very much improved” or “much improved”; 8 (18%) patients were “minimally improved”; 7 (16%) reflected “no change” or “minimal worsening,” and 5 (11%) were rated as “much worse” or “very much worse.”
The following 4 cases illustrate the various clinical courses of the patients.
Case 1
A 49-year-old woman with concomitant diagnoses of chronic fatigue syndrome and fibromyalgia had previously been treated individually and in combination with several SSRIs and venlafaxine with only minimal improvement. She showed partial response to phenelzine, but stopped taking it because of ankle edema and carbohydrate craving. After a suitable washout period, she was prescribed reboxetine (4 mg daily). She experienced initial urinary hesitancy, but this decreased in severity by the second month. The patient preferred to take the medication as 2 mg twice daily and was discharged to a community psychiatrist “doing well” after 4 months.
Case 2
A 41-year-old woman who had responded favourably to paroxetine during a prior depressive episode but failed to respond to several antidepressants, including paroxetine, during the index episode was treated with mirtazapine to 45 mg. She improved but complained of excess sedation. Dose decrements of mirtazapine monotherapy to 15 mg resulted in a deterioration of mood state. However, when 4 mg of reboxetine was added, there was a marked improvement in mood and energy; this improvement was sustained and allowed the patient to return to work.
Case 3
A 55-year-old man who had failed to respond to all available SSRIs at higher than usual doses experienced a partial response to moclobemide, the reversible inhibitor of monoamine oxidase A, but developed insomnia. Combination treatment with nefazodone was somewhat helpful initially but did not prevent a return of further insomnia. A trial of bupropion was “spectacular” for approximately 4 weeks but faded, despite increases to 600 mg. Phenelzine also helped but caused dizziness and blurred vision and was discontinued. A trial of reboxetine up to a dose of 8 mg was initiated. The patient complained of dry mouth and constipation but acknowledged feeling more alert. He did not experience any significant mood improvement, however, so he unilaterally discontinued treatment after 2 months to restart monoamine oxidase inhibitor therapy.
Case 4
A 57-year-old man with a diagnosis of bipolar depression had been “stuck” for up to 2 years in a retarded depressed state. He failed to adequately respond to multiple medications or to ECT. There had been partial responses to tranylcypromine, venlafaxine and fluoxetine at various points, but none were sustained. Lithium, divalproex sodium, gabapentin and lamotrigine had also been tried in various combinations. Reboxetine, up to 8 mg daily, was added to venlafaxine and gabapentin. There was initially no benefit, and the patient was admitted to hospital for a further course of ECT. Three days after admission and before ECT was initiated, the patient showed a moderate response, which included comments of mild elation but not hypomania. He was therefore discharged from hospital without ECT. For the first time in 2 years, he began to follow up with job interviews, and he was more functional than he had been at any time in the past.
Discussion
These results reflect the experience of 6 centres across Canada in the use of the selective noradrenergic reuptake inhibitor reboxetine within the Special Access Program. Of the 45 subjects who received reboxetine, over half, as rated by the CGI Global Improvement Scale, were “very much improved” or “much improved.” Unfortunately, data are not available to compare responders to reboxetine monotherapy with those who received a combination of reboxetine and SSRIs or other agents. Considering that most patients in this study were severely depressed and treatment-resistant, we conclude that there is a definite role for the agent in the treatment of MDD. Although these results are limited by the retrospective open-label design of the study, we believe that reboxetine is a promising alternative for patients who have been unable to tolerate or have failed to respond to other standard treatments. We recommend the use of prospective research designs that incorporate standard assessment measures to evaluate new treatments available through the Special Access Program.
Footnotes
Medical subject headings: adrenergic uptake inhibitors; antidepressive agents; depressive disorder; treatment outcome.
Competing interests: None declared for Ms. Cohen or Drs. Rosenbluth and Chue. Dr. Kennedy has received research support from Pfizer, AstraZeneca, Organon and Boehringer Ingelheim; is on the speakers’ bureaus of Lundbeck, Organon, Wyeth-Ayerst and Glaxo-SmithKline; and serves on advisory boards for Pfizer, the Lundbeck Foundation, Eli Lilly, GlaxoSmithKline and Servier. Dr. Lam has received speaker fees from Cyberonics Inc., Eli Lilly, GlaxoSmith-Kline, Litebook Inc., Lundbeck, Organon, Pfizer and Wyeth-Ayerst. Dr. Sokolov has received speaker fees from Eli Lilly and Glaxo-SmithKline and consultancy fees from Eli Lilly. Dr. McIntyre is on the speakers’ bureaus of GlaxoSmithKline, Lundbeck, Wyeth-Ayerst, Organon, Janssen-Ortho, Eli Lilly, Pfizer, AstraZeneca and Boehringer Ingelheim and has received travel assistance from Eli Lilly, Janssen-Ortho, AstraZeneca, Lundbeck, Wyeth-Ayerst, Organon and Bristol-Myers Squibb. Dr. Craigen has received travel assistance from Wyeth-Ayerst Canada.
- Received August 1, 2001.
- Revision received March 15, 2002.
- Accepted May 6, 2002.
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