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An evaluation of efficacy and safety of reboxetine in elderly patients affected by “retarded” post-stroke depression
Archives of Gerontology and Geriatrics 40 (2005) 275–285 www.elsevier.com/locate/archger
An evaluation of efficacy and safety of reboxetine in elderly patients affected by ‘‘retarded’’ post-stroke depression A random, placebo-controlled study Liborio Rampelloa,*, Alessandro Alvanoa, Santina Chiechiob, Rocco Raffaelea, Ignazio Vecchioa, Mariano Malaguarnerac a
Department of Neurosciences, University of Catania, Azienda Policlinico-Neurologia, Via S. Sofia 78, Catania I-95125, Italy b Department of Pharmaceutical Sciences, University of Catania, V.A. Doria 6, Catania I-95123, Italy c Department of Longevity Sciences, Urology and Neurology, University of Catania, Cannizzaro Hospital, Via Messina 829, Catania I-95124, Italy Received 13 March 2004; received in revised form 20 September 2004; accepted 29 September 2004 Available online 7 December 2004
Abstract Depression occurs frequently in post-stroke patients and appears to be associated with an impairment in their rehabilitation and functional recovery. Although selective serotonin reuptake inhibitors (SSRI) are often used in post-stroke depression (PSD), it has been observed that only a subset of patients is responsive to this treatment. Other patients respond to tricyclic antidepressants or MAO inhibitors, which, however, may not have a favorable profile of safety and tolerability in poststroke patients. In this double-blinded, placebo-controlled study, we evaluated the efficacy and tolerability of the noradrenaline reuptake inhibitor, reboxetine, in a subset of PSD patients classified as affected by ‘‘retarded’’ depression. Reboxetine (4 mg, twice daily, for 16 weeks) was administered to patients that developed depression after a single ischaemic or hemorrhagic stroke. We assessed the severity of depressive symptoms by the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS). HDRS and BDI scores (mean S.D.) at baseline were, respectively, 24 1.31 and 19.87 1.46 in the placebo group, 24.06 1.52 and 20.56 2.16 in the reboxetine group. After 16 weeks, HDRS and BDI mean scores were respectively 22.73 2.4 and 18.4 3.33 in the placebo group, 9.26 2.15 and 8.06 3.43 in the reboxetine group [p < 0.01 versus the respective baseline (paired t-test); #p < 0.01 versus retarded depressed patients treated with placebo (one-way analysis of variance (ANOVA) applied to the difference from baseline, associated with
* Corresponding author. Tel.: +39 095 3782622; fax: +39 095 3782622. E-mail address: [email protected] (L. Rampello). 0167-4943/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2004.09.004
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Dunnett’s t-test to isolate the differences)]. Reboxetine showed a good efficacy, safety and tolerability in PSD patients affected by ‘‘retarded’’ depression. We conclude that reboxetine is well tolerated and may be a useful therapeutic option in PSD patients with ‘‘retarded’’ depression. # 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Post-stroke depression; Reboxetine; Noradrenaline reuptake inhibitors (NARI)
1. Introduction Post-stroke depression (PSD) affects a percentage from 20 to 50% of the patients within 1 year after a brain stroke event (Andersen et al., 1994, 1995; Gustafson et al., 1995; Paolucci, 1999; Wiart et al., 2000; Aben et al., 2001). While some authors favor an ‘‘organic hypothesis’’, based with correlation between PSD and left (Robinson et al., 1990; Hermann and Wallesh, 1993; Gonzalez Torrecillas et al., 1997; Robinson, 1997; Jolobe, 1998; Lyketsos et al., 1998; Mayberg et al., 1998; Ramasubbu et al., 1998) or right hemispheric lesions (Carson et al., 2000), others favor a ‘‘reactive hypothesis’’ (Robins, 1976; Charatan and Fisk, 1978; Turner and Beiser, 1990; Gainotti et al., 1997; The Sunnybrook Stroke Study, 2000). PSD represents an unfavorable prognostic factor, since it significantly affects the functional recovery and rehabilitation of post-stroke patients (Gainotti et al., 2001). Although selective serotonin reuptake inhibitors (SSRI), such as citalopram and fluoxetine, have shown good efficacy and tolerability in the treatment of PSD (Muldoon, 1996; Patris et al., 1996; Willetts et al., 1999; Wiart et al., 2000), it is noteworthy that the response of the PSD patients is not homogeneous. This might depend on the existence of two distinct subsets of depression: ‘‘anxious’’ and ‘‘retarded’’, similarly to what observed for primary depression (Rampello et al., 1991, 1995, 2000). Retarded depression may be defined as a state of clinical depression in which the individual is lethargic, slow to initiate action and shows anergia, hypokinesia, hypomimia, and other symptoms whose presence distinguish this subtype of depression from anxious depression, that instead, is a clinical depressed state characterized by symptoms such as anxiety, insomnia, hostility, restlessness, and trepidation (Rampello et al., 1991, 1995, 2000). While patients affected by anxious depression are responsive to SSRI, those affected by retarded depression are more responsive to treatment with disinhibitor antidepressants such as desimipramine, nortriptiline, or MAO inhibitors. However, in PSD patients with ‘‘retarded depression’’ the use of the latter drugs is limited by their low profile of safety and tolerability. We now report that ‘‘retarded’’ PSD patients show a good response to the noradrenaline reuptake inhibitor (NARI), reboxetine, which is devoid of the side effects typical of tricyclic antidepressants or MAO inhibitors. Reboxetine is a selective noradrenaline reuptake inhibitor and represents the first of a new class of antidepressant agents with specificity for the noradrenergic system (Kasper et al., 2000). It has neither affinity for serotonin or dopamine uptake sites nor for muscarinic, histaminic, or anoradrenergic receptors (Riva et al., 1989; Wong et al., 2000). Reboxetine is rapidly absorbed and reaches peak plasma concentrations within 2 h. Its elimination half-life is approximately 13 h, so that the usual dosage range is 4–12 mg in two daily doses (Kasper
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et al., 2000). Reboxetine has been shown to be effective both for symptomatologic treatment of depressed patients (Berzewski et al., 1997; Ban et al., 1998; Katona et al., 1999; Massana et al., 1999; Versiani et al., 2000) and in improving social functioning in depressed patients (Dubini et al., 1997; Katona et al., 1999; Massana et al., 1999; Venditti et al., 2000). Furthermore, reboxetine is reported to be well tolerated during the acute and long-term treatment phase (Ban et al., 1998; Katona et al., 1999; Massana et al., 1999; Versiani et al., 2000). Reboxetine represents a significant addition to the currently available pharmacologic armamentarium for the treatment of depression, 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 (Kennedy et al., 2002). It is conceivable that ischaemic damage of the noradrenergic or serotonergic pathways might result in retarded and anxious PSD, respectively, explaining the different response of anxious and retarded depression to antidepressants and the rationale of this study, that is to evaluate the efficacy, tolerability, and safety of reboxetine in the treatment of post-stroke patients affected by ‘‘retarded’’ depression.
2. Patients and methods This is a double-blinded, placebo-controlled, community-based study, and the original number of eligible patients was 98. The study population was made up of patients affected by depression and previous stroke, who had appeared at our outpatient’s department within 12 months after the stroke. Thirty-one patients were selected based on the following criteria. Inclusion criteria: (a) presence of a recent (<12 months) single ischaemic or hemorrhagic stroke, which was documented by cerebral CT scanning or MRI before enrolment; (b) presence of major or minor depression, according to DSM IV criteria, with a Hamilton Depression Rating Scale (HDRS) score over 20 and a Beck Depression Inventory (BDI) score over 15; (c) presence of retarded depression, according to the Synoptic Table shown in Table 1 (total score of the Synoptic Table 130); (d) lack of treatment with antidepressants during the 2 weeks preceding the beginning of the study; (e) absence of treatment with neuroleptic drugs, cinnarizine, or flunarizine during 3 months before enrolment; and (f) informed consent. Exclusion criteria: (a) previous degenerative or expansive neurologic disease, tumors, multiple sclerosis, amyotrophic lateral sclerosis, and hydrocephalus; (b) subarachnoid hemorrhage, Binswanger’s disease; (c) history of psychiatric illness (other than depression); and (d) severe aphasia, severe cognitive deficit, chronic alcoholism. A computer-generated randomization was carried out by a physician who was not involved in the evaluation of patients, such that patients have been divided into two groups, treated with reboxetine (4 mg in two daily doses, one in the morning and the other in the afternoon, for 16 weeks, N = 16), and placebo (N = 15), respectively. Only patients affected by moderate post-stroke depression (according to Hamilton’s Scale and Beck Depression Inventory), and classified as ‘‘retarded’’ depressed patients according to the Synoptic Table reported in Table 1, were enrolled (Table 2). The Synoptic Table is a useful instrument to differentiate retarded depressed from anxious depressed patients, on the ground of the
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Table 1 Synoptic Table of two critical symptomatologic clusters (1–13 and 14–26) for the prediction of antidepressant response Symptoms
Supposed biochemical dysfunction: DA-NA: retarded depression
Supposed biochemical dysfunction: 5-HT: anxious depression
Anergia Hypokinesia Reduction of speech Hypophonia Salivation Hypersomnia Parinaud sign (paralysis of conjugate upward movement of the eyes without paralysis of convergence) Slowness Hypomimia Reduction of sexual activity Hypotension Dysphagia Drowsiness Anxiety Feeling of internal tremor Impulsivity Compulsivity (compulsoriness) Early insomnia Late insomnia Hostility Hyperperspiration Palpitation Pollakiuria Restlessness Phobias Trepidation
+++ +++ +++ +++ +++ +++ ++
+/0 0 +/0 0 0 0 0
+++ +++ +++ ++ ++/+ +++ 0 0 0 0 +/0 +/0 0 0 0 0 0 0 0
+/0 +/0 +/0 0 0 +/0 +++ ++ +++/++ ++/+ +++ +++/++ +++/++ +++/+ ++/+ ++/+ +++/++ ++/0 +++
A score ranging from 0 to 20 has been assigned to any specific symptom of anxious depression, where 0 = absent, 10 = mild, 20 = severe. A score from 0 to 20 (0 = absent, 10 = mild, 20 = severe) was instead assigned to symptoms of retarded depression. Patients were classified as affected by ‘‘anxious’’ and ‘‘retarded’’ depression when the total score was >130 and < 130, respectively, and only patients with a total Synoptic Table score < 130, were enrolled in the study. Symbols: (+++) severe; (++) moderate; (+) mild; (0) absent. These data represent the widespread modality of presentation of symptomatology in the two different subtypes of depression.
Synoptic Table score (Rampello et al., 1991, 1995, 2000). A score ranging from 0 to 20 has been assigned to any specific symptom of anxious depression, where 0 = absent, 10 = mild, 20 = severe. A score from 0 to 20 (0 = absent, 10 = mild, 20 = severe) was instead assigned to symptoms of retarded depression. Patients were classified as affected by ‘‘anxious’’ and ‘‘retarded’’ depression when the total score was >130 and < 130, respectively. We did enrol only patients with a total Synoptic Table score < 130. The generator of randomization assigned a code number (0) to patients who were treated with reboxetine, and a different code (1) was given to patients treated with placebo. Code 0 was stuck on totally white boxes, without any marks, sealed, containing the tablets of
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Table 2 General characteristics of the patients entering the trial Age (mean S.D.) Male sex, n Female sex, n Time since stroke, weeks (mean S.D.) Left-side lesions on TC Right-side lesions on TC Bilateral lesions on TC Baseline HDRS score Basal BDI score
Reboxetine
Placebo
p*
77.5 4 7 9 12.06 4.23 8 7 1 24.06 1.52 20.56 2.16
77.26 3.6 7 8 12.26 4.77 8 6 1 24 1.31 19.87 1.46
NS NS NS NS NS NS NS NS NS
reboxetine, round-shaped, white colored, without any recognizable marks. Code 1 was stuck on boxes exactly alike to the former, sealed, containing the tablets of placebo, exactly alike to the tablets of reboxetine as for size and color, and of similar shape. The generator of randomization handed over, for each patient, the box marked with the code and containing the tablets that should be taken. The other physician was in charge of the follow-up visits and of the evaluation of the outcome measures. The study lasted 16 weeks. HDRS and BDI scores were calculated at baseline and after 4, 8, and 16 weeks. At the end of the study, the generator of the randomization disclosed the code to the responsible for the follow-up visits, which had surveyed the outcomes, and the boxes with the remaining tablets were given back by the patients, so that we were able to evaluate their compliance. Side effects were registered during follow-up visits, by asking patients about any problems occurred during the study. Electrocardiograms were taken before entry and during the study. Statistic analysis has been performed by using paired t-test or one-way analysis of variance (ANOVA) associated with Dunnett’s t-test. SPSS version has been used for the statistic analysis.
3. Results After randomization, 31 patients were divided into two subgroups: the first group of 16 patients was treated for 16 weeks with reboxetine; the second group was treated for 16 weeks with placebo. The sample represented in each of the two subgroups was homogeneous for age, sex, side of lesions, and depression stage at baseline. Two parameters of efficacy were considered: (i) variations in HDRS and BDI scores and (ii) variations in the Synoptic Table scores. Recorded variations in HDRS and BDI scores during, and at the end of the study are reported in Table 3. In both groups, a reduction in HDRS and BDI scores was however observed; this reduction was significantly greater only in the group treated with reboxetine. The therapeutic gain (i.e., the difference between response to reboxetine and placebo) was reported in Table 4. Reboxetine led to a statistically significant variation in the Synoptic Table score with respect to the ‘‘retarded’’ symptomatologic cluster, which is expected to reflect primarily an impairment of noradrenergic transmission. At each visit, side effects reported by the patients were
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Table 3 Variations in HDRS and BDI scores during and after treatment in comparison to baseline Weeks of treatment
0 4 8 16
Retarded depressed patients treated with reboxetine (n = 16)
Retarded depressed patients treated placebo (n = 15)
HDRS
BDI
HDRS
BDI
24.06 1.52 14.66 1.49*,# 11.8 2*,# 9.26 2.15*,#
20.56 2.16 12.56 2.36*,# 9.62 2.87*,# 8.06 3.43*,#
24 1.31 23.87 1.41 23.87 2.06 22.73 2.4
19.87 1.46 19.8 2.54 19.47 2.47 18.4 3.33
Values are means S.D. * p < 0.01 vs. the respective baseline (paired t-test). # p < 0.01 vs. retarded depressed patients treated with placebo (one-way ANOVA applied to the difference from baseline, associated with Dunnett’s t-test to isolate the differences).
Table 4 Mean Synoptic Table scores at baseline and after 16 weeks of treatment with reboxetine or placebo Symptoms
Anergia Hypokinesia Reduction of speech Hypophonia Salivation Hypersomnia Parinaud Slowness Hypomimia Reduction of sexual activity Hypotension Dysphagia Drowsiness Anxiety Feeling of internal tremor Impulsivity Compulsivity Early insomnia Late insomnia Hostility Hyperperspiration Palpitation Pollakiuria Restlessness Phobias Trepidation
Retarded depressed patients treated with reboxetine (n = 16)
Retarded depressed patients treated with placebo (n = 15)
Week 0
Week 0
18.6 1.02 18.75 0.93 16.81 0.83 16.98 1.34 7.06 1.12 9.75 1.8 6.19 0.31 16.68 0.95 14.75 0.93 9.87 1.53 6.19 0.31 6.06 1.18 16.81 0.83 3.07 1.22 2.8 0.93 2.07 0.8 1.87 0.64 5.27 0.8 3.13 0.64 0.87 0.64 1.4 0.83 2.6 1.24 3.53 1.36 1.73 0.96 1.07 1.03 1.27 0.96
Week 16 4.5 1.03* 4.62 0.81* 5 0.97* 14.19 0.98* 1.37 0.96* 3.31 1.35* 3.56 1.03* 4.82 0.95* 4.62 0.81* 3.44 1.21* 3.56 1.03* 3.44 1.09* 5 0.97* 3.93 1.83 2.8 0.86 2.47 0.92 2 0.53 6.2 2.4 4 2.5 0.8 0.77 1.2 0.94 3.73 2.09 3.8 1.26 3.2 2.88 1 0.93 2.07 2.52
18.47 1.60 18.4 1.59 16.87 1.19 16.8 1.52 6.73 1.44 10.2 1.37 6.94 1.18 16.93 1.22 14.4 1.59 10.13 1.35 7 1.32 7 1.32 16.93 1.22 2.73 1.1 3.6 0.99 1.87 1.06 1.53 0.99 5.27 0.8 3.13 1.64 1.33 0.98 2.07 1.22 2.67 1.54 3.27 1.1 1.8 0.68 1.07 0.70 1.2 0.68
Week 16 17.6 1.8 17.53 1.77 15.87 1.68 16.27 1.54 6.2 1.90 9.57 1.78 6.6 1.4 15.93 1.71 14.53 1.77 9.5 1.74 6.67 1.54 6.67 1.54 15.93 1.71 2.8 1.21 3.6 0.91 1.73 0.7 1.53 0.99 6.2 2.4 3.2 1.61 1.2 1.21 2 1.13 2.53 1.36 3 1.2 1.73 0.7 1.27 0.7 1.13 0.64
For each symptom 0 = absent, 10 = mild, 20 = severe. Baseline and final mean scores S.D. of each symptom of the two symptomatologic clusters for each group of patients are given. * p < 0.01 vs. the respective baseline (paired t-test).
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Table 5 Side effects recorded during the study
Dryness of fauces Constipation Hyperperspiration Insomnia Drowsiness Urinary wavering or urinary retention Hypotension Sinusal tachycardia
Reboxetine (%)
Placebo (%)
22 18 16 4 3 4 8 7
19 15 12 5 5 0 2 1
Numbers correspond to the % of patients of each group in all visits.
recorded, and compliance was tested by asking the patients whether they remembered to take the tablets regularly. Side effects recorded during the study are reported in Table 5. No patients dropped out the study.
4. Discussion Depression deeply affects the functional recovery and rehabilitation of post-stroke patients (Gainotti et al., 2001) and, therefore, has a negative prognostic value (Torta and Berra, 2002). There are no specific guidelines for the treatment of PSD, because of the lack of clinical studies recording a large number of cases and of the variability in the response to the treatment. Physicians are often reluctant to start a treatment with antidepressant drugs in elderly post-stroke patients, that often take several drugs for associated pathologies. In addition, the patients affected by PSD particularly are vulnerable to the side effects of tricyclic antidepressants or MAO inhibitors. Although SSRI, like citalopram and fluoxetine, have shown a favorable profile of safety and tolerability (Muldoon, 1996; Patris et al., 1996; Fruhwald et al., 1999; Rigler, 1999; Willetts et al., 1999; Barret, 2000; Goodnick and Hernandez, 2000; Wiart et al., 2000; Breitner, 2001), it is noteworthy that not all patients respond to SSRI; we have assumed that the heterogeneity in the response could be related to the existence of a different subtype of PSD in analogy to what described for primary depression (Rampello et al., 1991, 1995, 2000). In a simplistic view, ischaemic damage of the noradrenergic or serotonergic pathways might result into two different clinical pictures, i.e., in retarded and anxious PSD, respectively. While SSRIs are effective in the treatment of anxious depression, patients with retarded depression show a lower response to SSRI and benefit more from treatment with disinhibiting antidepressants (Rampello et al., 1991, 1995, 2000). For this reason, we decided to evaluate the efficacy, tolerability, and safety of reboxetine, in the treatment of post-stroke patients affected by ‘‘retarded’’ depression. Reboxetine is the prototype of a new family of antidepressant drugs called NARI because they specifically inhibit noradrenaline reuptake (Dubini et al., 1997; Hindmarch, 1997; Montgomery, 1997, 1998; Mucci, 1997; Burrows et al., 1998; Andreoli et al., 1999; Aguglia, 2000; Bergmann et al., 2000; Kasper et al., 2000; Poggesi et al., 2000; Scates and Doraiswamy, 2000; Versiani et al., 2000; Johnson and Johnson, 2001). Its mechanism of
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action consists in binding with a specific carrier and blocking, in pre-synaptic terminations, the reuptake of noradrenaline, whose involvement in the physiopathology of depression has been widely proved by several clinical and experimental studies (Maas, 1975; Vetulani and Sulser, 1975; Karege et al., 1992; Piletz et al., 1996; Leonard, 1997). The noradrenaline reuptake inhibition caused by reboxetine strengthens the effect of this neurotransmitter in the CNS. Reboxetine does not interfere with dopamine and serotonin reuptake and has no affinity for adrenergic, cholinergic, and histaminergic receptors (Dubini et al., 1997; Hindmarch, 1997; Montgomery, 1997, 1998; Mucci, 1997; Burrows et al., 1998; Andreoli et al., 1999; Aguglia, 2000; Bergmann et al., 2000; Kasper et al., 2000; Poggesi et al., 2000; Scates and Doraiswamy, 2000; Versiani et al., 2000; Johnson and Johnson, 2001). Only few reports have been published on the clinical use of reboxetine, and there are no data on safety and efficacy in elderly patients. We therefore examined the efficacy, safety, and tolerability of reboxetine in PSD patients as related to the characteristics of the depression. The subgroup division into ‘‘anxious’’ and ‘‘retarded’’ depression was based on a careful evaluation of the clinical features of PSD. Reboxetine was effective in the subgroup of patients affected by ‘‘retarded’’ PSD. No serious side effects were recorded. The low dose of reboxetine we used was well tolerated, although our patients were sometimes in precarious clinical conditions. Some clinical trials showed the efficacy of reboxetine in adult and also elderly depressed patients but its use in elderly patients is still debated because of the lack of placebocontrolled studies (Andreoli et al., 1999; Aguglia, 2000; Poggesi et al., 2000; Versiani et al., 2000). This study supports the use of reboxetine in two daily doses of 2 mg in elderly patients suffering from PSD. As regarding the small sample size, it had not been planned in advance, but it was the maximum number of patients meeting the inclusion criteria which we could enrol; even if it might to limit the power of the study, on the ground of results, it is conceivable that this pilot study adds a new important instrument to the treatment of PSD patients that fail to respond to standard treatment with SSRI because they show symptoms that fall into the cluster typical of retarded depression (Rampello et al., 1991, 1995, 2000). As there are no reliable biologic markers of ‘‘anxious’’ and ‘‘retarded’’ depression, the Synoptic Table (Table 2), can be of help in order to sub classify PSD patients, thus allowing the predictability of the clinical response to a specific pharmacologic antidepressant treatment. Biochemical dysfunction resulting from ischaemic damage of the noradrenergic pathways might cause a retarded subtype of PSD that benefit from treatment with disinhibiting antidepressants, explaining the good efficacy of reboxetine and the low placebo response observed in this study. Therefore, patients affected by retarded PSD may represent a target for treatment with reboxetine, a NARI that assures a good therapeutic efficacy and, at the same time, unlike tricyclic antidepressant offers wide margins of tolerability and safety also in elderly patients because of its selective action. References Aben, I., Verhey, F., Honig, A., Lodder, J., Lousberg, R., Maes, M., 2001. Research into the specificity of depression after stroke: a review on an unresolved issue. Prog. Neuropsychopharmacol. Biol. Psychiat. 25, 671–689.
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An evaluation of efficacy and safety of reboxetine in elderly patients affected by ‘‘retarded’’ post-stroke depression A random, placebo-controlled study Liborio Rampelloa,*, Alessandro Alvanoa, Santina Chiechiob, Rocco Raffaelea, Ignazio Vecchioa, Mariano Malaguarnerac a
Department of Neurosciences, University of Catania, Azienda Policlinico-Neurologia, Via S. Sofia 78, Catania I-95125, Italy b Department of Pharmaceutical Sciences, University of Catania, V.A. Doria 6, Catania I-95123, Italy c Department of Longevity Sciences, Urology and Neurology, University of Catania, Cannizzaro Hospital, Via Messina 829, Catania I-95124, Italy Received 13 March 2004; received in revised form 20 September 2004; accepted 29 September 2004 Available online 7 December 2004
Abstract Depression occurs frequently in post-stroke patients and appears to be associated with an impairment in their rehabilitation and functional recovery. Although selective serotonin reuptake inhibitors (SSRI) are often used in post-stroke depression (PSD), it has been observed that only a subset of patients is responsive to this treatment. Other patients respond to tricyclic antidepressants or MAO inhibitors, which, however, may not have a favorable profile of safety and tolerability in poststroke patients. In this double-blinded, placebo-controlled study, we evaluated the efficacy and tolerability of the noradrenaline reuptake inhibitor, reboxetine, in a subset of PSD patients classified as affected by ‘‘retarded’’ depression. Reboxetine (4 mg, twice daily, for 16 weeks) was administered to patients that developed depression after a single ischaemic or hemorrhagic stroke. We assessed the severity of depressive symptoms by the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS). HDRS and BDI scores (mean S.D.) at baseline were, respectively, 24 1.31 and 19.87 1.46 in the placebo group, 24.06 1.52 and 20.56 2.16 in the reboxetine group. After 16 weeks, HDRS and BDI mean scores were respectively 22.73 2.4 and 18.4 3.33 in the placebo group, 9.26 2.15 and 8.06 3.43 in the reboxetine group [p < 0.01 versus the respective baseline (paired t-test); #p < 0.01 versus retarded depressed patients treated with placebo (one-way analysis of variance (ANOVA) applied to the difference from baseline, associated with
* Corresponding author. Tel.: +39 095 3782622; fax: +39 095 3782622. E-mail address: [email protected] (L. Rampello). 0167-4943/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2004.09.004
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Dunnett’s t-test to isolate the differences)]. Reboxetine showed a good efficacy, safety and tolerability in PSD patients affected by ‘‘retarded’’ depression. We conclude that reboxetine is well tolerated and may be a useful therapeutic option in PSD patients with ‘‘retarded’’ depression. # 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Post-stroke depression; Reboxetine; Noradrenaline reuptake inhibitors (NARI)
1. Introduction Post-stroke depression (PSD) affects a percentage from 20 to 50% of the patients within 1 year after a brain stroke event (Andersen et al., 1994, 1995; Gustafson et al., 1995; Paolucci, 1999; Wiart et al., 2000; Aben et al., 2001). While some authors favor an ‘‘organic hypothesis’’, based with correlation between PSD and left (Robinson et al., 1990; Hermann and Wallesh, 1993; Gonzalez Torrecillas et al., 1997; Robinson, 1997; Jolobe, 1998; Lyketsos et al., 1998; Mayberg et al., 1998; Ramasubbu et al., 1998) or right hemispheric lesions (Carson et al., 2000), others favor a ‘‘reactive hypothesis’’ (Robins, 1976; Charatan and Fisk, 1978; Turner and Beiser, 1990; Gainotti et al., 1997; The Sunnybrook Stroke Study, 2000). PSD represents an unfavorable prognostic factor, since it significantly affects the functional recovery and rehabilitation of post-stroke patients (Gainotti et al., 2001). Although selective serotonin reuptake inhibitors (SSRI), such as citalopram and fluoxetine, have shown good efficacy and tolerability in the treatment of PSD (Muldoon, 1996; Patris et al., 1996; Willetts et al., 1999; Wiart et al., 2000), it is noteworthy that the response of the PSD patients is not homogeneous. This might depend on the existence of two distinct subsets of depression: ‘‘anxious’’ and ‘‘retarded’’, similarly to what observed for primary depression (Rampello et al., 1991, 1995, 2000). Retarded depression may be defined as a state of clinical depression in which the individual is lethargic, slow to initiate action and shows anergia, hypokinesia, hypomimia, and other symptoms whose presence distinguish this subtype of depression from anxious depression, that instead, is a clinical depressed state characterized by symptoms such as anxiety, insomnia, hostility, restlessness, and trepidation (Rampello et al., 1991, 1995, 2000). While patients affected by anxious depression are responsive to SSRI, those affected by retarded depression are more responsive to treatment with disinhibitor antidepressants such as desimipramine, nortriptiline, or MAO inhibitors. However, in PSD patients with ‘‘retarded depression’’ the use of the latter drugs is limited by their low profile of safety and tolerability. We now report that ‘‘retarded’’ PSD patients show a good response to the noradrenaline reuptake inhibitor (NARI), reboxetine, which is devoid of the side effects typical of tricyclic antidepressants or MAO inhibitors. Reboxetine is a selective noradrenaline reuptake inhibitor and represents the first of a new class of antidepressant agents with specificity for the noradrenergic system (Kasper et al., 2000). It has neither affinity for serotonin or dopamine uptake sites nor for muscarinic, histaminic, or anoradrenergic receptors (Riva et al., 1989; Wong et al., 2000). Reboxetine is rapidly absorbed and reaches peak plasma concentrations within 2 h. Its elimination half-life is approximately 13 h, so that the usual dosage range is 4–12 mg in two daily doses (Kasper
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et al., 2000). Reboxetine has been shown to be effective both for symptomatologic treatment of depressed patients (Berzewski et al., 1997; Ban et al., 1998; Katona et al., 1999; Massana et al., 1999; Versiani et al., 2000) and in improving social functioning in depressed patients (Dubini et al., 1997; Katona et al., 1999; Massana et al., 1999; Venditti et al., 2000). Furthermore, reboxetine is reported to be well tolerated during the acute and long-term treatment phase (Ban et al., 1998; Katona et al., 1999; Massana et al., 1999; Versiani et al., 2000). Reboxetine represents a significant addition to the currently available pharmacologic armamentarium for the treatment of depression, 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 (Kennedy et al., 2002). It is conceivable that ischaemic damage of the noradrenergic or serotonergic pathways might result in retarded and anxious PSD, respectively, explaining the different response of anxious and retarded depression to antidepressants and the rationale of this study, that is to evaluate the efficacy, tolerability, and safety of reboxetine in the treatment of post-stroke patients affected by ‘‘retarded’’ depression.
2. Patients and methods This is a double-blinded, placebo-controlled, community-based study, and the original number of eligible patients was 98. The study population was made up of patients affected by depression and previous stroke, who had appeared at our outpatient’s department within 12 months after the stroke. Thirty-one patients were selected based on the following criteria. Inclusion criteria: (a) presence of a recent (<12 months) single ischaemic or hemorrhagic stroke, which was documented by cerebral CT scanning or MRI before enrolment; (b) presence of major or minor depression, according to DSM IV criteria, with a Hamilton Depression Rating Scale (HDRS) score over 20 and a Beck Depression Inventory (BDI) score over 15; (c) presence of retarded depression, according to the Synoptic Table shown in Table 1 (total score of the Synoptic Table 130); (d) lack of treatment with antidepressants during the 2 weeks preceding the beginning of the study; (e) absence of treatment with neuroleptic drugs, cinnarizine, or flunarizine during 3 months before enrolment; and (f) informed consent. Exclusion criteria: (a) previous degenerative or expansive neurologic disease, tumors, multiple sclerosis, amyotrophic lateral sclerosis, and hydrocephalus; (b) subarachnoid hemorrhage, Binswanger’s disease; (c) history of psychiatric illness (other than depression); and (d) severe aphasia, severe cognitive deficit, chronic alcoholism. A computer-generated randomization was carried out by a physician who was not involved in the evaluation of patients, such that patients have been divided into two groups, treated with reboxetine (4 mg in two daily doses, one in the morning and the other in the afternoon, for 16 weeks, N = 16), and placebo (N = 15), respectively. Only patients affected by moderate post-stroke depression (according to Hamilton’s Scale and Beck Depression Inventory), and classified as ‘‘retarded’’ depressed patients according to the Synoptic Table reported in Table 1, were enrolled (Table 2). The Synoptic Table is a useful instrument to differentiate retarded depressed from anxious depressed patients, on the ground of the
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Table 1 Synoptic Table of two critical symptomatologic clusters (1–13 and 14–26) for the prediction of antidepressant response Symptoms
Supposed biochemical dysfunction: DA-NA: retarded depression
Supposed biochemical dysfunction: 5-HT: anxious depression
Anergia Hypokinesia Reduction of speech Hypophonia Salivation Hypersomnia Parinaud sign (paralysis of conjugate upward movement of the eyes without paralysis of convergence) Slowness Hypomimia Reduction of sexual activity Hypotension Dysphagia Drowsiness Anxiety Feeling of internal tremor Impulsivity Compulsivity (compulsoriness) Early insomnia Late insomnia Hostility Hyperperspiration Palpitation Pollakiuria Restlessness Phobias Trepidation
+++ +++ +++ +++ +++ +++ ++
+/0 0 +/0 0 0 0 0
+++ +++ +++ ++ ++/+ +++ 0 0 0 0 +/0 +/0 0 0 0 0 0 0 0
+/0 +/0 +/0 0 0 +/0 +++ ++ +++/++ ++/+ +++ +++/++ +++/++ +++/+ ++/+ ++/+ +++/++ ++/0 +++
A score ranging from 0 to 20 has been assigned to any specific symptom of anxious depression, where 0 = absent, 10 = mild, 20 = severe. A score from 0 to 20 (0 = absent, 10 = mild, 20 = severe) was instead assigned to symptoms of retarded depression. Patients were classified as affected by ‘‘anxious’’ and ‘‘retarded’’ depression when the total score was >130 and < 130, respectively, and only patients with a total Synoptic Table score < 130, were enrolled in the study. Symbols: (+++) severe; (++) moderate; (+) mild; (0) absent. These data represent the widespread modality of presentation of symptomatology in the two different subtypes of depression.
Synoptic Table score (Rampello et al., 1991, 1995, 2000). A score ranging from 0 to 20 has been assigned to any specific symptom of anxious depression, where 0 = absent, 10 = mild, 20 = severe. A score from 0 to 20 (0 = absent, 10 = mild, 20 = severe) was instead assigned to symptoms of retarded depression. Patients were classified as affected by ‘‘anxious’’ and ‘‘retarded’’ depression when the total score was >130 and < 130, respectively. We did enrol only patients with a total Synoptic Table score < 130. The generator of randomization assigned a code number (0) to patients who were treated with reboxetine, and a different code (1) was given to patients treated with placebo. Code 0 was stuck on totally white boxes, without any marks, sealed, containing the tablets of
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Table 2 General characteristics of the patients entering the trial Age (mean S.D.) Male sex, n Female sex, n Time since stroke, weeks (mean S.D.) Left-side lesions on TC Right-side lesions on TC Bilateral lesions on TC Baseline HDRS score Basal BDI score
Reboxetine
Placebo
p*
77.5 4 7 9 12.06 4.23 8 7 1 24.06 1.52 20.56 2.16
77.26 3.6 7 8 12.26 4.77 8 6 1 24 1.31 19.87 1.46
NS NS NS NS NS NS NS NS NS
reboxetine, round-shaped, white colored, without any recognizable marks. Code 1 was stuck on boxes exactly alike to the former, sealed, containing the tablets of placebo, exactly alike to the tablets of reboxetine as for size and color, and of similar shape. The generator of randomization handed over, for each patient, the box marked with the code and containing the tablets that should be taken. The other physician was in charge of the follow-up visits and of the evaluation of the outcome measures. The study lasted 16 weeks. HDRS and BDI scores were calculated at baseline and after 4, 8, and 16 weeks. At the end of the study, the generator of the randomization disclosed the code to the responsible for the follow-up visits, which had surveyed the outcomes, and the boxes with the remaining tablets were given back by the patients, so that we were able to evaluate their compliance. Side effects were registered during follow-up visits, by asking patients about any problems occurred during the study. Electrocardiograms were taken before entry and during the study. Statistic analysis has been performed by using paired t-test or one-way analysis of variance (ANOVA) associated with Dunnett’s t-test. SPSS version has been used for the statistic analysis.
3. Results After randomization, 31 patients were divided into two subgroups: the first group of 16 patients was treated for 16 weeks with reboxetine; the second group was treated for 16 weeks with placebo. The sample represented in each of the two subgroups was homogeneous for age, sex, side of lesions, and depression stage at baseline. Two parameters of efficacy were considered: (i) variations in HDRS and BDI scores and (ii) variations in the Synoptic Table scores. Recorded variations in HDRS and BDI scores during, and at the end of the study are reported in Table 3. In both groups, a reduction in HDRS and BDI scores was however observed; this reduction was significantly greater only in the group treated with reboxetine. The therapeutic gain (i.e., the difference between response to reboxetine and placebo) was reported in Table 4. Reboxetine led to a statistically significant variation in the Synoptic Table score with respect to the ‘‘retarded’’ symptomatologic cluster, which is expected to reflect primarily an impairment of noradrenergic transmission. At each visit, side effects reported by the patients were
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Table 3 Variations in HDRS and BDI scores during and after treatment in comparison to baseline Weeks of treatment
0 4 8 16
Retarded depressed patients treated with reboxetine (n = 16)
Retarded depressed patients treated placebo (n = 15)
HDRS
BDI
HDRS
BDI
24.06 1.52 14.66 1.49*,# 11.8 2*,# 9.26 2.15*,#
20.56 2.16 12.56 2.36*,# 9.62 2.87*,# 8.06 3.43*,#
24 1.31 23.87 1.41 23.87 2.06 22.73 2.4
19.87 1.46 19.8 2.54 19.47 2.47 18.4 3.33
Values are means S.D. * p < 0.01 vs. the respective baseline (paired t-test). # p < 0.01 vs. retarded depressed patients treated with placebo (one-way ANOVA applied to the difference from baseline, associated with Dunnett’s t-test to isolate the differences).
Table 4 Mean Synoptic Table scores at baseline and after 16 weeks of treatment with reboxetine or placebo Symptoms
Anergia Hypokinesia Reduction of speech Hypophonia Salivation Hypersomnia Parinaud Slowness Hypomimia Reduction of sexual activity Hypotension Dysphagia Drowsiness Anxiety Feeling of internal tremor Impulsivity Compulsivity Early insomnia Late insomnia Hostility Hyperperspiration Palpitation Pollakiuria Restlessness Phobias Trepidation
Retarded depressed patients treated with reboxetine (n = 16)
Retarded depressed patients treated with placebo (n = 15)
Week 0
Week 0
18.6 1.02 18.75 0.93 16.81 0.83 16.98 1.34 7.06 1.12 9.75 1.8 6.19 0.31 16.68 0.95 14.75 0.93 9.87 1.53 6.19 0.31 6.06 1.18 16.81 0.83 3.07 1.22 2.8 0.93 2.07 0.8 1.87 0.64 5.27 0.8 3.13 0.64 0.87 0.64 1.4 0.83 2.6 1.24 3.53 1.36 1.73 0.96 1.07 1.03 1.27 0.96
Week 16 4.5 1.03* 4.62 0.81* 5 0.97* 14.19 0.98* 1.37 0.96* 3.31 1.35* 3.56 1.03* 4.82 0.95* 4.62 0.81* 3.44 1.21* 3.56 1.03* 3.44 1.09* 5 0.97* 3.93 1.83 2.8 0.86 2.47 0.92 2 0.53 6.2 2.4 4 2.5 0.8 0.77 1.2 0.94 3.73 2.09 3.8 1.26 3.2 2.88 1 0.93 2.07 2.52
18.47 1.60 18.4 1.59 16.87 1.19 16.8 1.52 6.73 1.44 10.2 1.37 6.94 1.18 16.93 1.22 14.4 1.59 10.13 1.35 7 1.32 7 1.32 16.93 1.22 2.73 1.1 3.6 0.99 1.87 1.06 1.53 0.99 5.27 0.8 3.13 1.64 1.33 0.98 2.07 1.22 2.67 1.54 3.27 1.1 1.8 0.68 1.07 0.70 1.2 0.68
Week 16 17.6 1.8 17.53 1.77 15.87 1.68 16.27 1.54 6.2 1.90 9.57 1.78 6.6 1.4 15.93 1.71 14.53 1.77 9.5 1.74 6.67 1.54 6.67 1.54 15.93 1.71 2.8 1.21 3.6 0.91 1.73 0.7 1.53 0.99 6.2 2.4 3.2 1.61 1.2 1.21 2 1.13 2.53 1.36 3 1.2 1.73 0.7 1.27 0.7 1.13 0.64
For each symptom 0 = absent, 10 = mild, 20 = severe. Baseline and final mean scores S.D. of each symptom of the two symptomatologic clusters for each group of patients are given. * p < 0.01 vs. the respective baseline (paired t-test).
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Table 5 Side effects recorded during the study
Dryness of fauces Constipation Hyperperspiration Insomnia Drowsiness Urinary wavering or urinary retention Hypotension Sinusal tachycardia
Reboxetine (%)
Placebo (%)
22 18 16 4 3 4 8 7
19 15 12 5 5 0 2 1
Numbers correspond to the % of patients of each group in all visits.
recorded, and compliance was tested by asking the patients whether they remembered to take the tablets regularly. Side effects recorded during the study are reported in Table 5. No patients dropped out the study.
4. Discussion Depression deeply affects the functional recovery and rehabilitation of post-stroke patients (Gainotti et al., 2001) and, therefore, has a negative prognostic value (Torta and Berra, 2002). There are no specific guidelines for the treatment of PSD, because of the lack of clinical studies recording a large number of cases and of the variability in the response to the treatment. Physicians are often reluctant to start a treatment with antidepressant drugs in elderly post-stroke patients, that often take several drugs for associated pathologies. In addition, the patients affected by PSD particularly are vulnerable to the side effects of tricyclic antidepressants or MAO inhibitors. Although SSRI, like citalopram and fluoxetine, have shown a favorable profile of safety and tolerability (Muldoon, 1996; Patris et al., 1996; Fruhwald et al., 1999; Rigler, 1999; Willetts et al., 1999; Barret, 2000; Goodnick and Hernandez, 2000; Wiart et al., 2000; Breitner, 2001), it is noteworthy that not all patients respond to SSRI; we have assumed that the heterogeneity in the response could be related to the existence of a different subtype of PSD in analogy to what described for primary depression (Rampello et al., 1991, 1995, 2000). In a simplistic view, ischaemic damage of the noradrenergic or serotonergic pathways might result into two different clinical pictures, i.e., in retarded and anxious PSD, respectively. While SSRIs are effective in the treatment of anxious depression, patients with retarded depression show a lower response to SSRI and benefit more from treatment with disinhibiting antidepressants (Rampello et al., 1991, 1995, 2000). For this reason, we decided to evaluate the efficacy, tolerability, and safety of reboxetine, in the treatment of post-stroke patients affected by ‘‘retarded’’ depression. Reboxetine is the prototype of a new family of antidepressant drugs called NARI because they specifically inhibit noradrenaline reuptake (Dubini et al., 1997; Hindmarch, 1997; Montgomery, 1997, 1998; Mucci, 1997; Burrows et al., 1998; Andreoli et al., 1999; Aguglia, 2000; Bergmann et al., 2000; Kasper et al., 2000; Poggesi et al., 2000; Scates and Doraiswamy, 2000; Versiani et al., 2000; Johnson and Johnson, 2001). Its mechanism of
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action consists in binding with a specific carrier and blocking, in pre-synaptic terminations, the reuptake of noradrenaline, whose involvement in the physiopathology of depression has been widely proved by several clinical and experimental studies (Maas, 1975; Vetulani and Sulser, 1975; Karege et al., 1992; Piletz et al., 1996; Leonard, 1997). The noradrenaline reuptake inhibition caused by reboxetine strengthens the effect of this neurotransmitter in the CNS. Reboxetine does not interfere with dopamine and serotonin reuptake and has no affinity for adrenergic, cholinergic, and histaminergic receptors (Dubini et al., 1997; Hindmarch, 1997; Montgomery, 1997, 1998; Mucci, 1997; Burrows et al., 1998; Andreoli et al., 1999; Aguglia, 2000; Bergmann et al., 2000; Kasper et al., 2000; Poggesi et al., 2000; Scates and Doraiswamy, 2000; Versiani et al., 2000; Johnson and Johnson, 2001). Only few reports have been published on the clinical use of reboxetine, and there are no data on safety and efficacy in elderly patients. We therefore examined the efficacy, safety, and tolerability of reboxetine in PSD patients as related to the characteristics of the depression. The subgroup division into ‘‘anxious’’ and ‘‘retarded’’ depression was based on a careful evaluation of the clinical features of PSD. Reboxetine was effective in the subgroup of patients affected by ‘‘retarded’’ PSD. No serious side effects were recorded. The low dose of reboxetine we used was well tolerated, although our patients were sometimes in precarious clinical conditions. Some clinical trials showed the efficacy of reboxetine in adult and also elderly depressed patients but its use in elderly patients is still debated because of the lack of placebocontrolled studies (Andreoli et al., 1999; Aguglia, 2000; Poggesi et al., 2000; Versiani et al., 2000). This study supports the use of reboxetine in two daily doses of 2 mg in elderly patients suffering from PSD. As regarding the small sample size, it had not been planned in advance, but it was the maximum number of patients meeting the inclusion criteria which we could enrol; even if it might to limit the power of the study, on the ground of results, it is conceivable that this pilot study adds a new important instrument to the treatment of PSD patients that fail to respond to standard treatment with SSRI because they show symptoms that fall into the cluster typical of retarded depression (Rampello et al., 1991, 1995, 2000). As there are no reliable biologic markers of ‘‘anxious’’ and ‘‘retarded’’ depression, the Synoptic Table (Table 2), can be of help in order to sub classify PSD patients, thus allowing the predictability of the clinical response to a specific pharmacologic antidepressant treatment. Biochemical dysfunction resulting from ischaemic damage of the noradrenergic pathways might cause a retarded subtype of PSD that benefit from treatment with disinhibiting antidepressants, explaining the good efficacy of reboxetine and the low placebo response observed in this study. Therefore, patients affected by retarded PSD may represent a target for treatment with reboxetine, a NARI that assures a good therapeutic efficacy and, at the same time, unlike tricyclic antidepressant offers wide margins of tolerability and safety also in elderly patients because of its selective action. References Aben, I., Verhey, F., Honig, A., Lodder, J., Lousberg, R., Maes, M., 2001. Research into the specificity of depression after stroke: a review on an unresolved issue. Prog. Neuropsychopharmacol. Biol. Psychiat. 25, 671–689.
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