www.elsevier.com/locate/jad

Journal of Affective Disorders 81 (2004) 67–72

Brief report

Reboxetine adjunct for partial or nonresponders

to antidepressant treatment

Gabriel Rubioa, Luis Sanb, Francisco Lopez-Munozc,*, Cecilio Alamoc

aPsychiatry Service, ‘‘La Paz’’ University Hospital, Madrid, Spainb ‘‘Benito Menni’’ Mental Health Care Institute, Sant Boi, Barcelona, Spain

cNeuropsychopharmacology Unit, Pharmacology Department, Faculty of Medicine,

University of Alcala, C/Juan Ignacio Luca de Tena, 8, 28027 Madrid, Spain

Received 28 February 2003; received in revised form 4 August 2003; accepted 8 August 2003

Abstract

Background: To investigate the usefulness of the combination therapy with two antidepressants from different

pharmacological families in treatment-resistant depressive patients. Methods: In this prospective 6 weeks open-label study,

we assessed the effectiveness of the addition of reboxetine to 61 depressive patients that had previously not responded, or had

done so only in a partial way, to conventional treatment, in monotherapy, with selective serotonin reuptake inhibitors (SSRIs),

venlafaxine or mirtazapine. Data were analyzed on an intent-to-treat basis, using the last-observation-carried-forward (LOCF)

method. Results: Mean decrease on the 21-item Hamilton Depression Rating Scale (HDRS) score was 48.9% and on the

Clinical Global Impressions Scale (CGI), 38.9%. At the end of the treatment, 62.3% of the patients were evaluated as

improvement (CGI < 4), 54.1% as responders (HDRSV 50%) and 45.9% in remission (HDRSV 10). No serious side effects

were observed during combination therapy, being more frequent increased sweating (8.2%) and dry mouth (6.6%). Conclusions:

These findings suggest that the strategy of combination with reboxetine may be an effective and well-tolerated tool in treatment-

resistant patients who have failed to adequately respond to monotherapy with SSRIs, venlafaxine or mirtazapine.

D 2003 Elsevier B.V. All rights reserved.

Keywords: Resistant depression; Combination treatment; Reboxetine

1. Introduction

It is estimated that 30–40% of the depressive

patients do not respond adequately to antidepressant

therapy, at the correct dose, regime and duration

(Nierenberg and Amsterdam, 1990; Fawcett, 1994;

Sokolov and Joffe, 1995; Thase and Rush, 1995;

0165-0327/$ - see front matter D 2003 Elsevier B.V. All rights reserved.

doi:10.1016/j.jad.2003.08.001

* Corresponding author. Tel.: +34-91-7248207; fax: +34-91-

7248205.

E-mail address: frlopez@juste.net (F. Lopez-Munoz).

Amsterdam and Hornig-Rohan, 1996). Despite these

data, there is currently no consensus on the definition

of treatment-resistant depression or refractory depres-

sion (Burrows et al., 1994; Fava and Davidson, 1996;

Lam et al., 2002). Opinions vary, and take into

account aspects such as suitability of the drug admin-

istered, dose, duration of treatment, therapeutic histo-

ry, etc. (Thase and Rush, 1995; Sackeim, 2001).

Therefore, there is increasing use of the terms ‘‘non-

response’’ and ‘‘partial response’’ to antidepressant

therapy (Hirschfeld et al., 2002).

G. Rubio et al. / Journal of Affective Disorders 81 (2004) 67–7268

In dealing with partial or nonresponders to antide-

pressant treatment, various alternatives have been pro-

posed (Fava, 2000; Nelson, 2000; Hirschfeld et al.,

2002), such as optimization of the posological regime,

switching of the antidepressant or the addition of a new

drug, which may be other antidepressant (combination

strategy) or another drug that is not an antidepressant

per se, such as lithium salts, buspirone, pindolol,

thyroid hormones, etc. (augmentation strategy).

Recently, some open studies have shown rebox-

etine to be promising as an adjunct in nonresponders

to selective serotonin reuptake inhibitors (SSRIs)

alone (Devarajan and Dursun, 2000; Lucca et al.,

2000; Serretti et al., 2001). Reboxetine is the first

drug in a new family of antidepressants: selective nora-

drenaline reuptake inhibitors (Montgomery, 1997).

Their receptorial affinity is very low (Wong et al.,

2000), so that their use is not associated with the typical

adverse effects of the tricyclic antidepressants (TCAs)

(Tanum, 2000).

The aims of the present study was the assessment

of the efficacy, as a combination strategy, of the

addition of reboxetine in patients that had not previ-

ously responded, or had done so only partially, over 6

Table 1

Demographic and psychiatric diagnosis baseline data

Fluoxetine Paroxetine Venlafaxine Mirtaz

n 16 16 12 6

Age (years) 45.6F 11.9 46.1F12.1 52.4F 8.9 42.2FSex

F (%) 8 (50) 13 (81.25) 9 (75) 5 (83.3

M (%) 8 (50) 3 (18.75) 3 (25) 1 (16.7

Diagnosisa

MDD 13 12 8 3

Single episode 2 3 3 –

Recurrent 11 9 5 3

Dysthymia – 2 2 3

DD-NOS 3 2 2 –

No. episodesb 2.4F 2.6 4.9F 4.1 3.6F 1.7 3F 2.8

Mean dosec 25.6F 8.9 30 156.3F 67.6 30F 1

HDRS 25.4F 7.3 28.4F 5.8 24.9F 4.9 22.2FCGI-SI 4.3F 0.7 4.7F 0.7 4.2F 0.4 4.5F

MMD (Major Depressive Disorder); DD-NOS (Depressive Disorder Not

CGI-SI (Clinical Global Impression-Severity of Illness).

There were no significant differences between the groups with regard to d

maintenance doses of reboxetine), according to the ANOVA carried out.a According to DSM-IV criteria.b Number of previous depressive episodes.c Current antidepressant: mean daily dose (mg/day) at study entry.

weeks of conventional pharmacological treatment

with SSRIs, venlafaxine or mirtazapine.

2. Methods

This open-label, prospective and multicentric study,

of 6 weeks duration, included 61 outpatients, selected

in Madrid and Barcelona, diagnosed with depressive

disorder, according to DSM-IV criteria, nonresponders

or partial responders to previous treatment, in mono-

therapy, with SSRIs, venlafaxine or mirtazapine (de-

crease in the score on the Hamilton Scale for

depression < 50%, over a period of 6 weeks of

treatment, according to the criteria of Hirschfeld et

al., 2002). The dose of reboxetine as an adjunct ranged

from 2 to 8 mg/day (maintenance mean dose of

4.7F 1.9 mg/day). All patients gave informed consent

before participation in the study. Demographic data of

patients are shown in Table 1.

Evaluation of antidepressant efficacy was carried

out through the application of the 21-item Hamilton

Depression Rating Scale (HDRS) and the Clinical

Global Impressions—Global Improvement Scale

apine Sertraline Citalopram Fluvoxamine Total

5 4 2 61

10.9 34.5F 15.6 45.0F 15.6 51.5F 6.4 46.2F 11.5

) 5 (100) 3 (75) 2 (100) 45 (73.8)

) 0 (0) 1 (25) 0 (0) 16 (26.2)

4 4 1 45

2 3 – 13

2 1 1 32

– – – 7

1 – 1 9

3 2 3 3.5F 2.9

2.1 100F 61.2 42.5F 12.6 200F 141 –

5.6 25.2F 4.4 22.2F 4.4 20.5F 9.2 25.4F 6.1

0.5 4.6F 0.9 4.5F 0.6 3.5F 0.7 4.4F 0.7

Otherwise Specified); HDRS (Hamilton Depression Rating Scale);

istribution (age of patients, baseline score on HDRS and CGI, and

(HDRStotalscoreV10)afteradditionofreboxetine

Week6

Responders

Rem

ission

eter

LOCF

Completer

LOCF

Completer

(69.2)d,e

9/16(56.2)

9/12(56.2)

9/16(56.2)

9/12(75)

(21.4)

7/16(43.7)

7/11(63.6)

5/16(31.2)

5/11(45.4)

(25)

8/12(66.7)

8/12(66.7)

6/12(50)

6/12(50)

(50)

3/6

(50)

3/6

(50)

3/6

(50)

3/6

(50)

3/5

(60)

3/4

(75)

2/5

(40)

2/4

(50)

(25)

2/4

(50)

2/3

(66.7)

2/4

(50)

2/3

(66.7)

(50)

1/2

(50)

1/2

(50)

1/2

(50)

1/2

(50)

(36.4)

33/61(54.1)

33/50(66)

28/61(45.9)

28/50(56)

G. Rubio et al. / Journal of Affective Disorders 81 (2004) 67–72 69

(CGI-I) in weeks 2, 4 and 6. The primary efficacy

assessment was defined as the absolute decrease of the

HDRS total score. Responders were defined as patients

with decrease in HDRS total score z 50%. Remission

was defined as the absolute value of HDRS score V 10.

As secondary variables of efficacy, we also considered

variation in the score on the CGI-I scale, as well as the

percentage of improved patients (score < 4 points on

the CGI-I scale). We made a comparative analysis

among the three subgroups with the largest number

of patients (fluoxetine, paroxetine and venlafaxine). In

the analysis of the adverse events, only treatment-

emergent signs and symptoms were considered.

Data were analyzed on an intent-to-treat basis,

using the last-observation-carried-forward (LOCF)

method for missing data. All statistical analyses

(ANOVA, Student t-test, chi-squared test) were per-

formed by statistical software MINITAB, release

12.21 (Minitab, 1998). Statistical significance was

set at the p < 0.05 level.

Table

2

Number

ofpatients(percentageofpatients)classified

asresponders(H

DRSV50%)andas

inremission

Week2

Week4

Responders

Rem

ission

Responders

Rem

ission

LOCF

LOCF

Completer

LOCF

Compl

Fluoxetine

3/16(18.7)

2/16(12.5)

8/16(50)a

8/13(56.2)b

9/16(56.2)c

9/13

Paroxetine

1/16(6.2)

0/16

5/16(31.2)

5/14(35.7)

3/16(18.7)

3/14

Venlafaxine

1/12(8.3)

0/12

2/12(16.7)

2/12(16.7)

3/12(25)

3/12

Mirtazapine

1/6

(16.7)

1/6

(16.7)

2/6

(33.3)

2/6

(33.3)

3/6

(50)

3/6

Sertraline

0/5

0/5

0/5

0/4

0/5

0/4

Citalopram

1/4

(25)

1/4

(25)

2/4

(50)

2/4

(50)

1/4

(25)

1/4

Fluvoxam

ine

0/2

0/2

1/2

(50)

1/2

(50)

1/2

(50)

1/2

Total

7/61(11.5)

4/61(6.6)

20/61(32.8)

20/55(36.4)

20/61(32.8)

20/55

LOCFanalysis.

ap=0.043versusvenlafaxine.

bp=0.009versusvenlafaxine.

cp=0.017versusparoxetine.

dp=0.005versusparoxetine.

ep=0.013versusvenlafaxine.

3. Results

Mean score on the HDRS at baseline was 25.39F6.13, falling to 12.98F 7.86 in week 6 (mean decrease

of 48.9%, p < 0.0001). No statistically significant dif-

ferences were found between the subgroups (fluoxe-

tine: � 13.94F 10.51, paroxetine: � 12.31F 8.19,

venlafaxine: � 13.75F 5.28). As regards type of

diagnosis, the dysthymic patients showed a signifi-

cantly lower decrease in HDRS score (� 7.14F 5.61)

versus the patients with MDD (� 13.33F 8.38)

( p = 0.031). The percentages of responders and

patients considered as benefiting from complete re-

mission (Table 2) at 6 weeks were 54.1% and 45.9%,

respectively. There were no differences between the

three subgroups analyzed as regards number of res-

ponders (v2 = 1.482, p = 0.477) and number of patients

in remission (v2 = 2.154, p = 0.341).By the end of the treatment, a mean decrease in

CGI-I score of � 1.721F1.306 was obtained

( p < 0.0001 versus baseline values). Percentage of

patients improving was 62.3%, with no statistically

significant differences among the three subgroups

(fluoxetine: 62.5%, paroxetine: 50%, venlafaxine:

75%, v2 = 1.821, p = 0.402). In the subpopulation of

patients classified as markedly to severely ill at

Table 3

Frequency of adverse events after addition of reboxetine

Fluoxetine Paroxetine Venlafaxine Mirtazapine Sertraline Citalopram Fluvoxamine Total

Increased sweating 1 (6.25) 3 (25) 1 (25) 5 (8.19)

Dry mouth 1 (6.25) 1 (6.25) 1 (8.33) 1 (16.66) 4 (6.58)

Tremor 1 (6.25) 1 (8.33) 1 (16.66) 3 (4.92)

Nervousness 2 (12.5) 1 (25) 3 (4.92)

Insomnia 1 (6.25) 1 (16.66) 1 (25) 3 (4.92)

Urinary hesitancy 1 (6.25) 1 (6.25) 2 (3.28)

Those adverse events reported, at least, in two patients are shown.

G. Rubio et al. / Journal of Affective Disorders 81 (2004) 67–7270

admission (CGI-S score z 5), mean decrease in

HDRS total score was � 13.67F 9.49. In this sub-

group, the percentages of improving patients (41.7%),

responders (45.8%) and those in remission (29.2%)

were substantially lower at the end of the treatment.

There were 11 drop-outs: one patient for ineffec-

tiveness (paroxetine group), 6 for adverse effects (3 in

fluoxetine, 2 in paroxetine and 1 in citalopram group)

and 4 for personal reasons. The adverse effects

reported during the 6 weeks of the study, judged as

being of mild or moderate severity, are shown in Table

3. Of six drop-outs for adverse effects, four were

related by the researchers to reboxetine (two cases of

nervousness with insomnia, one case of urine reten-

tion and one of periorbital edema).

4. Discussion

Given the lack of consensus on the conceptualiza-

tion of treatment-resistant depression (Fava and

Davidson, 1996; Berman et al., 1997), we have

considered as ‘‘patients resistant to antidepressant

treatment’’ (Lam et al., 2002) those patients that fail

to respond or do so only partially (Hirschfeld et al.,

2002), to previous treatment in monotherapy with

modern antidepressants, over a period of 6 weeks, a

time considered ‘‘adequate’’ for assessing the antide-

pressant response by the majority of authors (Berman

et al., 1997). Obviously, the results of open studies are

methodologically questionable. Nevertheless, the use

of placebo in this type of patient would also be

questionable from an ethical point of view, given that

the risk of suicide is markedly higher (Stanley, 1988).

The combination strategy should be considered as

the first choice in cases of a partial response to the

drug employed, since gradual suspension of the treat-

ment in course would be avoided, conserving the

partial beneficial effects obtained (Sokolov and Joffe,

1995). The combination strategy provides another

series of advantages: minimizing the demoralizing

psychological effect of failure for the patient, avoiding

the appearance of withdrawal symptoms for the anti-

depressant, permitting the use of lower doses of the

antidepressants employed, reducing the possibility of

adverse effects, and the possibility of obtaining a more

rapid response than that obtained by the switching

strategy (Lam et al., 2002). Nevertheless, we must

also consider the possibility of the appearance of

pharmacological interactions.

The combination strategies that are most well-

documented in the literature are those of SSRIs with

TCAs (Nelson et al., 1991; Fava et al., 1994; Szegesi et

al., 1996; Amsterdam et al., 1997), SSRIs with mirta-

zapine (Carpenter et al., 1999, 2002) and SSRIs with

bupropion (Bodkin et al., 1997; Kennedy et al., 2002).

Recently, several studies have suggested the suitability

of combining SSRIs and reboxetine (Devarajan and

Dursun, 2000; Lucca et al., 2000; Serretti et al., 2001).

In general, combination strategies tend to be

effective in 50–60% of cases, though this varies

according to the drug employed (Joffe, 1999). In

our study, the results confirm these data, with a

proportion of ‘‘improved’’ patients of 62.3%, of

responders to combination treatment of 54.1% and

of patients in remission of 45.9%. Similar results

have been reported in the three open studies pub-

lished to date with reboxetine, even though the

number of patients included is considerably smaller.

Serretti et al. (2001) published their results with the

greatest group of patients (27 subjects with major

depression, without (n = 24) or with (n= 3) psychotic

features). Of the total of the sample, 44.4% of

patients showed complete remission, 29.6% partial

remission and 26% did not improve; markedly neg-

ative was the case of the patients with psychotic

G. Rubio et al. / Journal of Affective Disorders 81 (2004) 67–72 71

features. In our study, it is the dysthymic patients that

show the least favourable evolution, a finding also

made in studies of patients in monotherapy with

reboxetine (Katona et al., 1999). Nevertheless, the

small sample size of this subgroup (n = 7) prevents us

from drawing definitive conclusions.

The results of these preliminary studies, together

with our own, permit us to suggest the appropriateness

of combination therapy in nonresponders to conven-

tional treatment with SSRIs, given that the action

mechanisms of these agents work on different neuro-

transmission routes (Nelson, 1998). In this regard, it

has been postulated that the antagonism of the presyn-

aptic a2-adrenoceptors may complement the action of

the blocking of serotonin and noradrenaline reuptake,

thus increasing the clinical response (Kent, 2000).

In conclusion, we can state that the combination

strategy with reboxetine is a potentially useful tool in

cases of treatment-resistant depression with SSRIs,

venlafaxine and mirtazapine. Nevertheless, further

controlled trials are needed to determine the efficacy

of reboxetine adjunct for partial or nonresponders to

monotherapy with new antidepressant drugs.

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