A comparative study of milnacipran and paroxetine in outpatients with major depression

Journal of Affective Disorders 83 (2004) 233 – 236 www.elsevier.com/locate/jad

Brief report

A comparative study of milnacipran and paroxetine in outpatients with major depression Daniel Sechtera,*, Pierre Vandela, Emmanuel Weillerb, Nicole Pezousb, Fabienne Cabanacb, Alain Tournouxb and the study co-coordinators1 a

Service de Psychiatrie de l’Adulte, Centre Hospitalier Universitaire St Jacques, Besanc¸on, Cedex F-25030, France b Institut de Recherche Pierre Fabre, Boulogne, France Received 8 March 2004; received in revised form 12 July 2004; accepted 12 July 2004

Abstract Background: Milnacipran is a dual-action antidepressant which inhibits both serotonin and noradrenaline reuptake with no affinity for any neurotransmitter receptor studied. Methods: A 6-week double-blind multicentre study compared milnacipran (100 mg/day) with paroxetine (20 mg/day) in 300 outpatients with major depression. Efficacy was evaluated using HAMD17, MADRS and CGI for severity of illness and global improvement. Data were analysed on an intention to treat, last observation carried forward, basis. Results: Milnacipran and paroxetine were both effective and well tolerated with no significant difference in their effects. After treatment discontinuation, milnacipran was associated with significantly less emergent symptoms. Responders, at endpoint, to milnacipran had significantly greater levels of psychomotor retardation at baseline than non-responders. Limitations: The study did not include a placebo group so that it is impossible to determine absolute levels of efficacy. Conclusions: Both milnacipran and paroxetine were effective and well tolerated by outpatients with major depression treated for 6 weeks. After treatment discontinuation milnacipran was associated with less emergent symptoms. Psychomotor retardation at baseline may be a predictive factor of a favourable response to milnacipran. D 2004 Elsevier B.V. All rights reserved. Keywords: Milnacipran; Paroxetine; Outpatients; Major depression; Predictors of response to antidepressants; Psychomotor retardation

* Corresponding author. E-mail address: [email protected] (D. Sechter). 1 List of study coordinators: D. Baldwin (UK), G. Cassano (Italy), A. Delini-Stula (Switzerland), H. D’Haenen (Belgium), P. Haffmans (The Netherlands), H.J. Mfller (Germany), A. Otero (Spain), A. Pahla (Portugal), D. Sechter (France). 0165-0327/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2004.07.002

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1. Introduction Milnacipran, inhibits the reuptake of both serotonin and noradrenaline (Moret et al., 1985) but, unlike the TCA, has no affinity for any neurotransmitter receptor studied (Briley et al., 1996). Placebo-controlled and comparative studies have demonstrated the efficacy and tolerance of milnacipran in moderate to severe depression (Puech et al., 1997; Kasper et al., 1996; Lecrubier et al., 1996; Montgomery et al., 1996; Lopez-Ibor et al., 1996). Antidepressants which target selectively the reuptake of serotonin have been suggested to be less efficacious than tricyclic antidepressants (TCA) and other dual action antidepressants such as venlafaxine and milnacipran (DUAG, 1986, 1990; Clerc et al., 1994; Anderson and Tomenson, 1994; Thase 2003; Lopez-Ibor et al., 1996) especially in more severe depressed patients. The present 6-week study compared the efficacy and safety of milnacipran (100 mg/day; 50 mg bid) and paroxetine (20 mg/day; 20 mg od) in outpatients with major depression.

2. Method The double blind, controlled and randomised study was conducted in 42 European centres. Outpatients meeting DSM-IV criteria for unipolar major depression, without psychotic features, with MADRS total score z20, aged 18–70 years, were included in the study. Patients with a significant suicide risk, a lack of response to two adequate antidepressant treatments, a history of psychotic disorder, a major personality disorder, a current primary diagnosis of panic disorder, agoraphobia, social phobia, or obsessive compulsive disorder, current alcohol or drug abuse or dependence, were excluded. Patients were randomised to receive milnacipran 100 mg/day (50 mg bid) or paroxetine 20 mg/day (20 mg od) for 6 weeks. Patients who discontinued therapy were followed for an additional week. Patients were evaluated at inclusion and on Day 7; Day 14; Day 28; Day 42; with a post-treatment assessment 7 days after treatment discontinuation. The HAMD17 total score, the MADRS total score, the clinical global impression scale (CGI) for severity of illness and global improvement from Day 0 were determined at each visit.

Data were analysed on an intention to treat basis with last observation carried forward (ITT-LOCF). Mean changes HAMD17 and MADRS between baseline and end-point were compared using Student’s ttest. The rate of responders, defined as patients with an improvement on the CGI of 1 or 2, a decrease of at least 50% in the HAMD17 total score, or a decrease of at least 50% in the MADRS total score at endpoint were compared between treatment groups by a chi2 test. Logistic regression models (backward and stepwise selection of variables) were performed in order to identify predictive factors of response to each of the study drugs.

3. Results A total of 302 patients were randomised (149 to milnacipran and 153 to paroxetine). Sixty-two patients (29 on milnacipran and 33 on paroxetine) withdrew prematurely. Withdrawals were due to adverse events (12.2%; 17 patients on milnacipran and 20 on paroxetine); withdrawal of consent (34, 11.2%; 16 patients on milnacipran and 18 on paroxetine); lack of efficacy (5%; 9 patients on milnacipran and 6 on paroxetine); lost to follow up (1 patient on paroxetine); and poor compliance (1 patient on paroxetine). Some patients had more than one reason for withdrawing. A third of the withdrawals (21 patients) occurred during the first week. Since 2 patients withdrew before taking active medication only 300 patients (148 milnacipran, 152 paroxetine) were included in the ITT-safety analysis. The efficacy analysis was based on data from 299 patients (148 milnacipran, 151 paroxetine) because one patient failed to return after inclusion. The baseline characteristics of the two groups were well balanced (Table 1) and mean baseline HAMD17 and MADRS scores were not significantly different (Table 1). Mean HAMD17 score decreased by a clinically significant degree in both groups between Day 0 and Day 42 (Table 2, Fig. 1) with no statistically significant difference between the two groups ( p=0.85). Similarly, decreases in the mean MADRS (Table 2) were not significantly different between the two groups ( p=0.66).

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Table 1 Baseline characteristics of patients

Mean age (SD) Sex ratio (M/F) Mean MADRS score (SD) Mean HAMD17 score (SD) Melancholic features Previous treatment with antidepressant

Milnacipran (n=148)

Paroxetine (n=151)

44.8 (11.6) 46/102 29.8 (5.5) 23.7 (4.2) 87 (58.7%) 39 (26.3%)

42.8 (11.2) 41/110 29.6 (5.0) 23.4 (4.3) 84 (55.6%) 42 (27.8%)

There were no statistically significant differences in responder rates at endpoint on either the HAMD17 ( p=0.70), MADRS (0.71) or the CGI (0.72) (Table 2). Remission rates at endpoint were also similar in both groups for both the HAMD17 ( p=0.72) and MADRS ( p=0.68). A similar proportion of patients in each treatment group reported at least one adverse event (77.7% (115) for milnacipran and 70.4% (107) for paroxetine ( p=0.15)). Overall, the tolerance profiles were similar, with a majority of gastro-intestinal adverse events. Increased sweating was more common in milnacipran-treated patients (18.9% versus 7.2%) while dizziness was more frequent during paroxetine treatment (8.6% versus 3.4%). Similar numbers of patients in each group experienced at least one adverse event which led to premature withdrawal from the study (17 (11.5%) of the milnacipran-treated patients and 20 (13.2%) of the paroxetine-treated patients). Most of these adverse Table 2 Comparative efficacy of milnacipran and paroxetine

HDRS17 score Baseline Endpoint MADRS score Baseline Endpoint Responders HAMD17 MADRS CGI Remissions HAMD17 (V 7) MADRS (V10)

Milnacipran (n=148)

Paroxetine (n=151)

23.7 11.9

23.4 11.4

29.8 13.6

29.6 12.8

58.1% 62.8% 66.2%

60.3% 64.9% 64.2%

33.1% 45.3%

35.1% 47.7%

There were no significant differences between the two groups.

Fig. 1. Total mean HAMD17 scores over time (milnacipran (solid line and circles) n=148; paroxetine (dashed line and open circles) n=151).

events, which were mainly gastro-intestinal in both groups but also neurological or psychiatric in the paroxetine arm, occurred at the beginning of the study. After treatment discontinuation, significantly more emergent symptoms were observed in paroxetinetreated patients (31.8%) compared to milnaciprantreated patients (13.0%) ( p=0.032). Most of the discontinuation emergent symptoms affected the central nervous system (Table 3). Table 3 Treatment discontinuation emergent symptoms (ITT-safety) MilnacipranParoxetinetreated patients treated patients (n=46) (n=44) Patients with at least one discontinuation emergent symptom Psychiatric disorders

Anxiety Insomnia Nervousness Aggravated depression Depression Paranoia Central and Parasthesia peripheral Tremor nervous system Dizziness disorders Convulsions Gastro-intestinal Nausea system disorders Oesophagitis Urinary system Haematuria disorders Respiratory Sinusitis system disorders

6 (13.0%)

14 (31.8%)

3 1 1 1

3 2 3 1

(6.8%) (4.5%) (6.8%) (2.3%)

2 2 – – 4 1 1 – –

(4.5%) (4.5%)

– – 1 1 – – 1 1 1 –

(6.5%) (2.2%) (2.2%) (2.2%)

(2.2%) (2.2%)

(2.2%) (2.2%) (2.2%)

(9.1%) (2.3%) (2.3%)

1 (2.3%)

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A descriptive comparison of baseline mean values for each HAMD17 item in responder and nonresponder patients, using the Fisher Exact test showed that the only HAMD17 item score which differed significantly ( p=0.047) between milnacipran responders and non-responders was the mean baseline score for item 8 (Retardation-slowness of thought and speech; impaired ability to concentrate; decreased motor activity). Milnacipran responders had a baseline score of 1.48 compared to 1.15 for non-responders. By contrast, there was no significant difference between paroxetine responders and non-responders in terms of baseline retardation scores or any other HAMD17 item. Logistic regression analyses confirmed these findings of the descriptive analysis with an odds ratio of 1.83 ( p=0.009). No HAMD17 item could be identified as a predictor of a clinical response to paroxetine.

4. Discussion In this population of outpatients with major depression treatment for 6 weeks with milnacipran and paroxetine was equally effective and well tolerated. After treatment discontinuation, however, milnacipran was associated with significantly less emergent symptoms. Responders, at endpoint, to milnacipran had significantly greater levels of psychomotor retardation at baseline than non-responders. A regression analysis also suggested that patients with high levels of psychomotor retardation are more likely to respond to therapy with milnacipran. These findings are consistent with earlier suggestions (Small, 1991) that patients with high levels of retardation should derive more benefit from an antidepressant which acts on the NA systems.

Acknowledgements The present study was sponsored by Pierre Fabre Me´dicament, inventors and manufacturers of milna-

cipran. The authors thank Dr. Mike Briley for his help in the preparation of the manuscript.

References Anderson, I., Tomenson, B., 1994. The efficacy of selective serotonin re-uptake inhibitors in depression: a meta-analysis of studies against tricyclic antidepressants. J. Psychopharmacol. 8, 238 – 249. Briley, M., Prost, J., Moret, C., 1996. Preclinical pharmacology of milnacipran. Int. Clin. Psychopharmacol. 11 (Suppl. 4), 9 – 14. Clerc, G.E., Ruimy, P., Verdeau-Palles, J., 1994. A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. The Venlafaxine French Inpatient Study Group. Int. Clin. Psychopharmacol. 9, 139 – 143. Danish University Antidepressant Group, 1986. Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology 90, 131 – 138. Danish University Antidepressant Group, 1990. Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J. Affect. Disord. 18, 289 – 299. Kasper, S., Pletan, Y., Solles, A., Tournoux, A., 1996. Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results. Int. Clin. Psychopharmacol. 11 (Suppl. 4), 35 – 39. Lecrubier, L., Pletan, Y., Solles, A., Tournoux, A., Magne, V., 1996. Clinical efficacy of milnacipran: placebo controlled trials. Int. Clin. Psychopharmacol. 11 (Suppl. 4), 29 – 33. Lopez-Ibor, J., Guelfi, J., Pletan, Y., Tournoux, A., Prost, J., 1996. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int. Clin. Psychopharmacol. 11 (Suppl. 4), 41 – 46. Montgomery, S., Prost, J., Solles, A., Briley, M., 1996. Efficacy and tolerability of milnacipran: an overview. Int. Clin. Psychopharmacol. 11 (Suppl. 4), 47 – 51. Moret, C., Charveron, M., Finberg, J., Couzinier, J., Briley, M., 1985. Biochemical profile of minalcipran (F 2207), 1-phenyl-1diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Neuropharmacology 24, 1211 – 1219. Puech, A., Montgomery, S., Prost, J., Solles, A., Briley, M., 1997. Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability. Int. Clin. Psychopharmacol. 12, 99 – 108. Small, G.W., 1991. Recognition and treatment of depression in the elderly. J. Clin. Psychiatry (52 Suppl.), 11 – 22. Thase, M.E., 2003. Effectiveness of antidepressants: comparative remission rates. J. Clin. Psychiatry (64 Suppl.), 3 – 7.