Efficacy and Safety of Venlafaxine ER vs. Amitriptyline ER in Patients with Major Depression of Moderate Severity

Introduction: A double-blind, randomized phase-III study was conducted with the aim to compare the efficacy and safety of venlafaxine ER (extended release) with that of amitriptyline ER in moderately depressed outpatients.

Methods: Patients with major depression of moderate severity, HAM-D (Hamilton Depression scale, 21 items) score 20 - 26, were given a six-week double-blind treatment with venlafaxine ER and amitriptyline ER in a dosis of 75 mg each, which could be increased to 150 mg, if necessary. Efficacy was assessed using HAM-D and CGI (clinical global impression) scores. Safety analysis was carried out using the HAM-D item 3 to assess suicidality, the d2 test to evaluate attention and drug screening for benzodiazepines. Adverse events were recorded at each visit.

Results: 160 patients were randomized. There were 151 patients available for analysis in the intent-to-treat (ITT) population. The according-to-protocol (ATP) population consisted of 117 patients, with 60 patients in the venlafaxine ER group and 57 in the amitriptyline ER (extended release) group. The non-inferiority of venlafaxine ER compared to amitriptyline ER with reference to the primary efficacy parameter, the change of HAM-D total score, could be proven in both the ITT population and the ATP population. There were no significant differences between groups in the HAM-D response rates and the CGI scores of items 1 (severity) and 2 (improvement). Venlafaxine ER showed a more favorable safety profile than amitriptyline ER: adverse drug reactions were less frequent under venlafaxine ER than under amitriptyline ER. Most of the discontinuations in the amitriptyline ER group were due to dry mouth. The d2 test showed greater improvement of performance under venlafaxine ER.

Discussion: In this study with patients treated for major depression of moderate severity, the non-inferiority of venlafaxine ER compared to amitriptyline ER with respect to the chosen efficacy parameter could be demonstrated. Venlafaxine ER showed a more favorable safety profile than amitriptyline ER.

References

• 1 Anderson I M. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability.  J Affect Disord. 2000;  58 19-36
• 2 Ballus C, Quiros G, De Flores T, de la Torre J, Palao D, Rojo L ,. et al . The efficacy and tolerability of venlafaxine and paroxetine in outpatients with depressive disorder or dysthymia.  Int Clin Psychopharmacol. 2000;  15 43-48
• 3 Benkert O, Gründer G, Wetzel H. A randomized double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia.  J Psychiatr Res. 1996;  30 441-451
• 4 Brickenkamp R. Test d2 - Aufmerksamkeits-Belastungs-Test. Hogrefe Verlag für Psychologie Göttingen; 1994
• 5 Cohn C K, Shrivastava R, Mendels J, Cohn J B, Fabre L F, Claghorn J L. et al . Double-blind comparison of sertraline an amitriptyline in elderly depressed patients.  J Clin Psychiatry. 1990;  52 28-33
• 6 Collegium Internationale Psychiatriae scalarum. BeltzTest Göttingen; 1996
• 7 Cunningham L A. Once-daily venlafaxine extended release (XR) and venlafaxine immediate release (IR) in outpatients with major depression. Venlafaxine XR 208 Study Group.  Ann Clin Psychiatry. 1997;  9 157-64
• 8 Danjou P, Hackett D. Safety and tolerance profile of venlafaxine.  Int Clin Psychopharmacol. 1995;  10 10-20
• 9 Gentil V, Kerr-Correa F, Moreno R, D’Arrigo Busnello E, de Campos J A, Juruena M F. et al . Double-blind comparison of venlafaxine and amitriptyline in outpatients with major depression with and without melancholia.  J Psychopharmacol. 2000;  14 61-66
• 10 Green W L, Concato J, Feinstein A R. Claims of equivalence in medical research: are they supported by the evidence?.  Ann Int Med. 2000;  132 715-722
• 11 Lecrubier Y, Bourin M, Moon C A, Schifano F, Blanchard C, Danjou P, Hackett D. Efficacy of venlafaxine in depressive illness in general practice.  Acta Psychiatr Scand.. 1997;  95 485-93
• 12 Laakmann G, Blascke D, Engel R, Schwarz A. Fluoxetine vs amitriptyline in the treatment of depressed outpatients.  Br J Psychiatry. 1988;  153 (Suppl.) 64-68
• 13 Laux G. Cost-benefit analysis of newer versus older antidepressants.  Pharmacopsychiatry. 2001;  34 1-5
• 14 Mackay F R, Dunn N R, Martin R M, Pearce G L, Freemantle S N, Mann R D. Newer antidepressants: a comparison of tolerability in general practice.  Br J Gen Pract. 1999;  49 892-896
• 15 Mendels J, Johnston R, Mattes J, Riesenberg R. Efficacy and safety of b. i. d. doses of venlafaxine in a dose-response study.  Psychopharmacol Bull. 1993;  29 169-174
• 16 Möller H J, Glaser K, Leverkus F, Göbel C. Double-blind, multicenter comparative study of sertraline vs. amitriptyline in outpatients with major depression.  Pharmacopsychiatry. 2000;  33 206-212
• 17 Moyer J A, Andree T h, Haskins J T. The preclinical pharmacological profile of venlafaxine: a novel antidepressant agent.  J Clin Neuropharmacol. 1992;  15 (Suppl.) 435
• 18 Muth E A, Haskins J T, Moyer J A, Husbands J E, Nielsen S T, Sigg S B. Antidepressant biochemical profile of the novel bicyclic compound Wy-45.030, an ethyl cyclohexanol derivative.  Biochem Pharmacol. 1986;  35 4493-4497
• 19 Reimherr F W, Chouinard G, Cohn C K, Cole J O, Itil T M, LaPierre Y D, Masco H L, Mendels J. Antidepressant efficacy of sertraline: a double-blind, placebo- and amitriptyline-controlled, multicenter comparison study in outpatients with major depression.  J Clin Psychiatry. 1990;  51 18-27
• 20 Remschmidt H, Mewe F, Dauner I, Merschmann W. The influence of thioridazin (Melleril-Sandoz) on psychomotor functions, concentration power and reactivity in children with behaviour disturbances.  Pharmakopsychiatr Neuropsychopharmakol. 1977;  10 1-9
• 21 Rickels K, Derivan A, Entsuah R. et al . Rapid onset of antidepressant activity with venlafaxine treatment.  Depression. 1995;  3 146-153
• 22 Riedel-Heller S G, Matschinger H, Schork A, Angermeyer M C. The utilization of antidepressant in community-dwelling and institutionalized elderly - results form a representative survey in germany.  Pharmacopsychiatry. 2001;  34 6-12
• 23 Rudolph R L, Feiger A D. A double-blind, randomized, placebo-controlled trial of once-daily venlafaxine extended release (XR) and fluoxetine for the treatment of depression.  J Affect Disorders. 1999;  56 171-181
• 24 Salinas E. Once-daily venlafaxine XR versus paroxetine in outpatients with major depression. Presented at the XXIst CINP Glasgow, Scotland; July 1998
• 25 Schweizer E, Feighner J, Mandos L A, Rickels K. Comparison of venlafaxine and imipramine in the acute treatment of major depression in outpatients.  J Clin Psychiatry. 1994;  55 104-108
• 26 Smith W T, Glaudin V, Panagides J, Gilvary E. Mirtazapine vs. amitriptyline vs. placebo in the treatment of major depressive disorder.  Psychopharmacology Bulletin. 1990;  26 191-196
• 27 Smith D, Dempster C, Glanvill J, Freemantle N, Anderson I. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a meta-analysis.  Brit J of Psychiatry. 2002;  180 396-404
• 28 Ulrich S, Northoff G, Wurthmann C, Partscht G, Pester U, Herscu H, Meyer F P. Serum levels of amitriptyline and therapeutic effect in non-delusional moderately to severely depressed in-patients: a therapeutic window relationship.  Pharmacopsychiatry. 2001;  34 33-40