Skip to main content Accessibility help

Is trazodone more effective than clomipramine in major depressed outpatients? A single-blind study with intravenous and oral administration

  • Massimiliano Buoli (a1), Chiara Rovera (a1), Sara Maria Pozzoli (a1), Alessio Fiorentini (a1), Laura Cremaschi (a1), Alice Caldiroli (a1) and A. Carlo Altamura (a1)...



Some antidepressants, such as trazodone or clomipramine, can be administered intravenously in patients with major depressive disorder (MDD), with potential benefits compared to the standard oral treatment, but available data about their efficacy are limited. The present study was aimed to compare the effectiveness of trazodone and clomipramine (intravenous [i.v.] followed by oral administration).


Some 42 patients with a diagnosis of MDD according to the DSM–5 were selected and treated with i.v. trazodone or clomipramine according to clinical judgment. The Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Montgomery-Åsberg Depression Rating Scale were administered at baseline, after 2 weeks, and after 6 weeks, as well as after 1 week of intravenous antidepressant administration. Raters were blinded to type of treatment.


No significant differences were found between treatment groups in terms of effectiveness at endpoint. Borderline statistical significance was found in terms of number of responders in favor of trazodone. In addition, patients treated with trazodone reported fewer total side effects than those treated with clomipramine.


Both i.v. trazodone and clomipramine are rapid and effective options for improving depressive symptoms, although trazodone appears to be tolerated better. Further studies with larger samples and double-blind conditions are warranted to confirm our results.


Corresponding author

*Address for correspondence: Alice Caldiroli, Department of Psychiatry, University of Milan, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy. (Email:


Hide All
1.Wittchen, HU, Jacobi, F. Size and burden of mental disorders in Europe: a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol. 2005; 15(4): 357376.
2.Kirino, E, Gitoh, M. Rapid improvement of depressive symptoms in suicide attempters following treatment with milnacipran and tricyclic antidepressants: a case series. Neuropsychiatr Dis Treat. 2011; 7: 723728.
3.Bauer, M, Pfennig, A, Severus, E, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013; 14(5): 334385.
4.Altamura, AC, Buoli, M, Serati, M. Duration of illness and duration of untreated illness in relation to drug response in psychiatric disorders. Neuropsychiatry. 2011; 1: 8190.
5.Buoli, M, Cumerlato Melter, C, Caldiroli, A, Altamura, AC. Are antidepressants equally effective in the long-term treatment of major depressive disorder? Hum Psychopharmacol. 2015; 30(1): 2127.
6.Chang, T, Fava, M. The future of psychopharmacology of depression. J Clin Psychiatry. 2010; 71(8): 971975.
7.Machado, M, Iskedjian, M, Ruiz, I, Einarson, TR. Remissions, dropouts, and adverse drugs reactions rates in major depressive disorder: a meta-analysis of head-to-head trials. Curr Med Res Opin. 2006; 22(9): 18251837.
8.Buoli, M, Dell’Osso, B, Bosi, MF, Altamura, AC. Slow vs. standard up-titration of paroxetine in the treatment of panic disorder: a prospective randomized trial. Psychiatry Clin Neurosci. 2010; 64(6): 612619.
9.Dell’Osso, B, Buoli, M, Baldwin, DS, Altamura, AC. Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders: a comprehensive review of their clinical efficacy. Hum Psychopharmacol. 2010; 25(1): 1729.
10.Fava, M. Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry. 2004; 65(Suppl 16): 2732.
11.Fava, M, Hoog, SL, Judge, RA, Kopp, JB, Nilsson, ME, Gonzales, JS. Acute efficacy of fluoxetine versus sertraline and paroxetine in major depressive disorder including effects of baseline insomnia. J Clin Psychopharmacol. 2002; 22(2): 137147.
12.Altamura, AC, Dell’Osso, B, Buoli, M, Zanoni, S, Mundo, E. Intravenous augmentative citalopram versus clomipramine in partial/nonresponder depressed patients: a short-term, low dose, randomized, placebo-controlled study. J Clin Psychopharmacol. 2008; 28(4): 406410.
13.Altamura, AC, Dell’Osso, B, Buoli, M, Bosi, M, Mundo, E. Short-term intravenous citalopram augmentation in partial/nonresponders with major depression: a randomized placebo-controlled study. Int Clin Psychopharmacol. 2008; 23(4): 198202.
14.Gastpar, M, Ngo Khac, T, Gilsdorf, U, Baumann, P. Comparison of oral and intravenous treatment of depressive states: preliminary results of a WHO collaborative study. Clin Neuropharmacol. 1986; 9(Suppl 4): 434436.
15.Bareggi, SR, Cavallaro, R, Pirola, R, Altamura, AC. Pharmacokinetics and adverse effects of single doses of dothiepin in young and elderly subjects. Prog Neuropsychopharmacol Biol Psychiatry. 1990; 14(2): 163170.
16.Guelfi, JD, Strub, N, Loft, H. Efficacy of intravenous citalopram compared with oral citalopram for severe depression. Safety and efficacy data from a double-blind, double-dummy trial. J Affect Disord. 2000; 58(3): 201209.
17.Moukaddam, NJ, Hirschfeld, RM. Intravenous antidepressants: a review. Depress Anxiety. 2004; 19(1): 19.
18.Kelly, MW, Myers, CW. Clomipramine: a tricyclic antidepressant effective in obsessive compulsive disorder. DICP. 1990; 24(7–8): 739744.
19.Luscombe, DK, Wright, J, Jain, VK. Plasma level studies of clomipramine and desmethylclomipramine following intravenous infusions of clomipramine in depressive patients. Postgrad Med J. 1977; 53(Suppl 4): 8896.
20.Dudley, DL, Volberding, N, Loebel, P. Intravenous chlorimipramine and refractory depression. Gen Hosp Psychiatry. 1980; 2(1): 6164.
21.Pollock, BG, Perel, JM, Nathan, RS, Kupfer, DJ. Acute antidepressant effect following pulse loading with intravenous and oral clomipramine. Arch Gen Psychiatry. 1989; 46(1): 2935.
22.Sallee, FR, Pollock, BG, Perel, JM, Ryan, ND, Stiller, RL. Intravenous pulse loading of clomipramine in adolescents with depression. Psychopharmacol Bull. 1989; 25(1): 114118.
23.Sallee, FR, Vrindavanam, NS, Deas-Nesmith, D, Carson, SW, Sethuraman, G. Pulse intravenous clomipramine for depressed adolescents: double-blind, controlled trial. Am J Psychiatry. 1997; 154(5): 668673.
24.Stahl, SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr. 2009; 14(10): 536546.
25.Khouzam, HR. A review of trazodone use in psychiatric and medical conditions. Postgrad Med. 2017; 129(1): 140148.
26.Fagiolini, A, Comandini, A, Catena Dell’Osso, M, Kasper, S. Rediscovering trazodone for the treatment of major depressive disorder. CNS Drugs. 2012; 26(12): 10331049.
27.Savarese, M, Carnicelli, M, Cardinali, V, Mogavero, MP, Federico, F. Subjective hypnotic efficacy of trazodone and mirtazapine in patients with chronic insomnia: a retrospective, comparative study. Arch Ital Biol. 2015; 153(2–3): 231238.
28.Goracci, A, Forgione, RN, De Giorgi, R, Coluccia, A, Cuomo, A, Fagiolini, A. Practical guidance for prescribing trazodone extended-release in major depression. Expert Opin Pharmacother. 2016; 17(3): 433441.
29.Gerner, R, Estabrook, W, Steuer, J, Jarvik, L. Treatment of geriatric depression with trazodone, imipramine, and placebo: a double-blind study. J Clin Psychiatry. 1980; 41(6): 216220.
30.Altamura, AC, Mauri, MC, Colacurcio, F, et al. Trazodone in late life depressive states: a double-blind multicenter study versus amitriptyline and mianserin. Psychopharmacology (Berl). 1988; 95(Suppl): 3436.
31.Altamura, AC, Mauri, MC, Rudas, N, et al. Clinical activity and tolerability of trazodone, mianserin, and amitriptyline in elderly subjects with major depression: a controlled multicenter trial. Clin Neuropharmacol. 1989; 12(Suppl 1): 2533.
32.Monteleone, P, Gnocchi, G. Evidence for a linear relationship between plasma trazodone levels and clinical response in depression in the elderly. Clin Neuropharmacol. 1990; 13(Suppl 1): 84989.
33.Altamura, AC, Mauri, MC, Moro, AR. Fluvoxamine: a novel 5-hydroxytryptamine uptake inhibitor: present and future clinical application. In. Headache and Depression: Serotonin Pathways as a Common Clue. New York: Raven Press; 1991.
34.Schroeck, JL, Ford, J, Conway, EL, et al. Review of safety and efficacy of sleep medicines in older adults. Clin Ther. 2016; 38(11): 23402372.
35.Roccatagliata, G, Abbruzzese, G, Albano, C, Cocito, L, Gandolfo, C. Trazodone by intravenous infusion in depressions secondary to organic disease. Int Pharmacopsychiatry. 1977; 12(2): 7279.
36.Berzewski, H. Clinical experience with antidepressive infusion therapy: trazodone. Psychopharmacology (Berl). 1988; 95(Suppl): 3133.
37.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. [DSM–5]. Arlington, VA: American Psychiatric Press; 2013.
38.Wijeratne, C, Sachdev, P. Treatment-resistant depression: critique of current approaches. Aust N Z J Psychiatry. 2008; 42(9): 751762.
39.Fagiolini, A, Amodeo, G, Goracci, A, Blardi, P. Trazodone Contramid® in clinical practice: personalizing antidepressant intervention [in Italian]. Riv Psichiatr. 2016; 51(4): 123128.
40.Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23: 56.
41.Montgomery, SA, Åsberg, M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979; 134: 382389.
42.Hamilton, M. The assessment of anxiety states by rating. Br J Med Psychol. 1959; 32(1): 50.
43.Amsterdam, JD, Horning, M, Nierenberg, AA. Treatment-Resistant Mood Disorders. Cambridge: Cambridge University Press; 2001.
44.Flight, L, Julious, SA. Practical guide to sample size calculations: an introduction. Pharm Stat. 2016; 15(1): 6874.
45.Nil, R, Lütolf, S, Seifritz, E. Residual symptoms and functionality in depressed outpatients: a one-year observational study in Switzerland with escitalopram. J Affect Disord. 2016; 197: 245250.
46.Greenspan, D. Xerostomia: diagnosis and management. Oncology (Williston Park). 1996; 10(3 Suppl): 711.
47.Núñez, R, Perel, JM. Comparative neurotransmitter reuptake and anticholinergic potencies of the 8-hydroxy metabolites of clomipramine. Psychopharmacol Bull. 1995; 31(2): 217221.
48.Kasper, S, Müller-Spahn, F. Intravenous antidepressant treatment: focus on citalopram. Eur Arch Psychiatry Clin Neurosci. 2002; 252(3): 105109.
49.Bouchard, JM, Strub, N, Nil, R. Citalopram and viloxazine in the treatment of depression by means of slow drop infusion: a double-blind comparative trial. J Affect Disord. 1997; 46(1): 51958.
50.Hosaka, T, Aoki, T, Watanabe, T, Okuyama, T, Kurosawa, H. General hospital psychiatry from the perspective of medical economics. Psychiatry Clin Neurosci. 1999; 53(4): 449453.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
  • URL: /core/journals/cns-spectrums
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed