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Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis

  • Corrado Barbui (a1), Andrea Cipriani (a1), Vikram Patel (a2), José L. Ayuso-Mateos (a3) and Mark van Ommeren (a4)...

Depression is a common condition that has been frequently treated with psychotropics.


To review systematically the evidence of efficacy and acceptability of antidepressant and benzodiazepine treatments for patients with minor depression.


A systematic review and meta-analysis of double-blind randomised controlled trials comparing antidepressants or benzodiazepines v. placebo in adults with minor depression. Data were obtained from MEDLINE, CINAHL, EMBASE, PsycInfo, Cochrane Controlled Trials Register and pharmaceutical company websites. Risk of bias was assessed for the generation of the allocation sequence, allocation concealment, masking, incomplete outcome data, and sponsorship bias.


Six studies met inclusion criteria. Three studies compared paroxetine with placebo; fluoxetine, amitriptyline and isocarboxazid were studied in one study each. No studies compared benzodiazepines with placebo. In terms of failures to respond to treatment (6 studies, 234 patients treated with antidepressants and 234 with placebo) no significant difference between antidepressants and placebo was found (relative risk (RR) 0.94, 95% CI 0.81–1.08). In terms of acceptability, data extracted from two studies (93 patients treated with antidepressants and 93 with placebo) showed no statistically significant difference between antidepressants and placebo (RR = 1.06, 95% CI 0.65–1.73). There was no statistically significant between-study heterogeneity for any of the reported analyses.


There is evidence showing there is unlikely to be a clinically important advantage for antidepressants over placebo in individuals with minor depression. For benzodiazepines, no evidence is available, and thus it is not possible to determine their potential therapeutic role in this condition.

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This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial licence (, which permits noncommercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.
Corresponding author
Dr Corrado Barbui, Department of Public Health and Community Medicine, Section of Psychiatry and Clinical Psychology, University of Verona, Policlinico GB Rossi, 37134 Verona, Italy. Email:
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This systematic review was financially supported by the Department of Mental Health and Substance Abuse, World Health Organization (WHO), Geneva, Switzerland. The views expressed in this article are those of the authors solely and do not necessarily represent the views, policies and decisions of WHO. C.B. and A.C. are grateful to the Fondazione Cariverona, who provided a three-year grant to the WHO Collaborating Centre for Research and Training in Mental Health and Service Organization at the University of Verona, directed by Professor Michele Tansella. V.P. is supported by a Wellcome Trust Senior Research Fellowship.

Declaration of interest

J.L.A-M. received consultancy fees from Lundbeck and Risk Management Resources LLC and provided expert testimony for Sanofi-aventis.

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1 Anonymous. Mild depression in general practice: time for a rethink? Drug Ther Bull 2003; 41: 60–4.
2 Pincus, HA, Davis, WW, McQueen, LE. ‘Subthreshold’ mental disorders. A review and synthesis of studies on minor depression and other ‘brand names’. Br J Psychiatry 1999; 174: 288–96.
3 Judd, LL, Rapaport, MH, Paulus, MP, Brown, JL. Subsyndromal symptomatic depression: a new mood disorder? J Clin Psychiatry 1994; 55 (suppl): 1828.
4 Ayuso-Mateos, JL, Nuevo, R, Verdes, E, Naidoo, N, Chatterji, S. From depressive symptoms to depressive disorders: the relevance of thresholds. Br J Psychiatry 2010; 196: 365–71.
5 Rucci, P, Gherardi, S, Tansella, M, Piccinelli, M, Berardi, D, Bisoffi, G, et al. Subthreshold psychiatric disorders in primary care: prevalence and associated characteristics. J Affect Disord 2003; 76: 171–81.
6 Veerman, JL, Dowrick, C, Ayuso-Mateos, JL, Dunn, G, Barendregt, JJ. Population prevalence of depression and mean Beck Depression Inventory score. Br J Psychiatry 2009; 195: 516–9.
7 Preisig, M, Merikangas, KR, Angst, J. Clinical significance and comorbidity of subthreshold depression and anxiety in the community. Acta Psychiatr Scand 2001; 104: 96103.
8 Rapaport, MH, Judd, LL. Minor depressive disorder and subsyndromal depressive symptoms: functional impairment and response to treatment. J Affect Disord 1998; 48: 227–32.
9 Blazer, DG, Kessler, RC, Swartz, MS. Epidemiology of recurrent major and minor depression with a seasonal pattern. The National Comorbidity Survey. Br J Psychiatry 1998; 172: 164–7.
10 Kessler, RC, Zhao, S, Blazer, DG, Swartz, M. Prevalence, correlates, and course of minor depression and major depression in the National Comorbidity Survey. J Affect Disord 1997; 45: 1930.
11 Cuijpers, P, Smit, F. Subthreshold depression as a risk indicator for major depressive disorder: a systematic review of prospective studies. Acta Psychiatr Scand 2004; 109: 325–31.
12 Penninx, BW, Geerlings, SW, Deeg, DJ, van Eijk, JT, van, TW, Beekman, AT. Minor and major depression and the risk of death in older persons. Arch Gen Psychiatry 1999; 56: 889–95.
13 Esposito, E, Wang, JL, Adair, CE, Williams, JV, Dobson, K, Schopflocher, D, et al. Frequency and adequacy of depression treatment in a Canadian population sample. Can J Psychiatry 2007; 52: 780–9.
14 Demyttenaere, K, Bonnewyn, A, Bruffaerts, R, De Girolamo, G, Gasquet, I, Kovess, V, Haro, JM, et al. Clinical factors influencing the prescription of antidepressants and benzodiazepines: results from the European study of the epidemiology of mental disorders (ESEMeD). J Affect Disord 2008; 110:8493.
15 Cheng, JS, Huang, WF, Lin, KM, Shih, YT. Characteristics associated with benzodiazepine usage in elderly outpatients in Taiwan. Int J Geriatr Psychiatry 2008; 23: 618–24.
16 Srisurapanont, M, Garner, P, Critchley, J, Wongpakaran, N. Benzodiazepine prescribing behaviour and attitudes: a survey among general practitioners practicing in northern Thailand. BMC Fam Pract 2005; 6: 27.
17 Voyer, P, Landreville, P, Moisan, J, Tousignant, M, Preville, M. Insomnia, depression and anxiety disorders and their association with benzodiazepine drug use among the community-dwelling elderly: implications for mental health nursing. Int J Psychiatr Nurs Res 2005; 10: 1093–116.
18 Valenstein, M, Taylor, KK, Austin, K, Kales, HC, McCarthy, JF, Blow, FC. Benzodiazepine use among depressed patients treated in mental health settings. Am J Psychiatry 2004; 161: 654–61.
19 Ackermann, RT, Williams, JW Jr. Rational treatment choices for non-major depressions in primary care: an evidence-based review. J Gen Intern Med 2002; 17: 293301.
20 Oxman, TE, Sengupta, A. Treatment of minor depression. Am J Geriatr Psychiatry 2002; 10: 256–64.
21 Birkenhager, TK, Moleman, P, Nolen, WA. Benzodiazepines for depression? A review of the literature. Int Clin Psychopharmacol 1995; 10: 181–95.
22 Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 5662.
23 Montgomery, SA, Åsberg, M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–9.
24 Guy, W. ECDEU Assessment Manual for Psychopharmacology. Superintendent of Documents, US Government Printing Office, US Department of Health, Education and Welfare Publication, 1976.
25 Moher, D, Liberati, A, Tetzlaff, J, Altman, DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535.
26 Norman, GR. Issues in the use of change scores in randomized trials. J Clin Epidemiol 1989; 42: 1097–105.
27 Higgins, J, Green, S. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 [updated September 2006]. John Wiley & Sons, 2006.
28 Altman, DG, Bland, JM. Detecting skewness from summary information. BMJ 1996; 313: 1200.
29 Furukawa, TA, Barbui, C, Cipriani, A, Brambilla, P, Watanabe, N. Imputing missing standard deviations in meta-analyses can provide accurate results. J Clin Epidemiol 2006; 59: 710.
30 Furukawa, TA, Cipriani, A, Barbui, C, Brambilla, P, Watanabe, N. Imputing response rates from means and standard deviations in meta-analyses. Int Clin Psychopharmacol 2005; 20: 4952.
31 Cipriani, A, Furukawa, TA, Salanti, G, Geddes, JR, Higgins, JP, Churchill, R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009; 373:746–58.
32 Higgins, JP, Thompson, SG, Deeks, JJ, Altman, DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–60.
33 Guyatt, GH, Oxman, AD, Kunz, R, Vist, GE, Falck-Ytter, Y, Schunemann, HJ. What is ‘quality of evidence’ and why is it important to clinicians? BMJ 2008; 336:995–8.
34 Guyatt, GH, Oxman, AD, Vist, GE, Kunz, R, Falck-Ytter, Y, Alonso-Coello, P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924–6.
35 Barrett, JE, Williams, JW Jr, Oxman, TE, Frank, E, Katon, W, Sullivan, M, et al. Treatment of dysthymia and minor depression in primary care: a randomized trial in patients aged 18 to 59 years. J Fam Pract 2001; 50: 405–12.
36 Burrows, AB, Salzman, C, Satlin, A, Noble, K, Pollock, BG, Gersh, T. A randomized, placebo-controlled trial of paroxetine in nursing home residents with non-major depression. Depress Anxiety 2002; 15: 102–10.
37 Davidson, JR, Giller, EL, Zisook, S, Overall, JE. An efficacy study of isocarboxazid and placebo in depression, and its relationship to depressive nosology. Arch Gen Psychiatry 1988; 45: 120–7.
38 Judd, LL, Rapaport, MH, Yonkers, KA, Rush, AJ, Frank, E, Thase, ME, et al. Randomized, placebo-controlled trial of fluoxetine for acute treatment of minor depressive disorder. Am J Psychiatry 2004; 161: 1864–71.
39 Paykel, ES, Hollyman, JA, Freeling, P, Sedgwick, P. Predictors of therapeutic benefit from amitriptyline in mild depression: a general practice placebo-controlled trial. J Affect Disord 1988; 14: 8395.
40 Hollyman, JA, Freeling, P, Paykel, ES, Bhat, A, Sedgwick, P. Double-blind placebo-controlled trial of amitriptyline among depressed patients in general practice. J R Coll Gen Pract 1988; 38: 393–7.
41 Paykel, ES, Freeling, P, Hollyman, JA. Are tricyclic antidepressants useful for mild depression? A placebo controlled trial. Pharmacopsychiatry 1988; 21: 15–8.
42 Williams, JW Jr, Barrett, J, Oxman, T, Frank, E, Katon, W, Sullivan, M, et al. Treatment of dysthymia and minor depression in primary care: a randomized controlled trial in older adults. JAMA 2000; 284: 1519–26.
43 Frank, E, Rucci, P, Katon, W, Barrett, J, Williams, JW Jr, Oxman, T, et al. Correlates of remission in primary care patients treated for minor depression. Gen Hosp Psychiatry 2002; 24: 12–9.
44 Oxman, TE, Barrett, JE, Sengupta, A, Katon, W, Williams, JW Jr, Frank, E, et al. Status of minor depression or dysthymia in primary care following a randomized controlled treatment. Gen Hosp Psychiatry 2001; 23: 301–10.
45 Sullivan, MD, Katon, WJ, Russo, JE, Frank, E, Barrett, JE, Oxman, TE, et al. Patient beliefs predict response to paroxetine among primary care patients with dysthymia and minor depression. J Am Board Fam Pract 2003; 16: 2231.
46 Moncrieff, J, Kirsch, I. Efficacy of antidepressants in adults. BMJ 2005; 331: 155–7.
47 National Collaborating Centre for Mental Health. Depression: Management of Depression in Primary and Secondary Care (Clinical Guideline 23). National Institute for Clinical Excellence, 2004.
48 Kroenke, K. Minor depression: midway between major depression and euthymia. Ann Intern Med 2006; 144: 528–30.
49 Geiselmann, B, Bauer, M. Subthreshold depression in the elderly: qualitative or quantitative distinction? Compr Psychiatry 2000; 41 (2 suppl 1): 32–8.
50 Kirsch, I, Deacon, BJ, Huedo-Medina, TB, Scoboria, A, Moore, TJ, Johnson, BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008; 5: e45.
51 Fournier, JC, DeRubeis, RJ, Hollon, SD, Dimidjian, S, Amsterdam, JD, Shelton, RC, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010; 303: 4753.
52 Cuijpers, P, Smit, F, van, SA. Psychological treatments of subthreshold depression: a meta-analytic review. Acta Psychiatr Scand 2007; 115: 434–41.
53 World Health Organization. Benzodiazepines and Therapeutic Counselling: Report from WHO Collaborating Study. Springer Verlag, 1988.
54 Johnson, DA. The use of benzodiazepines in depression. Br J Clin Pharmacol 1985; 19 (suppl 1): S315.
55 World Health Organization. Scaling up Care for Mental, Neurological, and Substance Use Disorders. WHO, 2006 (
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Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis

  • Corrado Barbui (a1), Andrea Cipriani (a1), Vikram Patel (a2), José L. Ayuso-Mateos (a3) and Mark van Ommeren (a4)...
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