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Effectiveness of antidepressants

Meta-analysis of dose-effect relationships in randomised clinical trials

Published online by Cambridge University Press:  02 January 2018

Paola Bollini ,
Sandro Pampaliona ,
Giuseppe Tibaldi ,
Bruce Kupelnick  and
Carmine Munizza
Paola Bollini*
Affiliation:
for Med, Evolène, Switzerland
Sandro Pampaliona
Affiliation:
for Med, Evolène, Switzerland
Giuseppe Tibaldi
Affiliation:
Centro Studi e Ricerche in Psichiatria, Turin, Italy
Bruce Kupelnick
Affiliation:
for Med, Evolène, Switzerland
Carmine Munizza
Affiliation:
Centro Studi e Richerche in Psichiatria, Turin, Italy
*
Dr Carmine Munizza, Centro Studi e Ricerche in Psichiatria, Piazza del Donatore di Sangue, 3, 10154 Torino, Italy
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Abstract

Background

Antidepressant drugs are usually prescribed at low doses, possibly to avoid adverse reactions. No comprehensive review has addressed the issue of dose, clinical response and tolerability in a quantitative way.

Aims

To determine whether high doses of antidepressants are more effective than lowdoses, and how safety is affected by dose.

Method

Trials comparing two or more doses of the same antidepressant were located, and all antidepressants administered were converted to the equivalent dose of imipramine. Generalised estimating equations were used to analyse percentage improvement and adverse event rate according to dose level.

Results

Thirty-three studies were identified. The dose level 100-200 mg imipramine equivalents showed an average improvement of 53% by ‘intention-to-treat’. Higher doses were not accompanied by increased efficacy, while lower doses showed reduction in efficacy. Adverse events significantly increased with dose.

Conclusions

With a low dose of antidepressants, clinicians trade off a slightly reduced chance of improvement for a higher chance of avoiding adverse reactions.

Type
Review Articles
Information
The British Journal of Psychiatry , Volume 174 , Issue 4 , April 1999 , pp. 297 - 303
Copyright
Copyright © 1999 The Royal College of Psychiatrists 

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Footnotes

Declaration of interest

Supported by the Centro Studi Richerche in Psichiatria (Turin, Italy), and by Angelini, Eli Lilli, Lundbeck, Ravizza. Roerig, Smith Kline Beecham and Solvay Pharma.

References

Altamura, A. C., Montgomery, S. A. & Werniclce, J. F. (1998) The evidence for 20 mg a day of fluoxetine as the optimal dose in the treatment of depression. British Journal of Psychiatry. 153 (suppl. 3), 109–112.CrossRefGoogle Scholar
American Psychiatric Association (1976) Diagnostic and Statistical Manual of Mental Disorders (2nd edn) (DSM–II). Washington, DC: APA.Google Scholar
American Psychiatric Association (1980) Diagnostic and Statistical Manual of Mental Disorders (3rd edn) (DSM–III). Washington. DC: APA.Google Scholar
American Psychiatric Association (1987) Diagnostic and Statistical Manual of Mental Disorders (3rd edn, revised) (DSM–III–R). Washington. DC: APA.Google Scholar
Anderson, I. M. & Tomeson, B. M. (1995) Treatment discontinuation with selective serotonin re-uptake inhibitors compared with tricyclic antidepressants: a meta-analysis. British Medical Journal, 310, 1433–1437.CrossRefGoogle Scholar
Barnes, R. J. & Guarino, R. A. (1980) Single- versus multiple-dose comparative trial of desipramine hydrochloride: a double-placebo method. Journal of Clinical Pharmacology, 20, 681–688.CrossRefGoogle ScholarPubMed
Beasley, C. M. Jr., Sayler, M. E., Weiss, A. M., et al (1992) Fluaxetine: activating and sedating effects at multiple fixed doses. Journal of Clinical Psychophormocology, 12, 328–333.Google Scholar
Benkert, O., Szegedi, A. & Wetzel, H. (1996) Minimum effective dose for antidepressants – an obligatory requirement for antidepressant drug evaluation? International Clinical Psychopharmacology, 11, 177–185.CrossRefGoogle ScholarPubMed
Bjerkenstedt, L., Edman, G., Fiyckt, L., et al (1985) Clinical and biochemical effects of citalopram, a selective 5-HT reuptake inhibitor – a dose–response study in depressed patients. Psychopharmacology, 87, 253–259.CrossRefGoogle ScholarPubMed
Blashki, T. G., Mowbray, R. & Davies, B. (1971) Controlled trial of amitriptyline in general practice. British Medical Journal, i, 133–138.CrossRefGoogle Scholar
Branconnier, R. L., Cole, J. O., Ghazvinian, S., et al (1983) Clinical pharmacology of bupropion and imipramine in elderly depressives. Journal of Clinical Psychiatry, 44, 130–133.Google ScholarPubMed
Brugha, T. S., Bebbington, P. F., Maccarthy, B., et al (1992) Antidepressants may not assist recovery in practice: a naturalistic prospective survey. Acta Psychiatrica Scandinavica, 86, 5–11.CrossRefGoogle Scholar
Craig Nelson, J. (1997) Safety and tolerability of the new antidepressants. Journal of Clinical Psychiatry, 58, 26–31.Google Scholar
D'Amico, M. F., Roberts, D. L., Robinson, D. S., et al (1990) Placebo-controlled dose-ranging trial designs in phase II development of nefazodone. Psychopharmacology Bulletin, 26, 147–150.Google ScholarPubMed
Diggel, P., Liang, K. Y. & Zeger, S. L. (1994) Analysis of Longitudinal Data. New York: Oxford University Press.Google Scholar
Donoghue, J. M. & Tylee, A. (1996) The treatment of depression: prescribing patterns of antidepressants in primary care in the UK. British Journal of Psychiatry, 168, 164–168.CrossRefGoogle ScholarPubMed
Dunlop, S., Dornseif, B., Wernicke, J. F. (1990) Pattern analysis shows beneficial effect of fluoxetine treatment in mild depression. Psychopharmacology Bulletin, 26, 173–180.Google ScholarPubMed
Dunner, D. L. & Dunbar, G. C. (1992) Optimal dose regimen for paroxetine. Journal of Clinical Psychiatry, 53, 21–26.Google ScholarPubMed
Fabre, L. F. & Putman, H. P. (1987) A fixed-dose trial of fluoxetine in outpatients with major depression. Journal of Clinical Psychiatry, 48, 406–408.Google ScholarPubMed
Fawcett, J. & Barkin, R. L. (1997) Efficacy issues with antidepressants. Journal of Clinical Psychiatry, 58 (suppl. 6), 32–39.Google ScholarPubMed
Gram, L. F. (1990) Inadequate dosing and pharmacokinetic variability as confounding factors in assessment of efficacy of antidepressants. Clinical Neuropharmacology, 13 (suppl. I). S35–S44.CrossRefGoogle ScholarPubMed
Greenberg, R. P. & Fisher, S. (1989) Examining antidepressant effectiveness: findings, ambiguities, and some vexing puzzles. In The Limits of Biological Treatments for Psychological Distress. Comparisons with Psychotherapy and Placebo (eds Fisher, S. & Greenberg, R. P.), pp. 1–38. Hillsdale, NJ: Lawrence Erlbaum.Google Scholar
Guy, W. (1976) ECDEU Assessment Manual for Psychopharmacology. Revised DHEW Pub. (ADM). Rockville, MD: National Institute for Mental Health.Google Scholar
Halaris, A. E., Stern, W. C., van Wyck Fleet, J., et al (1983) Evaluation of the safety and efficacy of bupropion in depression. Journal of Clinical Psychiatry, 44, 101–103.Google ScholarPubMed
Hamilton, M. (1960) A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56–62.CrossRefGoogle ScholarPubMed
Hebenstreit, G. F., Felklerer, K., Zochling, R., et al (1989) A pharmacokinetic dose titration study in adult and elderly depressed patients. Acta Psychiatrica Scandinavica, 80 (suppl. 350). 81–84.CrossRefGoogle Scholar
Hotopf, M., Hardy, R. & Lewis, G. (1997a) Discontinuation rates of SSRIs and tricyclic antidepressants: a meta-analysis and investigation of heterogeneity. British Journal of Psychiatry, 170, 120–127.CrossRefGoogle ScholarPubMed
Hotopf, M., Lewis, G. & Normand, C. (1997b) Putting trials on trial – the costs and consequences of small trials in depression: a systematic review of methodology. Journal of Epidemiology and Community Health, 51, 354–358.CrossRefGoogle ScholarPubMed
Jadad, A., Moore, R. A., Carroll, D., et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials, 17, 1–12.CrossRefGoogle ScholarPubMed
Katon, W., von Korff, M., Lin, E., et al (1992) Adequacy and duration of antidepressant treatment in primary care. Medical Care, 30, 67–76.CrossRefGoogle ScholarPubMed
Kendrick, T. (1996) Prescribing antidepressants in general practice (and subsequent letters). British Medical Journal. 313, 829–830; 314, 826–829.CrossRefGoogle Scholar
Khan, A., Fabre, L. F. & Rudolph, R. (1991) Venlafaxine in depressed outpatients. Psychopharmacology Bulletin, 27, 141–144.Google ScholarPubMed
Martin, R. M., Hilton, S. R., Kelly, S. M., et al (1997) General practitioners' perceptions of the tolerability of antidepressant drugs: a comparison of selective serotonin reuptake inhibitors and tricyclic antidepressants. British Medical Journal, 314, 646–651.CrossRefGoogle ScholarPubMed
Moncrieff, J., Wessely, S. & Hardy, R. (1998) Metaanalysis of trials comparing antidepressants with active placebos. British Journal of Psychiatry, 172, 227–231.CrossRefGoogle ScholarPubMed
Montgomery, S. A., Rasmussen, J. G., Lyby, K., et al (1992) Dose response relationship of citalopram 20 mg, citalopram 40 mg and placebo in the treatment of moderate and severe depression. International Clinical Psychopharmacology, 6 (suppl. 5), 65–70.CrossRefGoogle ScholarPubMed
Munizza, C., Tibaldi, F., Bollini, P., et al (1995) Prescription pattern of antidepressants in out-patient psychiatric practice. Psychological Medicine, 25, 771–778.CrossRefGoogle ScholarPubMed
Preskorn, S. H. (1994) Antidepressant drug selection: criteria and options. Journal of Clinical Psychiatry, 55 (suppl. A), 6–24.Google ScholarPubMed
Schiwy, W., Heath, W. R. & Delini-Stuia, A. (1909) Therapeutic and side-effect profile of a selective and reversible MAO-A inhibitor, brofaromine. Results of dose-finding trials in depressed patients. Journal of Neural Transmission. 28, 33–44.Google Scholar
Spitzer, R. L., Endicott, J. & Robins, E. (1978) Research Diagnostic Criteria: rationale and reliability. Archives of General Psychiatry. 35, 773–782.CrossRefGoogle ScholarPubMed
Wernicke, J. F., Bosomworth, J. C. & Ashbrook, E. (1909) Fluoxetine at 20 mg per day: the recommended and therapeutic dose in the treatment of depression. International Clinical Psychopharmacology, 4, 63–67.Google Scholar
Wilcox, C. S., Ferguson, J. M., Dale, J. L., et al (1996) A double-blind trial of low-and high-dose ranges of gepiron-ER compared with placebo in treatment of depressed patients. Psychopharmacology Bulletin, 32, 335–341.Google Scholar
World Health Organization (1978) Mental Disorders: Glossary and Guide to their Classification in Accordance with the Ninth Revision of the International Classification of Diseases (ICD–9). Geneva: WHO.Google Scholar
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