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Combining antidepressants: a review of evidence

  • Lena Palaniyappan, Lisa Insole and Nicol Ferrier


Sequenced (stepped) treatment approaches are widely endorsed in the management of depression. Combining antidepressants is a recognised step for those failing to respond to monotherapy. Despite the limited evidence base, this strategy is widely used by clinicians in practice. Not every combination used clinically has a sound neuropharmacological rationale and the use of such combinations may increase the side-effect burden without any additional advantage to the patient. Efficacy of various antidepressant combinations along with the data on side-effect profile and toxicity of such combined treatments are reviewed here. The different combinations are considered by each class of antidepressant available in the UK.

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Corresponding author

Professor Nicol Ferrier, Institute of Neuroscience, Newcastle University, Leazes Wing, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK. Email:


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Declaration of Interest

N.F. has received speaker fees and educational grants from most major pharmaceutical companies. He has been on advisory boards for Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly and Servier in the past 2 years but has no consultancies with or pecuniary interests in any pharmaceutical company.



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Combining antidepressants: a review of evidence

  • Lena Palaniyappan, Lisa Insole and Nicol Ferrier


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Combining antidepressants: a review of evidence

  • Lena Palaniyappan, Lisa Insole and Nicol Ferrier
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Antidepressants and bleeding.

Andrew Al-Adwani, Consultant psychiatrist
06 March 2009

In this useful article the side-effects of combination treatments neatly follow the description of each combination but none has included bleeding. Abnormal bleeding with serotonin reuptake inhibitors (SRIs) has been studied and reviewed. One of the authors, has written on the subject (Paton and Ferrier,2006) and recommended caution when prescribing SRIs to patients at risk of gastrointestinal (GI) bleeds in particular. The authors note that the best evidenced combination antidepressant treatment is an SRI plus either a noradrenergic specific serotonergic antidepressant or trazodone. Meijer, et al (2004) have demonstrated that degree of inhibition of serotonin reuptake is associated with risk of abnormal bleeding. Abajo, et al (1999) though found the highest association between antidepressant use and GI bleeds occurred with trazodone despite it being a weak SRI. It may be reasonable, therefore, to expect the combination of an SRI and trazodone, through differing mechanisms, to be associated with significant abnormal bleeding.


Paton C and Ferrier IN. (2005) SSRIs and gastrointestinal bleeding. BMJ 331, 529-30.

Palaniyappan L., Insole L. and Ferrier N. (2009)Combining antidepressants: a review of evidence. Advances in Psychiatric Treatment, 15, 90-99.

Meijer W.E.E., Heerdink E.R., Nolen W.A., Herings R.M.C., Leufkens H.G.M., Egberts A.C.G. (2004)Association of risk of abnormal bleeding with degree of serotonin reuptakeinhibition by antidepressants.Arch Intern Med, 164, 2367 - 2370.

de Abajo F.J., Rodríguez L.A.G., and Montero D. (1999)Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case control study. BMJ, 319,1106-1109.
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