Review
To combine or not to combine? A literature review of antidepressant combination therapy

https://doi.org/10.1016/j.jad.2005.08.012Get rights and content

Abstract

Objective

Treatment resistant depression is a common clinical problem and a major public health concern. The use of antidepressant combinations to overcome treatment resistance, while somewhat controversial, is a popular strategy in practice. This paper reviews published trials on combination antidepressants with a view to inform clinical practice.

Method

A systematic but selective review of the published literature was conducted using EMBASE, PSYCHLIT and MEDLINE with relevant search terms.

Results

A number of trials suggesting efficacy of combination antidepressants were found. These are incorporated into a number of treatment guidelines for the management of treatment refractory depression. Clinicians should be cautious regarding pharmacokinetic and pharmacodynamic interactions, including the serotonin syndrome, however combination strategies are an effective option.

Conclusions

Many antidepressants can be usefully combined especially if they engage separate mechanisms of action. Clinically, antidepressant combinations provide a useful resort in otherwise treatment resistant individuals. However, much further research is needed to determine relative efficacy and determine long term outcome.

Introduction

Depression which has not responded adequately using conventional approaches to treatment is a constant challenge to clinicians, and is a significant source of suffering, death and economic loss (Judd et al., 1997, Nierenberg et al., 1999). It is estimated that depression is not fully eradicated to the point of recovery in 2 out of 3 cases (Fava and Davidson, 1996, Paykel et al., 1995). Vos et al. (2004) using a Monte Carlo simulation model found that in a 5-year period following an episode of depressive illness treated with episodic treatments, treatment administered for each episode rather than maintained over the 5-year study period, the mean number of subsequent episodes was 2.4 and the mean proportion of time spent in major depression was 20.8%. In such circumstances, the burden of ongoing and untreated illness needs to be weighed against potential benefits and risks of treatments. In the face of such pervasive illness it is useful to assess recent reports on combination antidepressant treatment strategies in patients who have not responded to traditional therapies.

When a depressed patient fails to respond or only does so partially to an adequate trial of antidepressant monotherapy, a variety of strategies have been proposed as regards what to do next. Unfortunately, the majority of these recommendations are unsupported by evidence. Reasons for this include that a history of treatment-resistant depression (TRD) is an exclusion criterion for most antidepressant clinical trials. Consequently the reported therapeutic interventions in this group are primarily naturalistic studies, though a small number of studies with other experimental designs have been produced.

In this paper the evidence demonstrating the efficacy and utility of combinations of antidepressants for the treatment of TRD is reviewed.

Section snippets

Method

A systematic literature search of published literature, up to and including January 2005, was conducted using PubMED with the key terms; antidepressant, polypharmacy, combination, depression, resistant, refractory, treatment resistant, trials, randomised, controlled, placebo and the names of individual antidepressants. Terms were combined variously to identify papers that specifically addressed the use of combinations of antidepressants for the treatment of depression. Reference sections of

Results

The use of combination antidepressant therapies has received relatively little attention in the medical literature and only 70 pertinent references were identified. Furthermore the clinical importance of the topic is not reflected by the level of evidence furnished by these studies. In total only eight randomised trials of combination therapies were identified (Carpenter et al., 2002, Davidson et al., 1978, Fava et al., 1994, Ferreri et al., 2001, Licht and Qvitzau, 2002, Maes et al., 1999,

Discussion

When faced with a patient with potential TRD the clinician's first task is to investigate the root causes of their non-response. The diagnosis needs to be confirmed, including checking for the presence of a comorbid medical condition. The possibility of a personality disorder and/or a bipolar spectrum disorder needs to be considered and excluded. Patient compliance needs to be verified and context issues such as an adverse domestic or social situation need to be explored (Grote and Frank, 2003

Conclusion

Despite the urgent need for well-designed, large-scale, placebo-controlled trials investigating the efficacy of antidepressant combination therapies, there is an increasing body of empirical evidence to suggest that these therapies should have an important role in the treatment of TRD. Data suggests that combining antidepressants with different mechanisms of action is a worthwhile strategy with some observed success with combinations of bupropion plus an SSRI, reboxetine plus an SSRI,

References (60)

  • D. Souery et al.

    Treatment resistant depression: methodological overview and operational criteria

    Eur. Neuropsychopharmacol.

    (1999)
  • J.D. Amsterdam et al.

    Clomipramine augmentation in treatment-resistant depression

    Depress. Anxiety

    (1997)
  • D. Bakish et al.

    Moclobemide and specific serotonin re-uptake inhibitor combination treatment of resistant anxiety and depressive disorders

    Hum. Psychopharmacol.

    (1995)
  • G. Bondolfi et al.

    Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation

    Psychopharmacology (Berl.)

    (1996)
  • L.L. Carpenter et al.

    Mirtazapine augmentation in the treatment of refractory depression

    J. Clin. Psychiatry

    (1999)
  • M.L. Crismon et al.

    The Texas medication algorithm project: report of the Texas consensus conference panel on medication treatment of major depressive disorder

    J. Clin. Psychiatry

    (1999)
  • J. Davidson et al.

    A comparison of electroconvulsive therapy and combined phenelzine–amitriptyline in refractory depression

    Arch. Gen. Psychiatry

    (1978)
  • C. DeBattista et al.

    A prospective trial of bupropion SR augmentation of partial and non-responders to serotonergic antidepressants

    J. Clin. Psychopharmacol.

    (2003)
  • S. Devarajan et al.

    Citalopram plus reboxetine in treatment-resistant depression

    Can. J. Psychiatry

    (2000)
  • D. Dimellis

    Serotonin syndrome produced by a combination of venlafaxine and mirtazapine

    World J. Biol. Psychiatry

    (2002)
  • S.M. Dursun et al.

    Reboxetine plus citalopram for refractory depression not responding to venlafaxine: possible mechanisms

    Psychopharmacology (Berl.)

    (2001)
  • M. Fava

    Augmentation and combination strategies in treatment-resistant depression

    J. Clin. Psychiatry

    (2001)
  • M. Fava et al.

    Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression: a double-blind, controlled study

    Am. J. Psychiatry

    (1994)
  • M. Fava et al.

    Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine

    J. Clin. Psychopharmacol.

    (2002)
  • M. Ferreri et al.

    Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone

    Acta Psychiatr. Scand.

    (2001)
  • S.J. Fredman et al.

    Partial response, nonresponse, and relapse with selective serotonin reuptake inhibitors in major depression: a survey of current “next-step” practices

    J. Clin. Psychiatry

    (2000)
  • M.A. Frye et al.

    The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study

    J. Clin. Psychiatry

    (2000)
  • J.W. Goethe et al.

    Polypharmacy with antidepressants

  • J.M. Gomez Gomez et al.

    Combined treatment with venlafaxine and tricyclic antidepressants in depressed patients who had partial response to clomipramine or imipramine: initial findings

    J. Clin. Psychiatry

    (2000)
  • C.J. Hawley et al.

    Safety and tolerability of combined treatment with moclobemide and SSRIs: a systematic study of 50 patients

    Int. Clin. Psychopharmacol.

    (1996)
  • Cited by (95)

    • An acute dose-ranging evaluation of the antidepressant properties of Sceletium tortuosum (Zembrin®) versus escitalopram in the Flinders Sensitive Line rat.

      2022, Journal of Ethnopharmacology
      Citation Excerpt :

      These preliminary findings prompt interest in the therapeutic potential of Zembrin® in the treatment of MDD. However, further studies need to consider chronic treatment paradigms (Carhart-Harris and Nutt, 2017), evaluate concomitant effects on appropriate biomarkers of MDD, e.g. monoamines, neurotrophins, immune-inflammatory components etc (Brand et al., 2015), study additional behavioural parameters akin to MDD, e.g. anxiety, anhedonia, cognition, and investigate its possible synergistic actions when combined with traditional treatments (Dodd et al., 2005; Sarris, 2018). Albeit preliminary, this is the first investigation of Zembrin® versus an SSRI in a genetic rodent model of MDD that provides an evidence-based ethnopharmacological basis for the traditional and modern day use of Sceletium tortuosum in the treatment of mood disorders.

    • Subgenual Cingulate Deep Brain Stimulation for Treatment-Resistant Depression

      2018, Neuromodulation: Comprehensive Textbook of Principles, Technologies, and Therapies, Second Edition: Volume 1-3
    View all citing articles on Scopus
    View full text