CLINICAL Combination David Horgan Seetal Dodd antidepressants Use by GPs and psychiatrists minority of patients who may benefit from this Background approach. Current treatment of depression fails to achieve remission in 50% of patients. Combinations of two antidepressants are used by some Australian psychiatrists. Australian and international Objective views This article investigates the pros and cons of combination antidepressant therapy and A number of guidelines have been published provides suggestions for when to consider their use, which combinations to choose, and since 2008, summarising psychiatric practice how to introduce combination antidepressant therapies. in various countries. In the United Kingdom, Discussion the 2009 National Institute for Health and Combining two antidepressants is a controversial strategy, with supporters and critics Clinical Excellence (NICE) National Clinical arguing its efficacy and safety from opposing perspectives. The use of combination Practice Guideline 90 stated that ‘combining antidepressant therapies may facilitate remission from depression. However, there is antidepressant drugs with different modes of limited evidence supporting these treatments, and safety concerns are often cited. There action is increasingly used in clinical practice’;2 is some support for combination therapies in selected cases from international bodies. and the 2009 Maudsley Prescribing Guidelines After considering risks and benefits on a case-by-case basis, careful use of selected describe a selective serotonin reuptake inhibitor combination antidepressant therapy may be one of a range of effective treatments for (SSRI) or venlafaxine combined with mirtazepine some individuals suffering from depression. or mianserin for refractory depression as Keywords: depression; combination antidepressants options among the ‘commonly used treatments generally well supported by published literature’.3 In Canada, the 2009 Canadian Network for Mood and Anxiety Treatments (CANMAT) For 50% of sufferers, depression is a guidelines state (with respect to combination lifelong illness. A 23 year follow up of first antidepressants) ‘the best available evidence is episode depression showed the illness to for add on treatment with mirtazapine/mianserin, be unremitting in 15% of patients, and or bupropion’, and state there is level 2 evidence recurrent in 35%.1 Analogous to cancer, for these combinations.4 The 2010 depression failure to achieve total eradication of treatment guidelines of the American Psychiatric depressive illness (remission) by vigorous Association state that, for refractory depression, treatment worsens the prognosis ‘the addition of a second non-MAOI [monoamine regarding recovery and relapse. oxidase inhibitors] antidepressant may be helpful, particularly for patients who have had a partial Despite government initiatives in recent years, response to antidepressant monotherapy’.5 many doctors still report to the authors a lack The Australian Therapeutic Guidelines: of easy access to psychiatrists for advanced Psychotropic (2008) take a different position, pharmacological management of depression, stating ‘there is little evidence supporting the increasing the burden on general practitioners. use of combined antidepressants in treatment This article aims to examine the evidence resistant depression, and there are significant regarding combination antidepressants, and concerns regarding the potential for serious drug discusses practical aspects of their use in the interactions’.6 Reprinted from AUSTRALIAN FAMILY PHYSICIAN VOL. 40, NO. 6, JUNE 2011 397 CLINICAL Combination antidepressants – use by GPs and psychiatrists A 2004 survey sent to all Australian antidepressant group, with no significant that has partially responded to an antidepressant. consultants and nonconsultants in psychiatry difference in side effect burden when compared to However, many of these options also have limited (with a 33% response rate) showed that 76% monotherapy.13 evidence bases, limited efficacy or their own of respondents (including 79% of consultant A double blind study of 61 patients showed safety concerns. Where such strategies have psychiatrists) had already used combination significant benefit when paroxetine was combined failed, or are not feasible financially, combination antidepressants.7 Some Australian authors with mirtazapine, compared with monotherapy antidepressants may represent an effective have argued that, due to a paucity of evidence, with either medication alone. Nonresponders to next step. Initiating a nonpharmacological combination antidepressant therapies should only either antidepressant did significantly better when (psychological) therapy may be useful and is be used as a last resort in specialist settings.8 the other antidepressant was added.14 In a recent supported by both sides of this controversy. study, 105 patients were randomly assigned In Australia, combination antidepressants are What is the evidence base? over 6 weeks to fluoxetine alone (25% achieved used more commonly as a later treatment option, The only published, well funded trial of remission), or to three different combinations of especially for partial responders to monotherapy. combination antidepressants has been as a antidepressants, achieving 52% remission for Blier et al15 point out that half of all patients treatment arm involving 565 patients as part of mirtazapine plus fluoxetine, 58% remission for discontinue antidepressant treatment within 6 the STAR*D study.9 In this study, in part funded by mirtazapine plus venlafaxine, and 46% remission weeks from initiating treatment, highlighting the the United States of America National Institute for mirtazapine plus bupropion. Furthermore, importance of initiating treatment with effective of Health, no additional safety precautions were double blind withdrawal of one component medications, or moving rapidly to consolidate considered necessary for the combinations used of the combination over 6 months produced a and hopefully add to initial, but limited, treatment in this trial, being citalopram with the addition relapse in 40% of subjects.15 In the same journal, gains. of sustained release bupropion (not available on examination of the findings raised issues such as How to combine antidepressants the Pharmaceutical Benefits Scheme [PBS] in the low dose of fluoxetine used and the 6 week Australia for the treatment of depression), and duration of the trial. The results were seen as In the absence of robust large trials in this area, at another level in the trial being venlafaxine mainly supporting the addition of mirtazapine to Table 1 represents the experience and specialist combined with mirtazepine. reuptake inhibitors.16 discussions of one author (DH), who has used Small and medium sized trials, and multiple A search of clinical trial registries shows combination antidepressants in selected patients case reports, suggest there are benefits from that many further trials are underway or recently over a 20 year period. The second antidepressant combination antidepressants.10 In a meta-analysis completed, including a National Institute of should ideally have a complementary biochemical of 27 trials involving 667 patients failing to Health funded trial of combinations of bupropion, mechanism of action and acceptable side effects, respond adequately to monotherapy, Lam et al11 escitalopram, mirtazapine, and venlafaxine such as adding reboxetine or mirtazapine to an reported a 62% response rate from combination (ClinicalTrials.gov Identifier: NCT00590863). SSRI. antidepressants. This result must be tempered by Ongoing titration of antidepressants to the the very small number of randomised controlled When to combine patient’s symptoms is very useful in achieving trials and the large number of small case series antidepressants compliance and remission. Patients can be included in this meta-analysis. Before considering treatment for depression it is advised to contact their doctor if there is symptom Carpenter et al12 reported a double necessary to first consider and exclude any factors recurrence, such as when faced with extra stress, blind placebo controlled trial of adjunctive which may prevent remission, including accurate after a virus, or premenstrually, or if symptoms mirtazapine or placebo after failure to respond diagnosis, comorbitities, psychosocial factors and of overmedication appear, such as the ‘YES’ to antidepressant monotherapy in depressed treatment adherence.10 Psychological therapies syndrome (Yawning, Expression/word finding patients (N=26), showing that 64% of combination should also be considered as a first line treatment difficulty, Silly mistakes).17 The effects of dose antidepressant treated patients responded, or as an add-on to pharmacotherapy. change are usually evident within 2–3 days (based including 45.4% achieving remission, whereas While the evidence base for antidepressant on the author’s clinical experience with many only 20% of monotherapy treated patients monotherapy as a first line treatment for patients). As the use of combined antidepressants responded and 13.3% achieved remission. depression is strong, the evidence base for second remains controversial in Australia, and is outside Comparing combining antidepressants with line treatments when remission is not achieved manufacturers’ guidelines, it is appropriate to switching antidepressants, half of the 61 patients is not as strong. Before considering combination notate that you have discussed this