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clinical Combination

David Horgan Seetal Dodd 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 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 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 inhibitor combination antidepressant therapy may be one of a range of effective treatments for (SSRI) or combined with mirtazepine some individuals suffering from depression. or 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 /mianserin, be unremitting in 15% of patients, and or ’, 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 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 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 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 , 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 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 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 , mirtazapine, and venlafaxine such as adding 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 issue with the who failed to respond to two monotherapy trials antidepressants, numerous alternative therapies patient, and ideally with a psychiatrist, if this can were given a third monotherapy of citalopram or can be chosen, including antidepressant dose be arranged. bupropion, while the other half took combined escalation, or switching to another antidepressant Which medications to combine citalopram and bupropion. Remission was monotherapy. It is generally agreed that the four times more common in the combination addition of or of atypical The ideal aim is to supplement the initial antidepressant group than in the switched are effective treatment strategies for depression antidepressant (usually an SSRI) with an

398 Reprinted from Australian Family Physician Vol. 40, No. 6, JUNE 2011 Combination antidepressants – use by GPs and psychiatrists clinical antidepressant utilising a different chemical the antidepressant of choice for addition to Table 2. Australian psychiatrists’ use mechanism of action. A survey of Australian SSRIs. In the USA, the antidepressant bupropion of combination antidepressants7 psychiatrists showed that combinations of various (indicated in Australia only for tobacco cessation) antidepressants with mirtazapine or reboxetine is frequently combined with SSRIs. Combination of any two 76% antidepressants (both involving noradrenergic mechanisms) were Weighing relative risks among the most commonly used (Table 2).7 This SSRI + tricylic 41% survey preceded the recent reservations about Critics often highlight unsafe combinations, Venlafaxine + mirtazepine 40% the effectiveness of reboxetine as monotherapy. which often include MAOIs resulting in severe SSRI + mirtazepine 37% In all combinations, one must be aware of reactions. However, MAOI combinations are now Other antidepressants + 21% the potential extra side effects involving the not recommended for general use by proponents mirtazepine use of two antidepressants, such as weight of combination therapies. The most commonly Reboxetine + other 34% gain from mirtazapine, sexual problems from reported life threatening situations due to the antidepressants SSRIs, and anticholinergic side effects from serotonin syndrome involve the use of MAOIs in reboxetine. The newly released antidepressant combination with serotonin reuptake inhibitors, antidepressants, but monitoring of blood pressure, agomelatine (which is reported not to have these such as SSRIs and the phenylpiperidine series biochemistry, haematology and electrocardiogram side effects) states in its product information .19 An Australian review stated ‘most cases should be considered. The burden that it does not interact with paroxetine.18 of serotonin syndrome are self limiting’.20 Rare of antidepressant combination treatment may Agomelatine has no effect on serotonin, so the severe or life threatening cases were associated approximate the cumulative adverse effect burden serotonin syndrome would not be expected; it mainly with the use of MAOIs as part of combined of the individual antidepressants. However, in acts on , noradrenaline and antidepressants. It is therefore strongly advised two trials of antidepressants combined with pathways. Agomelatine may therefore become that MAOIs not be initiated within 14 days of bupropion or placebo, the sexual side effects stopping any other antidepressant (or within 5 of monotherapy were reduced,23 suggesting Table 1. How to combine weeks of stopping fluoxetine). Similarly, 14 days that in some cases, antidepressant combination antidepressants with an SSRI or SNRI needs to elapse after ceasing an irreversible therapy may have a side effect burden less than • Increase the dose of the initial MAOI, before initiating another antidepressant. the cumulative adverse effect burden of the antidepressant at 1–2 week intervals As the rate of combination antidepressant individual antidepressant. while progressive improvement use is unknown in Australia, the frequency risk occurs, up to the maximum of the serotonin syndrome cannot be measured. Combination antidepressants recommended dose or maximum tolerated dose Serotonin syndrome usually occurs within in general practice • Revert to previous dose when no 24–48 hours of increased serotonin availability, In the survey of Australian psychiatrists improvement has occurred with the manifesting initially with sweating, tachycardia, quoted earlier, 75% of respondents stated they last dose increase. Consider adding tremor and hyper-reflexia. Abdominal cramps, believed GPs should be educated in the use of lithium or an atypical , diarrhoea, tachycardia and blood pressure combination antidepressants.7 Balancing efficacy or second antidepressant changes may also occur. Agitation, confusion and and safety, and considering at what stage to • Add a low dose of a second coma are more serious events, and some fatalities commence combination therapies, as well as antidepressant, eg. add mirtazepine or reboxetine to an SSRI have occurred in the past. 8–16 whether or not such therapy requires a specialist • Avoid combinations with MAOIs or mg reverses the symptoms in less severe cases, setting or can be initiated by a GP, need to be together with withdrawal of the causative agent. decided ideally by considering the evidence. • If benefit appears within 2 weeks, Patients with severe symptoms should be referred However, the evidence is equivocal, and the further increases in this second immediately to an emergency department.6,20 same evidence has been used to justify very antidepressant are indicated Failure to achieve full remission from depression different conclusions. There are no clear results • Titrate doses of antidepressants in is associated with more chronic and recurrent based on solid, evidence based medicine to response to symptom relapse, or illness, increased medical and psychiatric guide doctors in dealing with treatment resistant overmedication symptoms such comorbidities, poorer social and functional depression. General practitioners will have to as yawning and word finding 21 difficulties. If using (not the outcomes, and increased economic costs. consider the evidence for themselves and decide ideal combination), measure trough Depression which has not been effectively treated which, if any, combination therapy to initiate, serum levels is highly correlated with Australia’s weekly rate and when to do so. • Normal concentration and of 40 suicides and an estimated 1300 episodes of Combination antidepressants are one are the endpoint hallmarks of good deliberate self harm.22 of several next-step options after limited biochemical control There is no established evidence of long benefit from an initial antidepressant; other • Expert opinion term complications from the use of combination options (especially dose escalation, switching

Reprinted from Australian Family Physician Vol. 40, No. 6, JUNE 2011 399 clinical Combination antidepressants – use by GPs and psychiatrists antidepressants, lithium and antipsychotics) are Medical Research Foundation, Eli Lilly, Glaxo good idea? Am J Psychiatry 2010;167:241–3. 17. Horgan D. Antidepressant overshoot: the YES syn- 24 summarised elsewhere. This article describes SmithKline, Organon, Mayne Pharma and Servier. drome. Aust N Z J Psychiatry 2007;41:90–1. the rationale and mechanism for adding a second He has received speakers fees from Eli Lilly. 18. Valdoxan® Product Information, 2010. Available at www.medicines.org.au/files/sepvaldx.pdf [Accessed antidepressant to build upon the benefits of the References 15 April 2011]. first antidepressant. Referral may therefore be 1. Eaton WW, Shao H, Nestadt G, Lee HB, Bienvenu 19. Therapeutic Goods Administration. Report of the essential for doctors, especially when faced OJ, Zandi P. Population-based study of first onset psychiatric drug safety expert advisory panel. 2009. Available at www.tga.gov.au/alerts/medicines/ with treatment resistant depression and its and chronicity in major depressive disorder. Arch Gen Psychiatry 2008;65:513–20. pdseap-report2009.pdf [Accessed 15 April 2011]. foreseeable consequences. The ideal scenario 2. National Institute for Health and Clinical Excellence. 20 Hall M, Buckley N. Serotonin syndrome. Australian is to have such therapy from a psychiatrist, or Depression: the treatment and management of Prescriber 2003;26:62–3. 21. McIntyre RS, O’Donovan C. The human cost of to have regular telephone or email access to a depression in adults, National Clinical Practice Guideline 90, London, UK: 2009, p.479. not achieving full remission in depression. Can J psychiatrist (such as psychsupport.com.au or 3. Taylor D, Paton C. The Maudsley Prescribing Psychiatry 2004;49(3 Suppl 1):10-6S. 1800 200 588). However, where such specialist Guidelines, 10th edn. London, UK: Martin Dunitz; 22. Teesson M, Slade T, Mills K. Comorbidity in Australia: findings of the 2007 National Survey of 2009, p.179. advice is not available, or where the advice is Mental Health and Wellbeing. Aust N Z J Psychiatry 4. lam RW, Kennedy SH, Grigoriadis S, et al. Canadian 2009;43:606–14. not acceptable to patients (such as advocating Network for Mood and Anxiety Treatments 23. Rudkin L, Taylor MJ, Hawton K. Strategies for (CANMAT) clinical guidelines for the manage- voluntary psychiatric hospitalisation and managing sexual dysfunction induced by antide- ment of major depressive disorder in adults. III. electroconvulsive therapy), there are potential pressant medication. Cochrane Database Syst Rev Pharmacotherapy. J Affect Disord 2009;117(Suppl 2004:CD003382. benefits from considering the use of combination 1):S26–43. 24. Malhi GS, Adams D, Porter R, et al. Clinical practice 5. Gelenberg AJ, Freeman MP, Markowitz JC, et al. antidepressants. recommendations for depression. Acta Psychiatr Practice guideline for the treatment of patients Scand Suppl 2009;439:8–26. with major depressive disorder. p 54 American Conclusion Psychiatric Association; 2010 doi: 10.1176/appi. There are many steps to potentiate the books.9780890423387.654001. Available at www. psychiatryonline.com/pracGuide/PracticePDFs/ benefits of antidepressants, including lithium, PG_Depression3rdEd.pdf [Accessed 15 April 2011]. antipsychotics and antidepressant combinations. 6. Psychotropic Expert Group. Therapeutic guidelines: Some combinations are associated with greater psychotropic. Version 6. Melbourne, Australia: Therapeutic Guidelines Limited, 2008. efficacy and equivalent safety compared to 7. Horgan D, Dodd S, Berk M. A survey of combination antidepressant monotherapy. As the evidence antidepressant use in Australia. Australas Psychiatry base has grown, and clinical experience has 2007;15:26–9. 8. Keks NA, Burrows GD, Copolov DL, et al. Beyond the increased, combination antidepressants have evidence: is there a place for antidepressant combi- been used more commonly in specialist settings. nations in the pharmacotherapy of depression? Med This article suggests that when adequate J Aust 2007;186:142–4. 9. Trivedi MH, Fava M, Wisniewski SR, et al. trials of monotherapy have not resulted in Medication augmentation after the failure of SSRIs remission, a possible approach is to add a second for depression. N Engl J Med 2006;354:1243–52. 10. Dodd S, Horgan D, Malhi GS, Berk M. To combine or antidepressant with a different mechanism of not to combine? A literature review of antidepressant action, ideally with specialist review or liaison. combination therapy. J Affect Disord 2005;89:1–11. Combination antidepressant treatment is widely 11. lam RW, Wan DD, Cohen NL, Kennedy SH. Combining antidepressants for treatment-resistant accepted in many countries, particularly in large depression: a review. J Clin Psychiatry 2002;63:685– populations such as Canada and the USA. 93. 12. Carpenter LL, Yasmin S, Price LH. A double-blind, Authors placebo-controlled study of antidepressant David Horgan MBBCh, BAO, FRANZCP, MRCPsych, augmentation with mirtazapine. Biol Psychiatry DPM, MPhil, MD, is Clinical Associate Professor, 2002;51:183–8. 13. lam RW, Hossie H, Solomons K, Yatham LN. Department of Psychiatry, University of Citalopram and bupropion-SR: combining versus Melbourne, Victoria. [email protected] switching in patients with treatment-resistant Seetal Dodd BSc, DipEd, MSc, PhD, is Senior depression. J Clin Psychiatry 2004;65:337–40. Fellow, Department of Psychiatry, University of 14. Blier P, Gobbi G, Turcotte JE, et al. Mirtazapine Melbourne, Victoria. and paroxetine in major depression: a comparison of monotherapy versus their combination from Conflict of interest: David Horgan has received treatment initiation. Eur Neuropsychopharmacol 2009;19:457–65. speaker fees, advisory board fees and travel 15. Blier P, Ward HE, Tremblay P, Laberge L, Hebert C, grants from multiple pharmaceutical companies. Bergeron R. Combination of antidepressant medica- Seetal Dodd has received research support or tions from treatment initiation for major depressive disorder: a double-blind randomized study. Am J funding from the Stanley Medical Research Psychiatry 2008;167:281–8. Foundation, NHMRC, beyondblue, Geelong 16. Rush AJ. Combining antidepressant medications: a

400 Reprinted from Australian Family Physician Vol. 40, No. 6, JUNE 2011