Combination Antidepressants are not yet Proven Therapy in the Treatment of Depression

Abstract

DEAR SIR,

We were alarmed on reading the results of a recent survey of Australian doctors working in mental health that reported that 79% had used combination antidepressants in the treatment of depression. 1 This figure is in stark contrast to rates published from similar international surveys that suggest the use of combination antidepressants is between 2 and 15%. 2 Even in the home of this practice, combination antidepressants appear to be used by only 3% of psychiatrists in the United States. 3 Have Australian doctors been seduced by the latest fashion in psychopharmacology?

The survey, reported by Horgan et al., 1 defined “combination antidepressant therapy” as the use of two antidepressants “simultaneously”. This would include the common practice of cross tapering during the switching from one antidepressant monotherapy to another and the older practice of co-prescription of small doses of a sedating antidepressant as a hypnotic in order to reduce dependence on benzodiazepine hypnotics. The survey may have reported a considerably reduced rate of combination antidepressant use had the question been: “Have you ever co-prescribed antidepressants in therapeutic doses as a course of therapy with the intention of treating core symptoms of depression?”. An Australian study of co-prescription of SSRIs and TCAs suggested a 6-month prevalence of around 5%, which is in line with international studies. 4 Whatever the real rate, the frequency of combination antidepressant use dose not, on its own, legitimize the practice which needs to be seen in the context of the evidence base.

There is substantial controlled trial evidence for a number of psychopharmacologic approaches when a depressed patient does not respond to usual doses of the first antidepressant trialled. These include increasing the dose, switching to another antidepressant, 5 lithium augmentation, 6 tri-iodothyronine (T3) augmentation 7 and electroconvulsive therapy (ECT). The evidence from controlled trials for combination antidepressants is inconsistent.

A positive review of the controlled trial evidence for the use of combination antidepressants was recently published by the authors of the Australian survey. 8 A critical re-appraisal of these eight studies shows inconsistent results. In two studies, antidepressant combinations were inferior to standard treatment including ECT 9 and increased dose of fluoxetine. 10 Fluoxetine/desipramine combination was no better than an increased dose of fluoxetine in a third study 11 and this combination showed mixed results in a fourth study where there were improvements in remission rates but no differences in depression end-point ratings or response rates. 12 Importantly, this study did not include a fluoxetine (20 mg) dose-increase arm. The comparison of a combination of sertraline/mianserin with ongoing sertraline (100 mg) showed no differences in a group who had not previously responded to 6 weeks of sertraline (50–100 mg) treatment. 13 In the three studies that suggested advantages in the combination antidepressant group over monotherapy, none included a dose-increase comparison arm as is standard clinical practice. 14 ^– 16 In two of these studies, fluoxetine doses remained at 20 mg for the duration of the trial. 14 , 15 The lack of a dose-increase arm in the Ferreri et al. study severely limits the conclusions of this report since patients were already non-responsive to this dose of fluoxetine after at least 6 weeks of treatment. 14 In the third of these studies, mixed results were reported with significantly increased response rates but no differences in remission rates in those treated with combination therapy compared with ongoing treatment of a failed antidepressant monotherapy. 16 Finally, a controlled trial of trimipramine monotherapy, MAOI monotherapy and the combination, not included in the Horgan et al. review, 1 reported superiority of TCA monotherapy in comparison with the dangerous TCA/MAOI combination. 17 In summary, three controlled trials suggest inferiority of combination antidepressants compared with standard approaches, three trials showed no consistent differences, and the three trials reporting usefulness had major methodological problems.

Protagonists of both sides of the combination antidepressant debate are anticipating the results of the Sequenced Treatment Alternatives to Relieve Depression (STAR∗D) study. The STAR∗D study aims to recruit 4000 patients with depression. All will be initially treated with citalopram and non-responders will be sequentially trialled with a number of treatment options including switching to another antidepressant, cognitive therapy, combination antidepressant therapy and augmentation of antidepressant therapy. 18 The methodology of this study may not allow full resolution of the issue since ECT is excluded (having been considered by the authors of STAR∗D to already be a proven therapy) and the currently well-established augmentation strategies of lithium and T3 are consigned to level 3 behind combination antidepressants, which will have them pitched against increasingly treatment-resistant patients. The initial publications from this study are now emerging confirming the value of switching strategies. 19 The first report of combination antidepressants (citalopram/buproprion compared with citalopram/buspirone) showed no difference between the groups on the primary measure (HAMD remission rates). 20 The absence of a placebo control group does not exclude the possibility of spontaneous improvement with time or delayed efficacy of citalopram in patients treated with the augmentation strategies. While the STAR∗D study may yet provide evidence for the contribution of combination antidepressants, it has yet to do so.

We can agree with the 88% of respondents to the survey who felt that patients have the right to be informed of the published literature pertaining to combination antidepressant in the treatment of depression. 1 This information should include details of the robust evidence for increasing dose, switching of antidepressant, augmentation with lithium and T3, and ECT. It should also include a statement that while the practice of combination antidepressants may be less dangerous than it used to be, there is no consistent evidence for its effectiveness. As Horgan et al. point out, it is the patient's “legal and ethical right” to know. 1

References

1. Horgan

Dodd

Berk

. A survey of combination antidepressant use in Australia. Australasian Psychiatry 2007; 15: 26–29.

2. Aguera

Rojo

de la Gandara

ii . Antidepressant combinations: Epidemiological considerations. Acta Psychiatrica Scandinavica 2005; 112(Suppl. 428)7–10.

3. Freedman

Fava

Kienke

. Partial response, nonresponse, and relapse with selective serotonin reuptake inhibitors in major depression: a survey of current “next-step” practices. Journal of Clinical Psychiatry 2000; 61: 403–408.

4. McManus

Mant

Mitchell

. Co-prescription of SSRIs and TCAs in Australia: how often does it occur and who is doing it?. British Journal of Clinical Pharmacology 2001; 51: 93–98.

5. Ruhe

Huyser

Swinkels

. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: A systemic review. Journal of Clinical Psychiatry 2006; 67: 1836–1855.

6. Bauer

Dopfmer

. Lithium augmentation in treatment-resistant depression: Meta-analysis of placebo-controlled studies. Journal of Clinical Psychopharmacology 1999; 19: 427–434.

7. Jackson

. Does thyroid hormone have a role as adjunctive therapy in depression?. Thyroid 1996; 6: 63–67.

8. Dodd

Horgan

Malhi

. To combine or not to combine? A literature review of antidepressant combination therapy. Journal of Affective Disorders 2005; 89: 1–11.

9. Davidson

McLeod

Law-Yone

. A comparison of electrovconvulsive therapy and combined phenelzine-amitriptyline in refractory depression. Archives of General Psychiatry 1978; 35: 639–642.

10.

10. Fava

Rosenbaum

McGrath

. Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression: a double-blind, controlled study. American Journal of Psychiatry 1994; 151: 1372–1374.

11.

11. Fava

Alpert

Nierenberg

. Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and non-responders to fluoxetine. Journal of Clinical Psychopharmacology 2002; 22: 379–387.

12.

12. Nelson

Mazure

Jatlow

. Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: A double-blind, randomised study. Biological Psychiatry 2004; 55: 296–300.

13.

13. Licht

Qvitzau

. Treatment strategies in patients with major depression not responding to first-line sertraline treatment. Psychopharmacology 2002; 161: 143–151.

14.

14. Ferreri

Lavergne

Berlin

. Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone. Acta Psychiatrica Scandinavica 2001; 103: 66–72.

15.

15. Maes

Libbrecht

van Hunsel

. Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalised major depressed patients, including those with treatment resistance. Journal of Clinical Psychopharmacology 1999; 19: 177–182.

16.

16. Carpenter

, Yasmin

, Price

. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biological Psychiatry 2002; 51: 183–188.

17.

17. Young

JPR

Lader

Hughes

. Controlled trial of trimipramine, monoamine oxidase inhibitors, and combined treatment in depressed outpatients. British Medical Journal 1979; 2: 1315–1317.

18.

18. Fava

Rush

Trivedi

. Background and rationale for the Sequenced Treatment Alternatives to Relieve Depression (STAR∗D) study. Psychiatric Clinics of North America 2003; 26: 457–494.

19.

19. Rush

Trivedi

Wisniewski

. Buproprion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. New England Journal of Medicine 2006; 354: 1231–1242.

20.

20. Trivedi

Fava

Wisniewski

. Medication augmentation after the failure of SSRIs for depression. New England Journal of Medicine 2006; 354: 1243–1252.