How should you manage a depressed patient unresponsive to an SSRI?

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Clinical Inquiries

How should you manage a depressed patient unresponsive to an SSRI?

J Fam Pract. 2006 December;55(12):1081-1087

By

Daniel Triezenberg, MD

Dominic Vachon, PhD

Jennifer Helmen, BA

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References

1. Rush AJ, Trivedi MH, Wisniewski SR, et al. STAR*D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006;354:1231-1242.

2. Crismon ML, Trivedi M, Pigott TA, 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;60:142-156.

3. Nelson JC. Managing treatment-resistant major depression. J Clin Psychiatry 2003;64(suppl 1):5-12.

4. Quitkin FM, Petkova E, McGrath PJ, et al. When should a trial of fluoxetine for major depression be declared failed? Am J Psychiatry 2003;160:734-740.

5. Fava M, Rush AJ, Wisneiwski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: A STAR*D report. Am J Psychiatry 2006;163:1161-1172.

6. Lam RW, Hossie H, Solons K, Yatham LN. Citalopram and bupropion-SR: combining versus switching in patients with treatment-resistant depression. J Clin Psychiatry 2004;65:337-340.

7. Trivedi MH and others for the STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006;354:1243-1252.

8. Bauer M, Döpfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol 1999;19:427-434.

9. Worthington JJ, 3rd, Kinrys G, Wygant LE, Pollack MH. Aripriprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients. Int Clin Psychopharm 2005;20:9-11.

10. Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry 2003;64:403-407.

11. McPherson S, Cairns P, Carlyle J, et al. The effectiveness of psychological treatments for treatment-resistant depression: a systematic review. Acta Psychiatr Scand 2005;111:331-340.

12. Devanand DP, Sackheim HA, Prudic J. Electroconvulsive therapy in the treatment-resistant patient. Psychiatr Clin North Am 1991;14:905-923.

13. American Psychiatric Association Work Group on Major Depressive Disorder. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry 2000;157(supplement):1-45.

14. Schwenk TL, et al. UMHS Depression Guideline. Updated: May 2004. Available at: www.med.umich.edu/depression/depressguidelines04.pdf. Accessed on November 13, 2006.

15. Institute for Clinical Systems Improvement (ICSI). Major depression in adults in primary care. Bloomington, Minn: Institute for Clinical Systems Improvement (ICSI); updated May 2006. 81 p. Available at: www.icsi.org/knowledge/detail.asp?catID=29&itemID=180. Accessed on November 13, 2006.

EVIDENCE-BASED ANSWER

The best approach among studied alternatives to manage a patient with treatment-resistant depression is not clear from the evidence. All of the options reviewed seem to have about a 25% to 30% success rate.

Switching to other antidepressants or augmenting with non-antidepressant drugs has the best supporting evidence (strength of recommendation [SOR]: B).¹ Adding additional antidepressants (SOR: B), using psychotherapy (SOR: B), and initiating electroconvulsive therapy (ECT) (SOR: C) are options. Various antidepressants are used as add-on therapy. Psychotherapy is often recommended, though the evidence of benefit after a failed course of initial therapy is sparse. The evidence supporting use of ECT in treatment-resistant depression is weak.

Comparison among the options is based on expert opinion (SOR: C). Additional reports from the STAR*D trial may improve the quality of the evidence in the near future.

CLINICAL COMMENTARY

Optimize initial drug dose and duration, then change to a different medication if needed
David Schneider, MD
Sutter Health Center, Santa Rosa, Calif

Although “epidemics” of obesity and avian influenza steal headlines, depression remains an American scourge, with a lifetime prevalence of 13% and rising. Major depressive disorder is often a chronic or relapsing illness, with recurrence rates of more than 40% at 2 years. Treatment resistance may be associated with pain (which is a presenting symptom in two thirds of depressed patients), psychosocial factors, psychiatric comorbidities, or the presence of bipolar disorder rather than unipolar depression.

Various forms of counseling and psychotherapy, alone or in combination with medications, are effective in treating depression, and I recommend them liberally when resources permit. Like the authors of this review, I first optimize initial drug dose and duration, then change to a different medication if needed. Some evidence suggests benefit from a combined serotonin and norepinephrine agent, such as venlafaxine (Effexor) or imipramine (Tofranil), which may also alleviate pain. I often add a noradrenergic tricyclic antidepressant, such as nortriptyline or desipramine, or the newer agent mirtazapine (Remeron), to a selective serotonin reuptake inhibitor (SSRI) for augmentation. I encourage physicians not to fear tricyclics, although I am hesitant to use lithium, thyroxine, or atypical antipsychotics in depression because of their hazards.

Evidence summary

In general, strategies for addressing treatment-resistant depression have not been compared in head-to-head studies. Guidelines at this time are based mainly on expert opinion^2,3 and gradually accumulating data from a few randomized controlled studies or low-quality cohort studies.

While it makes sense, as the question implies, to first optimize the dose and duration of SSRI treatment in treatment-resistant depression, it is not clear which strategy to employ next. Switch, augmentation, and combination strategies may each improve clinical outcomes, but which strategy is best is based on expert opinion at this time.

Optimize. The first step in treatment-resistant depression should be optimizing dose and duration of therapy.⁴ For fluoxetine (Prozac), based on a nonrandomized open trial, patients should receive 8 weeks of treatment before the SSRI course is deemed adequate. Only 23% of patients who have not responded to 8 weeks of fluoxetine respond to a still longer course of fluoxetine.

FAST TRACK

First optimize the initial drug dose and duration; then change to a different medication if needed

Switch. The strongest evidence is from the recent STAR*D trial, a randomized study that assigned patients in one arm of the study who had no relief from (or did not tolerate) therapy with citalopram (Celexa) to 1 of 3 drugs—sustained-release bupropion (Wellbutrin SR), sertraline (Zoloft), or extended-release venlafaxine (Effexor XR). The study concluded that approximately 1 in 4 patients have remission after switching to an antidepressant from another drug class.¹ Further switches in antidepressant monotherapy have a low success rate (10%–20%).⁵

Add/combine. Mixed evidence supports combining different antidepressants. There is cohort study evidence that combining citalopram and bupropion is more effective than switching to the alternate antidepressant,⁶ but other cohort studies did not find a significant difference between switching and augmenting. An arm of the STAR*D trial added either sustained-release bupropion or buspirone (Buspar) to the failed citalopram therapy. Thirty percent of patients with depression unresponsive to citalopram had remission when bupropion-SR or buspirone was added.⁷ The STAR*D reports do not compare the 2 strategies of switching or combining drugs directly.

Evidence-based answers from the Family Physicians Inquiries Network