* 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.
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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.
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.
Augment. Evidence from a meta-analysis with aggregate data from 3 studies representing a total of 110 patients showed that augmentation of various antidepressants with lithium leads to improved outcomes (number needed to treat [NNT]=3.7). (8) A cohort study of augmentation with an atypical antipsychotic agent such as aripiprazole (Abilify) suggest improved outcomes, but similar studies found no benefit. (9) A small (23-patient) randomized trial of lamotrigine (Lamictal) suggests that it may augment the effect of fluoxetine. (10)
Psychotherapy. A systematic review of psychological therapies in treatment-resistant depression found 2 controlled studies (of cognitive therapy and cognitive behavioral therapy) out of 12 total studies meeting their inclusion criteria that demonstrated improved scores on the Hamilton Rating Scale for Depression. Further study of these therapies was recommended. (11)
ECT. The evidence supporting use of ECT for treatment-resistant depression comes from studies following failure of treatment with tricyclic antidepressants and monoamine oxidase (MAO) inhibitors. Methodological problems in these older studies do not permit an estimate of response rate. (12)
Recommendations by others
The American Psychiatric Association treatment guideline recommends changing antidepressant, adding or changing to psychotherapy, or ECT if no response to 4 to 8 weeks of the initial therapy in depression. (13) A guideline from the University of Michigan recommends referral to a psychiatrist if patients have treatment refractory depression (defined in their guideline as failure of 2 successive trials of antidepressants). (14) The Institute for Clinical Systems Improvement guideline recommends considering switch, augmentation, or other therapies (including adding or modifying psychotherapy). (15)
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.