Defeating Depression When the First SSRI Doesn't Work

Internal Medicine World ReportJuly 2006
Volume 0
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Treatment-resistant depression has become so common that it may now seem the norm. The results of 2 recent studies suggest plausible next steps when the initial choice of a selective serotonin reuptake inhibitor (SSRI) is ineffective, and a third study offers hope for battling recurrence in the elderly.


N Engl J Med

Medication augmentation, which is frequently tried when initial antidepressant therapy does not produce results, has for the first time been subjected to rigorous evaluation (. 2006;354:1243-1252). The study included 565 adult outpatients with nonpsychotic major depressive disorder who had not entered remission (ie, absence of depressive symptoms) despite 3 months of citalopram (Celexa) therapy.

Participants were randomly assigned to 1 of 2 commonly used augmentation agents: sustained-release bupropion (Budeprion SR, Wellbutrin SR; up to 400 mg/d) or buspirone (BuSpar; up to 60 mg/d).

After 6 weeks of therapy, remission rates were similar in both augmentation groups, based on Hamilton Rating Scale for Depression and the clinician-rated Quick Inventory of Depressive Symptomatology (QIDS) scores, as were QIDS response rates (ie, symptom reduction from baseline of ≥50%), but when judged by improvement from baseline QIDS score, bupropion SR outperformed buspirone (Table). In addition, the former was much better tolerated (with a dropout rate of 12.5% vs 20.6% with buspirone).

“Remission rates in our trial should be generalizable to most outpatients with nonpsychotic major depressive disorder who are seen in both primary and psychiatric settings,” the investigators write.


N Engl J Med

In the second study (. 2006;354:1231-1242), switching patients from an ineffective or intolerable SSRI to any 1 of 3 other antidepressants alleviated symptoms in 1 of every 4 patients.

The 727 adult outpatients with nonpsychotic major depressive disorder had either not had remission with the SSRI citalopram or could not tolerate it (56%). They were randomized to monotherapy with bupropion SR (up to 400 mg/d), the SSRI sertraline (Zoloft; up to 200 mg/d), or the SSRI extended-release (ER) venlafaxine (Effexor ER; up to 375 mg/d).

At 14 weeks’ follow-up, remission and response rates were similar in all 3 groups. No significant differences were evident in side effects, although slightly more patients stopped taking bupropion SR because of adverse events (27.2%) compared with sertraline or venlafaxine ER (about 21% for each).

These findings “confirm that intolerance or failure to respond to an SSRI does not predict a lack of efficacy or intolerance of another SSRI,” writes editorialist David R. Rubinow, MD, of the University of North Carolina, Chapel Hill (pages 1305-1307).

He found the results of both studies to be “simultaneously illuminating and disconcerting,” noting that they demonstrated that at least half of all patients never enjoy symptom relief, regardless of the strategy tried.

Preventing Recurrence in the Elderly

N Engl J Med

Older adults have a 50% to 90% chance of their depression recurring within 2 to 3 years of remission. The first study to evaluate SSRI maintenance therapy in this age-group has shown that maintenance can reduce the risk of recurrence by more than 2-fold (. 2006;354: 1130-1138).

All 116 participants (aged ≥70 years) had responded to short-term treatment for major depression and were randomly assigned to 1 of 4 maintenance therapies: paroxetine (Paxil) or placebo plus either monthly psychotherapy or clinical-management sessions to assess their symptoms and side effects.

At up to 2 years of follow-up, depression recurred in 35% of those receiving paroxetine plus psychotherapy, 37% receiving paroxetine plus clinical-management sessions, 68% receiving placebo plus psychotherapy, and 58% receiving placebo plus clinical-management sessions. Compared with the paroxetine groups, the placebo groups had a 2.4 relative risk of recurrence.

A surprising finding was that maintenance psychotherapy was not helpful in preventing recurrence.

In an accompanying editorial (pages 1189-1190), Burton V. Reifler, MD, MPH, of Wake Forest University School of Medicine, Winston-Salem, NC, cautioned that it would be “premature” to recommend lifelong therapy after 1 depressive episode, but added, “In my judgment, it is better to view an older person who has fully recovered from depression as a patient who is in remission, rather than a patient who has been cured.”

Augmentation with a second antidepressant, switching to another agent, and maintenance therapy have all been found successful strategies for battling depression.

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