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July 2007

New Studies on GAD
Pregabalin and duloxetine (Cymbalta) may be efficacious for adults and venlafaxine (Effexor) for children with generalized anxiety disorder.

Methadone Prolongs QTc Interval
Long-term, high-dose methadone treatment is linked to prolonged QTc intervals.

In Brief
Augmentation for Clozapine Nonresponders; Quetiapine Ineffective for Psychosis/Agitation in Dementia

As Depression Becomes More Treatment-Resistant…
For patients who do not respond to initial antidepressant therapy, augmentation, or switch strategies, further augmentation or switching with different agents can bring about remission—but at a lower rate.

Effects of Antidepressants on 2D6 Enzymes
Duloxetine (Cymbalta) has substantial and escitalopram (Lexapro) and sertraline (Zoloft and others) more modest inhibiting effects on CYP 2D6.

As Depression Becomes More Treatment-Resistant…

July 2007

Abundant evidence suggests that only about 30% of patients with major depressive disorder can expect to achieve remission—a virtual cessation of symptoms—from their first treatment. In an attempt to address "real world" issues in the treatment of treatment-resistant depression, the National Institute of Mental Health spent $35 million on a 6-year study called the Sequenced Treatment Alternatives to Relieve Depression (STAR*D). STAR*D was designed to assess the effectiveness of medications or cognitive therapy for outpatients with nonpsychotic major depressive disorder who had failed to respond to one or more sequential treatments. Patients who did not achieve remission or could not tolerate initial monotherapy with citalopram (Celexa and others) were treated with one of a series of augmentation or switching strategies. We reported previously (BTP 2006;29:33-35) that whether the nonresponsive patient was switched to another selective serotonin reuptake inhibitor (SSRI)—sertraline (Zoloft and others)—extended-release venlafaxine (Effexor XR), or sustained-release bupropion (Wellbutrin SR and others), the remission rates were virtually the same (between 17.6% and 24.8%).1 For patients put on augmentation strategy, remission rates were also similar between the two options: 29.7% with bupropion and 31.1% with buspirone (Buspar and others).2

New data from STAR*D reveal outcomes for patients who failed the first two levels of treatment. Fava and colleagues describe what was considered level 3 in STAR*D—ie, patients who had not achieved response or could not tolerate treatment with citalopram alone or the augmentation or switch options described above.3 Two hundred thirty-five such patients were randomly assigned to 14 weeks of treatment with either mirtazapine (Remeron and others), up to 60 mg/day, or nortriptyline (Pamelor and others), up to 200 mg/day. As in the earlier phases of this collaborative trial, remission was the goal of treatment. For both treatment groups, remission rates were disappointingly low. Using the Hamilton Rating Scale for Depression criterion, remission was achieved by 12.3% of patients treated with mirtazapine and 19.8% in the group taking nortriptyline. Although the rate with nortriptyline was better than that with mirtazapine, the differences did not achieve statistical significance.

The other option for patients at level 3 was one of two augmentation strategies.4 One hundred forty-two adult patients were randomly augmented with either lithium, up to 900 mg/day, or triiodothyronine (T3), up to 50 µg/day, for as long as 14 weeks. Patients remained on therapy for an average of 9.6 weeks. The rate of remission was numerically superior for T3 augmentation (24.7%) versus lithium augmentation (15.9%), but the difference was not statistically significant. Lithium caused significantly more side effects, and more patients discontinued lithium because of adverse effects (23.2% vs. 9.6%, P = .027). Even though lithium is the augmentation strategy with the greatest evidence of efficacy in placebo-controlled trials, Dr Nierenberg's group recommends T3 augmentation ahead of lithium because of its more favorable side-effect profile and lack of need for blood level monitoring.

McGrath and coauthors studied 109 patients who were unfortunate enough to reach the next level of treatment resistance—ie, lack of remission or insufficient tolerance to three previous treatments.5 This group was randomly assigned either to the combination of venlafaxine, up to 300 mg/day, plus mirtazapine, up to 45 mg/day, or the monoamine oxidase inhibitor tranylcypromine (Parnate), up to 60 mg/day. The percentage of patients achieving remission was disappointing: 6.9% with tranylcypromine and 13.7% with the venlafaxine/mirtazapine combination. Tranylcypromine produced less symptom reduction and a higher dropout rate due to side effects. These authors recommend the use of venlafaxine plus mirtazapine ahead of tranylcypromine because of the lower side-effect burden and lack of dietary requirements.

In an accompanying editorial, Dr Marcia Valenstein observes that none of the treatment options used in STAR*D emerged as "a miracle intervention for patients with treatment-resistant depression" and points out the urgent need for better treatments.6 With the interventions studied, the odds of success diminish with each sequential failure. In another editorial, Dr Matthew Menza notes limitations of STAR*D and alternate strategies that were not tested in this large trial.7

The various treatments used in STAR*D are widely applied in clinical practice and, until a "miracle intervention" becomes available, should continue to be employed. The STAR*D results give us some guidance for sequence, as noted above, largely based on tolerability. For the most highly treatment-resistant depressed population, electroconvulsive therapy (ECT) remains a mainstay of treatment. Repeated transcranial magnetic stimulation (rTMS) is still experimental (BTP 2007;30:21), but vagus nerve stimulation (VNS) is now approved by the US Food and Drug Administration for use in depression (although few insurers will pay for it). Deep brain stimulation (DBS) is experimental and may ultimately hold promise for the most refractory patients. Data from STAR*D remind us that when depressed patients fail to achieve timely remission on one treatment, it is time to shift to a different intervention—independent of theories about mechanisms.

1Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores-Wilson K, Niederehe G, Fava M, STAR*D Study Team: Buproprion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006;354:1231-1242.

2Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ, STAR*D Study Team: Medical augmentation after the failure of SSRIs for depression. N Engl J Med 2006;354:1243-1252.

3Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert JE, McGrath PJ, Thase ME, Warden D, Biggs M, Luther JF, Niederehe G, Ritz L, Trivedi MH, STAR*D Study Team: 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.

4Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ, Alpert JE, Warden D, Luther JF, Niederehe G, Lebowitz B, Shores-Wilson K, Rush AJ, STAR*D Study Team: A comparison of lithium and T3 augmentation following two failed medication treatments for depression: A STAR*D report. Am J Psychiatry 2006;163:1519-1530.

5McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, Luther JF, Niederehe G, Warden D, Rush AJ, STAR*D Study Team: Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: A STAR*D report. Am J Psychiatry 2006;163:1531-1541.

6Valenstein M: Keeping our eyes on STAR*D. Am J Psychiatry 2006;163:1484-1486.

7Menza M: STAR*D: The results begin to roll in. Am J Psychiatry 2006;163:1123-1125.