Lithium and T3 augmentation both work
A 1999 systematic review of 9 double-blind RCTs (N=234) reported that patients treated with lithium augmentation (250-1200 mg per day, or a serum level of ≥0.5 mmol/L for ≥2 weeks) had a 45% improvement in depressive symptoms (HAM-D), whereas the placebo group showed 18% improvement (NNT=3.7; 95% confidence interval [CI], 2.6-6.6).9 An updated meta-analysis of 10 RCTs confirmed the efficacy of lithium augmentation compared with placebo (41% vs 14.4% improvement; NNT=5).10
Recently, the STAR*D study (N=142) reported that augmentation with either lithium or triiodothyronine (T3) after 2 antidepressant failures was equally effective (lithium response 15.9%; T3 response 24.7%; NNT T3-lithium=11; P=.43). However, lithium was more often associated with side effects (number needed to harm [NNH]=7; P=.045).11
Bupropion and buspirone augmentation are comparable
An unblinded RCT found that patients who failed to respond to citalopram responded when augmented with either bupropion-SR or buspirone.12 After 8 weeks of treatment, the bupropion-SR group (n=565, as much as 400 mg per day) had remission rates of 29.7% (HAM-D) and 39.9% (QIDS); the buspirone group (n=286, as much as 60 mg per day) had remission rates of 30.1% (HAM-D) and 26.9% (QIDS) (NNT buspirone-bupropion-SR=10). However, the bupropion-SR group had a lower dropout rate because of intolerance (12.5% vs 20.6%; NNH=12; P<.009).
Augmentation with atypical antipsychotics works
A recent meta-analysis of 10 RCTs (N=1500 outpatients) assessed the effectiveness of augmenting various antidepressants with atypical antipsychotic agents (olanzapine, risperidone, and quetiapine) for treatment-resistant major depressive disorder.13 The pooled remission and response rates favored augmentation with atypical antipsychotics over adjunctive placebo (47% vs 22.3% and 67.2% vs 35.4%, respectively).
Another randomized study of 362 patients with incomplete response to standard antidepressant treatment found adjunctive aripiprazole was effective and well tolerated (mean change in Montgomery-Åsberg Depression Rating Scale score: –8.8 in the aripiprazole group vs –5.8 in the placebo group; P<.001).14
Agents that aren’t recommended
Expert review doesn’t recommend routine use of other agents that have been studied for augmentation therapy, including dopaminergic drugs, pyschostimulants, modafinil, anticonvulsants, inositol, opiates, estrogen, dehydroepiandrosterone, folate and S-adenosylmethionine, tryptophan, omega-3 fatty acid, pindolol, and monoamine oxidase inhibitors.15
Recommendations
The Institute for Clinical Systems Improvement16 and the American Psychiatric Association17 recommend evaluating the dose and duration of medication, the patient’s adherence to medication, and the accuracy of diagnosis or impact of comorbidities for patients who don’t respond adequately to treatment. Physicians also may consider other strategies, including switch therapy, augmentation therapies, psychotherapy, and electroconvulsive therapy.