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SGAs for resistant depression

Vol. 5, No. 12 / December 2006

Thanks to readers who commented on the October Instant Poll concerning my article on use of second-generation antipsychotics (SGAs) in treatment-resistant unipolar depression (Current Psychiatry, October 2006). Let me respond to several comments:

“Using SGAs in resistant depression is an unusual strategy, though they can be used as mood stabilizers.”

This reader raises an important point I would like to clarify on using SGAs for mood disorders. SGAs have acute antimanic effects and are effective for treating mixed bipolar states, rapid cycling, and psychotic features. Long-term data support use of some SGAs as mood stabilizers.October), weight gain and attendant metabolic syndrome as well as tardive dyskinesia and hyperprolactinemia temper enthusiasm for SGA use. Of note, at least two SGAs—aripiprazole3,4 and ziprasidone5—have not shown problematic metabolic effects, although evidence supporting the use of these drugs for resistant unipolar depression is limited. Taken together, these risks warrant reserving SGAs for unipolar depression that has not responded to antidepressants.

“After two failed SSRIs trials, I would try a serotonin-norepinephrine reuptake inhibitor (SNRI) and/or bupropion. Then it would depend on symptoms and risk factors.”

Compared with SNRI monotherapy or combination SSRI/bupropion therapy, a higher level of evidence supports SGAs’ benefits in resistant depression. Given the risks associated with SGAs, however, try an SNRI and SSRI/bupropion therapy before adding an SGA for most patients.

“I would not use an SGA in resistant depression without evidence of psychosis.”

SGAs’ benefit in nonpsychotic, unipolar major depression resistant to two classes of antidepressants is reasonably well-established. Psychotic depression, however, is one of the few diagnostic groups for which an SGA added to an antidepressant should be considered first line.

Richard C. Shelton, MD
James G. Blakemore Research Professor
Vanderbilt University
Nashville, TN


1. Berk M, Dodd S. Efficacy of atypical antipsychotics in bipolar disorder. Drugs 2005;65:257-69.

2. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158:131-4.

3. Papakostas GI, Petersen TJ, Kinrys G, et al. Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J Clin Psychiatry 2005;66:1326-30.

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

5. Papakostas GI, Petersen TJ, Nierenberg AA, et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry 2004;65:217-21.

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