Barbee et al27 reported the results of a retrospective case series of aripiprazole augmentation in depressed patients who had not responded adequately to multiple medication trials, including SGAs. Fourteen of 30 patients (46.7%) were rated “much improved” or “very improved” with added aripiprazole, based on Prospective Global Assessment of Functioning and Clinical Global Impressions- Improvement scores. But 9 patients (30%) did not complete the full course of therapy, and 6 of the 14 responders (42.9%) relapsed while taking aripiprazole. The net response rate across 6 weeks was 27%.
Although this study involved only aripiprazole, the results suggest that trying a second SGA may not be more effective after a first SGA fails to improve treatment-resistant depression.
Quetiapine. A 9-week, open-label, variable-dose study of 11 patients28 first suggested that augmenting SSRIs with quetiapine could improve residual anxiety in resistant depression. Subsequently, 112 patients with major depression and anxiety were randomly assigned to single-blind treatment with paroxetine, ≥60 mg/d, with or without quetiapine, ≥200 mg/d. After 8 weeks, the 58 patients receiving quetiapine augmentation showed greater improvement than the 54 receiving SSRI monotherapy, based on Hamilton Anxiety Scale (HAM-A) and HAM-D scores.29
Adding quetiapine to antidepressant therapy was then examined in a randomized, placebo-controlled trial by McIntyre et al.30 Fifty-eight patients with unipolar depression who had not responded adequately after 6 weeks of SSRI or SNRI therapy were randomly assigned to quetiapine, 50 to 600 mg/d (mean dose 202±93 mg/d) or placebo for 8 weeks. Adjunctive quetiapine was significantly more effective than placebo, as measured by HAM-D scores. Patients receiving quetiapine also showed significantly better HAM-A scores at all points except week 8.
The dropout rate was relatively high for both groups—11 of 29 (38%) receiving quetiapine and 13 of 29 (45%) receiving placebo. The main reasons for discontinuation were side effects with quetiapine (sedation, dry mouth, and weight gain) and lack of effect with placebo.
These results are similar to those of another double-blind, placebo-controlled trial,31 in which 32 patients with SSRI/SNRI-resistant depression received adjunctive quetiapine, 200 to 400 mg/d (mean 268 mg/d) or placebo for 8 weeks.
Though small, these studies indicate that quetiapine may be effective as augmentation for treatment-resistant unipolar depression. Controlled data from a larger study are needed.
Discussion. Because of insufficient data, we do not know if SGAs are equivalent when used to augment antidepressant therapy in unipolar major depression. Olanzapine has been studied more than other SGAs in treatmentresistant depression and has shown efficacy in several—but not all—short- and long-term augmentation trials. Evidence on other SGAs is limited, and no head-to-head comparisons have been reported.
Adverse effects
Some SGAs may be effective in treatment-resistant depression, but any discussion of using them must also include their potential for adverse effects.
Weight gain and subsequent metabolic syndrome have been associated with olanzapine and—to a lesser degree—with quetiapine and risperidone. Ziprasidone and aripiprazole have relatively little effect on patients’ weight.
Extrapyramidal symptoms. All SGAs carry a risk of tardive dyskinesia. The risk is lower with SGAs than with first-generation antipsychotics (FGAs) but is an important clinical consideration.32
Hyperprolactinemia. Risperidone has been associated with an elevated risk of hyperprolactinemia, although less than that associated with FGAs.33 This risk does not appear to be a problem with quetiapine34 and aripiprazole;35 it is low with olanzapine (except at higher dosages);36 and the prolactin increase associated with ziprasidone may resolve within the first month of treatment.37
Prescribing rationale
‘Overcautious’ treatment. Even with careful management of side effects, SGAs are not preferred to strategies such as switching antidepressants or adding bupropion for treatment-resistant unipolar depression. But do not exclude SGAs solely because of their potential for adverse effects.
I am concerned about anecdotal reports of overcautious clinicians basing medication choices largely on safety—and, by extension, legal—considerations rather than on effectiveness. Certainly, safety concerns should prevail when two options are equally effective. But we do our patients no service by selecting ineffective drugs just because they have a low potential for adverse effects or by dosing effective drugs below the therapeutic range (Table 2).
When a drug is effective and may be the best choice for the patient, the question becomes, “Can I manage the potential for adverse effects?” When prescribing SGAs, it is important to monitor patients’ weight and serum lipid and glucose levels and regularly to look for abnormal involuntary movements.
An important question remains: Where do SGAs belong in the hierarchy of treatment options? Unfortunately, treatment guidelines for depression do not typically mention antipsychotics. Because of relative safety issues, two trials of monotherapies of different classes and, perhaps, combination therapy with bupropion would come before SGAs. However, it remains unclear exactly where.