Evidence-Based Reviews

Treatment-resistant depression: Are atypical antipsychotics effective and safe enough?

Current Psychiatry. 2006 October;5(10):31-44

References

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13. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60(11):1079-88.

14. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158(1):131-4.

15. Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 1999;60(4):256-9.

16. Shelton RC. The combination of olanzapine and fluoxetine in mood disorders. Expert Opin Pharmacother 2003;4(7):1175-83.

17. Shelton RC, Williamson DJ, Corya SA, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 2005;66(10):1289-97.

18. Thase ME, Corya SA, Olawale O, et al. Olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. Presented at: Society of Biological Psychiatry annual meeting; May 18-20, 2006; Toronto, Ontario.

19. Nemeroff CB. Use of atypical antipsychotics in refractory depression and anxiety. J Clin Psychiatry 2005;66(suppl 8):13-21.

20. Dunner DL, Amsterdam JD, Shelton RC, et al. Adjunctive ziprasidone in treatment-resistant depression: a randomized, double-blind, 8-week pilot study. Presented at: American College of Neuropsychopharmacology annual meeting; December 12-16, 2004; San Juan, PR.

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olanzapine, mean 12.5 mg/d, plus placebo (n=8)
a continuation of fluoxetine, mean 52 mg/d, plus placebo (n=10)
or olanzapine/fluoxetine, mean 13.5/52 mg/d (n=10).

Continuing fluoxetine produced essentially no additional therapeutic benefit. Olanzapine plus placebo showed an initial effect, but patients relapsed to baseline depression symptoms after 3 weeks. This is consistent with residual fluoxetine levels during that period after patients stopped taking the SSRI. The olanzapine/fluoxetine combination resulted in significantly greater improvement in depressive symptoms during the 8-week study, compared with either monotherapy.

Final depression remission rates (HAM-D score ≤8 for 2 weeks) were:

60% with olanzapine/fluoxetine
25% with olanzapine alone
20% with continuation fluoxetine.

The olanzapine/fluoxetine combination’s benefits were maintained during a subsequent 8-week extension.

Until recently, researchers had been unable to replicate these results or extend this study in larger populations because of high response rates in the monotherapy treatment groups.^16,17 In May 2006, however, Thase et al¹⁸ presented data from a large-scale replication trial that confirmed the finding of a more robust effect with fixed-dose olanzapine/fluoxetine in unipolar major depression, compared with olanzapine or fluoxetine monotherapy.

Box 2

Antidepressant-like effects included in SGAs’ ‘atypical’ qualities

Second-generation antipsychotics (SGAs) differ from first-generation antipsychotics (FGAs) in their putative mechanisms of action.

FGAs’ antipsychotic effects depend largely on central dopamine type 2 (D2) receptor blockade. Their additional receptor-binding characteristics—blocking cholinergic, histamine, and alpha adrenergic receptors—appear to confer side effects but no added therapeutic benefit.⁹

SGAs bind weakly to D2 receptors and in varying degrees to serotonin (5-HT) receptors, including 5-HT subtypes 1A, 2A, 2C, 5, 7, and others. The SGAs also have other transmitter effects.¹⁰ On balance, the SGAs’ effects are more complex than those of the FGAs.

SGAs are called “atypical” because their beneficial and adverse clinical actions do not follow the FGAs’ usual pattern. FGAs’ relative potency in reducing psychosis is proportional to the propensity to cause extrapyramidal symptoms (EPS). Both the clinical effect and EPS are functions of D2 receptor blockade.¹¹ In contrast, clozapine—the prototypical SGA—is a potent antipsychotic that exerts essentially no EPS.

Compared with FGAs, clozapine’s more complicated psychopharmacology has been shown to produce an enhanced effect on negative, cognitive, and mood symptoms in some patients with schizophrenia.¹⁰

Ziprasidone. Case series, open-label trials, and blinded controlled studies of other SGAs have produced varying results.^19,20 Dunner et al²⁰ conducted an 8-week, randomized, open-label trial of ziprasidone augmentation in 64 patients who had not responded to an SSRI. Patients were randomly assigned to:

sertraline, 100 to 200 mg/d
sertraline plus ziprasidone, 80 mg/d
or sertraline plus ziprasidone, 160 mg/d.

Depressive symptoms improved in all groups, based on mean Montgomery-Åsberg Depression Rating Scale scores (–4.5 points with sertraline alone, –6.0 points with sertraline plus ziprasidone, 80 mg/d, and –8.3 points with sertraline plus ziprasidone, 160 mg/d). Differences in these scores were not statistically significant.

Risperidone. One three-phase study²¹ evaluated the long-term efficacy of adding risperidone to citalopram in 489 patients with treatment-resistant depression. The design was:

phase 1: 4 to 6 weeks of open-label citalopram, 20 to 60 mg/d (N=489)
phase 2: 4 to 6 weeks of citalopram plus open-label risperidone, 0.25 to 2 mg/d (N=386)
phase 3: 24 weeks of citalopram plus double-blind risperidone or placebo (N=241).

The study’s primary outcome was time to relapse during phase 3. Phase 1 patients whose HAM-D scores improved

Median time to relapse in phase 3 was 102 days with risperidone augmentation and 85 days with placebo—not a statistically significant difference. Relapse rates were 53.3% with risperidone and 54.6% in the control group. These results suggest that risperidone had an initial acute effect that was not sustained.

In another study,²² 463 depressed patients received an optimized antidepressant trial. The 274 who did not respond sufficiently were randomly assigned to risperidone, 1 to 2 mg/d, or placebo for 6 weeks. Mean HAM-D scores fell from 24.2 to 15.2 in the risperidone group and from 24.6 to 17.5 in the control group—a modest but statistically significant difference in favor of risperidone. The baseline-toendpoint change in this study is similar to that reported in a trial of risperidone, 1 to 4 mg/d, plus paroxetine, 20 to 40 mg/d, in bipolar depression.²³

Shelton²⁴ compared the effectiveness of adding risperidone or bupropion to SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) for 6 weeks. Risperidone and bupropion were similarly effective as augmentation, but risperidone had a more rapid effect—producing statistically significant greater benefits within the first week of treatment.

Aripiprazole. Two open-label trials showed that aripiprazole combined with SSRIs exerts generally beneficial effects in treatment-resistant depression.^25,26 Simon and Nemeroff²⁵ began by adding aripiprazole at 10 mg/d, but emerging akathisia prompted them to reduce the starting dosage to 2.5 mg/d.