Ostroff and Nelson8 added 0.5 to 1 mg/d of risperidone(Drug information on risperidone) to the treatment regimens of 8 patients with depression who had "incomplete" responses to 16 weeks of treatment with fluoxetine(Drug information on fluoxetine) or paroxetine(Drug information on paroxetine). In this open-label trial, all of the patients' depressive symptoms remitted in less than 1 week.
In a more substantial 8-week, double-blind trial, Shelton and colleagues9 randomly assigned 28 patients with nonpsychotic treatment-resistant depression to olanzapine(Drug information on olanzapine) plus placebo (n = 8), fluoxetine plus placebo (n = 10), or olanzapine plus fluoxetine (n = 10). The symptoms of patients taking a combination of olanzapine and fluoxetine improved significantly more than the symptoms of those receiving either monotherapy.
In the 2 studies cited above, patients had poor responses to treatment with antidepressants before atypical antipsychotic augmentation was initiated. Hirose and Ashby10 conducted an open- label study of 36 patients with depression who were administered a combination of fluvoxamine(Drug information on fluvoxamine) and risperidone as first-line treatment for 6 weeks. Of the 30 patients who completed the study, 93% had a positive response to the combined treatment (as signified by the percentage of reductions in the Hamilton rating scale for depression).
In another open-label study of 20 patients with depression who failed to respond to an adequate trial of an SSRI, Papakostas and colleagues11 augmented antidepressant treatment with ziprasidone(Drug information on ziprasidone). Thirteen patients completed the study (suggesting a high discontinuation rate). At completion, 25% of the patients remitted and 50% responded to the augmentation.
In a retrospective chart review, olanzapine, risperidone, quetiapine(Drug information on quetiapine), and ziprasidone were given in a fee-for- service setting as augmenting agents to patients with treatment-resistant depression (N = 49).12 Barbee and associates12 found an overall response rate of 65%, based on clinical global impression scale ratings. There was no difference in response rates between the different atypical agents.
The question of whether patients' responses to atypical antipsychotic augmentation are greater in those who have been pretreated with antidepressants than in those in whom antidepressants and atypical antipsychotics are started together continues to be a focus of investigation. Twenty patients with major depression were treated with antidepressants for 2 weeks and showed minimal or no improvement. The patients were then randomly assigned to augmentation with placebo or olanzapine for an additional 4 weeks.
Improvement rates between the 2 groups (45% and 43%, respectively) were no different, although of the 12 primary responders, 8 were in the olanzapine group and 4 were in the placebo augmentation groups. Four patients did not improve with placebo augmentation and showed a "distinct and rapid" effect with subsequent olanzapine augmentation.13 This study suggests—as may be the case with lithium(Drug information on lithium) augmentation—that pretreatment with an antidepressant may be needed in order for the patient to benefit from augmentation with an atypical antipsychotic.
Another small open-label study (N = 12) reported on the effects of aripiprazole(Drug information on aripiprazole) augmentation of SSRIs for patients with treatment-resistant depressive disorders.14 In this 8-week trial, 9 patients completed the study; 5 were classified as "responders." For those who did respond, the improvement was reported as "robust and rapid" by the end of the first week of treatment.
Similarly, in a small open-label study, 15 depressed patients responded poorly to 8 weeks of antidepressant therapy.15 In these patients, treatment was augmented for another 4 weeks with aripiprazole. Remission rates were 40% by the first week and 60% by the second week of treatment. Response rates were faster and higher in patients receiving 10 mg/d of aripiprazole; however, more patients in that group discontinued treatment because of adverse effects than in the group who received 2.5 mg/d.
Shelton and associates16 conducted a large (N = 500), multisite (71 sites) study of patients with treatment-resistant depression. All patients were treated with nortriptyline(Drug information on nortriptyline) for 7 weeks. Those patients who had less than 30% improvement were randomly assigned to 8 weeks of double-blind treatment with olanzapine plus fluoxetine (n = 146), olanzapine plus placebo (n = 144), or fluoxetine plus placebo (n = 142) or were kept on nortriptyline plus placebo (n = 68). In contrast to the small open-label studies described earlier, overall response rates were low; this was similar in all groups (20% to 30%) by week 8. Patients in the olanzapine-plus-fluoxetine group showed quicker response (by weeks 1 through 3) than did those in the monotherapy groups; however, all groups had comparable response rates by week 8.
Another large (N = 386), multicenter study assessed the usefulness of risperidone continuation-phase augmentation for treatment-resistant depression. In a 4- to 6-week open-label phase trial, 63% of patients improved with risperidone augmentation; 241 of these patients then entered a 24-week, double-blind, placebo-controlled continuation-phase trial.17 The mean number of days to relapse was 102 in the risperidone augmentation group and 85 in the placebo augmentation group, which was a nonsignificant difference.