Table 3

Trials of atypical antipsychotics as augmentation therapy for major depression

Author, YearSubjectsNTreatmentsDurationOutcomes
Shelton, 2001 47DSM-IV criteria for recurrent major depression without psychotic features, resistant to conventional antidepressant therapy; HAM-D score of > 20; and non-response in a 6-week lead-in phase with fluoxetine28Olanzapine (mean dose = 12.5 mg/day)

Fluoxetine (mean dose = 52 mg/day)

Olanzapine (mean dose = 13.5 mg/day) + fluoxetine (mean dose = 52 mg/day)

8 weeksOlanzapine and fluoxetine resulted in significantly greater improvements on the HAM-D scale than olanzapine alone, but were not significantly better than fluoxetine alone. Combination therapy was also significantly better than either monotherapy in improvements on the MADRS.
Shelton, 2005 76DSM-IV criteria for unipolar, non-psychotic major depressive disorder and at least 1 past treatment failure with an SRI with at least 4 weeks of therapy at a therapeutic dose; and non- response to a 7-week lead- in phase with nortriptyline.500Olanzapine (mean dose = 8.3 mg/day)

Olanzapine (mean dose = 8.5 mg/day) + fluoxetine (mean dose = 35.6 mg/day)

Fluoxetine (mean dose = 35.8 mg/day)

Nortriptyline (mean dose = 103.5 mg/day)
8 weeksNo significant differences among groups at 8 weeks in MADRS.
Significantly greater improvements for combination therapy at weeks 2–4.
Corya, 2005 77DSM-IV criteria for major depressive disorder, single episode or recurrent, without psychotic features; with a CGI-severity score of 4 or greater; documented history of failure to achieve satisfactory response to at least 6 weeks of SRI therapy at therapeutic doses; and non-response to a 7-week lead-in phase with venlafaxine483Olanzapine + Fluoxetine in several different doses

Olanzapine (mean dose = 7.9 mg/day)

Fluoxetine (mean dose = 37.5 mg/day)

Venlafaxine (mean dose =275.4 mg/day)
12 weeksNo significant difference between combination therapy and any other group except olanzapine alone in MADRS at 12 weeks.
Significantly greater improvements for combination therapy at weeks 2–6.
Yargic, 2004 30DSM-IV criteria for major depression and HAM-D scores or HAM-A scores indicating depression and anxiety112Paroxetine (mean dose = 28 mg/day)

Paroxetine (mean dose = 27mg/day) + Quetiapine (mean dose “about” 60 mg/day at the end of the study).
8 weeksNo difference between groups in mean HAM-D or HAM-A score at week 8, but a suggestion that improvement was faster in patients treated with combination therapy.
Levitt, 2004 44“unipolar non-psychotic major depression” and failed an adequate trial of an SRI or venlafaxine43Risperidone added to antidepressant

Olanzapine added to antidepressant
6 weeksNo difference between groups for HAM-D.
Dunner, 2003 78Major depression without psychotic features and a history of non-response to an adequate trial of at least 4 weeks of antidepressant therapy; a minimum MADRS score of 20; and non-response to a run-in period with sertraline64Sertraline (100–200 mg/day)

Sertraline (100–200 mg/day) + Ziprasidone (80 mg/day)
Sertraline (100–200 mg/day) + Ziprasidone (160 mg/day)
8 weeksComparisons across groups were not presented, but when stratified by a history of non-response (SRI or non-SRI), only those patients who had a prior history of non-SRI treatment resistance showed an improvement in MADRS score at 8 weeks.
Gharabawi, 2004 43DSM-IV diagnosis of major depressive disorder, single or recurrent episode; 98% did not have psychotic features; failure to respond to other antidepressants given at adequate doses for at least 6 weeks; with non- response in a 4–6 week lead-in phase with citalopram386Citalopram

Citalopram + risperidone (flexible dose)
24 weeksNo data on initial response to therapy; suggestion of a benefit in terms of time to relapse (102 days v. 85 days).

HAM-D = Hamilton Depression Scale

HAM-A = Hamilton Anxiety Scale

MADRS = Montgomery – Asberg Depression Rating Scale

From: 3, Results

Cover of Efficacy and Comparative Effectiveness of Off-Label Use of Atypical Antipsychotics
Efficacy and Comparative Effectiveness of Off-Label Use of Atypical Antipsychotics [Internet].
Comparative Effectiveness Reviews, No. 6.
Shekelle P, Maglione M, Bagley S, et al.

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