Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes

Atypical antipsychotic medications are widely prescribed for the adjunctive treatment of depression, yet their total risk-benefit profile is not well understood. We thus conducted a systematic review of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression

Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes

Background: Atypical antipsychotic medications are widely prescribed for the adjunctive treatment of depression, yet their total risk–benefit profile is not well understood. We thus conducted a systematic review of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression. Methods and Findings: We included randomized trials comparing adjunctive antipsychotic medication to placebo for treatment-resistant depression in adults. Our literature search (conducted in December 2011 and updated on December 14, 2012) identified 14 short-term trials of aripiprazole, olanzapine/fluoxetine combination (OFC), quetiapine, and risperidone. When possible, we supplemented published literature with data from manufacturers' clinical trial registries and US Food and Drug Administration New Drug Applications. Study duration ranged from 4 to 12 wk. All four drugs had statistically significant effects on remission, as follows: aripiprazole (odds ratio [OR], 2.01; 95% CI, 1.48–2.73), OFC (OR, 1.42; 95% CI, 1.01–2.0), quetiapine (OR, 1.79; 95% CI, 1.33–2.42), and risperidone (OR, 2.37; 95% CI, 1.31–4.30). The number needed to treat (NNT) was 19 for OFC and nine for each other drug. All drugs with the exception of OFC also had statistically significant effects on response rates, as follows: aripiprazole (OR, 2.07; 95% CI, 1.58–2.72; NNT, 7), OFC (OR, 1.30, 95% CI, 0.87–1.93), quetiapine (OR, 1.53, 95% CI, 1.17–2.0; NNT, 10), and risperidone (OR, 1.83, 95% CI, 1.16–2.88; NNT, 8). All four drugs showed statistically significant effects on clinician-rated depression severity measures (Hedges' g ranged from 0.26 to 0.48; mean difference of 2.69 points on the Montgomery–Asberg Depression Rating Scale across drugs). On measures of functioning and quality of life, these medications produced either no benefit or a very small benefit, except for risperidone, which had a small-to-moderate effect on quality of life (g = 0.49). Treatment was linked to several adverse events, including akathisia (aripiprazole), sedation (quetiapine, OFC, and aripiprazole), abnormal metabolic laboratory results (quetiapine and OFC), and weight gain (all four drugs, especially OFC). Shortcomings in study design and data reporting, as well as use of post hoc analyses, may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events. Conclusions: Atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms, but clinicians should interpret these findings cautiously in light of (1) the small-to-moderate-sized benefits, (2) the lack of benefit with regards to quality of life or functional impairment, and (3) the abundant evidence of potential treatment-related harm

BRIDGE study warrants critique

David M. Allen, Peter I. Parry, Robert Purssey, Glen I. Spielmans, Jon Jureidini, Nicholas Z. Rosenlicht, David Healy, Irwin Feinber

Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature

A systematic search of the literature reveals limited evidence to support use of aripiprazole, a second-generation antipsychotic medication, in maintenance therapy of bipolar disorder, despite widespread use

Remission rates by drug and overall.

<p>Remission rates by drug and overall.</p

Response rates by drug and overall.

<p>Response rates by drug and overall.</p

Effect sizes and heterogeneity of effect sizes on continuous measures.

a<p>The FDA statistical review noted that many participants violated study protocol, often as a result of taking non-allowed medications. The numbers in parentheses represent data from only participants who did not violate the study protocol.</p>b<p>As data were not presented clearly for two of three trials, we opted to not treat the single study with clearly reported data as representative of the three aripiprazole studies; thus, we provide no summary effect size calculation for sexual functioning.</p>c<p>“ns” indicates no statistically significant difference versus placebo; data were not reported in a more detailed manner.</p>d<p>OFC had a greater increase in prolactin versus fluoxetine (0.31 nmol/l, <i>p</i><0.001) and versus nortriptyline (0.37 nmol/l, <i>p</i><0.001). Given the inexact <i>p</i>-values, we did not calculate an effect size.</p>e<p>OFC had a greater increase in mean total nonfasting cholesterol versus fluoxetine (0.30 mmol/l, <i>p</i><0.001) and nortriptyline (0.33 mmol/l, <i>p</i> = 0.004). Given the inexact <i>p</i>-value of the OFC versus fluoxetine comparison, we did not calculate an effect size.</p>f<p>Hedges' <i>g</i> includes effects from all three trials, whereas the raw unit analysis includes only change on the MADRS, which was not used in the McIntyre et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001403#pmed.1001403-McIntyre1" target="_blank">[84]</a> study.</p>g<p>It was reported that 150 mg of quetiapine was superior to placebo, with an associated <i>p</i>-value of 0.095, from which a <i>d</i> = 0.20 was calculated. For the 300-mg dose, the <i>p</i>-value was reported as <0.05, so it was not possible to calculate an exact effect size, as a standard deviation for this measure was not provided.</p>h<p>There were “no apparent differences among the treatment groups” according to the El-Khalili et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001403#pmed.1001403-ElKhalili1" target="_blank">[83]</a> clinical trial registry report. Given the lack of clarity regarding sexual functioning data, we provide no summary effect size calculation for sexual functioning.</p>i<p>“ns” indicates no statistically significant difference versus placebo; data were not reported in a more detailed manner.</p>j<p>The primary efficacy end point in the Mahmoud et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001403#pmed.1001403-Mahmoud1" target="_blank">[44]</a> study was 4 wk, so data in parentheses indicate data from this a priori end point rather than from the 6-wk end point that was emphasized much more heavily in the study publication.</p>k<p>Hedges' <i>g</i> pools data from Mahmoud et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001403#pmed.1001403-Mahmoud1" target="_blank">[44]</a> and Reeves et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001403#pmed.1001403-Reeves1" target="_blank">[77]</a>. We provide no summary estimate of mean differences on the MADRS, as only the small Reeves et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001403#pmed.1001403-Reeves1" target="_blank">[77]</a> study reported these data.</p>l<p>Mahmoud et al.'s primary end point was 4 wk <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001403#pmed.1001403-Mahmoud1" target="_blank">[44]</a>, but these data are presented at 6 wk. These results may be inflated relative to the primary end point, given that the effect favoring risperidone on the HAM-D was smaller at week 4 than at week 6.</p>m<p>Prolactin levels were apparently not measured in these trials.</p>n<p>Pooled raw units are for MADRS only.</p>o<p>These data are pooled across the SDS, Q-LES-Q, SF-36 Mental Component Summary, and SF-36 Physical Component Summary.</p><p>CGI-S, Clinical Global Impressions–Severity; CSFQ, Changes in Sexual Function Questionnaire; IDS-SR, Inventory of Depressive Symptomatology–Self Report; QoL, quality of life; SF-36 MCS, SF-36 Mental Component Summary; SF-36 PCS, SF-36 Physical Component Summary; SFI, Sexual Function Inventory.</p

Funnel plot of trim and fill analysis.

<p>Open circles represent published studies; filled circles represent imputed unpublished studies. The overall effect size changes from 0.34 to 0.32 when including these imputed trials.</p

Characteristics of included studies.

a<p>Number of participants included in the intent-to-treat or modified intent-to-treat analysis on the primary depression rating scale in the trial.</p>b<p>If no interview was explicitly mentioned, then this variable was coded as “?”; MINI, Mini International Psychiatric Interview; SCID, Structured Clinical Interview for DSM-IV.</p>c<p>Indicates measures used to define remission and/or response in each study.</p>d<p>“CTR” indicates a clinical trial registry report from the sponsor's online database; “FDA” indicates an FDA statistical review.</p>e<p>Blinded raters rated outcomes on the MADRS and HAM-D, whereas the study psychiatrist, who also elicited reports of adverse events, rated the Clinical Global Impressions–Severity.</p>f<p>Adverse events reported by fewer than two of the 29 patients in each group were categorized as “other” in the study's table.</p>g<p>Data for these two trials were reported separately for some variables but jointly for others.</p><p>M, mean.</p

Adverse events individually and by category.

a<p>Trials with no events in either study arm are not included in summary OR calculations.</p>b<p>The clinical registry report indicated that statistically significant differences emerged between drug and placebo in glucose, total cholesterol, fasting LDL cholesterol, nonfasting and fasting triglycerides, and prolactin. These differences were not reported quantitatively and were described as not “clinically meaningful.”</p>c<p>Median levels of change in fasting total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and fasting plasma glucose were reported. Categorical measures (i.e., numbers of patients who had abnormal scores) were not reported. The clinical trial registry noted that there was a statistically significant but clinically nonmeaningful difference between drug and placebo on nonfasting LDL cholesterol.</p>d<p>Data on metabolic parameters were reported in terms of median change, but no categorical reporting of laboratory abnormalities was provided. Differences between drug and placebo were reported as not statistically significant in terms of median change on glucose, cholesterol, and triglycerides.</p>e<p>Because the total number of events in the OFC group was higher than the sample size of the group, an effect size could not be calculated, and it was thus not factored into the overall effect size estimate for sedation. Given the very small sample of the study, this makes virtually no difference in the overall effect size estimate.</p>f<p>The number of participants providing data differed substantially across metabolic testing parameters. The average sample size across the metabolic testing groups provided the denominator for the pooled number of abnormal metabolic test results in each trial, with the total number of participants who experienced an abnormal metabolic testing result comprising the numerator. A participant may have experienced more than one event. Also, boundaries of abnormal tests were defined by standard Lilly reference ranges, a resource not available to our research team.</p>g<p>Boundaries of abnormal tests were defined by standard Lilly reference ranges, a resource not available to our research team.</p>h<p>Triglycerides and unclearly described laboratory tests were completed in this study, but the results were described only as yielding “no clinically significant differences” between groups.</p>i<p>Abnormal metabolic laboratory values were defined as follows: fasting glucose ≥126 mg/dl, LDL cholesterol ≥160 mg/dl, HDL cholesterol ≤40 mg/dl, total cholesterol ≥240 mg/dl, and triglycerides ≥200 mg/dl.</p>j<p>The clinical trial registry entry noted that approximately 17% of patients taking quetiapine met this criterion, compared to 6% of placebo patients. We extracted numbers of patients based on these percentages.</p>k<p>Defined as >20 ng/ml for males and >30 ng/ml for females.</p>l<p>These parameters were apparently not measured.</p>m<p>Weight gain was provided in terms of means and standard deviations; however, no categorical measure of significant weight gain was reported.</p><p>AIMS, Abnormal Involuntary Movement Scale; Barnes, Barnes Akathisia Scale; HbA1c, glycated hemoglobin; SAS, Simpson-Angus Scale.</p