{"id":34164,"date":"2013-03-14T22:12:50","date_gmt":"2013-03-15T02:12:50","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=34164"},"modified":"2013-03-15T01:06:43","modified_gmt":"2013-03-15T05:06:43","slug":"and-14","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2013\/03\/14\/and-14\/","title":{"rendered":"and…"},"content":{"rendered":"\n

Years ago I joked, "What they might as well do is make a table with all the DSM diagnoses down the side and all the psychiatric meds across the top and then just fill in the blanks.<\/em>" I was making fun of the endless clinical trials that were choking our journals. One of my more astute partners laughed as she said, "You’re sooooo far behind. They’ve already done that. Now they’re doing them two drugs at a time. Much bigger table!<\/em>" But of all the combo drug strategies that came along, the one I least understood was adding atypical antipsychotics to antidepressants. That made some sense with severe cases of psychotic depression, but those are not common and most people being given the combination treatment didn’t seem to have those symptoms. What was the rationale for antipsychotics? Beats me. The drugs are anxiolytic, but there are plenty of much safer things to do to treat anxiety. So I’ve generally been suspicious that the atypical augmentation was a marketing ploy. Here, we are presented with a new meta-analysis of the studies to date that met solid study criteria. These are all industry funded studies with one being a joint industry\/NIMH study: <\/p>\n

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Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes<\/a>
PLoS Medicine<\/font><\/strong>
by Glen I. Spielmans, Margit I. Berman, Eftihia Linardatos, Nicholas Z. Rosenlicht, Angela Perry, and Alexander C. Tsai.
March 13, 2013
[full text on-line<\/a>]<\/div>\n

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Background<\/font><\/u>: 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.<\/strong><\/sup><\/div>\n
Methods and Findings<\/font><\/u>: 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 [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].<\/strong><\/sup><\/div>\n
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].<\/strong><\/sup><\/div>\n
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.<\/strong><\/sup><\/div>\n
Conclusions<\/font><\/u>: 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.<\/strong><\/sup><\/div>\n<\/blockquote>\n
I will quickly admit that the ins and outs of meta-analyses are new to me, but they’ve become something of major importance especially in psychiatry where there has been so much outside interference, conflict of interest, and scientific misbehavior in our literature [also so many clinical trials]. The point of a meta-analysis is to look at all the studies and separate the ‘wheat from the chaff’ – to come up with something that can be believed. I think this is a good one, so at the risk of living up to my moniker [one boring old man], I’m going to assume that the reader is as meta-analysis-naive as I was and go through this one in a bit of detail – at least the efficacy part [I do have something in mind to say besides writing a meta-analysis primer, but it’s at the end]. <\/div>\n

The whole point of a randomized placebo controlled clinical trial is to see if a medication has the desired clinical effect compared to placebo on some predefined outcome, with three usual measures of success: statistics<\/em>, strength of effect<\/em>, and overall improvement<\/em>. The outcomes for the first two focus on some objective parameter [ie rating scale] and measure the percent achieving response<\/em> or remission<\/em>, or they measure the magnitude of difference<\/em> in the actual outcome scores. The strength of the drug’s effect on the non-parametric [yes-no] parameters of response<\/em> or remission <\/em>are quantified by the Odds Ratio<\/em> [OR] or the Number Needed to Treat<\/em> [NNT]. The strength of the parametric [continuous scale] magnitude of difference<\/em> is measured by the effect size<\/em>. If you already know this stuff, this paragraph is boring and simplified. If you don’t know it, it may still be Greek, but I maybe it will help below.<\/p>\n