{"id":38224,"date":"2013-07-01T01:19:34","date_gmt":"2013-07-01T05:19:34","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=38224"},"modified":"2013-07-01T06:30:06","modified_gmt":"2013-07-01T10:30:06","slug":"the-mother-of-meta","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2013\/07\/01\/the-mother-of-meta\/","title":{"rendered":"the mother of meta…"},"content":{"rendered":"
I said a few days ago that I never met a graph I didn’t like, but there’s been a graph that I’ve wanted to see for years, but I never found the data to draw it. But as of today, I can put all of that behind me: <\/div>\n
<\/div>\n
On the left, the Efficacy of the Antipsychotics plotted against the year the drug was introduced [the higher Efficacy is up]. On the right, the discontinuation rate plotted against the year the drug was introduced [the higher discontinuation rate is up]. Why have I wanted to draw this graph? Because it feels like we haven’t gotten very far – and that’s more or less true. Side effect profiles may have changed over the years, but by patient vote [discontinuation rate] there’s not a lot to crow about. A more interesting question is, How did I draw this graph? It’s because the Lancet has published the mother of all meta-analyses of the antipsychotics: <\/div>\n
\n
Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis<\/a><\/div>\n
by Prof Stefan Leucht MD, Andrea Cipriani MD, Loukia Spineli, Dimitris Mavridis PhD, Deniz Örey MD, Franziska Richter MD, Myrto Samara MD, Prof Corrado Barbui MD, Prof Rolf R Engel PhD, Prof John R Geddes MD, Werner Kissling MD, Marko Paul Stapf, Bettina Lässig, Georgia Salanti PhD, Prof John M Davis MD<\/div>\n
The Lancet<\/font><\/strong>, Early Online Publication, 27 June 2013, doi:10.1016\/S0140-6736[13]61032-6<\/div>\n

<\/p>\n

Background<\/font><\/strong>: The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs.<\/div>\n
Methods<\/font><\/strong>: We did a Bayesian-framework, multiple-treatments meta-analysis [which uses both direct and indirect comparisons] of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group’s specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation.<\/div>\n
Findings<\/font><\/strong>: We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73—1·03; amisulpride 0·66, 0·53—0·78; olanzapine 0·59, 0·53—0·65; risperidone 0·56, 0·50—0·63; paliperidone 0·50, 0·39—0·60; zotepine 0·49, 0·31—0·66; haloperidol 0·45, 0·39—0·51; quetiapine 0·44, 0·35—0·52; aripiprazole 0·43, 0·34—0·52; sertindole 0·39, 0·26—0·52; ziprasidone 0·39, 0·30—0·49; chlorpromazine 0·38, 0·23—0·54; asenapine 0·38, 0·25—0·51; lurasidone 0·33, 0·21—0·45; and iloperidone 0·33, 0·22—0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug [amisulpride] to 0·80 for the worst drug [haloperidol]; for extrapyramidal side-effects 0·30 [clozapine] to 4·76 [haloperidol]; and for sedation 1·42 [amisulpride] to 8·82 [clozapine]. Standardised mean differences compared with placebo for weight gain varied from −0·09 for the best drug [haloperidol] to −0·74 for the worst drug [olanzapine], for prolactin increase 0·22 [aripiprazole] to −1·30 [paliperidone], and for QTc prolongation 0·10 [lurasidone] to −0·90 [sertindole]. Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses.<\/div>\n
Interpretation<\/font><\/strong>: Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines.<\/div>\n
<\/div>\n<\/blockquote>\n
The article remains behind a pay-wall. I would hope that it will become freely available on-line at some point. The forest plot above is for efficacy [as in the abstract], but they have one for each in the article itself: discontinuation, weight gain, EPS, Prolactin, QT prolongation, and sedation. Not satisfied with that, there are tables showing the comparative results in studies with active comparators for these parameters. I had a go at plotting Efficacy against Discontinuation Rate [two linear regressions – with and without Clozapine]. We usually think of discontinuation as being a function of adverse effects, but the regression lines suggest the efficacy is a significant factor:<\/div>\n
<\/div>\n
It’s kind of interesting to think back on my own training in the 1970s. Other than Haldol, the drugs we used then aren’t even on the list: Fluphenazine [Prolixin]; Perphenazine [Trilafon]; Thioridazine [Mellaril]; Trifluoperazine [Stelazine]; Thiothixene [Navane]. In those days, we ruminated the relative merits and profiles of each of those drugs just like I’m sure the recent residents obsess about the Atypicals. Haldol was barely the first-line drug then, but it appears to be the only one that survived to the present. The article itself has a lot of information about the trails themselves [212!]. I report it here to mark that it exists. I think it needs some time to digest before making much in the way of commentary. <\/div>\n","protected":false},"excerpt":{"rendered":"

I said a few days ago that I never met a graph I didn’t like, but there’s been a graph that I’ve wanted to see for years, but I never found the data to draw it. But as of today, I can put all of that behind me: On the left, the Efficacy of the […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_bbp_topic_count":0,"_bbp_reply_count":0,"_bbp_total_topic_count":0,"_bbp_total_reply_count":0,"_bbp_voice_count":0,"_bbp_anonymous_reply_count":0,"_bbp_topic_count_hidden":0,"_bbp_reply_count_hidden":0,"_bbp_forum_subforum_count":0,"footnotes":""},"categories":[2],"tags":[],"class_list":["post-38224","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/38224","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/comments?post=38224"}],"version-history":[{"count":20,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/38224\/revisions"}],"predecessor-version":[{"id":38245,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/38224\/revisions\/38245"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=38224"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=38224"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=38224"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}