{"id":69144,"date":"2016-11-21T09:00:29","date_gmt":"2016-11-21T14:00:29","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=69144"},"modified":"2016-11-20T20:49:58","modified_gmt":"2016-11-21T01:49:58","slug":"activation-agitation-akasthisia-agita","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2016\/11\/21\/activation-agitation-akasthisia-agita\/","title":{"rendered":"activation, agitation, akasthisia, agita…"},"content":{"rendered":"\n
The presidential election is finally over and I want to get back to where I left off last month in the post in polite company…<\/a> when I said:<\/div>\n
\n
Articles like these are part of a great big wake-up call, and I’m not sure they’re reaching the right audience in the right ways. For the moment, I’ll just add them to the growing catalog, and pick back up next week after the national election is behind us. Right now, diversion time – World Series, Game 7!<\/font><\/em><\/div>\n<\/blockquote>\n
Here’s an abbreviated reference to that article\/meta-analysis: <\/div>\n
\n
Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers<\/a><\/div>\n
by Andreas Ø Bielefeldt, Pia B. Danborg, and Peter C. Gøtzsche<\/div>\n
Journal of the Royal Society of Medicine<\/strong>. 2016 109[10]:381-392.<\/div>\n
[full text on-line<\/a>] <\/div>\n
Objective<\/font><\/strong><\/em><\/u>: To quantify the risk of suicidality and violence when selective serotonin and serotonin-norepinephrine reuptake inhibitors are given to adult healthy volunteers with no signs of a mental disorder.<\/div>\n
…<\/div>\n
Conclusions<\/font><\/strong><\/em><\/u>: Antidepressants double the occurrence of events in adult healthy volunteers that can lead to suicide and violence. <\/font><\/strong><\/em><\/div>\n<\/blockquote>\n

<\/p>\n

But in the ensuing several weeks, Peter C. Gøtzsche and others added yet a second study to the one mentioned above. This one is an analysis of some unpublished studies from a 2001-2002 EMA submission of Duloxetine for stress urinary incontinence [that was not approved]:<\/div>\n
\n
Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical study reports<\/a><\/div>\n
by Emma Maund, Louise Schow Guski, and Peter C. Gøtzsche<\/div>\n
Canadian Medical Association Journal.<\/font><\/strong> First published online ahead of print on November 14, 2016.<\/div>\n
[full text on-line<\/a>]<\/div>\n

<\/p>\n

Background:<\/font><\/strong><\/em><\/u> The European Medicines Agency makes clinical study reports publicly available and publishes reasons for not approving applications for marketing authorization. Duloxetine has been approved in Europe for the treatment of stress urinary incontinence in women. The reported adverse effects of duloxetine include mental health problems and suicidality. We obtained clinical study reports from the European Medicines Agency concerning use of this drug for stress urinary incontinence.<\/div>\n
Methods:<\/font><\/strong><\/em><\/u> We performed a meta-analysis of 4 randomized placebo-controlled trials of duloxetine [involving a total of 1913 patients] submitted to the European Medicines Agency for marketing approval for the indication of stress urinary incontinence in women. We used data from the clinical study reports [totalling 6870 pages and including individual patient data] to assess benefits [including frequency of incontinence and changes in quality-of-life scores, such as Patient Global Impression of Improvement rating] and harms {both general harms, including discontinuation because of adverse events, and harms related to suicidality, violent behaviour and their potential precursors, such as akathisia and activation [stimulating effects such as insomnia, anxiety and agitation]}. <\/div>\n
Results:<\/font><\/strong><\/em><\/u> Duloxetine was significantly better than placebo in terms of percentage change in weekly incontinence episodes [mean difference -13.56%, 95% confidence interval [CI] -21.59% to -5.53%] and change in Incontinence Quality of Life total score [mean difference 3.24, 95% CI 2.00 to 4.48]. However, the effect sizes were small, and a sensitivity analysis [with removal of one trial] showed that the number needed to treat for a Patient Global Impression of Improvement rating of "much better or very much better" was 8 [95% CI 6 to 13]. The numbers needed to harm were 7 [95% CI 6 to 8] for discontinuing because of an adverse event and 7 [95% CI 6 to 9] for experiencing an activation event. No suicidality, violence or akathisia events were noted. <\/div>\n
Interpretation:<\/font><\/strong><\/em><\/u> Although duloxetine is effective for stress urinary incontinence in women, the rates of associated harm were high when individual patient data were analyzed, and the harms outweighed the benefits.<\/div>\n<\/blockquote>\n


[truncated from the original]<\/sup><\/p>\n

The two papers combined report seventeen blinded clinical trials [scattered over 28 years] with some ~1300 non-depressed<\/font><\/em> subjects on SSRI\/SNRI drugs compared with ~1200 placebo controls. The findings of an increased signal for suicidality with these drugs have been traditionally discounted by critics with various rationales because the medications are being given to depressed people [who are suicide-prone anyway]. So here’s a large cohort of studied patients where that explanation obviously won’t fly. And in each case, the forest plots still show that the target adverse events are significantly more prevalent in the drug treatment group than in the placebo controls. The question then becomes, "What were those target Adverse Events?<\/font><\/em>"<\/div>\n

And what of the numerous and compelling case histories of suicide, homicide, violence, agitation in some people taking SSRIs\/SNRIs? They are often discounted as "anecdotes<\/font>" – lacking the statistical\/mathematical certifcation that comes from clinical trials. They are infrequent and just don’t show up with strong signals in RCTs or population studies. So these meta-analyses are attempts at quantifying the phenomena. But again, the question becomes, "What were those target Adverse Events?<\/font><\/em>" "What do they mean by precursors to suicidality?<\/font><\/em>"<\/p>\n

Here are the criteria they used in searching through the articles\/reports in these meta-analyses:<\/p>\n


[<\/sup>Bielefeldt et al]<\/sup><\/p>\n


[Maund et al]<\/sup><\/p>\n

In the Bielfield et al [healthy volunteers] paper, they report on "suicidal or violent events or precursors to such events<\/font><\/em>" without breaking them down. And in Maund et al [duloxetine in stress incontinence] they do break them down [above]. In this latter study they mention that there were no suicidal or violent events reported in these trials [it’s worth taking a look at this paper for the suicidal info that wasn’t reported].<\/p>\n

There was a time when I might have read these papers that talk about "suicidal or violent events or precursors to such events<\/strong><\/font><\/em>" yet report no actual suicidal or violent events and been mighty skeptical. But that’s not true any more – at least for me. In fact, in our recent second Paxil Study 329<\/font> paper [Study 329 continuation phase: Safety and efficacy of paroxetine and imipramine in extended treatment of adolescent major depressio<\/a>n], we used similar criteria. Here’s a chart I made along the way that didn’t make it into the published paper [my made-up word ‘AGITA<\/font><\/em>‘ being roughly similar to the "Activation" categories above]:<\/p>\n

<\/p>\n

These two meta-analyses [Bielefeldt et al and Maund et al] follow-up on an older paper from 2000 reporting suicidality in several non-depressed healthy volunteers on an SSRI [Zoloft]:<\/div>\n
\n
Emergence of antidepressant induced suicidality<\/a><\/div>\n
by David Healy<\/div>\n
Primary Care Psychiatry<\/font><\/strong>. 2000 6:25-28.<\/div>\n
[full text online<\/a>]<\/div>\n

<\/p>\n

In the course of a randomised double-blind crossover study comparing the effects of reboxetine and sertraline in a group of healthy volunteers, two volunteers became suicidal on sertraline. This paper describes the characteristics of the reactions experienced by both subjects. These problems were associated with a combination of akathisia and disinhihition. Dysphoric or akathisic responses on their own to either drug did not lead to suicidality in this group of subjects.<\/div>\n<\/blockquote>\n
The Bielefeldt et al<\/font> paper mentions a suicide in a healthy volunteer in a Duloxetine Trial that wasn’t included in these meta-analyses:<\/div>\n
\n
"In one of the two crossover trials we excluded because we did not have data on the first period separately, a healthy volunteer committed suicide, which was mentioned in both published articles. She had received duloxetine in increasing doses for 16 days, tapered off the maximum dose of 400 mg daily very quickly [in just four days according to the design of the study] and killed herself four days later while on placebo. The authors, several of whom were employees of Eli Lilly or owned stock in the company, judged her suicide lto be unrelated to study drug treatment, although it is well known that the suicide risk is high when an antidepressant is stopped abruptly…<\/div>\n<\/blockquote>\n
This case is discussed in more detail in a 2005 Slate<\/font> article<\/a> by Jeane Lenzer.<\/div>\n
\n
If there’s an area where more has been written about a single controversy than the question of suicidality\/akathisia as an adverse effect of the SSRI\/SNRI medications, I don’t know what it would be. Prozac was introduced in 1987, and by 1990, the issue of suicidality was soon on the front burner…<\/div>\n
\n
In 1990, Teicher and colleagues reported on the emergence of suicidality on fluoxetine in a group of six patients. These reports were followed-up by reports from King et al., Creaney et al. , Rothschild and Locke  and Wirshing et al., among others, reporting other cases where suicidality appeared to emerge in individuals taking fluoxetine.<\/div>\n
from Healy2000<\/sub> <\/div>\n<\/blockquote>\n
… where it continues to simmer to this day with a history too long to even think about summarizing. These two meta-analyses approach  one of the lingering controversies, "Can these drugs cause the Akathisia syndrome, a precursor of violence and suicidality, in normal non-depressed people.<\/font><\/em>" But one can almost hear the critics in the background saying, "Wait a minute. There’s no suicides, suicidality, or violence in any of these trials. You mean to say that<\/font><\/em> activation<\/font><\/em><\/strong>,<\/font><\/em> agitation<\/font><\/em>,<\/font> akathisia<\/font><\/em><\/strong>, or<\/font><\/em> agita<\/font><\/em><\/strong> are enough for you to extrapolate forward to say they are precursors to suicide or violence? Where’s your evidence!?<\/font><\/em>" And the believer might come back with, "Have you looked at all the case histories posted on<\/font><\/em> SSRIstories<\/a><\/em> [see also<\/font><\/em> The Story of SSRI Stories<\/a><\/em>] and elsewhere!?<\/font><\/em>" And in another version, this kind of back and forth has gone on with the black box warnings of suicidality on all antidepressants since 2004 almost ad infinitum. What’s a practicing physician to take from all 29 years [2016 – 1987 = 29<\/font><\/em>]<\/span> of these dueling reports and studies?<\/div>\n
[stay tuned…<\/font><\/em>] <\/div>\n","protected":false},"excerpt":{"rendered":"

The presidential election is finally over and I want to get back to where I left off last month in the post in polite company… when I said: Articles like these are part of a great big wake-up call, and I’m not sure they’re reaching the right audience in the right ways. For the moment, […]<\/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_forum_subforum_count":0,"footnotes":""},"categories":[5],"tags":[],"class_list":["post-69144","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/69144","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=69144"}],"version-history":[{"count":43,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/69144\/revisions"}],"predecessor-version":[{"id":69194,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/69144\/revisions\/69194"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=69144"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=69144"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=69144"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}