{"id":52971,"date":"2015-01-07T09:10:38","date_gmt":"2015-01-07T14:10:38","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=52971"},"modified":"2015-01-07T20:20:04","modified_gmt":"2015-01-08T01:20:04","slug":"boxes-black-are-back-ii-a-confusion-of-tongues","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2015\/01\/07\/boxes-black-are-back-ii-a-confusion-of-tongues\/","title":{"rendered":"boxes black are back II: a confusion of tongues<\/em>\u2026"},"content":{"rendered":"\n

I’m obviously not writing about this because I’m conflicted about the Black Box Warning. I’ve seen enough adolescent patients with the Akathisia syndrome from SSRIs to know it’s a real thing. And I know of completed suicides that I am convinced were SSRI induced. In addition, I am underwhelmed<\/em> with the claimed efficacy of SSRIs in adolescents in Clinical Trials [I think I’ve read them all in the course of researching for this blog]. I would and have prescribed SSRIs to adolescents in situations where both the teen and some responsible adult will listen to the warnings and agree to being closely observed. The few cases where I’ve done that have been with habitual compulsive behaviors [bulemia, cutting, etc] with  success. So I am perfectly fine about the Black Box Warning staying exactly like it is. Good job FDA… <\/p>\n

I am writing about this once again because of the confusion of tongues<\/font><\/strong><\/em> that swirls around this issue. The one solid fact that emerged from the population studies is that the prescription rate of antidepressants either leveled out or fell [instead of continuing to increase] in response to the Warning. In Lu et al<\/a>, this was true for adolescents, young adults, and older adults – even though that initial warning only pertained to the adolescents.  <\/p>\n

In the two articles in PSYCHIATRIC<\/font>NEWS<\/font><\/strong> [boxes black are back I…<\/a>], Dr. Darrel Regier proposed that the reason for the fall-off in prescribing had to do with the widespread press coverage of the warning, scaring away doctors and patients alike [particularly primary care doctors who were prescribing the majority of antidepressants]. Regier proposed that the primary care doctors couldn’t follow the patients as closely as recommended, and were afraid of getting sued. He went further, saying that the drop in prescribing was not matched by referral for some other treatment modality [eg CBT], presuming that meant that depressed kids just weren’t being treated – a point echoed by Dr. Michael Thase in the article. Child Psychiatrist Dr. David Fassler [former APA Board member]  felt that the press coverage implied that the antidepressants increased the suicide rate, something unintended by the FDA – a point backed up by Dr. Thomas Laughren, team leader of the Psychiatric Drug Group within the FDA during the 2004 FDA hearings.<\/p>\n

All of this speculation about the psychology of the primary care physicians strikes me as hyperbole. If I were to wax eloquent about Drs. Regier’s and Fassler’s own inner workings, I expect they would break out singing some evidence-based medicine anthem in three part harmony [and accuse me of being a loose cannon]. And they sure don’t paint a very flattering portrait of primary care doctors – fear of lawsuits, basing clinical decisions on newspaper reports, turning away depressed adolescents "untreated." And further, they’re assuming that the abrupt halt to the escalating antidepressant prescription rate was a bad thing, rather than something perfectly reasonable – slowing down an avalanche.<\/p>\n

The time leading up to the 2004 Black Box Warning was the heyday of psychopharmacology when drugs continued to flow from the mythical PHARMA pipeline. Direct-to-Consumer ads for antidepressants blanketed the media. Drug reps detailing<\/em> psychoactive drugs and KOLs speaker’s bureaus were focusing on primary care physicians, specifically because of the much broader market than that reached by psychiatrists. Rather than see the de-escalation of antidepressant prescriptions as ignoring depressed teens, it seems much more plausible to suppose that the Black Box Warning appropriately neutralized the hype that had bombarded the general practitioners in those days – leading to more rational prescribing.<\/p>\n

\n

And so to the confusion of tongues<\/font><\/strong><\/em>…<\/p>\n

    \n
  1. \n
    The arguments in the two articles are not primarily against the content of the Black Box Warning – the reported signal for suicidal thoughts or behavior in RCTs of adolescents treated with SSRIs or the case reports of suicides presented to the FDA Hearing. These arguments are focused on the decrease in prescription of SSRIs that followed actually adding the Black Box Warning – a reproducible finding in multiple studies – and suggest that the quantity and quality of the media reporting at the time inappropriately scared clinicians and patients alike; leading to a fall in prescription rates; meaning that many depressed adolescents were being deprived of necessary treatment<\/font><\/em> or were not even being brought for treatment;<\/font><\/em> meaning that they were therefore vulnerable to depressive <\/em>suicide. <\/div>\n<\/li>\n
  2. \n
    The Randomized Clinical Trials of these drugs in adolescents have been the subject of intense scrutiny and many meta-analyses of both efficacy and adverse effects, specifically suicidality. Most of them have been reviewed in this blog along the way. The RCTs are industry funded, conducted by Clinical Research Organizations, and several are clearly ghost-written by agents working for the industry sponsor. A 2012 extensive Cochrane Collaboration Systematic Review concluded:<\/div>\n
    \n
    Newer generation antidepressants for depressive disorders in children and adolescents [Review]<\/a> <\/div>\n
    by Hetrick SE, McKenzie JE, Cox GR, Simmons MB, and Merry SN<\/div>\n
    Cochrane Database of Systematic Reviews<\/font><\/strong>. 2012 Issue 11. Art. No.: CD004851.<\/div>\n

    The Abstract<\/font>[abstracted]<\/sub><\/font><\/strong><\/em><\/p>\n

    BACKGROUND<\/font><\/strong><\/u>: Depressive disorders are common in young people and are associated with significant negative impacts. Newer generation antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are often used, however evidence of their effectiveness in children and adolescents is not clear. Furthermore, there have been warnings against their use in this population due to concerns about increased risk of suicidal ideation and behaviour.<\/div>\n
    OBJECTIVES<\/font><\/strong><\/u>: To determine the efficacy and adverse outcomes, including definitive suicidal behaviour and suicidal ideation, of newer generation antidepressants compared with placebo in the treatment of depressive disorders in children and adolescents.<\/div>\n
    SEARCH METHODS<\/font><\/strong><\/u>:…<\/div>\n
    SELECTION CRITERIA<\/font><\/strong><\/u>:… <\/div>\n
    DATA COLLECTION AND ANALYSIS<\/font><\/strong><\/u>:…<\/div>\n
    MAIN RESULTS<\/font><\/strong><\/u>: Nineteen trials of a range of newer antidepressants compared with placebo, containing 3335 participants, were included. The trials excluded young people at high risk of suicide and many co-morbid conditions and the participants are likely to be less unwell than those seen in clinical practice. We judged none of these trials to be at low risk of bias, with limited information about many aspects of risk of bias, high drop out rates and issues regarding measurement instruments and the clinical usefulness of outcomes, which were often variously defined across trials. Overall, there was evidence that those treated with an antidepressant had lower depression severity scores and higher rates of response\/remission than those on placebo. <\/font>However, the size of these effects was small with a reduction in depression symptoms of 3.51 on a scale from 17 to 113 (14 trials; N = 2490; MD -3.51; 95% confidence interval (CI) -4.55 to -2.47). Remission rates increased from 380 per 1000 to 448 per 1000 for those treated with an antidepressant. There was evidence of an increased risk (58%) of suicide-related outcome for those on antidepressants compared with a placebo (17 trials; N = 3229; RR 1.58; 95% CI 1.02 to 2.45). This equates to an increased risk in a group with a median baseline risk from 25 in 1000 to 40 in 1000. Where rates of adverse events were reported, this was higher for those prescribed an antidepressant.<\/font><\/strong> There was no evidence that the magnitude of intervention effects (compared with placebo) were modified by individual drug class.<\/div>\n
    AUTHORS’ CONCLUSIONS<\/font><\/strong>: Caution is required in interpreting the results given the methodological limitations of the included trials in terms of internal and external validity. Further, the size and clinical meaningfulness of statistically significant results are uncertain. However, given the risks of untreated depression in terms of completed suicide and impacts on functioning, if a decision to use medication is agreed, then fluoxetine might be the medication of first choice given guideline recommendations. Clinicians need to keep in mind that there is evidence of an increased risk of suicide-related outcomes in those treated with antidepressant medications.<\/div>\n

    from the Review:<\/em><\/p>\n

    A U T H O R S ’ C O N C L U S I O N S<\/font><\/strong><\/div>\n
    Implications for practice<\/font><\/u><\/div>\n
    The evidence for the effectiveness of newer generation antidepressants compared with placebo in the treatment of depressive disorder in children and adolescents is not compelling; the overall effects of antidepressants compared with placebo were not modified by drug. The methodological shortcomings of the trials make it difficult to interpret outcome data on the efficacy of newer generation antidepressant medications. This is a particularly unsatisfactory since large numbers of children and adolescents have participated in trials, and we are still unable to answer the important clinical question of whether antidepressant medications are effective in treating depressive disorders<\/font><\/strong>. The search for treatments that reliably lead to good clinical outcomes must continue. Even when there is evidence that newer generation antidepressants reduce depression symptom severity, it is unclear whether the difference in effect between antidepressants and placebo reflects a difference that is of clinical importance to patients… <\/div>\n<\/blockquote>\n
    I would say this review is, if anything, too forgiving…<\/div>\n<\/li>\n<\/ol>\n

    My borrowed title [the confusion of tongues<\/font><\/strong><\/em>] refers to two communications [1. and 2.] that pass on the street as strangers with neither mutual recognition nor resolution. The scenario in 1. describes a vital treatment which, if missed, may have dire consequences. Whereas, the evidence in 2. suggests that the same treatment for the same problem is borderline effective, if at all, and, if used, may have the same dire consequences. The Black Box Warning being challenged is backed by independent meta-analyses and numerous case reports. The opposition to the Black Box Warning proposes that the physicians and patients who responded to it by failing to continue an escalating usage pattern were swayed by the initial media response and are neglecting real medical and psychiatric needs out of fear, yet no credible evidence has been mustered to support that hypothesis after a decade of persistent trying. The argument [1.] still rests on unsubstantiated speculations about the motivations of a large, heterogeneous group of physicians and guesses about the original intentions of the FDA, rather than scientific evidence. And the burden of both commercial and ideological bias is clearly carried by those opposing the Black Box Warning.<\/p>\n

    There is a second confusion of tongues<\/font><\/strong><\/em> in this story. In my view, Medicine is practiced at the interface between the physicians’ learning from groups and the experiences of the physician and patient in the room. The groups are the history of Medicine passed through school, training, lifelong learning, journals, meetings, supervisors, colleagues, previous experience with other patients, mistakes and successes, life, etc. The patient brings their own learning, their life, and their complaint\/dis-ease. So it’s at that interface where the knowledge from groups [evidence-based medicine, n=many] and the needs of the unique individual come together [n=1]. The point of meeting is to arrive at the best case path into the future for that patient – the real<\/u> meaning of "personalized medicine." In this controversy [the Black Box Warning], we’re operating in an area where the group information has been contaminated by commercial interests and ideological struggles. The influential groups opposing the Black Box Warning represent an ideological group who are speculating about another amorphous group – clinicians. They are proposing that warning the clinicians of a potential problem has lead to an error, so we shouldn’t warn them?? however rare?? Operating without being warned, they may ultimately help more people in their ignorance [or silence]?? And perhaps we shouldn’t warn our patients either so they’ll follow our [proxied] advice?? There’s nothing I know about Medicine that supports that confusion of tongues<\/font><\/strong><\/em>. These highly placed doctors are are not thinking like clinicians, and their group-think has no place in the hierarchy of Medicine as I know it. They’re not speaking the right language in argument 1. Individual physicians have to construct an individualized risk\/benefit<\/font><\/strong><\/em> ratio on every shared decision from a baby aspirin a day to dangerous and life threatening chemotherapy using known poisons. You can’t do that living in the dark about risk…<\/div>\n
    \n
    Added response to a query<\/font><\/strong>:  The term<\/font> confusion of tongues<\/font><\/strong> originated in the initial fragmentation of human languages described in the Book of Genesis 11:1–9, as a result of the construction of the Tower of Babel. My "borrowing" was from the 1924 paper Confusion of the Tongues Between the Adults and the Child [The Language of Tenderness and of Passion]<\/u> by S\u00e1ndor Ferenczi about the resulting problems experienced by sexually abused children from that kind of confusion…<\/font><\/em><\/div>\n","protected":false},"excerpt":{"rendered":"

    I’m obviously not writing about this because I’m conflicted about the Black Box Warning. I’ve seen enough adolescent patients with the Akathisia syndrome from SSRIs to know it’s a real thing. And I know of completed suicides that I am convinced were SSRI induced. In addition, I am underwhelmed with the claimed efficacy of SSRIs […]<\/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-52971","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/52971","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=52971"}],"version-history":[{"count":58,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/52971\/revisions"}],"predecessor-version":[{"id":53030,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/52971\/revisions\/53030"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=52971"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=52971"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=52971"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}