Lead Story: The FDA AD suicide warning - a detailed follow-up

Also in this issue:  Thank you, readers, Britney Spears suicide video, Spongebob Squarepants, Yoga for Depression, Talking therapy vs AD, New BP depression guidelines, SSRIs for heart patients, Atherosclerosis, Dual dx, Lithium orotate, What's a BP’s life worth? Rowan Atkinson, The Mad Poet’s Society, A depressed elephant story, Next Week, McMan's Web, Donations

The Plot Thickens

Newsletter 6#7 was entirely devoted to the issues that went into the FDA’s March decision to require manufacturers to issue suicide-risk warnings and other related cautions on their antidepressants. The FDA based its decision on its analysis of 25 pediatric antidepressant trials (16 related to depression) involving 4,000 kids, and the testimony of its own experts plus more than 60 members of the public. Three months earlier, the FDA’s counterpart in the UK, the MHRA, contraindicated all new generation antidepressants for pediatric use except for Prozac.

Some authorities contend that in small groups of patients suicidal behavior and mental agitation may emerge as a result of antidepressant treatment independent of depression. The FDA did not weigh in on the matter of causation, but clearly acted on the basis of a perceived association. In its public deliberations, an FDA panel expressed its concern over the low success rate of pediatric antidepressant trials. A pair of articles in the British Medical Journal and The Lancet carry the issue further, namely:

In an article in the BMJ, Jurendi et al analyzed the quality of six of the seven published pediatric studies (one was considered irrelevant) of the newer antidepressants underwritten by the pharmaceutical companies. In just two trials did the antidepressant show a clear advantage over the placebo. Of 42 reported measures in all the studies, say the authors, "only 14 showed a statistical advantage for an antidepressant." Claims for effectiveness were based entirely on ratings by doctors. Of 10 measures relying on patient or parent reports, none "showed significant clinical advantage for an antidepressant." No study presented data on rates of attempted self-harm, emergency treatment, or school attendance. Drop-out rates ranged from 17 to 32 percent for those on antidepressants and 17 to 46 percent for placebo-treated patients, too high, say the authors to produce reliable results, notwithstanding statistical fictions such as "last observation carried forward."

In an aside, the authors note that eight of nine unpublished studies failed.

Jurendi et al criticized the authors of the published studies for exaggerating the drug’s benefits or downplaying their harm or both. For example, one trial of 93 kids on Paxil produced 11 serious adverse events in a short space of time compared with two of 87 in the placebo group. Despite this, together with the fact that seven of the patients were admitted to the hospital, the authors of that study concluded that the drug "was generally well tolerated in this adolescent population, and most adverse effects were not serious."

Since doctors increasingly rely on online abstracts, which publish the misleading claims but not the contradictory data, the potential for mischief is high, Jurendi et al contend.

Meanwhile, in one Paxil study and two Prozac studies the primary outcome measures were changed after the fact. Despite a review of the Prozac studies by the US Center for Drug Evaluation and Research that determined that "the sponsor did not win ... based on the protocol specified endpoint," and that the evidence based on the pre-specified endpoint was not convincing, the FDA approved Prozac for pediatric depression.

In the Lancet article, Whittington et al examined 11 published and unpublished pediatric trials involving five newer antidepressants, concluding that only Prozac suggested a favorable risk-benefit profile. Published data from one Paxil trial produced mixed results, but when pooled with data from two unpublished studies the risks outweighed the benefits. Pooled data from two published Zoloft studies showed similar mixed results plus a new study outcome (brought to light by a UK public authority ) that did not support the drug.

The authors note that published trials form the basis of treatment guidelines, but that suppressing unpublished data "can ultimately lead to recommendations for treatments that are ineffective, cause harm, or both." The authors of the BMJ article make a similar point, concluding that "accurate trial reports are a foundation of good medical care. It is vital that authors, reviewers, and editors ensure that published interpretations of data are more reasonable and balanced than is the case in the industry dominated literature on childhood antidepressants."

Say no more.

An Important Consideration

It must be emphasized that just because drug industry data leaves a lot to be desired does not necessarily mean antidepressants should be off-limits to kids. One piece of data that cannot be ignored is that older youth male suicide rates, after tripling over four decades, began dramatically dropping in North America, Europe, and other regions soon after SSRIs were introduced.

The Case for Warnings

Arguably the most convincing case that antidepressants carry clear warnings came from the written testimony to the FDA of the Child and Adolescent Bipolar Foundation, whose members comprise parents of bipolar kids (its oral testimony was briefly cited in Newsletter 6#7). In January, the CABF surveyed its 17,000 members. Of the 15 percent who responded, 89 percent reported that their child was treated with an antidepressant. Of these, 55 percent reported that their children had become suicidal before taking an antidepressant, and 45 percent that their child had become suicidal some time after first taking an antidepressant - 1.4 percent of these within 24 hours, 11 percent in one to seven days, and 15 percent between eight and 30 days. Four parents reported that their child committed suicide while taking or after taking an antidepressant.

Twenty percent of the survey responders were convinced that their own children became suicidal due to treatment with an antidepressant. One parent reported their six-year-old son became "hyper" on his first antidepressant, and "very agitated" on the second. Despite this, the doctor increased the dose, sending the boy into a total psychotic state that included hallucinations, severe suicidality, severe paranoia, and homicidality, all new symptoms. Another reported that after trying his first antidepressant, their nine-year-old son tried to run out into traffic. The second antidepressant initially seemed to help, but three weeks later he started cutting himself with a knife.

According to the CABF: "Clinicians lack data on how to distinguish between bipolar depression and unipolar depression, or how to predict which children with depression will develop bipolar disorder, although there are some theories under study. Children with depression are at high risk to switch to bipolar disorder: in one study by Dr Barbara Geller of 72 pre-pubertal children with depression, up to 48 percent developed mania (and thus, bipolar disorder) by age 20."

Moreover: "Many parents also report that the treating clinician did not ask about other family members with mood disorders to determine if the child might be at elevated risk for bipolar illness, nor do doctors often inquire as to any history of manic symptoms in their patient, the child, before prescribing an antidepressant."

The CABF acknowledged that they had received positive comments from parents, noting cases where suicidal ideation stopped after their children were put on antidepressants. They also noted a large decline in the older adolescent suicide rate corresponding with the rise in the use of antidepressants. Accordingly, the CABF opposed the ban of any off-label use of antidepressants or other psychiatric meds for children, but recommended that "the FDA require antidepressant manufacturers to add a black box warning to their labeling, similar to the black box on the labeling for Accutane, informing clinicians and parents of a possible potential for the drug triggering or worsening suicidality, as well as mania or rapid-cycling bipolar disorder, in some children. Such a warning would alert clinicians and parents of the need to watch carefully for the emergence of these behaviors and take protective action immediately if the behaviors emerge."

Outrage of the Year

After promising to remove a controversial bathtub suicide scene from her new music video, "Everytime," following a public outcry, Britney Spears left in the scene anyway, slightly modified, claiming the video is about reincarnation rather than suicide. The video shows her in a clearly distressed mood retreating to the bathroom following a violent argument with her explosive boyfriend. In the tub, her exposed wrist reveals a dripping thin line of blood. She opens her fist to reveal more blood on her palm. Behind her, there is blood on the edge of the tub. She slides beneath the surface to yet another display of blood, this time mixing with the bath water. A series of surrealistic scenes follow, with Britney belting out her new tune as she is drawn to the light, as a medical team attempts to revive her, as a woman in a nearby unit is giving birth, and as she is receding from the light. The refrain includes:

"I see your face, you're haunting me /I guess I need you baby"

The final scene shows Britney buoyantly emerging from beneath the bath water - no blood in sight - as if she had merely rinsed her hair.

Said Don Austin, founder of Thursday’s Child, a national service for at risk kids, to the SF Chronicle: "Britney Spears is one of the most influential teen role models on the planet, and this video is frightening in terms of its potential repercussions. When kids see this video over and over, it has a desensitizing effect. There are a lot of confused kids around, and Britney's not considering the copycat effect. Instead, she's selfishly using controversy to market herself."

Meanwhile, Yahoo! prominently promoted the video on its homepage for at least two days.

Who Lives in a Pineapple Under the Sea?

At last we have a bipolar TV character who comes across as lovable - Nickelodeon’s ubiquitous Spongebob Squarepants, whose underwater misadventures make Jessica Simpson look like a charter member of Mensa. Says creator Stephen Hillenberg on a 2003 Spongebob DVD: "Spongebob spends a lot of time laughing and crying. He’s a total bipolar character. Always the extremes. There’s no in between with Spongebob. He’s either completely giddy and ecstatic or so far down in the dumps."

Oops!

Last Newsletter messed up the title of Amy Weintraub’s excellent new book on yoga and depression. The correct title is "Yoga for Depression: A Compassionate Guide to Relieve Suffering Through Yoga." You can purchase Yoga For Depression at Amazon.com and help support this Newsletter in the process by clicking the above link.

IPT OK

A University of Pittsburgh study of 32 depressed women found that, "contrary to expectations," those who received eight-session interpersonal therapy "improved more quickly" than those who received Zolft.

Treating BP Depression

An international panel of experts has published a consensus guideline for treating bipolar I depression. Main recommendations, as reported in an article on Medscape, include:

Other points:

The Mad Poets Society

A California State University at San Bernardino study of 1,987 dead writers has found that poets lived on average 62 years, playwrights 63, novelists 66, and nonfiction writers 68. Female poets were much more likely to suffer from mental illness, what study author James Kaufman labeled as "the Sylvia Plath effect."

Jumbo-Sized Depression

Apparently elephants can get depressed. Mensry, a performing elephant in the Spanish Circus touring in Argentina was left in police custody as a result of a town ordinance forbidding animals from participating in public shows. Local vets pronounced her as suffering from depression and stress as a result of separation from her loved ones. Authorities resolved to move Mensry to more comfortable quarters and get her depression treated until she is able to rejoin the circus.

Do you start a five-ton mammal on three buckets of Prozac or five?

Next Week

I will be attending the American Psychiatric Association's annual meeting in New York, May 1-6, where I will be listening to a lot of very smart people.  Accordingly, there will be no Newsletter for the next couple of weeks, but you can look forward to a wealth of APA-generated stories soon after my return.

McMan's Web

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"Knowledge is necessity."