"repeated studies have shown antidepressant drugs are no more effective in children than placebos." - Dr. Joseph Glenmullen

The literature is mixed on this topic. It is far from conclusive. I'm sure there will be more on that later, if the thread has some life.
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First some points from the author of the quote above and his book, Prozac backlash.

The president of American Psychiatric Association to labeled the contents in the book Prozac Backlash to be, "total nonsense".

The president of the National Mental Health Association said, "the truth about depression and its treatment is just the opposite of what the book claims...Our organization has worked hard over the past decade to raise awareness about depression and the need to get help. We're concerned that people may decide against seeking appropriate treatment for this serious illness after hearing about this book."

Furthermore, a researcher who is quoted by Glenmullen had this to say about the author; "In cases where Dr. Glenmullen quoted studies published by me, he quotes the work out of context to fit his needs....This book is misleading, and does a great disservice to people with depression"." said Anthony Rothschild, MD, professor of psychiatry at the University of Massachusetts Medical School.

Rosenbaum also questioned a book-jacket mention of Glenmullen as a clinical instructor at Harvard Medical School. 'I've been at Harvard Medical School 25 years and I've never seen, heard or met the guy.'"

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If you want creditability as a Scientist you would do anything possible to distance yourself from the likes of Dr. Peter Breggin. Breggin claims Glenmullen based much of initial research from himself and his wife. Wiki goes on to state that Glenmullen never countered Breggin's claim that he was at a ICSPP conference in 2004. The ICSPP is organization that Breggin founded and is totally antipsych. They would have us believe that ADHD and Schizophrenia do not exist.

Glenmullen's personal website is called ->http://www.prozacbacklash.com/
In a similar vain antipsych Dr. Baughman's personal website is entitled ->http://www.ADHDFRAD.com

From the horses mouth in CCHR ->"Despite the repeated references to the genetics of ADHD being unequivocal, no claim of a gene for a psychiatric condition has stood the test of time, in spite of popular misinformation."

He has never published in a medical journal. He also was at the forefront of the recent, antidepressants cause people to commit suicide debate and the unsuccessful warning label change.

SO-whats you query?-or are you taking your teaching role, out of the classroom here?

Not sure where the tone is coming from Attention, but there you go. :rolleyes:

I haven't digested the lot of that information yet scuro, but I was glad to have the post.
Cheers!

Thanks Scuro :) its always good to see new information, especially as I transit from an incorrect chronic depression DX to the proper BPII DX!

Very helpful stuff and lacking in "tones" ;). We all have something to teach now don't we?

I'm going to quote myself because I'm to lazy to retype all of this. I'm not anti medication. I'm just quoting some sources that have really made me question it's effectivness for children. This author William Appleton, MD (another Harvard Medical School Professor) is saying the same thing as Glenmullen in his book The New Anti Depressants and Antianxieties.

His book comes highly recommended by Dr. Michael Ebert, editor of the Journal of Clinical Psychology who wrote, "Excellent...although the book is easy to read, it is actually quite dense with facts...useful for the physician or layperson". This book takes a very positive tone on the effects of anti depressant medication, but not it's superiority to placebo when it comes to children.

Quote:
<TABLE cellSpacing=0 cellPadding=6 width="100%" border=0><TBODY><TR><TD class=alt2 style="BORDER-RIGHT: 1px inset; BORDER-TOP: 1px inset; BORDER-LEFT: 1px inset; BORDER-BOTTOM: 1px inset">Originally Posted by The New Anti Depressants and Antianxieties


"Despite several attempts at placebo-controlled studies of antidepressants in children and adolescent depression, no difference has been found between the effects of the drug and those of the placebo. Unfortunately, no psychotherapy or drug therapy of early-onset depression has been effective in uni-polar or bipolar children or adolescents. Nonetheless, Prozac and other antidepressants are widely used in depressed young people by clinicians who believe them to be effective. There is no general consensus as to which children are most likely to benefit at what dose and how long they should be treated. Children and adolescents do respond well to Prozac; it is just that they respond well to a placebo, too, and it is this high placebo response rate that makes it so difficult ot establish Prozac's superiority over a sugar pill......However, in severe childhood and adolescent depression, neither Prozac or a placebo seems to do much good. (Appleton, p. 118).


</TD></TR></TBODY></TABLE>
I don't have an ax to grind on this topic. Just trying to share relevent information on both sides of the discussion.

Hey, I know anti depressants can work -- they worked great for me -- took care of my migraines, mild depression/anxiety/OCD. impulsivity and so on -- I had terrible and I expect rather rare side effects but Prozac worked great on what I took it for but I'm not a child either (childish at times, but that's a whole 'nother discussion:p ).

Scattered

I found this article by the American Pediatric Association and found it interesting on some of the controvery concerning placebo vs anti depressant for children and adolescents. It bothers me that unfavorable studies are frequently not reported -- I think we need all relevent information. I've high lighted a couple things I found particularly interesting.


http://www.dbpeds.org/articles/detail.cfm?TextID=2ffice





Psychopharmacologic treatment of depression in children and adolescents has become increasingly common in the . There have been dramatic increases in the number of prescriptions written for antidepressant medication to children and adolescents. The majority of prescriptions for antidepressant medications in youth are written by primary care physicians.

Clinical trial evidence

Until 1997 no double blind placebo controlled trial had demonstrated efficacy of antidepressant medications in the treatment of youth with major depression. There had been a number of prior trials effected with a number of different medications including a number of tricyclic antidepressants and monoamine oxidase inhibitors. All earlier trials had negative results.

The first double blind placebo controlled trial to demonstrate efficacy in the treatment of major depression in youth was a study of fluoxetine with 97 subjects in an 8-week fixed dose (20 milligram) trial. Fifty-six percent responded on active drug versus 33% on placebo. A larger, more extensive trial was then done with fluoxetine. In this 9-week trial, there was also evidence of positive benefit, 41% achieving remission on active drug versus 20% on placebo, and 65% responding versus 53%. As a result of the two positive trials, an FDA indication was obtained for fluoxetine for treatment of major depression in children and adolescents.

March et al presented results in May,2004 of the "TADS" study of the effects of fluoxetine and cognitive behavioral therapy on major depression, fluoxetine combined with cognitive behavioral therapy was superior (71% response rate) to fluoxetine alone (63% response rate) cognitive behavioral therapy (43% response rate) and placebo (31% response rate).

Specific agents

Paroxetine was investigated in an 8-week trial comparing it to imipramine and placebo in a study of 180 subjects aged 12-18. Whereas there was evidence of statistical superiority for paroxetine for some measures, not all of the a priori primary indicators noted significant efficacy.

Sertraline was studied in two large trials that were combined into a single report with statistical analysis of both groups of subjects. Sixty-nine percent of subjects responded as compared to 59% on placebo, as measured by the Child Depression Rating Scale - Revised (CDRS-R).

Citalopram was studied in an 8 week double blind placebo controlled trial of 174 children and adolescents. The mean dose was 24 milligram/day. The primary outcome measure was response on the CDRS-R, defined as a score of 28 or less. There was a significantly different response rate on citalopram (36%) versus placebo (24%). The effect size was 2.9. The active drug was well tolerated in this study.

SO-whats you query?-or are you taking your teaching role, out of the classroom here?
Life is always about learning. I wouldn't be on this board if there was nothing to learn.

The quote came up on another thread. Unfortuneatly, another member was complaining that we should stick to the subject at hand which wasn't Depression medication. So I thought why not start a new thread, this topic is current and one should take the time to understand it, if such a blanket statement is to have any credence. The first thing I did was to examine the credibility of the author and there were many things that troubled me. I've posted my concerns above.

That doesn't make the statement invalid but if I am to consider the quote to be a valid statement, I would like to hear Scientists in the field state that.

American Academic of Pediatrics article continued from previous page:

http://www.dbpeds.org/articles/detail.cfm?TextID=2

I managed to screw up the address and name (hopefully I got it right this time) -- sorry.



A nefazodone trial has been conducted and presented in scientific meetings, but not published in refereed scientific journal. Benefit was reported in an 8 week, placebo controlled trial.


The picture, however, is complicated. There have been other published or presented negative studies. Milin investigated paroxetine and found no evidence of benefit. There was a lso a study of venlafaxine, which showed no evidence of improvement versus placebo.


Unpublished Reports with Negative Results


Further, there have been a number of negative studies which have been neither presented nor published. This includes trials on paroxetine, citalopram, venlafaxine and nefazodone. In addition, no double blind placebo controlled trials have been done in youth with other
depressive illnesses including dysthymia, adjustment disorder with depressed mood, and depression, NOS. In the placebo controlled trials, there are often exclusionary criteria for youth with suicidal ideation and other severity markers, which makes it difficult to generalize to common clinical situations.


A debate has arisen, as well as formal regulatory action, in Great Britain and the United
States. In June 2003, the British MHRA announced that paroxetine was contraindicated for the treatment of major depression. A week later, a warning was issued by the FDA in the United States cautioning against the use of paroxetine in the treatment of major depression in youth.


This debate has accelerated with a number of other medication delcared contraindicated in Great Britain including paroxetine, venlafaxine, citalopram, s-citalopram, sertraline, nefazodone and mirtazapine for the treatment of depression in youth. A meta-analysis of placebo controlled trial concluded that the risk benefit ratio was favorable only for fluoxetine. Concerns include the extent of benefit in the trials reported as positive, the several unpublished trials with negative results, and possible mood related side effects.

In the United States a parallel review process was undertaken by the FDA with a public hearing in February 2004 with the results of issuing heightened warning in children, adolescents and adults regarding the possible association of antidepressants and mood related side effects.


Not all experts agree with FDA


The majority of academicians responding to this issue in the United States has taken exception to these cautionary recommendations, who cite evidence of statistical improvement in at least some placebo controlled trials of antidepressants in youth and evidence that the side effect profiles of active drug versus placebo were not statistically different.


The controvery is occuring in the context of modest differences in active drug versus placebo in many of the trials which are identified as positive, and in the rising concern over a number of extensive trials that were undertaken and not published. There are differences of opinion across the Atlantic. At least some trials do indicate benefit.


The current consensus view in the United States is that SSRI's, particularly fluoxetine, are helpful in the treatment of major depression and they are very commonly prescribed. The appropriate practice when antidepressants are used in this era must include attention to informed consent about possible side effect issues and careful monitoring of mood and suicidal ideation.

This is a huge topic and I'm going to avoid the battle of citations for now. Instead, I'll provide a little reading so that all who are interested in the topic can get more background info.

http://www.contemporarypediatrics.com/contpeds/article/articleDetail.jsp?id=306590&pageID=2
Demystifying the black box warning on antidepressants: A protocol for safe prescribing in your practice
Don't let the FDA warning about suicidality discourage you from prescribing an antidepressant for the child or adolescent who needs it. These recommendations provide a guide to monitoring patients for suicidal ideation and other adverse effects.
Feb 1, 2006
By: Peter M. Ferren, MD, MPH
Contemporary Pediatrics

DR. FERREN is assistant clinical professor of psychiatry and child and adolescent psychiatry at the University of California, San Francisco and based in the Child and Adolescent Services clinic at San Francisco General Hospital.

Staff editors: KAREN BARDOSSI, Senior Editor, and JOHN BARANOWSKI, Editor, Contemporary Pediatrics

The author, manuscript reviewers, and staff editors have nothing to disclose in regard to affiliations with, or financial interests in, any organization that may have an interest in any part of this article.

The black box warning added to antidepressant medications for children and adolescents by the United States Food and Drug Administration (FDA) on October 15, 2004 1 has forced pediatricians throughout the US to reconsider their prescribing practice, address a flood of difficult questions from parents, and assume a new risk in prescribing. They must confront these issues armed only with limited resources for learning how to minimize risk and provide safe care.

Although the black box warning, which is rare on medications for pediatric use, is the strongest caution from the FDA to prescribers and patients regarding possible adverse effects, it is not a contraindication to using antidepressants in children. Antidepressant medication is an important treatment for the appropriate pediatric patient. American children and families cannot afford to have pediatricians withdraw from prescribing antidepressants when they are indicated; the risk of psychiatric morbidity and mortality for depressed and anxious children is far greater than the comparatively rare risk of developing suicidal ideation.

As one of the approximately 7,000 child and adolescent psychiatrists in the US,2 I commend those of you in primary care pediatrics who screen children for depression and anxiety, develop treatment plans for these disabling disorders, and prescribe antidepressant medication when it is appropriate. It is no surprise to any of you who have tried to refer a patient to a member of my specialty that we are few and far between, depending on where you practice, and we often have a long waiting list or a full practice. The American Academy of Child and Adolescent Psychiatry (AACAP) has been working tirelessly to address the tremendous work force shortage, but no easy solution exists. As a result, more American children are prescribed antidepressants by general practitioners and pediatricians than by child psychiatrists.3 The guidelines presented here are designed to decrease your anxiety about prescribing antidepressants and encourage you to continue to provide this important intervention to children who may otherwise have no access to medical treatment for psychiatric disorders.

A chronology of the SSRI controversy

In May 2003, the FDA and the United Kingdom's Medicines and Healthcare Products Regulatory Agency received a report from GlaxoSmithKline regarding the efficacy and safety of paroxetine (Paxil) in pediatric populations. One of three clinical trial data sets submitted suggested an increased risk of "possibly suicide related" events and "suicide attempts."4 Subsequently, the FDA issued its first Public Health Advisory recommending that paroxetine not be used in children and adolescents with depression and requested data on eight other antidepressants.4


The FDA’s black box warning

When summary data did not provide conclusive answers, the FDA solicited patient-level pediatric data; sought an independent, external review and classification of suicidality events by experts at Columbia University; and issued a second Public Health Advisory and talk paper noting "an excess in reports of suicidality for several antidepressants."4 By July 2004, the completed Columbia University analysis concluded that there was a small but real effect. Two months later, the discussion moved from the scientific community to the political arena when the US House of Representatives' Energy and Commerce Committee's Subcommittee on Investigations and Oversight held its first hearing on disclosure and publication of the clinical trials data. In addition, the FDA's Psychopharmacologic Drugs and Pediatric Advisory committees recommended a black box warning, and the House subcommittee demanded immediate FDA action. Lastly, two representatives threatened to introduce legislation banning the prescribing of antidepressants to anyone under 18 years of age if the FDA did not "act forcefully and swiftly to protect America's children."4 This culminated in the issuance of the black box warning on October 15, 2004.

The evidence for using antidepressants in children

Two months before the FDA issued the black box warning, the Journal of the American Medical Association published the Treatment for Adolescents with Depression Study (TADS), which provides the strongest evidence to date of the effectiveness of antidepressants in pediatric patients. TADS concluded that 71% of adolescents studied responded positively to a combination of cognitive behavioral therapy (CBT) and fluoxetine (twice the 35% placebo rate), and 60% responded positively to fluoxetine alone.5 For every three patients treated, therefore, one will improve from the effects of medication, one will improve because of a placebo effect, and one will not improve. This study is especially significant because demonstrating efficacy in pediatric patients presents a number of challenges:

* Pediatric patients are a small market share for pharmaceutical companies, resulting in fewer studies of children than adults
* Patent-extension incentives to include pediatric patients have contributed to potential bias in industry research
* Recruiting pediatric subjects is difficult
* Pediatric patients have a high placebo response rate to antidepressants, necessitating larger samples to demonstrate efficacy
* Antidepressant medications may have different efficacy across the life span.

Because of these challenges, TADS has become a professional counterargument to the sociopolitical forces that fuel the decline in prescribing antidepressants to children.

The rationale behind the black box warning

The Columbia University experts on suicidality consulted by the FDA retrospectively conducted a meta-analysis of 24 placebo-controlled trials of nine antidepressants of less than four months duration that enrolled 4,400 pediatric patients with major depressive, obsessive compulsive, and other psychiatric disorders. They concluded that the average risk of developing suicidal ideation while taking antidepressant medication was 4%, compared to a 2% risk while taking placebo.1 One in 50 children, therefore, developed suicidal ideation that could be attributed to antidepressant medication—although there were no completed suicides among the 4,400 patients.

In the opinion of one epidemiologist-general pediatrician member of the FDA Pediatric Advisory Committee, published to coincide with the issuance of the FDA directive: "Some FDA staff and committee members expressed reservations about the data used for this analysis. For example, there was a relatively small number of events, the trials had not been designed to evaluate suicidality, and the methods of ascertainment and classification of the events in the various trials were not uniform. To me, however, these concerns only made the results more compelling. Inadequate sample size and misclassification of outcomes make it more—not less—difficult to detect differences between outcomes in randomized, blinded trials. The fact that an association emerged from the meta-analysis with a p value of 0.00005, for an outcome that the sponsors of the trials were not looking for, and presumably did not wish to find, was quite convincing."6

Two weeks after the FDA's directive, the president of the AACAP sent a letter to members asserting: "It should be noted that only 78 of the 4,400 patients experienced suicidal thinking or suicidal behavior, but no suicides occurred in these trials.... The FDA research has shown a 2% increase [in suicidal ideation] over that created by the use of placebo...[Coupled with the findings of the TADS study,] on average each practitioner would need to treat just three patients to see a strong response to fluoxetine...in contrast to the need to treat over 50 patients in order to see evidence of the medication causing suicidal ideation or suicidal behavior."7

These opinions from professionals in leadership positions regarding the risk-benefit ratio of antidepressants for children illustrate the two poles of the ongoing debate.

Professional organizations respond

Soon after the FDA issued the black box warning, the American Academy of Pediatrics (AAP) voiced its support but urged the FDA to reconsider and alter the warning to preserve patient safety and decrease liability concerns.8 Specifically, the AAP expressed concern that:

* The monitoring program ("weekly face-to-face contact with patients or their family members or caregivers during the first four weeks of treatment...") is not appropriate for practice and clinic settings

* The word "ideally" may be interpreted as a gold standard that opens physicians to lawsuits for anything less

* The inclusion of "other psychiatric disorders" suggests that obsessive-compulsive disorder and social anxiety need equivalent monitoring
* Poor reimbursement for service may reduce access to care—that is, public and private insurance companies may not pay for the weekly visits recommended by the warning, and self-paying patients may not be able to afford weekly visits.

The Assembly of Regional Organizations of Child and Adolescent Psychiatry, a subgroup of AACAP, wrote: "This decision will frighten and confuse parents, families, and legal guardians and reduce the likelihood that they will seek treatment for their children with psychiatric disorders. Others may discontinue effective treatment...We are also concerned that pediatricians and family practice physicians will become more reluctant to prescribe these medications, only further restricting the availability of help to youngsters in need."9

Since the controversy began in 2003, the number of antidepressant prescriptions written for children and adolescents has decreased substantially.10 Although a certain percentage of children may have been prescribed these medications inappropriately, a significant likelihood exists that they are not being offered to children who would benefit from them. The American Psychiatric Association and AACAP have jointly prepared medications guides for physicians and parents that are available on the World Wide Web (www.parentsmedguide.org) as educational resources for physicians and families.11

Which medications must carry the warning?


Table 1: Drugs required to carry the black box warning on suicidality in children and adolescents
The black box warning is not limited to SSRI antidepressants. At least 32 brand-name medications (29 generics), including selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and novel medications with antidepressant properties, also carry the warning (Table 1).12 The rationale is twofold. First, although the warning is based on data for SSRIs, the mechanism is unknown and may be relevant to other psychoactive medications. Second, the SSRIs remain revolutionary in their overall safety in comparison to older medications such as MAO inhibitors and tricyclic antidepressants, which have proven ineffective in treating depression in children despite their utility in adults.13 For this reason, the FDA did not want to drive prescribers toward ineffective medications that have their own significant medical risks (Newman TB: Personal communication, September 14, 2004). It is important to note that some medications that carry the warning are commonly prescribed for nonpsychiatric purposes, such as pain or insomnia, in children who are neither depressed nor anxious. Nevertheless, the same disclosures must be made and precautions taken.

The real problem: Accurate diagnosis

In my opinion, pediatricians in primary practice are more likely to struggle with accurately distinguishing straightforward depression and anxiety in children from more complex disorders (bipolar disorder, posttraumatic stress disorder) and identifying environmental stressors (trauma, abuse) than with safely monitoring their patients' response to antidepressants. Pediatric training and practice are not designed to promote the thorough assessments that are the standards of training and care for child and adolescent psychiatrists. Mental health assessments require extensive history-taking and collaboration with parents, agencies, and schools to glean an accurate diagnosis from multiple confounding environmental factors. Prescribing medication without understanding the child's context is a prescription for a problem rather than a solution.

So what are you to do? I recommend that you identify pediatric mental health providers in your community whose diagnostic and treatment skills you trust and develop collaborative partnerships with them. A skilled and experienced psychologist (PhD or PsyD), licensed clinical social worker (LCSW), or master's in family therapy (MFT) may be available when a child psychiatrist is not. Such professionals can assist you with diagnosis and implement psychotherapy treatment plans, which are also crucial for many children who are prescribed medication.


Table 2 : Adverse effects of antidepressant medication
It is up to you, however, to acquire the medical knowledge of both common and rare antidepressant side effects—including how to identify phenomena such as activation, irritability, hypomania, and akathisia (Table 2)—that may be linked to the emergence of suicidal ideation. Lastly, knowing how to screen children for suicidal ideation should be a routine part of pediatric practice, regardless of whether the child is on psychiatric medication.

A monitoring tool for the pediatrician

Before the FDA directive, a child psychiatrist might follow up at monthly intervals with a low-risk patient who was newly prescribed an antidepressant and instruct the family to call with questions or concerns between appointments. The new recommendation for six follow-up visits in the first eight weeks of antidepressant treatment may seem discouraging and burdensome to both physicians and patients, but it is not an unattainable goal.

When the FDA issued its directive, a standardized monitoring tool for physicians was unavailable. At San Francisco General Hospital, a teaching hospital affiliated with the University of California, San Francisco, I am piloting a documentation tool designed to allow the primary care provider to capture the essential elements of a safety assessment and direct them to an appropriate action based on a child psychiatrist's assessment and thought process. Although the tool has not been validated, neither is the FDA's recommendation for weekly monitoring evidence-based or known to be effective. Both the FDA recommendation, accepted by AAP and AACAP, and the monitoring tool can be considered good-faith efforts to address a poorly understood phenomenon as we await evidence-based practice parameters based on prospective research.


Table 3 : SSRI monitoring form for a primary-care physician














Table 3 is for the primary-care pediatriction and Table 3A is for the primary care pediatric nurse practitioner or physician assistant supported by a physician


Table 3A

Essential elements of the tool include documenting:

* the parent or guardian's presence and contribution to the safety assessment
* whether the parent and child are adhering correctly to the medication regimen as prescribed
* minor, common side effects
* worrisome side effects, including frank suicidal ideation
* the practitioner's own assessment of the patient
* four standardized assessments linked with directive actions.

A protocol for prescribing in pediatric practice


Table 4 : Protocol for pediatric prescribing
Table 4 summarizes the steps that you can take in your practice to adapt to the new monitoring recommendations for antidepressants prescribed to children and adolescents. Although the stakes may seem higher than those associated with a weekly follow-up appointment for antibiotic-treated otitis media and other common pediatric ailments, the principle is the same: Ensure that treatment is effective and that complications are recognized.

By increasing your knowledge of both the positive and adverse effects of antidepressant medications; by partnering with skilled, nonmedical child mental health providers; and by using a monitoring tool, you can continue to prescribe antidepressants to children in your primary care practice. You'll also become confident that you will recognize and respond to the rare antidepressant-induced emergency—just as you do to a suicidal child in your practice who is not taking antidepressant medication.

and more ...
http://www.neuropsychiatryreviews.com/dec04/npr_dec04_FDAblackbox.html
FDA BLACK BOX WARNING ON ANTIDEPRESSANTS CREATES CONCERNS FOR CLINICIANS

WASHINGTON, DC— Physicians who treat children with depression are left with many unanswered questions in the wake of the FDA’s recent request that a black box warning be put on the labels of all antidepressant medications. As part of its multipronged public health advisory issued in October, the agency directed drug manufacturers to add the more prominent warning regarding an increased risk in suicidal thoughts and behavior for children and adolescents taking antidepressants, and it also emphasized the need for close monitoring of patients who begin these medications. The FDA is also compiling a Patient Medication Guide that will be given to patients who use the drugs to advise them of this risk as well as precautions that can be taken. The new language does not prohibit the use of antidepressants in children and adolescents but rather, in essence, may shift more focus and responsibility to health care professionals as far as assessing the risks and benefits of the medications they prescribe for their patients.

“The present issue for pharmacotherapy is that the risk/benefit ratio for pediatric patients remains favorable with fluoxetine, [which] will likely be the only antidepressant in the near future with an indication for pediatric major depressive disorder,” said Bruce Waslick, MD, who is an Associate Clinical Professor of Psychiatry and Director of the Children’s Day Unit at the Columbia University Medical Center in New York City. “There’s really no clear guideline to something that we are thinking a lot about—What do we do if somebody does not do well on fluoxetine? What are we going to do as the next step? Do we [prescribe] another selective serotonin reuptake inhibitor (SSRI), even though there is no robust efficacy, no indication, plus the black box warning? Do we add things to SSRIs?”

Complicating matters is the inherent difficulty in trying to differentiate between children who develop suicidal thoughts as a result of medication and those who become suicidal due to their depression. “If you are treating depressed kids, you are going to see some getting suicidal,” Dr. Waslick continued. “It’s not clear to me how you are going to identify the kids who are having an adverse medication reaction versus kids who are getting suicidal during the course of their depression. And there’s nothing given from the data that would lead you to suggest that you can actually distinguish those two things. If kids get suicidal and they are on an antidepressant, should we wait longer and see if they will get better from the antidepressant, or should we get them off because we have to assume that they are all adverse events? It’s not clear to me how we’re going to be able to do that. We’re going to get some experience with it over the next few years.” Dr. Waslick made his comments during a presentation at the 51st Annual Meeting of the American Academy of Child and Adolescent Psychiatry.

Potential medical-legal liability that may arise from a child who has an adverse event is a cloudy issue at the moment. Considering the fact that, according to the FDA, on average there is one adverse event for every 50 patients treated with SSRIs, many clinicians will eventually encounter such a case. “Does the black box warning protect the company but hurt the physician?” asked Dr. Waslick. “Does it help the physician if you institute the monitoring and some bad thing happens? Are [physicians] going to be more or less liable? I’m not sure what medical-legal issues are going to result from this. It makes me nervous. It makes me cautious and conservative. I’m not sure what the physician liability responsibilities are here.”

REVIEW OF EFFICACY DATA

The leading medical journals are lagging behind in terms of published efficacy data concerning antidepressants, with the FDA basing its actions in the past year largely on unpublished data, according to Dr. Waslick. In looking at the published efficacy data that are available, tricyclic antidepressants, for example, have been shown to have a “reasonably robust positive effect” in adults, Dr. Waslick noted. They also have been studied in children and adolescents with depression in sample sizes ranging from nine to 60. In comparison, some of the SSRI studies that were in the FDA pool were as large as 220 subjects. With tricyclic antidepressants, “one of the real compromises with all the studies that have been reviewed in terms of efficacy and safety is that we really only have short-term outcomes,” said Dr. Waslick. “No single study ever demonstrated any efficacy of a tricyclic above and beyond what you would achieve with placebo. Even if you put together these studies in a meta-analysis, the meta-analysis fails to support the superiority of tricyclic antidepressants compared with placebo in pediatric patients. So the tricyclic antidepressants didn’t seem to be a particularly promising treatment for kids.”

Thus far, there have been six published studies concerning efficacy of SSRIs, as well as one published serotonin norepinephrine reuptake inhibitor (SNRI) study, which was negative. Simeon et al found that children who took fluoxetine did not appear to improve more than did those who took placebo. The other five studies were all reported as positive, beginning with Emslie and colleagues’ 1997 trial with fluoxetine, which found that kids who took it did better than did those who got placebo in a short-term time frame.

Keller and colleagues’ report in 2001 may have sparked the first concerns about suicidality in children being treated with SSRIs. This large, three-arm study randomly assigned adolescents to short-term treatment with paroxetine, imipramine, or placebo. The trial was designed “to take the two active medications and compare them with placebo, not really to compare the two active arms,” Dr. Waslick pointed out. “There were significant positive effects for paroxetine compared with placebo. Imipramine really showed no difference from placebo in any of the primary outcome measures. [Keller] reported that paroxetine was well tolerated, although there were high placebo rates. If you read this article closely, you actually find that the two primary outcome measures that the investigators had a priori decided would be the test of efficacy were actually not significantly different from placebo in the paroxetine group. There are a lot of secondary measures, supplementary measures. But the two primary outcome measures looked like they were moving in the right direction, but they weren’t significantly different than placebo. That becomes important when you hear what the FDA looks at in terms of this study.”

What caught people’s attention in Keller’s study was what the investigators referred to under an adverse events heading as emotional lability, along with a parenthetical reference to suicidality, suicide ideation, and suicidal experiences. “There were higher rates of what they called emotional lability in the kids who got paroxetine compared to the placebo group,” commented Dr. Waslick. “Some of that emotional lability was a larger heading for issues regarding suicidality. Some people seemed to notice that and got the ball rolling on this.”

In another multisite study with fluoxetine involving 219 children and adolescents, Emslie et al found overall response rates of 65% in the fluoxetine group and 53% in those taking placebo. Remission rates were 41% in the fluoxetine group, and 20% for placebo, a number “somewhat compromised by the 38% drop-out rate in the placebo arm,” noted Dr. Waslick. “There were no indications in this particular trial of risks of suicidality. Overall, [it was] considered a positive study.... So, if we summarized the five published positive SSRI trials, one was supported by nonprivate funding, four were supported by private industry, and the total [number of subjects] of the published trials is about 1,100 by my calculation. There was mild to moderate support for the short-term efficacy of SSRIs, namely fluoxetine, paroxetine, sertraline, and citalopram.”

THE TURNING TIDE

About a year ago, when the FDA announced that it was reviewing data concerning antidepressant drugs from about 24 studies and 4,400 patients, “I realized that there was a whole slew of unpublished data that the FDA was actually looking at, which was a warning,” said Dr. Waslick. At about the same time, the Medicines and Healthcare Products Regulatory Agency (MHPRA)—the UK equivalent of the FDA—issued summary findings of its own after systematically analyzing each antidepressant medication’s development program. “The MHPRA found that there was no evidence for efficacy for any SSRIs, and no efficacy for any of the SNRIs except for fluoxetine,” stated Dr. Waslick. “It also concluded that the adverse events rates exceeded placebo in most of the medications, which is not really that surprising.”

The MHPRA had specific concerns about suicide-related events in a variety of the medications and determined that the risk/benefit ratio was unfavorable for the entire class of drugs except for fluoxetine in children and adolescents, which led it to issue a contraindication in the UK. At the same time, the UK agency also found no deaths in any of the trials, and “that’s been consistent throughout the MHPRA and the FDA work,” said Dr. Waslick. “So there’s a confusion between the published and unpublished data. Only six of the 15 pediatric depression trials available to the MHPRA have made it to peer-reviewed publication as of October 2004. Five of the six published trials are positive. Negative trials tend to go unpublished.... The MHPRA, and I think the FDA has followed suit, concluded that two of the positive published trials are really not positive by their criteria of a priori–defined primary outcome measures. So they don’t consider the Keller study [and others] robust evidence of efficacy enough to say that these are really positive studies. There are hints of positive signals, but they are not robustly positive. That gets confusing, because what is coming out in the published literature is not being accepted by regulatory agencies as positive data.... When we are out there trying to make evidence-based treatment recommendations, we tend to rely too much on the published literature, but we have to remember that the published literature may be biased in terms of positive results.”

In summing up the overall efficacy data, “there really is, at least in the data from the drug company industry, underwhelming evidence of efficacy of most of the antidepressants in children and adolescents outside of fluoxetine,” affirmed Dr. Waslick. “At least the industry-sponsored studies have exhibited, if not been compromised by, relatively high placebo rates in the clinical trial data. It’s very hard to show that your medication or treatment works if you are getting placebo response rates of 60% to 65%. And you might make very different conclusions if you relied only on the published literature [rather] than combining the published literature with the unpublished literature.”

FDA TAKES AIM

In February 2004, the FDA held its first public hearing regarding antidepressant use in pediatric populations. The hearing was used to gather information and to discuss with the agency’s advisory boards ways in which available data could be analyzed. In March, the FDA issued a general warning about antidepressant drugs being associated with, but not causing, a risk in suicide. “It strengthened concerns about suicidality developing during treatment that had already been in the labeling for all the antidepressants,” stated Dr. Waslick. “It didn’t really make it specific to kids or to any type of illness or indication—a general warning for monitoring your patients closely for worsening of depression or development of suicidality. It didn’t talk about medications causing suicidality; it just really encouraged clinicians to warn. In the meantime, they were setting up a second analytic strategy, which was to take a look at some of the adverse events data, reclassified as to the presence or absence of suicidality using a more expert classification system.”

In September, after the reanalysis was completed, the FDA held a second public hearing. Members of an FDA advisory committee voted 15 to eight in favor of recommending a black box warning, and on October 15 the FDA ultimately issued its strongest possible warning on the issue. “The conclusions that came out of the September FDA hearing, which has really set off the chain of events leading to where we are today, is that the FDA analysis, using the classifications from the Columbia University–led investigators, ... concluded that there is a low- magnitude, low-frequency, suicide signal in the adverse events and serious adverse events data set,” Dr. Waslick commented. “And [the FDA] feels at this point that it can sort of make definitive conclusions that there is a causal link—SSRIs, second-generation antidepressants are causally linked to suicidality. I thought it would be more of an association, but [the FDA] is talking about causal links. At the same time, evaluation of systematically collected data on depression rating scales [showed] ... there really was no signal. The adverse events, which are more spontaneously collected, versus systematically collected data, are a little bit at odds here, but they really represent different things.”

The FDA also concluded that there appeared to be a class effect among all drugs regarding suicidal signals, meaning that although certain medicines seemed to have a stronger or weaker association, no analysis basically absolved any medication of a risk. “[The FDA] felt that there was a class effect, and that’s why it didn’t contraindicate or put labels on particular medications,” explained Dr. Waslick. “It basically concluded that no medicine in the class is without risk. [The FDA] is going to differentially label things, but it’s not around the risk, it’s going to be around the efficacy.”

The FDA did take into account data from the Treatment for Adolescents With Depression Study (TADS), the only study that has found an increased risk of suicidality among patients in the fluoxetine trials. Investigators who conducted TADS found that for moderately to severely depressed adolescents, a combination treatment of medicine and cognitive behavioral therapy appeared to work best. “Cognitive behavioral therapy alone did not really distinguish itself from placebo,” noted Dr. Waslick. “So the most effective treatments we have for depression include at least a component of medication. We have to remember that even though we are going to have those black box warnings.”

Dr. Waslick called attention to the fact that treatment-emergent suicidality per the FDA database included the full range, from passive suicidal thinking to serious suicide attempts. “It’s just not the kids who are having the most severe reactions,” he said. “There are kids who are having a very wide range of suicidal experiences. You can’t just say, well, it is a suicide attempt or it’s [adolescents] who start obsessively planning suicide. It could even include people who have impulsive suicidal crises.”

RECOMMENDED MONITORING GUIDELINES

In addition to issuing the warning, the FDA is also recommending that pediatric patients being treated with antidepressants for any indication should be closely monitored for clinical worsening, as well as agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of drug therapy or during dosage changes. The agency has advised that such observation would ideally include at least weekly face-to-face contact with patients or their family members or caregivers during the first four weeks of treatment, then visits every other week for the next four weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. “That’s a very high frequency of monitoring SSRIs,” commented Dr. Waslick. “It’s probably more closely than I monitor kids generally on SSRIs.”

Dr. Waslick also addressed concerns about any potential liability resulting from undertreating patients. He again advised that based on the TADS data, combination treatment is best for moderately to severely depressed children and that close monitoring should be done for all patients. “That’s what I am going to recommend at this point in time,” he commented. “I think it would be a great loss to mental health care if people just stop prescribing these medicines or don’t get educated and trained. I think we have to come up with more reasonable guidelines. I think the monitoring level is hard for a child psychiatrist to follow, never mind a pediatrician or a family practitioner. [The FDA] does use the word ‘ideally.’ It doesn’t mean you have to. But, ideally, you would do it.... I still think the full story is not told with these medications.”

—Colby Stong

"repeated studies have shown antidepressant drugs are no more effective in children than placebos." - Dr. Joseph Glenmullen
This statement is true if you cherry pick the studies you are looking at, as it appears Glenmullen did. Fluoxetine in particular seems to be a drug that has been shown to be clinically effective and also seems to be used as a first line of defence by practicing Dr.s.

Appleton seems legit. Plus he also seem balanced although there is not much on the net on him beyond book reviews. I did find this quote and thought you might enjoy it. :)


"One of the interesting things about drugs is they're a little bit like shopping centers. They come in clean and brand-new and full of hope. They go out old and tired and dirty."

Semi related


Depressed individuals who are slow with regard to thinking,speaking, and reacting may have a dopamine deficiency. Thus,an SSRI antidepressant might not help them.

In spite of the plethora of antidepressants available to patients, cliniciansstill have no easy way of determining whether a patient will respondto one better than another.

However, a quick test to identify patients who will not respondto the SSRI antidepressants may have been found. It is calledthe Controlled Oral Word Association Test FAS (FAS test forshort) and reveals impaired verbal fluency.

Various lines of study have suggested that there is a link between psychomotorretardation—that is, sluggish thinking, speaking, moving, andreacting—and reduced functioning of the neurotransmitterdopamine in the brain. Moreover, psychomotor retardation exhibitedby a sub-group of depressed patients also has been associatedwith decreased dopamine function. So Bonnie Taylor, Ph.D., aninstructor in psychology at the New York State Psychiatric Institute,and coworkers suspected that depressed patients with lower psychomotorskills might not respond to an SSRI antidepressant because a dopaminedeficit causes or contributes to their depression and becausean SSRI would not correct their dopamine deficit. They decidedto test this hypothesis.

Forty-seven subjects were recruited from an outpatient researchclinic at the New York State Psychiatric Institute. All metDSM-IV criteria for major depressive disorder and were between18 and 65 years old. The researchers gave neuropsychologicaltests to all of the subjects before they started a 12-week opentrial of fluoxetine treatment. The tests concerned not onlypsychomotor skills, but also attention, executive functioning,verbal intelligence, and visuospatial functioning.

Of the 37 subjects who finished the study, 25 were rated asfluoxetine responders and 12 as nonresponders. The researchersfound that the two groups did not perform any differently onthe attention, executive functioning, verbal intelligence, andvisuospatial functioning tests, but they did perform differentlyon the psychomotor functioning ones. Specifically, even when baselinedepression severity was taken into consideration, the nonresponders performedsignificantly worse in verbal fluency on the FAS. They alsotended to perform worse than the responders on the Stroop Colorand Word Test in both color naming and word reading and on theWAIS-III digit symbol subtest.

The investigators also obtained FAS test scores for a healthygroup matched to the depressed subjects by age and level ofeducation. They found that all depressed subjects who scoredabove the norm responded to fluoxetine, compared with 40 percentof subjects who scored below the norm.

Thus, the results, which appeared in the January American Journalof Psychiatry, tended to confirm the researchers' hypothesis—that depressedpatients with slow psychomotor skills were not apt to respondto an SSRI antidepressant. Also, the FAS test did a better jobthan the other psychomotor tests at predicting SSRI response.The FAS test could ultimately prove to be of value to clinicalpsychiatrists, "but we obviously need to do more work on it,"Patrick McGrath, M.D., an associate professor of clinical psychiatryat Columbia University and one of the study investigators, saidin an interview.

"The hope is that if we can get a simple, inexpensive test,which this is, which doesn't require fancy technology, whichcan be done in the office, and which takes a few minutes, itwould help us better estimate people's chances of respondingto antidepressant treatment."

Indeed, the FAS "is a very simple test to administer," Taylor concurred."Patients are asked to say as many words as they can think of thatstart with the letters `F,' `A,' and `S' for one minute each.The psychiatrist writes all of the words down and counts thetotal number of words produced in three minutes."

Taylor and her team will now attempt to replicate their findings.

The study was funded by Eli Lilly and Co.
http://pn.psychiatryonline.org/cgi/content/full/41/3/24

Those subjrcts sound like SCT - adhders.
http://www.addforums.com/forums/showthread.php?t=25541&highlight=sct

If Depression for some people, has genetic underpinnings, and we choose not to treat the first major episode, could that choice to not medicate have a statistical negative outcome? Can some antidepressants for children actually make future relapses less common or less severe?

http://www.health.harvard.edu/newsweek/Depression_in_Children_Part_I.htm
Genetics of Childhood Depression

According to the 1992 National Comorbidity Survey, at any given time, nearly 2% of children ages 7–12 in the United States have major depression. The rate of 6%–9% among late adolescents is similar to the adult rate. The rate of dysthymia is 4%–8% among children ages 7–18, and more than two-thirds of children with dysthymia develop major depression within five years. Until puberty, boys and girls are equally likely to become depressed, but afterward depression becomes more common in girls, reaching the 2:1 adult ratio in late adolescence. As in adults, major depression in children and adolescents is a recurrent illness with repeated relapses. About one-third relapse within two years, and 70% relapse at least once. In 20%–30% of depressed children, bipolar illness develops in the late teens or early 20s. Among adults with bipolar disorder, 25%–45% say their first episode of mania came before age 21.

The genetic contribution to mood disorders is especially high when the symptoms first appear in childhood or adolescence. For children of a depressed parent, the risk of depression is much higher than average. According to one report, more than 50% of children with a parent who has a history of major depression have an episode of depression themselves by age 20. Identical twins are highly concordant (matched) for childhood depression, and even more concordant for childhood bipolar disorder. But fraternal twins are no more concordant than any other brothers or sisters. A family history of personality disorders, panic disorder, or alcoholism also raises the risk of early depression. The heritability (proportion of individual differences in susceptibility associated with genetic difference) of childhood depression is estimated at 50% or more.
Other Causes

What causes a genetically vulnerable child to develop the symptoms is not known, although both common sense and psychological theory have suggested many possibilities: the death or divorce of parents; a child’s inability to conform to an unattainable ideal or live according to rigid moral convictions instilled by parents; failure to establish emotional bonds in infancy because of rejection or neglect; too much punishment and criticism with too little reward and praise; anger turned inward because there is no safe way to express it. Sexual or physical abuse may lead to depression by causing lasting changes in the regulation of stress-related hormones and neurotransmitters. And depressed parents influence the child’s environment as well as passing on their genes. They are often too preoccupied with personal misery to show much sensitivity to their children’s needs. The children’s resulting withdrawal and apathy reinforce the parents’ feelings of inadequacy, further raising the risk that the children will become depressed.

Causes of adolescent depression are particularly easy to suggest. Teenagers may have trouble giving up childhood comforts and pleasures while trying to establish an adult identity. Hormonal changes subject them to sexual tensions and aggressive impulses they don’t know how to cope with. They may feel the need to deny dependence on their parents while also living up to what they suppose to be their parents’ expectations. All the while, they have the intellectual capacity for self-criticism without the experience needed to put minor failures into perspective. Homosexual adolescents may be at especially high risk because isolation, concealment, social stigma, and family misunderstanding often make sexual development more emotionally difficult.

But many of the family conditions suggested as causes could instead be the effects of a child’s or a parent’s depression, or even of genetic vulnerability. There is no reliable evidence for a single biological, psychological, or social explanation of childhood depression. Twin and adoption studies have not shown that a common family environment affects the chance that a child will become depressed. After adjusting for genetic predispositions, it does not seem to matter whether the father is present, how many children there are, or even whether there is serious family conflict. The rate of depression in adopted children is correlated with the rate in their biological rather than their adoptive parents.

The childhood problems usually persist in adult life. About 90% of people who have manic episodes in childhood will also have them in adulthood. Depressed children are also vulnerable to a variety of personality disorders. According to research, the odds of antisocial, histrionic, and borderline personality are increased four times in adolescents with depression or bipolar disorder, regardless of social class, family conflict, other psychiatric disorders, or a history of child abuse or neglect.