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Acnp exec sum final edited.pdf


American College of Neuropsychopharmacology
EXECUTIVE SUMMARY
PRELIMINARY REPORT OF THE
TASK FORCE ON
SSRIs AND SUICIDAL BEHAVIOR IN YOUTH
January 21, 2004 American College of Neuropsychopharmacology
EXECUTIVE SUMMARY
PRELIMINARY REPORT OF THE TASK FORCE ON
SSRIs AND SUICIDAL BEHAVIOR IN YOUTH

This is the Executive Summary of a Task Force report by the American College of
Neuropsychopharmacology (ACNP) which evaluated the safety and efficacy of SSRI1
antidepressants for depressed youth under 18 years. The report was undertaken after
regulatory agencies in the United States and United Kingdom voiced concerns in 2003 about
the possibility that treatment of depression in children and adolescents with SSRIs may
increase the risk of suicidal thinking or suicide attempts. The ACNP Task Force emphasizes
that its findings and recommendations are preliminary because it did not have access to all
the data held by regulatory agencies and pharmaceutical companies.
The Debate over SSRIs and Suicidal Behavior in Youth

The U.K. Department of Health, beginning in the summer of 2003, warned doctors against
prescribing any SSRI antidepressant drug except fluoxetine for depressed youth under 18
years of age. On the basis of clinical trial results, the agency had concerns that SSRIs, with
the exception of fluoxetine (Prozac®), were not effective for youth with depression, and may
increase the risk of suicidal thinking or suicide attempts.
The U.S. FDA also warned against the use of one SSRI, paroxetine, but stopped short of
warning against use of other SSRIs in youth. It later announced that it was conducting a
thorough investigation of eight antidepressants, including all currently approved SSRIs. The
FDA said that the evidence it had reviewed so far was insufficient to determine whether or
not a link exists between SSRIs and suicidal behavior in youth. Instead, the FDA advised
physicians to monitor children and adolescents for changes in their clinical state and for
increased suicidal risk. FDA said it planned to hold a public hearing on February 2, 2004.
The debate over SSRIs use in youth actually began more than 10 years ago with case reports
in the medical literature describing a small number of individuals (primarily adults) whose
suicidal tendencies worsened during SSRI treatment, and, in some cases, appeared to
improve after stopping the SSRI.
First ACNP Task Force Convenes in 1993

Responding to the early case reports, the ACNP convened its first Task Force to study the
matter in 1993. After carefully evaluating the evidence, the Task Force concluded that there
was no scientific evidence indicating that SSRIs could trigger suicidal behavior. Nevertheless,
as a matter of prudence, the Task Force advised clinicians caring for suicidal patients to
remain vigilant for a worsening of their patients' condition, whether due to illness (most
commonly depression), or whether due to the side effects of SSRIs. The Task Force also
1 Selective Serotonin Reuptake Inhibitors (SSRI) recommended more research into the safety and efficacy of antidepressants in depressed and
suicidal patients.
New ACNP Task Force Convenes in September 2003
ACNP took the initiative to appoint a new Task Force in September 2003 soon after
announcements by drug regulatory agencies. The Task Force evaluated the evidence of
safety and effectiveness of SSRIs in youth, including all evidence published after its 1993
Task Force report. Not only did the new Task Force examine all published clinical trial data
in youth, but it also sought and obtained for its review unpublished data from several drug
sponsors, and data reported to the U.K. drug regulatory agency.2 However, because the
Task Force did not have access to a substantial amount of unpublished data,
including detailed findings held by drug sponsors, this report is preliminary.

The members of the Task Force are: Graham Emslie, M.D., J. John Mann, M.D., William
Beardslee, M.D., Jan Fawcett, M.D., Andrew Leon, Ph.D., Herbert Meltzer, M.D., Fredrick
Goodwin, M.D., David Shaffer, M.D., Karen Wagner M.D. Ph.D, and Neal Ryan, M.D. A
list of Task Force members and their academic affiliation is attached, as is disclosure of
potential conflicts of interest for each member. The ACNP is a non-profit, professional
society with revenues from a variety of sources including membership dues, publication
sales, registration fees, and unrestricted educational grants from the pharmaceutical industry.
The ACNP Task Force on SSRIs and Suicide was supported solely by the ACNP. There was
no financial support from the pharmaceutical industry for this Task Force.
The full version of the ACNP Task Force report will be released in the spring or early
summer of 2004.
TASK FORCE FINDINGS
Depression in Youth is a Serious Public Health Problem with a Risk of Suicide
Suicide is the third leading cause of death among 15-24 year olds in the U.S. Depression and
other psychiatric disorders are the major causes of suicide. Depression annually occurs in
about 10% of youth. Most cases of depression are untreated and undiagnosed. Untreated
depression is frequently behind most suicides, according to studies of adults and youth.
Although a suicide death is still rare in youth (less than 1% of youth per year3), suicidal
thinking or suicide attempts are relatively common. Every year, 19% of teenagers (age 15-
19) in the general population think about suicide (known as suicidal ideation) and nearly 9%
of teenagers make an actual suicide attempt.
The rates of suicidal thinking and suicide attempts are even more frequent in youth receiving
care for depression. Studies find that 35-50% of these youth have made, or will make, a
2 The UK Medicines And Healthcare Products Regulatory Agency (MHRA) 3 0.008% 12-month incidence in ages 15-19 (Anderson, 2002). suicide attempt. Between 2 and 8% will actually commit suicide over the course of about a
decade.
Considering the frequent occurrence of suicidal behavior in depressed youth (whether in
treatment or not), case reports of a small number of youth becoming suicidal while taking
SSRIs are expected. The Task Force considered two possible explanations for the case
reports. One is that SSRIs fail to relieve the suicidal behavior that is part of the depression.
A second possibility is that the SSRIs trigger a novel set of suicidal emotions or behaviors.
The Task Force report examined the evidence regarding the possibility that SSRIs increase
the risk for suicidal ideation or attempts, but first asked what are the benefits of SSRIs for
depressed youth, and what alternatives are available.
Several SSRIs Are Effective for Treating Depression in Youth
Depression in youth not only is a major cause of death, but also causes tremendous suffering
and problems in learning, social relationships, and community activities. Depression, if not
properly diagnosed and treated when it first appears, can lead to dropping out of school and
lifelong problems in adulthood.
The Task Force reviewed the results of 15 clinical trials on the efficacy of SSRIs and other
new antidepressant medications (in therapeutic classes other than SSRIs) 4 for depression in
youth. The results of these trials, covering a total of more than 2,000 youth, were reported to
drug regulatory agencies. Some, but not all, of the results have been published in medical
journals.
Each clinical trial typically was double-blind, randomized and placebo-controlled, meaning
that youth were randomly assigned by researchers to receive either the drug or a placebo (an
inert pill). Most of the clinical trial findings were published in the last three years.
To complicate matters, the clinical trials often use more than one outcome measure to study
a medication's efficacy. Selecting different outcome measures can lead to different
interpretations of a study's findings. The UK drug regulators, for example, interpreted
findings from several SSRI trials as being a negative study, while the Task Force selected
other measures indicating a positive study. A negative study means no difference in efficacy
between the drug and the placebo, whereas a positive study means the drug is efficacious in
comparison with the placebo. A negative study could mean a treatment does not work, or
the placebo response rate is high and an active drug effect cannot be detected, or the patient
population as a whole is drug resistant (also known as a failed study).
The Task Force, after reviewing the clinical trials summarized in Table 1, identified five
SSRIs or other related new antidepressants as being significantly more effective than placebo
in at least one trial each: fluoxetine, sertraline, paroxetine, citalopram, and nefazodone. The
latter three drugs (paroxetine, citalopram, and nefazodone) were also found to be no
4 SSRIs are fluoxetine, paroxetine, sertraline, and citalopram. Other new types of antidepressants, which are not SSRIs, are nefazodone, venlafaxine, and mirtazepine. different from placebo in one or more separate clinical trials. Venlafaxine was no better than
placebo in two clinical trials. No published data were available for mirtazapine. 5
Across the positive clinical trials, the degree of efficacy varied, depending on the trial's size
and methodology. The largest single clinical trial, of sertraline, pooled data from 376
children and adolescents in the U.S., Canada, India, and other countries. It found that nearly
70% of children and adolescents responded, compared to 60% in the placebo group, a
statistically significant difference (Wagner et al, 2003). The difference was even greater in
two other large trials of fluoxetine and nefazodone. In those trials nearly half or more of
youth responded, compared with somewhat more than a third of those receiving the placebo
(Emslie et al, 2002a, 2002b).
Thus, based on published and some unpublished clinical trials, the Task Force believes that
there is sufficient evidence to conclude that, overall, SSRIs are effective in treating
depression in children and adolescents. There are no convincing differences in efficacy
outcome across the clinical trials that cannot be explained by different methods of study.
Alternatives Not Effective or Readily Available

SSRIs are the only antidepressant drugs shown to be effective for treating depression in
children and adolescents. Another drug class introduced into the market in the 1960s, the
tricyclic antidepressants, is not effective for youth. That was the conclusion of a
sophisticated type of study known as a meta-analysis, which pooled results from several
clinical trials (Hazell et al, 2002). Further, tricyclic antidepressants have more side effects.
Tricyclic antidepressants are therefore not recommended as a first-line treatment for
depressed youth.
The only potential alternative to SSRIs in depressed youth is a particular form of
psychotherapy known as cognitive behavioral therapy. The problem is that this
psychotherapy has only been tested in depressed adolescents, not in children. In the
adolescent clinical trials, cognitive behavioral therapy was found to work for most
adolescents, but a very sizable percentageabout 40%did not respond (Brent et al, 1997;
Clarke et al, 1999). Another problem is that cognitive behavioral therapy is not readily
available in most communities.

Weak Evidence Links SSRIs to Suicidal Behavior in Youth
The possibility that SSRIs may trigger suicidal behavior was first raised over a decade ago in
a series of case reports describing a small number of individuals whose suicidality worsened
during treatment and then sometimes improved after stopping the SSRI. All except one of
those reports (King et al. 1991) were in adults (Teicher et al, 1990; Masand et al, 1991;
Rothschild et al, 1991; Creaney et al, 1991; Wirshing et al. 1992; Lane et al, 1998). In a few
cases, patients were re-started on the SSRIs and the suicidal behavior re-emerged.
5 This paragraph and the remainder of the summary lists the drug's generic names. The brand names (with generic names) are: Prozac (fluoxetine), Paxil (paroxetine), Zoloft (sertraline), Effexor (venlafaxine), Cexela (citalopram), (Remeron) mirtazepine, and Serzone (nefazodone). In medicine, any report of an individual case, or a series of cases, represents a weak form of evidence. Case reports or case series cannot be used alone to draw conclusions about causation (e.g., IOM, 2003). Physicians and scientists use case reports only to raise questions that can be studied more thoroughly in larger and well-designed controlled clinical trials. Controlled clinical trials offer the best kind of evidence from which to infer whether a drug causes a particular effect. Other questions about the value of the case reports linking SSRIs to suicidal behavior were raised in a separate analysis published in 1992. The analysis found similar case reports of suicidal behavior with every class of antidepressants, as well as with drugs against psychosis and anxiety (Kapur et al, 1992). The analysis also found no consistent relationship between suicidal behavior and (1) the dose of the drug; (2) the time of onset after starting the medication; or (3) raising the dose. The authors concluded that there was no evidence from these case reports of an effect confined to one pharmacological class of drug, or a clear dose-response relationship. They suggested that the one common feature in these reports was a psychiatric disorder known to carry a risk of suicidality. The 1992 analysis, combined with further review of the evidence then available, including
meta-analyses of controlled clinical studies of three antidepressants, was key to the ACNP
Task Force report's 1993 conclusion that there was no scientific evidence indicating that
SSRIs could trigger suicidal behavior.

Apart from the case reports, one study examined a UK database of adverse drug reaction
reports (Medawar and Herxheimer, 2003). These are reports from professionals or
consumers submitted to a drug regulatory agency. On the basis of its analysis, the study
recommended restrictions on the use of paroxetine and perhaps other SSRIs. But one
problem with the study was that there was no control group (i.e., a comparable number of
untreated individuals). Another problem was that the study was conducted after a widely
viewed television program that might have encouraged greater reporting of a particular type
of side effect and a particular medication.
Even in the absence of proof that SSRIs can trigger suicidal ideation or attempts, some
speculate that SSRIs may trigger a mixed mood state of mania and depression, which, in
turn, carries a greater risk of suicidal behavior. Whether or not SSRIs have such an effect on
mood in youth and adolescents also remains to be proven.
Moreover, the diagnosis of bipolar disorder in youth is difficult for even highly experienced
clinicians. This further complicates the question of whether the drugs induce suicidality. For
example, up to 75% of adults diagnosed with bipolar disorder report having had significant
symptoms in childhood, largely in the form of depressed mood. Predicting which children
with symptoms of depression will be the ones who later develop bipolar disorder is not
possible. Consequently, it is also impossible to determine which children, as a possible result
of taking antidepressants, are at higher risk for suicide attempts. A family history of bipolar
disorder might be a clue. But answers will only emerge from clinical trials of mood
stabilizers with antidepressant properties, or of mood stabilizers in combination with
antidepressants in children and adolescents. Those types of studies are needed to determine
whether there are other effective therapeutic alternatives.
No Significant Increase in Suicidal Behavior in Clinical Trials of Youth
In the same clinical trials in youth described earlier, investigators also studied the safety of
SSRIs. This part of a clinical trial covers what types of side effects (known as adverse events)
occurred during the trial. Table 2 brings together all the data available to the Task Force on
these five antidepressants: citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.
There were no data available from clinical trials of mirtazapine and nefazodone.
First, a caveat: across the trials, suicidal behavior was captured in the adverse events reports,
but the trials did not set out specifically to determine whether the medications lead to
suicidal behavior. As a result, the definition of suicidal behavior as an adverse event was left
up to the individual clinicians that saw patients in the trial. Therefore, the definition of
suicidal behavior was not uniform across the trials or even within the trials.
What is striking is that in none of the trials, involving more than 2,000 subjects, did a single
young patient die by suicide.
Regarding suicidal behavior and ideation, the Task Force found no significant difference
between drug and placebo for any of the medications (Table 2). The rate of suicidal
behavior and ideation among youth on the antidepressant was not statistically different from
youth on a placebo.
When looking at suicide attempts, it is important to distinguish attempts with low lethality
versus those with high lethality. The profile of someone who attempts suicide in the context
of a mood disorder varies by demographic, clinical and biological factors. For example,
suicide and very lethal suicide attempts are more common in men, are planned and are
associated with a deficiency in the brain serotonin transmitter system. Low lethality,
impulsive attempts are made mostly by women in the setting of an inter-personal conflict
and not associated with a serotonin deficiency. Thus, to establish a risk for suicide, the rate
of more lethal suicide attempts (such as those requiring significant medical intervention)
must be shown to be increased on antidepressants relative to placebo. Low lethality suicide
attempts and ideation are poorer indicators of risk for suicide than high lethality attempts.
Yet no distinction of type of suicidal behavior has been made in data presented by the UK
regulatory agency.
(See URL: http://medicines.mhra.gov.uk/aboutagency/regframework/csm/csmhome.htm)
The report of the UK drug regulatory agency often states that the rate of suicidal behavior
was higher in the antidepressant medication group. But the slight apparent difference, usually
by no more than 2%, was not statistically significant for any SSRI. Furthermore, despite the
fact that youth on citalopram showed more improvement on suicide ratings than placebo in
two clinical trials, the UK report concluded that citalopram may increase self-harm on the
basis of reports of suicidal acts or self injury.
Three clinical trials addressed the suicidal risk of paroxetine, but the sponsor,
GlaxoSmithKline, only provided a summary statement that combined results from the three.
The results from individual trials were not provided. The results were from nearly 400
patients on paroxetine versus nearly 300 treated with placebo. The statement reported that
3.7% of paroxetine-treated patients versus 2.5% of the placebo group experienced suicidal
thinking or suicide attempts, but the difference was not statistically significant.
Although patients considered at high risk for suicide are generally excluded from these trials,
suicidal behavior and ideation (i.e., thoughts, gestures) in youth are common. The rates
appear to be lower in the clinical trials, by virtue of the exclusion and perhaps the therapeutic
benefit of the care and attention delivered during a treatment trial, and do not occur at rates
that permit detection of a specific beneficial effect of medication. Reports of adverse events
do not systematically assess potential benefits of medications on suicidal thoughts.
In an unpublished study of open treatment with fluoxetine in youth, supported by the
National Institute of Mental Health, the first 100 youth were rated for suicidal behavior.
Based on a suicide item on a depression rating scale, scores from baseline and outcome were
analyzed to evaluate improvement or worsening on this item. Forty seven percent of youth
showed improvement in the suicide rating by the end of the 12-week study. Forty nine
percent showed no change (in many cases there was no suicidal behavior at the start of the
study, so there was no room for improvement.) Only 4% showed a worsening of suicidality
(G. Emslie, personal communication). It is important to note that the item assessing
suicidality is a single item on a depression scale, and this was not the primary intent of the
study.
In studies of adults, which analyzed the single suicidal ideation and behavior item in a
depression rating scale, SSRIs were sometimes found to be more effective, and never less
effective, than placebo in relieving suicidal ideation and behavior or preventing new or
emergent suicidality during acute treatment.
In summary, the available data from clinical trials of young people indicate no significant
increase in risk of suicidal behavior in those treated with SSRIs for depression. And there
were no completed suicides in any of the trials.
Additional Evidence Supports Benefits of SSRIs in Reducing Suicide
There are two other lines of evidence, from toxicology and epidemiology, suggesting the
benefits of SSRIs in lowering suicidal risk. Those lines of evidence support one of the
fluoxetine clinical trials, described above, which also found a benefit.
Toxicology Studies in Autopsies

One way to determine whether SSRIs trigger suicide is through toxicological analysis of
individuals dying from suicide. In a study of more than 5000 adult suicides, one research
team found that most victims had not taken an antidepressant (most commonly SSRIs or
other new generation antidepressants) immediately before their death, even though the
majority had been depressed (Isacsson et al, 1997). Only 4% had toxic concentrations of
antidepressants, meaning that the drugs were used in an intentional overdose.
In a study of 49 adolescent suicides, a research team in Utah recently reported in an abstract
that 24 percent had been prescribed antidepressants, but none tested positive for SSRIs at the
time of their death (Gray et al, 2003).

These two studies, taken together, suggest that suicide is more likely when depressed
individuals do not take their medication, rather than when they take it.
Epidemiology Studies
Another strong line of evidence supporting a reduction in suicidal risk with SSRIs comes
from studies of populations. A distinct reduction in the suicide rate of youth (ages 15-24),
averaging about 33%, has occurred across at least 15 countries over the past fourteen years
(WHO, 2003). The reduction followed three decades of increases. The greatest reductions
were in Australia (52%) and Switzerland (50%), and the lowest was (14%) in Japan. In only
three countries did the start of the decline precede the introduction of an SSRI. The
reduction was unexpected, and it occurred in countries where quite different methods are
used for committing suicide.
The decline in the youth suicide rate from epidemiology studies cannot be explained by a
reduction in exposure to drugs and alcohol, for their use—at least in the United States—
remained constant during the period of the declining suicide rate. Nor can the decrease be
explained by better firearm control, for it has been noted in nations where firearms were
only rarely used to commit suicide, and where effective firearm control was implemented (as
in Australia), alternative methods took the place of firearms (De Leo et a l. 2003).
The decline in youth suicide rates coincides, to a striking extent, with significant increases in
the prescription of antidepressants to adolescents, mostly SSRIs (Carlsten et al. 2001; Hall et
al. 2003; Isacsson 2000; Middleton et al. 2001; Olfson et al. 2002; Rihmer et al. 2000;
Rushton and Whitmire 2001; Zito et al. 2003).
Publications drawing attention to the relationship between decreasing youth suicide rates and
increasing prescription rates have emerged from three major countries: Sweden (Carlsten et
al. 2001), Finland (Ohberg et al. 1998), and the United States (Olfson et al. 2003).
Supporting evidence also comes from a natural experiment in Japan. In that country, the
youth suicide rate remained stubbornly high, showing none of the decline in other developed
countries. It was not until 1997 that the Japanese government gave approval for the
manufacture and importation of SSRIs, which previously had not been permitted. In the
following year, youth suicide rates started to decline.
No Increases in Suicide Found in Clinical Trials of Adults
More than 20,000 adults have been studied in clinical trials of SSRIs and other
antidepressants. This figure is much higher than the number of youth studied in clinical
trials.
A large body of evidencemore than 15 studieshas investigated the safety of SSRIs in
adults, largely in clinical trials. The overwhelming majority of the studies have reported no
convincing evidence of an increased risk of suicide with SSRIs (see report for citations).
The most important of these studies pooled and then analyzed the evidence from a very
large FDA database of clinical trials. The database contained information from more than
20,000 adults studied in randomized controlled trials. Analyses of the database found no
relationship between SSRIs and suicidal attempts or actual suicides in adults (Khan et al,
2003, 2002, 2001, 2000).
To further examine the validity of this conclusion, the Task Force undertook its own analysis
of whether the database analyses by Khan and co-authors had enough patients, and thus
enough statistical power, to detect an increase or decrease in suicidal behavior. The Task
Force calculated that the database analyses were very robust: they had the power to detect as
little as 2-3% change in rates per drug. This calculation reinforced the Task Force's
confidence in the conclusion that SSRIs are not associated with suicide attempts or suicides
in adults.
In addition to the evidence from clinical trials, epidemiology studies also have found no
instances of increase in suicide or suicidal behavior associated with SSRIs use, and in some
instances a decrease of suicidal behavior, in adults (e.g., Zaninelli, R. & Meister, 1997).
Summary of Findings:

Depression in youth is a serious public health problem that carries a risk of suicide. Suicide
is the third leading cause of death among 15-24 year-olds in the United States and the
leading cause of death in several other countries. Because suicide most commonly occurs in
untreated depression, diagnosis and treatment of depression require urgent attention.
The ACNP Task Force thoroughly reviewed published and some new unpublished data to
evaluate the benefits and risks of SSRIs and other new generation antidepressants for youth
under 18 years of age.
The Task Force found several SSRI trials that showed efficacy in treating depression in
youth, while other trials failed to demonstrate efficacy. They noted that differences in drug
effectiveness across clinical trials may be from differences in methodology and
recommended additional study.
The Task Force also found that the category of antidepressants known as tricyclics were
ineffective in youth. Other forms of treatment were found to be not widely available to
youth, or insufficient data was available to support their effectiveness.
The Task Force concluded that taking SSRIs or other new generation antidepressant drugs
do not increase the risk of suicidal thinking or suicide attempts. Three strong lines of
evidence in youthfrom clinical trials, epidemiology, and autopsy studiesled to this
conclusion.
First, clinical trials of more than 2,000 youth found that there were no statistically significant
increases in suicidal behavior and suicidal thinking. Most strikingly, there were no suicide
deaths in any of the trials. Further, clinical trials of more than 20,000 adults also find that
SSRIs are not linked to suicide. Although no convincing evidence supports a link, the Task Force plans to conduct further analyses in the forthcoming final version of its report. Second, epidemiology studies from several countries suggest that increased use of SSRIs and other antidepressant drugs lowers the risk of suicide. The rate of youth suicide in 15 countries has declined by an average of 33% over the past fifteen years. This period of time has coincided with increases in prescribing of SSRIs. Third, autopsy studies suggest that suicide is more likely when depressed individuals do not take their medication, rather than when they take it. The evidence from case reports linking SSRIs to suicidal behavior is weak. The most likely explanation for cases of suicide or attempted suicide while taking SSRIs is that the underlying depression is responsible, not the SSRIs. The Task Force, after reviewing the evidence as a whole, concluded that the benefits of SSRIs for treating depression in youth outweigh the risks of suicidal thinking or suicide attempts. The Task Force emphasizes that its findings and recommendations are preliminary. While ACNP reviewed all published data and some unpublished data, it does not have access to a substantial amount of data available to the FDA or to pharmaceutical companies.
Recommendations
The seriousness of depression and suicide in youth underscores the importance of available
treatments and of the need to stimulate research and analysis by academic researchers, drug
sponsors, and drug regulatory agencies to identify the most effective and safest treatments
for depression in youth.
The Task Force makes the following recommendations:
1. The Task Force recommends continued use of SSRIs and other new generation
antidepressants as an effective and readily available treatment against depression in youth. It also urges clinicians to ask depressed patients about suicide, suicidal thinking, and plans for suicide. 2. The Task Force urges that all data held by FDA or pharmaceutical companies should be made rapidly available to allow ACNP and other research organizations to conduct an independent evaluation of the risks and benefits of SSRIs in youth and adults with depression and other mood disorders. The data forming the basis of drug approval decisions that are in the public domain and obtainable under the Freedom of Information Act should be placed on a readily accessible website. 3. More attention is needed to: 1) find better measures and systematic assessment procedures for evaluating suicidal behavior in clinical trials; 2) include subjects with suicide risk in clinical treatment trials or developing treatment trials specifically for suicidal children and adolescents; and 3) evaluate other risk factors associated with suicidal behavior (i.e., past suicide attempt). 4. Clinical trials need to be designed in a more uniform and consistent manner. Areas needing more attention include outcome measures, length of treatment, and dosing. For example, rather than doing two fixed-dose, placebo-controlled trials where the optimal dose in this age group is uncertain, resources would be better utilized by conducting a dose-finding study prior to a fixed-dose, placebo-controlled trial. 5. The FDA's plan to pool the data from all antidepressant trials (both in depressed and anxious populations) is highly important. A large data set will allow a variety of variables to be controlled for, such as previous history of a suicide attempt and dosing. This data set should be made available to academic organizations, such as the ACNP, for independent analysis. 6. Some methodological issues in risk assessment need to be addressed at a regulatory level. 1). Actual "suicidal events" in the studies reviewed here are poorly defined. Attempts were defined by the treating clinician at the site, and therefore varied not only across studies, but across sites within a study. Therefore, as recommended by the FDA, a blind re-evaluation of each suicidal event based on case reports is needed. 2) Events that occur up to one month after medication has ceased need to be treated differently in any analysis. 3) Systematic inquiry should be required of past and current suicidal behavior and ideation in any randomized controlled trial being submitted to the FDA of youth or adult depression, regardless of treatment agent. A past suicide attempt is the best-known predictor of future suicide or suicide attempts and potential stratification effects need to be considered. 4) For both randomized clinical trials, as well as for adverse events during a trial, and adverse event reporting post marketing, a control population is essential in order to draw any meaningful conclusions, given the high rates of suicidal behavior and ideation particularly in adolescents. An emphasis should be placed on monitoring rates of more lethal suicide attempts as a better guide to the risk of suicide. 7. More effective treatments are needed urgently. Randomized controlled trials should not routinely exclude all currently suicidal patients. Additional trials should be conducted in high risk patients, such as those with a history of suicidal behavior, such as the type of study currently funded by the NIMH in bipolar disorder and the recently published clozapine versus olanzapine study. Fears of litigation discourage the development of urgently needed treatments. Ongoing and potential future investigations of the pharmacological treatment of depression and youth may not be ethically feasible if governmental regulatory agencies prematurely judge these compounds to be ineffective and/or dangerous and eliminate the possibility of an erroneous judgment being discovered and reversed. REFERENCES
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Efficacy and safety of nefazodone in the treatment of adolescents with major depressive disorder. Abstracted in the 42nd Annual Meeting of NCDEU; Orlando, FL. Emslie GJ, Heiligenstein JH, Wagner KD, et al (2002b). Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Ch Adolesc Psychiatry 41(10): 1205-1215. Emslie GJ, Rush AJ, Weinberg WA, et al (1997). Double-blind, randomized placebo-controlled trial of fluoxetine in depressed children and adolescents. Arch Gen Psychiatry 54: 1031-7. De Leo D, Dwyer J, Firman D, Neulinger K (2003). Trends in hanging and firearm suicide rates in Australia: Substitution of method? Suicide Life Threat Behav 33(2): 151–164. Gray D, Moskos M, Keller T (2003, April 25). Utah Youth Suicide Study New Findings. Presented at the annual meeting of the American Association of Suicidology, Sante Fe, New Mexico. Hall WD, Mant A, Mitchell PB, Rendle VA, Hickie IB, McManus P (2003). Association between antidepressant prescribing and suicide in Australia, 1991–2000: Trend analysis. BMJ 326(7397): 1008. Hazell P, O'Connell D, Heathcote D, Henry D (2002). Tricyclic drugs for depression in children and adolescents. Cochrane Database of Systematic Reviews (3):CD002317. IOM ( Institute of Medicine), 2003. Gulf War and Health Gulf: Volume 2. Insecticides and Solvents, Committee on Gulf War and Health: Literature Review of Pesticides and Solvents. Washington, DC: National Academies Press. Isacsson G (2000). Suicide prevention-a medical breakthrough? Acta Psychiatr Scand 102(2):113-7. Isacsson G, Holmgren P, Druid H, Bergman U: The utilization of antidepressants—a key issue in the prevention of suicide: an analysis of 5281 suicides in Sweden during the period 1992–1994. Acta Psychiatr Scand 96(2):94–100, 1997. Jick SS, Kremers HM, Vasilakis-Scaramozza C (2000). Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 136(10): 1231–1236. Kapur, S., Mieczkowski, T. & Mann, J. J. (1992) Antidepressant medications and the relative risk of suicide attempt and suicide. Journal of the American Medical Association, 268: 3441-3445. Khan A, Khan S, Kolts R, Brown WA (2003). Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: Analysis of FDA reports. Am J Psychiatry 160(4): 790–792. Khan A, Khan SR, Leventhal RM, Brown WA (2001). Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: a replication analysis of the Food and Drug Administration database. Int J Neuropsychopharmacol 4:113-8. Khan A, Leventhal RM, Kahn S, Brown WA. Suicide risk in patients with anxiety disorders: a meta-analysis of the FDA database. J Affective Disorders 2002; 68:183-190. Khan A, Warner HA, Brown WA (2000). Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials. Arch Gen Psychiatry 57:311-7. 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J Am Acad Child Adolesc Psychiatry 41(5): 514–521. Rihmer Z, Appleby L, Rihmer A, Belso N (2000). Decreasing suicide in Hungary. Br J Psychiatry 177: 84. Rushton JL, Whitmire JT (2001). Pediatric stimulant and selective serotonin reuptake inhibitor prescription trends: 1992 to 1998. Arch Pediatr Adolesc Med 155(5): 560–565. Rothschild AJ, Locke CA (1991). Re-exposure to fluoxetine after serious suicide attempts by 3 patients: the role of akathisia. J Clin Psychiatry 52:491-3. Teicher, M. H., Glod, C. A. & Cole, J. O. (1993) Antidepressant drugs and the emergence of suicidal tendencies. Drug Saf, 8: 186-212. Wagner KD, Ambrosini PJ, Rynn M, et al (2003). Efficacy of Sertraline in the Treatment of Children and Adolescents with Major Depressive Disorder. J Am Med Assoc 290(8): 1033-1041. World Health Organization (WHO), 2003. (http://www.who.int/mental_health/prevention/suicide/country_reports/en/) Zaninelli, R. & Meister, W. (1997) The treatment of depression with paroxetine in psychiatric practice in Germany: The possibilities and current limitations of drug monitoring. Pharmacopsychiatry, 30: 9-20. Zito JM, Safer DJ, dosReis S, Gardner JF, Magder L, Soeken K, Boles M, Lynch F, Riddle MA (2003). Psychotropic practice patterns for youth: A 10-year perspective. Arch Pediatr Adolesc Med 157(1): 17–25. Table 1: Efficacy of Antidepressants for Treating Pediatric Major Depressive Disorder
Medication
Duration
Participant
Continuous
Categorical
Reference
Response:
Response:
Difference between Much or Very Much (drug & placebo)
drug and placebo in improved on the scale of depressive symptoms (drug vs. placebo)* (drug vs placebo)** SSRIs (Selective Serotonin Reuptake Inhibitors)
(209 flx, 210 pb) (93 par, 95 imp, 61% vs. 58% (NS) (187 par, 99 pb) GSK, Final Clinical Report (Study 377) Data unavailable (124 cit, 120 pb) (continued on next page) Table 1 (continued): Efficacy of Antidepressants for Treating Pediatric Major Depressive Disorder
63% vs. 53% (p=.05) Wagner et al., 189 sert, 187 pb Other New Generation Antidepressants (non-SSRI)
Data unavailable Data unavailable (165 mirt, 85 pb) baseline (p=.055; Data Unavailable Data unavailable Data unavailable Physician letter; Executive summary section Physician letter; Executive summary section Categorical response was defined in all cases as a Clinical Global Improvement of depression of "much" or "very much improved." Continuous response: Difference between drug and placebo in the amount of improvement of depressive symptoms (based on Children's Depression Rating Scale – Revised {CDRS-R}). *** Continuous response: Rates of response based on a percent improvement on a depression rating scale (CDRS-R; 30% on fluoxetine trials; 40% on sertraline trials). **** Continuous response: Rates of response based on minimal symptoms of depression (Hamilton Depression Rating Scale =8). ***** Continuous response: Rates of response based on a percent improvement on a depression rating scale (Montgomery Asperg Depressio n Rating Scale {MADRS}; =50% improvement). Table 2. Rates of suicide deaths and suicidal behavior or ideation in clinical trials of
children and adolescents with Major Depressive Disorder
Percent of youth with suicidal behavior or ideation Statistical Significance Placebo*
*Number inside parenthesis is actual number of youth NA=Not available **Total number of youth given antidepressant and placebo Sources: Data from published clinical trials, unpublished clinical trials provided to ACNP by drug sponsor, and clinical trial data compiled by the UK drug regulatory agency (MHRA). American College of Neuropsychopharmacology
Task Force on SSRIs and Suicidal Behavior
Task Force Members and Disclosures

J. John Mann, M.D.
Task Force Co-Chair
Professor of Psychiatry and Radiology, Columbia University College of Physicians and Surgeons
Chief, Department of Neuroscience,
New York State Psychiatric Institute
ACNP
Industry Affiliations: v Consultant: GlaxoSmithKline, Pfizer, 2001 (expert trial witness) v Grants/Research Support: Pfizer v Attended 2002 GlaxoSmithKline Advisory group meeting on lamotrigine

Graham Emslie, M.D.

Task Force Co-Chair
Chief, Division of Child and Adolescent Psychiatry and Professor of Psychiatry,
The University of Texas Southwestern Medical Center at Dallas
ACNP
Industry Affiliations: v Consultant/Speaker's Bureau: Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, McNeil, Otsuka, Pfizer, Inc., Wyeth-Ayerst v Grants/Research Support: Eli Lilly, Novartis, Organon
William Beardslee, M.D.
Psychiatrist-in-Chief and Chair, Children's Hospital Department of Psychiatry
Professor of Child Psychiatry, Harvard Medical School
No Industry Affiliations Task Force Members and Disclosures
(continued)

Jan Fawcett, M.D.
Professor of Psychiatry, University of New Mexico
ACNP
Industry Affiliations: v Consultant: Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Laboratories, Janssen Pharmaceutica, GlaxoSmithKline, Merck & Co., Inc., Pfizer, Inc., Pharmacia & Upjohn, Wyeth-Ayerst Laboratories v Speaker's Bureau: Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer/Roerig, Pharmacia, GlaxoSmithKline, Solvay Pharmaceuticals, Inc., Wyeth-Ayerst Laboratories v Grants/Research Support: National Institute of Mental Health, Abbott Laboratories, Astra Zeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly and Company, Organon, Pfizer, Inc., Wyeth-Ayerst Laboratories

Fred Goodwin, M.D.
Research Professor of Psychiatry and Director, Psychopharmacology Research Center,
George Washington University
ACNP
Industry Affiliations: v Consultant: Glaxo, Lilly, Pfizer, Bristol Myers Squibb, Solvay. Elan, Novartis v Speakers Bureau: Bristol Myers Squibb, Solvay, Glaxo, Pfizer, Janssen, Lilly, v Grants/Research Support: Abbott Laboratories, Glaxo, Solvay, Janssen, Pfizer, Lilly,
Andrew Leon, Ph.D.
Professor of Biostatistics in Psychiatry and Professor of Public Health,
Weill Medical College of Cornell University. Industry Affiliations: v Consultant: Cyberonics, Inc., Cortex Pharmaceuticals v Delivered a presentation and prepared a manuscript for Forest Labs titled "Are Two Antidepressant Mechanisms Better than One? Issues in Clinical Trial Design and Analysis" Task Force Members and Disclosures
(continued)

Herb Meltzer, M.D.
Professor of Psychiatry & Pharmacology, Director Division of Psychopharmacology
President, Collegium Internationale Neuropsychopharmacologicum (CINP),
Vanderbilt University Medical Center
ACNP
Industry Affiliations: v Consultant, Speaker's Bureau, Honorarium, Grant/Research Support: Eli Lilly, Pfizer, GlaxoSmithKline, Janssen, AstraZeneca Neal Ryan, M.D.
Professor of Psychiatry, Western Psychiatric Institute & Clinic, University of Pittsburgh
ACNP

Industry Affiliations: v Consultant: GlaxoSmithKline (designed study and a performance site for the GSK study of paroxetine in adolescents and was second author on the resulting publication as well as a co-author on related letters to the editor including one letter related to suicidality assessment in that study) v Consultant: GlaxoSmithKline (examination of their data related to suicidality in their aggregate paroxetine data.) v Consultant (design of studies of antidepressants in youth): Pfizer, GSK, and Wyeth v Primary Investigator: Wyeth (Pittsburgh performance site for the study of Venlafaxine
David Shaffer, M.D.
Professor of Child Psychiatry, and Professor of Psychiatry and Pediatrics,
Columbia University College of Physicians and Surgeons
Director, Division of Child Psychiatry, New York State Psychiatric Institute
Industry Affiliations: v Consultant: Hoffman la Roche, Wyeth (expert trial witness) v Consultant: GlaxoSmithKline (on the matter of paroxetine and adolescent suicide)

(continued)
Task Force Members and Disclosures (continued) Karen Wagner, M.D., Ph.D.
Director, Division of Child and Adolescent Psychiatry,
Professor and Vice Chair, Department of Psychiatry and Behavioral Sciences,
University of Texas Medical Branch, Galveston
ACNP

Industry Affiliations: v Consultant: Abbott Laboratories, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Forest Laboratories, Glaxo-Smith Kline, Janssen, Novartis, Otskua, Pfizer, UCB Pharma, Wyeth-Ayerst v Speaker's Bureau: Abbott Laboratories, Eli Lilly and Co., Forest Laboratories, Glaxo- Smith Kline, Janssen, Novartis, Pfizer Inc. v Advisory Board: Abbott Laboratories, Eli Lilly and Co., Forest Laboratories, Glaxo- Smith Kline, Janssen, Novartis, Otsuka, Pfizer, UCB Pharma, Wyeth-Ayerst v Research Support: Abbott, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Organon, Pfizer, Wyeth-Ayerst, National Institute of Mental Health Assistance in writing the executive summary was provided by medical writer Miriam Davis,
Ph.D., LLC
, Adjunct Assistant Professor, Department of Epidemiology and Biostatistics, School
of Public Health and Health Services, George Washington University

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Noncollinear magnetic ground state of PrFeAsO This article has been downloaded from IOPscience. Please scroll down to see the full text article. 2011 EPL 93 17003 Download details: IP Address: 128.130.131.2 The article was downloaded on 25/04/2012 at 12:30 Please note that EPL, 93 (2011) 17003 Noncollinear magnetic ground state of PrFeAsO J. Liu , B. Luo , R. Laskowski

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Le bulletin d'information thérapeutique pour les malades Mars 2007 Nous avons l'habitude que la question du sida chez les femmes, la prise en comptede leurs spécificités (hors transmission mère/enfant), leur place dans les essais, ne Protocoles est le bulletin d'information soient ni entendues et ni présentées, et quand elles le sont, c'est avec beaucoup de