NEJM: On Zoloft Homicidal Ideation Frequent In Those 17 & Under

Since I believe that people should always get credit for the hard work and contribution they make in life I want to give our thanks to Rosie Meysenburg for getting this out to us today and for her comments on it. Rosie has done so much, along with her husband Gene, in posting our years and years worth of work gathering these SSRI & SNRI cases together for the _www.ssristories.drugawareness.org_
( site.

“This Adverse Event Report, from a study appearing in the New England Journal of Medicine, shows that of 133 children 17 & under on Zoloft there were 2 who reported “Homicidal Ideation”. There were no reports of “Homicidal Ideation” in the placebo group.

[According to the Physicians Desk Reference, a Frequent adverse reaction is one that occurs in 100 people or less.  Homicidal Ideation occurred in 1 in 66 children on Zoloft aged 17  and under.]

“According to the Physicians Desk Reference, a Frequent adverse reaction is one that occurs in 100 people or less. Homicidal Ideation occurred in 1 in 66 children on Zoloft aged 17 and under.

“This Adverse Event Report was the appendix for this study in the New England Journal of Medicine.”

adverse event report1.pdf

This Adverse Event Report was the appendix for this study in the New England Journal of Medicine:

And with this new information from the New England Journal of Medicine I want to include information out of Australia which is that Pfizer, the maker of Zoloft, along with the Therapeutic Goods Administration (TGA similar to our FDA), recommends that any SSRI antidepressant should not be prescribed to Australians under the age of 24. Funny, but I missed that warning from Pfizer for Americans under 24, didn’t you?

Next I will send that article that just came out over the weekend because it ties in so closely with this new information on Zoloft. And because there is so much to read in this article alone I am going to cut my comments at this point and let the article speak for itself.

Ann Blake-Tracy, Executive Director,
International Coalition for Drug Awareness
_www.drugawareness.org_ ( &
_www.ssristories.org_ (
Author of Prozac: Panacea or Pandora? – Our
Serotonin Nightmare & the audio, Help! I Can’t
Get Off My Antidepressant!!! ()

_atracyphd1@…_ (mailto:atracyphd1@…)


Published at October 30, 2008 (10.1056/NEJMoa0804633)
Cognitive Behavioral Therapy, Sertraline, or a Combination in Childhood

John T. Walkup, M.D., Anne Marie Albano, Ph.D., John Piacentini, Ph.D.,
Boris Birmaher, M.D., Scott N. Compton, Ph.D., Joel T. Sherrill, Ph.D., Golda
S. Ginsburg, Ph.D., Moira A. Rynn, M.D., James McCracken, M.D., Bruce Waslick,
M.D., Satish Iyengar, Ph.D., John S. March, M.D., M.P.H., and Philip C. Kendall, Ph.D.

Background Anxiety disorders are common psychiatric conditions affecting children and adolescents. Although cognitive behavioral therapy and selective serotonin-reuptake inhibitors have shown efficacy in treating these disorders, little is known about their relative or combined efficacy.

Methods In this randomized, controlled trial, we assigned 488 children between the ages of 7 and 17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia to receive 14 sessions of cognitive behavioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 ratio. We administered categorical and dimensional ratings of anxiety severity and impairment at baseline and at
weeks 4, 8, and 12.

Results The percentages of children who were rated as very much or much improved on the Clinician Global Impression “Improvement scale were 80.7% for combination therapy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for sertraline (P<0.001); all therapies were superior to placebo
(23.7%). Combination therapy was superior to both monotherapies (P<0.001).

Results on the Pediatric Anxiety Rating Scale documented a similar magnitude and pattern of response; combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and homicidal
ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline.

Both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders; a combination of the two therapies had a superior response rate.

( number,
NCT00052078 _[]_
) .)

Anxiety disorders are common in children and cause substantial impairment in
school, in family relationships, and in social functioning._1_
( ,_2_
( Such disorders
also predict adult anxiety disorders and major depression._3_
( ,_4_
( ,_5_
( ,_6_
( Despite a high
prevalence (10 to 20%_3_
,_7_ ( ,_8_
( ) and substantial
morbidity, anxiety disorders in childhood remain underrecognized and
undertreated._1_ (


An improvement in outcomes for children with anxiety disorders would have important public health
implications.In clinical trials, separation and generalized anxiety disorders and social
phobia are often grouped together because of the high degree of overlap in
symptoms and the distinction from other anxiety disorders (e.g., obsessive compulsive disorder). Efficacious treatments for these disorders include cognitive behavioral therapy_10_
( ,_11_
( and
the use of selective serotonin-reuptake inhibitors (SSRIs)._12_
( ,_13_

However, randomized, controlled trials comparing cognitive behavioral therapy, the use of an SSRI, or the combination of both therapies with a control are lacking. The evaluation of combination therapy is particularly important because approximately 40 to 50% of children with these disorders do not have a response to short-term treatment with either monotherapy.
_14_( ,_15_

Our study, called the Child “Adolescent Anxiety Multimodal Study, was designed to address the current gaps in the treatment literature by evaluating the relative efficacy of cognitive behavioral therapy, sertraline, a combination of the two therapies, and a placebo drug. This article reports the results of short-term treatment.


Study Design and Implementation

This study was designed as a two-phase, multicenter, randomized, controlled trial for children and adolescents between the ages of 7 and 17 years who had separation or generalized anxiety disorder or social phobia. Phase 1 was a 12-week trial of short-term treatment comparing cognitive behavioral therapy, sertraline, and their combination with a placebo drug. Phase 2 is a 6-month open extension for patients who had a response in phase 1.

The authors designed the study, wrote the manuscript, and vouch for the data gathering and analysis. Pfizer provided sertraline and matching placebo free of charge but was not involved in the design or implementation of the study, the analysis or interpretation of data, the preparation or review of the manuscript, or the decision to publish the results of the study.

Study Subjects

Children between the ages of 7 and 17 years with a primary diagnosis of separation or generalized anxiety disorder or social phobia (according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision
( ),
substantial impairment, and an IQ of 80 or more were eligible to participate. Children with coexisting psychiatric diagnoses of lesser severity than the three target disorders were also allowed to participate;
such diagnoses included attention deficit–hyperactivity disorder (ADHD) whilereceiving stable doses of stimulant and obsessive compulsive, post-traumatic stress, oppositional defiant, and conduct disorders. Children were excluded if they had an unstable medical condition, were refusing to attend school
because of anxiety, or had not had a response to two adequate trials of SSRIs or an adequate trial of cognitive behavioral therapy.

Girls who were pregnant or were sexually active and were not using an effective method of birth control
were also excluded. Children who were receiving psychoactive medications other than stable doses of stimulants and who had psychiatric diagnoses that made participation in the study clinically inappropriate (i.e., current majordepressive or substance-use disorder; type ADHD; or a lifetime history of bipolar, psychotic, or pervasive developmental disorders) or who presented an acute risk to themselves or others were also excluded.

Recruitment occurred from December 2002 through May 2007 at Duke University Medical Center, New York State Psychiatric Institute Columbia University Medical Center New York University, Johns Hopkins Medical Institutions, Temple University University of Pennsylvania, University of California, Los Angeles,and
Western Psychiatric Institute and Clinic University of Pittsburgh Medical Center. The protocol was approved and monitored by institutional review boards at each center and by the data and safety monitoring board of the National Institute of Mental Health. Subjects and at least one parent provided written informed consent.


Cognitive behavioral therapy involved fourteen 60-minute sessions, which included review and ratings of the severity of subjects’ anxiety, response to treatment, and adverse events. Therapy was based on the Coping Cat program,_17_ ( ,_18_
( which was adapted for the
subjects’ age and the duration of the study._19_ (

Each subject who was assigned to receive cognitive behavioral therapy received training in anxiety-management skills, followed by behavioral exposure to anxiety-provoking situations. Parents
attended weekly check-ins and two parent-only sessions. Experienced psychotherapists, certified in the Coping Cat protocol, received regular site-level and cross-site supervision.

Pharmacotherapy involved eight sessions of 30 to 60 minutes each that included review and ratings of the severity of subjects’ anxiety, their response to treatment, and adverse events. Sertraline (Zoloft) and matching placebo were administered on a fixed flexible schedule beginning with 25 mg per day and adjusted up to 200 mg per day by week 8. Through week 8, subjects who were considered to be mildly ill or worse and who had minimal side effects were eligible for dose increases.

Psychiatrists and nurse clinicians with experience in medicating children with anxiety disorders were certified in the study pharmacotherapy protocol and received regular site-level and cross-site supervision.
Pill counts and medication diaries were used to facilitate and document adherence. Combination therapy consisted of the administration of sertraline and cognitive behavioral therapy. Whenever possible, therapy and medication sessions occurred on the same day for the convenience of subjects.

Study objectives were, first, to compare the relative efficacy of the three active treatments with placebo; second, to compare combination therapy with either sertraline or cognitive behavioral therapy alone; and third, to assess the safety and tolerability of sertraline, as compared with placebo. We hypothesized that all three active treatments would be superior to placebo and that combination therapy would be superior to either sertraline or cognitive behavioral therapy alone.

Outcome Assessments
We obtained demographic information, information on symptoms of anxiety, and data on coexisting disorders and psychosocial functioning using reports from both the subjects and their parents and from interviews of subjects and parents at the time of screening, at baseline, and at weeks 4, 8, and 12.

The interviews were administered by independent evaluators who were unaware of study-group assignments.
We used the Anxiety Disorders Interview Schedule for DSM-IV-TR, Child Version,_20_ ( to establish diagnostic eligibility. The categorical primary outcome was the treatment response at week 12, which was defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression Improvement scale,_21_
( which ranges from 1 to 7, with lower scores indicating more improvement, as compared with baseline. A score of 1 or 2 reflects a substantial, clinically meaningful improvement in anxiety severity and normal functioning. The dimensional primary
outcome was anxiety severity as measured on the Pediatric Anxiety Rating Scale, computed by the summation of six items assessing anxiety severity, frequency, distress, avoidance, and interference during the previous week._22_(

Total scores on this scale range from 0 to 30, with scores above 13 indicating clinically meaningful anxiety. The Children’s Global Assessment Scale_23_ ( was used to rate
overall impairment.

Scores on this scale range from 1 to 100; scores of 60 or lower are considered to indicate a need for treatment, and a score of 50 corresponds to moderate impairment that affects most life situations and is readily observable. Agreement among the raters was high for anxiety severity (r=0.85) and diagnostic
status (intraclass correlation coefficient= 0.82 to 0.88) on the basis of a videotaped review of 10% of assessments by independent evaluators that were performed at baseline and at week 12.

Adverse Events
Adverse events were defined as any unfavorable change in the subjects’ pretreatment condition, regardless of its relationship to a particular therapy. Serious adverse events were life-threatening events, hospitalization, or events leading to major incapacity. Harm-related adverse events were defined as thoughts of harm to self or others or related behaviors. All subjects were interviewed at the start of each visit by the study coordinator with the use of a standardized script. Identified adverse events and harm-related events were then evaluated and rated by each subject’s study clinician.

This report presents data on all serious adverse events, all harm-related adverse events, andmoderate and severe (i.e., functionally impairing) adverse events that occurred in 3% or more of subjects in any study group. The data and safety monitoring board of the National Institute of Mental Health performed a quarterly review
of reported adverse events. Given the greater number of study visits (and hence more reporting
opportunities) and the unblinded administration of sertraline in the combination-therapy group, the test of the adverse-event profile of sertraline focused on statistical comparisons between sertraline and placebo and sertraline and cognitive behavioral therapy.

Randomization and Masking
The randomization sequence in a 2:2:2:1 ratio was determined by a computer-generated algorithm and maintained by the central pharmacy, with stratification according to age, sex, and study center. Subjects were assigned to study groups after being deemed eligible and undergoing verbal reconsent with a study investigator. Subjects in the sertraline and placebo groups did not know whether they were receiving active therapy, nor did their clinicians. However, subjects who received combination therapy knew they were receiving active sertraline. The study protocol called for independent evaluators who completed assessments to be unaware of all treatment assignments.

Statistical Analysis
On the basis of previous studies,_10_
( ,_11_
( ,_12_
,_13_ ( ,_14_
( ,_15_
we hypothesized that 80% of children in the combination-therapy group, 60% in either the sertraline group
or the cognitive-behavioral-therapy group, and 30% in the placebo group would be considered to have had a response to treatment at week 12. We determined that we needed to enroll 136 subjects in each active-treatment group and 70 subjects in the placebo group for the study to have a power of 80% to detect a minimum difference of 17% between any two study groups in the rate of response, assuming an alpha of 0.05 and a two-tailed test with no adjustment for multiple comparisons.

Analyses were performed with the use of SAS software, version 9.1.3 (SAS Institute). For categorical outcomes (including data regarding adverse events), treatments were compared with the use of Pearson’s chi-square test, Fisher’s exact test, or logistic regression, as appropriate. Logistic-regression models included the study center as a covariate. For dimensional outcomes, linear mixed-effects models (implemented with the use of PROC MIXED) were used to determine predicted mean values at each assessment point (weeks 4, 8, and 12)
and to test the study hypotheses with respect to between-group differences at week 12.

In each linear mixed-effects model, time and study group were included as fixed effects, with linear and quadratic time and time-by-treatment group interaction terms. Each model also began with a limited number of covariates (e.g., age, sex, and race), followed by backward stepping to identify thebest-fitting and most parsimonious model. In all models, random effects included intercept and linear slope terms, and an unstructured covariance was used to account for within-subject correlation over time. All comparisons were planned and tests were two-sided. A P value of less than 0.05 was considered to indicate statistical significance. The sequential Dunnett test was used to control the overall (familywise) error rate._24_

We analyzed data from all subjects according to study group. Sensitivity analyses were performed with the last observation carried forward (LOCF) and multiple imputation assuming missingness at random. Results were similar for the two missing-data methods. We report the results of the LOCF analysis because the
response rates were lower and hence provide a more conservative estimate of outcomes.

A total of 3066 potentially eligible subjects were screened by telephone
(_Figure 1_ ( ). Of these subjects, 761 signed consent forms and completed the inclusion and exclusion evaluation, 524 were deemed to be eligible and completed the baseline assessment, and 488 underwent randomization. Eleven subjects (2.3%) stopped
treatment but were included in the assessment (treatment withdrawals); 46 subjects (9.4%) stopped both treatment and assessment (study withdrawals).

On the basis of logistic-regression analyses, pairwise comparisons indicated that subjects in the cognitive-behavioral-therapy group were significantly less likely to withdraw from treatment than were those in the sertraline group (odds ratio, 0.33; 95% confidence interval [CI], 0.13 to 0.87; P=0.03) or the placebo
group (odds ratio, 0.24; 95% CI; 0.09 to 0.67; P=0.006). Of the 488 subjects who underwent randomization, 459 (94.1%) completed at least one postbaseline assessment, 396 (81.1%) completed all four assessments, and 440 (90.2%) completed the assessment at week 12. Subjects were recruited primarily through advertisements (52.2%) or clinical referrals (44.1%).
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Figure 1. Enrollment and Outcomes.

Subjects who are shown as having withdrawn from treatment discontinued their assigned therapy but continued to undergo study assessment. Subjects who are shown as having withdrawn from the study discontinued both therapy and assessment. CBT denotes cognitive behavioral therapy.

Of 14 possible sessions of cognitive behavioral therapy, the mean (±SD) number of sessions completed was 12.7±2.8 in the combination-therapy group and 13.2±2.0 in the cognitive-behavioral-therapy group. The mean dose of sertraline at the final visit was 133.7±59.8 mg per day (range, 25 to 200) in the combination-therapy group, 146.0±60.8 mg per day (range, 25 to 200) in the sertraline group, and 175.8±43.7 mg per day (range, 50 to 200) in the placebo group.

Demographic and Clinical Characteristics
There were no significant differences among study groups with respect to baseline demographic and clinical characteristics (_Table 1_ ( ). The mean age of participants was 10.7±2.8 years, with 74.2% under the age of 13 years.

There were nearly equal numbers of male and female subjects. Most subjects were white (78.9%), with
other racial and ethnic groups represented. Subjects came from predominantly middle-class and upper-middle-class families (74.6%) and lived with both biologic parents (70.3%). Most subjects had received the diagnosis of two or more primary anxiety disorders (78.7%) and one or more secondary disorders
(55.3%). At baseline, subjects had moderate-to-severe anxiety and impairment (_Table
2_ ( ).

Given the geographic diversity among study centers, there were significant differences among sites on several baseline demographic variables (e.g., race and socioeconomic status). Overall, these variables were equally distributed among study groups within each center; however, three centers had one instance each of
unequal distribution for sex, race, or socioeconomic status.

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Table 1. Baseline Characteristics of the Subjects and Recruitment According
to Study Center.

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Table 2. Key Outcomes at 12 Weeks.

Clinical Response
In the intention-to-treat analysis, the percentages of children who were rated as 1 (very much improved) or 2 (much improved) on the Clinical Global Impression–Improvement scale at 12 weeks were 80.7% (95% CI, 73.3 to 86.4) in the combination-therapy group, 59.7% (95% CI, 51.4 to 67.5) in the cognitive-behavioral-therapy group, 54.9% (95% CI, 46.4 to 63.1) in the sertraline group, and
23.7% (95% CI, 15.5 to 34.5) in the placebo group (_Table 2_ ( ).

With the study center as a covariate, planned pairwise comparisons from a logistic-regression model showed
that each active treatment was superior to placebo as follows: combination therapy versus placebo, P<0.001 (odds ratio, 13.6; 95% CI, 6.9 to 26.8); cognitive behavioral therapy versus placebo, P<0.001 (odds ratio, 4.8; 95% CI, 2.6 to 9.0); and sertraline versus placebo, P<0.001 (odds ratio, 3.9; 95% CI, 2.1 to 7.4). Similar pairwise comparisons revealed that combination therapy was superior to either sertraline alone (odds ratio, 3.4; 95% CI, 2.0 to 5.9; P<0.001) or cognitive behavioral therapy alone (odds ratio, 2.8; 95% CI, 1.6 to 4.8; P=0.001). However, there was no significant difference between sertraline and cognitive behavioral therapy (P=0.41).

There was no main effect for center (P=0.69); however, a comparison among centers according to study group revealed a significant difference in response to combination therapy but no differences with respect to the response to sertraline alone (P=0.15) or cognitive behavioral therapy alone (P=0.25).

Further evaluation of response rates revealed that the average response rate for combination therapy at one center was significantly lower than at the other centers (P=0.002). A sensitivity analysis of site response rates showed that when data from the one site were removed, the average response rate of the other sites was consistent with that of the full sample.

The mixed-effects model for the Pediatric Anxiety Rating Scale revealed a significant quadratic effect for time (P<0.001) and a significant quadratic time-by-treatment interaction for cognitive behavioral therapy versus placebo (P=0.01) but not for either combination therapy or sertraline versus placebo. In other words, as compared with placebo, cognitive behavioral therapy had a linear mean trajectory (_Figure 2_
( ). Planned pairwise comparisons of the expected mean scores on the Pediatric Anxiety Rating Scale at week 12 revealed a similar ordering of
outcomes, with all active treatments superior to placebo, according to the following comparisons: combination therapy versus placebo, t=–5.94 (P<0.001); cognitive behavioral therapy versus placebo, t=–2.11 (P=0.04); and sertraline versus placebo, t=–3.15 (P=0.002). In addition, combination therapy was
superior to both sertraline alone (t=–3.26, P=0.001) and cognitive behavioral therapy alone (t=–4.73, P<0.001). No significant difference was found between sertraline and cognitive behavioral therapy (t=1.32, P=0.19). The same magnitude and pattern of outcome was found for the Clinical Global Impressio Severity
scale and the Children’s Global Assessment Scale.
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Figure 2. Scores on the Pediatric Anxiety Rating Scale during the 12-Week

Scores on the Pediatric Anxiety Rating Scale range from 0 to 30, with scores higher than 13 consistent with moderate levels of anxiety and a diagnosis of an anxiety disorder. The expected mean score is the mean of the sampling distribution of the mean.

Estimates of the effect size (Hedges’ g) and the number needed to treatbetween the active-treatment groups and the placebo group were calculated. Effect sizes are based on the expected mean scores on the Pediatric Anxiety
Rating Scale, derived from the mixed-effects model. The number needed to treat is based on the dichotomized, end-of-treatment scores on the Clinical Global Impression–Improvement scale with the use of LOCF. The effect size was 0.86 (95% CI, 0.56 to 1.15) for combination therapy, 0.45 (95% CI, 0.17 to 0.74) for
sertraline, and 0.31 (95% CI, 0.02 to 0.59) for cognitive behavioral treatment.

The number needed to treat was 1.7 (95% CI, 1.7 to 1.9) for combination therapy, 3.2 (95% CI, 3.2 to 3.5) for sertraline, and 2.8 (95% CI, 2.7 to 3.0) for cognitive behavioral therapy. Treatment and Study Withdrawals
Most treatment and study withdrawals were attributed to reasons other than adverse events (43 of 57, 75.4%) (_Table 3_
( ).

Of the 14 withdrawals that were attributed to an adverse event, 11 (78.6%) were in the groups receiving either sertraline alone or placebo and consisted of 3 physical events (headache, stomach pains, and tremor) and 8 psychiatric adverse events (worsening of symptoms, 3 subjects; agitation or disinhibition, 3; hyperactivity, 1; and nonsuicidal self-harm and homicidal ideation, 1).
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Table 3. Subjects Who Withdrew from Treatment or the Study.

Serious Adverse Events
Three subjects had serious adverse events during the study period. One child in the sertraline group had a worsening of behavior that was attributed to the parents’ increased limit setting on avoidance behavior; the event was considered to be possibly related to sertraline. A child in the combination-therapy
group had a worsening of preexisting oppositional defiant behavior that resulted in psychiatric hospitalization; this event was considered to be unrelated to a study treatment. The third subject was hospitalized for a tonsillectomy, which was also considered to be unrelated to a study treatment
4_ ( ).
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Table 4. Moderate-to-Severe Adverse Events at 12 Weeks.

Adverse Events
Subjects in the combination-therapy group had a greater number of study visits and therefore significantly more opportunities for elicitation of adverse events than did those in the other study groups, with a mean of 12.8±4.0 opportunities (range, 1 to 22) in the combination-therapy group, as compared with 9.9±3.6 (range, 1 to 14) in the sertraline group, 10.6±2.0 (range, 1 to 14) in the cognitive-behavioral-therapy group, and 9.7±4.2 (range, 1 to 14) in the placebo group (P<0.001 for all comparisons). Rates of adverse events,
including suicidal and homicidal ideation, were not significantly greater in the sertraline group than in the placebo group. No child in the study attempted suicide. Among children in the cognitive-behavioral-therapy group, there were fewer reports of insomnia, fatigue, sedation, and restlessness or fidgeting than in the sertraline group (P<0.05 for all comparisons). For a list of mild adverse events that were not associated with functional impairment, as well as moderate and severe events, see the _Supplementary Appendix_
( ,

available with the full text of this article at

Our study examined therapies that many clinicians consider to be the most promising treatments for childhood anxiety disorders. Our findings indicate that as compared with placebo, the three active therapies combination therapy with both cognitive behavioral therapy and sertraline, cognitive behavioral therapy alone, and sertraline alone — are effective short-term treatments for children with separation and generalized anxiety disorders and social phobia, with combination treatment having superior response rates. No physical,psychiatric, or harm-related adverse events were reported more frequently in the sertraline group than in the placebo group, a finding similar to that for SSRIs, as identified in previous studies of anxious children._12_
( ,_13_
( ,_25_

Few withdrawals from either treatment or the study were attributed to adverse events. Suicidal ideation and homicidal ideation were uncommon. No child attempted suicide during the study period. Since they were recruited at multiple centers and locations, the study subjects were racially and ethnically diverse. However, despite intense outreach, the sample did not include the most socioeconomically disadvantaged children.
Subjects were predominantly younger children and included those with ADHD and other anxiety disorders, factors that allow for generalization of the results to these populations.

Conversely, the exclusion of children and teens with major depression and pervasive developmental disorders may have limited the generalizability of the results to these populations.The observed advantage of combination therapy over either cognitive behavioral therapy or sertraline alone during short-term treatment (an improvement of 21 to 25%) suggests that among these effective therapies, combination therapy
provides the best chance for a positive outcome. The superiority of combination therapy might be due to additive or synergistic effects of the two therapies. However, additional contact time in the combination-therapy group, which was unblinded, and expectancy effects on the part of both subjects and
clinicians cannot be ruled out as alternative explanations.

Nonetheless, the magnitude of the treatment effect in the combination-therapy group (with two
subjects as the number needed to treat to prevent one additional event) suggests that children with anxiety disorders who receive quality combination therapy can consistently expect a substantial reduction in the severity of anxiety. An increased number of visits in the combination-therapy group resulted in increased opportunities for elicitation of adverse events. Consequently, the potential for expectancies among subjects, parents, and clinicians regarding the side effects of medications in the context of more visits may have increased the rate of some adverse events in the combination-therapy group and may limit conclusions that can be drawn regarding the rates of adverse events in combination therapy.

The positive benefit of cognitive behavioral therapy, as compared with placebo, adds new information to the existing literature._26_ (
The number needed to treat for cognitive behavioral therapy in this study (three subjects) is the same as that
identified in a meta-analysis of studies comparing subjects who were assigned to cognitive behavioral therapy with those assigned to a waiting list for therapy or to sessions without active therapy._14_

Our study’s test of cognitive behavioral therapy included children with moderate-to-severe anxiety and addresses criticism of previous trials that included children with only mild-to-moderate
anxiety._14_ (
Before our study, cognitive behavioral therapy for childhood anxiety was considered to be
“probably efficacious.”_26_

This evaluation of cognitive behavioral therapy and other recent studies_27_ (
,_28_ ( suggests that
such therapy for childhood anxiety is a well-established, evidenced-based treatment._29_ (

Given that the risk of some adverse events was lower in the behavioral-therapy group than in the sertraline group, some parents and their children may consider choosing cognitive behavioral therapy as their initial treatment.

The results of our study confirm the short-term efficacy of sertraline for children with generalized anxiety disorder_25_ ( and show that
sertraline is effective for children with separation anxiety disorder and social phobia. The number needed
to treat for sertraline in our study (three subjects) was the same as that previously identified in a meta-analysis_15_ ( of six
randomized, placebo-controlled trials of SSRIs for childhood anxiety disorders._12_
( ,_13_
( ,_25_
,_30_ ( ,_31_

These studies and others_27_ (
suggest that SSRIs, as a class, are the medication of choice for these conditions. The titration schedule that we used, which emphasized upward dose adjustment in the absence of response and adverse events, suggests that the average end-point dose of sertraline in this study is the highest dose consistent with good outcome and tolerability. No adverse events were observed more frequently in the sertraline group than in the placebo group. In contrast to the apparent risk of suicidal ideation and behavior in studies of depression in children and
adolescents,_15_ ( our study did not demonstrate any increased risk for suicidal behavior in the sertraline group. Given the benefit of sertraline alone or in combination with cognitive behavioral therapy and the limited risk of adverse events associated with the drug in our study, the well-monitored use of sertraline and other SSRIs in the treatment of childhood anxiety disorders is indicated.

Cognitive behavioral therapy and sertraline either in combination or as monotherapies appear to be effective treatments for these commonly occurring childhood anxiety disorders. Results confirm those of previous studies of SSRIs and cognitive behavioral therapy and, most important, show that combination
therapy offers children the best chance for a positive outcome. Our findings indicate that all three of the treatment options may be recommended, taking into consideration the family’s treatment preferences, treatment availability, cost, and time burden. To inform more prescriptive selection of patients for
treatment, further analysis of predictors and moderators of treatment response may identify who is most likely to respond to which_32_
( of these
effective alternatives.
Supported by grants (U01 MH064089, to Dr. Walkup; U01 MH64092, to Dr.
Albano; U01 MH64003, to Dr. Birmaher; U01 MH63747, to Dr. Kendall; U01 MH64107,
to Dr. March; U01 MH64088, to Dr. Piacentini; and U01 MH064003, to Dr. Compton)
from the National Institute of Mental Health (NIMH).

Sertraline and matching placebo were supplied free of charge by Pfizer. Dr. Walkup reports receiving consulting fees from Eli Lilly and Jazz Pharmaceuticals and fees for legal consultation to defense counsel and
submission of written reports in litigation involving GlaxoSmithKline, receiving lecture fees from CMP Media, Medical Education Reviews, McMahon Group, and DiMedix, and receiving support in the form of free medication and matching placebo from Eli Lilly and free medication from Abbott for clinical trials funded by the NIMH; Dr. Albano, receiving royalties from Oxford University Press for the Anxiety Disorders Interview Schedule for DSM-IV, Child and Parent Versions, but not for interviews used in this study, and royalties from the Guilford Press; Dr. Piacentini, receiving royalties from Oxford University Press for treatmentmanuals on childhood obsessive compulsive disorder and tic disorders and from the Guilford Press and APA Books for other books on child mental health and receiving lecture fees from Janssen-Cilag; Dr. Birmaher, receiving consulting fees from Jazz Pharmaceuticals, Solvay Pharmaceuticals, and Abcomm, lecture fees from Solvay, and royalties from Random House for a book on children with bipolar disorder; Dr. Rynn, receiving grant support from Neuropharm, BoehringerIngelheim Pharmaceuticals, and Wyeth Pharmaceuticals, consulting fees from Wyeth, and royalties from APPI for a book chapter on pediatric anxiety disorders; Dr. McCracken, receiving consulting fees from Sanofi-Aventis and Wyeth, lecture fees from Shire and UCB, and grant support from Aspect, Johnson & Johnson, Bristol-Myers Squibb, and Eli Lilly; Dr. Waslick, receiving grant support from Baystate Health, Somerset Pharmaceuticals, and GlaxoSmithKline; Dr. Iyengar, receiving consulting fees from Westinghouse for statistical consultation; Dr. March, receiving study medications from Eli Lilly for an NIMH-funded clinical trial and receiving royalties from Pearson for being the author of the Multidimensional Anxiety Scale for Children, receiving consulting fees from Eli Lilly, Pfizer, Wyeth, and GlaxoSmithKline, having an equity interest in MedAvante, and serving on an advisory board for AstraZeneca and Johnson & Johnson; and Dr. Kendall, receiving royalties from Workbook Publishing for anxiety-treatment materials.

No other potential conflict of interest relevant to this article was reported.

The views expressed in this article are those of the authors and do not necessarily represent the official views of the NIMH, the National Institutes of Health, or the Department of Health and Human Services.
We thank the children and their families who made this study possible; and J. Chisar, J. Fried, R. Klein, E. Menvielle, S. Olin, J. Severe, D. Almirall, and members of NIMH’s data and safety monitoring board.
* The study investigators are listed in the Appendix.

Source Information
From the Johns Hopkins Medical Institutions, Baltimore (J.T.W., G.S.G.); New York State Psychiatric Institute–Columbia University Medical Center, New York (A.M.A., M.A.R.); the University of California at Los Angeles, Los Angeles (J.P., J.M.); Western Psychiatric Institute and Clinic University of Pittsburgh Medical Center, Pittsburgh (B.B., S.I.); Duke University Medical Center, Durham, NC (S.N.C., J.S.M.); the Division of Services and Intervention Research, National Institute of Mental Health, Bethesda, MD (J.T.S.); Baystate
Medical Center, Springfield, MA (B.W.); and Temple University, Philadelphia

This article (10.1056/NEJMoa0804633) was published at on
October 30, 2008. It will appear in the December 25 issue of the Journal.
Address reprint requests to Dr. Walkup at the Division of Child and
Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Johns
Hopkins Medical Institutions, 600 N. Wolfe St., Baltimore, MD 21287.
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16. Diagnostic and statistical manual of mental disorders, 4th ed., text
rev.: DSM-IV-TR. Washington, DC: American Psychiatric Association, 2000.
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18. Idem. Coping Cat workbook. 2nd ed.. Ardmore, PA: Workbook
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Psychiatry 2001;158:2008-2014. _<NOBR Full Text]_
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28. Kendall PC, Hudson JL, Gosch E, Flannery-Schroeder E, Suveg C.
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Full Text]_
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a paradigm. Psychol Bull 1966;65:110-136. _[CrossRef]_
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The following investigators participated in this study: Steering Committee:
J. Walkup (chair), A. Albano (cochair); Statistics–Experimental Design: S.
Compton, S. Iyengar, J. March; Cognitive Behavioral Therapy: P. Kendall, G.
Ginsburg; Pharmacotherapy: M. Rynn, J. McCracken; Assessment: J. Piacentini,
A. Albano; Study Coordinators: C. Keeton, H. Koo, S. Aschenbrand, L. Bardsley,
R. Beidas, J. Catena, K. Dever, K. Drake, R. Dublin, E. Fontaine, J. Furr, A.
Gonzalez, K. Hedtke, L. Hunt, M. Keller, J. Kingery, A. Krain, K. Miller, J.
Podell, P. Rentas, M. Rozenmann, C. Suveg, C. Weiner, M. Wilson, T. Zoulas;
Data Center: M. Fletcher, K. Sullivan; Cognitive Behavior Therapists: E.
Gosch, C. Alfano, A. Angelosante, S. Aschenbrand, A. Barmish, L. Bergman, S.
Best, J. Comer, S. Compton, W. Copeland, M. Cwik, M. Desari, K. Drake, E.
Fontaine, J. Furr, P. Gammon, C. Gaze, R. Grover, H. Harmon, A. Hughes, K.
Hutchinson, J. Jones, C. Keeton, H. Kepley, J. Kingery, A. Krain, A. Langley,
J. Lee, J. Levitt, J. Manetti-Cusa, E. Martin, C. Mauro, K. McKnight, T. Peris, K.
Poling, L. Preuss, A. Puliafico, J. Robin, T. Roblek, J. Samson, M.
Schlossberg, M. Sweeney, C. Suveg, O. Velting, T. Verduin; Pharmacotherapists:
M. Rynn, J. McCracken, A. Adegbola, P. Ambrosini, D. Axelson, S. Barnett, A. Baskina,
B. Birmaher, C. Cagande, A. Chrisman, B. Chung, H. Courvoisie, B. Dave, A.
Desai, K. Dever, M. Gazzola, E. Harris, G. Hirsh, V. Howells, L. Hsu, I.
Hypolite, F. Kampmeier, S. Khalid-Khan, B. Kim, D. Kondo, L. Kotler, M.
Krushelnycky, J. Larson, J. Lee, P. Lee, C. Lopez, L. Maayan, J. McCracken, R.
Means,L. Miller, A. Parr, C. Pataki, C. Peterson, P. Pilania, R. Pizarro, H. Ravi,
S. Reinblatt, M. Riddle, M. Rodowski, D. Sakolsky, A. Scharko, R. Suddath, C.
Suarez, J. Walkup, B. Waslick; Independent Evaluators: A. Albano, G.
Ginsburg, B. Asche, A. Barmish, M. Beaudry, S. Chang, M. Choudhury, B. Chu, S.
Crawley, J. Curry, G. Danner, N. Deily, R. Dingfelder, D. Fitzgerald, P.
Gammon, S. Hofflich, E. Kastelic, J. Keener, T. Lipani, K. Lukin, M. Masarik, T.
Peris, T. Piacentini, S. Pimentel, A. Puliafico, T. Roblek, M. Schlossberg, E.
Sood, S. Tiwari, J. Trachtenberg, P. van de Velde; Pharmacy: K. Truelove, H.
Kim; Research Assistants: S. Allard, S. Avny, D. Beckmann, C. Brice, B.
Buzzella, E. Capelli, A. Chiu, M. Coles, J. Freeman, M. Gringle, S. Hefton, D.
Hood, M. Jacoby, J. King, A. Kolos, B. Lourea-Wadell, L. Lu, J. Lusky, R. Maid, C.
Merolli, Y. Ojo, A. Pearlman, J. Regan, S. Rock, M. Rooney, N. Simone, S.
Tiwari, S. Yeager.

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4/26/2001 – Part 2 – Luvox study on anxiety

Drug Found to Curb Kids’ Debilitating Social Anxiety

By Shankar Vedantam
Washington Post Staff Writer
Thursday, April 26, 2001; Page A01

Children who are so shy or so attached to their parents that they are afraid
to go to school or sleep alone do much better when given a psychiatric drug,
according to a major study with profound — and controversial —
ramifications for millions of children.

The study of 128 children ages 6 to 17 found that the drug Luvox, widely
prescribed for adults with depression, alleviated the debilitating symptoms
of social phobia, separation anxiety and generalized anxiety — psychiatric
illnesses that afflict as many as 1 in 10 U.S. children.

The effects of the medicine were dramatic, but experts were divided about its
appropriateness: The medicine can help children with severe emotional
problems, but it might also be abused as a chemical quick fix for normal
anxiousness, with lasting effects on growing brains.

“Although the results seem impressive, they nevertheless raise some very
important questions about the use of psychotropic medications in children,”
said Joseph Coyle, chairman of psychiatry at Harvard Medical School, in an
article accompanying the findings in today’s New England Journal of Medicine.

“Any drug that is effective is not going to be innocuous,” he said in an
interview. Children and adolescents diagnosed with these disorders should
first try a form of therapy known as cognitive behavioral therapy, and turn
to medication only if that fails, he said.

An estimated 575,000 children nationwide were diagnosed with anxiety
disorders in the 12 months ending in March, including 136,000 under age 10.
Doctors recommended 390,000 children be put on medicines such as Zoloft,
Paxil and Prozac. Of these, 89,000 were under age 10, according to IMS
Health, a private company that tracks the pharmaceutical industry.

Such vast numbers leave critics aghast. Too many children are being put on
powerful brain-altering drugs for behaviors that may be merely troublesome,
critics say. But other experts point out that many children suffer from
distress that, left untreated, can cause impairment well into adulthood.

“Researchers found that anxiety was among the most common problems that kids
have,” said Daniel Pine of the National Institute of Mental Health. He led
the study. “When researchers follow children with anxiety over time,
sometimes anxiety developed into more chronic problems. It could be the
harbinger of problems with depression, panic attacks and all different kinds
of problems.”

The study, the first large, well-designed survey to examine the effectiveness
of a psychiatric drug for a wide range of anxiety disorders in children, was
partly funded by the National Institute of Mental Health and by Solvay
Pharmaceuticals, which sells Luvox. The drug, which like Prozac increases
levels of the brain chemical serotonin, has been approved for the treatment
of obsessive compulsive disorder in children. Luvox sales were more than $2
billion in the United States last year, according to IMS Health.

Scientists at Johns Hopkins University, Columbia University, New York
University, Duke University and the University of California at Los Angeles
studied the drug over eight weeks in children with anxiety disorders.

An example of a child with severe social phobia would be one who refused to
go to school for two weeks, said Mark Riddle of the Johns Hopkins University
School of Medicine, one of the study’s authors. A milder example, he said,
would be a child who went to school and participated in clubs and group
events, but with intense discomfort.

Extreme separation anxiety disorder, he said, would be displayed in a child
who avoided birthday parties and sleepovers. A medium-grade example would be
children who refused to sleep in their own rooms and wanted to get into bed
with their parents.

Generalized anxiety disorder, Riddle said, were “the worrywarts.”

“A lot of it would be about performance — getting very preoccupied with a
test at school, a lot of fussing about day-to-day things,” he said.

“We don’t want a Prozac nation,” he said about the medication of children.
“We want to make sure we are not doing anything to harm youngsters. On the
other hand, it can be a huge disservice to children to minimize the true
significance of psychiatric impairments that do require treatments. It’s the
latter that can get lost in the very easy and popular position to take, which
is ‘Don’t drug our kids.’ ”

Richard Harding, president-elect of the American Psychiatric Association,
said clinicians should carefully evaluate anxious children to find out
whether their fears are caused by an underlying personality problem — which
would merit psychotherapy or medication — or by a social problem, such as a
bully in school or child abuse at home, in which case medication would be

“A good clinician will not commit a child to a life sentence on medicine,”
said Riddle. “A good clinician will look to stop medication after the
youngster has had a chance to regroup. You want to work with a clinician who
says we are going to get John off this medication.”

It is unclear what impact this study will have in clinical practice, where
doctors are prescribing children such medicines “off-label” — meaning they
have not been approved for such uses by the Food and Drug Administration.

“Given our current medical-economic system in practice, I suspect both
doctors and parents will be strongly attracted to the quick-fix nature of
this intervention,” said Lawrence Diller, a behavioral pediatrician in Walnut
Creek, Calif., and the author of “Running on Ritalin.”

“We have highly effective psychosocial interventions for these problems,” he
said. But “they are more expensive and take longer.”

He said that helping families come up with parenting strategies could ease
children’s anxieties. “Children are highly responsive to their environments,
and the home is the practice arena to deal with life,” he said. “This is not
parent-blaming — children are difficult to raise. But when the parent makes
changes, you see very rapid changes in the child.”

“It doesn’t negate the value of the medications,” he added. But “with
uncertainty on both sides, effective psychosocial treatments — first do no
harm — take preference.”

More extreme critics, such as Bethesda psychiatrist Peter Breggin, said the
study was produced by scientists who are part of an “old boys’ network of
drug pushers.” He said the psychiatric drugs cause harm — some data have
shown that the drugs cause lasting alterations in the brains of young animals.

Researchers involved in the new study said the drug was well tolerated and

© 2001 The Washington Post Company

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4/13/2001 – Drugs not genes cause birth defects in babies of epileptic women

Thanks to our director in Norway we have this new information out of the
Guardian in the UK on anti-seizure meds. Anti-seizure meds are often given
along with antidepressants due to the seizure activity induced by the
antidepressants. This seizure activity manifests itself in various forms
including mania – a condition in which the brain is in a continuous mild
seizure activity that alters ones consciousness and behavior.

Note this statement in particular: “They found that the babies of women who
had taken drugs for epilepsy had a much higher rate of birth defects – 20.6%
of infants exposed to one drug, and 28% of infants exposed to two or more
drugs in the womb. This figure compared with 8.5% of those having birth
defects and mothers who had taken nothing.”

With that information in mind recall that Jeffrey Dahmer’s mother was taking
23 pills daily, the large majority of those being anti-seizure meds. What
were his chances of birth defects or various forms of retarded development?
Why can we not understand that when a mother is on a mind-altering medication
that the baby’s brain is certainly going to be affected as well?

What a shame that these mothers are not made aware of simple alternatives
such as Omega 3 oils for seizures or Noni, the fruit juice out of Tahiti.
These are a couple of simple non-toxic solutions to the seizures for which
they are taking these damaging drugs.

Ann Blake-Tracy, Executive Director,
International Coalition for Drug Awareness,4273,4169237,00.html

Drugs not genes cause birth defects in babies of epileptic women

Sarah Boseley, health editor


Thursday April 12, 2001

Birth defects in the babies of women who take medicine for epilepsy while
they are pregnant are caused by the drugs and not by the epilepsy, according
to new research reported in the US.

The study, published in the New England Journal of Medicine today, claims
that the idea that the genetic abnormalities which cause the epilepsy are
then passed on to the foetus, is wrong.

Lewis B Holmes and his colleagues from the paediatric service of
Massachusetts general hospital, in Boston, say it is the medication which is
to blame for the children’s defects.

Since the 1970s it has been recognised that women taking the drugs most
frequently given to prevent epileptic fits, have a higher risk than usual of
giving birth to babies with certain malformations, such as abnormalities of
the face and fingers, and retarded growth.

The Massachusetts team examined 316 babies born to women who had taken
anticonvulsant drugs during pregnancy and 98 babies of women with a history
of epilepsy who had not had the medication.

They compared the babies with 508 other babies whose mothers did not have
epilepsy and had not taken medication while pregnant.

They found that the babies of women who had taken drugs for epilepsy had a
much higher rate of birth defects – 20.6% of infants exposed to one drug, and
28% of infants exposed to two or more drugs in the womb. This figure compared
with 8.5% of those having birth defects and mothers who had taken nothing.

Women with epilepsy who had not taken drugs in pregnancy were no more likely
to have a baby with birth defects than women who had no history of the

The research poses a big dilemma for women with epilepsy, as stopping the
medication would put some women and their unborn babies at risk of damage
from seizures.

A spokeswoman for the British Epilepsy Association said it might not always
occur to GPs to raise the issue with their female patients. “But it is really
important for all women with epilepsy who are planning a family to go and
seek specialist advice beforehand so that the medication can be looked at and
then possibly changed,” she said.

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4/09/2001 – Ghostwriting Articles for Medical Journals

Dennis Silver, who serves as webmaster for the Prozac: Panacea or Pandora?
website (, has just brought to our attention an
amazing article from CBS Health Watch. In the ten years I have been fighting
this battle to get the truth out to the public about what goes on behind the
scenes in medcine this strikes at the heart of the issue like no other!

As I did the research for my book I was appalled at the difference in the
studies on serotonin BEFORE the development of the SSRIs and the studies
being published on serotonin AFTER and during the development of the SSRI
antidepressants. It was clear to me that the drug companies were manipulating
the science to build a market for their drugs. It was as if the new studies
were contradicting the old studies. Truth is consistent not variable. It was
clear something had changed. I say BRAVO!!! to CBS and to Dr. Marcia Angell,
former editor of the New England Journal of Medicine, who has worked hard to
expose this situation over the last year or so! Thank you for demonstrating
that integrity still exists in our country by exposing those with no
knowledge of what integrity is.

Note how the spokesperson for Wythe Ayers justifies their criminal behavior
with the same old line: “well everyone else does it too.”

Ann Blake-Tracy, Executive Director,
International Coalition For Drug Awareness


Ghostwriting Articles for Medical Journals

April 5 (CBS) Amidst the billion-dollar competition to create the newest
blockbuster drug, there’s one thing worth more than all the ads money can
buy: a single positive mention in a respected medical journal. Doctors rely
so heavily on what’s printed in journals that a drug’s success or failure may
be directly affected.

Now, many drug companies are actually writing those articles and then paying
doctors to sign their names to them. It’s called ghostwriting, reports CBS
News Correspondent Sharyl Attkisson.

“The articles are written by drug company researchers, given to an outside
doctor to review and sign his or her name to, and then submitted to a
journal. In effect, it’s like washing dirty money,” explains Douglas Peters,
a medical malpractice attorney.

It’s not illegal, but it can be misleading.

Critics say that’s just what happened when Wyeth-Ayerst wanted to create a
market demand for its “fen-phen” diet drug, Redux.

Wyeth hired a middleman, a company called Excerpta Medica, to write and get
published nine medical journal articles on Redux. Excerpta paid doctors to
review and sign the articles, then submitted them to journals with no mention
of Wyeth. Excerpta claims it told the doctors that Wyeth was behind all of

But Dr. Richard Atkinson, a professor of medicine and nutritional sciences
and the director of the Beers-Murphy Clinical Nutrition Center at the
University of Wisconsin Madison Medical School, says he wasn’t told. He
reviewed and signed one of those Redux papers thinking Excerpta was an
independent researcher, he says.

“If I knew that a drug company had some role, whatever role, in sponsoring a
talk, an article, a symposium, whatever, I think I would be more on my guard
to make sure that there was not any bias introduced,” says Atkinson.

Biased literature can make a drug sound better or safer than it really is.
And unbeknownst to most doctors, it’s even finding its way into the most
respected medical journals.

Dr. Marcia Angell, former editor of the New England Journal of Medicine, says
that as time passed she was getting more and more ghostwritten papers.

“A drug company that controls the data and has a ghostwriter writing the
paper may neglect to write about the side effects of a drug,” says Angell.

In a deposition on January 15, 1999, former Wyeth executive Jo Alene Dolan
said all drug companies ghostwrite, but it doesn’t mean the articles aren’t

When questioned about Atkinson’s article, she said, “Apparently we wrote this
article for him.” She was then asked if it was bought and paid for by
Wyeth-Ayerst and replied, “I’m not sure that’s the way I would characterize
it. It was funded by Wyeth-Ayerst.”

Yet Wyeth’s middleman, Excerpta Medica, claims it doesn’t ghostwrite. It says
it “facilitates,” that doctors always know about drug industry involvement,
and that “the author has final editing authority.”

Atkinson did tell Excerpta that article may make Redux “sound better than it
really is” and suggested some changes. But before the article could be
published, Redux was linked to heart and lung problems and pulled from the

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5/31/2000 – Is Academic Medicine for Sale? – New England Jour of Med

The New England Journal of Medicine
May 18, 2000 — Vol. 342, No. 20

Is Academic Medicine for Sale?

by Marcia Angell, M.D., editor,

In 1984 the Journal became the first of the major medical journals to
require authors of original research articles to disclose any financial ties
with companies that make products discussed in papers submitted to us. (1)
We were aware that such ties were becoming fairly common, and we thought it
reasonable to disclose them to readers.

Although we came to this issue early, no one could have foreseen at the time
just how ubiquitous and manifold such financial associations would become.
The article by Keller et al. (2) in this issue of the Journal provides a
striking example. The authors’ ties with companies that make antidepressant
drugs were so extensive that it would have used too much space to disclose
them fully in the Journal. We decided merely to summarize them and to
provide the details on our Web site.

Finding an editorialist to write about the article presented another
problem. Our conflict-of-interest policy for editorialists, established in
1990, (3) is stricter than that for authors of original research papers.
Since editorialists do not provide data, but instead selectively review the
literature and offer their judgments, we require that they have no important
financial ties to companies that make products related to the issues they
discuss. We do not believe disclosure is enough to deal with the problem of
possible bias. This policy is analogous to the requirement that judges recuse
themselves from hearing cases if they have financial ties to a litigant. Just
as a judge’s disclosure would not be sufficiently reassuring to the other
side in a court
case, so we believe that a policy of caveat emptor is not enough for readers
who depend on the opinion of editorialists.

But as we spoke with research psychiatrists about writing an editorial
on the treatment of depression, we found very few who did not have financial
ties to drug companies that make antidepressants. (Fortunately, Dr. Jan
Scott, who is eminently qualified to write the editorial, (4) met our
standards with respect to conflicts of interest.) The problem is by no means
unique to psychiatry. We routinely encounter similar difficulties in finding
editorialists in other specialties, particularly those that involve the
heavy use of expensive drugs and devices.

In this editorial, I wish to discuss the extent to which academic
medicine has become intertwined with the pharmaceutical and biotechnology
industries, and the benefits and risks of this state of affairs.
Bodenheimer, in his Health Policy Report elsewhere in this issue of the
Journal, (5) provides a detailed view of an overlapping issue — the
relations between clinical investigators and the pharmaceutical industry.

The ties between clinical researchers and industry include not only
grant support, but also a host of other financial arrangements.
Researchers serve as consultants to companies whose products they are
studying, join advisory boards and speakers’ bureaus, enter into patent and
royalty arrangements, agree to be the listed authors of articles
ghostwritten by interested companies, promote drugs and devices at
company-sponsored symposiums, and allow themselves to be plied with expensive
gifts and trips to luxurious settings. Many also have equity interest in the

Although most medical schools have guidelines to regulate financial
ties between their faculty members and industry, the rules are generally
quite relaxed and are likely to become even more so. For some years, Harvard
Medical School prided itself on having unusually strict guidelines. For
example, Harvard has prohibited researchers from having more than $20,000
worth of stock in companies whose products they are studying. (6) But now
the medical school is in the process of softening its guidelines. Those
reviewing the Harvard policy claim that the guidelines need to be modified
to prevent the loss of star faculty members to other schools. The executive
dean for academic programs was reported to say, “I’m not sure what will come
of the proposal. But the impetus is to make sure our faculty has reasonable
opportunities.” (7) Academic medical institutions are themselves growing
increasingly beholden to industry. How can they justify rigorous
conflict-of-interest policies for individual researchers when their own ties
are so extensive? Some academic institutions have entered into partnerships
with drug companies to set up research centers and teaching programs in which
students and faculty members essentially carry out industry research. Both
sides see great benefit in this arrangement. For financially struggling
medical centers, it means cash. For the companies that make the drugs and
devices, it means access to research talent, as well as affiliation with a
prestigious “brand.” The
time-honored custom of drug companies’ gaining entry into teaching hospitals
by bestowing small gifts on house officers has reached new levels of
munificence. Trainees now receive free meals and other substantial favors
from drug companies virtually daily, and they are often invited to opulent
dinners and other
quasi-social events to hear lectures on various medical topics. All of this
is done with the acquiescence of the teaching hospitals.

What is the justification for this large-scale breaching of the
boundaries between academic medicine and for-profit industry? Two reasons
are usually offered, one emphasized more than the other. The first is that
ties to industry are necessary to facilitate technology transfer — that is,
the movement of new drugs and devices from the laboratory to the
marketplace. The term “technology transfer” entered the lexicon in 1980,
with the passage of federal legislation, called the Bayh-Dole Act, (8) that
encouraged academic institutions supported by federal grants to patent and
license new products developed by their faculty members and to share
royalties with the researchers. The Bayh-Dole Act is now frequently invoked
to justify the ubiquitous ties between academia and industry. It is argued
that the more contacts there are between academia and industry, the better it
is for clinical medicine; the fact that money changes hands is considered
merely the way of the world.

A second rationale, less often invoked explicitly, is simply that
academic medical centers need the money. Many of the most prestigious
institutions in the country are bleeding red ink as a result of the
reductions in Medicare reimbursements contained in the 1997 Balanced Budget
Act and the hard bargaining of other third-party payers to
keep hospital costs down. Deals with drug companies can help make up for the
shortfall, so that academic medical centers can continue to carry out their
crucial missions of education, research, and the provision of clinical care
for the sickest and neediest. Under the circumstances, it is not surprising
that institutions feel justified in accepting help from any source.

I believe the claim that extensive ties between academic researchers and
industry are necessary for technology transfer is greatly exaggerated,
particularly with regard to clinical research. There may be some merit to
the claim for basic research, but in most clinical research, including
clinical trials, the “technology” is essentially already developed.
Researchers are simply testing it. Furthermore, whether financial
arrangements facilitate technology transfer depends crucially on what those
arrangements are. Certainly grant support is constructive, if administered
properly. But it is highly doubtful whether many of the other financial
arrangements facilitate technology transfer or confer any other social
benefit. For example, there is no conceivable social benefit in researchers’
having equity interest in companies whose products they are studying.
Traveling around the world to appear at industry-sponsored symposiums has
much more to do with
marketing than with technology transfer. Consulting arrangements may be more
likely to further the development of useful products, but even this is
arguable. Industry may ask clinical researchers to become consultants more
to obtain their goodwill than to benefit from their expertise. The goodwill
of academic researchers is a very valuable commodity for drug and device
manufacturers. Finally, it is by no means necessary for technology transfer
that researchers be personally rewarded. One could imagine a different
system for accomplishing the same purpose. For example, income from
consulting might go to a pool earmarked to support research or any other
mission of the medical center.

What is wrong with the current situation? Why shouldn’t clinical researchers
have close ties to industry? One obvious concern is that these ties will
bias research, both the kind of work that is done and the way it is reported.
Researchers might undertake studies on the basis of whether they
can get industry funding, not whether the studies are scientifically
important. That would mean more research on drugs and devices and less
designed to gain insights into the causes and mechanisms of disease. It
would also skew research toward finding trivial differences between drugs,
because those differences can be exploited for marketing. Of even greater
concern is the possibility that financial ties may influence the outcome of
research studies.

As summarized by Bodenheimer, (5) there is now considerable evidence
that researchers with ties to drug companies are indeed more likely to
report results that are favorable to the products of those companies than
researchers without such ties. That does not conclusively prove that
researchers are influenced by their financial ties to industry. Conceivably,
drug companies seek out researchers who happen to be getting positive
results. But I believe bias is the most likely explanation, and in either
case, it is clear that the more enthusiastic researchers are, the more
assured they can be of industry funding.

Many researchers profess that they are outraged by the very notion that
their financial ties to industry could affect their work. They insist that,
as scientists, they can remain objective, no matter what the blandishments.
In short, they cannot be bought. What is at issue is not whether researchers
can be “bought,” in the sense of a quid pro quo. It is that close and
remunerative collaboration with a company naturally creates goodwill on the
part of researchers and the hope that the largesse will continue. This
attitude can subtly influence scientific judgment in ways that may be
difficult to discern. Can we really believe that clinical researchers are
more immune to self-interest than
other people?

When the boundaries between industry and academic medicine become as
blurred as they now are, the business goals of industry influence the
mission of the medical schools in multiple ways. In terms of education,
medical students and house officers, under the constant tutelage of industry
representatives, learn to rely on drugs and devices more than they probably
should. As the critics of medicine so often charge, young physicians learn
that for every problem, there is a pill (and a drug company representative to
explain it). They also become accustomed to receiving gifts and favors from
an industry that uses these courtesies to influence their continuing
education. The
academic medical centers, in allowing themselves to become research outposts
for industry, contribute to the overemphasis on drugs and devices. Finally,
there is the issue of conflicts of commitment. Faculty members who do
extensive work for industry may be distracted from their commitment to the
school’s educational mission.

All of this is not to gainsay the importance of the spectacular
advances in therapy and diagnosis made possible by new drugs and devices.
Nor is it to deny the value of cooperation between academia and industry.
But that cooperation should be at arm’s length, with both sides maintaining
their own standards and ethical norms. The incentives of the marketplace
should not become woven into the fabric of academic medicine. We need to
remember that for-profit businesses are pledged to increase the value of
their investors’ stock. That is a very different goal from the mission of
medical schools.

What needs to be done — or undone? Softening its conflict-of-interest
guidelines is exactly the wrong thing for Harvard Medical School to do.
Instead, it should seek to encourage other institutions to adopt stronger
ones. If there were general agreement among the major medical schools on
uniform and rigorous rules, the concern about losing faculty to more lax
schools — and the consequent race to the bottom — would end. Certain
financial ties should be prohibited altogether, including equity interest and
many of the writing and speaking arrangements.Rules regarding conflicts of
commitment should also be enforced. It is difficult to believe that full-time
faculty members can generate outside
income greater than their salaries without shortchanging their institutions
and students.

As Rothman urges, teaching hospitals should forbid drug-company
representatives from coming into the hospital to promote their wares and
offer gifts to students and house officers. (9) House officers should buy
their own pizza, and hospitals should pay them enough to do so. To the
argument that these gifts are too inconsequential to constitute bribes, the
answer is that the drug companies are not engaging in charity. These gifts
are intended to buy the goodwill of young physicians with long prescribing
lives ahead of them. Similarly, academic medical centers should be wary of
partnerships in which they make available their precious resources of talent
and prestige to carry out research that serves primarily the interests of
the companies. That is ultimately a Faustian bargain.

It is well to remember that the costs of the industry-sponsored trips,
meals, gifts, conferences, and symposiums and the honorariums, consulting
fees, and research grants are simply added to the prices of drugs and
devices. The Clinton administration and Congress are now grappling with the
serious problem of escalating drug prices in this country. In these difficult
times, academic medicine depends more than ever on the public’s trust and
goodwill. If the public begins to perceive academic medical institutions and
clinical researchers as gaining inappropriately from cozy relations with
industry — relations that create conflicts of interest and contribute to
rising drug prices — there will be little sympathy for their difficulties.
Academic institutions and their
clinical faculty members must take care not to be open to the charge that
they are for sale.

Marcia Angell, M.D.

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