Treatment for Adolescents with Depression Study

The Treatment for Adolescents with Depression Study (TADS)
is a
major NIH-sponsored study of the treatment of adolescents with
depression, in which href="" rel="tag">fluoxetine-only,
rel="tag">cognitive-behavioral therapy
only, combination treatment, and placebo are compared.  The
is expected to generate a number of papers.  One was published
few days ago in the Archives of General Psychiatry.  The paper
not yet open-access.  The study team, however, has a href="">website
with information about the study, including their href="">assessment
and treatment manuals (which somehow manage to be both
interesting and incredibly dull at the same time).  In this
post, I discuss the study, add some editorial comments, and review
pending legislation that addresses some of the pertinent issues.

The abstract of the report follows:


Treatment for Adolescents With Depression Study (TADS)

Long-term Effectiveness and Safety Outcomes

Arch Gen Psychiatry. 2007;64:1132-1143

Context  The
Treatment for Adolescents
With Depression Study evaluates the effectiveness of fluoxetine
hydrochloride therapy, cognitive behavior therapy (CBT), and their
combination in adolescents with major depressive disorder.

Objective  To report
effectiveness outcomes across 36 weeks of randomized treatment.

Design and Setting 
Randomized, controlled trial
conducted in 13 academic and community sites in the United States.
Cognitive behavior and combination therapies were not masked, whereas
administration of placebo and fluoxetine was double-blind through 12
weeks, after which treatments were unblinded. Patients assigned to
placebo were treated openly after week 12, and the placebo group is not
included in these analyses by design.

Participants  Three hundred
twenty-seven patients aged 12 to 17 years with a primary DSM-IV
diagnosis of major depressive disorder.

Interventions  All treatments
were administered per protocol.

Main Outcome Measures  The
primary dependent
measures rated blind to treatment status by an independent evaluator
were the Children's Depression Rating Scale–Revised total
and the response rate, defined as a Clinical Global
Impressions–Improvement score of much or very much improved.

Results  Intention-to-treat
analyses on the
Children's Depression Rating Scale–Revised identified a
significant time x treatment interaction (P < .001). Rates of
response were 73% for combination therapy, 62% for fluoxetine therapy,
and 48% for CBT at week 12; 85% for combination therapy, 69% for
fluoxetine therapy, and 65% for CBT at week 18; and 86% for combination
therapy, 81% for fluoxetine therapy, and 81% for CBT at week 36.
Suicidal ideation decreased with treatment, but less so with fluoxetine
therapy than with combination therapy or CBT. Suicidal events were more
common in patients receiving fluoxetine therapy (14.7%) than
combination therapy (8.4%) or CBT (6.3%).

Conclusions  In adolescents
with moderate to severe
depression, treatment with fluoxetine alone or in combination with CBT
accelerates the response. Adding CBT to medication enhances the safety
of medication. Taking benefits and harms into account, combined
treatment appears superior to either monotherapy as a treatment for
major depression in adolescents.

No big surprises here.  As we have seen in numerous studies
adults, any decent treatment is better than nothing, psychotherapy
alone has a positive effect, medication alone is better, but the best
results are seen with medication combined with psychotherapy.
 Like other studies, medication alone appear to increase the
of suicidal thinking and attempts, but there were no suicides in the
study.  An important finding is that kids who got both
and psychotherapy

There are a couple of obvious points to make.  One, the
effectiveness of all treatment arms converged toward the end of the
study.  Two, the findings regarding suicidality indicate that
is wisest to provide psychotherapy too, if medication is to be given.

The problem with that is that is hard to find qualified persons to
provide psychotherapy to adolescents with severe depression, and the
duration of treatment required is beyond that which some insurance
companies will pay for.  The drug used in the study,
can be gotten at places such as Wal-Mart, K-Mart, and Target for four
to five dollars per month.  (Although the average dose used in
study was 30mg/day, so the average drug cost would be six dollars per
month.)  It is impossible to provide psychotherapy for prices

There are some less obvious points to make about the study.

For one, it may be tempting to assume that any antidepressant, or
perhaps any SSRI, would have comparable results.  That tends
to be
true with adults, but we don't have as much data for adolescents.
 Plus, there is some evidence that different antidepressants
different risks of suicidal thinking.  So it would be good to
careful about generalizing the findings from this study to make
assumptions about other drugs.

Additionally, the authors of the study comment in the (not open-access)
text that the findings should be generalizable to the general
population of adolescents who present for treatment in outpatient
settings.  Assessing the generalizability of a study is a
matter.  I notice that, of the patients in the study, 26.7%
been suspended or expelled from school.  That does make me
if this truly was a representative sample; it suggests that the sample
might better represent a more disturbed population.  Minor
it does not affect the validity of the main conclusions.  If
anything, it suggests that perhaps better results could be expected in
a population with less evidence of academic impairment.  

The authors do mention that there was a lot of comorbidity (other
conditions present in addition to depression):

Including dysthymia, more than half of the
(52.0%) was comorbid for at least 1 other psychiatric disorder.
Forty-one of 327 patients (12.5%) met DSM-IV criteria for
attention-deficit/hyperactivity disorder and, of these, 9 of 41 (22.0%)
were taking a psychostimulant at study entry.

I would be curious to see if there were any differences in response, or
any differences in suicidality, among the subset taking a stimulant.
 However, the number is this study was too small to permit any
meaningful conclusions about that population.

Getting back to the point about the relative availability and costs of
the treatments, I'd like to add a little editorial.  There are
two problems here: one is discrimination in the insurance industry; the
second is the limited number of qualified professionals.  

The insurance problems are described as a lack of href="">parity.
 Insurance company can, in many circumstances, place
restrictions on payment for mental health services, restrictions that
are more severe than those placed on payment for other health care.
 This was partly alleviated in 1996, with the passage of US
Senator rel="tag">Pete Domenici's href="">Mental
Health Parity Act of 1996.  The Act did not really
establish parity, but was a step in the right direction.  The
Act was renewed in 2001, and will expire at the end of this year
(2007).  Domenici and US Senator href="" rel="tag"> Edward
Kennedy have introduced a new version, href="">S.558,
which has href="">passed
the Senate.  Unfortunately the House has not taken
any action.  My impression is that the proposed Act is better
than the old one, but admittedly, it sometimes is hard to read
legislation and know for sure what it really says.

The second problem is that, even with improved insurance coverage, it
still would be hard for the health care system to provide the optimum
level of service.  Although any primary care provider who sees
adolescents could see a kid and write a prescription, the TADS
indicates that this is not the optimum treatment.  Few primary
care providers would have the qualifications, or the time, to offer
CBT.  Out nation has a disgraceful href="">shortage
of child and adolescent psychiatrists.  More
importantly with regard to CBT, there is a shortage of therapists to
provide treatment for children and adolescents.  Domenici's
colleague, , has introduced legislation, The href="">Child
Health Care Crisis Relief Act of 2007 ( href="">S.1572),
to address this.  This is accompanied by a House bill,
H.R.2073.  The House bill was introduced by US Representative href="" rel="tag">Patrick
Kennedy.  However, neither the Senate nor the House
bill has passed.

Note that the funding problem and the problem with an undersupply of
professionals are related: if more funding were available, more people
would enter the applicable professions.  In addition to the
Child Health Care Crisis Relief Act of 2007, SCHIP would be helpful in
this regard.  

We have data that show us what the optimal treatment is, but we as a
Nation cannot provide it.  It might be helpful if people would
contact Congress and urge support for the pertinent legislation.

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Science Daily Brain imaging has revealed a breakdown in normal patterns of emotional processing that impairs the ability of people with clinical depression to suppress negative emotional states. Efforts by depressed patients to suppress their feelings when viewing emotionally negative images enhanced activity in several brain areas, including the amygdala, known to play a role in generating emotion, according to a report in the August 15 issue of The Journal of Neuroscience.
"Identifying areas in the nervous system that correlate to pathological mood states is one of the pressing questions in mental illness today," says Carol Tamminga, MD, of the University of Texas Southwest Medical Center. Tamminga was not involved in the study.
Tom Johnstone, PhD, of the University of Wisconsin, and colleagues there and at Tufts University studied 21 adults diagnosed with major depressive disorder and 18 healthy subjects of comparable ages. Participants were asked to view a series of emotionally positive and negative images and then indicate their reaction to each one. Four seconds after the presentation of each picture, participants were asked either to increase their emotional response (for example, imagining a loved one experiencing what was depicted in the image), to decrease it, or simply to continue watching the image.
During the test, a functional magnetic resonance imaging scanner detected changes in neural activity. Johnstone and his colleagues also recorded levels of emotional excitement by measuring pupil dilation.
The data showed distinctive patterns of activity in the ventromedial prefrontal cortex (VMPFC) and the right prefrontal cortex (PFC), areas that regulate the emotional output generated from the amygdala. The VMPFC is compromised in depression, likely because of the inappropriate engagement of right PFC circuitry in depressed individuals.
"These findings underscore the importance of emotional regulation deficits in depression," says Johnstone. "They also suggest targets for therapeutic intervention."
According to previous research, normal interaction between the amygdala and the VMPFC may underlie the proper adaptation of levels of the stress hormone cortisol on a daily basis. These levels do not vary as widely in people with major depressive disorder; future research may now be able to clarify the mechanism that underlies this aspect of depression. It could also examine the possibility of using measurements of activity in the amygdala to predict the effectiveness of treatments for depression such as cognitive behavioral therapy.
The work was supported by the National Institute of Mental Health, part of the National Institutes of Health, and Wyeth-Ayerst Pharmaceuticals.
Note: This story has been adapted from material provided by Society for Neuroscience.

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