The public health would benefit significantly if the decision makers who
determine coverage limitations in private and public insurance plans listened
to, and learned from, the major take-home messages produced by recent studies
funded by the National Institute of Mental Health (NIMH), says the lead
researcher on one of those clinical trials.
He is John March, M.D., M.P.H., a professor of psychiatry and chief of
child and adolescent psychiatry at Duke University Medical Center. He heads up
the Treatment of Adolescents With Depression Study (TADS) on which of series
of reports appeared in the December 2006 Journal of the American Academy
of Child and Adolescent Psychiatry (JAACAP).
In the TADS, March and his colleagues showed that across numerous outcome
domains, the combination of the antidepressant medication fluoxetine and
cognitive-behavioral therapy (CBT) yielded the most effective weapon against
adolescent depression, compared with medication alone, CBT alone, or
Most importantly, March said, the TADS team documented a direct effect
particular to pairing the SSRI fluoxetine with CBT (COMB)—a near
complete elimination of suicidal thoughts and behaviors in the depressed
"Depending upon whose numbers you cite, there are about 2 million
kids each year in the U.S. who end up getting medical attention because of a
suicide attempt," March noted. "Conservatively, if even half of
those received COMB treatment, and then only half of those who received COMB
saw a significant reduction or complete alleviation of their suicidality,
think about the number of lives that would be positively impacted."
In the JAACAP report series, March and his fellow TADS
investigators detailed the secondary outcomes of the TADS. Without exception,
the data confirmed researchers' initial reports that COMB was more effective
across numerous secondary domains at treating adolescent depression than
fluoxetine alone, CBT alone, or clinical management plus a placebo pill.
"If you want the treatment that gives you the best chance of benefit
and the smallest risk, it's definitely the COMB treatment. It doesn't matter
what [outcome variable] you look at," March told Psychiatric
News. "COMB is better across multiple domains: better [at
promoting] remission, better [at improving] patient functionality, better in
[maintaining or improving] quality of life, better [as measured] by adolescent
self-report. And COMB is associated with fewer side effects."
The TADS protocol involved researchers and clinicians who treated 439
adolescents with major depression at 13 academic centers across the country.
The goal was to evaluate the effectiveness in a real-world setting of CBT
alone, fluoxetine alone, and the combination of CBT and fluoxetine and then
compare them with placebo.
The CBT arm of the study involved a "skills-oriented treatment based
on the assumption that depression is either caused by or maintained by
depressive thought patterns and a lack of active, positively reinforcing
In the first phase of the study, which ran 12 weeks, the patients in the
CBT group completed 15 50- to 60-minute sessions. The patients in the
fluoxetine and placebo groups were monitored in six 20- to 30-minute
Two primary outcome measures were used: the patients' change in score on
the Children's Depression Rating Scale-Revised (CDRS-R) at weeks 6 and 12,
compared with baseline; and the 12-week rating on the Clinical Global
Impression—Improvement (CGI) scale. A CGI score of 1 (much improved) or
2 (very much improved) was defined as a "response" to
The overall comparative effectiveness of the four treatments was reported
in 2004 (Psychiatric News, September 3, 2004). Briefly, all 439
patients improved from baseline through week 6 and from week 6 through week
12. At week 12, 71 percent of patients in the COMB group were rated as
responders, compared with 60.6 percent in the fluoxetine group, 43.3 percent
in the CBT group, and 34.8 percent in the placebo group. The superiority of
the COMB and fluoxetine treatments, compared with the CBT and placebo groups,
was statistically significant. A report on outcomes at 36 weeks is currently
under review for publication.
As reported in the December JAACAP series, secondary outcome
measures studied at the 12-week mark included comparative rates of remission
(as opposed to the previously reported rates of response), speed of response,
function and quality of life, predictors and/or moderators of outcome, and
safety. Overall, 16 clinical outcome measures were compared between the four
The COMB treatment proved to be superior to placebo on 15 of the 16
secondary outcome measures, to CBT on 14 of 16, and to fluoxetine on 8 out of
the 16 measures (see table).
Fluoxetine proved to be superior to CBT on eight of the 16 measures and to
placebo on 7 of the 16 measures. CBT did not differ from placebo on any of the
secondary outcome measures.
The TADS protocol was finalized well before the reemergence of concern in
2003 over the possibility of an increased risk of suicidality associated with
antidepressant medications (see
page 1). However, TADS
researchers used several secondary measures to assess baseline suicidality and
to monitor for potential changes in suicidality over time within the four
study groups, including the potential for treatment-emergent suicidality
possibly associated with fluoxetine. Suicidality was assessed using the
Suicidal Ideation Questionnaire (SIQ), the suicide item on the Children's
Depression Rating Scale—Revised (CDRS-R), and the Clinical Global
At baseline, nearly 30 percent of TADS patients were found to have
clinically significant suicidality, and 2 percent were rated as"
Even though suicidality improved markedly across all of the treatment
conditions, 24 clinician-identified suicide-related events occurred over the
course of the 12-week study. Suicide-related events occurred more frequently
in the fluoxetine group (10 patients with events, or 9.2 percent of the
group), compared with the COMB group (5 patients, 4.7 percent) and the CBT
group (5 patients, 4.5 percent). The placebo group had the lowest number of
events (3 patients, 2.7 percent).
While no suicides occurred, there were five suicide attempts (two in the
COMB group, two in the fluoxetine group, and one in the CBT group).
"One of the most striking results out of TADS," March told
Psychiatric News, "is the fact that a patient's assignment to
the COMB treatment group [significantly reduces] the small risk that you have
for a suicidal event when taking fluoxetine alone. That suggests that CBT in
TADS had a direct effect of mitigating suicidality—it demonstrated a
"From a public health point of view," March continued,"
it would be a tremendous benefit if the take-home messages from TADS
were operationalized by [both large private and public insurers]."
First, he pointed out, "the COMB treatment is clearly better than
either monotherapy alone; second, the COMB treatment [appears to significantly
reduce] the risk of suicidality you might encounter if you take medication
alone; and third, the TADS findings are robust enough that they probably
should always be mentioned during informed consent when a patient is
considering treatment options."
Access to mental health services in the United States, March continued, is
woefully inadequate and not based on the most recent scientific findings. With
other medical disorders, he explained, multi-modal treatment is not
discouraged, but rather highly encouraged.
"You would never today be able to tell orthopedists or
rheumatologists that they can't [prescribe] physical therapy for their
arthritis patients in addition to taking medications," March said."
You would never be able to tell a diabetic patient that there is no
such thing as nutritional counseling or diet and exercise programs to
supplement their medication."
Why, March asked, does the health care system in the U.S. today still allow
limits on coverage so that many patients have access only to antidepressant
medications, with little if any possibility of accessing other proven
treatment tools, including proven psychotherapy techniques and other
"It simply makes absolutely no sense at all," March concluded,"
CBT is the physical therapy of mental health care."
The potential benefit to the public health of using COMB treatment for
adolescents is enormous, March said. If combination treatment—with both
antidepressant medications and psychotherapy—were the standard of care,"
we would almost certainly see improvements in multiple outcomes,
including a direct reduction in suicidality among depressed
JAACAP's special section on TADS can be accessed online at<www.jaacap.com/pt/re/jaacap/toc.00004583-200612000-00000.htm>.▪