| bobwhelan 2004-09-21, 3:08 am |
| Drug/CBT Combo Effective In Treating Depressed Youth
Jim Rosack
Findings from a landmark government-sponsored study that fluoxetine
combined with CBT does a better job of treating adolescent depression
than either alone should resolve some of the controversy surrounding
the efficacy of treatments for this disorder.
The release of the stage 1 results from the National Institute of
Mental Health's Treatment of Adolescent Depression Study (TADS) could
not have come at a more appropriate—or highly charged—time.
Right in the middle of a series of Food and Drug Administration (FDA)
hearings, Congressional inquiries, and widespread debate over the use
of antidepressants to treat youth with depression, the TADS results
answer at least one key question.
"These results should really put to rest the debate over whether
medication is effective in adolescents with major depression,"
declared Peter Jensen, M.D., Ruane professor of child and adolescent
psychiatry at Columbia University. "Fluoxetine clearly works in
carefully selected, properly diagnosed teenagers with moderate to
severe major depression."
"It was noteworthy that suicide-related ideation and self-harm-related
behaviors dropped dramatically in all groups, along with the
substantial clinical benefits from getting effective treatment with
medication, with or without CBT. Of course, this benefit of medication
still doesn't rule out the possibility or rare but real adverse events
in kids on meds. Even though penicillin can be be lifesaving in
certain circumstances, some people have bad reactions to it, and
doctors always need to be cautious and monitor the patient carefully,
regardless of the medication. But we don't stop using penicillin
because of rare adverse events; that would harm many more people."
Jensen, director of the Center for the Advancement of Children's
Mental Health at Columbia, was not a part of the TADS research team.
The TADS group was led by John March, M.D., professor of child and
adolescent psychiatry at Duke university School of Medicine. March led
a large group of researchers and clinicians at 13 academic centers
across the country who studied 439 adolescents with major depression
in the multiyear, multimillion-dollar project funded by NIMH.
The goal was to evaluate the effectiveness in a real-world setting of
four specific treatments: cognitive-behavioral therapy (CBT), the SSRI
fluoxetine (Prozac) alone, or the combination of both CBT and
fluoxetine, all compared with a single control group that received a
placebo pill. The CBT arms 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 behavior patterns." Patients completed 15 CBT
sessions of 50 to 60 minutes over the 12 weeks of the study. Patients
on fluoxetine or placebo were monitored during six 20-minute to
30-minute sessions over the 12 weeks. A pharmacotherapist checked
clinical status and medication effects and depending on clinical
ratings was able to adjust doses of fluoxetine or placebo. In
addition, patient education was provided including encouragement on
the effectiveness of pharmacotherapy for depression.
The study involved multiple stages. Stage 1 lasted 12 weeks and
compared the four treatment groups' acute response. The results of
stage 1 were reported in the August 18 Journal of the American Medical
Association. Further reports from other stages will be reported in the
future.
All 439 patients across the four treatment groups improved from
baseline through six weeks and on to the 12-week assessment that
closed stage 1. Two primary outcomes were chosen: scores on the
Children's Depression Rating Scale-Revised (CDRS-R), at weeks six 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
treatment.
Significantly, response rates varied widely between the four groups.
Of the group receiving CBT/fluoxetine, 71 percent were rated at 12
weeks as responders. Among those taking fluoxetine alone, 60.6 percent
responded. For those who received CBT alone the response rate was 43.3
percent. And for those receiving a pill placebo, the response rate was
34.8 percent.
Two things are significant about those numbers, noted Graham Emslie,
M.D., the Charles E. and Sarah M. Seay Chair in Child Psychiatry and
professor of psychiatry in the Graduate School of Biomedical Sciences
at the university of Texas Southwestern Medical Center at Dallas, who
was the principal investigator for TADS at Southwestern.
"It's unusual, first of all to see a placebo effect actually so
relatively low," Emslie said, adding, "it's also nice to then see such
a good degree of separation between the active treatments and
placebo."
Emslie believes the results are at least in part attributable to the
strength of the protocol's patient-selection criteria. At the time of
entrance to the study, patients had to have been ill for at least six
weeks without improvement. Another three weeks on average passed
during assessment and patients being randomly assigned to their
treatment group. After nine weeks of consistent depressive illness,
the researchers thought it unlikely that patients would respond
strongly to placebo.
Compared with placebo, CBT/fluoxetine was the strongest therapeutic
approach, with improvement on the CDRS-R scores of patients on the
combination being statistically significant. CBT/fluoxetine was also
statistically significantly superior to either fluoxetine alone or CBT
alone. Fluoxetine alone was superior to CBT alone as well; however,
CBT was not statistically significantly different from placebo.
When the researchers examined patients' scores on the Suicidal
Ideation Questionnaire (SIQ) -Jr. High School Version, an interesting
trend appeared. At baseline, 29 percent of the total population in the
study met criteria for clinically significant suicidal thinking. All
four groups' scores on the SIQ improved (see table at left), with the
CBT/fluoxetine group again showing the most improvement. However, the
group receiving CBT alone had the second greatest improvement,
followed by the fluoxetine group.
Both Jensen and Emslie pointed out that the data on harm-related and
suicide-related adverse events during stage 1 indicate that the events
were clustered in the groups that received fluoxetine, either alone or
with CBT. The group receiving fluoxetine alone, however, was the
highest in both the harm-related and suicide-related categories of
serious events.
Patients receiving fluoxetine alone had the highest risk (calculated
as an odds-ratio) of experiencing a harm-related event, compared with
those receiving placebo. Patients in the CBT/fluoxetine group were
less likely than those taking fluoxetine alone, but more likely than
those receiving placebo to experience a harm-related event. Compared
to placebo, those in the CBT alone group were slightly less likely to
harm themselves or others compared to placebo.
However, because the actual numbers of patients in any of the four
groups experiencing a harm-related event were small, the confidence
intervals for the calculated odds ratios were quite wide, and none of
the odds ratios statistically significant. Only when the researchers
combined all patients taking an SSRI (those in the fluoxetine group
plus those in the CBT/fluoxetine group) and compared those with all
patients not getting any drug, did the odds ratio become significant.
Those taking an SSRI were more likely to experience a harm-related
event than those taking no drug (odds ratio 2.19, 95 percent
confidence interval 1.03 to 4.62). In addition, when the researchers
pooled all patients receiving CBT (with or without fluoxetine) and
compared them with all patients not receiving CBT (placebo plus
fluoxetine groups), again those receiving CBT appeared to be less
likely to experience a harm-related event, though this result also was
not statistically significant.
A similar pattern emerged with the same comparisons for
suicide-related events; however, none of the suicide-related event
odds ratios reached statistical significance.
"CBT appeared to be exerting some sort of protective effect, whereas
fluoxetine appeared to be associated with harm-related and
suicide-related events," Emslie pointed out. Seven of the 439 patients
attempted suicide during the trial, six of which were in either the
fluoxetine-plus-CBT or the fluoxetine-alone group, while one was in
the placebo group. "There certainly looks like there is something
there, but what exactly it is, I don't think we understand yet. But
fluoxetine is probably not alone. We need to figure out what other
medications might display this same pattern. Interestingly, looking
even closer," Emslie continued, "there was a stepwise increase in
suicide-related events along with increasing response. It could be
that the old theory of improved energy and activation actually is tied
to increased risk. But it is still only a theory."
What is clear is that all patients must be monitored closely, both
Jensen and Emslie stressed. "You can't just write a prescription and
send them on their way. That is clearly not the best practice," Jensen
said. "Careful diagnosis plus careful assessment then should always
lead to careful selection of medication—preferably along with some
therapy—and close monitoring."
Psychiatric News September 3, 2004
Volume 39 Number 17
© 2004 American Psychiatric Association
--
bobwhelan
"Studies have found that after 3 months of antidepressant
treatment between 50% and 65% of the people who take them
will be much improved. This compares
with 25 - 30% of people given an inactive "dummy" pill,
or placebo."
- The British Journal of Psychiatry
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