Selective serotonin reuptake inhibitors (SSRIs) work faster than
cognitive-behavioral therapy (CBT) in treating adolescents with depression,
but CBT beats SSRIs in effectiveness and safety in treating children with
Preschoolers metabolize methylphenidate less efficiently than older
children, and feedback from both parents and teachers is necessary to
determine the best dosage of methylphenidate for children with
attention-deficit/hyperactivity disorder (ADHD).
These are some of the practical lessons being gleaned from several large
clinical trials funded by the National Institute of Mental Health (NIMH).
Researchers who had led these studies summarized these lessons and other
practice implications at the American Academy of Child and Adolescent
Psychiatry annual meeting in Boston in October.
Unlike most industry-sponsored clinical trials, which seek to find out a
drug's safety, efficacy, and mechanism of action and are conducted in tightly
controlled, ideal conditions, these clinical trials enrolled subjects from the
community who often have comorbidities. The trials were designed to reflect
real-world clinical practice and tried to answer complex questions, explained
John March, M.D., a professor of psychiatry and chief of Child and Adolescent
Psychiatry at Duke University Medical Center.
Furthermore, most of these studies made head-to-head comparisons among
medications, CBT, and a combination of both to clarify their relative safety
and efficacy in this vulnerable population. "These kind of studies have
to be supported by public money," Benedetto Vitiello, M.D., chief of the
Child and Adolescent Treatment and Preventive Intervention Research Branch at
NIMH, pointed out. "There is no interest from the industry to look at
One of the lessons from the Multi-modal Treatment Study of Children with
ADHD (MTA) described at the meeting was the importance of obtaining both
parents' and teachers' feedback on a child's ADHD symptoms, as parents may not
observe some aspects of children's difficulties that are more apparent in
school, explained Peter Jensen, M.D., director and CEO of the REACH (Resource
for Advancing Children's Health) Institute. During the study, the researchers
found that teachers' assessment of ADHD symptoms was critical for
methylphenidate dose adjustment, while parents provided important feedback
about the side effects. The MTA study compared the effectiveness and safety of
methylphenidate, CBT, a combination of both, and usual community care in
children aged 7 to 10 with ADHD. It demonstrated the important role of
medication in the overall treatment plan for most patients (Psychiatric
News, August 17).
The greater effectiveness seen in the medication and combination treatments
compared with community care, Jensen suggested, could be attributed partially
to the frequent interaction of patients and their parents with study
"Families don't particularly like medicine," he said. The dose
increase in the medication and combination group was more aggressive than in
the community-care group, a process facilitated by the families' trust and
relationship with care-givers that grew out of the frequent and in-depth
visits by the intervention groups.
Another message gleamed from the study was the differential effectiveness
of methylphenidate in subgroups of ADHD patients with comorbidities. Children
with ADHD and anxiety, for example, responded far better to CBT with
medication than did those without anxiety. Nonetheless, "medicine did
the same with or without [CBT] for the 'clean' ADHD type," said Jensen."
Kids with ODD [oppositional defiance disorder] or CD [conduct disorder]
did not respond [generally] to behavioral therapy."
Despite the Food and Drug Administration (FDA) warnings against giving
children younger than 6 years old methylphenidate, many preschoolers are
diagnosed with ADHD and treated with the drug, said Laurence Greenhill, M.D.,
a professor of clinical psychiatry and director of the Research Unit of
Pediatric Psychopharmacology at Columbia University and the New York State
Psychiatric Institute. This was the impetus for conducting the Preschool ADHD
Treatment Study (PATS) in children aged 3 to 5-and-a-half years who were
diagnosed with ADHD that caused moderate to severe impairment and who had
failed a course of intervention based on parent training (Psychiatric
News, December 15, 2006).
Greenhill pointed out that the effect size of methyphenidate treatment in
the PATS was smaller than that in the MTA study, and the therapeutic dose
after titration was an average of 14 mg/day for the preschoolers, far lower
than the therapeutic dose for school-aged children in the MTA study. In
addition to higher severity of ADHD among children in PATS, Greenhill cited a
pharmacokinetic study based on their data, which "suggested that the
clearance of methylphenidate in preschoolers was half the rate of school-aged
kids. The same dose of methylphenidate may lead to higher exposure [in younger
children] because of slower metabolism." Moreover, psychiatric
comorbidities such as conduct disorder or anxiety hampered the effectiveness
of methylphenidate, and patients with three or more comorbidities had
essentially no response to the medication.
Greenhill emphasized the side effects seen in subjects in the PATS were
generally similar to those seen in school-aged children (for example,
irritability, difficulty falling asleep, decreased appetite) in the MTA study,
with one exception: younger patients seemed to have more intense outbursts."
It was more of a brittle, tantrum-throwing kind of reaction, even
though they were on average less hyperactive," said Greenhill.
Meanwhile, long-term, cumulative exposure to methylphenidate was shown to slow
children's expected height and weight growth. The clinician should start with
the lowest dose, he recommended.
The Pediatric OCD Treatment Study (POTS) was conducted by NIMH and
collaborating researchers from 2000 to 2003 (Psychiatric News,
December 3, 2004) and compared the effectiveness of CBT alone, sertraline
alone, combined CBT and sertraline, and placebo over 12 weeks for treating
children and adolescents with OCD.
CBT showed a clear overall advantage over medication in these patients.
While the effect size was greater in the sertraline-CBT combination group, CBT
alone worked better than sertraline alone, said March. The remission rate was
similar between combination treatment and CBT alone, which was significantly
higher than for sertraline alone.
"One of the implications of this study," said March, "is
that it is no longer adequate to not offer CBT to parents and patients, even
if CBT is not available at your practice." He urged psychiatrists to
offer standardize CBT to treat OCD or partner with practitioners who can
provide the therapy.
He also noted that in the study, the quality of CBT varied from site to
site, and the combination of medication and CBT seemed to provide favorable
outcomes more reliably than CBT alone.
The Treatment for Adolescents With Depression Study (TADS) compared
fluoxetine, CBT, a combination of both, and placebo to provide real-world data
relevant to clinicians. Fluoxetine- and combination-treatment groups improved
significantly more than CBT and placebo groups at three months, but the
effectiveness of CBT alone caught up with medication over time, and by the end
of week 36, all three groups had similar rates of improvement (Psychiatric
News, November 2).
Vitiello emphasized that the combination treatment was superior to either
medication or CBT alone in terms of remission rate, functioning, and quality
of life. "If remission is the most relevant outcome for your patient,
combination therapy is more powerful," he said.
In addition, the combination therapy seemed to have a protective effect
against the increased suicidality associated with fluoxetine use, as the
combination-therapy group saw a similar rate of suicidal events as the
CBT-alone group, and both were significantly less than the fluoxetine-alone
group. The reason for this potential effect of CBT is unknown. March suggested
that CBT might have modified the risks of suicide in part because "it
teaches kids the skills to manage emotional dysregulation and stress and
reduces family conflicts."
Audience members commented that while the studies were of high quality and
directly relevant to clinical practice, the dissemination and application of
this wealth of knowledge seemed slow.
Given the benefits of CBT demonstrated in these large trials, the
implementation is sometimes hindered by practice variability and inadequate
insurance coverage for the service, as March and other presenters pointed out.
The panel concurred that there is a lag from the publication of the trial
results to improved quality of care despite important public implications.
Practice guidelines can be slow to incorporate scientific evidence, while
continuing medical education programs supported by industry funding and
provided by private vendors often lack credibility and objectivity among
practitioners, as several panelists pointed out. March urged clinicians to
participate in the Child and Adolescent Psychiatry Trials Network
to help improve the research and practice of evidence-based medicine.▪