Over half of adolescents who don't respond to a first antidepressant
improve when switched to a combination of a different antidepressant and
cognitive-behavioral therapy (CBT). This is a key finding of an NIMH-funded
clinical trial, the Treatment of SSRI-Resistant Depression in Adolescents
A Switch in Time Makes a Big Difference
The combined therapy also produced a greater response than placing patients
on another medication alone, suggesting that persistence may pay off in this
population, said the authors in the February 27 Journal of the American
Previous trials have shown that SSRI antidepressants or CBT or the
combination can produce an adequate clinical response in up to 60 percent of
treated adolescents, the authors noted, but, "There are no empirical
studies to guide clinicians regarding the management of adolescents with
depression not responsive to an initial treatment with an SSRI."
Previously, the Treatment of Adolescent Depression Study (TADS)
demonstrated a similar benefit for combined therapy, but it tested a
treatment-naïve group of depressed adolescents. TORDIA differed in two
ways from TADS. It was aimed at youth who had not responded to a first round
of treatment, and it included more chronically depressed adolescents
(averaging two years) and more with suicidal ideation (59
percent)—groups often excluded from clinical trials, said lead author
David Brent, M.D., in an interview with Psychiatric News.
"This was a much more difficult-to-treat sample," said Brent, a
professor of psychiatry at the University of Pittsburgh School of Medicine and
Western Psychiatric Institute and Clinic. "We came to see that it would
be unethical not to study people at high risk."
The TORDIA study recruited young people, aged 12 to 18, who had not
responded to at least an eight-week regimen of an SSRI antidepressant and who
were not receiving CBT. In all, 334 patients at six institutions were
randomized to one of four treatment options: a new SSRI alone (fluoxetine,
paroxetine, or citalopram); an SSRI along with CBT; venlaflaxine with CBT; and
venlaflaxine alone. Venlaflaxine, an SSRI/SNRI, was included because it has
shown value in some trials in adults, said the authors.
The FDA's black-box warning, issued in the midst of the trial, may have cut
into recruitment efforts, but may also have prompted improved procedures for
monitoring any emergence of suicidal ideation or behavior and helped to
fine-tune rescue protocols for intervention if signs of suicidality appeared,
About 86 percent of the participants completed 12 weeks of the treatment
protocol. Those who left did so because of adverse effects, nonadherence or
withdrawal of consent, or need for out-of-protocol treatments. Participants
were mostly white (82 percent), female (70 percent), and middle class ($61,000
annual median family income). However, compared with other trials, such as
TADS, participants showed higher rates of two risk factors—chronicity
and suicidal ideation—that made this sample more like the patients seen
in routine community practice.
About 55 percent (91 of 166) of patients treated with CBT and an
antidepressant evinced an adequate clinical response, compared with those
treated with an SSRI (47 percent, 79 of 168) or venlafaxine (48 percent, 80 of
166) but without CBT.
Patients were evaluated with the Clinical Global Impressions-Improvement
Subscale and the Children's Depression Rating Scale-Revised.
The trial results extend TADS to "a more chronically depressed,
treatment-resistant population," the authors said.
Results with CBT were achieved with a median of nine sessions, leading the
authors to speculate that more sessions might produce a larger effect.
When planning the study, the researchers thought that switching to
venlafaxine would prove superior to use of another SSRI, but that hypothesis
was not borne out by TORDIA's findings. Treatment effects were similar to
those for SSRIs, but side effects were slightly more frequent.
Regarding the lack of superiority for venlafaxine, Brent said, "I
would suggest avoiding it as a second step although it might be useful as a
One unexpected finding from TORDIA was that patients who used sleep
medications had a poor response to treatment.
"We don't know if this was due to the hypnotic drugs themselves, or
to drug-drug interactions, or to the underlying sleep problems," said
Brent. "But it's important to pay attention to sleep difficulties when
treating refractory depression."
There was no difference between the treatment arms in the proportion of
harm-related events (suicidal ideation, suicide attempt, or self-injurious
behavior). There were 18 suicide attempts, but no completed suicides among the
participants despite a greater incidence of suicidality at intake than is
usual in most clinical trials, said Brent.
The authors also noted that the response to CBT varied from site to site
despite consistent training and monitoring of therapists. Those variations
were due to baseline variables among study participants (such as hopelessness)
that predict outcomes, said Brent. Adjusting for those differences eliminated
the variations. Anyone planning future multisite trials should understand that
such variability is inevitable and will have to be factored in when
calculating sample size to achieve the power needed in the trial, he said.
In the end, clinicians can offer some hope to adolescents with depression
who have not responded to a first course of antidepressants, the researchers
said. "[D]espite a first unsuccessful treatment for depression,
persistence with additional appropriate interventions can result in
substantial clinical improvement."
Brent and his coauthors are continuing to follow the trial participants."
We're working now on delineating the response at six months and have
followed these patients out to 72 weeks," he said. "But I predict
that the data will be difficult to interpret. A lot of things can happen over
that time, and what happens during the initial treatment becomes less and less
An abstract of "Switching to Another SSRI or to Venlafaxine
With or Without Cognitive Behavioral Therapy for Adolescents With
SSRI-Resistant Depression" is posted at<http://jama.ama-assn.org/cgi/content/abstract/299/8/901>.▪