TADS: Combination Therapy Achieves Remission Earlier Than Monotherapy in Adolescent Depression

Pauline Anderson

February 17, 2009 — The majority of adolescents with depression will experience a remission of their symptoms if they continue therapy for 9 months. However, teens treated with a combination of an antidepressant and cognitive behavioral therapy (CBT) will remit earlier than those who receive either treatment alone, a large randomized, placebo-controlled trial suggests.

The most recent results from the Treatment for Adolescents with Depression Study (TADS) show that the overall remission rate at 36 weeks was about 60%. The rates were similar in each of the 3 treatment groups: antidepressant fluoxetine alone (55%), cognitive behavior therapy (CBT) alone (64%), or a combination of these 2 therapies (60%)

In addition, the overall remission rate was more than double the 23% rate reported earlier after 12 weeks of treatment.

Importantly, while children enjoyed the same higher remission rate at 36 weeks regardless of which treatment they received, those who were on combination therapy remitted earlier.

"If you select monotherapy — either medication or CBT — you could be delaying remission for up to 2 to 3 months," principal investigator Betsy D. Kennard, PsyD, from the University of Texas (UT) Southwestern, in Dallas, told Medscape Psychiatry.

That, she added, can mean prolonged suffering. "The children who received medicine only or CBT only got to the same point at 9 months [as those on combination therapy], but it took them longer to get there, and as a parent, you would not want your child to suffer that long."

This most recent remission rate is comparable to 9-month rates reported in adults (67%).

The study is published in the February issue of the Journal of the American Academy of Child & Adolescent Psychiatry.

Do Not Give Up

The message for clinicians is to not give up on treating teens with depression, said Dr. Kennard. It is a sentiment echoed by Neal Ryan, MD, from the University of Pittsburgh, in Pennsylvania. "It's important to persist in the treatment, because a really meaningful number of kids in the study improved; so don't give up, even if things are rocky at 12 weeks," said Dr. Ryan, referring to the earlier 23% remission rate reported by TADS researchers.

The study originally included 439 adolescents aged 12 to 18 years who met Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV) criteria for major depressive disorder (MDD) and had a score of 45 or higher on the 17-item Children's Depression Rating Scale-Revised (CDRS-R).

Subjects were randomized to receive fluoxetine, CBT, combination therapy, or placebo. Patients on medication were started on 10 mg a day, a dose that was increased to 20 mg a day the second week and subsequently increased as needed to a maximum of 40 mg/day. Patients on CBT received 15 one-hour sessions during the first 12 weeks and had less frequent sessions following this initial 3-month period.

"Disappointing" 12-week Remission Rate

In the first published report, TADS investigators found that at 12 weeks (following the acute-treatment phase), 73% of patients receiving combination therapy responded, compared with 62% of those on the medication and 48% of those who received CBT. Although the earlier study found a "disappointing" overall remission rate (defined as a CDRS-R score of 28 or lower) of 23%, youngsters on combination therapy had a higher remission rate of 37%, said Dr. Kennard.

After 12 weeks, children on placebo were offered active treatment, and the remaining study subjects were asked to remain on their assigned therapy (most did, but some did not). Those originally on placebo were not included in this most recent analysis, which included 327 children.

According to these latest results, combination therapy was superior to both monotherapies as early as week 6. This trend continued past week 18 (completion of the continuous-treatment phase).

By 36 weeks (following the maintenance phase), all 3 active treatment groups had converged with respect to clinical response, with more than 80% showing response in each group.

As for the 36-week recovery rates — considered to be more stringent criteria — the new study found that between 65% (for acute-phase remitters) and 71% (continuation-phase remitters) of those children who achieved remission maintained it.

Room for Improvement

Those rates are concerning. "We still have more than a third who remain symptomatic or have symptoms, so I think there's still room for improvement," said Dr. Kennard.

Dr. Ryan agreed, saying that although the overall remission and recovery rates were "pretty good," many of the subjects continued to need treatment at the end of the study. "There were a bunch of kids who didn't remit or recover, and a significant number of those kids who did have at least some response got worse," he told Medscape Psychiatry.

The study found that having residual symptoms at the end of the acute-treatment phase predicted failure to achieve remission at 18 and 36 weeks.

"One of the important messages from this study is that the more residual symptoms that an adolescent with depression has following acute treatment, the greater the risk for a less optimal outcome later on," said Dr. Kennard. That might seem apparent, but it is important to stress, she said. "Highlighting this would help clinicians because it suggests that it takes more aggressive treatment to take care of those residual symptoms."

The study also highlights the need to use CBT alone for longer than 12 weeks in adolescents, said Dr. Kennard, adding that it takes from 18 to 24 weeks for this therapy to be as effective as medication. "CBT experts felt there just wasn't enough CBT for children to have responded by week 12, that they needed 6 more weeks."

Most studies of CBT in children do not include subjects younger than 12 years, "primarily because you have to have a certain level of cognitive development for it to be effective," said Dr. Kennard. However, there is research, including some studies at UT Southwestern, that includes children as young as 8 years, she said.

CBT Just as Effective in Teens

Although much more CBT research has been reported in adults than in adolescents, Dr. Ryan says his sense is that CBT is just as effective in adolescents as it is in older patients. Positive results in studies such as this suggest that "we may need to change people's training and reimbursement for CBT," he added.

At present, CBT is not widely available and there is a problem with lack of trained practitioners, said Dr. Ryan. He distinguished between formalized CBT and "nonspecific psychotherapy," which, he said, "gives some but not all of the benefits of CBT."

Like Dr. Kennard, Dr. Ryan said the delayed remission time among some of the subjects is cause for concern. "Not only were they miserable longer, but it may also have a greater impact on their life."

This variable time for youngsters to get better "is generally considered to be meaningful in terms of clinical treatment," said Dr. Ryan.

Will TADS change clinical practice? "I think by and large people will continue to do what they are already doing," said Dr. Ryan. "The study is saying what we already know, that therapy does work in a lot of kids, that it does take more than the 3 months in a lot of kids, and that despite treatment there are still a significant number of kids with symptoms," said Dr. Ryan. "It says the trivial but important thing — that we do need to study this some more."

However, he added, these data underline the fact that symptoms persist for a period of time in youngsters and serve as another reminder to physicians "not to give up."

Dr. Kennard reports no conflicts of interest. Disclosures for the coauthors are listed in the paper.

J Am Acad Child Adolesc Psychiatry. 2009;48:186-195.