CBT Best First-Line Treatment for Major Depression in Youth?

Batya Swift Yasgur, MA, LSW

August 07, 2019

Adding an antidepressant to cognitive behavioral therapy (CBT) appears to provide no additional benefit over CBT alone in reducing symptoms in youth with major depression, new research suggests.

Investigators compared 12 weeks of treatment with a combination of CBT and the selective serotonin reuptake inhibitor fluoxetine to CBT plus placebo in 153 youth (aged 15 to 25 years) with moderate-to-severe major depressive disorder (MDD).

They found no evidence that adding fluoxetine vs placebo to CBT further reduced depressive symptoms, although exploratory analysis did suggest that the addition of medication might be helpful for patients with comorbid anxiety symptoms and for older youth.

"We found that combined treatment with CBT and fluoxetine was not more effective than CBT and placebo, and in secondary analyses, we showed that this was especially the case for participants who were younger than 18," lead author Christopher Davey, MD, PhD, associate director of clinical services at Orygen Youth Health in Parkville, Australia, told Medscape Medical News.

"The results of the trial should make clinicians more cautious about rushing to start depressed young people on medication, especially when they haven't given [CBT] therapy a proper chance," said Davey who is also principal research fellow and head of mood disorders research at Orygen.

The study was published online July 29 in Lancet Psychiatry.

Uncertain Benefit

Davey said he was "motivated to undertake the study because of ongoing uncertainty about the benefits of antidepressant medications for young people."

"There is reasonably good evidence that CBT is effective and should be offered as first-line treatment, but there hasn't been much support for the common practice of starting antidepressant medication concurrently, especially for young people experiencing relatively severe depression," he said.

To investigate the question, the researchers conducted the Youth Depression Alleviation–Combined Treatment (YoDA-C) trial that randomly assigned 153 individuals aged 15 to 25 years (mean [SD] 19.6 [2.7] years) to receive either CBT plus placebo (n = 77) or CBT plus fluoxetine (n = 76).

Eligibility requirements were "broad and designed to reflect the real-world characteristics" of young people presenting to clinical centers.

Participants could take benzodiazepines or benzodiazepine-like medications during the trial, but not antipsychotics or mood stabilizers.

Participants were required to have diagnosed MDD based on the Structured Clinical Interview for DSM-IV Axis 1 Disorders (SCID-IV) and to have scored 20 or higher on the Montgomery-Åsberg Depression Rating Scale (MADRS), "indicating depression of at least moderate severity."

Patients with past or current psychosis, bipolar I or bipolar II disorder, pregnancy, or acute or unstable medical disorders were excluded.

Participants began by taking one 20-mg capsule of fluoxetine or 1 placebo pill daily, with a possibility of increasing to fluoxetine 40 mg daily (or 2 placebo pills) in the event of insufficient clinical response after the first 4 weeks.

All participants received CBT in weekly 50-minute sessions and were assessed at baseline, then at weeks 4, 8, and 12.

The primary outcome measure was change in MADRS score at 12 weeks, although scores on other tests, including the Quick Inventory of Depressive Symptoms [QIDS] and the Generalized Anxiety Disorder 7-item scale [GAD7], were also assessed.

Secondary analyses examined treatment response in separately for participants younger than 18 years and those 18 years or older.

Age Matters

Most participants had severe depression, with high prevalence of comorbid anxiety disorders and suicidal ideation in the past month.

Overall, participants were in the early stages of depression, with 40% experiencing a first depressive episode.

At baseline, participants in the CBT plus placebo and CBT plus fluoxetine groups had severe depression (mean [SD] MADRS score 33.6 [5.1] and 32.2 [5.6], respectively).

A "high proportion" of participants in both groups had anxiety disorder comorbidity (61% in the CBT plus placebo group and 64% in the CBT plus fluoxetine group) as well as past-month suicidal ideation (71% in the CBT plus placebo group and 78% in the CBT plus fluoxetine group).

Slightly more participants in the CBT plus fluoxetine group vs the CBT plus placebo group completed follow-up at week 12 (84% vs 77%, respectively).

Participants in both groups showed a reduction in MADRS scores after 12 weeks: −13.7; 95% confidence interval, −16.0 to −11.4 in the CBT+placebo group; and −15.1; 95% CI, −17.4 to −12.9 in the CBT+fluoxetine group.

No significant between-group differences were found in MADRS scores (−1.4; 95% CI, −4.7 to 1.8; P = .39) between the two groups.

Similarly, there were no significant between-group differences found for changes in self-reported depressive symptoms, measured with the QIDS (−1.0; 95% CI, −2.7 to 0.7; P = .26).

On the other hand, greater reduction in anxiety symptoms, as measured by the GAD7, was found in the CBT plus fluoxetine group, compared with the CBT plus placebo group (−2.1; 95% CI, −3.9 to −0.3; P = .02).

Rates of remission (defined as MADRS scores ≤7) did not differ between the groups.

There were five suicide attempts in the CBT plus placebo group vs 1 suicide attempt in the CBT plus fluoxetine group; there were no significant between-group differences for other suicidal behaviors.

In a post-hoc analysis, researchers examined the impact of age on treatment response and found no significant between-group differences for MADRS scores.

However, in patients aged 18 years and older, the CBT plus fluoxetine group showed some evidence for a greater reduction in both MADRS and QIDS scores, compared with the CBT plus placebo group.

Similarly, in patients aged 18 years and older, the CBT plus fluoxetine group showed a significantly greater reduction in GAD7 scores compared with the CBT plus placebo group.

There were notable differences in remission rates between the age groups: in those under 18, remission was achieved in 39% of participants in the CBT plus placebo group vs 26% of participants in the CBT plus fluoxetine group (odds ratio [OR], 0.6; 95% CI, 0.1 - 2.3; P = .53).

By contrast, in participants 18 years and older, remission was achieved in 9% in the CBT plus placebo group vs 23% in the CBT plus fluoxetine group (OR, 3.2; 95% CI, 0.8 - 14.8]; P = .09). 

"We showed some evidence that the addition of fluoxetine [to CBT] improved depression and anxiety symptoms in participants who were 18 and older, mainly because they seemed to get less benefit from CBT alone," Davey commented.

Two-Step Process

Commenting on the study for Medscape Medical News, Benedetto Vitiello, MD, professor of child and adolescent neuropsychiatry at the University of Turin in Italy, called it "interesting and important." Vitiello authored an accompanying editorial on the study.

The strength of the study was that it "compared the combination of psychotherapy plus antidepressant with psychotherapy plus placebo," Vitiello said, "and in this way, you really get a very high level of validity from an experimental point of view because you have a placebo, leading to an unbiased assessment."

On the other hand, "the limitation of the study is that placebo is not a real treatment you can use in clinical practice, and is not equivalent to the absence of treatment," he said. "The study has strong internal validity from an experimental point of view and is very strong and persuasive internally, but when you expose the results to reality, you can't give placebo."

However, together with other data already available and recent reviews, "one can probably recommend the use of one modality — maybe psychotherapy — as a first step, and if that doesn't work then turn to medication rather than starting both treatments at the same time," Vitiello suggested.

This implies "two steps, rather than starting right at the beginning with two different treatments altogether," he added.

The study authors note that rates of remission were generally low, "which emphasizes the need for more effective treatments for young people with severe depressive illnesses."

The study was funded by the Australian National Health and Medical Research Council (NHMRC). Funding to individual researchers is listed in the original article. Davey has received grant support from the Brain and Behavior Foundation, National Health and Medical Research Council, Simons Autism Foundation, Stanley Medical Research Institute, Lilly, and ASBDD/Servier; and in-kind support from BioMedica Nutraceuticals, NutritionCare and Bioceuticals. The other authors' disclosures are listed in the original article. Vitiello reports personal fees from Medice and Teva outside of the submitted work.

Lancet Psychiatry. Published online July 29, 2019. Abstract, Editorial

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