Combination Therapy Best Option for Severe Pediatric Anxiety

Liam Davenport

October 12, 2017

A combination of medication and behavioral therapy nearly triples remission rates in children and adolescents with severe anxiety and should be the standard of care for this patient population, new research suggests.

The secondary analysis of outcomes in the Child/Adolescent Anxiety Multimodal Study (CAMS) showed that children and adolescents who were treated with the selective serotonin reuptake inhibitor (SSRI) sertraline ( Zoloft, Pfizer), cognitive-behavioral therapy (CBT), both treatments together, or placebo showed that among severely anxious children, combined therapy almost tripled the likelihood of remission.

In contrast, use of sertraline or CBT alone was not associated with a significant increase in remission rates compared with placebo.

"Our study clarifies that severity plays a key role in determining appropriate treatment," Eli Lebowitz, PhD, assistant professor in the Child Study Center, Yale School of Medicine, New Haven, Connecticut, and colleagues write.

"In cases of severe anxiety, the most sensible thing may often be to start combined treatment right away," Dr Lebowitz added in a release.

The research was published online September 28 in the Journal of Clinical Child and Adolescent Psychology.

Largest Trial to Date

Anxiety disorders are among the most common mental health disorders in children, the investigators note. Further, they point out that if these disorders are not treated successfully, they can lead to significant long- and short-term impairment and "tremendous societal cost."

CAMS is the largest randomized controlled trial for childhood anxiety disorders to date.

Published in 2008, the original findings gave empirical support to the use of sertraline and CBT; the combined treatment yielded the best outcomes. At that time, the investigators stated that all three treatments could be recommended for pediatric anxiety.

The upshot was that many physicians and parents opted for CBT as first-line therapy before starting medication. In the current secondary analysis of the CAMS data, the investigators sought to identify predictors and moderators that may affect various treatment outcomes and to help physicians prescribe the most effective therapy for particular patient populations.

They integrated baseline anxiety levels and receiver operating characteristics into the analysis and examined predictors and moderators of parent- and child-rated anxiety outcomes.

The study included 488 individuals aged 7 to 17 years with generalized anxiety disorder (GAD), social phobia (SoP), or separation anxiety disorder (SAD). The patients were randomly assigned to receive treatment with sertraline, CBT, both treatments together (COMB), or placebo.

The majority of the participants (74%) were aged 7 to 12 years, 79% were white, and 50% were female. SoP was identified in 82% of the participants, 79% had GAD, and 54% had SAD. Comorbid obsessive-compulsive disorder (OCD) was diagnosed in 9%.

Participants were randomly assigned in a 2:2:2:1 fashion to receive sertraline, CBT, COMB, or placebo. At week 12, 90% of patients were assessed for degree of anxiety through child, parent, and independent evaluator (IE) ratings on the Pediatric Anxiety Rating Scale (PARS). Other measures included the child and parent disorder―specific subscales of the Screen for Child Anxiety-Related Emotional Disorders (SCARED) and the Anxiety Disorder Interview Schedule-Child/Parent Version (ADIS-C/P).

The investigators found that remission rates, assessed with the ADIS-C/P, ranged from 20% to 79%; with the PARS, remission rates ranged from 22% to 83%.

A baseline anxiety cutoff score on the PARS of <20 was the most discriminative predictor of IE-related remission. Among participants with a high degree of baseline anxiety (defined as a PARS score ≥20), COMB was the most discriminative predictor of remission.

Further analysis showed that COMB was the only treatment significantly associated with an increased likelihood of remission in comparisoin with placebo, at a relative risk of remission on the ADIS-C/P of 2.93 ( P = .001). This compared with a relative risk of 1.34 (P = .46) for sertraline alone and 1.59 (P = .19) for CBT alone.

These findings were reflected in the number of severely anxious patient that a clinician would need to treat for one patient to benefit relative to use of placebo. For sertraline, the number needed to treat for one patient to benefit was 14; for CBT, eight; and for COMB, only three.

"It is important to note that, although sertraline and CBT did not demonstrate significant superiority over placebo, CAMS was not powered to detect treatment effects after stratification by anxiety severity," the investigators write.

The same results were not found for participants with lower anxiety levels.

The team identified several other predictors of independent evaluator-rated anxiety outcome, including baseline OCD, lower socioeconomic status (SES), and higher scores on the Social Phobia subscale of SCARED.

Furthermore, Hispanic ethnicity was associated with higher PARS scores following CBT, and global parental psychopathology predicted lower PARS scores following treatment with sertraline and higher scores following CBT.

Overall, the best-fitting combined model explained 33% of the variance in independent evaluator-rated PARS scores at week 12.

Synergistic Effect

Lead author Jerome H. Taylor, MD, formerly of the Child Study Center, Yale University, and now at the University of Pennsylvania School of Medicine, Philadelphia, told Medscape Medical News that one of the reasons that the degree to which the severity of anxiety affects treatment outcomes has not been identified previously may be "because it's really hard and expensive to do these large clinical trials."

Although he anticipates there could be barriers in accessing combined therapy, he hopes that the "research highlights the need for both of them, so that insurance companies and treatment leaders are able to recommend both medication and psychotherapy confidently, knowing there's a synergistic effect between the two that's especially important in severe anxiety.

"Usually, the kids with severe anxiety are the kids who need treatment most. Those are those kids who are having difficulty going to school because of their anxiety, or having difficulties with peer relationships because of their anxiety, and it's usually really hard to get them engaged in treatment. But once they are engaged in treatment, I think it's really important that they are engaged in a treatment that's most likely to be effective," Dr Taylor added.

Regarding the fact that low SES was found to be associated with anxiety treatment outcomes, Dr Taylor pointed out that SES is "often a marker for lots of other indicators."

However, it is not clear at this stage why children with low SES did not respond as well to therapy. "It may be just that the idea of mental health treatment and education around the subject of mental health treatment is not as well recognized in those communities," he said.

Dr Taylor believes it is important that clinical trials include participants from underserved and underresourced communities in order that researchers can gain insight into the best treatment options for these patients.

He added that the aim of the study was not to provide a "one-size-fits-all" recommendation.

"It really does depend on patient preference and the family preference and what they're comfortable with. I do think it's important for therapists to lay out the option of combined treatment, but if, for some reason, the patient is only comfortable with therapy or isn't able to do cognitive-behavioral therapy...trying one is still better than no treatment at all. So, the take-home message is that, yes, combined treatment is best, but monotherapy still has its place in the range of treatment options," said Dr Taylor.

Important Clinical Implications

Commenting on the findings for Medscape Medical News, David Fassler, MD, clinical professor, the Larner College of Medicine, the University of Vermont, Burlington, who was not involved in the study, described the results as "generally consistent with clinical experience.

"Children and adolescents with mild or moderate anxiety disorders often respond well to CBT. However, young people with more severe anxiety disorders are more likely to respond to a combination of interventions, typically including medication," he said

Dr Fassler noted that the analysis was limited because the original CAMS study was not designed or powered to detect differences between treatments on the basis of symptom severity.

He also agreed with the authors that there is a need for more empirical studies on the efficacy of various treatments for children and adolescents with more severe anxiety disorders.

Despite its limitations, the study represents a contribution to the field. He is optimistic the findings "will help inform current treatment decisions and the design of future research initiatives.

"These findings have potentially important clinical practice implications. Oftentimes, descriptions of the CAMS results emphasize that all three treatments (CBT only, sertraline only, or combined treatment) are effective and can be considered first-line treatments.

"Some guidelines, in fact, recommend monotherapy (psychotherapy only) as the first-line treatment in pediatric anxiety. For instance, the National Institute for Health and Care Excellence guidelines [2013] state: 'Do not routinely offer drug interventions to treat social anxiety disorder in children and young people.'"

The study was supported by a National Institute of Mental Health grant to Johns Hopkins University. The researchers received support from the National Institutes of Health/National Institute of Mental Health, the Patterson Trust, the American Psychiatric Association/Substance Abuse, and the Mental Health Services Administration Minority Fellowship Program. Dr Silverman receives royalties for the Anxiety Disorders Interview Schedule for Children and Parents.

J Child Adolesc Psychol. Published online September 28, 2017. Full text

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