A recent large, randomized, controlled trial showed fluvoxamine to be effective in treating anxiety disorders in children. The eight-week trial raises many questions about anxiety, the most common psychiatric disorder in children. A panel of experts looks at past and future research.
According to the National Institute of Mental Health, anxiety disorders are the most common of childhood psychiatric conditions, affecting an estimated 13% of children during any six-month period. As with other psychiatric disorders of childhood, they tend to go untreated, and, in the absence of effective treatment, children do not simply grow out of them. On the contrary, anxious children often grow up to be adults with anxiety, depression or another affective disorder. According to Daniel Pine, M.D., chief of NIMH's section on development and affective neuroscience, "A large percentage of adult problems, anxiety as well as depression, really begin as anxiety disorders in childhood." About half of children recover, Pine explained in an interview with Psychiatric Times, but "those children who do continue to have problems will account for a large proportion of adults with both anxiety and mood disorders."
In a recent prospective study that followed 776 adolescents into adulthood, Pine et al. (1998) found that adolescent anxiety or depressive disorders predicted an approximate two- to threefold increased risk for adulthood anxiety or depressive disorders.
Researchers and clinicians are hoping that a better understanding of children's anxiety disorders and more effective treatments will not only alleviate children's suffering but also prevent the development of affective disorders later on. "We'd like to believe that early intervention will reduce downstream morbidity," John March, M.D., M.P.H., told PT. Only large-scale prospective studies will be able to show if this is the case.
Pharmacologic Treatment of Anxiety Disorders
The first large, randomized, controlled study of the pharmacologic treatment of anxiety disorders in children was published in spring of this year (The Research Unit on Pediatric Psychopharmacology [RUPP] Anxiety Study Group, 2001). In this multisite NIMH-funded trial, 128 children between the ages of 6 and 17 who met the criteria for social phobia, separation anxiety disorder or generalized anxiety disorder were randomly assigned to receive either fluvoxamine (Luvox) (maximum dose: 300 mg per day in adolescents; 250 mg per day in children less than 12 years of age) or placebo for eight weeks. By week 3 of the trial, significant differences between the treated and untreated groups were evident on the Pediatric Anxiety Rating Scale. Symptoms continued to improve through week 6, with little change during the final two weeks of the trial.
At the end of the study, patients in the fluvoxamine group had a mean decrease of 9.76.9 points and an average rating below 10-a score reflective of mild anxiety. In the placebo group, patients had a decrease of 3.14.8 points and an average rating of 14 or higher-indicative of high anxiety. On the Clinical Global Impressions (CGI)-Improvement scale, 48 of 63 children in the fluvoxamine group (76%), compared to only 19 of 65 children in the placebo group (29%) responded well to the treatment and had scores of less than 4.
Five children dropped out of the fluvoxamine group, and one child in the placebo group, because of adverse events. Abdominal discomfort was the only adverse event that was significantly more prevalent in the fluvoxamine group. There was also a trend toward a greater frequency of increased motor activity in the fluvoxamine group, an observation that has been found inconsistently in previous trials of selective serotonin reuptake inhibitors in children. When found, this increase seems to occur most often in younger children (Lalellarte et al., 1999, as cited in RUPP, 2001).
Asked to comment on the significance of the study, Pine, one of the study's authors, said, "The magnitude of the effect was dramatic, and even more impressive because it was largely the same across the five study sites."
This study suggested that fluvoxamine is an effective treatment for acute anxiety disorders in childhood, although it leaves many questions about the proper use of pharmacotherapy in treating children with anxiety disorders. The American Academy of Child and Adolescent Psychiatry's Practice Parameters for the Assessment and Treatment of Children and Adolescents with Anxiety Disorders, which have not been revised since 1997, recommend that medication be used only as an adjunct or after a behavioral or psychotherapeutic intervention trial has failed, not as a stand-alone treatment (Bernstein and Shaw, 1997). This philosophy is advocated by the experts interviewed for this story, most of whom would use cognitive-behavioral therapy (CBT) first whenever possible.
The fluvoxamine trial continued for only eight weeks and could not address the questions of optimal duration of treatment in those children for whom pharmacotherapy is warranted, likelihood of relapse when treatment is discontinued or the benefit-risk of ongoing treatment in children. "We don't have randomized evidence for how long to continue this treatment or for how and when to discontinue it," said March, a member of the RUPP study and director of the program in child and adolescent anxiety disorders at Duke University. "We do have a pretty good understanding of what to do now for initial treatment with single agents, either SSRIs or cognitive-behavioral therapy."
Growing Body of Data Supports CBT
In 1994, Philip Kendall, Ph.D., director of the child and adolescent anxiety disorder clinic at Temple University, reported on the first randomized clinical trial of CBT for anxiety-disordered children. Forty-seven children between the ages of 9 and 13 who met DSM-III-R criteria for overanxious disorder, separation anxiety or avoidant disorder received a 16-session treatment (Kendall, 1994). Post-treatment, 64% of the children were free of the diagnosis for which they were treated. Kendall later replicated these findings with a similar group of 94 patients (Kendall et al., 1997). Follow-up with the first group at 3.35 years showed that about two-thirds of the treated children maintained their treatment gains (Kendall and Southam-Gerow, 1996). The follow-up did not allow for comparison with an untreated control group since the original wait-listed group had gone on to receive therapy. Kendall and his team are now in the process of conducting an eight-year follow-up of the subjects in the 1997 study.
An Australian group led by Paula Barrett, Ph.D., has had similar results using a manualized form of Kendall's therapy (Barrett et al., 1996). They recently published the longest follow-up to date of CBT in anxious children, with an analysis of the clients six-years post-treatment (Barrett et al., 2001). The 52 clients, aged 14 to 21 years (out of an original study group of 79), had received CBT for overanxious disorder, separation anxiety or social phobia. Of these subjects, 42 (85.7%) no longer met the diagnostic criteria for any anxiety disorder. Long-term outcomes did not differ significantly on the basis of either the initial diagnosis or the presence of comorbidity. There was no follow-up control.
Asked by PT to summarize the findings to date on cognitive behavioral therapy and anxiety disorders in children, Kendall said, "In children with separation anxiety, generalized anxiety disorder and social phobia, CBT is effective in 66% to 72% of the patients. On follow-up of a year or more, about two-thirds of the responders maintain their gains."
What are the unique features of CBT that have been shown to be effective with anxious children? According to Kendall, there is an emphasis on exposure tasks during which the child is asked to do what they are most afraid of. There are also systematic attempts to change the child's internal dialogue or "self-talk." "Depending on the child's developmental level, instead of talking about self-talk, we might look at a cartoon with a blank thought bubble and fill it in," he said, adding, "There are lots of role plays, a lot of practice opportunities shaped and guided by the therapist."
For example, in the case of a child who worries a lot about "their mother forgetting and not picking them up on time at school," Kendall would "organize multiple opportunities for the kid to have to wait for mom to pick them up" in the context of the therapy. While waiting with the child, the therapist would help them to list all the potential reasons why the parent could be late (e.g., traffic, last-minute phone call). The dreaded "being forgotten about" becomes only one among many far more likely possibilities.
Anne Marie Albano, Ph.D., also considers a critical element of the treatment its "normalizing of the experience of anxiety" itself. Although research has yet to clarify whether, and in exactly what ways, anxiety-disordered children's arousal, neurochemistry or brain function is actually different from normal children in the face of anxiety-provoking situations, it is clear that these children find their own experience of being anxious as less tolerable.
"Part of what you do with exposure therapy is to help them to feel their anxiety," said Albano, who is director of the anxiety and mood disorders clinical research service in New York University's child study center. "Let them feel their heart rates go up, while you stay in and manage the situation." The more exposure they have to their own anxiety, Albano explained, the less they focus on their heart rate racing or the butterflies in their stomach. After successfully completing the exposure tasks, "All the children say, 'I didn't even notice I was nervous anymore,'" she said.
Although it is common for practitioners to utilize some form of CBT as part of an eclectic package of therapy techniques, what is being offered may not provide the essential components of Kendall's protocol. "My concern," said Pine, "is that there aren't very many true experts in cognitive-behavioral therapy with children out there in the community."
March agreed, "There's so much heterogeneity of practice, and that directly predicts heterogeneity in quality of care."
The parents of Albano's New York City patients often claim their children have already "failed cognitive-behavioral therapy." What Albano finds with further investigation is that the previous practitioners may have done "something CBT-like" but without the systematic thought and planning that goes into gearing the exposure to the specific child and their disorder.
A number of variables may be important in determining the success or failure of CBT, according to Kendall. In at least one study (Treadwell and Kendall, 1996), the reduction in the child's negative self-talk was very significant. "We measured positive and negative self-talk at the beginning of treatment, at its end and one year later. Positive self-talk did not change but there was a significant reduction in the negative self-talk, and this reduction was a significant mediator of therapeutic change," he said. Gender, age, ethnicity and socioeconomic status were not significant variables in success or failure, and there were no differences in outcome on the basis of individual diagnosis or comorbidity.
Other forms of psychotherapy to treat anxiety disorders in children have not been subjected to randomized controlled trials. Psychoanalyst Peter Fonagy, Ph.D., is developing a study that will compare CBT and a manualized form of psychodynamic therapy for "severely disordered anxious children" in the United Kingdom. Fonagy, director of research at London's Anna Freud Centre, contended that psychodynamic therapy may have broader and more long-lasting developmental effects than CBT.
Comparison of CBT, SSRIs and Combination Therapy
In a press release commenting on the fluvoxamine trial, NIMH director Steven E. Hyman, M.D., called for the need to "compare the efficacy of existing therapies, including cognitive-behavior therapy to, or in combination with, medication." An ambitious multisite, randomized, controlled trial to evaluate SSRIs, CBT and combination therapy is currently awaiting NIMH funding. The study will enroll children between the ages of 7 and 14. By standardizing the diagnostic criteria, the study will ensure that the patients receiving CBT and those receiving pharmacotherapy are truly comparable. Outcome measures, which have varied from study to study, will also be rigorous and standardized, ensuring that success will be measured in the same way across treatments. Kendall's manualized CBT will be used (Kendall, 2000), with all practitioners overseen by Kendall's group to ensure consistency and treatment integrity. The trial will probably continue for 12 weeks with a six-month follow-up, enough time to allow researchers to measure relapse if it occurs.
If all goes well, the study may help clinicians to determine if combination therapy has advantages over monotherapies, or if it works for patients who have failed other treatments. Based on his own clinical experience, March suspects that combined treatment may confer "an advantage for the sickest, most comorbid children." He anticipated that this trial and others like it will resolve at least some of the open questions in the treatment of children with anxiety disorders.
He said, "Five to seven years from now, we're going to have a much better idea of which treatments work best for which kids with which problems across the range of internalizing disorders."
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