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Anxiety disorders in children and adolescents are highly prevalent psychopathologies affecting as many as 10% of youth (1–3). These disorders are frequently associated with psychosocial difficulties, school difficulties, and risk for more serious conditions including depression, suicide, and substance abuse. The goals of treatment are to target overwhelming, incapacitating anxiety that interferes with functioning in social or academic spheres and to prevent a chronic course of remissions and exacerbations that can continue into adulthood (4,5). The treatment of children and adolescents with anxiety disorders requires a multimodal approach. The Practice Parameters for the Assessment and Treatment of Anxiety Disorders (6) recommend that the following components be considered: education of the parents and child about the specific disorder, consultation with primary care physicians and school personnel, cognitive-behavioural approaches, psychodynamic psychotherapy, family therapy, and pharmacotherapy. Pharmacotherapy and cognitive-behavioural therapy (CBT), however, have been subjected to empirical evaluation and are therefore usually considered “first-line” treatments. Many anxious children are treated with both of these treatment modalities. It is therefore surprising that there are no studies examining interactions between these modalities. By comparing children participating in a CBT outcome evaluation trial who received psychotropic medication (mainly selective serotonin reuptake inhibitors [SSRIs]) with those who did not, the present exploratory study begins to address this gap in the literature. Studies of psychotropic medication and CBT in childhood anxiety disorders are reviewed to provide a context for this study. Psychotropic Medication in Childhood Anxiety DisordersWith the exception of OCD (7), data supporting the efficacy of pharmacologic treatments for anxiety disorders in children and adolescents are scarce. One large randomized controlled trial (RCT) has been done on the efficacy of serotonergic medication in this population (8). This 8-week, multisite trial of fluvoxamine in 128 patients aged 6 to 17 years suffering from various anxiety disorders found clear therapeutic superiority of fluvoxamine over placebo (response rate was 76% for fluvoxamine and 29% for placebo [P < 0.001]). In the same study, possible moderators and mediators of pharmacologic treatment effects were examined (9). Children with lower baseline depression on parent report and better treatment adherence were more likely to improve with pharmacotherapy and children with social phobia or greater severity of illness were less likely to improve. Smaller controlled trials showing efficacy of SSRIs in anxious children have been done for fluoxetine and sertraline (10,11). Additional small controlled trials (single site) have been done to examine the efficacy of tricyclic antidepressants and benzodiazepines. Results have been mixed, with some studies showing superiority to placebo (12,13) and others not (14–16). Owing to their risk of cardiac toxicity and potential anticholinergic side effects, tricyclics have recently fallen out of favour in the treatment of childhood anxiety disorders. No studies have systematically compared pharmacotherapy, or combined pharmacotherapy and psychotherapy treatment with nonpharmacologic interventions. Thus, systematic evaluation of the most appropriate role of pharmacotherapy in the treatment of anxiety in children and adolescents awaits further research. Prescribing Practices in ChildrenDespite a dramatic increase in the use of pediatric psychopharmacology (17), little has been written about the psychological meanings of medication to children and parents. When considering medication for children, clinicians need to be attuned to developmental and temperamental issues (18). Bastiens advocates that clinicians consider the efficacy and side effects of medication, whether parents are comfortable giving medication, and whether children are comfortable receiving it (19). Several factors may decrease the likelihood of children receiving psychotropic medication, even when it appears warranted. These are reviewed in Rappaport and Chubinsky (20) and include 1) the conventional notion that mental and emotional disturbances are related to child-rearing practices; 2) the tendency to think that the problem will go away as the child matures; 3) uncertainty about the benefits of psychotropic medications; and 4) concerns about the safety of medications, especially in the longer term (21). Further, there is a lack of consensus among clinicians about which situations warrant medication. The literature suggests that, in severely impaired children, the benefits of medication outweigh the risks. In practice, other factors may play a role in the decision. These include 1) availability of therapists with expertise in CBT, 2) factors precluding CBT (for example, when a child has cognitive limitations or is not fluent in English), 3) familial concerns regarding medication (for example, fear of medication may be greater when parents are anxious themselves), 4) environmental factors that may increase the child’s apparent impairment (for example, high family conflict or other psychosocial stress), and 5) an externalizing comorbidity in the child (children who are distressing to others may be more likely to receive medication than those that are not). Systematic studies of such factors have not been previously done. CBT for Childhood AnxietyCBT is the most established evidence-based psychotherapy in childhood anxiety disorders. The main goals of cognitive- behavioural intervention with anxious children and families are 1) management of anxiety, 2) reduction of personal distress, and 3) increasing mastery and coping skills (22,23). Numerous RCTs in North America and Australia have now demonstrated the efficacy of CBT in childhood anxiety disorders (23–28). Many CBT trials have excluded children on psychotropic medication to avoid confounding psychotherapeutic and medication effects. This practice has precluded an examination of CBT–medication interactions. Therefore, it is unclear whether combining the 2 treatment modalities results in synergistic treatment effects, whether one modality interferes with the other, or whether they operate independently with no interaction. Hypothetically, medication could reduce severe anxiety to a more manageable level, enhancing participation in CBT. Alternatively, the symptomatic relief associated with medication could reduce CBT treatment motivation in the child. Similarly, family participation in treatment could also be affected by the knowledge that the child is receiving psychotropic medication. To take a first step toward clarifying these issues, the present study compared psychotherapeutic benefits for medicated and unmedicated anxious children. The study also compared various individual and family characteristics of the 2 groups and attempted to relate these to previous literature reviewed above. We hypothesized that medicated children would show higher parental psychopathology, higher family frustration, lower family functioning, and more comorbid behavioural problems than unmedicated children. We also hypothesized that, although these factors were not targeted directly in treatment, CBT would result in improvements in some of them. Given the discussion above, we were uncertain whether medicated or unmedicated children would show greater CBT treatment gains but also examined this question. MethodsSubjects Primary care physicians and mental health professionals referred the families to the Anxiety Disorders Clinic of a large children’s hospital for treatment. All children met the criteria for at least 1 DSM-IV anxiety disorder, and this disorder accounted for the main clinical problem presented. Children who had psychotic disorders, had a medical condition that would interfere with treatment, or were not proficient in the English language were excluded from participation. Children with estimated IQs less than 80 (based on vocabulary and block-design subtests of the Wechsler Intelligence Scale for Children-III [WISC-III]; 29) or with learning problems that would interfere with their understanding and participation in treatment (based on school information and clinician judgment) were also excluded from participation. We had 18 children in our sample who were on psychotropic medications: 11 were receiving one of the SSRIs and 7 were on psychostimulants. Procedure The treatment process and research study were explained to children and parents. If interest was expressed in the research, parent consent and child assent were attained. Children and parents then completed questionnaires assessing various family functioning factors and the child’s anxiety symptoms. After the initial assessment, children were randomly assigned to either individual or group treatment conditions. Children in both conditions received a cognitive-behavioural treatment program using the Coping Bear manual (unpublished), an adaptation of The Coping Cat developed by Philip Kendall (22). Parents in both conditions received a psychoeducational parent-training program modelled after the book Keys to Parenting Your Anxious Child (32). There was no control condition; numerous previous studies have demonstrated that children’s anxiety symptoms are stable over a wait-list control period and improve with CBT (reviewed in 33). Treatment attendance was very good, with an average attendance of 10.5 of 12 sessions for children and parents, and this did not differ significantly between medicated and unmedicated children. After treatment, children and parents completed the same questionnaires as those given before treatment. No significant differences in treatment outcome were found between children who completed individual or group therapy (33). Therefore, treatment condition was not included as a factor in the analyses. Similarly, correlations between age and treatment outcome were not significant, so age was not included as a factor in the analysis. Measures Outcome Measures. Outcome measures were chosen to allow multiple informants to report on changes in the child’s anxiety symptoms and global functioning, as correspondence between informants tends to be only fair for childhood anxiety (35), and to test the specific hypothesis described above. The Multidimensional Anxiety Scale for Children (MASC) (child and parent report) (36) and the Children’s Global Assessment Scale (CGAS) (37) were considered key outcome measures. All informants (child, parent, and clinician) also completed the Global Improvement Scale (38). This 8-point Likert scale ranging from 1 (”completely recovered”) to 8 (”much worse”) assesses the child’s current condition in comparison with that prior to treatment. Children completed the MASC (36) and the Children’s Depression Inventory (CDI) (39). The MASC is a 39-item, 4-point Likert scale to assess a broad spectrum of anxiety symptoms in children. High internal and test–retest reliability have been demonstrated. The CDI is a 27-item, 3-point self-report inventory for the assessment of depression in children in the previous 2 weeks. The items address cognitive, affective, and behavioural signs of depression, and when summed, they yield a total depression score. The scale has high internal consistency and moderate test–retest reliability (39). Parents completed the MASC about their children’s symptoms and completed the Conners Parent Rating Scale (40). This 48-item, 4-point Likert scale ranging from 0 (“not at all”) to 3 (“very much”) inquires about various externalizing and internalizing symptoms. Items are summed to yield 6 subscales: Conduct Problems, Learning Problems, Psychosomatic, Hyperactive, Anxiety, and Hyperactivity Index. The Hyper-activity Index has been validated extensively, although teacher information is required when it is issued diagnostically. Clinicians completed the CGAS (37). This measure is a clinician rating of children’s (aged 4 to 16 years) adaptive functioning during the previous month. It is rated on a 100-point scale with 1 being the most impaired and 100 being the least impaired. Descriptors are given for each 10-point interval. Clinicians select the interval that best describes the child’s current functioning and then assign an exact rating within that interval. To obtain an unbiased rating, 3 clinicians not involved in the study estimated the children’s global functioning before and after treatment using all clinical data from the initial (for pretreatment CGAS ratings) and posttreatment (for posttreatment CGAS ratings) assessments. They were blind to the pre- vs posttreatment status and to type of treatment received. Measures of Family Functioning Completed by Child and Parents: Brief Family Assessment Measure-III. The Brief Family Assessment Measure-III (FAM) is a well-validated 14-item child- and parent-reported measure of overall family functioning. Participants are asked to answer questions about how family members relate to each other on a 4-point scale ranging from “strongly disagree” to “strongly agree” (41). Items are summed to yield a total score, which is converted into a T score using available norms. Measures of Family Functioning Completed by Child and Parents: Parental Frustration Questionnaire. The Parental Frustration Questionnaire (PFQ) (unpublished) is an 8-item child- and parent-related measure assessing how frustrated mothers and fathers are with their child’s behaviour. It examines separately how often (“more than once a day,” “more than once a week,” “more than once a month,” “less than once a month,” and “never”) mothers and fathers get angry, irritable, or critical with their child. The child-rated version examines both maternal and paternal frustration. Child responses are summed to yield a Total Maternal Frustration score and Total Paternal frustration score (with low scores indicating low frustration). Responses on the parent-rated version are summed to yield a Total Frustration score. Data Analysis To test our hypotheses, we began by examining factors that might differentiate medicated from unmedicated children. Medicated and unmedicated children were compared using t-tests for continuous measures (age, SES, pretreatment severity on all standardized measures) and chi-square tests for discrete measures (sex, primary diagnosis, medication status, and parental past psychiatric treatment). Because this was an exploratory study, results were not corrected for number of comparisons. Next, we wanted to determine whether depression, externalizing behaviour, family functioning, or family frustration changed with CBT, even though these factors were not directly targeted in treatment. A previous study had already shown significant improvement in anxiety symptoms and overall functioning with CBT in this sample (33). Further, we were interested in whether changes in all clinical measures were related to medication status. To examine these questions, repeated measures analyses of variance were done with time (pre- vs posttreatment) as the within-subject factor and medication status (medicated vs unmedicated) as the among- subject factor. ResultsOur demographic measure revealed that medicated and unmedicated groups did not differ significantly by age, sex, SES, family status (1-parent vs 2-parent), or parental history of psychiatric treatment. Diagnostic profiles for each group are shown in Table 1. As shown, groups did not differ significantly in the distribution of primary diagnoses, but there was a nonsignificant trend toward greater comorbidity (that is, presence of more than 1 diagnosis) in the medicated group. Secondary diagnoses occurred in 12/18 (67%) medicated children vs 39/84 (46%) unmedicated children. The most frequent comorbid condition in both groups was another anxiety disorder (40%), but there was a nonsignificant trend toward more externalizing comorbidity in the medicated group. Four of 18 medicated children had externalizing disorders (22%), while 7/84 unmedicated children did (8%).
Initial symptom rating scores on anxiety, depression, and externalizing behaviours did not differ significantly by medication status (Table 2). Initial global functioning (clinician report) was also comparable between groups. Initial levels of family dysfunction and family frustration, however, were significantly higher in the medicated group by child report (t = –2.71, P < 0.01; t = –3.31, P < 0.01, respectively).
Analyses of variance revealed significant main effects for time on depression by child report (F2,100 = 12.67, P < 0.001), hyperactivity by parent reports (F2,100 = 12.56, P < 0.001 for mother; F2,100 = 17.73, P < 0.001 for father), and frustration by all informants (F2,100 = 7.31, P < 0.01 for child; F2,100 = 14.94, P < 0.001 for mother; F2,100 = 12.58, P < 0.001 for father). Mothers and children also reported changes in family functioning (F2,100 = 4.63, P < 0.05; F2,100 = 3.70, P < 0.05; respectively). These changes were in addition to the reductions in anxiety symptoms and improvements in global functioning reported previously (33). There were 2 analyses that also revealed time × medication status interaction effects: child-reported frustration (F2,100 = 7.31, P < 0.01) and clinician-reported global functioning (F2,100 = 5.50, P < 0.05). These interaction effects are illustrated in Figure 1 and Figure 2. Children on medication appeared to experience greater initial parental frustration than unmedicated children, but their level of frustration declined more dramatically with CBT. Both groups appeared to improve in global functioning with CBT, but improvements were greater for unmedicated children. There were no significant group differences in global improvement ratings by any informant (t-tests). Figure 1 Child Global Assessment Scale pre- and posttreatment (means) Figure 2 Child Frustration Scale pre- and posttreatment (means) DiscussionAlthough limited by the few medicated children seen and the nonrandom design of our comparison, this project nevertheless raised some intriguing possibilities for further study. We found that family functioning and family frustration appeared to distinguish medicated from unmedicated children, with a trend toward greater externalizing comorbidity in the medicated group. The direction of these effects, however, merits further exploration. It is possible that poorer family functioning increases the likelihood of anxious children needing medication in addition to CBT to control their symptoms. Highly frustrated parent–child interactions may also contribute to children’s anxiety, or at least interfere with parents’ ability to provide appropriate reassurance and encouragement. Alternatively, children’s need for medication may reflect greater temperamental difficulty or more complex psychopathology, making these children more difficult and frustrating to parent. The trend toward externalizing comorbidity in this group lends some support to this hypothesis. Finally, children who perceive their families more negatively may have a generally more negative cognitive set, making it more difficult to treat their anxiety effectively without medication. The lack of difference in pretreatment global functioning between groups was initially surprising. Because global functioning was assessed when children on medication had already been stabilized, however, it may have been lower in these children prior to medication stabilization. The groups were also comparable in the incidence of parental mental health treatment. However, this is a fairly crude measure of psychopathology, and more detailed measures of parental psychological functioning are clearly indicated. Treatment-related improvements in child-reported depression, parent-reported hyperactivity, family frustration (all informants), and family functioning (mother and child report) were also noted, even though these factors were not directly targeted in treatment. The improvements in children’s depression symptoms may be due to the optimism generated by mastering anxiety symptoms. Similarly, children who are less anxious are often perceived by their parents as being less restless or less disruptive. The improvements in parental frustration have 2 possible explanations. First, these changes may relate to the parents’ participation in a psychoeducational program teaching them how to understand and help manage child anxiety. As a result of this program, it is likely that parents became more tolerant and less frustrated by their child’s behaviour. This change, in turn, may have helped to create more positive parent–child interactions, consequently decreasing family dysfunction. Alternatively, decreased anxiety symptoms in the children may have reduced parental stress, allowing for less frustration and more harmonious family functioning. The greater reduction in parental frustration reported by medicated children must be interpreted in the context of them having very high initial frustration levels. In other words, there was significant room for improvement on this variable for medicated children, while frustration levels were consistently low before and after treatment for unmedicated children. This finding suggests that the parent component of treatment may be particularly useful for families of medicated children. Interestingly, in a related study of this sample of anxious children, Crawford and Manassis demonstrated that pretreatment family frustration and family dysfunction predicted poorer treatment outcome in the sample as a whole (43). Thus, the lower levels of improvement in global functioning among medicated children may relate to higher initial parental frustration levels. Parental frustration may have made it more difficult for these families to support their children’s progress in CBT or to model adaptive coping strategies for them, at least initially. Alternatively, medication may have affected treatment motivation among children or parents. Attendance did not differ significantly between medicated and unmedicated groups, but more subtle differences in treatment involvement may have occurred. For example, signs of progress among medicated children may have been attributed to medication rather than to CBT strategies, reducing the desire to further practice the strategies and hence reducing the overall benefit of CBT. The slightly higher comorbidity among medicated children may also have limited their gains in global functioning, as the treatment was focused exclusively on anxiety. Finally, if medicated children were somewhat more impaired than their unmedicated peers prior to starting medication (as discussed above), their more limited gains would be consistent with the findings of the Research Units on Pediatric Psychopharmacology Anxiety Study Group (9), who found that greater severity of illness predicted less likelihood of treatment-related improvement. These findings must be interpreted in the context of a small, exploratory study that did not randomize with respect to medication status and did not correct for the number of comparisons between medicated and unmedicated children. The direction of various familial influences on treatment outcome (for example, whether family frustration contributes to poor outcome or merely reflects a more seriously ill child) also requires further elucidation. Studies that include observational measures of family interactions, as well as questionnaires, would be helpful in this regard. Studies examining potential mechanisms of interaction between medical and nonmedical interventions are also clearly needed. Finally, samples from more culturally and educationally diverse populations would improve the generalizability of these findings. Clinical Implications Funding and SupportThe authors acknowledge the generous support of the Ontario Mental Health Foundation for this study. References1. Anderson JC, Williams S, McGee R, Silva PA. DSM-III disorders in preadolescent children. Arch Gen Psychiatry 1987; 44:69–76. 2. Bell-Dolan DJ, Last CG, Strauss CC. Symptoms of anxiety disorders in normal children. J Am Acad Child Adolesc Psychiatry 1990;29:759–65. 3. Kashani JH, Orvaschel H. A community study of anxiety in children and adolescents. Am J Psychiatry 1990;147:313–8. 4. Bernstein GA, Borchardt CM, Perwien AR. Anxiety disorders in children and adolescents: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1996;35:1110–9. 5. Keller MB, Lavori P, Wunder J, Beardslee WR, Schwarts CF, Roth J. Chronic course of anxiety disorders in children and adolescents. J Am Acad Child Adolesc Psychiatry 1992;147:313–8. 6. Bernstein GA, Shaw K, editors. Practice Parameters for the Assessment and Treatment of Children and Adolescents with Anxiety Disorders. J Am Acad Child Adolesc Psychiatry 1997; 36(Suppl 110). 7. 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Treating anxiety disorders in children: results of a randomized clinical trial. J Consult Clinical Psychol 1994;62:100–10. 24. Barrett P, Dadds MR, Rapee RM. Family treatment of childhood anxiety: a controlled trial. J Consult Clin Psychol 1996;30:519–2. 25. Barrett P. Evaluation of cognitive behavioral group treatments for childhood anxiety. J Clin Child Psychol 1998;27:459–68. 26. Kendall P, Flannery-Schroeder E, Panichelli-Mindel SM, Southam-Gerow M, Henin A, Warman M. Therapy for youth with anxiety disorders: a second randomized clinical trial. J Consult Clin Psychol 1997;65:366–80. 27. Mendlowitz S, Manassis K, Bradley S, Scapillato D, Miezitis S, Shaw B. Cognitive behavioral group treatments in childhood anxiety disorders: the role of parental involvement. J Am Acad Child Adolesc Psychiatry 1999;38:1223–9. 28. Silverman WK, Kurtines WM, Ginsburg GS, Weems CF, Lumpkin PW, Carmichael DH. Treating anxiety disorders in children with group cognitive behavioral therapy: a randomized clinical trial. J Consult Clin Psychol 1999;67:995–1003. 29. Psychological Corporation. The Wechsler Intelligence Scale for Children. 3rd ed. New York: Psychological Corporation; 1991. 30. Reich W, Welner Z. Diagnostic Inventory for Children and Adolescents, Revised Parent Version. Toronto: Multi-Health Systems; 1988. 31. Reich W, Welner Z, Herjanic B, and Multi-Health Systems Staff. Computerized Diagnostic Interview for Children and Adolescents-IV (Windows Version). Toronto: Multi-Health Systems; 1997. 32. Manassis K. Keys to parenting your anxious child. Hauppauge (NY): Barron’s Educational Series; 1996. 33. Manassis K, Mendlowitz S, Scapillato D, Avery D, Fiksenbaum L, Freire M, Monga S, Owens M. Group and individual cognitive behavioral therapy for childhood anxiety disorders: a randomized trial. J Am Acad Child Adolesc Psychiatry 2002;41:1423–30. 34. Boyle M, Offord DR, Racine Y. Evaluation of the Revised Ontario Child Health Study scales. J Child Psychol Psychiatry 1993;43:189–213. 35. Klein RG. Parent–child agreement in clinical assessment of anxiety and other psychopathology: a review. J Anx Disord 1991;5:187–98. 36. March J. Multidimensional Anxiety Scale for Children. Toronto: Multi-Health Systems; 1998. 37. Shaffer D, Gould MS, Brasie D. A Children’s Global Assessment Scale. Arch Gen Psychiatry 1983;40:1228–31. 38. Guy W, editor. ECDEU assessment manual for psychopharmacology. Publication ADM 76-338. Washington (DC): US Department of Health, Education, and Welfare; 1976. p 218-222. 39. Kovacs M. Children’s Depression Inventory Manual. New York: Multi-Health Systems; 1992. 40. Conners CK. Manual for Conners Rating Scales. Toronto: Multi-Health Systems; 1989. 41. Skinner H, Steinhauer P, Santa-Barbara J. Manual For Family Assessment Measure-III. Toronto: Multi-Health Systems; 1995. 42. Norusis M. SPSS advanced statistics user’s guide. Version 10.1. Chicago (IL): SPSS Inc; 2000. 43. Crawford AM, Manassis K. Familial predictors of treatment outcome in childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry 2001;40:1182–9. 44. Manassis K, Monga S. A theraupeutic approach to children and adolescents with anxiety disorders and associated comorbid conditions. J Am Acad Child Adolesc Psychiatry 2001;40:115–7. AuthorsManuscript received March 2003, revised, and accepted May 2003. Previously presented as a paper at the Canadian Academy of Child and Adolescent Psychiatry Annual Meeting; November 2002; Banff (AB). 1. Clinical Research Fellow in Child Psychiatry, Hospital for Sick Children, Toronto, Ontario. 2. Staff Psychiatrist, Hospital for Sick Children, Toronto, Ontario; Associate Professor, Department of Psychiatry, University of Toronto, Toronto, Ontario. Address for correspondence: Dr K Manassis, Department of Psychiatry, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8 e-mail: katharina.manassis@sickkids.ca
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