Comparative Studies of Pharmacotherapy for School Refusal GAIL A. BERNSTEIN, M.D., BARRY D. GARFINKEL, M.D., F.R.C.P.(C), CARRIE M. BORCHARDT, M.D.

AND

Abstract. Two studies compared alprazolam and imipramine in the treatment of school refusal. In an open label study (N = 17), two-thirds of the subjects completing a trial in both the alprazolam and imipramine groups showed moderate to marked global improvement in symptoms of anxiety and depression. In the double-blind, placebo-controlled study (N = 24), posttreatment scores calculated as change from baseline on the Anxiety Rating for Children were significantly different (P = .03) among the three treatment groups, with the active medication groups showing the most improvement. Additionally, on all depression rating scales, similar trends were evident with the alprazolam and imipramine groups demonstrating greater improvement than the placebo group. However, analyses of covariance (with pretreatment scores as the covariates) showed no significant differences among the three treatment groups on change in anxiety and depression scales. Thus, additional research is needed to determine whether trends in this study are explained by drug effect or baseline differences on rating scales. J. Am. Acad. ChildAdolesc. Psychiatry, 1990,29, 5:773-781. Key Words: alprazolam, imipramine, school refusal. Although anxiety and depressive symptoms have long been recognized in children with school refusal (school phobia), the literature contains few reports of medication trials for the treatment of this disruptive and often debilitating syndrome. Separation anxiety is a common presentation in school refusal (Waldron et aI., 1975; Gittelman and Klein, 1984). Overanxious disorder is also represented in school refusers (Kendall, 1989, personal communication). In the School Refusal Clinic at Minnesota, children with anxiety disorders may present with concurrent diagnoses of separation anxiety disorder and overanxious disorder (Bernstein and Garfinkel, 1986). In addition, depressive symptoms have been described in children with school refusal (Agras, 1959; Hersov, 1960a,b; Davidson, 1961; Waldron et aI., 1975; McDonald and Sheperd, 1976; Baker and Wills, 1978; Tisher, 1983; Kolvin et aI., 1984; Bernstein and Garfinkel, 1986). Since both anxiety and depressive symptoms have been identified in school refusers, medications that target these symptoms need to be evaluated. D' Amato (1962) described the use of chlordiazepoxide for preadolescent school refusal. In this study, nine children were treated with 10 to 30 mg daily, with all but one attending school by the end of the second week. The investigator reported these results to be much better than his previous AcceptedNovember 21, 1989. Dr. Bernstein is Assistant Professor and Director of Outpatient Services ofthe Division ofChild & Adolescent Psychiatry at the University ofMinnesota Medical School. Dr. Garfinkel is Director ofthe Division of Child and Adolescent Psychiatry, and Dr. Borchardt is Assistant

Professor in the Division of Child and Adolescent Psychiatry at the University ofMinnesota. The authors acknowledge the Upjohn.Companyfor their grant support and assistance. The authors also acknowledge Ann Voelker, R.N., M.S., for coordinating clinical aspects of the studies and thank David Wallinga, M.D. .for chart reviews ofattendance data. Dr. Wallinga was a medical student when this research was completed. Reprint requests to: Dr. Bernstein, University ofMinnesota , Division of Child & Adolescent Psychiatry, Box 95 UMHC, Harvard Street at East River Road, Minneapolis, MN 55455. 0890-8567/90/2905-0773$02.0010© 1990 by the American Academy of Child and Adolescent Psychiatry.

773

nonpharmacological treatment of school refusal. Kraft and colleagues (1965) reported on an open trial of chlordiazepoxide, dose range 30 to 130 mg per day, in a group of children with mixed psychiatric disorders. Those children with school refusal responded best, with 14 of 18 achieving a rating of good to excellent response. Frommer (1967) employed a double-blind, crossover design that compared phenelzine plus chlordiazepoxide to phenobarbital in a study of 15 phobic children. The combination treatment appeared superior to the barbiturate. Diagnosis and therapeutic outcome were not systematically studied. The two studies with chlordiazepoxide alone were not double-blind and did not employ a control group. While the Frommer (1967) study was double-blind with a crossover design, two drugs in combination were reported as superior to a third, different drug. It is unknown if benefit was primarily due to the benzodiazepine or the monoamine oxidase inhibitor. Despite limitations in design of these three small studies, potential benefits from benzodiazepines in the treatment of school refusal are suggested. Gittelman-Klein and Klein (1971, 1973) reported a doubleblind, placebo controlled study of imipramine in 35 school refusal children, ages 6 to 14, with separation anxiety who were refractory to psychotherapy. Imipramine (dose range 100 to 200 mg/day) was significantly better than placebo in returning the children to school. Imipramine was associated with school return in 81%, placebo in 47%. Although 47% returned to school while on placebo, these children were often still symptomatic. Psychiatrists, mothers, and children rated the imipramine group as showing significantly greater improvement, including a decrease in fearfulness and somatic complaints. Abe (1975), in an open administration of sulpiride to 21 school phobic children, reported that 13 returned to school within the first week of drug treatment with a decrease in symptoms of anxiety and depression. Three improved clinically, but remained at home, and five showed no improvement. Of the eight who did not return to school, six were subsequently placed on imipramine, with two showing a response. Berney et al. (1981) reported a double-blind, placebo controlled study of 40 to 75 mg clomipramine in 51

BERNSTEIN ET AL.

school refusers (ages 9 to 14). The authors reported no significant difference between placebo and clomipramine in decreasing symptomatology or facilitating a return to school. Several factors may explain the conflicting results of the studies involving tricyclic antidepressants. The antidepressant dosage in the Gittelman-Klein and Klein study was higher than that used in the Berney et al. study. Patient samples differed between the two studies, with the Berney et al. study having slightly older and more depressed patients than the Gittelman-Klein and Klein study. The studies also differed in the psychosocial therapies administered concurrent with medication. The Gittelman-Klein and Klein study used persuasive and desensitization techniques, while the Berney et al. study used concurrent individual psychotherapy for the child and casework with the parents. Alprazolam, a new benzodiazepine, is one ofthe drugs used to treat school refusers in the comparative studies reported in this article. This drug has been shown to decrease anticipatory anxiety, block panic attacks, and decrease symptoms of depression in adults (Chouinard et aI., 1982; Feighner et aI., 1983). Alprazolam has been used in studies of children with acute anxiety associated with medical procedures and in children with anxiety disorders. Pfefferbaum et al. (1987) reported an open trial of alprazolam for the treatment of anticipatory and acute situational anxiety and panic associated with bone marrow aspirations and spinal taps in 13 children being treated for cancer. Nine of 13 children showed some beneficial response in this drug trial. Simeon and Ferguson (1987) presented an open clinical trial of alprazolam in 12 children with overanxious and/or avoidant disorders. Clinical global improvement was marked in one patient, moderate in six patients, minimal in four, and absent in one. The authors are unaware of other published studies on the use of alprazolam in children. The existing literature includes several studies with methodological limitations suggesting the potential benefit of benzodiazepines in treating children and adolescents with school refusal. The two previous studies reporting on tricyclic antidepressants in the treatment of school refusal are controlled, but present contrasting results most likely explained by differences in patient samples (the Berney et al. [1981] study with older, more depressed patients) and in medication dosages. The current studies are unique because they compare a new benzodiazepine and a tricyclic antidepressant. In addition, the second study is double-blind and placebo controlled. The present studies employed a1prazolam and imipramine for the treatment of school refusal because both drugs have potential for targeting symptoms of anxiety and depression. It was hypothesized that alprazolam and imipramine would have equal efficacy for decreasing symptoms of anxiety and depression in school refusal individuals and that both active medications would be superior to placebo. Method OPEN DRUG STUDY OF ALPRAZOLAM AND IMIPRAMINE IN SCHOOL REFUSAL

Subjects

Seventeen school refusers, nine males and eight females,

774

were treated in an open trial with either alprazolam or imipramine. These children and adolescents were recruited from the School Refusal Outpatient Clinic in the Division of Child and Adolescent Psychiatry at the University of Minnesota. The mean age ± SD was 14.17 ± 1.92 years, with the range from 9.50-17.00 years. On structured interview, 11 (65%) met DSM-lll criteria for both depressive disorder (major depression or adjustment disorder with depressed mood) and anxiety disorder (separation anxiety disorder or overanxious disorder), four (23%) met criteria for depression only, and two (12%) did not meet criteria for a DSM-Ill diagnosis but did have symptoms of depression and anxiety. Procedure

Following a clinical diagnostic interview, each subject received the Diagnostic Interview for Children and Adolescents, a structured psychiatric interview (Herjanic and Campbell, 1977). Information regarding risks and benefits of the medications was presented and informed consent was obtained from subjects and their parents. Then each patient was assigned to a multi modal treatment program, including school reentry program, psychotherapy, and medication. Ten patients received alprazolam and seven received imipramine. Alprazolam was administered two or three times daily and imipramine was given at bedtime. Alprazolam was increased 0.25 mg every 3 days and imipramine was raised 25 mg every 3 days. Duration of medication treatment was individualized for each patient. Global improvement and return to school were usually obtained after approximately eight weeks of treatment. Results

The mean dosage ± SD of alprazolam attained was 1.43 ± 0.97 mg daily (range 0.75 mg to 4.0 mg). Mean dosage ± SD for imipramine was 135.42 ± 47.41 mg daily (range 50 mg to 175 mg). Plasma imipramine levels were obtained on all except one patient on imipramine. All blood levels, except one, were in the therapeutic range (125-250 ng/ml) for treatment of depression in children (Preskorn et aI., 1982). This range has been demonstrated to be safe in treating children (Preskorn et aI., 1983). One patient had a subtherapeutic level (imipramine plus despiramine = 55 ng/ml) but still showed a marked clinical improvement. One alprazolam patient dropped out in the third week of treatment because of sedation and the feeling that the medication was not helpful. Of the seven patients started on imipramine, one patient discontinued the drug because of side, effects (occipital headaches). Of the nine patients completing an alprazolam trial, six (67%) were rated by the psychiatrist as showing moderate or marked improvement in anxiety and depression. Of these patients, five (55%) returned to school (Table 1). Of the six patients completing an imipramine trial, four (67%) were rated as showing moderate or marked improvement. In the imipramine group, three (50%) returned to school (Table 1). With alprazolam, sedation was reported by some patients. On imipramine, most patients described lightheadedness as the medication was titrated upwards. On imipramine, a few l.Am.Acad. Child Adolesc. Psychiatry, 29:5, September 1990

PHARMACOTHERAPY FOR SCHOOL REFUSAL TABLE

1. An Open Drug Trial ofAlprazolam and Imipramine in School Refusal Global Improvement Rating by Psychiatrist

Alprazo1am Imipramine

Return to School

No. of Subjects

Marked

Moderate

Mild

None

Yes

No

9 6

2 2

4 2

2 2

1 0

5 3

4 3

each complained of gastrointestinal discomfort, sedation, and/or dry mouth. There were no significant adverse drug effect in the patients who completed the open drug trial of alprazolam or imipramine. Shortcomings of the above study included the open-label design and the fact that ratings of response were limited to global improvement assessed nonblind. With the above limitations in mind, the authors proceeded with a double-blind, placebo-controlled study of alprazolam versus imipramine for school refusal. Method DOUBLE-BLIND PLACEBO CONTROLLED STUDY OF ALPRAZOLAM VERSUS IMIPRAMINE IN SCHOOL REFUSAL

Subjects

Twenty-four children not included in the open-label study participated. All had a history of poor school attendance secondary to psychological difficulties without known medical illness. Inclusion criterion was having a diagnosis of an anxiety and/or depressive disorder. Subjects between ages 7 to 18 were included. Exclusion criteria included chronic or severe medical illness, being on psychotropic medications, and significant abnormalities on pretreatment laboratory studies. Patients with concurrent diagnoses of attention deficit hyperactivity disorder, somatization disorder, conduct disorder, mental retardation, and pervasive developmental disorder were eliminated to help minimize the heterogeneity in the treatment sample. This sample included 13 males and 11 females, mean age ±SD of 14.12 ±1.98 years (range of 7.66 to 17.58 years). Independent chart review of 100% of the charts by the senior author (GB) and by a senior child psychiatry resident was the method of assigning subjects to diagnostic groups. Interrater agreement was 75% (18 of 24) after initial chart reviews. Disagreements were resolved by a second chart review and discussion by the senior author and senior resident. DSM-III diagnoses were: major depression or adjustment disorder with depressed mood (depressive disorder only,N = 10);separation anxiety disorder and/or overanxious disorder (anxiety disorder only,N = 4); and a combination of . at least one diagnosis from each of the previous two categories (anxiety and depressive disorder, N = 10). There was only one patient with an adjustment disorder with depressed mood. This patient was included in the depressive disorder only group since, clinically, the patient was most similar to the subjects in this group. Procedure

All patients were evaluated in the School Refusal OutpaJ. Am. Acad. Child Adolesc. Psychiatry. 29:5. September 1990

tient Clinic by a child psychiatry resident under the supervision of a child and adolescent psychiatrist. A research assistant with a master's degree administered anxiety and depression rating scales. This staff person has extensive experience administering the clinician rating scales, having given them to over 130 patients. The assessment was followed by an interpretive meeting attended by the child psychiatry trainee, psychiatrist, family, and school representative the following week. The possibility of participating in the study was presented at the initial evaluation. At the interpretive session, those children and their parents who were interested in participating provided informed consent. Subjects were randomized into one of three treatment groups: alprazolam, imipramine, or placebo. All subjects had laboratory studies at baseline and at the end of the medication trial, including electrocardiogram, complete blood count with differential, and liver function tests (aspartate aminotransferase and gamma glutamyl transferase). No subjects were eliminated based on laboratory screening. Data from the open trial of alprazolam versus imipramine for school refusal showed clinical response of patients at an average dose of 1.4 mg alprazolam and 135 mg imipramine. Medication was supplied as identical appearing capsules of .25 mg alprazolam, 25 mg imipramine, or placebo. These strengths allowed for gradual titration of dosage. Medication was titrated at week 3 to 0.03 mg/kg per day for alprazolam and 3 mg/kg per day for imipramine. This maximum dosage of alprazolam was chosen since alprazolam is considered to be ten times as potent as diazepam (Dawson et al., 1984). Medication was given as a divided dose (3 times a day) in all treatment groups. Following week 8, patients were tapered off medications over 1 to 2 weeks to avoid seizures or rebound anxiety from alprazolam or other complications from rapid drug withdrawal. Subjects were seen weekly for monitoring of medication by a nurse clinician who was not blind to medication status. Limitations on psychotherapeutic interventions by the nurse clinician were followed (i.e., only instructions, providing information, reassurance, encouragement). All other study personnel and family members were blind to medication group. At medication visits, pulse and blood pressure were checked. Side effects were recorded by the nurse clinician from mild to severe on a checklist based on patients' reports. Side effects were managed with reassurance or by decreasing the dose to the previous dose with a gradual attempt to increase the dose in the manner described. At weeks 4 and 8 of the medication trial, all subjects had blood drawn from medication level. Only the imipramine samples were analyzed. Imipramine dose was adjusted, per 775

BERNSTEIN ET AL. TABLE

2. Distribution of Diagnoses of Patients within

Each Treatment Group Alprazolam Diagnosis Anxiety and depressive disorders Depressive disorder only Anxiety disorder only

Imipramine

Placebo

(N= 9)

(N= 7)

3

5

5 0

2 2

2 3 2

(N =

8f

DOne subject's data were not included in subsequent data analysis due to elevation on Lie scale of the Revised Children's Manifest Anxiety Scale and obvious underreporting of symptoms.

recommendation of the nurse clinician to a physician, at week 4 as indicated by the blood level. To maintain blindness, the nurse clinician recommended an increase in the number of pills when a patient had a low imipramine level and a decrease in the number of pills if the imipramine level was toxic, with a simultaneous recommendation to increase or decrease the number of pills in a patient in the placebo group. Thus, physicians and family members could not assume that a change in dose at week 4 indicated assignment to an active medication group . At baseline, weeks 4 and 8, a research assistant administered the following rating scales to the subjects: the Anxiety Rating for Children (ARC) (Erbaugh, unpublished instrument, 1984), Revised Children's Manifest Anxiety Scale (RCMAS) (Reynolds and Richman, 1978), revised form of the Children's Depression Rating Scale (CDRS) (Poznanski et al. , 1985), Children's Depression Inventory (CDI) (Kovacs and Beck, 1977), and Children's Depression Scale (CDS) (Lang and Tisher, 1978). In addition to active medication or placebo, all subjects participated in a school reentry plan. School reentry was individualized to a subject's needs, but generally consisted of gradually expanding the number of hours per day in the classroom , providing a support person at school , and attending possibly 1 to several hours per day in a classroom for emotionally and behaviorally disturbed students. Special attention was paid to particularly difficult areas for an individual student. Special attention was paid to particularly difficult areas for an individual student (e.g. , riding the school bus, eating in the lunch room, or going to gym class). Also, each subject was treated with weekly individual psychotherapy throughout the study with a child psychologist or a child psychiatry resident under the supervision of a child psychiatrist. After the study was completed, all charts were reviewed to obtain information about school attendance. Whether or not a consistent return to school was accomplished by week 8 was noted. In addition, attendance pattern before entry into the study and at week 8 was rated with a 1 to 5 scale with 1 = complete refusal to 5 = daily attendance . In some cases, not enough information was available to make an accurate rating to a definite number category. However, it was possible to determine if the attendance pattern had improved (rating had changed from a lower to a higher number) . 776

Psychometric Instruments Anxiety scales . (1) The ARC is a clinician rating of anxiety based on a semistructured interview with the child . This instrument consists of seven subscales; items were adapted from the Hamilton Anxiety Scale for Adults. Each subscale is rated from 0 (absence of symptoms) to 3 (severe symptoms) . Thus , the range of scores is 0 to 21 with up to 7 in the mild range , 8 to 14 in the moderate range , and 15 to 21 consistent with severe symptoms . The mean ± SD for a group of school refusal children and adolescents with a DSMIII anxiety diagnosis is 12.1 ±4.2, compared to 8.0 ±4.4 (p ~ 0 .05) for school refusers without an anxiety diagnosis (Bernstein and Garfinkel, 1986). (2) The RCMAS is a selfreport measure of a child's general state of anxiety . The scale includes 28 anxiety items and nine Lie scale items. Anxiety scores range from 0 to 28. Psychometric properties are considered acceptable. Depression scales. (1) The CDRS is a clinician's rating scale of depression based on a semistructured interview with the child. (2) The CDI is a self-rating scale and is a modification of the items from the Adult Beck Depression Inventory. (3) The CDS is a self-report measure of depression using a card sorting game format. Results

Demographics

The demographic date from this sample of 24 school phobics were compared to demographics from a different sample of 53 patients from the School Refusal Clinic . There were no significant differences between the two groups, suggesting this sample is representative of all students seen in the School Refusal Clinic . Approximately half (N = 13) were from single-parent families. Ninety-six percent (N = 23) of the SUbjects were from middle or lower socioeconomic status homes as determined by the Hollingshead (1957) two-factor index of social status. Symptoms of school refusal had been present for greater than 2 years in just over half the sample (N = 13). The majority (N = 21) had received previous treatment. Close to one third (N = 7) had a truancy petition filed by the school pending in court. Distribution of diagnoses among the three treatment groups is in Table 2. Due to the small number of subjects per cell, a statistical test to analyze the distribution of diagnoses among the three treatment groups was not possible. In subsequent results, one subject was excluded from data analysis because of elevation of the Lie scale on the RCMAS and obviously aberrant test scores due to marked underreporting of symptomatology. One subject dropped out in the alprazolam group between weeks 4 and 8, three subjects dropped out from the imipramine group , two before week 4 and one between weeks 4 and 8, and one subject dropped out in the placebo group between weeks 4 and 8. The five dropouts were compared with the 19 other subjects on baseline rating scale scores, and analyses showed no significant differences between the two groups. One subject was hospitalized for increasing depressive symptomatology including the emergence of suicidal ideation. This patient was one of the previously mentioned subjects l .Am.Acad. Child Adolesc.Psychiatry, 29:5, September 1990

PHARMACOTHERAPY FOR SCHOOL REFUSAL TABLE3. Pretreatment Rating Scale Scores

Scales Anxiety scales ARC RCMAS Depression scales CDRS COl CDS

Alprazolam (N = 7)

Imipramine (N = 9)

Placebo (N= 7 )

X SD

X SD

X SD

F

df

P

16 .4 16 .9

2.9 5.1

9 .7 12 .8

4 .7 4 .8

7.2 10.4

2.7 4 .8

11.05 3.07

2 . 19 2. 19

0 .001 0.07

54.0 21.6 87.4

6.9 9.8 11.0

41.0 13.3 68.1

12.2 8.4 25.1

36.5 8.9 55.9

3.4 5.1 30.0

7.00 4.51 3.19

2 .19 2.20 2.20

0 .005 0.02 0.06

Note: ARC = Anxiety Ratin g for Children , RCMAS = Rev ised Children' s Manifest Anxiety Scale, CDRS COl = Children's Depre ssion Inventory , CDS = Children's Depression Scale .

= Children's Depression Rating Scale ,

TABLE 4 . Rating Scale Changes after Eight Weeks ofTreatmen f Alprazolam (N = 7)" Scales Anxiety scales ARC' RCMAS Depression scales CDRS" CDf CDS

X

SD

Imipramine (N = 9)b

Placebo (N = 7)"

X SD

X SD

F

df

P

10. 0 5. 2

5.7 8.8

4 .8 7 .5

3.8 4 .2

2.4 4 .4

3.0 6. 5

4.41 0.32

2.14 2 . 14

0 .03 0 .73

17.5 8.7 23 .5

13.0 6. 8 25.7

11.5 6.8 27.2

14.7 9.3 25. 1

6.4 1.8 8.8

10.4 5. 1 18.0

1.00 1.4 1 1.05

2. 14 2.15 2. 15

0 .39 0 .27 0 .37

Note: See Table 3 for identification of scales. "Change score (baseline- week 8); positive score indicates improvement, larger number indicates greater improvement. ~umber of subje cts per measure varies due to missing data or dropouts . 'Significantly different baseline sco res between group s at p < 0 .05 by ANOV A.

who dropped out of the imipramine group before week 4 . One patient on placebo was started on the study while hospitalized for depression . Ratin g Scales

Premedication baseline anxiety and depression rating scale scores were compared among treatment groups and are presented in Table 3. Statist ically significant differences at baseline were present between groups on the ARC , CORS , . and COl (Table 3). Improvement or lack of improvement based on rating scale scores after 4 or 8 weeks of treatment was evaluated using analyses of variance (ANOYA) with a change score calculated by subtracting scores at week 4 or week 8 from scores at baseline . No significant differences and no consistent trends between groups are present at week 4. At week 8, however, statistically significant differences between treatment groups is documented by the ARC (F = 4.41 , df = 2,14, P = 0.03), with the alprazolam group showing the most improvement , the imipramine group showing intermediate improvement , and placebo group with the least improvement (Table 4) . On all other ratings scales except the RCMAS, similar trends are apparent, that is, the alprazolam and imipramine groups show more improvement than the placebo group. Week 4 data are compared to week 8 data in Figures 1 and 2. l .Am.Acad. Child Adolesc . Psychiatry , 29:5 , Septemb er 1990

However, analyses of covariance (ANCOYA) with the baseline scores as the covariates showed no significant differences between groups on change in rating scales at 8 weeks, including on the ARC (F = 0.16, df = 2, P = NS). The covariate (baseline scores) on the ARC was significant (F = 21.8 6, df = 1, P = 0.0001 ). Data were also analyzed with nonparametric statistics. Using Kruskal-Wallis's ANOYA, subjects' scores at week 8 were rank ordered and , and analyses by group were done for each rating scale. There were no significant differences between groups on any rating scales. Medication Dosages and Plasma Tricycli c Levels

In the alprazolam group , maximum dosages ranged from 0.02 to 0.03 mg/kg/day (l .0 to 3.0 mg/day). The mean ± DS maximum alprazolam dosage was 1.82 ± 0.61 mg/day. In the imipramine group, the maximum dosages ranged from 2.64 to 3.30 mg/kg/day (I 50 to 200 mg/day). The mean ± SO maximum imipramine dosage was 164.29 ± 19.67 mg. Plasma tricyclic antidepressant levels were obtained on the six patients who completed the imipramine trial. At week 4, imipramine plus desipramine levels ranged from 102 to 303, (therapeutic range = 125 to 250 ng/mI). The mean ± SO was 176.5 ± 70.3 . One patient had a subtherapeutic level (102 ng/ml) at week 4 . This patient had a dosage 777

BERNSTEIN ET AL.

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2. Changes in depression scales after 4 and 8 weeks of treatment for each group.

increase at week 4 and a repeat plasma level within 1 to 2 weeks with subsequent plasma level in the therapeutic range. Side Effects No subject had any side effects rated higher than " mild,

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does not interfere with functioning. " See Table 5 for a summary of side effects . No premedication ratings of side effects were obtained. Abdominal pain and headaches were common in all groups throughout the study. Drowsiness was also reported by subjects in all treatment groups . In general, J . Am . Acad . Child Adolesc . Psychiatry, 29:5. September 1990

PHARMACOTHERAPY FOR SCHOOL REFUSAL TABLE

5. Side Effects Reported by Subjects in Each Treatment Group a Alprazolam Imipramine (N = 7)

Abdominalpain Blurredvision Constipation Dizziness Dizziness with standing Drowsiness Dry mouth Headache Nausea Urinaryretention

(N = 9)

Placebo (N = 7)

N

%

N

%

N

%

5 1 2 5 3 4 3 5 4

71 14 28 71 43 57 43 71 57

5 2 2 5

55 22 22 55

4

57

0 0 0

0 0 0

6

66

4 5 7 4

44 55 78

1 4

14 57

0

0

4

57

0

0

0

44 0

0 0

0 0

aA side effect was included as present if it was reported by the subject at least once during the medication trial.

fewer side effects were recorded in the placebo group than in the active medication groups. Blurred vision, constipation, and dry mouth were reported by some of the subjects in the alprazolam and imipramine groups. Cardiovascular side effects of dizziness and dizziness upon standing were described by patients in the imipramine group and alprazolam group. Attendance Data Excluding all dropouts, there were six subjects in each group to evaluate for school attendance (Table 6). In both active medication groups, all other subjects returned to school with improved attendance. In the placebo group, all but one subject returned to school with improved attendance.

Discussion As in the Gittelman-Klein and Klein (1971, 1973) and Berney et al. (1981) studies, the double-blind trial evaluates medication versus placebo in combination with a psychosocial therapy. WithANOVA based on change scores , theARC, a clinician rating scale of anxiety, significantly differentiated between placebo and medication treatments at week 8. The results of other rating scales show trends in the same direction, with both medications appearing superior to placebo. The ANCOV A showed no significant differences between groups on change in rating scale scores after treatment. Therefore, the results from the ANOVA are considered tentative since there were significant pretreatment differences on the ARC. The significant difference among treatment groups on the ARC may result from a difference in baseline scores rather than a drug effect. Nevertheless, the trends in this study are promising and suggest additional study is indicated. The lack of statistically significant differences on other rating scales is explained by several factors. The primary explanation is the small sample size, which became smaller by the week 8 comparison after some subjects dropped out. Another reason for lack of statistical significance is some large standard deviations. This is explained by variable subject responses within groups, with some individuals showing marked improvement as documented with rating scales and J. Am. Acad. Child Ado/esc. Psychiatry, 29:5, September 1990

others with less dramatic responses. This sample of youngsters was largely comprised of patients with dual diagnoses (anxiety and depressive disorders-42%) and pure depressive disorders (additional 42%). A previous study (Bernstein and Garfinkel, 1986) showed that school refusers meeting criteria for both anxiety and depressive disorders have the highest scores on anxiety and depression rating scales among four diagnostic subgroups of school refusers. Thus, this study is evaluating treatment response in a sample of severely symptomatic young adolescents. This sample of adolescents had been treatment resistant with 88% (N = 21) having failed previous therapy. Symptoms of school refusal had been present for greater than 2 years in over 50% of the subjects. The sample in this study more closely parallels the children and adolescents in the Berney et al. (1981) tricyclic medication study rather than the subjects in the Gittelman-Klein and Klein (1971, 1973) study. In the study by Berney and colleagues, 44% of the school refusers were rated as suffering from a significant degree of depression (compared to 84% diagnosed with depression in this trial), while the GittelmanKlein and Klein study treated children with pure separation anxiety disorder. Antidepressant dosages in the Gittelman-Klein and Klein study (1971, 1973) and this study were higher than that achieved in the Berney et al. (1981) drug trial. The Gittelman-Klein and Klein dosage mean was 152 mg. The children in the Gittelman-Klein and Klein study were younger (6 to 14 years, mean = 10.8 years) so their study probably had a higher mg/kg/day dosage than this study. This is the first study to report tricyclic blood levels in the management of school refusal. It is not known whether the same therapeutic range is needed for the treatment of anxiety disorders or mixed anxiety-depression as is needed for pure depression. Most of the patients had pure depression or anxiety and depressive disorders, suggesting that in this study therapeutic blood levels for treatment of depression would likely be needed. The dosage of alprazolam was very conservative. A higher dosage of alprazolam may have been more effective in ameliorating patients' symptoms. In the Pfefferbaum et al. study (1987), a one-time dose of 0.003 to 0.025 mg/kg was used with benefit. In that study, side effects were reported as mild. In this study, headache and abdominal pain were reported by all three treatment groups and probably represented common somatic symptoms associated with anxiety in school refusers (Schmitt, 1971) rather than medication side effects. To document this in future studies, baseline side effects must be recorded. Simeon and Ferguson (1987) employed a maximum daily dosage of 0.5 to 1.5 mg with rare, transient side effects. Alprazolam, at the dosage used in this study, was tolerated with side effects all in the mild range. No withdrawal symptoms were observed with tapering. In future studies, it appears that the dosage could be placed at a higher level while monitoring for side effects. Placebo response has been demonstrated to be an important factor in the treatment of school phobia and childhood depression. In the Gittelman-Klein and Klein study (1971, 1973), 47% of school phobic children returned to school on placebo. 779

BERNSTEIN ET AL. TABLE

6. Change in Attendance after Eight Weeks ofTreatment Return to School

Alprazolam Imipramine Placebo

Number of Subjects Completing Trial"

Yes

No

6 6 6

5 5 3

0 0 I

Not Applicable Ib Ib 2b ,c

Improved Attendance Yes

No

6 6 4

0 0 I

Not Applicable

I

C

"Dropouts excluded. bOne patient attending school regularly before trial, but symptomatic. 'One patient hospitalized until summer vacation.

In a double-blind study of prepubertal major depression, response rate was 56% in the imipramine group and 68% in the placebo group (Puig-Antich et aI., 1987). For these reasons, active medication effects need to be extremely strong to exceed placebo effects. In the authors' double-blind study at 8 weeks, the placebo group reported an average 4.4 point decrease in self-reported anxiety on the RCMAS, an 8.8 point decrease in self-reported depression on the CDS, and there was an average 6.4 point decrease in clinician rated depression on the CDRS. The other rating scales changed minimally with placebo treatment. The decreases in rating scale scores in the placebo group were achieved by week 4 with only minimal additional improvement by week 8. In the drug treatment groups, only partial remission of symptoms was apparent at week 4, with additional benefit by week 8. It appears that between 4 and 8 weeks is needed to appreciate the benefits of active medication treatments in combination with psychotherapeutic treatment. It is not unexpected that maximum symptom relief from placebo is more rapid than medication response since placebo response is based on psychological factors influencing the amelioration of symptoms. Since treatment of depression with tricyclic antidepressants may require a minimum of 3 to 4 weeks to appreciate a response, additional benefit beyond 4 weeks is expected, as seen in this study. This is consistent with the Gittelman-Klein and Klein (1971, 1973) study in which imipramine effects could not be detected after 3 weeks of treatment but were firmly established after 6 weeks. However, since alprazolam has a relatively short half-life and maximum dosage was achieved by week 3, it is somewhat surprising that it takes 8 weeks to appreciate the benefit of the anxiolytic. This may be explained by the concept that treatment in this study reflects a combination of medication with psychosocial intervention. It is possible that additional benefit from the psychosocial intervention was apparent between weeks 4 to 8, after the medication had decreased the target symptoms and thus allowed the children to be more amenable to psychotherapy. The attendance pattern of all subjects in the active medication groups and all except one subject in the placebo group improved by 8 weeks. This was better than the return to school rate in the open label study. Rather than global rating of change in attendance pattern, the second study was based on careful chart review of data regarding attendance. However, the sample size is too small to draw conclusions about effect

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of medication treatment on return to school. It would be important to follow subjects longitudinally to determine if attendance continued to improve and if reinitiation of active medication was needed to insure the improvement. The study of Gittelman-Klein and Klein (1971, 1973) showed that 47% of children on placebo returned to school but they were significantly more symptomatic than those returning to school on imipramine. A crossover design was considered with each child receiving alprazolam, imipramine, and placebo but was not chosen for this study. It is thought that 8 weeks of treatment with one drug would be a minimum amount of time to observe change in symptoms of anxiety and depression and to evaluate return to school. Changing to a second drug or placebo as in a crossover design would require a minimum of 16 weeks, adding a third treatment would require 24 weeks. In addition, a crossover design may mean that treatment responders would lose the remission gained with the first or second 8-week intervention. Also, it would not allow for the longitudinal study of these children and adolescents. Shortcomings of these studies include the difficulty in controlling the adjunctive treatments of school reentry and weekly individual psychotherapy. In future studies, it will be necessary to employ a therapy manual to maximize the likelihood of each patient receiving similar psychotherapeutic interventions. Another limitation in the double-blind study was the lack of consistent recording of school attendance preand postmedication. Thus it was difficult to use return to school and attendance pattern as criteria for treatment success or failure. These results present intriguing trends supporting the authors' clinical observation that medication may be an important part of the treatment regimen in patients with school refusal. This is the first controlled study employing a benzodiazepine versus placebo in school refusal. Trends in the data indicate that both alprazolam and imipramine may be efficacious in treating symptoms of anxiety and depression associated with school refusal. This adds to the small literature on the pharmacological treatment of school refusal that indicates benzodiazepines and tricyclic antidepressants may both be helpful treatments. Potential advantages of a benzodiazepine include fewer side effects, shorter half life with more rapid onset of action than a tricyclic antidepressant and possible shorter course of treatment. Medication dependence should be considered a potential hazard of benzodiazepines but in this carefully monitored, time limited, J. Am. Acad. Child Adolesc. Psychiatry, 29:5, September 1990

PHARMACOTHERAPY FOR SCHOOL REFUSAL

low dosage, clinical trial, this was not a problem. Potential advantages of a tricyclic antidepressant include that imipramine has been found efficacious in the controlled study of school refusers with separation anxiety disorder (GittelmanKlein and Klein, 1971, 1973). Child and adolescent psychiatrists have more clinical experience using imipramine, and imipramine trials can be monitored with plasma levels. Like the other medication studies (Berney et al., 1981; Puig-Antich et al., 1987), this one suffers from lack of statistically significant differences between placebo and medication groups. Nevertheless, it is important to report results given the limited number of patients studied in the literature. Clarity will only come through a synthesis of multiple studies and with the outcome of better designed studies. Additional investigation of alprazolam and imipramine in the treatment of school refusal is warranted. A future study would require improvements in design and methodology including larger sample size as determined by power analysis from data collected in the double-blind, placebo-controlled study, higher dosage of alprazolam in order to find the optimal dosage range, rigorous systematic weekly documentation of school attendance by parents in corroboration with school attendance records, and tighter control of adjunctive psychotherapy including the use of a therapy manual. Additional research should clarify whether some children respond better to one medication than the other and, if so, whether drug response is predicted by diagnosis or symptom cluster, particularly since children with school refusal may have anxiety disorder only, depressive disorder alone, or anxiety and depressive disorders (Bernstein and Garfinkel, 1986). Another direction for future studies is to design studies to determine the optimal combination of behavioral, psychotherapeutic, and medication intervention to produce the best outcome.

References Abe, K. (1975), Sulpiride in school phobia. PsychiatricClinica, 8:9598. Agras, S. (1959), The relationship of school phobia to childhood depres-

sion.Am.J. Psychiatry, 116:533-536. Baker, H. & Wills, U. (1978), School phobia: classification and treatment. Br.J. Psychiatry, 132:492-499. Berney, T.,Kolvin,l., Bhate, S. R., Garside,R. F.,Jeans,1.,Kay,B. & Scarth, L. (1981), School phobia: a therapeutic trial with clomipramine and short-term outcome. Br.J. Psychiatry, 138:110-118. Bernstein, G. A. & Garfinkel, B. D. (1986), School phobia: the overlap of affective and anxiety disorders. J. Am. Acad. Child Psychiatry, 25:235-241. Chouinard, G., Annabler, L., Fontaine, R. & Solyom, L. (1982), AIprazolam in the treatment of generalized anxiety and panic disorders: a double-blind placebo-controlled study.Psychopharmacology, 77:229-233. D' Amato, G. (1962), Chlordiazepoxide in management of school phobia. Diseases ofthe Nervous System, 23:292-295. Davidson, S. (1961), School phobia as a manifestation of family disturbance: its structure and treatment. J. Child Psychol. Psychiatry, 1:270-287.

J.Am.Acad. Child Ado/esc. Psychiatry, 29:5, September 1990

Dawson, G.W., Jue, S.G. & Brogden, R.N. (1984), Alprazolam: a review of its pharmacodynamic properties and efficacy in the treatment of anxiety and depression. Drugs, 27: 132-147. Feighner,1. P., Aden, G. C., Fabre, L. F., Rickels, K.& Smith, W. T. (1983), Comparison of alprazolam, imipramine, and placebo in the treatment of depression. JAMA, 249:3057-3063. Frommer, E. A. (1967), Treatment of childhood depression with antidepressantdrugs. Br.Med.J., 1:729-732. Gittelman, R. & Klein, D. F. (1984), Relationship between separation anxiety and panic and agoraphobic disorders. Psychopathology, 17(Suppl.l):56-65. Gittelman-Klein, R. & Klein, D. F. (1973), School phobia: diagnostic considerations in the light of imipramine effects. J. Nerv, Ment. Dis., 156:199-215. - - - - (1971), Controlled imipramine treatment of school phobia. Arch. Gen. Psychiatry, 25:204-207. Herjanic, B. & Campbell, W. (1977), Differentiating psychiatrically disturbed children on the basis of a structured interview. J. Abnorm. ChildPsychol., 5:127-134. Hersov, L. A. (1960a), Persistent non-attendance at school. J. Child Psychol. Psychiatry, I: 130-136. - - (1960b), Refusal to go to school. J. Child Psychol. Psychiatry, 1:137-145. Hollingshead, A. B. (1957), Two Factor Index ofSocial Position (available from 1965 Yale Station, New Haven, Conn.). Kolvin, I., Berney, T. P. & Bhate, S. R. (1984), Classification and diagnosis of depression in school phobia. Br. J. Psychiatry, 145:347357. Kovacs, M. & Beck, A. (1977), An empirical-clinical approach toward a definition of childhood depression. In: Depression in Childhood, ed. J. G. Schulterbrandt & A. Raskin. New York: Raven Press, pp. 1-25. Kraft, I. A., Ardali, C., Duffy, J. H., Hart, 1. T. & Pearce, P. (1965), A clinical study of chlordiazepoxide used in psychiatric disorders of children. International Journal ofNeuropsychiatry , 1:433-437. Lang, M. & Tisher, M. (1978), Children's Depression Scale. Melbourne: Australian Council for Educational Research. McDonald, J. E. & Sheperd, G. (1976), School phobia: an overview. Journal ofSchool Psychology, 14:291-306. Pfefferbaum, B., Overall, J. E., Boren, H. A., Frankel, L. S., Sullivan, M. P. & Johnson, K. (1987), Alprazolam in the treatment of anticipatory and acute situational anxiety in children with cancer. J. Am. Acad.

ChildAdolesc. Psychiatry, 26:532-535. Poznanski, E. 0., Freeman, L. N. & Mokros, H. B. (1985), Children's depression rating scale-revised (September 1984). Psychopharmacol. Bull. ,21:979-989. Preskorn, S. H., Weller, E. B., Weller, R. A. & Glotzbach, E. (1983), Plasma levels of imipramine and adverse effects in children. Am. J. Psychiatry, 140:1332-1335. - - - - - - (1982), Depression in children: relationship between plasma imipramine levels and response. J. Clin. Psychiatry, 43:450453. Puig-Antich, J., Perel, 1. M., Lupatkin, W. et al. (1987), Imipramine in prepubertal major depressive disorders. Arch. Gen. Psychiatry ,44: 8189. Reynolds, C. R. & Richman, B. O. (1978), What I think and feel: a revised measure of children's manifest anxiety. J. Abnorm. Child

Psychol.,6:271-280. Schmitt, B. D. (1971), School phobia-the great imitator: a pediatrician's viewpoint. Pediatrics,48:433-441. Simeon, J. G. & Ferguson, H. B. (1987), Alprazolameffectsofchildren with anxiety disorders. Can.J. Psychiatry, 32:570-574. Tisher, M. (1983), School refusal: a depressive equivalent? In: Affective Disorders in Childhood and Adolescence: An Update, eds. D. P. Cantwell & G. A. Carlson. New York: Spectrum Publications, Inc., pp.129-144. Waldron, S., Shrier, D. K., Stone, B. & Tobin, F. (1975), School phobia and other childhood neuroses: a systematic study of the children and theirfamilies. Am.J.Psychiatry, 132:802-808.

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