A Double-blind Placebo Controlled Study of Desipramine in the Treatment of ADD: III. Lack of Impact of Comorbidity and Family History Factors on Clinical Response

A Double-blind Placebo Controlled Study of Desipramine in the Treatment of ADD: III. Lack of Impact of Comorbidity and Family History Factors on Clinical Response JOSEPH BIEDERMAN, M.D., ROSS 1. BALDESSARINI, M.D., VIRGINIA WRIGHT, B.A., KATE KEENAN, B.A., AND STEPHEN FARAONE, PH.D. Abstract. A 6-week randomized, double-blind, placebo controlled trial of desipramine (DMI) in daily doses averaging 4 to 5 mglkg for the treatment of children and adolescents with attention deficit disorder with hyperactivity (ADDH) was further analyzed. Investigators examined whether comorbidity of ADDH with conduct disorder, major depression, an anxiety disorder, or a family history of ADDH predicted response to DMI treatment. There was a highly significant effect of treatment with DMI in outcome assessments, but responses to DMI were indistinguishable in ADDH patients with and without a comorbid disorder or familial ADDH. Cases of "pure" ADDH (lacking comorbidity with depression, anxiety, or conduct disorder and having a positive family history of ADDH) showed a trend toward lesser placebo responses and a corresponding greater DMI-placebo difference. These findings suggest that (I) DMI is effective in simple, noncomorbid cases, (2) DMI is not selective for comorbid cases, but (3) a response to DMI can be obtained even in complex cases of ADDH with associated comorbidity. J. Am. Acad. Child Adolesc. Psychiatry, 1993, 32, I: 199-204. Key Words: attention deficit disorder, desipramine, children, adolescents, comorbidity. The authors previously reported results of a 6-week randomized, double-blind, placebo controlled trial of the tricyclic antidepressant (TCA) drug desipramine hydrochloride (DMI) for the treatment of children and adolescents with attention deficit disorder with hyperactivity (ADDH) (Biederman et aI., 1989a). Clinically and statistically significant differences in behavioral improvement over placebo were found at an average daily dose of DMI of 4.6 mg/kg. DMI was well tolerated, even at the relatively high doses employed, and only minor, but statistically significant, increases in diastolic blood pressure, heart rate, and electrocardiographic conduction parameters were found (Biederman et aI., 1989b). These findings indicated that DMI is an effective treatment for pediatric patients with ADDH. However, the reported results did not provide information as to whether some identifiable patients are more Accepted January 16, 1992. Dr. Biederman is Chiefofthe Pediatric Psychopharmacology Unit, Massachusetts General Hospital, and Associate Professor of Psychiatry, Consolidated Department ofPsychiatry, Harvard Medical School; Dr. Baldessarini is Director of Laboratories of Psychiatric Research, Mailman Research Center, McLean Hospital, and Professor of Psychiatry and in Neuroscience, Consolidated Department ofPsychiatry, Harvard Medical School; at the time this study was conducted, Ms. Wright and Ms. Keenan were with the Pediatric Psychopharmacology Unit, Massachusetts General Hospital; Dr. Faraone is Director of Research, Pediatric Psychopharmacology Unit, Massachusetts General Hospital, and Assistant Professor of Psychiatry, Consolidated Department of Psychiatry, Harvard Medical School. This work was supported, in part, by grants from Merrell-Dow Pharmaceutical Company and the Charlupski Foundation (to J. B.) as well as USPHS (NIMH) award and grants MH-31154, MH-36224, and MH-47370 (R. J. B.). Reprint requests to Dr. Biederman, Pediatric Psychopharmacology Unit, ACC 725, Massachusetts General Hospital, 15 Parkman Street, Boston, MA 02114. 0890-8567/93/3201-Q199$03.00/0©1993 by the American Academy of Child and Adolescent Psychiatry. J. Am. Acad. Child Adolesc. Psychiatry, 32:1, January 1993

likely to respond to DMI treatment than were others. Because ADDH probably is a heterogeneous disorder (Bieder.man et aI., 1991), it is important to try to identify children who are especially likely to respond to specific therapeutic interventions. One approach aimed at identifying potentially meaningful subgroups among ADDH patients considered comorbidity (Biederman et aI., 1991) and family history (Biederman et aI., 1992). There is increasing recognition that ADDH is a heterogeneous disorder with considerable comorbidity with conduct, depressive, and anxiety disorders (Biederman et aI., 1991). Stratification of ADDH patients based on the presence or absence of other psychiatric diagnoses may help identify more homogeneous subgroups within ADDH and may lead to refinements in their treatment (Biederman et aI., 1991). Family studies consistently have found relatives of ADDH probands to be at increased risk for ADDH (Biederman et aI., 1986; Biederman et aI., 1990; Biederman et aI., 1992; Cantwell, 1972; Loney et aI., 1982; Morrison and Stewart, 1971; Morrison, 1980; Schachar and Wachsmuth, 1990; Stewart et aI., 1980, Weiner et aI., 1977), suggesting that familial ADDH may represent another subtype of ADDH worthy of further investigation with respect to treatment responses. This report examines findings from our controlled DMI study and evaluates whether comorbidity of ADDH with conduct disorder (CD), major depressive disorder (MDD), an anxiety disorder (ANX), or a family history (FH) of ADDH predicts the response to DMI treatment. Because TCAs can have beneficial effects on mood and anxiety disorders, it was predicted that subgroups of patients with ADDH and an associated mood or anxiety disorder would respond more favorably to DMI than would ADDH patients without these comorbid diagnoses. Similarly, because familial ADDH may be a more homogeneous subtype, it also was

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predicted that a positive family history would be associated with a better response to DMI than would non-familial cases. Methods The clinical methods employed are detailed in earlier reports (Biederman et al., 1989a; Biederman et aI., 1989b). Briefly, patients were drawn from consecutive referrals to the Pediatric Psychopharmacology Unit and Child Psychiatry Service of the Massachusetts General Hospital in Boston. Patients ranged in age from 6 to 17 years; 42 children were younger than 12 years, and 20 adolescents were aged 12 to 17 years. All patients met clinical criteria for a DSM-III (American Psychiatric Association, 1980) diagnosis of ADDH, manifested symptoms in at least two of three settings (home, school, clinic), and attained a score of 2: 15 (out of 30) on the Conners Abbreviated Questionnaire (Guy, 1976) by parent or teacher. The trial used a 6-week, doubleblind, parallel group, placebo-controlled protocol. Patients were assigned randomly to receive DMI (N = 31) or an equivalent amount of placebo (N = 31) in identical-appearing tablets. The dose was increased to the nearest convenient number of tablets to seek a dose 2: 5.0 mg/kg given in two portions daily, by week 3. Response to treatments was assessed using the Conners Abbreviated Questionnaires (10 items, maximum score = 30) which were completed by parents (weekly) and teachers (pre- and end-of-treatment) and physician-rated Clinical Global Impression (CGI) Scale (National Institute of Mental Health [NIMH], 1985a) (weekly), which includes ratings of Global Severity (1 = not ill to 7 = extremely ill), Global Improvement (GI; 1 = very much improved to 7 = very much worse), and an Efficacy Index (EI; 1 = markedly improved with no side effects to 16 = worse with marked side effects). The Children's Depression Inventory (CDI) (Kovacs, 1985) (maximum score = 54) was completed independently by each subject and mother before and at the end of treatment to evaluate depressive symptoms. Adverse effects during treatment were assessed systematically at each weekly clinical contact with the physician-rated Subjective TreatmentEmergent Symptoms Scale (STESS) (National Institute of Mental Health [NIMH], 1985b). The patients and all available first-degree biological relatives were evaluated using structured diagnostic interviews by trained evaluators as reported elsewhere (Biederman et aI., 1986; Biederman et aI., 1990). Evaluators were held "blind" to clinical diagnosis, treatment, or response. Psychiatric assessments of probands and their siblings were based on interviews with their mothers, using the Diagnostic Interview for Children and Adolescents-Parent Version (DICA-P) (Herjanic and Campbell, 1977; Herjanic and Reich, 1982). Assessments of parents were based on direct interviews with each parent, using the National Institute of Mental Health Diagnostic Interview Schedule (NIMH-DIS) (Robins et aI., 1981; Vonkorff and Anthony, 1982) for adult disorders, with an addendum based on the DICA-P (Herjanic and Campbell, 1977; Herjanic and Reich, 1982) to cover childhood disorders. Kappa coefficients of agreement between raters were> 0.95 for diagnoses of children and adults except major depression in adults (K = 0.83). A positive 200

family history for ADDH was defined by the presence of DSM-III ADDH in at least one first-degree biological relative. Comorbidity data were obtained for 55 patients and family data for 48. In this analysis of the effects of treatment outcome, data were examined after stratification of probands into nonmutually exclusive subgroups based on the presence of a comorbidity with conduct disorder (ADDH+CD; 94% males; 72% children younger than 12 years), major depressive disorder (ADDH+MDD; 87% males; 53% children), an anxiety disorder (separation anxiety, overanxious, avoidant, or phobic disorder; ADDH+ANX; 83% males; 83% children) and the presence of a family history of ADDH (+FH ADDH; 90% males; 72% children). Eighty two percent of subjects (N = 45) had at least one comorbidity. Differences between clinical effects associated with DMI and placebo were expressed as percent change scores on outcome measures calculated for each subject as: ([end baseline]/baseline) X 100. Data were analyzed by two-factor ANOVA with repeated measures on one axis (main effect A = before vs. during treatment; main effect B = comorbidity vs. no comorbidity; and interaction effect = A X B). All analyses were two-tailed, and statistical significance was defined at the 5% level; data are reported as means::!: SEM unless otherwise stated. Results Responses to DMI were indistinguishable in ADDH patients with and without comorbid conduct disorder, major depression, or an anxiety disorder, and in those with and without familial ADDH (Table 1). Outcome was assessed with physician's (Clinical Global Severity), parent (Abbrevia:ted Parent Conners), and teacher (Abbreviated Teachers Conners) measures. ANOVA revealed a highly significant (all p < 0.001) effect of DMI with respect to all three of these outcome assessments. The effect of DMI treatment on the CDI, as a measure of depression, was superior to that of placebo in all subgroups, particularly in the ADDH + MDD comorbid subgroup, for whom differences attained statistical significance (Table 1). An interaction effect was observed between treatment responses (Abbreviated Parent and Abbreviated Teachers Conners questionnaires) and the presence of major depression. In addition, no significant effect was detected for any other form of comorbidity or for the familial ADDH subtype and, with the exception of the ADDH + MDD comorbid subgroup, no interaction effects were detected. Although differences between DMI and placebo in the subgroups with and without comorbidity or a positive family history of ADDH were of similar magnitude, DMI versus placebo differences attained statistical significance for ADDH + CD and for + FH only (Figure 1). It is of note that no placebo response was found in the familial subgroup. To better assess the overall impact of comorbidity in treatment response, global improvement data were analyzed by stratifying the sample by the presence of at least one comorbidity (ADDH + any comorbidity). This analysis revealed that the DMI (N = 23) vs. placebo (N = 22) response in patients with ADDH + any comorbidity was 70% vs. 9% (p < 0.0001), and J. Am. Acad. Child Adolesc. Psychiatry, 32: 1, January 1993

DESIPRAMINE IN ADD TABLE

I. Comorbidity Subgroups and Placebo vs. DMI Response (% Change) in Pediatric ADDH

Clinician's Global Rating

Comorbidity Subgroup ADDH ± conduct disorder Placebo (N = 15) DMI (N = 17) Effect A Effect B A X B interaction ADDH + major depression Placebo (N = 7) DMI (N = 8) Effect A Effect B A X B interaction (F,p) ADDH ± anxiety disorder Placebo (N = II) DMI (N = 7) Effect A Effect B A X B interaction ADDH ± family history of ADDH Placebo (N = 23) DMI (N = 25) Effect A Effect B A X B interaction

9.2 ± 6.1 33.3 ± 5.4 F = 25.6, p = 0.0001

NS NS 8.6 ± 8.6 34.6 ± 6.2 19.9, P = 0.0001

NS NS 15.0 ± 8.5 37.4 ± 9.1 21.5, p = 0.0001

NS NS 8.0 ± 5.0 36.9 ± 5.3 F = 22.4, p = 0.0001

NS NS

Abbreviated Parent Conners

Abbreviated Teacher Conners

9.9 ± 7.2 42.7 ± 5.9 24.8, P = 0.0001

19.4 ± 10.4 32.9 ± 7.7 21.1, p = 0.0001

NS NS

NS NS

27.1 ± 10.9 39.3 ± 10.4 11.9, P = 0.001

21.4 ± 9.8 23.8 ± 8.8 6.3, p = 0.02

NS

NS = 0.004

5.06, p = 0.03

9.22, p

15.3 ± 8.9 43.8 ± 5.7 20.4, p = 0.0001

- 7.7 ± 12.9 26.8 ± 12.1 16.4, p = 0.0002

NS NS

NS NS

3.1 ± 4.3 42.7 ± 5.5 17.7, p = 0.0001

1.6 ± 8.2 45.3 ± 7.6 19.3, p = 0.0001

NS NS

NS NS

Children's Depression Inventory - 9.0 ± 27.4 23.8 ± 13.2 3.7, p = 0.06

NS NS - 9.5 ± 22.6 41.2 ± 16.8 4.8, P = 0.03

NS NS 4.8 ± 13.4 22.0 ± 21.4 4.1, p = 0.05

NS NS - 22.2 ± 21.8 25.5 ± 14.5 3.46, p = 0.07

NS NS

Note: Data are means ± SEM; (-) implies worsening. Effect A = treatment baseline vs. endpoint, Effect B + comorbidity or family history vs. (-) comorbidity or family history.

for patients with no comorbidity, DMI (N = 5) vs. placebo (N = 5) responses were 80% vs. 0% (p = 0.05). Correlation analysis failed to reveal any significant association (r = 0.18) between the number of comorbid disorders and the improvement score in the CGI. Also, there were no differences in the rate of side effects when they were examined by comorbidity or family history. Discussion

Contrary to our expectations, neither comorbidity with depression, anxiety, or conduct disorder nor a family history of ADDH yielded differential responses to DMI treatment that could be distinguished from those observed in children without such characteristics. Overall, the response rates of DMI-treated patients with and without comorbidity or a positive family history of ADDH were much higher than that of placebo-treated cases, with improvement in characteristic symptoms of ADDH as reported by parents, teachers, and physician's ratings. Moreover, response in ADDH was not accounted for by the presence of DMI-responsive comorbidity as indicated by the finding that comorbidity with any of the assessed disorders increased the likelihood of a placebo response but did not change the response to DMI. It is also noteworthy that no placebo response was found in the familial subgroup. These findings suggest that response to DMI is due to its effects on ADDH and not the comorbid disorders. It is also possible these findings may have resulted from the high efficacy of treatment with DMI, so that little variance remained to be explained by the subtypes investiJ. Am. Acad. Child Adolesc. Psychiatry, 32:1, January 1993

gated. Nonetheless, these results indicate that a robust response to DMI can be obtained even in complex cases with associated comorbidity. Available research indicates that comorbid symptoms and disorders develop commonly among persons with ADDH in childhood, adolescence, and adulthood, and that their manifestation may not be benign (Biederman et aI., 1991). If not recognized and treated early, the combination of comorbid illness and ADDH may lead to high morbidity and disability with a poor long-term prognosis (Biederman et aI., 1991). For example, there is increasing evidence that children with ADDH plus conduct disorder, compared with those without, may have particularly severe dysfunction with increased risk fOr delinquency, criminality, and substance abuse (Mannuzza et aI., 1989). Although research on ADDH plus depressive or anxiety disorders is evolving (Biederman et aI., 1991a; Biederman et aI., 1991b), available evidence suggests that when ADDH occurs with depressive or anxiety disorders, it often is associated with severe morbidity and poor long-term outcome (Biederman et aI., 1991). Despite increasing recognition that ADDH is a probable heterogeneous disorder, little attention has been paid to the impact of comorbidity on treatment response. In recent studies of the effects of methylphenidate on ADDH children with and without conduct disorder (Barkley, 1989; Barkley et aI., 1989; Klorman et aI., 1988a; Klorman et aI., 1989; Klorman et aI., 1988b), both subgroups demonstrated positive cognitive, attentional, and academic improvements. Consistent with the hypothesis that clinical subtypes might 201

BIEDERMAN ET AL.

100

100

A.

CONDUCT DISORDER

80

p<.OO I

p<.O 1

p<.OO 1 60

40

40

20

20

N=t5

N-17

PRESENT

N=12

N= 11

0

N=7

ABSENT

100

MAJOR DEPRESSION

80

60

0

B.

N-8

PRESENT

N=20

N=20

ABSENT

100

C.

D.

ANXIETY DISORDER

80

P<.OO I

FAMILY HISTORY OF ATTENTION OEFI CIT HYPERACTI VITY 01 SORDER

80 p<.05

60

60

40

40

20

20

0

N= 11

N=7

PRESENT Open bars = placebo-treated SUbjects;

N=16

N=21

0

ABSENT

N=14

N=15

PRESENT

N=9

N=IO

ABSENT

Shaded bars= DM 1- treated sUbjects

FIG. I. Rates of improvement stratified by comorbidity and family history.

predict differential treatment responses, Garfinkel et a!. (1983) reported that stimulants were superior for symptoms of inattentiveness while TCAs were superior for symptoms of depression in children with ADDH. In contrast to the potential antianxiety (Biederman, 1990) and antidepressant (Garfinkel et a!., 1983; Pliszka, 1987) effects of DMI, there is evidence that stimulants can induce anxiety (Gittelman and Koplewicz, 1986; Swanson et aI., 1978) or depression (Barkley, 1977; Barkley, 1990; Gittelman and Koplewicz, 1986; Wilens and Biederman, 1992) in some children. There is also some evidence that children with ADDH who are highly anxious or depressed have a poorer response to stimulants than those not affected by these symptoms (Voelker et aI., 1983). Our findings indicate that DMI-treated pediatric ADDH patients showed a substantial reduction in depressive symptoms compared with placebo-treated patients (Biederman et a!., 1989a). Also, the similarly successful treatment outcome that was observed for measures of ADDH in children with and without comorbid major depression or an anxiety disorder suggests that DMI may be a particularly appropriate choice of treatment in children with those comorbidities and ADDH. Our results, added to the several other studies already discussed, provide 202

support for the suggestion that a TCA may be superior to a stimulant in cases of ADDH when depression or anxiety are prominent comorbidities. Although differences between DMI and placebo in the subgroups with and without comorbidity or a positive family history of ADDH were of similar magnitude to those found in the other subgroups, only findings for ADDH + CD and + FH attained statistical significance (Fig. I). This outcome was most likely owing to the limited statistical power in some of the comorbidity subgroups. Power tables show that to attain 80% power with a level of significance of 5% and a large effect size, at least 31 subjects will be needed (Cohen, 1977). In this study, the sizes of the ADDH + ANX (N = 18) and ADDH + MDD (N = 18) subgroups were not large enough to show a significant result. Although statistical power was lacking to examine adequately the specificity of TCA treatment in "pure" ADDH (absence of depression, anxiety, or conduct disorder and presence of a positive family history of ADDH) versus complex or nonfamilial cases, it is noteworthy that "pure" cases showed a trend toward lesser placebo response and a correspondingly greater DMI versus placebo difference (Fig. I). These findings suggest that DMI is not selective for comorJ. Am. A cad. Child Ado/esc. Psychiatry, 32: I, January 1993

DESIPRAMINE IN ADD

bid cases but can be effective also in simple, noncomorbid cases. Treatment with DMI (especially at daily doses of above 3.5 mg/kg or at serum levels higher than 150 ng/mL) may increase the risk of asymptomatic electrocardiographic changes (especially of slight prolongation of the PR interval, as well as moderate increases in QRS duration) indicative of delayed cardiac conduction, as well as minor increments in diastolic blood pressure and heart rate (Biederman, 1991). The full clinical implications of these findings are not yet clear and require further investigation as it is not certain whether minor cardiac conduction deficits predict later, evidently rare, adverse cardiovascular effects (Biederman et aI., 1989b; Biederman, 1991). Careful consideration of the risks and benefits of treatment with DMI recently has received added attention with the report of three cases of sudden death in 8- to 9-year-old children during routine treatment with DMI (The Medical Letter, 1990). In cases of ADDH children who failed to respond to conventional treatment with stimulants or in those with severe comorbidity, the remote possibility of a serious complication should be weighed against a much higher risk for psychiatric morbidity, distress, incapacitation, severe demoralization and failure, substance abuse, delinquency and criminality, suicide and homicide that can be associated with the disorders for which treatment with DMI could be helpful (Biederman, 1991). In conclusion, the present analysis adds to clinical experience with DMI in ADDH, indicating that DMI may be an effective and well-tolerated treatment for ADDH children with associated conduct, depressive, or anxiety disorders and may be especially superior to placebo in "pure" and familial subtypes of ADDH. Studies with larger samples are needed to test these initial impressions further and to evaluate whether daily doses of TCA as high as 4 to 5 mg/kg are required in patients with and without comorbidity or familiality. References American Psychiatric Association (1980), Diagnostic and Statistical Manual of Mental Disorders 3rd edition (DSM-III). Washington, DC: American Psychiatric Association. Barkley, R. A. (1977), A review of stimulant drug research with hyperactive children. J. Child Psycho!. Psychiatry, 18:137-165. Barkley, R. A (1989), Hyperactive girls and boys: stimulants drug effects on mother-child interactions. J. Child Psycho!. Psychiatry, 30:379-390. Barkley, R. A. (1990), Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. New York: The Guilford Press. Barkley, R. A, McMurray, M. B., Edelbrock, C. S. & Robbins, K. (1989), The response of aggressive and nonaggressive ADHD children to two doses of methylphenidate. J. Am. Acad. Child Adolesc. Psychiatry, 28:873-881. Biederman, J. (1990), The diagnosis and treatment of adolescent anxiety disorders. J. Clin. Psychiatry, 51 :20--26. Biederman, J. (1991), Sudden death in children treated with a tricyclic antidepressant: a commentary. J. Am. Acad. ChildAdolesc. Psychiatry, 30:495--497. Biederman, J., Munir, K., Knee, D., Habelow, W., Armentano, M., Autor, S., Hoge, S. K. & Waternaux, C. (1986), A family study of patients with attention deficit disorder and normal controls. J. Psychiatr. Res., 20:263-274.

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