A Double-Blind Placebo Controlled Study of Desipramine in the Treatment of ADD: I. Efficacy

A Double-Blind Placebo Controlled Study of Desipramine in the Treatment of ADD: I. Efficacy JOSEPH BIEDERMAN, M.D., ROSS J. BALDESSARINI, M.D., VIRGINIA WRIGHT, B.A., DEBRA KNEE, B.A., AND JEROLD S. HARMATZ Abstract. The tricyclic antidepressant drug desipramine (OMI) was evaluated in the treatment of young patients with attention deficit disorder with hyperactivity (AOOH) in an unselected sample of 62 clinically referred patients, 43 (69%) of whom previously responded poorly to psychostimulant treatment. The 42 children and 20 adolescents were assigned randomly to receive OMI (N = 31) or placebo (N = 31) for up to 6 weeks in a parallel groups, double-blind study. Clinically and statistically significant differences in behavioral improvement were found for OMI over placebo, at an average (±SEM) maximal daily dose of 4.6 ± 0.2 mg/kg; 68% of OM I-treated patients were considered very much or much improved, compared with only 10% of placebo patients (p < 0.001). OMI was well tolerated, even at the relatively high doses used. These findings suggest that OMI can be an effective treatment in the management of pediatric patients with ADDH, including patients who failed to respond to stimulants. J. Am. Acad. Child Adolesc. Psychiatry, 1989, 28, 5:777-784. Key Words: attention deficit disorder, desipramine. there is little information regarding appropriate pharmacotherapy in the older age groups despite the increasingly frequent recognition of such patients (Varley, 1985). Concerns about treating adolescents with stimulant medication include at least the hypothetical risk of abuse and dependence by the patient or his associates (Goyer et al., 1982), and the common dislike by adolescents of the subjective effects of stimulant medication (Sleator et al., 1982). These problems encourage the search for effective and safe alternatives to stimulant drugs in the treatment of ADDH. Tricyclic antidepressants (TCAs), mainly imipramine, have been proposed as an alternative treatment for this disorder (Gross, 1973; Huessy and Wright, 1970; Krakowski, 1965; Kupietz and Balka, 1976; Watter and Dreyfus, 1973; Zametkin and Rapoport, 1983). Possible advantages of TCAs over stimulants include a longer duration of action and the feasibility of once-daily dosing without symptom-rebound or insomnia, greater flexibility in dosage, the readily available option of monitoring plasma drug-levels (Preskorn et al., 1983), and minimal risk of abuse or dependence (Gittelman, 1980; Rapoport and Mikkelsen, 1978). Initial open trials (Gross, 1973; Huessy and Wright, 1970; Krakowski, 1965; Kupietz and Balka, 1976; Watter and Dreyfus, 1973), were followed by controlled studies (Greenberg et al., 1975; Rapoportetal., 1974;Waizeretal., 1974;Werry, 1980;Winsberg

Stimulants have been used widely in the treatment of attention deficit disorder with hyperactivity (ADDH). Yet, as many as 30% of children so treated do not improve (Barkley, 1977; Biederman and Jellinek, 1984). Because stimulants are short-acting drugs, their use is complicated by the need to take medicine in school and by a sometimes troublesome reemergence of symptoms on weekends and in the evening hours at home (Porrino et al., 1983). In addition, insomnia, dysphoric mood, tics, and some slowing of growth during development may occur with such treatment (Gittelman, 1980). Furthermore, although the ADDH syndrome and associated psychiatric symptoms can persist into adolescence and adulthood in at least 30% to 50% of patients who manifest ADDH as children (Gittelman et al., 1985; Weisset al., 1985), Accepted April 25, 1989. Dr. Biederman. Ms. Wright. and Ms. Knee are with the Pediatric Psychopharmacology Unit. Massachusetts General Hospital. Boston. MA. Dr. Biederman is also associated with the Department of Psychiatry. Harvard Medical School. Boston. Dr. Baldessarini is associated with the Department ofPsychiatry and the Neuroscience Program of Harvard Medical School and the Mailman Research Center, McLean Hospital, Belmont. MA. Mr. Harmatz is with the Division of Clinical Pharmacology, Tufts University School of Medicine and New England Medical Center. Boston, MA. This work was supported in part by grants from Merrell-Dow Pharmaceutical Company and the Charlupski Foundation (to J.B.). as well as USPHS (N1MH) award and grants MH-31 154, MH-36224, and MH-47370 (R.J.B.). The authors thank Peter Rosenberger. M.D.. David Gastfriend. M.D .. and Kate Keenan for their help with this project. and Michael Jellinek, M.D .•for encouragement. Partial abstracts and preliminary presentations of some material in this manuscript werepresented at Annual Meeting. NCDEU. 1987; Annual Meeting. American Academy of Child and Adolescent Psychiatry. New Research Section, 1987; and Annual Meeting. American Psychiatric Association. 1988. Reprint requests to Dr. Biederman, Pediatric Psychopharmacology Unit. ACC 625. Massachusetts General Hospital. 15 Parkman Street, Boston. MA 02JJ4. 0890-8567/89/2805-Q777$02.00/0© 1989 by the American Academy of Child and Adolescent Psychiatry.

et al., 1972; Yepes et al., 1977) that generally showed TCAs

to be superior to a placebo, although not always as effective as methylphenidate. Desipramine (DMI) has not been well studied in pediatric populations until recently. Although similar to its precursor imipramine, DMI has relatively high selectivity against neuronal uptake of norepinephrine and, like other TCAs, appears eventually to enhance functional availability of norepinephrine and its activity at central alpha-I adrenergic receptors (Baldessarini, 1985). Compared with other TCAs, DMI has relatively low affinity at muscarinic and histaminergic receptors and only moderate affinity at alpha-I-adrenergic receptors, and it is very weak against alpha-2, beta-adrenergic, and 777

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dopaminergic receptors (Baldessarini, 1985). Because of its pharmacologic properties, DMI may be associated with somewhat lesser risks of adverse effects than the tertiary-amine TCAs such as amitriptyline, clomipramine, doxepin, and imipramine. Several open (Biederman et aI., 1986; Gastfriend et aI., 1984, 1985) and controlled (Donnelly et aI., 1986; Garfinkel et aI., 1983) studies have investigated the efficacy and toxicity of DMI in children with ADDH. In a double-blind, placebocontrolled, crossover study of 3 weeks duration for each phase, Garfinkel et al. (1983) compared the effects of methylphenidate, clomipramine, DMI, and placebo in 12 prepubertal boys with ADDH using daily doses of the TCAs up to 3.5 mg/kg, DMI and clomipramine were more beneficial than placebo, but somewhat less so than methylphenidate, in improving attentional and behavioral symptoms of ADDH; there was no improvement in cognitive performance with either of the TCA treatments. There were no important adverse effects and only mild increases in pulse rate and diastolic blood pressure were associated with all active drugs. Donnelly et al. (1986) studied 29 boys aged 6 to 12 years with ADDH in a parallel groups, double-blind, placebo-controlled study: 17 received DMI (mean daily dose, 3.4 mg/kg) and 12 received placebo for 14 days. Behavioral improvement with DMI was detected as early as day 3 and was sustained over the 2 weeks of the study. There were no important adverse effects, and only mild increases in pulse rate and diastolic blood pressure, with DMI treatment. The authors have also reported favorable results in open, dose ranging, long-term trials of DMI in an unselected group of 12 adolescents (Gastfriend et aI., 1984, 1985) and 18 children (Biederman et aI., 1986) with ADDH, using daily doses of up to 5 mg/kg that were continued for up to 1 year. In these studies, 73% of the 30 patients had received pharmacologic treatments previously with an inadequate response or intolerable adverse effects but, after a mean period of 27 weeks (range 4-52 weeks) of follow-up, 80% of the patients were considered moderately or markedly improved on DMI. Adverse effects were mild, most appeared in the first 4 weeks of treatment, and were alleviated by dose reduction. Because of remaining uncertainties about the safety of TCAs in children, the authors also evaluated systematically the short- (4 to 12 weeks) and long- (13 to 52 weeks) term effects of DMI treatment on the cardiovascular system (Biederman et aI., 1985) but found no symptomatic cardiovascular effects and only minor ECG changes associated with DMI treatment in daily oral doses as high as 5 mg/kg. Based on these preliminary studies and clinical experience with DMI, it was hypothesized that DMI at daily doses up to 5 mg/kg can be a safe and effective treatment for children and adolescents with ADDH. The present study reports the effects of DMI in a prospective, double-blind, placebo-controlled study of a total of 62 children and adolescents with ADDH. This is one of the largest experimental therapeutic trials of ADDH and the largest controlled trial of DMI in the pediatric population. Method Patients were drawn from consecutive outpatient referrals to the Pediatric Psychopharmacology Unit and Child Psychiatry Service of the Massachusetts General Hospital, Bos-

ton. All but two patients initially considered for study (N = 73) met clinical criteria for DSM-III ADDH, manifested symptoms in at least two of three settings (home, school, clinic), and attained a score of 15 or more (out of 30) on the Conners Abbreviated Questionnaire by parent or teacher (see (Guy, 1976); two children, aged 7 and 15 years, met clinical criteria for ADD without hyperactivity. The clinical diagnosis was confirmed in each case by using the module on attention deficit disorder from the Diagnostic Interview for Children and Adolescents, Parent Version (DICA-P) (Herjanic and Reich, 1982; Orvaschel, 1985). No patient needed to be excluded by having mental retardation (full scale IQ < 70), autism, psychosis, or another medical or neurological disorder or by abnormal results of psychiatric and medical evaluations given, including routine laboratory tests and initial ECG. Eleven patients failed to complete the protocol. The 62 subjects completing at least 3 weeks of the protocol ranged in age from 6 to 17 years; 42 were younger than 12 years, and 20 were 12 or older. All drugs were discontinued for at least 1 week before entering the protocol. The trial was designed as a 6-week, double-blind, parallel groups, placebo-controlled protocol. Assenting patients were accepted into the study after their parents provided written informed consent under conditions approved by the hospital's Institutional Review Board. Patients were assigned randomly by a computer generated list to receive desipramine hydrochloride (DMI) (N = 31) or an equivalent amount of placebo (N = 31) in identical-appearing tablets. The dose was to be increased to the nearest convenient number of tablets to yield a dose ~5.0 rug/kg by week 3 and resulted in a daily dose of DMI (or the equivalent amount of placebo) of s5.6 mg/kg given in two portions daily. However, in 22/31 DMI (as well as 16/31 placebo) treated patients, the maximal dose had to be lowered or increased more slowly due to apparent adverse effects, but no further increments were made after week 5. Compliance with treatment was monitored by weekly pill counts. No other psychotropic agents or formal psychological or behavioral therapy were administered during the study. At the end of the study, placebo-treated patients who did not improve were offered an open trial of DMI and all study procedures were repeated for another 6 weeks. In addition, patients who responded to DMI could continue its use under clinical treatment conditions. After the final clinical ratings were obtained under doubleblind conditions, the treatment code was opened to facilitate final laboratory assessments as well as follow-up dispositions. To reduce costs, only DMI-treated patients had end-of-treatment blood and ECG testing. Blood was drawn by antecubital venepuncture at 12 hours after last prior dose of DMI, after a minimum of I week on a stable drug regimen, for assay of the approximately steady-state serum level of DMI, as well as liver function tests and a complete blood count. DMI was separated by high performance liquid chromatography (HPLC) and detected with dual wave-length ultraviolet spectrometry sensitive to 20 ng/ml; intra- and interassay coefficients of variation (SD/mean) were <3% and <5%, respectively. In addition to the baseline ECGs given to all subjects, the DMI-treated patients also had an end-of-treatment ECG at the same time as the blood studies. Laboratory tests and ECGs were performed by the clinical laboratories of Massa-

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chusetts General Hospital. Laboratory personnel were unaware of the patients' clinical status or response to treatment. DMI plasma levels and cardiovascular findings are reported separately (see Biederman et al., 1989). Response to treatment was assessed using the Conners Abbreviated Parent and Teacher Questionnaires (10 items, maximum score = 30) (Guy, 1976) completed by parents (weekly) and teachers (pre- and end-of-treatment); and physician-rated Clinical Global Impression (CGI) Scale (CGI, 1985) (weekly), which includes scales rating of Global Severity I = not ill, to 7 = extremely ill) and Global Improvement (GI, I = very much improved, to 7 = very much worse), and an Efficacy Index (I = markedly improved with no side effects, to 16 = worse with marked side effects). The Continuous Performance Task (CPT) (Conners, 1985) and Paired Associated Learning Task (PALT) (Swanson et aI., 1979; Swanson, 1985) were administered by a trained research assistant as laboratory measurements of cognition before and at the end of treatment. The Children's Depression Inventory (COl) (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 Treatment-Emergent Symptoms Scale (STESS, 1985), which records reported and observed new symptoms. In addition, sitting and standing pulse and blood pressures were recorded by the supervising research physician at each visit. Of the 73 patients screened, 62 (85%,31 in each treatment condition) completed at least 3 weeks of the study protocol to provide useable data. The II patients (15%) who terminated prematurely (before week 3) were not included in the data analysis: four never started the protocol for administra-

TABLE

tive reasons; one was dropped after a pharmacy error was discovered in which placebo was given in week I and DMI in week 2; five had incomplete data collections; and one patient developed a rash during the first week on DMI and was discontinued. Eight placebo and one DMI patient were terminated prematurely between weeks 3 and 6 due to a deteriorating clinical course but were included in the data analysis (end-of-treatment ratings). The final data base thus involved 62 patients; 31 received DMI and 31 placebo. 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. Treatments were contrasted by application of independent Student's z-tests to each dimension for continuous data and by Yates-corrected chi-square analyses for categorical data. All analyses were two-tailed, and statistical significance was defined conservatively at the J% level; all data are reported as mean ± SEM unless otherwise stated. Because of the large number of patients (43/62 = 69%) included who by chance had received prior treatment with a stimulant without adequate benefit or with intolerable adverse effects, differences between DMI and placebo were reexamined by repeating all study analyses for this subsample with a prior history of treatment refractoriness. Results Placebo and DMI treatment groups were similar in socioeconomic status (respectively, SES = 3.1 ± 0.2 vs. 3.3 ± 0.2, NS), full scale IQ (99.6 ± 2.8 vs. 103.3 ± 2.7, NS), male to female ratio (29/2 each), children to adolescents ratio (19/12 vs. 23/9, NS), and all but four patients (2 in each group) were Caucasian. Patients in the placebo and DMI groups (N = 31 each) also had similar clinical characteristics at baseline as

I. Clinical Characteristics ofSample at Baseline and End-Point Analysis ofImprovement (Percent Change)

Baseline Placebo

Overall Clinician's Global Severity" Conners Questionnaire-Parent" Conners Questionnaire-Teacher" Children's Depression Inventory' Adolescents" Clinician's Global Severity Conners Questionnaire-Parent Conners Questionnaire-Teacher Children's Depression Inventory Prior Treatment Refractory" Clinician's Global Severity Conners Questionnaire-Parent Conners Questionnaire-Teacher Children's Depression Inventory

End of Treatment DMI

Placebo ±SEM

% Change

8.0 11.4 12.6 -2.4

±3.8 ±5.1 ±8.0 ±12.7

33.8 42.1 36.4 30.2

±0.3 ±0.8 ±3.2 ±3.6

7.1 23.9 20.7 14.7

±6.6 ±8.5 ±11.4 ±6.7

32.3 45.1 27.7 46.7

±6.0 ±8.9 ±1O.8 ±20.1

±0.2 ±0.9 ±1.7 ±2.0

7.4 6.9 10.0 -24.8

±3.8 ±4.8 ±7.7 ±18.8

34.2 41.0 37.8 19.5

±4.1*" ±5.6*** ±5.4* ±13.1

Mean

±SEM

Mean

±SEM

5.1 22.8 17.3 18.3

±O.I ±0.8 ±1.3 ±1.3

5.2 21.8 18.5 16.1

±O.I ±0.7 ±1.2 ±1.4

4.9 23.1 19.1 17.5

±0.2 ±1.5 ±2.1 ±1.3

5.1 20.2 13.7 15.4

5.3 23.4 18.4 19.5

±O.I ± 1.0 ±1.4 ±1.6

5.1 21.9 19.6 17.4

% Change

DMI ±SEM ±3.4*** ±4.5** ±4.9** ±9.4t

Note: by unpaired z-test (two-tailed); alpha = 1%; t p < 0.05 (strong trend); * p < 0.0 I; ** p < 0.00 I; *** p < 0.000 I. Physician-rated Global Severity (I = not ill, 7 = extremely ill); N = 62. h Conners Abbreviated Parent and Teacher Questionnaires (10 items, maximum score = 30); N = 59. 'Children's Depression Inventory (COl, maximum score = 54), completed by mother; N = 57. d Since the number of participating adolescents was too small, no statistical tests were performed; data are presented for comparison purposes. 'Patients with a prior history of failure to at least one stimulant trial. a

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expressed by the presence of comorbid psychiatric disorders, including learning difficulties (74.2% vs. 77.4%, NS), conduct disorder (35.5% vs. 38.7%, NS), and oppositional disorder (45.2% vs. 51.6%, NS). The groups also were closely similar in baseline ratings pertaining to AOOH by clinicians, parents, and teachers (Table I), and in cognitive measures (PALT % errors = 57.6% ± 4.2% vs. 59.5% ± 2.9%, t = 0.4, dj= 48, NS; CPT errors of commission = 24.8 ± 6.7 vs. 33.7 ± 10.1, t = 0.7, df = 53, NS; CPT errors of omission = 13.4 ± 3.1 vs. 14.2 ± 2.8, t = 0.2, dj= 53, NS, each for placebo and OMI, respectively). By chance, the previously treatment-refractory patients were somewhat unevenly distributed between the two treatment groups (OMI group, 18 [58%] vs, placebo group, 25 [81%]; Xl = 2.7, dj= I, N = 62, p = 0.10). Daily doses (mg/kg) were similar for placebo and OMI treatment groups throughout the 6 weeks of the study (week 1 = 1.6 ± 0.1 vs, 1.8 ± 0.1; week 2 = 3.0 ± 0.2 vs. 3.0 ± 0.2; week 3 = 4.2 ± 0.3 vs. 4.0 ± 0.2; week 4 = 4.5 ± 0.2 vs. 4.3 ± 0.2; week 5 = 4.7 ± 0.1 vs. 4.6 ± 0.1; week 6 = 4.8 ± 0.1 vs. 4.6 ± 0.2). Because of occasional missing data and early dropouts, weekly ratings for weeks 1 + 2, 3 + 4, and 5 + 6, were combined to represent each 2-week period. While no significant differences in clinical efficacy between OMI and placebo were observed by weeks I + 2 at average daily doses of placebo and OMI of 2.4 ± 0.2 and 2.3 ± 0.2 mg/kg, respectively, differences were detected by weeks 3 + 4 (at average daily doses of 4.2 ± 0.2 and 4.4 ± 0.2 mg/kg) on Global Clinical Severity ratings (23.4% vs. 9.2% improvement, t = 2.3, df = 41, p = 0.03, trend) and Abbreviated Conners Parent Questionnaire scores (43.0% vs. 14.7% improvement, t = 4.0, df = 40, p = 0.001). This selective improvement on OMI was maintained by the end of the trial (weeks 5 + 6, 33.8% ± 3.4% vs. 9.1% ± 4.1%, t = 4.7, dj= 56, p = 0.0001 and 42.1% ± 5.1% vs. 14.1 % ± 4.9%, t = 3.9, df = 56, p = 0.0003 for Global Clinical Severity and Abbreviated Parent Conners Questionnaire, respectively) (Fig. I). End-point analysis (weeks 3 to 6) showed that 21/31 OMI subjects (68%) were considered very much (Clinical Global Improvement [CGI] score = I) or much (CGI = 2) improved compared with only 3/31 (10%) of placebo subjects (Xl = 22.0, df = I, p = 0.000 I). OMI patients showed significantly more improvement than placebo patients in clinician's ratings, parent's ratings, and teacher's ratings (Table I). In addition, OMI patients showed substantially more improvement in depressive symptoms as expressed in parental reporting, although this trend was not statistically significant at the 1% criterion (COl-Parent mean [±SEM] percent change = 30.2% ± 9.4% vs. -2.4% ± 12.7%, t = 2.0, dj= 51, P = 0.05, trend). Cognitive measures did not change significantly in either the OMlor placebo group (mean percent change for OMI vs. placebo, respectively: PALT = 14.0% ± 8.2% vs, 8.2% ± 7.5%, t = 0.5, dj= 47, NS; CPT errors of commission = 13.8 ± 2.8 vs. 12.4 ± 3.0, t = 0.3, df = 53, NS; CPT errors of omission, 14.6 ± 2.7 vs. 16.6 ± 4.5, t = -0.4, dj= 53, NS). Because there were relatively few adolescents in this study (N = 20: 8 given OMI, and 12 given placebo), statistical comparison of children and adolescents is not appropriate. Nevertheless, the patterns of mean changes in AOOH-related clinical outcome measures for the adolescents resembled those of the children (Table I; Fig. 2).

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The appreciably higher (but statistically not significant) proportion of subjects previously unresponsive to stimulant treatment assigned, by chance, to the placebo group (25/31) than the OMI-treated group (18/31) raised concerns that the findings might be biased by this unequal distribution of possibly more difficult cases so as to favor OMI and disfavor placebo. Accordingly, the data for all 18 treatment-resistant subjects given OMI were reanalyzed and compared to the first 18 treatment-resistant subjects given placebo. This secondary analysis replicated the findings for the entire sample (at similar levels of statistical significance) concerning differences in improvement scores between OMI and placebo (overall rate of improvement [Global Improvement ~2] = 0/18 vs. 13/18, Xl = 20.3, dj = I, p = 0.000 I) (Table I and Fig. 2). A similar analysis was carried out to evaluate the effects of depressive symptoms on clinical outcome by stratifying subjects into two groups by the baseline scores on the COl-Parent version below ("low") or above ("high") the median score of 17. No signifi-

781

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2. Rate of improvement in subgroups. Percentage of subjects improved (Clinical Global Improvement, CGI = I or 2) for DMI- (solid (12 to 17 years), and for those with a prior history of failure to at least one stimulant trial. By chi-square (two-tailed) DMI vs, placebo *** p < 0.0001. FIG.

bars) and placebo-treated patients (open bars) for the entire sample, for adolescents

cant differences in outcome measures between OMI and placebo were detected in subjects with relatively high vs. low depressive scores. Overall, OMI treatment was well tolerated at the relatively high doses given. Adverse effectsgenerally were mild and only slightly more common in association with OMI than with placebo treatment (risk of any adverse effect = 80.6% vs, 48.4% for OMI vs. placebo; x 2 = 5.7, df= I, p = 0.02, strong trend). However, no significant differences were found in the rate of individual adverse effects between the OMI and placebo groups. Commonly reported adverse effects for OMI and placebo were dry mouth (32.3% vs. 19.4%), decreased appetite (29.0% vs. 12.9%), headaches (29.0% vs. 9.7%), abdominal discomfort (25.8% vs. 19.4%), tiredness (25.8% vs. 12.9%), dizziness (22.6% vs. 9.7%), and trouble sleeping (22.6% vs. 6.5%). No patient developed a serious complication. Only one female patient (not included in data analysis) was dropped for a side effect (rash); she was later treated again with DMI without recurrence of the rash (Biederman et aI., 1988). Only two OMI subjects (6.5%) sustained a loss> 5% of initial weight, compared with 0% in the placebo group (x 2 = 0.52, df= I, NS). Of the 28 (of 31) unimproved placebo patients, 27 (96%) consented to an open-label, 6-week, cross-over follow-up trial of OMI using a similar protocol to that of the double-blind phase and all but one showed clinical benefit without clinically significant adverse effects. Overall, 26 (96%) of patients were considered very much (Clinical Global Improvement [CGI] = I) or much (CGI = 2) improved. The magnitude of improvement (mean ± SEM) on ratings by clinician (Global Severity = 2.9 ± 0.1), by parents (Abbreviated Conners =

56.0% ± 5.3%) and by teachers (Abbreviated Conners = 43% ± 7.1%) on ratings of AOO symptoms, as well as parents' ratings of depression scores (CDI-Parent = 45.8% ± 8.5%) was similar to that observed in OMI-treated patients under double-blind conditions. Discussion

In a 6-week, randomized, placebo-controlled trial of children and adolescents with AOOH, treatment with the TCA drug OMI at an average oral daily dose of 4.6 mg/kg was consistently more effective than a placebo. Overall, the response rate of OMI-treated patients (68%) was much higher than that of placebo-treated cases (10%). OMI patients showed statistically significant improvement in characteristic symptoms of AOOH as reported by parents and teachers as well as by physician's ratings, with a clinically meaningful end-point percent improvement from baseline scores on the order of 42%, 36%, and 34%, respectively. It should be emphasized that this study, by chance, included a high (43/62 = 69%) and unequally distributed proportion (42% assigned to DMI and 58% to placebo) of cases of prior failure rate on at least one trial of a psychostimulant. This sampling pattern may have introduced a positive bias to OMI and a negative bias to the placebo response, both tending to favor OMI, and may limit the generalizability of these findings to largely treatment-refractory patients. However, secondary analysis of response measures for a sample selected to provide equal numbers of treatment-resistant cases treated with OMI or placebo (N = 18 cases in each group) yielded very similar results to those reported for the complete study sample (N = 31 per group) (Table I, Fig. 2). Nevertheless, in future studies,

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BIEDERMAN ET AL.

it may be appropriate to stratify subjects by prior history of treatment refractoriness. Avoidance of refractory patients altogether may be less feasible. Thus, many families of previously untreated children refused to participate in this study of a novel treatment for ADDH, and opted instead for conventional treatments. Others could appreciate the potential benefits of the proposed treatment but still refused to participate in a study with a 50% risk of assignment to placebo treatment for 6 weeks. This experience highlights the difficulty in recruiting subjects for pharmacological trials in a disorder for which effective treatments are widely available. Even though the present study could not fully evaluate the impact of DMI treatment of ADDH at specific ages due to the relatively small numbers of patients at each year of age, and the limited number ofadolescents included (8 adolescents given DMI and 12 given placebo), the findings for the adolescents yielded similar results to those reported for the complete study sample (Table I, Fig. 2), suggesting that DMI may also be effective in older patients. These results are consistent with an earlier open study at the Center that also found beneficial effects of DMI in adolescents with ADDH (Gastfriend et al., 1984, 1985). Although data are limited, the available literature suggests that stimulants too-particularly methylphenidatemay be effective in the treatment of adolescents with ADDH (Klorman et al., 1987; Varley, 1985) although stimulants may be less than ideal agents for this age group, as discussed in the Introduction. The search for appropriate alternative treatments for ADDH, particularly for adolescents and adults, has recently received renewed impetus since it is now evident that about 20% to 30% of children respond unsatisfactorily to stimulants and that in about 50% of cases of ADDH diagnosed in childhood, symptoms persist into adolescence and at least early adulthood (Gittelman et aI., 1985; Weiss et aI., 1985). The possible efficacy of DMI in the treatment of older cases of ADDH awaits confirmation in other studies with larger numbers of adolescent as well as adequate trials in adult patients. The present study required 3 to 4 weeks to reach a significant drug versus placebo difference in benefits (Fig. I). This slow response, even to a maximum daily dose ofDMI, appears to be inconsistent with previous reports of a more rapid response to imipramine (Greenberg et al., 1975; Rapoport et al., 1974; Waizer et aI., 1974; Werry, 1980; Winsberg et aI., 1972; Yepes et al., 1977) or DMI (Donnelly et aI., 1986; Garfinkel et aI., 1983) in ADDH. For instance, Donnelly et al. (1986) detected beneficial behavioral effects with DMI by day 3 (when the mean daily dose was 1.8 mg/kg), and these were sustained for the 2-week duration of the study at an average daily dose of 3.4 mgJkg. The design of the present study, requiring 3 weeks to reach daily doses in the 4.0 to 5.0 mg/kg range for reasons of safety, may account for the relative delay in observed response . A relatively high target daily dose ofDMI in the 4 to 5 mg/ kg range was chosen based on inconsistent results reported with DMI at lower daily doses averaging 3.5 mgJkg (Donnelly et aI., 1986; Garfinkel et al., 1983) and based on the authors' experience in preliminary open studies (Biederman et al., 1986; Gastfriend et aI., 1984, 1985). This latter experience suggested that clinical benefits of DMI may be greater and more sustained (up to 12 months) (Biederman et aI., 1986;

Gastfriend et aI., 1984, 1985) at daily doses higher than those of 2.5 to 3.5 mg/kg typical of earlier studies of TCAs in children (Biederman and Jellinek, 1984; Gittelman, 1980; Rapoport and Mikkelsen , 1978). In both the authors' previously reported open trials (73%) (Biederman et aI., 1986; Gastfriend et aI., 1984, 1985) and the present controlled study (69%), most patients (71%) were previously refractory to, or had troublesome side effects on, stimulant therapy. Accordingly, it is possible that a requirement of relatively high doses of DMI may be selective for the treatment of stimulantrefractory ADDH patients. Thus, whether lower doses might be effective for newly treated or stimulant-responsive patients is not known and requires further investigation before broad clinical guidelines for the use of DMI in ADDH can be adequately specified. For the present time, in clinical practice, it is suggested that TCA treatment be individualized by slowly increasing doses, aiming to use the lowest effective dose, and be guided in children by clinical response, adverse effects, serum drug assays, and ECG monitoring (see Biederman et aI., 1989). Although this 6-week study was longer than the two previously reported DMI studies (Donnelly et al., 1986; Garfinkel et aI., 1983), its findings provide evidence only for the shortterm efficacy of DMI in the management of young patients with ADDH. It should be noted that Gittelman-Klein (1974), Rapoport et al. (1974), and Quinn and Rapoport (1975) have noted that imipramine, though indistinguishable from the stimulants during the initial phase of treatment, failed to have sustained clinical efficacy in a substantial proportion of children given relatively low doses «3.0 mgJkg daily) of that tertiary-amine TCA. Moreover, Gittelman-Klein (1974) found in some cases that "over time, new difficulties appeared, such as temper outbursts, aggressiveness, and antagonistic behaviors." Other adverse effects of doses of imipramine in the 5 rng/kg dose range have included excitement, nightmares, insomnia, muscle pain, increased appetite, abdominal cramps, hiccups, bad taste, sweating, and flushed face, as well as a syndrome of forgetfulness and perplexity with marked irritability (Rapoport and Zametkin, 1980). We have not observed such effects with prolonged use of DMI in open, long-term trials at daily doses above 3.5 mg/kg, and only mild adverse effects but moderate to marked improvement in 80% of the 12 adolescents and 18 children with ADDH after a mean follow-up period of more than 6 months (27 weeks, range 4-52 weeks) (Biederman et aI., 1986; Gastfriend et al., 1984, 1985). In the present study, DMI was well tolerated and there were no serious adverse effects. Only one patient was discontinued due to an apparent side effect (rash) but was later given DMI again without re-emergence of the rash. In addition, in contrast to the risk of treatment-emergent dysphoria (Gittelman, 1980; Pliska, 1987) reported in children treated with stimulants, DMI-treated patients showed a substantial reduction in depressive symptoms compared with placebo-treated patients. This outcome is consistent with previous reports (Garfinkel et al., 1983; Pliska, 1987; Staton et al., 1981), suggesting that TCAs may be effective in improving depressive symptoms in children with ADDH. At the end of the present double-blind protocol , patients were given the option of an elective open-label but otherwise protocol-guided DMI follow-up treatment for placebo non-

783

DESIPRAMINE IN ADD responders. Despite the inherent limitations in such uncontrolled experience, it is interesting that of 28 (out of 31) unimproved placebo patients, 27 elected to participate in the open label study, and 26 (96%) showed clinical benefit without clinically significant adverse effects. In further contrast to reported results from other studies with tertiary-amine TCAs (imipramine or amitriptyline) (Ross et al., 1984; Watter and Dreyfus, 1973; Winsberg et aI., 1972), DMI treatment was not associated with significantly improved (or worsened) performance on short-term laboratory measures of cognition in the present study. This observation is consistent with other studies of DMI that examined cognitive variables in children with ADDH (Donnelly et al., 1986; Garfinkel et al., 1983) and in normal adults (Sprague and Sleator, 1977) and suggests that brief DMI treatment may affect behavior more than cognition or that measurable cognitive effects may require long-term assessment, perhaps under more academically realistic conditions (as by following grades and scholastic achievement test scores). More work needs to be done to evaluate positive or negative cognitive effects of prolonged drug treatment of ADDH patients with TCAs as well as with stimulants (Puig-Antich et ai., 1987). Additional results from this study, reported separately (see Biederman et al., 1989), indicate that DMI treatment led to asymptomatic and generally small, but sometimes statistically significant, effects in diastolic blood pressure, heart rate, and ECG cardiac conduction times (all increased). These cardiovascular changes were associated weakly with steady-state DMI serum concentrations above the median (152 ng/ml). Although the clinical significance of these findings is unknown, the conduction defects encountered may be dangerous and indicate that prudent practice includes routine ECG monitoring when doses of TCAs above 3.5 mg/kg are used, as was recommended previously (Hayes et aI., 1975). Since dose was not significantly associated with serum levels of DMI, but serum levels above 150 ng/rnl were associated with somewhat greater risk of reduced efficiency of cardiac conduction, monitoring of DMI serum levels as well as ECG during treatment are wise components of TCA therapy of children and adolescents so as to optimize the probability of beneficial response and reduce the risk of cardiovascular toxicity. The pharmacological mechanism of action of DMI in ADDH remains unknown. Donnelly et al. (1986) found that DMI treatment decreased both plasma norepinephrine levels and urinary excretion of its metabolite MHPG in children with ADDH. Since DMI has a powerful and selective inhibitory effect on the neuronal uptake of norepinephrine and alters its metabolism and effects on adrenergic receptors in the mammalian brain, these findings may suggest that the somewhat delayed anti-ADDH effects of DMI, like its antidepressant effects, may be related to the drug's actions on this central neurotransmitter system by actions partly shared with those of stimulants (Baldessarini, 1985). In conclusion, the present controlled study adds to clinical experience and other relatively short-term trials indicating that DMI may be an effective and well-tolerated treatment for many children with ADDH, including those who have failed to respond to stimulants and perhaps, for those for whom a long-acting medicine is preferable, or for those with

associated depressive symptoms. Additional studies are needed to test the impression that DMI may be useful in the treatment of adolescent or adult patients with a childhood history of ADDH and to evaluate whether daily doses of 4 to 5 mg/kg are also needed in medication-naive or stimulantresponsive patients. TCA therapy in children and adolescents, especially when daily doses above 3.5 mg/kg are employed, requires optimization clinically and by assay of serum drug levels and ECG. References Baldessarini, R. J. (l985), Chemotherapy in Psychiatry. Cambridge, MA: Harvard University Press, pp. 130-234. Barkley, R. A. (1977), A review of stimulant drug research with hyperactive children. J. Child Psychol. Psychiatry, 18:137-165. Biederman, J., Baldessarini, R. J., Wright, V. et al. (1989), A doubleblind placebo controlled study of desipramine in the treatment of ADD: II. Serum drug levels and cardiovascular findings. J. Am. Acad. Child Adolesc. Psychiatry, 28(5).

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