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.

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 as-
sociated 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 Psy-
chiatry. Harvard Medical School. Boston. Dr. Baldessarini is associ-
ated 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 Psy-
chiatry. 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 Acad-
emy of Child and Adolescent Psychiatry.
777
there is little information regarding appropriate pharmaco-
therapy in the older age groups despite the increasingly fre-
quent 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; Zamet-
kin and Rapoport, 1983). Possible advantages of TCAs over
stimulants include a longer duration of action and the feasi-
bility of once-daily dosing without symptom-rebound or in-
somnia, 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; Ra-
poportetal., 1974;Waizeretal., 1974;Werry, 1980;Winsberg
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 neu-
ronal uptake of norepinephrine and, like other TCAs, appears
eventually to enhance functional availability of norepineph-
rine and its activity at central alpha-I adrenergic receptors
(Baldessarini, 1985). Compared with other TCAs, DMI has
relatively low affinity at muscarinic and histaminergic recep-
tors and only moderate affinity at alpha-I-adrenergic recep-
tors, and it is very weak against alpha-2, beta-adrenergic, and
778 BIEDERMAN ET AL.
dopaminergic receptors (Baldessarini, 1985). Because of its
pharmacologic properties, DMI may be associated with some-
what 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, placebo-
controlled, crossover study of 3 weeks duration for each phase,
Garfinkel et al. (1983) compared the effects of methylpheni-
date, 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 phar-
macologic 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 chil-
dren, 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 chil-
dren 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 Psy-
chiatry 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 sub-
jects 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 hydro-
chloride (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 double-
blind 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-treat-
ment 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 spec-
trometry sensitive to 20 ng/ml; intra- and interassay coeffi-
cients of variation (SD/mean) were <3% and <5%, respec-
tively. 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-
 DESIPRAMINE IN ADD 779

chusetts General Hospital. Laboratory personnel were una-
ware 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 phy-
sician-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 Contin-
uous 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 termi-
nated prematurely (before week 3) were not included in the
data analysis: four never started the protocol for administra-
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 ter-
minated prematurely between weeks 3 and 6 due to a deteri-
orating 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 ade-
quate 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 socio-
economic 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

TABLE I. Clinical Characteristics ofSample at Baseline and End-Point Analysis ofImprovement (Percent Change)
Baseline End of Treatment
Placebo DMI Placebo DMI
Mean SEM Mean SEM % Change SEM % Change SEM
Overall
Clinician's Global Severity" 5.1 O.I 5.2 O.I 8.0 3.8 33.8 3.4***
Conners Questionnaire-Parent" 22.8 0.8 21.8 0.7 11.4 5.1 42.1 4.5**
Conners Questionnaire-Teacher" 17.3 1.3 18.5 1.2 12.6 8.0 36.4 4.9**
Children's Depression Inventory' 18.3 1.3 16.1 1.4 -2.4 12.7 30.2 9.4t
Adolescents"
Clinician's Global Severity 4.9 0.2 5.1 0.3 7.1 6.6 32.3 6.0
Conners Questionnaire-Parent 23.1 1.5 20.2 0.8 23.9 8.5 45.1 8.9
Conners Questionnaire-Teacher 19.1 2.1 13.7 3.2 20.7 11.4 27.7 1O.8
Children's Depression Inventory 17.5 1.3 15.4 3.6 14.7 6.7 46.7 20.1
Prior Treatment Refractory"
Clinician's Global Severity 5.3 O.I 5.1 0.2 7.4 3.8 34.2 4.1*"
Conners Questionnaire-Parent 23.4 1.0 21.9 0.9 6.9 4.8 41.0 5.6***
Conners Questionnaire-Teacher 18.4 1.4 19.6 1.7 10.0 7.7 37.8 5.4*
Children's Depression Inventory 19.5 1.6 17.4 2.0 -24.8 18.8 19.5 13.1
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.
a 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.

780 BIEDERMAN ET AL.

expressed by the presence of comorbid psychiatric disorders, 60 A.

including learning difficulties (74.2% vs. 77.4%, NS), conduct
disorder (35.5% vs. 38.7%, NS), and oppositional disorder I- 50
Z
(45.2% vs. 51.6%, NS). The groups also were closely similar w
~
w
in baseline ratings pertaining to AOOH by clinicians, parents, > 40
0
and teachers (Table I), and in cognitive measures (PALT % a:
Do
errors = 57.6% 4.2% vs. 59.5% 2.9%, t = 0.4, dj= 48, ! 30
I-
NS; CPT errors of commission = 24.8 6.7 vs. 33.7 10.1, Z
W
t = 0.7, df = 53, NS; CPT errors of omission = 13.4 3.1 vs. U
a:
w 20
14.2 2.8, t = 0.2, dj= 53, NS, each for placebo and OMI, Do
respectively). By chance, the previously treatment-refractory Z
C(
w
patients were somewhat unevenly distributed between the two :2
10
treatment groups (OMI group, 18 [58%] vs, placebo group,
25 [81%]; Xl = 2.7, dj= I, N = 62, p = 0.10). 0
N. 22 24 23 24
Daily doses (mg/kg) were similar for placebo and OMI 31 27

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 10o ~CEOO
OMI
I
vs. 4.6 0.2). Because of occasional missing data and early 6 B.
dropouts, weekly ratings for weeks 1 + 2, 3 + 4, and 5 + 6,
were combined to represent each 2-week period. While no
5
significant differences in clinical efficacy between OMI and
placebo were observed by weeks I + 2 at average daily doses
...::c..
6" ~
of placebo and OMI of 2.4 0.2 and 2.3 0.2 mg/kg, ~ 4
respectively, differences were detected by weeks 3 + 4 (at a
average daily doses of 4.2 0.2 and 4.4 0.2 mg/kg) on
~
w
l/l
3
........
Global Clinical Severity ratings (23.4% vs. 9.2% improve- 0
0
ment, t = 2.3, df = 41, p = 0.03, trend) and Abbreviated z
C( 2
Conners Parent Questionnaire scores (43.0% vs. 14.7% im- w
:2
provement, 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, o
df = 56, p = 0.0003 for Global Clinical Severity and Abbre- II.EJ< 1.2 34 5-6
viated Parent Conners Questionnaire, respectively) (Fig. I). FIG. 1. Weekly outcome and OM! dose. A, Mean (SEM) percent
End-point analysis (weeks 3 to 6) showed that 21/31 OMI change in Conners Abbreviated Parent Questionnaire scores and
subjects (68%) were considered very much (Clinical Global mean weight corrected daily doses (rug/kg). B. vs, duration of treat-
ment by week period with OM!- (solid bars) and placebo-treated
Improvement [CGI] score = I) or much (CGI = 2) improved patients (open bars). By unpaired r-test (two-tailed) OM! vs. placebo,
compared with only 3/31 (10%) of placebo subjects (Xl = .. p < 0.00 I;... P < 0.000 I.
22.0, df = I, p = 0.000 I). OMI patients showed significantly
more improvement than placebo patients in clinician's rat-
ings, parent's ratings, and teacher's ratings (Table I). In ad- The appreciably higher (but statistically not significant)
dition, OMI patients showed substantially more improvement proportion of subjects previously unresponsive to stimulant
in depressive symptoms as expressed in parental reporting, treatment assigned, by chance, to the placebo group (25/31)
although this trend was not statistically significant at the 1% than the OMI-treated group (18/31) raised concerns that the
criterion (COl-Parent mean [SEM] percent change = 30.2% findings might be biased by this unequal distribution of
9.4% vs. -2.4% 12.7%, t = 2.0, dj= 51, P = 0.05, trend). possibly more difficult cases so as to favor OMI and disfavor
Cognitive measures did not change significantly in either the placebo. Accordingly, the data for all 18 treatment-resistant
OMlor placebo group (mean percent change for OMI vs. subjects given OMI were reanalyzed and compared to the first
placebo, respectively: PALT = 14.0% 8.2% vs, 8.2% 18 treatment-resistant subjects given placebo. This secondary
7.5%, t = 0.5, dj= 47, NS; CPT errors of commission = 13.8 analysis replicated the findings for the entire sample (at similar
2.8 vs. 12.4 3.0, t = 0.3, df = 53, NS; CPT errors of levels of statistical significance) concerning differences in im-
omission, 14.6 2.7 vs. 16.6 4.5, t = -0.4, dj= 53, NS). provement scores between OMI and placebo (overall rate of
Because there were relatively few adolescents in this study (N improvement [Global Improvement ~2] = 0/18 vs. 13/18,
= 20: 8 given OMI, and 12 given placebo), statistical compar- Xl = 20.3, dj = I, p = 0.000 I) (Table I and Fig. 2). A similar
ison of children and adolescents is not appropriate. Neverthe- analysis was carried out to evaluate the effects of depressive
less, the patterns of mean changes in AOOH-related clinical symptoms on clinical outcome by stratifying subjects into two
outcome measures for the adolescents resembled those of the groups by the baseline scores on the COl-Parent version below
children (Table I; Fig. 2). ("low") or above ("high") the median score of 17. No signifi-
 DESIPRAMINE IN ADD 781
100
0 PlACEBO

o OMI

80 ***
c
w
*** r---
>
0
a:
-
l1.
:&! 60
-
en
~
U
..,
w
III
:l
en
...
0
40
~
Z
w
o
a:
w
l1.
20
-

a
N=
I 31 31 12 8
r---
18 18

OVERALL ADOLESCENTS PRIORTX REFRACTORY

FIG. 2. Rate of improvement in subgroups. Percentage of subjects improved (Clinical Global Improvement, CGI = I or 2) for DMI- (solid
bars) and placebo-treated patients (open bars) for the entire sample, for adolescents(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.

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 pla-
cebo 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 complica-
tion. 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 im-
provement (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 chil-
dren 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 re-
sponse 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,
782 BIEDERMAN ET AL.
it may be appropriate to stratify subjects by prior history of
treatment refractoriness. Avoidance of refractory patients al-
together may be less feasible. Thus, many families of previ-
ously untreated children refused to participate in this study
of a novel treatment for ADDH, and opted instead for con-
ventional treatments. Others could appreciate the potential
benefits of the proposed treatment but still refused to partic-
ipate 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 adoles-
cents 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 methylphenidate-
may 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 treat-
ments 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 diag-
nosed 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 signifi-
cant 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' previ-
ously 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. Accord-
ingly, it is possible that a requirement of relatively high doses
of DMI may be selective for the treatment of stimulant-
refractory 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 previ-
ously reported DMI studies (Donnelly et al., 1986; Garfinkel
et aI., 1983), its findings provide evidence only for the short-
term 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 chil-
dren 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 dys-
phoria (Gittelman, 1980; Pliska, 1987) reported in children
treated with stimulants, DMI-treated patients showed a sub-
stantial reduction in depressive symptoms compared with
placebo-treated patients. This outcome is consistent with pre-
vious 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-
 DESIPRAMINE IN ADD
responders. Despite the inherent limitations in such uncon-
trolled 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 with-
out 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 consist-
ent with other studies of DMI that examined cognitive vari-
ables 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 academi-
cally 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 cardio-
vascular changes were associated weakly with steady-state
DMI serum concentrations above the median (152 ng/ml).
Although the clinical significance of these findings is un-
known, the conduction defects encountered may be danger-
ous 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 con-
duction, 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 inhibi-
tory 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 anti-
depressant 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
783
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 stimulant-
responsive 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.
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