 |
|
 |
|
 |
 |
|
 |
 |
 |
 |
 |
 |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PEDIATRICS Vol. 104 No. 2 August 1999, p. e20
,
From the * Pediatric Psychopharmacology Unit, Massachusetts
General Hospital; Department of Epidemiology, Harvard School of
Public Health; and § Harvard Medical School, Boston, Massachusetts.
 |
ABSTRACT |
|---|
Top
Abstract
Methods
Results
Discussion
References
|
|---|
Objective. To assess the risk for substance use disorders (SUD) associated with previous exposure to psychotropic medication in a longitudinal study of boys with attention-deficit/hyperactivity disorder (ADHD).
Methods. The cumulative incidence of SUD throughout adolescence was compared in 56 medicated subjects with ADHD, 19 nonmedicated subjects with ADHD, and 137 non-ADHD control subjects.
Results. Unmedicated subjects with ADHD were at a significantly increased risk for any SUD at follow-up compared with non-ADHD control subjects (adjusted OR: 6.3 [1.8-21.6]). Subjects with ADHD medicated at baseline were at a significantly reduced risk for a SUD at follow-up relative to untreated subjects with ADHD (adjusted OR: 0.15 [0.04-0.6]). For each SUD subtype studied, the direction of the effect of exposure to pharmacotherapy was similar to that seen for the any SUD category.
Conclusions. Consistent with findings in untreated ADHD in adults, untreated ADHD was a significant risk factor for SUD in adolescence. In contrast, pharmacotherapy was associated with an 85% reduction in risk for SUD in ADHD youth. Key words: ADHD, pharmacotherapy substance use disorders.
As recently highlighted by Goldman et al,1 the
association between pharmacologic intervention in youth with
attention-deficit/hyperactivity disorder (ADHD) and subsequent
substance use disorder (SUD) remains a source of clinical and public
health concern. Goldman et al1 questioned whether exposure
to stimulant medication in youth with ADHD could lead to prescription
drug abuse or serve as a gateway to the abuse of other drugs. The focus
on the stimulants as a potential risk for SUD in ADHD youth is
understandable, because stimulants are the drugs prescribed most
commonly for this disorder. Given their well documented abuse
potential, their use by many youth with ADHD has been of concern to
both parents and clinicians.
Whether pharmacotherapy leads to SUD in ADHD children has serious
clinical implications. If such a link were documented, clinicians, patients, and families would need to weigh carefully the risk of SUD
against the therapeutic benefit of medication. On the other hand, if
pharmacotherapy does not lead to SUD, clinicians, patients, and
families could approach pharmacologic treatment issues without ungrounded fears. Decreased apprehension toward appropriate
pharmacotherapy in turn may lead to earlier intervention for affected
youth with its attendant benefits of avoiding the academic,
psychiatric, and interpersonal complications of ADHD.
Unfortunately, as reviews of the literature show, no controlled studies
of subjects with ADHD have evaluated adequately the putative link
between SUD and pharmacotherapy,1,2 and there are only two
published case reports of stimulant abuse by adolescents with ADHD
receiving these compounds therapeutically.3,4 Despite this
dearth of data, the idea that pharmacotherapy increases the risk for
SUD persists in diagnostic and treatment conferences5,6 and in the popular press.7,8
The purpose of this study was to assess the risk for SUD associated
with previous exposure to psychotropic medication in our longitudinal
follow-up of psychiatrically and pediatrically referred boys with ADHD
attending to co-morbidity with conduct disorder (CD), a well documented
risk factor for SUD.9-13 We examined three competing
hypotheses. The first is the null hypothesis that psychotropics would
have no effect on the development of SUD in children with ADHD. The
alternative hypothesis is that exposure to pharmacotherapy will be
associated with higher risk for SUD in general and stimulant abuse in
particular. Because SUD in children and adolescents with ADHD may arise
from an attempt at self-medication, the third competing hypothesis
posited that pharmacologic management would diminish the risk for SUD
by controlling the core features of ADHD and promoting adaptive
behavior and academic success.
Subjects
We analyzed data from a longitudinal family genetic study of
ADHD that we have presented in previous publications.14 The original sample included a total of 260 families chosen from psychiatric and nonpsychiatric settings based on the ADHD status of an
index child (140 subjects with ADHD and 120 normal control subjects).
All index children were white, non-Hispanic males 6 and 17 years of age
at first assessment. We obtained informed consent for all subjects
before their enrollment in the protocol.
At the 4-year follow-up, 91% of the 140 ADHD families and 91% of the
120 control families seen at baseline were reevaluated successfully and
provided 280 and 226 subjects, respectively, for analysis. Subjects
meeting criteria for ADHD were asked what forms of treatment, if any,
they had received. Of the 280 children of families ascertained via an
ADHD proband, 56% (n = 156) met criteria for ADHD, of
which 75% (n = 117) reported previous pharmacotherapy. A small proportion (3% [n = 6]) of the 226 children
of families ascertained via a non-ADHD control child met criteria for
ADHD, with none receiving pharmacotherapy. From the available subjects, three groups were defined 1) medicated subjects with ADHD
(n = 117); 2) nonmedicated subjects with ADHD
(n = 45); and 3) non-ADHD subjects (n = 344).
However, because the groups with ADHD were composed of predominantly
male subjects (97% medicated male subjects with ADHD [n = 114]; 84% nonmedicated of nonmedicated male
subjects with ADHD [n = 38]) and because the non-ADHD
group had significantly fewer males (64% [n = 221];
Measures
All diagnostic assessments used DSM-III-R-based structured
interviews. Psychiatric assessments of children relied on the Schedule of Affective Disorder and Schizophrenia for School-Age Children Epidemiologic Version.15 Diagnoses were based on
independent interviews with the mothers and direct interviews with
children, except for those younger than 12 years of age who were not
interviewed directly. At baseline and the 1-year follow-up, the
structured interviews assessed lifetime history of psychopathology; at
year 4, these assessments reflected the interval since the previous assessment. The assessment personnel were blind to family status (ADHD
or control) and ascertainment site (psychiatric or pediatric). All
follow-up assessments were made blind to previous assessments of the
same subjects and their family members.
The interviewers had undergraduate degrees in psychology and were
trained to high levels of interrater reliability. We computed Diagnoses were considered positive if, based on the interview results,
DSM-III-R criteria were met unequivocally to a clinically meaningful
degree. From the structured diagnostic interviews, diagnoses were made
for alcohol A/D. DSM-III-R criteria for substance dependence requires
at least three of the following symptoms: substance taken in
increasingly larger amounts; unsuccessful attempts at reducing
substance use; expending a great deal of time
acquiring/using/recovering from substance; frequent intoxication;
reduction in frequency of other activities; continued use despite the
functional complications of substance use; increased tolerance to the
effects of substance; symptoms of withdrawal; or use of substance to
avoid symptoms of withdrawal. Abuse requires either continued use
despite the functional complications associated with substance use or
recurrent use of substances in physically hazardous situations.
Diagnoses are analyzed here as any SUD, alcohol A/D, marijuana A/D,
hallucinogen A/D, stimulant A/D, and cocaine A/D. Tobacco A/D was
collected only at our follow-up assessment. Based on previous
reports,9-13 CD was considered a known risk factor for
SUD and is also analyzed here.
Statistical Analysis
Ordinary least squares regression analyzed continuous dependent
variables, and logistic regression analyzed binary responses. Because
siblings sampled from one family are not independent of each other,
standard tests of statistical significance will be incorrect. To
account for this bias, we adjusted our analyses by using
Huber's16 formula as implemented in STATA, version
5.017 to produce robust statistical tests for both
ordinary least squares and logistic regression models. Estimates of
variance according to Huber's16 correction are empiric and do not place any requirement on the distribution of the error terms. This robust estimate of variance enters family cluster scores
(not individual scores) into the formula for the estimate of variance
resulting in asymptotically unbiased estimates. Therefore, our analyses
adjust for the correlation among subjects of the same family and
produce unbiased P values. All statistical tests were
two-tailed and used the .05 level of statistical significance.
We restricted our analysis to those male subject older than 15 years of age (56 medicated subject with ADHD, 19 nonmedicated subject
with ADHD, and 137 non-ADHD subjects). On average, the children treated
at baseline were medicated for 4.4 ± 2.7 years of treatment, and
none of the nonmedicated subjects with ADHD were treated during our
follow-up period. We sampled referred subjects with ADHD from both
psychiatric and nonpsychiatric treatment facilities and control
subjects from outpatient clinics at the same institution as the source
of subjects with ADHD. There was a significant association between
source of ascertainment and study group status; 66% of the medicated
ADHD group were from the psychiatric clinic, whereas only 16% of the
unmedicated ADHD group came from the psychiatric clinic and 30% of the
control subjects came from the outpatient pediatric clinic at the same institution as the psychiatric clinic
( There were, however, statistically significant differences in the
subjects' age in years (17.2 ± 2.1, 18.5 ± 2.4, and
19.2 ± 4.3, respectively; F(2,146) = 6.4; P = .002), in socioeconomic status
(SES)18 (2.0 ± 1.0, 1.9 ± 1.1, and 1.6 ± 0.8, respectively; F(2,146) = 5.2;
P = .006), lifetime risk of CD at baseline (27%
[n = 15], 47% [n = 9], and 4%
[n = 6], respectively, As shown in Table 1, statistically
significant differences were identified among the medicated ADHD,
nonmedicated ADHD, and non-ADHD groups in rates of SUD at baseline and
follow-up and in tobacco A/D at follow-up. For each of the study
groups, alcohol and marijuana were the substance abused most
frequently, followed distantly by hallucinogens, stimulants, and
cocaine. Because at follow-up, the rates of stimulants and cocaine A/D were very low, we combined these subtypes into a single category (stimulant/cocaine A/D) for pairwise comparisons.
TABLE 1
METHODS
Top
Abstract
Methods
Results
Discussion
References
2(2) = 35.1; P < .001), females were excluded from this analysis. Similarly, because the
medicated subjects with ADHD were significantly younger than both the
nonmedicated subjects with ADHD and the non-ADHD control subjects
(15.7 ± 3.6 and 16.8 ± 5.5 years old), only subjects 
15
years were included in this analysis. Thus, we analyzed: 1) 56 medicated subjects with ADHD; 2) 19 nonmedicated subjects with ADHD;
and 3) 137 non-ADHD subjects. Although these exclusion criteria reduced
our sample size considerably, restricting our analysis to males older
than 15 years of age was the most complete method of controlling for
potential confounding by these variables.
coefficients of agreement by having experienced, board-certified child
and adult psychiatrists diagnose subjects from audiotaped interviews
conducted by the assessment staff. Based on 173 interviews, the median
statistic was 0.86. In addition, a committee of board-certified child and adult psychiatrists chaired by the senior author resolved all
diagnostic uncertainties. The committee members were blind to each
subject's ascertainment group, ascertainment site, data collected from
other family members, and all other information.
RESULTS
Top
Abstract
Methods
Results
Discussion
References
2(2) = 26.4; P < .001). However, the source of ascertainment was not associated with CD
(2(1) = 0.5; P = .5 and
2(1) = 0.3; P < .6) in
the ADHD groups or with SUD in the control group
(2(1) = 0.5; P < .5)
and, therefore, cannot be a confounder in these data.
2(2) = 26.9; P < .001)
and in a lifetime history of SUD in the subjects' parents (59%
[n = 33], 84% [n = 16], and 47%
[n = 64], respectively;
2(2) = 10.4; P < .006). Thus, our analyses were corrected for these confounders using
multiple logistic regression.
Prevalence of SUD Subtypes
As noted above, we used multiple logistic regression to adjust for potential confounding variables in testing pairwise comparisons. These models estimated the relative risk (OR) for each type of SUD associated with ADHD and with being exposed to pharmacotherapy. The cumulative incidence of SUD during follow-up was predicted from a model containing terms for ADHD, medication status, age at follow-up, SES, diagnosis of CD at baseline, diagnosis of SUD at baseline, and history of SUD in subjects' parents. By using medication status at baseline, a temporal order is established between exposure to medication and our measure of SUD 4 years later. Although this does not necessarily imply causal relationships, it allows us to extend beyond inferences of cross-sectional association and to make predictive conclusions.
The adjusted results from the multiple logistic regression models are
presented in Table 2. These analyses
showed that unmedicated subjects with ADHD were at a significantly
increased risk for any SUD at follow-up compared with non-ADHD control
subjects (Table 2). Using ORs <1 (the odds for outcome in exposed subjects being lower than the odds in unexposed subjects) as indicative of a protective association, subjects with ADHD medicated at baseline were at a significantly reduced risk for an SUD outcome at follow-up compared with nonmedicated subjects with ADHD. As expected, CD and
parental SUD were also associated with a significant increased risk for
an SUD (Table 2). However, there was no statistical interaction between
CD and ADHD or medication status (2(2) = 3.7; P = .15) indicating that the effect of
medication status in subjects with ADHD on subsequent SUD was not
modified by the presence of CD.
|
Although stratification of the sample by specific categories of A/D reduced power, the direction of the effect of exposure to pharmacotherapy for each of the SUD subtypes was similar to that seen for the any SUD category (Table 2). In each case, subjects with ADHD medicated at baseline were at a reduced risk relative to nonmedicated subjects with ADHD, and CD was associated consistently with a significantly increased risk for each type of SUD other than for stimulant/cocaine A/D. For tobacco A/D, the medicated group did not have a significantly different risk than did the unmedicated ADHD group, and the unmedicated subjects with ADHD were not at significantly increased risk relative to the non-ADHD control subjects.
| |
DISCUSSION |
|---|
|
Top
Abstract
Methods
Results
Discussion
References
|
|---|
In a large, well characterized sample of pediatrically and psychiatrically referred ADHD and non-ADHD youth, pharmacotherapy for ADHD did not predict an increased risk for SUD. We found instead that subjects with ADHD who did not receive pharmacologic treatment were at a significantly increased risk for SUD suggesting that pharmacotherapy may protect children with ADHD from this risk. Although we cannot address potential differences between stimulant and nonstimulant drugs, it is reasonable to assume that the majority of our subjects indeed were exposed to stimulants, because stimulants are the mainstay of the treatment of this disorder.1,19,20
Our results are consistent with a small body of literature examining the long-term effects of stimulant therapy on subsequent SUD onset in adolescents with ADHD. In a review of longitudinal studies of treated ADHD children, Hechtman et al2 found no evidence that stimulant exposure predicted later SUD and weak evidence that stimulant therapy prevented SUD.21-23 Since this review,2 there have been no systematic analyses addressing the risks or benefits of stimulant therapy in regards to SUD onset among youth with ADHD. By providing statistical evidence that pharmacotherapy for ADHD may protect children with ADHD from SUD onset, these results augment the equivocal findings of the extant literature.
Our results also indicate that medication status is an essential modifier of the ADHD-SUD association. This finding extends our previous report that the risk for SUD was indistinguishable in ADHD and non-ADHD youth.24 However, in that analysis we did not account for medication status.24 As we report now, stratification by medication reveals that untreated ADHD is a significant risk factor for SUD even after correcting for comorbid CD.
The increased risk for SUD in untreated youth with ADHD is consistent with our findings of significant ADHD-SUD associations in adults with ADHD.25,26 Because these adults had been primarily undiagnosed and untreated as children, they provide retrospective corroboration that ADHD, in the absence of pharmacotherapy, may increase the risk for SUD in subjects with ADHD.27 Although these findings require prospective confirmation, they suggest that adequate pharmacotherapy for ADHD in childhood may have a significant protective effect for the subsequent development of SUD in adulthood.
Our findings should be viewed in consideration of additional methodologic limitations. The first pertains to the lack of an ideal control group for assessing the independent effect of pharmacotherapy on SUD onset. We did not present the comparison between medicated subjects with ADHD and non-ADHD control subjects, because the control subjects did not have ADHD, and therefore, did not have a comparable baseline risk for SUD. In such a comparison, the protective effect of pharmacotherapy would be commingled with the deleterious effects of ADHD, and the result would be biased with respect to both the effects of ADHD and its pharmacotherapy. Thus, comparisons must be limited to those groups differing in only one potential risk factor (ie, within ADHD subjects, medication vs no medication or within nonmedicated subjects, ADHD vs non-ADHD).
There also were significant differences among medicated ADHD, unmedicated ADHD, and non-ADHD control groups in age, SES, risk of CD, and gender. We limited our analysis to males >15 years of age and corrected for other confounders with multiple logistic regression. Although logistic regression deals with the potential confounding attributable to the variables measured, it does not necessarily correct for the other unmeasured confounders that may be associated with those modeled. However, these unmeasured confounders are not likely to account completely for our findings, because they would need to be more prevalent and more strongly associated with SUD than are SES, CD, and parental history of SUD.
Despite having a large sample of ADHD and non-ADHD children, we lacked adequate statistical power to evaluate fully the effect on different SUD subtypes, especially for stimulant/cocaine use disorder and tobacco A/D. The result of this reduction in power was that our estimates of relative risk were not very precise, and null findings cannot be considered conclusive. Nevertheless, despite the low power to test our hypotheses, it is reassuring to know that only a very small proportion (2%) of many exposed subjects (n = 56) suffered stimulant or cocaine use disorders.
Finally, this study cannot make definitive conclusions regarding the risks associated with pharmacotherapy of ADHD beyond the age of our current sample, in females, or in nonwhite subjects. Only follow-up of this and of other samples of children treated for ADHD with stimulants and other medications will provide such answers. Despite these considerations, our results suggest that rather than inducing SUD in youth with ADHD, pharmacotherapy for ADHD may protect children with ADHD from this serious and deleterious outcome.
| |
ACKNOWLEDGMENTS |
|---|
This work was supported by National Institute of Mental Health Grant RO1-HD36317 (J.B.) and by National Institute of Drug Abuse Grant DA-R2911315 (T.W.).
We thank Jason Yeaw for his assistance with this manuscript.
| |
FOOTNOTES |
|---|
Received for publication Dec 18, 1998; accepted Mar 19, 1999.
Address correspondence to (J.B.) Massachusetts General Hospital, 15 Parkman St, WACC 725, Boston, MA 02114. E-mail: biederman{at}helix.mgh.harvard.edu
| |
ABBREVIATIONS |
|---|
ADHD, attention-deficit/hyperactivity disorder; SUD, substance use disorder; A/D, abuse or dependence; CD, conduct disorder; SES, socioeconomic status.
| |
REFERENCES |
|---|
|
Top
Abstract
Methods
Results
Discussion
References
|
|---|
This article has been cited by other articles:
 |
|
 |
|
  V A Harpin Medication options when treating children and adolescents with ADHD: interpreting the NICE guidance 2006 Arch. Dis. Child. Ed. Pract., April 1, 2008; 93(2): 58 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Ohlmeier, K. Peters, B. T. T. Wildt, M. Zedler, M. Ziegenbein, B. Wiese, H. M. Emrich, and U. Schneider Comorbidity of Alcohol and Substance Dependence with Attention-Deficit/Hyperactivity Disorder (ADHD) Alcohol Alcohol., March 7, 2008; (2008) agn014v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Rostain and J. R. Ramsay A Combined Treatment Approach for Adults With ADHD--Results of an Open Study of 43 Patients. J Atten Disord, November 1, 2006; 10(2): 150 - 159. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Ashton, P. Gallagher, and B. Moore The adult psychiatrist's dilemma: psychostimulant use in attention deficit/hyperactivity disorder J Psychopharmacol, September 1, 2006; 20(5): 602 - 610. [Abstract] [PDF]
|
|
|
|
 |
|
 J. A. Dopheide ASHP Therapeutic Position Statement on the Appropriate Use of Medications in the Treatment of Attention-Deficit/Hyperactivity Disorder in Pediatric Patients Am. J. Health Syst. Pharm., July 15, 2005; 62(14): 1502 - 1509. [Full Text] [PDF]
|
|
|
|
 |
|
 V A Harpin The effect of ADHD on the life of an individual, their family, and community from preschool to adult life Arch. Dis. Child., February 1, 2005; 90(suppl_1): i2 - i7. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. GILLIGAN and B. LEE The Psychopharmacologic Treatment of Violent Youth Ann. N.Y. Acad. Sci., December 1, 2004; 1036(1): 356 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Shaw, I Wagner, H Eastwood, and G Mitchell A qualitative study of Australian GPs' attitudes and practices in the diagnosis and management of attention-deficit/hyperactivity disorder (ADHD) Fam. Pract., April 1, 2003; 20(2): 129 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Coghill Current issues in child and adolescent psychopharmacology. Part 1: Attention-deficit hyperactivity and affective disorders Advan. Psychiatr. Treat., March 1, 2003; 9(2): 86 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Z. Weinberg Risk Factors for Adolescent Substance Abuse J Learn Disabil, July 1, 2001; 34(4): 343 - 351. [Abstract] [PDF]
|
|
|
|
|
|
D. J. MARKS, J. H. NEWCORN, and J. M. HALPERIN Comorbidity in Adults with Attention-Deficit/Hyperactivity Disorder Ann. N.Y. Acad. Sci., June 1, 2001; 931(1): 216 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. SULLIVAN and F. RUDNIK-LEVIN Attention Deficit/Hyperactivity Disorder and Substance Abuse: Diagnostic and Therapeutic Considerations Ann. N.Y. Acad. Sci., June 1, 2001; 931(1): 251 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. MULSOW, K. K. O'NEAL, and V. M. MURRY Adult Attention Deficit Hyperactivity Disorder, the Family, and Child Maltreatment Trauma Violence Abuse, January 1, 2001; 2(1): 36 - 50. [Abstract] [PDF]
|
|
Read all P3Rs
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
||
|
||
Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 1999 American Academy of Pediatrics. All rights reserved. |
||
|
||
