- Email: [email protected]
BEHAVIORAL INHIBITION AND DEVELOPMENTAL RISK: RESPONSE TO COMMENTARY
LETTERS TO THE EDITOR
treatment whatsoever and that many or most of those who are receiving medication are being inadequately treated. This fact is quite troubling, especially in view of the evidence for the remarkable effectiveness and safetyof stimulant medications as a treatment for children with ADHD (MTA Cooperative Group, 1999a,b). As these commentators note, misdiagnosis of ADHD is surely common. Yet the current emphasis on overdiagnosis runs the risk of ignoring the very substantial, apparently larger problems of "missed diagnosis." As we note (Jensen et aI., 1999b), and consistent with national data from 1995 (Jensen et al., 1999a), a balanced interpretation of the most scientifically sound information available leads to the conclusion that while over- and underprescribing both occur, such instances appear to be region-, community-, and provider-specific. Exaggerated reports of overdiagnosis as a general phenomenon, when in fact they are specific to a given site or region, are not harmless. Such claims, taken out of context from the larger problem of the many unrecognized, undertreated children with ADHD and other behavioral and emotional disorders, can only discourage parents from seeking treatment for their suffering children and otherwise increase the stigma and blame borne by families. Peter S. Jensen, M.D. Office of the Director, NIMH Currently on detail to: Center for the Advancement of Child and Adolescent Mental Health Department of Child Psychiatry New York State Psychiatric Institute Columbia University, New York Goldman LS, Gene! M, Bezman RJ, Sianetz PJ (1998), Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Council on Scientific Affairs, American Medical Association. JAMA 279: 1100-1107 IMS America (1995), National Disease and Therapeutic Index". Plymouth Meeting, PA: IMS Jensen P (1999), Pediatric psychopharmacology in the United States: issues and challenges in the diagnosis and treatment of ADHD. In: Ritalin: Theory and Practice, 2nd ed, Greenhill LL, Osman BB, eds. New York: Mary Ann Liebert Jensen P, Bharara V, Vitiello B, Hoagwood K, PeilM, Burke LB (1999a), Psychoactive medication prescribing practices for US children: gaps between researchand clinicalpractice. J AmAcad ChildAdolesc Psychiatry 38:557-565 Jensen PS, Kettle L, Roper MS et al. (l999b), Are stimulants overprescribed? Treatment of ADHD in four US communities. JAm Acad ChildAdoles
Psychiatry 38:797-804 MTA Cooperative Group (l999a), Fourteen-month randomized clinical trial of treatment strategies for attention deficit hyperactivity disorder. ArchGen Psychiatry 56: 1073-1086 MTA Cooperative Group (l999b), Moderator and mediator challenges to the MTA study: effects of cornorbid anxiety disorder, family poverty, session attendance, and community medication on treatment outcome. Arch Gen Psychiatry 56: 1088-1094 Sherman M, Herrzig ME (1991), Prescribing practices of Ritalin: the Suffolk County, New York study. In: Ritalin: Theory and Patient Management, Greenhill LL, Osman BB, eds. New York:Mary Ann Liebert, pp 187-193 Sloan M, Jensen P, Kettle L (1999), Assessing services for children with ADHD: gaps and opportunities.] Attention Disord3:13-29
J. AM.
ACAD. CHILD ADOLESC. PSYCHIATRY, 39:3, MARCH 2000
BEHAVIORAL INHIBITION AND DEVELOPMENTAL RISK: RESPONSE TO COMMENTARY
To the Editor: Dr. Weinberg raises some interesting possibilities for interpreting the data contained in our recent article, "Behavioral Inhibition in Children From Families at High Risk for Developing Alcoholism" (Hill et aI., 1999b). The commentary suggests that Dr. Weinberg agreesthat temperamental traits provide clues as to why children with the same diagnosis can follow varied courses. At an aggregate level, children of alcoholics may be more likely to display behaviorally inhibited temperaments. At the individual level,we expect that those children with a familial! genetic diathesis for alcoholism might be at increased risk if they had a behaviorally inhibited temperament. Whether this is so will, of course, depend on long-term follow-up. Several points in Dr. Weinberg's commentary deserve attention. First, she asks, "What is the developmental significance of behavioral inhibition in children?" (p. 417), commenting that behavioral inhibition does not predict adverse outcomes in a majority of cases. This is an overly modest view of the extant data. We readily agree that the association cannot imply causality, but the fact that children of depressed, panic-disordered, agoraphobic (Rosenbaum et al., 1988) or alcoholic parents (Hill et al., 1999b) display higher rates of behavioral inhibition than do children of parents without any psychiatric illness should give us pause. Moreover, Biederman et al. (1990) have shown that offspring of parents with panic disorder and agoraphobia, who had previously been classifiedas inhibited at 21 months in a laboratory protocol, were more often diagnosed with multiple anxiety, overanxious, and phobic disorders when evaluated with a structured psychiatric interview at 4 to 8 years. Therefore, while we agree that behavioral inhibition "does not represent an equation with internalizing disorders," there is clear evidence that children classifiedas behaviorally inhibited on the basis of the laboratory protocol developed by Kagan and colleagues are at increased risk for anxiety disorders (Biederman et aI., 1990). She then asks, "Is this finding [Hill et aI., 1999b] specific to alcoholic families, or is behavioral inhibition a nonspecific characteristic of high-risk offspring?" (p. 417). This is an important question. Many putative markers for psychiatric illnessultimately turn out to be nonspecific (e.g., dexamethasone suppression appears to be present in conditions other than major depressive disorder). We argue that this is exactly the reason one should first study families of alcoholics without comorbidity. Valid markers can then be extended to other samples with comorbidity to evaluate generalizability. The answer to her question "Will the findings of Hill and colleagues generalize to children from other alcoholic families?" (p. 417) is currently unknown. However, discoveriesin basic neuroscience are typically based on the most homogeneous samples of laboratory animals avail-
271
LETTERS TO THE EDITOR
able (same strain, gender, age, supplier), wirh further testing in additional strains to determine generalizability. No laboratory researcher would purposely select a few Sprague-Dawley, a few Long-Evans, and a few Wistar rats. Another major point was that "the laboratory paradigm used by many studies (including that by Hill et al.) does not assess cross-situational or long-term persistence of the pattern" (p, 417). We disagree. While the "ecological validity" of any laboratory procedure can be questioned, the psychiatric! psychological community has a long tradition of sampling behavior in a laboratory setting where controlled conditions are possible and then making inferences about the individual's predisposition to future behavior. The protocol described in the Hill et al. report is a behavioral observation, not a questionnaire filled out by the mother. Replication of testing conditions was ensured by using the protocol identical with that used by the Harvard investigators in their study of offspring of diverse clinically disordered parents (Harvard investigators came to the Pittsburgh site to assess the similarity of testing conditions). The only modification of the Harvard protocol was one addressing the issue of whether the behavior is situation-specific. Each child was paired with different children in up to 3 separate test sessions. Dr. Weinberg also asks, "Might language disorders play some role in the picture of behavioral inhibition in children from alcoholic pedigrees?" (p. 418). First, one should not expect language disorders to playa greater role in the likelihood of observing behavioral inhibition in children from alcoholic pedigrees than it would in children from other affected pedigrees (e.g., depression). Language deficits in children of alcoholics have not been observed uniformly; at least 2 studies did not observe differences (Hill et al., 1999a; Reich et al., 1993). Second, Dr. Weinberg seems to imply that if a behaviorally inhibited child were to have either a receptive or expressive language disorder, we should assume the child is not really behaviorally inhibited. We believe this assumption is faulty. Children who are withdrawn may have less experience conversing with others and, therefore, may have difficulties adequately expressing their thoughts and feelings. But can we say the language problem is the cause? Even if one were to assume that language difficulties contributed to the likelihood that a given child would be diagnosed as behaviorally inhibited, this would have a potential effect on only 2 (latency to speak to the other child, total time speaking to the other child) of the 5 different measures assessed (the additional 3 measures were latency to touch toys, time spent proximal to parent, and time spent staring at the other child). Offspring of alcoholics showed significantly more time staring at the child with whom they were paired in a play session and more time proximal to their parent than did control children. Finally, we should not require less evidence to assume a positive association between alcohol abuse and externalizing disorders than is required to establish the relationship between
272
internalizing disorders and alcohol abuse. A careful review of this literature suggests that frequently, adult antisocial alcoholics are interviewed regarding their previous histories of conduct disorder as children and adolescents. Few studies have been prospective; most are cross-sectional (see Sher et al., 1991, for a review). Also, while children of alcoholics appear to be at increased risk for externalizing disorders in childhood/ adolescence and at increased risk for developing alcoholism, it must be remembered that few studies have followed children of alcoholics into adulthood to document that those who actually develop alcohol dependence more frequently had diagnoses of externalizing disorders in adolescence. In fact, Caspi et al. (1996), studying children of alcoholics, found evidence for both externalizing and internalizing disorders predicting alcohol abuse. Our recent work (Hill et al., 1999a) involving an 8-year follow-up of 8- to 18-year-old children of alcoholics and controls suggests that children of alcoholics have significantly increased odds ratios for internalizing disorders (e.g., depression was 4.1) as well as externalizing disorders (conduct = 3.5; ADHD = 10.6). Although children of alcoholics have an increased risk for developing alcoholism, not all of these children become alcoholic. Therefore, it is critical to determine which factors in childhood and adolescence are risk or protective factors. Further work is needed that is open to the possible role of internalizing disorders in the development of adult alcohol abuse and alcoholism. This research should use prospective designs to determine which children of alcoholics are susceptible and which are resilient. Shirley Y. Hill, Ph.D. University of Pittsburgh School of Medicine Jerome Kagan, Ph.D. Department of Psychology Harvard University Cambridge, MA Biederman J, Rosenbaum JF, Hirshfeld DR er al. (1990), Psychiatric correlates of behavioral inhibition in young children of parents with and without psychiatric disorders. Arch GenPsychiatry 47:21-26 Caspi A, Moffitt TE, Newman DL, Silva PA (1996), Behavioral observations at age 3 years predict adult psychiatric disorders. Arch Gen Psychiatry 53: 1033-1039 Hill SY, Locke ], Lowers L, Connolly J (1999a), Psychopathology and achievement in children at high risk for developing alcoholism. ] Am Acad Child
Adolesc Psychiatry 38:883-891 Hill SY, LowersL, Locke], Snidman N, KaganJ (l999b), Behavioral inhibition in children from families at high risk for developing alcoholism.] Am Acad
ChildAdolesc Psychiatry 38:410-420 Reich W, Earls F, Frankel 0, Shayka JJ (1993), Psychopathology in children of alcoholics.] Am Acad ChildAdolesc Psychiatry 32:995-1002 Rosenbaum JF, Biederman J, Gersten M et al. (1988), Behavioral inhibition in children of parents with panic disorder and agoraphobia. Arch GenPsy-
chiatry 45:463-470 Sher KJ, Walitzer KS, Wood PK, Brent EE (1991), Characteristics of children of alcoholics: putative risk factors, substance use and abuse, and psychopathology.] Abnorm Psychol100:427-448
J.
AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 39:3. MARCH 2000
treatment whatsoever and that many or most of those who are receiving medication are being inadequately treated. This fact is quite troubling, especially in view of the evidence for the remarkable effectiveness and safetyof stimulant medications as a treatment for children with ADHD (MTA Cooperative Group, 1999a,b). As these commentators note, misdiagnosis of ADHD is surely common. Yet the current emphasis on overdiagnosis runs the risk of ignoring the very substantial, apparently larger problems of "missed diagnosis." As we note (Jensen et aI., 1999b), and consistent with national data from 1995 (Jensen et al., 1999a), a balanced interpretation of the most scientifically sound information available leads to the conclusion that while over- and underprescribing both occur, such instances appear to be region-, community-, and provider-specific. Exaggerated reports of overdiagnosis as a general phenomenon, when in fact they are specific to a given site or region, are not harmless. Such claims, taken out of context from the larger problem of the many unrecognized, undertreated children with ADHD and other behavioral and emotional disorders, can only discourage parents from seeking treatment for their suffering children and otherwise increase the stigma and blame borne by families. Peter S. Jensen, M.D. Office of the Director, NIMH Currently on detail to: Center for the Advancement of Child and Adolescent Mental Health Department of Child Psychiatry New York State Psychiatric Institute Columbia University, New York Goldman LS, Gene! M, Bezman RJ, Sianetz PJ (1998), Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Council on Scientific Affairs, American Medical Association. JAMA 279: 1100-1107 IMS America (1995), National Disease and Therapeutic Index". Plymouth Meeting, PA: IMS Jensen P (1999), Pediatric psychopharmacology in the United States: issues and challenges in the diagnosis and treatment of ADHD. In: Ritalin: Theory and Practice, 2nd ed, Greenhill LL, Osman BB, eds. New York: Mary Ann Liebert Jensen P, Bharara V, Vitiello B, Hoagwood K, PeilM, Burke LB (1999a), Psychoactive medication prescribing practices for US children: gaps between researchand clinicalpractice. J AmAcad ChildAdolesc Psychiatry 38:557-565 Jensen PS, Kettle L, Roper MS et al. (l999b), Are stimulants overprescribed? Treatment of ADHD in four US communities. JAm Acad ChildAdoles
Psychiatry 38:797-804 MTA Cooperative Group (l999a), Fourteen-month randomized clinical trial of treatment strategies for attention deficit hyperactivity disorder. ArchGen Psychiatry 56: 1073-1086 MTA Cooperative Group (l999b), Moderator and mediator challenges to the MTA study: effects of cornorbid anxiety disorder, family poverty, session attendance, and community medication on treatment outcome. Arch Gen Psychiatry 56: 1088-1094 Sherman M, Herrzig ME (1991), Prescribing practices of Ritalin: the Suffolk County, New York study. In: Ritalin: Theory and Patient Management, Greenhill LL, Osman BB, eds. New York:Mary Ann Liebert, pp 187-193 Sloan M, Jensen P, Kettle L (1999), Assessing services for children with ADHD: gaps and opportunities.] Attention Disord3:13-29
J. AM.
ACAD. CHILD ADOLESC. PSYCHIATRY, 39:3, MARCH 2000
BEHAVIORAL INHIBITION AND DEVELOPMENTAL RISK: RESPONSE TO COMMENTARY
To the Editor: Dr. Weinberg raises some interesting possibilities for interpreting the data contained in our recent article, "Behavioral Inhibition in Children From Families at High Risk for Developing Alcoholism" (Hill et aI., 1999b). The commentary suggests that Dr. Weinberg agreesthat temperamental traits provide clues as to why children with the same diagnosis can follow varied courses. At an aggregate level, children of alcoholics may be more likely to display behaviorally inhibited temperaments. At the individual level,we expect that those children with a familial! genetic diathesis for alcoholism might be at increased risk if they had a behaviorally inhibited temperament. Whether this is so will, of course, depend on long-term follow-up. Several points in Dr. Weinberg's commentary deserve attention. First, she asks, "What is the developmental significance of behavioral inhibition in children?" (p. 417), commenting that behavioral inhibition does not predict adverse outcomes in a majority of cases. This is an overly modest view of the extant data. We readily agree that the association cannot imply causality, but the fact that children of depressed, panic-disordered, agoraphobic (Rosenbaum et al., 1988) or alcoholic parents (Hill et al., 1999b) display higher rates of behavioral inhibition than do children of parents without any psychiatric illness should give us pause. Moreover, Biederman et al. (1990) have shown that offspring of parents with panic disorder and agoraphobia, who had previously been classifiedas inhibited at 21 months in a laboratory protocol, were more often diagnosed with multiple anxiety, overanxious, and phobic disorders when evaluated with a structured psychiatric interview at 4 to 8 years. Therefore, while we agree that behavioral inhibition "does not represent an equation with internalizing disorders," there is clear evidence that children classifiedas behaviorally inhibited on the basis of the laboratory protocol developed by Kagan and colleagues are at increased risk for anxiety disorders (Biederman et aI., 1990). She then asks, "Is this finding [Hill et aI., 1999b] specific to alcoholic families, or is behavioral inhibition a nonspecific characteristic of high-risk offspring?" (p. 417). This is an important question. Many putative markers for psychiatric illnessultimately turn out to be nonspecific (e.g., dexamethasone suppression appears to be present in conditions other than major depressive disorder). We argue that this is exactly the reason one should first study families of alcoholics without comorbidity. Valid markers can then be extended to other samples with comorbidity to evaluate generalizability. The answer to her question "Will the findings of Hill and colleagues generalize to children from other alcoholic families?" (p. 417) is currently unknown. However, discoveriesin basic neuroscience are typically based on the most homogeneous samples of laboratory animals avail-
271
LETTERS TO THE EDITOR
able (same strain, gender, age, supplier), wirh further testing in additional strains to determine generalizability. No laboratory researcher would purposely select a few Sprague-Dawley, a few Long-Evans, and a few Wistar rats. Another major point was that "the laboratory paradigm used by many studies (including that by Hill et al.) does not assess cross-situational or long-term persistence of the pattern" (p, 417). We disagree. While the "ecological validity" of any laboratory procedure can be questioned, the psychiatric! psychological community has a long tradition of sampling behavior in a laboratory setting where controlled conditions are possible and then making inferences about the individual's predisposition to future behavior. The protocol described in the Hill et al. report is a behavioral observation, not a questionnaire filled out by the mother. Replication of testing conditions was ensured by using the protocol identical with that used by the Harvard investigators in their study of offspring of diverse clinically disordered parents (Harvard investigators came to the Pittsburgh site to assess the similarity of testing conditions). The only modification of the Harvard protocol was one addressing the issue of whether the behavior is situation-specific. Each child was paired with different children in up to 3 separate test sessions. Dr. Weinberg also asks, "Might language disorders play some role in the picture of behavioral inhibition in children from alcoholic pedigrees?" (p. 418). First, one should not expect language disorders to playa greater role in the likelihood of observing behavioral inhibition in children from alcoholic pedigrees than it would in children from other affected pedigrees (e.g., depression). Language deficits in children of alcoholics have not been observed uniformly; at least 2 studies did not observe differences (Hill et al., 1999a; Reich et al., 1993). Second, Dr. Weinberg seems to imply that if a behaviorally inhibited child were to have either a receptive or expressive language disorder, we should assume the child is not really behaviorally inhibited. We believe this assumption is faulty. Children who are withdrawn may have less experience conversing with others and, therefore, may have difficulties adequately expressing their thoughts and feelings. But can we say the language problem is the cause? Even if one were to assume that language difficulties contributed to the likelihood that a given child would be diagnosed as behaviorally inhibited, this would have a potential effect on only 2 (latency to speak to the other child, total time speaking to the other child) of the 5 different measures assessed (the additional 3 measures were latency to touch toys, time spent proximal to parent, and time spent staring at the other child). Offspring of alcoholics showed significantly more time staring at the child with whom they were paired in a play session and more time proximal to their parent than did control children. Finally, we should not require less evidence to assume a positive association between alcohol abuse and externalizing disorders than is required to establish the relationship between
272
internalizing disorders and alcohol abuse. A careful review of this literature suggests that frequently, adult antisocial alcoholics are interviewed regarding their previous histories of conduct disorder as children and adolescents. Few studies have been prospective; most are cross-sectional (see Sher et al., 1991, for a review). Also, while children of alcoholics appear to be at increased risk for externalizing disorders in childhood/ adolescence and at increased risk for developing alcoholism, it must be remembered that few studies have followed children of alcoholics into adulthood to document that those who actually develop alcohol dependence more frequently had diagnoses of externalizing disorders in adolescence. In fact, Caspi et al. (1996), studying children of alcoholics, found evidence for both externalizing and internalizing disorders predicting alcohol abuse. Our recent work (Hill et al., 1999a) involving an 8-year follow-up of 8- to 18-year-old children of alcoholics and controls suggests that children of alcoholics have significantly increased odds ratios for internalizing disorders (e.g., depression was 4.1) as well as externalizing disorders (conduct = 3.5; ADHD = 10.6). Although children of alcoholics have an increased risk for developing alcoholism, not all of these children become alcoholic. Therefore, it is critical to determine which factors in childhood and adolescence are risk or protective factors. Further work is needed that is open to the possible role of internalizing disorders in the development of adult alcohol abuse and alcoholism. This research should use prospective designs to determine which children of alcoholics are susceptible and which are resilient. Shirley Y. Hill, Ph.D. University of Pittsburgh School of Medicine Jerome Kagan, Ph.D. Department of Psychology Harvard University Cambridge, MA Biederman J, Rosenbaum JF, Hirshfeld DR er al. (1990), Psychiatric correlates of behavioral inhibition in young children of parents with and without psychiatric disorders. Arch GenPsychiatry 47:21-26 Caspi A, Moffitt TE, Newman DL, Silva PA (1996), Behavioral observations at age 3 years predict adult psychiatric disorders. Arch Gen Psychiatry 53: 1033-1039 Hill SY, Locke ], Lowers L, Connolly J (1999a), Psychopathology and achievement in children at high risk for developing alcoholism. ] Am Acad Child
Adolesc Psychiatry 38:883-891 Hill SY, LowersL, Locke], Snidman N, KaganJ (l999b), Behavioral inhibition in children from families at high risk for developing alcoholism.] Am Acad
ChildAdolesc Psychiatry 38:410-420 Reich W, Earls F, Frankel 0, Shayka JJ (1993), Psychopathology in children of alcoholics.] Am Acad ChildAdolesc Psychiatry 32:995-1002 Rosenbaum JF, Biederman J, Gersten M et al. (1988), Behavioral inhibition in children of parents with panic disorder and agoraphobia. Arch GenPsy-
chiatry 45:463-470 Sher KJ, Walitzer KS, Wood PK, Brent EE (1991), Characteristics of children of alcoholics: putative risk factors, substance use and abuse, and psychopathology.] Abnorm Psychol100:427-448
J.
AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 39:3. MARCH 2000