Protective Factors: Independent or Interactive?

LETTERS TO THE ,EDITOR Low Dose Tricyclic Tachycardia To the Editor.' Although tricyclic antidepressants commonly increase heart rate, clinically significant tachycardia is unusual (Diamond, 1986). We report that two different tricyclic antidepressants used in treating an adolescent produced a sudden onset of severe tachycardia (heart rate of 170). To our knowledge, this is the first report of severe tachycardia in an adolescent as a result of treatment with tricyclic antidepressants. It is important to recognize this apparently infrequent but potentially dangerous side effect and to delineate predisposing factors. A. is a 16-year-old adopted, white female admitted to the inpatient psychiatry service because of violent and oppositional behavior. Before her hospitalization , she had become assaultive toward her parents, self-mutilative, and she had overdosed on medications . Her sleep, appetite, and concentration were poor. She denied feeling depressed but was tearful and stated she wished she would die. A. 's physical examination was notable for multiple, well-healed scars on her left upper and lower extremities from previous self-injurious episodes. Her head was small but symmetrical and measured at the 25th percentile. The inner canthus , outer canthus, and outer pupillary measurements were at the 3rd percentile for her age. All of her laboratory tests were normal, including screens for metabolic and genetic abnormalities. Magnetic resonance imaging of the head showed enlarged ventricles bilaterally. Her electroencephalogram was normal. Her full-scale IQ was 89, with a verbal IQ of 82, and a performance IQ of 100. A working diagnosis of major depression was made, and A. was started on the tricyclic antidepressant, nortriptyline. Her resting heart rate before the first dose of nortriptyline ranged from 80 to 90 beats per minute. Twenty mg of nortriptyline were given at bedtime for 2 nights then increased to 40 mg the third night. Approximately 16 hours after the third dose of nortriptyline , A.'s heart rate increased to 172 beats per mintue. She complained of dizziness and felt that her heart was racing. Nortriptyline was discontinued, and her heart rate returned to the 80s within 2 days. Desipramine was then started at 20 mg, twice daily. Within 2 hours after the fourth dose , her heart rate was 168 beats per minute, and again she complained of dizziness and palpitations. Desipramine was immediately discontinued, and her heart rate returned to the 80s within 5 days. Serum drug levels of nortriptyline and desipramine were not obtained because of the very brief duration of treatment. Electrocardiograms at the time of admission and during both episodes of tachycardia were normal, except for the increased heart rate . PR and QRS intervals did not lengthen after exposure to the medication. A pediatric cardiology consultation was obtained, and Holter monitoring was completed within 48 hours after desipramine was discontinued. Results during the 24-hour period of monitoring showed tachycardia at 140 beats per minute, associated with dizziness, dyspnea, chest pain, and nausea. This was believed to be secondary to previous doses of desipramine, and no additional evaluation was recommended. A. 's Cardiac echogram at age II was normal. Her heart rate during the remainder of her hospital stay (42 days) averaged 93 .2 beats per minute, with a range of 74 to 130. A study with children , aged 7-12 years, showed baseline heart rates between 85 to 90 beats per minute before treatment with imipramine (Preskorn et al., 1983). Serum blood levels greater than 225 ng/ml increased standing mean heart rate by 13 beats per minute. In contrast to our patient, these increases were measured after longer exposure to

J .Am.A cad . Child Adolesc. Psychiatry, 30 :1, January 1991

the medication and at therapeutic doses. Although tricyclic blood levels were not obtained in the case reported here, they could have ruled out the unlikely possibility of toxic levels. Children are thought to be at greater risk of developing side effects from tricyclic antidepressants because of the decreased ability of their blood proteins to bind to these drugs (Winsberg et al., 1974). In summary, our patient is unusual in that she developed a symptomatic tachycardia soon after taking two different tricyclic antidepressants, both in very low doses. Children are possibly more vulnerable to cardiac side effects because of the differences in metabolism of these medications in a young population. A.'s physical anomalies suggest the possibility of an undetected genetic abnormality, which could possibly affect cardiac conduction (i.e ., aberrant nodal pathways). Although this patient did not receive additional treatment with a tricyclic antidepressant, it might be possible if a B-blocker were administered concurrently (Hillard and Vieweg, 1983). Since tachycardia because of anticholinergic effects decreases with aging (Dauchot and Gravenstein, 1970), this patient may eventually tolerate treatment with a tricyclic antidepressant alone. Janell Giesler, M.D . Elizabeth Reeve, M.D . Carrie M. Borchardt, M.D. University of Minnesota Minneapolis, Minnesota REFERENCES

Dauchot, P. & Gravenstein, J . S. (1970) , Effects of atropine on the electrocardiogram in different age groups. Clin. Pharmacol. Ther. , 12:274-280. Diamond, J. M. (1986), Sudden-onset tachycardia induced in a child by imipramine. Am . J. Psychiatry , 143:1067. Hillard, J. R. & Vieweg, W. V. R. ( 1983), Marked sinus tachycardia resulting from the synergistic effects of marijuana and nortriptyline . Am. J. Psychiatry, 140:626-627. Preskorn, S. H., Weller, E. B., Weller, R. A. & Glotzbach, E. (1983), Plasma levels of imipramine and adverse effects in children. Am. J . Psychiatry , 140:1332-1335 . Winsberg, B. G. , Pevel, J. M. , Hurwic , M. J. & Klutch, A. (1974), Imipramine protein binding and pharmacokinetics in children. In: The Phenothiazines and Structurally Related Drugs, eds. I. S. Forest, C. J. Carr & E. Usdin. New York: Raven Press, pp. 425--431.

Protective Factors: Independent or Interactive? To the Editor: Drs. Jenkins and Smith are to be congratulated on an innovative, informative study of factors serving to protect children living in disharmonious homes (Jenkins and Smith, 1990). Quite rightly , they point out that the concept of a protective factor implies a modification of the effect of the stress factor, and that this means that there must be a statistical interaction between the stress and the putative protective factor and not simply a main effect from the latter. Their analyses were well designed to investigate this important issue, and their discussion of the findings is thoughtful and clinically helpful. Their rigorous and well-conceived investigation constitutes a model for other researchers to follow. However, I was most surprised to find in their introduction that I am cited as a researcher who has argued that protective factors represent independent main effects and not interactive mechanisms. Nothing could be farther from the truth. In my 1981 paper that they cite (Rutter, 1981), I argued, "The notion here, then,

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is of factors which are largely inert on their own but, to use a chemical analogy, serve as catalysts when combined with acute stressors of some type.... When they tend to reduce the effect of stressors, they are usually termed protective factors (as considered by Rutter, 1979)" (p. 340--341). The article then went on to consider the detection of statistical interaction effects in relation to the postulated protective influence of social networks and close personal relationships. The 1979 article stated: "The first point to make is the very great importance of interactive effects" (p.51). A more recent article (Rutter, 1987) dealt at length with the importance of the concept of protective mechanisms as interaction effects and of the implications for data analysis that flow from this recognition. In short, the theoretical position that I have advocated for over a decade is precisely that put forward by Jenkins and Smith and so elegantly dealt with in their own important empirical study. One additional point needs to be made, however, and that is that there are many circumstances in which it is misleading to equate interaction mechanisms with a statistically significant interaction term in the multivariate analysis. Some of the reasons why that is so are discussed in Rutter (1983), and a more extended conceptual and statistical account is provided in Rutter and Pickles (in press). Michael Rutter, M.D., F.R.S. Institute of Psychiatry London REFERENCES

Jenkins, J. M. & Smith, M. A. (1990), Factors protecting children living in disharmonious homes: maternal reports. J. Am. Acad. Child Adolesc. Psychiatry, 29:60--69. Rutter, M. (1979), Protective factors in children's responses to stress and disadvantage. In: Primary Prevention ofPsychopathology: Vol. 3: Social Competence in Children, eds. M. W. Kent & J. E. Rolf. Hanover, NH: University Press of New England. - - (1981), Stress, coping and development: some issues and some questions. J. Child Psychol. Psychiatry, 22:323-356. - - (1983), Statistical and personal interactions: facets and Perspectives. In: Human Development: An interactional perspective, eds. C. Magnusson & V. Allen. New York: Academic Press, pp. 295319. - - (1987), Psychosocial resilience and protective mechanisms. Am. J. Orthopsychiatry, 57:316-331. - - Pickles, A. (in press), Person-environment interactions: concepts, mechanisms and implications for data analysis. In: OrganismEnvironment Interaction, eds. R. Plomin & T. Wachs. Washington, DC: American Psychological Association.

Autism and Asperger's: Same or Different? To the Editor:

We found it interesting to read the paper by Szatmari and colleagues (1990) on the neurocognitive aspects of Asperger's syndrome (AS), which is likely to be a subcategory of the pervasive development disorders (POD) in ICD-lO (Rutter, 1989). However, general opinion among researchers and now Szatmari's group is that AS is merely a variant of high-functioning autism (HFA), raising the question of how discrete is the autistic syndrome. This paper is the first controlled study of the question of diagnostic subcategories among individuals who have POD but are not mentally retarded. Szatmari et al.'s careful, considered, analysis provides some fascinating and unexpected findings on the neuropsychological profile of the normal intelligence (lQ > 85) POD group as a whole but failed to find very important differences between HFA and AS. This appears to provide additional evidence for the unnecessary subclassifiction of POD, but the authors admit that there are reasons for considering limitations in their study. These include the wide age range of the subjects, varying recruitment

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sources, and mixed retrospective and prospective diagnostic assessments. We are in the process of studying children (5 to 12 years) who have POD (by DSM-III-R) and have a testable intelligence in the nonretarded range. They are being compared with language impaired and behavior disordered (control) children on a number of neuropsychological and neurobiological variables. Within the POD group, we believe there are three clinical subgroups; namely, classical (or Kanner's) autism, language impaired POD, and nonlanguage impaired POD. Only the latter would be considered AS by our criteria. After our review of this paper, we decided to assess the validity of our proposed groupings by analyzing preliminary data from the first 41 subjects (26 POD and 15 controls) we had assessed. To create our three PDD subgroups, we merely took the clinical data obtained from a parent interview, devised by Dr. Szatmari, for diagnosing POD and blindly rated for the presence of classical autism (i.e., aloofness, echolalia, pronoun reversal, need for sameness, etc., before 3 years of age). If the criteria were not fulfilled, the remaining subjects were differentiated by the presence or absence of developmental language disorder. We found that a discriminant analysis using the global scales of the Kaufman-ABC (five scores derived from the individual test scores of this battery) revealed a correct diagnostic classification 76% of the time (Kappa = 0.68). Only two POD subjects were placed in an alternative POD group. Given that there were overall IQ differences between groups, repeated discriminant analyses were performed on the mental processing composite score (MPC, comparable but not equivalent to an IQ score) alone and after deleting it from the analysis, which produced correct classifications of 41% and 37%, respectively. The analysis of MPC alone produced two groups, high and low functioning, in which POD subjects were evenly distributed independent of our subgroupings. It was therefore apparent that differentiation between groups was a consequence of the full range of neuropsychological skills. Furthermore, the groups showed fairly specific profiles on the subtests. The autistic group was typified by strengths in Gestalt closure, number recall, triangles, and reading/decoding and reading/understanding and by significant weakness in achievement measures requiring abstract processing (e.g., riddles). Language impaired PDD subjects were weak in all subtests. Nonlanguage impaired PDD subjects were comparatively weak in Gestalt closure, spatial memory, and photo series, but achievement scores were above intellectual expectation. We do not present this data to refute Szatmari's findings, not the least because we have not completed our studies, nor subjected them to peer scrutiny. However, we did find a more traditional pattern of psychological strengths and weaknesses in our autistic group. Given that diagnostic criteria for AS are unclear and if the remaining POD subjects were therefore grouped all as AS, there would be little likelihood of eliciting a difference between AS and HFA because their very different neuropsychological patterns would be lost in the group data. The differences we found may be because of different measures (Wechsler Intelligence Scale for Children-Revised versus KaufmanABC), different subject selection (more mild or subtle disorders in our cohort), or that we have merely selected three levels of severity of POD. Although these errors may prove to be true, this does not explain the different group profiles and would warrant caution in eliminating POD subgroups of clinical and heuristic value. John C. Pomeroy, MBBS, MRC Psych. Carol Friedman, Ph.D. Laurie Stephens, M.A. State University of New York at Stoney Brook REFERENCES

Rutter, M. (1989), Child psychiatric disorders in ICD-lO. J. Child Psychol. Psychiatry, 30:499-513. J.Am.Acad. Child Adolesc.Psychiatry, 30:1 ,January 1991