Plasma Cortisol and Aggression in Boys With ADHD

KURT P. SCHULZ, B.A., JEFFREY M. HALPERIN, PH.D., JEFFREY H. NEWCORN, M.D.,

VANSHDEEP SHARMA, M.D., AND STEPHEN GABRIEL, PH.D.

ABSTRACT

Objective: The results of several studies suggest an inverse relationship between cortisol secretion and aggressive

behavior. This study examined basal plasma cortisol levels in aggressive and nonaggressive boys with attention-deficit

hyperactivity disorder (ADHD). Method: The subjects were 23 aggressive and 27 nonaggressive boys with ADHD,

aged 7 to 11 years. After 3 days of a low monoamine diet and an overnight fast, an indwelling catheter was inserted

into a forearm vein. Samples for plasma cortisol levels were obtained 105 and 115 minutes after insertion of the catheter.

Results: A one-way analysis of covariance (ANCOVA) controlling for body mass revealed no significant difference in

plasma cortisol between the aggressive and nonaggressive boys. Furthermore, when the children were alternatively

divided on the basis of the presence or absence of a DSM-/II-R diagnosis of conduct disorder, a one-way ANCOVA

again revealed no significant difference in cortisol levels. Conclusions: The hypothesized inverse relationship between

cortisol secretion and aggressive behavior in boys with ADHD was not found. These findings are consistent with a large

body of literature indicating that the biological substrate of aggression is complex and that the identification of biological

laboratory markers of aggressive behavior is not a clinically useful strategy at this time. J. Am. Acad. Child Ado/esc.

Psychiatry, 1997, 36(5):605-609. Key Words: attention-deficit hyperactivity disorder, aggression, cortisol, plasma.

Considerable evidence indicates that aggressive behavioris relatively stable throughout the human life span(Loeber, 1991). However, concomitant biologicalmarkers of aggression identified in adults have notbeen as consistently found in aggressive children or inchildren with conduct disorder (CD). Several studieshave found decreased cortisol secretion co be associatedwith aggressive behavior in adults (Virkunnen, 1985;Woodman et aI., 1978), while studies in aggressive

Acupud Stpumbtr 6, 1996.Mr. Schulz is with tht Nruropsychowgy Doctoral Program. Dtpartmmt of

Psychowgy, City Univmity ofNrw York. Dr. Halptrin is with tht Nturopsychol­ogy Doctoral Program, Dtpartmmt of Psychowgy. City Univmity of NrwYork; Dtpartmmt ofPsychowgy, Quam Colkgt oftht City Univmity ofNrwYork; and Dtpartmmt of Psychiatry, Mount Sinai School ofMtdicint. Drs.Ntwcorn, Shanna. and Gabritl art with tht Dtpartmmt ofPsychiatry. MountSinai School ofMtdicint.

This rmarch was supporud by NIMH grant I ROI MH46448. ThtWilliam T. Grant Foundation, Faculty Scholar, Award Program. and grant5 MOl RR00011 to tht Mount Sinai Gmtral Clinical Rmarch Cmttr fromtht National Cmttr for Rmarch Rtsourw, NIH. Sptcial thanks to DtbbitLazarw for uchnical support.

Rtprint rtqums to Dr. Halptrin, Dtpartmmt ofPsychowgy, Quam Colkgt,65-30 Kissma Blvd.• Flushing, NY 11361; ttkphont: (212) 241-6142; fax:(212) 289-1812; t·mail: jtjfrry_Halptrin@QG.tdu

0890-8567/97/3605-0605$03.00/0© 1997 by the American Academyof Child and Adolescent Psychiatry.

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 36:5, MAY 1997

children have produced conflicting results (Kruesi et al.,1989; McBurnett et al., 1991; Moss et aI., 1995;Scerbo and Kolko, 1994; Stoff et al., 1992; Tennesand Kreye, 1985; Tennes et aI., 1986; Vanyukovet al., 1993).

Cortisol is synthesized by the adrenal cortex, whichis, in turn, regulated in a hierarchical fashion by theanterior pituitary and the hypothalamus (i.e., hypothal­amic-pituitary-adrenal axis [HPAJ). The adrenal cortexsecretes cortisol into the general circulation, whereit is bound by several plasma-borne proteins. Whencirculating levels ofcortisol exceed the binding capacityof these proteins, the unbound fraction is excreted intothe urine and saliva (for more details see Lightmanand Everitt, 1986). As a result, cortisol can be measuredin plasma, saliva, and urine, although they reflectslightly different aspects of HPA function. Urinarycortisol levels reflect the integrated function of theHPA over a period of time, whereas salivary and plasmacortisol levels reflect the state of the HPA at a specificpoint in time.

Two studies have reported a significant relationshipbetween urinary free cortisol and aggressive behaviorin second-grade children. Both hostility to the teacher(Tennes and Kreye, 1985) and aggression coward peers

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SCHULZ ET AL.

(Tennes et al., 1986) were found to be negativelycorrelated with urinary cortisol secretion over a 2-hourperiod. In contrast, Kruesi et al. (1989) found nodifference in 24-hour urinary free cortisol secretion in19 boys with attention-deficit hyperactivity disorder(ADHD) and/or CD and age-matched controls.

More recent investigations of the relationship be­tween HPA dysfunction and disruptive behavior disor­ders in children have used salivary measures of cortisolsecretion, which also assess circulating levels of free orunbound cortisol. Vanyukov et al. (1993) found thatsalivary cortisol levels correlated negatively with CDsymptom counts in boys with substance-abusing fa­thers. Cortisol levels were also lower in those boyswhose fathers had a childhood history of CD and thendeveloped antisocial personality disorder. McBurnettet al. (1991) found no difference in salivary cortisolbetween boys with CD and age-matched controls,although they did find a significant interaction betweenCD and anxiety disorder, such that the CD boys witha comorbid anxiety disorder had higher cortisol levelsrelative to nonanxious CD boys and normal controls.Finally, Scerbo and Kolko (1994) found no relationshipbetween salivary cortisol and aggressive behavior inchildren with disruptive behavior disorders.

Since cortisol is secreted by the adrenal cortex intothe general circulatory system and is subsequently ex­creted through saliva and urine, plasma measures oftotal cortisol may represent a more direct assessmentof HPA function. Furthermore, salivary and urinarycortisol levels reflect only the unbound fraction ofcirculating cortisol (Vinning et aI., 1983), not totalcortisol excreted, and therefore may be confounded bysuch factors as the availability of binding proteins.However, similar to salivary cortisol levels, plasma levelsof cortisol reflect the state of the HPA at specific pointin time. The only study to report plasma cortisol levelsin aggressive youth found no difference in basal cortisollevels between adolescents with disruptive behaviordisorders and normal controls (Stoff et al., 1992).However, the results of this study may be confoundedby the fact that plasma samples for baseline cortisolwere drawn immediately after venipuncture, which initself may cause a stress-induced rise in cortisol (Masonet at., 1973).

Thus, while some studies suggest an associationbetween low urinary and salivary cortisol and aggressive/disinhibited behavior in prepubescent children, there

606

have been inconsistent findings, which may vary bothas a function of the source of cortisol sampled andthe methodology used. The purpose of the presentstudy was to assess the relationship between basalplasma cortisol levels and aggression in a sample ofprepubertal boys with ADHD. It was hypothesizedthat the aggressive subjects would have lower basalcortisol levels than the nonaggressive subjects.

METHOD

Subjects

Subjects were 50 clinic-referred boys, aged 7 to 11 years, whoparticipated in a neuroendocrine challenge procedure (Halperinet aI., 1994, in press). Teacher ratings of behavior were obtainedusing the IOWA Conners Teacher's Questionnaire (CTQ) (Loneyand Milich, 1982). Parent ratings of behavior were ascertained usingthe Child Behavior Checklist (CBCL) (Achenbach and Edelbrock,1983). In addition, the Diagnostic Interview Schedule for ChildrenVersion 2.1 (DISC) (Shaffer et aI., 1989) was administered to

parents.All subjects met DSM-lIl-R criteria for ADHD based on parent

responses to the DISC. Children with a Full Scale IQ, as measuredby the WISC-R, of less than 70 were excluded from this study.Furthermore, to achieve a more homogenous sample of boys withADHD, those who met criteria for a current diagnosis of majoraffective disorder, pervasive developmental disorder, schizophrenia,or tic disorder were also excluded .

As described previously (Halperin et aI., 1994), all interviewand rating scale data for each child were independently reviewedand each child was rated as either "aggressive," "nonaggressive:'or "equivocal" by three investigators (J.M.H., ].H.N., V.S.) whowere blind to the biological data. This best-estimate procedure wasused instead of more traditional rating scale cutoffs because parentand teacher aggression scales tend to assess oppositional/defiantbehavior rather than physical aggression and because there isfrequent disparity between parent and teacher reports. The boyswere divided into subgroups on the basis of the presence or absenceof a persistent pattern of physically aggressive behaviot in thepreceding 6 months, as defined by at least one of the followingitems from the DSM-llI-R symptom list for CD: physically cruelto animals, forced someone into sexual activity, used a weapon inmore than one fight, frequently initiates physical fights, stealingwith confrontation of the victim, or physically cruel to people.There was perfect agreement across all three raters for 44 of the50 cases. The six discrepancies were all rated as equivocal by somereviewers and nonaggressive by others. They were not rated asaggressive by any reviewer and were therefore classified as nonaggres­sive by consensus. The final groups consisted of 23 aggressive and27 nonaggressive children.

As shown in Table I, the aggressive and nonaggressive groupsdid not differ in age, socioeconomic status, IQ, academic achieve­ment, or ratings of hyperactivity. As expected, the groups differedsignificantly in both parent ratings of aggression as indexed by theAggression subscale of the CBCL (t[48] = 4.76, P < .001) andteacher ratings of aggression as measured by the Aggression scaleof the CTQ (t[47] =4.17, P < .001). With regard to comorbidity,12 (52%) of 23 children in the aggressive group met DSM-llI-R

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 36:5, MAY 1997

PLASMA CORTISOL AND AGGRESSION IN ADHD BOYS

TABLE 1Demographic and Psychometric Characteristics and Cortisol Levels of Aggressive and Nonaggressive

Boys With Attention-Deficit Hyperactivity Disorder

Aggressive Nonaggressive(n = 23) (n = 23)

Variable Mean SO Mean SD t P

Age (yr) 9.0 1.4 9.0 1.2 0.26 NS·WlSC-R Full Scale IQb 94.2 13.6 100.8 11.4 1.85 NSIOWN

Inattention/Overactivity 11.5 2.8 10.3 2.6 1.51 NSAggression 10.0 4.1 5.3 3.6 4.17 <.001

Child Behavior ChecklistHyperactivity 75.2 8.6 71.7 8.6 1.44 NSAggression 80.6 11.1 66.5 9.4 4.76 <.001Delinquency 75.6 7.9 67.5 6.7 3.97 NS

Basal cortisol level 12.6 8.8 11.8 6.7 0.39 NS

"NS = not significant. p > .10.b The WISC-R was not administered to one child in the nonaggressive group.,. Teacher ratings were not obtained for two childten in the aggressive group.

critetia fOt CD. whereas only 1 child (3.7%) in the nonaggressivegroup had CD (;e [lJ = 16.08. P < .000 I). The aggressive andnonaggressive groups did not differ in the rate of anxiety disorders(Jerl] = 0.10. P > .10).

Procedure

This study was approved by the Queens College and MountSinai School of Medicine Institutional Review Boards. After theprotocol was thoroughly described to them. signed informed consentand verbal assent were obtained from the parent and child,respectively.

Subjects were medication-free for at least 4 weeks and maintainedon a low monoamine diet for 3 days before the biological procedure.After an overnight fast, an indwelling catheter was inserted into aforearm vein at 8:00 A.M. Subjects remained awake, supine, andfasting until the procedure ended. Samples for cortisol levels wereobtained at 9:45 A.M. and 9:55 A.M. Cortisol was sampled twice,105 and 115 minutes after insertion of the catheter. to achieve astable baseline measure, free of the confounding rise in cortisolsecretion due to the stress of venipuncture (Mason et aI., 1973).Samples were placed on ice until centrifugation (within 2 hours).After separation. samples of cortisol remained frozen at -80°Cuntil assayed by radioimmunoassay (Kahn et aI., 1994). Thesensitivity of the assay is 0.5 Ilg/l 00 mL, and the intra- andinterassay variability are less than 6% and 10%. respectively.

RESULTS

The two cortisol samples were highly correlated (r =

.84, P < .0001), and levels did not significantly differ(t[48] = 1.38, P > .10). Therefore, basal cortisol wascalculated as the mean of the two samples.

Cortisol level was significantly negatively correlatedwith age (r = - .32, P < .05) and body mass (r =

- .35, P < .05), which were both significantly intercor­related (r = .46, P < .01). Therefore, the data analysis

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 36:5. MAY 1997

was carried out using analyses of covariance (ANCO­VAs) with body mass as a covariant of cortisol levels.

One-way ANCOVA revealed no significant differ­ence between the basal cortisol levels of the aggressiveand nonaggressive groups (F[ 1,48] = .033, P > .10)(Table 1). Similarly, cortisol levels did not differ whenthe subjects were instead divided by the presence orabsence of CD (F[I,48] = 1.57, P > .10).

Post hoc analysis revealed no main effect of anxietydisorder on basal cortisol levels (F[ 1,48] = 1.81, P >.10). In addition, two-way ANCOVAs revealed nosignificant interaction between CD and anxiety disorderon cortisol levels (F[I,48] = 0.07, P > .10) or ofaggression and anxiety disorder on cortisol (F[ 1,48] =0.00, p > .10).

When these data were examined dimensionally, par­tial correlations controlling for body mass revealed norelationship between cortisol levels and the parents'ratings on the Aggression (r = -.10, P > .10), Delin­quency (r = - .08, P > .10), Hyperactivity (r = -.11,p> .10), and Internalizing scales (r = -.21, P > .10)of the CBCL. Consistent with this, no correlation wasfound between cortisol levels and the teachers' ratingson the Inattentive/Overactive scale (r = - .05, p >.10) and the Aggression scale (r = - .15, P > .10) ofthe CTQ.

DISCUSSION

The results of this study do not support the hypothe­sized inverse relationship between cortisol secretion

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and aggressive behavior in boys with ADHD. Further­more, no association was found berween basal cortisollevels and CD or CD with comorbid anxiery. Theseresults suggest that HPA function. as assessed by plasmameasures of total secretion of cortisol, is not decreasedin prepubertal aggressive or CD boys with ADHD.

Our results must be considered in the light of thefact that no normal controls were included in thisstudy, and therefore it is still possible that cortisollevels of the entire sample of boys with ADHD weredecreased. Virkunnen (1985) found that a lower basalurinary cortisol level was associated with a retrospectivechildhood history of ADHD. It is also possible thatbasal cortisol level is associated with certain characteris­tics of ADHD (i.e., impulsiviry, inattention), ratherthan being related to aggression or CD. Furthermore.this study is limited by the fact that cortisol wassampled at only one point in time, and not severaltimes over consecutive days.

Our results. which are consistent with the findingsof Scerbo and Kolko (I994), indicate that there is noclear relationship berween childhood aggression/CDand basal cortisol levels. That similar results have nowbeen found using urinary, salivary. and plasma measuresof cortisol suggests that this lack of an association isnot an artifact of sampling methods, nor is it a functionof or related to differences berween sampling cortisolsecretion over a period of time (i.e., urinary) or at aspecific point in time (i.e., salivary, plasma). Further­more, the lack of an association berween aggressivebehavior in children and decreased cortisol levels isnot a result of differences due to sampling bound (i.e.•plasma) and unbound (i.e., urinary, salivary) cortisol.

Our findings are not consistent with those ofMcBur­nett et al. (I991), who found elevated salivary cortisolin children with comorbid CD and anxiery. However,the post hoc nature of their finding makes the resultin need of replication. Our results are also not consistentwith the findings of Moss et al. (1995) and Vanyukovet al. (1993), who evaluated the sons of substance­abusing and alcoholic men, respectively. Vanyukovet al. (1993) reported an inverse association berweenbasal salivary cortisol and the number ofCD symptomsin sons of alcoholic men. However, the diagnosticstatus of the children in the study was not specified,making these findings difficult to interpret. Moss etal. (1995) found that sons of substance-abusing fatherswere rated as significantly more aggressive/delinquent

608

and exhibited significantly lower levels of salivary corti­sol relative to sons of normal controls, suggestingthat decreased cortisol is inversely related to aggressivebehavior. Alternatively, decreased salivary cortisol maybe a marker of risk for substance abuse or psychiatricillness in general, as the alcoholic fathers exhibitedsignificantly increased frequencies of several psychiatricdisorders (i.e., major depression, generalized anxiery)compared with the fathers in the control group.

The results of Scerbo and Kolko (I994) and thoseof the present study do not completely rule out thepossibility of an association berween aggression andcortisol secretion in children. Sampling of cortisol ata single point in time reflects the steady state of theadrenal cortex of an organism. while measuring cortisolbefore and after a stressor reflects the organism's adreno­cortical reactivity to its environment (Wolff et al .•1964). Cortisol secretion has been found to rise instressful or anxiety-provoking situations, although thereis considerable variabiliry in this rise berween individu­als (Mason, 1968). Furthermore, the cortisol responseto stress has been found to differ as a function ofintelligence (Tennes and Kreye, 1985). effective copingresponse (Tennes et al., 1977), and family history ofsubstance abuse (Moss et aI., 1995). It is interestingthat Moss et al. (1995) found that the decreased cortisolresponse to a mild "stressor" was associated with themagnitude of their subjects' impulsivity and aggression.Therefore. it is possible that there is a relationshipberween childhood aggressive behavior and the cortisolresponse to a stressor.

This study has implications for clinicians in that itsheds further light on the relationship berween biologi­cal indicators of stress and aggression in children.Contrary to previous findings, our results suggest thatcortisol secretion, which is higWy responsive to stress,may not be associated with aggressive behavior inchildren. More likely, the biological substrate ofaggres­sion is complex, and the identification of biologicalmarkers of aggressive behavior is not a clinically usefulstrategy at this time.

In summary, this study found no difference in basalplasma cortisol level berween prepubertal aggressiveand nonaggressive boys with ADHD. In addition,comorbid anxiety was not associated with differences inplasma cortisol levels. Future studies of the relationshipberween HPA function and childhood aggression/CD

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 36:5. MAY 1997

should focus on adrenocortical reactivity before andafter a stressor.

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