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JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 9, Number 2, 1999 Mary Ann Liebert, Inc. Pp. 85-91 Thermal Response to Serotonergic Challenge and Aggression in Attention Deficit Hyperactivity Disorder Children ANNE-MARIE DONOVAN, B.A.,1 JEFFREY M. HALPERIN, Ph.D.,1'2 JEFFREY H. NEWCORN, M.D.,2 and VANSHDEEP SHARMA, M.D.2 ABSTRACT Body temperature change in response to the serotonergic (5-HT) enhancer, d,l-fenfluramine (FEN), was examined in 27 prepubescent boys diagnosed with Attention Deficit Hyperac- tivity Disorder (ADHD) to determine (1) the utility of this measure as an index of central serotonergic function; and (2) if the magnitude of temperature change is associated with ag- gression. FEN, 1 mg/kg, produced a significant increase in body temperature, the magni- tude of which was correlated with plasma levels of the FEN metabolite, norfenfluramine (NORFEN). Furthermore, a significant inverse relationship was found between temperature response to FEN and teacher ratings of aggression. Parent ratings of aggression were not significantly correlated with the hyperthermic response to FEN. Interestingly, the magni- tude of the hyperthermic response was unrelated to changes in plasma levels of prolactin and cortisol, suggesting that thermal and neuroendocrine responses are mediated by distinct 5-HT mechanisms. The agreement of these finding with those of studies using other proce- dures to assess the relationship between 5-HT and aggression suggests that decreased cen- tral 5-HT is associated with increased aggression. Over the past two decades, considerable evidence has indicated an association between aggressive behavior and central serotonergic (5-HT) function. Numerous studies in rodents (Bonson et al. 1994; DeAlmeida and Lucion, 1994; Delville et al. 1996a; Fuller 1996; Mos et al. 1993; Oliver et al. 1995; Sanchez and Hytell, 1994; Taylor et al. 1996) and primates (Higley et al. 1992; Kyes et al. 1995; Mehlman et al. 1994) have demonstrated that decreased central 5-HT is associated with increased aggression. Similarly, in adult humans, the inverse correlation between aggression and central 5-HT activity has been demonstrated both via examination of cerebrospinal fluid (CSF) concentration of the 5-HT metabolite, 5- HIAA (Brown et al. 1982; Linnoila et al. 1983), and by use of neuroendocrine response to pharmacologi- cal probes. Administration of fenfluramine (FEN), a 5-HT releaser and reuptake inhibitor, results in dose- dependent increases in prolactin and cortisol. Studies indicate the presence of a blunted prolactin response to FEN in aggressive and violent adults (Coccarro et al. 1989; O'Keane et al. 1992). 'Department of Psychology, Queens College of the City University of New York, Flushing, New York, department of Psychiatry, The Mount Sinai School of Medicine, New York, New York. 85

Thermal Response to Serotonergic Challenge and Aggression in Attention Deficit Hyperactivity Disorder Children

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Page 1: Thermal Response to Serotonergic Challenge and Aggression in Attention Deficit Hyperactivity Disorder Children

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGYVolume 9, Number 2, 1999Mary Ann Liebert, Inc.Pp. 85-91

Thermal Response to Serotonergic Challenge andAggression in Attention Deficit Hyperactivity

Disorder Children

ANNE-MARIE DONOVAN, B.A.,1 JEFFREY M. HALPERIN, Ph.D.,1'2JEFFREY H. NEWCORN, M.D.,2 and VANSHDEEP SHARMA, M.D.2

ABSTRACT

Body temperature change in response to the serotonergic (5-HT) enhancer, d,l-fenfluramine(FEN), was examined in 27 prepubescent boys diagnosed with Attention Deficit Hyperac-tivity Disorder (ADHD) to determine (1) the utility of this measure as an index of centralserotonergic function; and (2) if the magnitude of temperature change is associated with ag-gression. FEN, 1 mg/kg, produced a significant increase in body temperature, the magni-tude of which was correlated with plasma levels of the FEN metabolite, norfenfluramine(NORFEN). Furthermore, a significant inverse relationship was found between temperatureresponse to FEN and teacher ratings of aggression. Parent ratings of aggression were notsignificantly correlated with the hyperthermic response to FEN. Interestingly, the magni-tude of the hyperthermic response was unrelated to changes in plasma levels of prolactinand cortisol, suggesting that thermal and neuroendocrine responses are mediated by distinct5-HT mechanisms. The agreement of these finding with those of studies using other proce-dures to assess the relationship between 5-HT and aggression suggests that decreased cen-

tral 5-HT is associated with increased aggression.

Over the past two decades, considerable evidence has indicated an association between aggressivebehavior and central serotonergic (5-HT) function. Numerous studies in rodents (Bonson et al. 1994;

DeAlmeida and Lucion, 1994; Delville et al. 1996a; Fuller 1996; Mos et al. 1993; Oliver et al. 1995; Sanchezand Hytell, 1994; Taylor et al. 1996) and primates (Higley et al. 1992; Kyes et al. 1995; Mehlman et al.1994) have demonstrated that decreased central 5-HT is associated with increased aggression.Similarly, in adult humans, the inverse correlation between aggression and central 5-HT activity has been

demonstrated both via examination of cerebrospinal fluid (CSF) concentration of the 5-HT metabolite, 5-HIAA (Brown et al. 1982; Linnoila et al. 1983), and by use of neuroendocrine response to pharmacologi-cal probes. Administration of fenfluramine (FEN), a 5-HT releaser and reuptake inhibitor, results in dose-dependent increases in prolactin and cortisol. Studies indicate the presence of a blunted prolactin responseto FEN in aggressive and violent adults (Coccarro et al. 1989; O'Keane et al. 1992).

'Department of Psychology, Queens College of the City University of New York, Flushing, New York,department of Psychiatry, The Mount Sinai School of Medicine, New York, New York.

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DONOVAN ET AL.

Whereas data in animals and adults have consistently indicated an inverse relationship between central5-HT function and aggression, the relationship between these two variables appears to be more complex inchildren. Studies of the relationship between central 5-HT and aggression in children with disruptive be-havior disorders have yielded mixed results. Consistent with the adult literature, some studies reported aninverse relationship between central 5-HT and aggression in children (Kruesi et al. 1990; Kruesi et al. 1992).However, others (Castellanos et al. 1995; Halperin et al. 1994; Pine 1996) have found a positive associa-tion between the two factors in children such that aggression was associated with evidence of higher 5-HTresponsivity. More recent data suggest that developmental (Halperin et al. 1997a) and family factors(Halperin et al. 1997b) may have an impact on the magnitude of prolactin response to FEN. Thus, the re-

lationship between aggression and central 5-HT functioning in children does not appear to be characterizedby a simple inverse correlation, as typically reported in animals and adults, and considerably more researchwill be necessary to elucidate the relationship.In addition to the dose-related increases in several hormones, FEN has been shown to increase body tem-

perature in both animals and adults. Therefore, another potential approach to assessing central 5-HT func-tion is via the thermal response to pharmacological probes. This method would eliminate the need for in-vasive procedures such as venipuncture and, thus, would be more palatable to children. Further, it wouldeliminate the cost of assays.

Body temperature response to substances acting on the central 5-HT system has been examined exten-sively in animals. Gudelsky, Koenig, Jackman, and Meltzer (1986) reported that the hyperthermic responseto FEN is most likely mediated by 5-HT2 receptors, since the hyperthermic response to 5-HT agonists can

be blocked using the 5-HT2 antagonists, ketanserin, mianserin, and pirenperone. Taken together with thefact that 5-HT increases body temperature when injected into the anterior-lateral portions of the hypothal-amus (Brodai, 1981), but not other areas of the hypothalamus, it appears that the hyperthermic effects ofFEN may be mediated by 5-HT2 receptors in anterior-lateral portions of the hypothalamus. Furthermore,several studies in animals have suggested a role for the lateral hypothalamus in the mediation of aggres-sive behavior (Delville et al. 1996a; 1996b; Han et al. 1996).In normal adults, the hyperthermic response to FEN can be blocked by ritanserin, a specific 5-HT2 an-

tagonist (Goodall et al. 1993), but not by the specific 5-HTia antagonist, pindolol (Stahl et al. 1993). Thethermal response to FEN challenge has been shown to distinguish unmedicated adults with and without ma-jor depressive disorder (Stahl et al. 1993).

Furthermore, a drop in temperature in response to other 5-HT probes has also been found to be relatedto aggression. Challenge with ipsapirone, a 5-HTia agonist that produces a hypothermie response, has beencorrelated with history of aggression in adult men with personality disorder, such that a greater tempera-ture decrease is associated with higher aggression (Coccaro 1995). However, the thermal response to 5-HTprobes has not been systematically studied as a measure of 5-HT function in children.This study was designed to examine the utility of body temperature change as a measure of central 5-

HT function in children by determining whether (a) FEN causes a consistent increase in body temperaturein children; (b) the magnitude of the thermal response is associated with neuroendocrine changes follow-ing FEN administration; and (c) temperature changes are associated with ratings of aggressive behavior inchildren with ADHD.

METHODS

ParticipantsThe participants were 27 prepubertal boys, ages 7-11 years, who met DSM-III-R criteria for ADHD. The

children were all referred for clinical evaluation because of behavioral difficulties presenting either at school,home, or in both settings. The mean age was 9.3 years (SD = 1.33). Following an initial screening usingthe IOWA Connors Teacher Questionnaire (Loney & Milich 1982) and the Child Behavior Checklist (CBCL)(Achenbach & Edelbroch 1983), parents were interviewed using the Diagnostic Interview Schedule for Chil-dren (DISC-P) to confirm the diagnosis of ADHD (Shaffer et al. 1989). In addition to ADHD, 14 childrenmet DSM-III-R criteria for Oppositional Defiant Disorder (ODD) and 6 had Conduct Disorder (CD) ac-

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cording to the DISC-P. No child was accepted if he had a Wechsler/Intelligence Scale for Children-Revised(WISC-R) Full Scale IQ below 70 or if he met diagnostic criteria for a tic disorder, major affective disor-der, schizophrenia, or pervasive developmental disorder.This study was approved by both the Queens College and Mount Sinai School of Medicine Institutional

Review Boards. Following a thorough description of the protocol, signed informed consent was obtainedfrom the subject's parent and verbal assent was obtained from the child.To systematically assess aggressive behavior in the children, parent (CAS-P) and teacher (CAS-T) ver-

sions of the Children's Aggression Scale (McKay et al. 1993) were completed approximately 2 weeks priorto the biological challenge procedure. These scales assess the frequency of aggressive acts of varying sever-

ity and generate five scores each including: Verbal Aggression, Aggression Against Objects and Animals,Provoked Physical Aggression, Initiated Physical Aggression, and Use of Weapons. The scoring algorithmfor these scales uses a weighting system that was designed to differentially weigh behaviors of varyingseverity within each subscale. For example, on the "Aggression Against Objects and Animals" subscale,"slammed a door, kicked a chair or thrown or broke objects in anger" is weighted less than "injured or tor-tured a pet or other living animal." The teacher version of the scale focuses exclusively on behavior withinthe school setting, and has a time window that varies from two months (minimum used) to 10 months, de-pending upon how long the student has been in that teacher's class. In contrast, the parent version assesses

behavior within and outside of the home, and has a time window of one year.

FEN challenge procedureSubjects were medication-free for a minimum of four weeks and maintained a low monoamine diet for

three days prior to the biological study, which was conducted in the General Clinical Research Center ofthe Mount Sinai Medical Center. For the low monoamine diet, parents were provided with a list of foodsthat the child should avoid including many cheeses, processed foods, and chocolate. The diet was moni-tored by parental report. The protocol began at 8:00 am, following an overnight fast, with the insertion ofan indwelling catheter into a forearm vein for the purpose of assessing plasma prolactin and cortisol, andplasma medication levels (i.e., FEN and its active metabolite norfenfluramine, NORFEN). At 10:00 am, a

single 1 mg/kg dose of d,l-FEN was administered orally up to a maximum of 60 mg. Subjects remainedsupine, awake, and fasting until 3:00 PM. Television and videotapes were provided to entertain the childthroughout the procedure. Baseline measures of oral body temperature and plasma levels of prolactin andcortisol were obtained (via the catheter) within 15 minutes prior to FEN administration. Temperature was

reassessed using a digital thermometer every half hour after FEN administration until 3:00 PM (i.e., 10times). Plasma levels of medication, prolactin, and cortisol were obtained every hour after FEN adminis-tration (i.e., five times). Peak body temperature was defined for each boy as his highest temperature pointfollowing the medication. Similarly, peak FEN, peak NORFEN, peak prolactin, and peak cortisol were de-fined separately for each child as the highest plasma levels of that substance following medication.

RESULTS

Compared to baseline, there was a small but consistent increase in body temperature following FENacross the whole sample. A paired i-test was used to compare baseline temperature (M = 98.41, SD = 0.76)to peak temperature following FEN (M = 99.34, SD = 0.53). A significant difference was found betweenthese two measures (t (26) = 7.03, p < .001, 2-tailed).There was a trend for body temperature to be positively correlated with plasma NORFEN levels at 120

(r = .47, p < .10, 2-tailed) and 180 (r = .40, p < .10, 2-tailed) minutes after medication administration.Body temperature, however, was not related to FEN levels at any time or to NORFEN during the first orlast two hours of the procedure.Partial correlations, controlling for baseline temperature, were performed to assess the relationship be-

tween ratings of behavior and peak temperature following FEN. As shown in Table 1, significant inverserelationships were found between peak temperature and ratings of verbal aggression, aggression against ob-jects and animals, provoked physical aggression, and initiated physical aggression as rated by teachers on

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Table 1. The Relationship Between Ratingsof Aggression and the Thermal Response to

Fenfluramine Challenge in Children with ADHD

Temperature

Ratings of aggression

Teacher ratingsVerbal -.53 .004

.003Against objects and animals —.55Provoked physical —.51 .007Initiated physical —.40 .038Weapon use -.34 N.S.

Parent ratingsVerbal -.23 N.S.Against objects and animals .10 N.S.Provoked physical —.07 N.S.Initiated physical —.01 N.S.Weapon use .09 N.S.

aPartial correlations controlling for baseline temperature.N.S., not significant.

the CAS-T. The magnitude of these correlations was within the medium to large range as defined by Co-hen (1978). Change in temperature was not significantly correlated with ratings of aggression or hyperac-tivity on the IOWA Connors scales. Neither parent ratings of aggression on the CAS-P nor aggression andhyperactivity on the CBCL were related to temperature change.

Because prolactin and cortisol responses to FEN have been used to assess central 5-HT function, partialcorrelations controlling for baseline levels were performed between these measures and temperature changein response to FEN. No significant relationships were found between change in body temperature andchanges in plasma levels of prolactin (r = .16, N.S.) or cortisol (r = .01, N.S.). Furthermore, changes inprolactin and cortisol in response to FEN were not related to each other (r = .03, N.S.).

DISCUSSION

This study examined whether body temperature change in response to FEN can serve as an index of cen-tral 5-HT functioning in children and whether this thermal response is related to ratings of aggression.FEN produced a significant increase in body temperature, a finding consistent with the adult and animal

literature. The fact that this thermal response was blocked in adults by the 5-HT2 antagonist, ritanserin(Goodall et al. 1993), but not by the specific 5-HTla antagonist, pindolol (Stahl et al. 1993), suggests thattemperature increase in response to FEN is mediated by a 5-HT2 receptor. Although we did not examinethermal response to FEN in the context of receptor-specific antagonists, we did find that the magnitude ofthe thermal response in children was correlated with plasma levels of NORFEN. NORFEN is an activemetabolite of FEN and a direct postsynaptic 5-HT agonist, which is likely to be acting on 5-HT2 receptors(Brown et al. 1982).

The magnitude of the hyperthermic response was not associated with changes in prolactin and cortisol,two other indices of central 5-HT functioning. However, prolactin and cortisol changes in response to FENwere also not associated with each other, either. This lack of concordance may be explained by different5-HT receptor subtypes and/or distinct anatomical sites involved in the response of these variables to FEN.A significant inverse relationship was found between body temperature change in response to FEN and

teacher ratings of aggression on the CAS-T, a finding that is consistent with studies examining the rela-tionship between central 5-HT and aggression in adults (Brown et al. 1982; Coccaro et al. 1989; Linnoila

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et al. 1983; O'Keane 1992), and some studies in children (Kruesi et al. 1990; Kruesi et al. 1992). However,no relationship was found between parent ratings of aggression and temperature change. It is likely that thisdiscrepancy between parent and teacher ratings of aggression is due to the fact that parents and teachersare likely to observe and therefore rate different behaviors. A study by Hinshaw et al. (1992) compared par-ent and teacher ratings of aggression to objective observations of behavior in play groups. They found thatteacher ratings of aggression, but not parent ratings, predicted observed aggressive behavior. Teachers rate

aggression based on behavior occurring in school, where children can be more readily observed interactingwith their peers. Parents, however, may rate aggression based on behavior occurring at home where thepresence or absence of siblings may contribute to their rating.

The data from this study must be interpreted cautiously because there was no placebo control group fromwhich temperature change was measured. A possible alternate explanation for the temperature change isthat it is part of a circadian cycle and present in all individuals rather than due to FEN. However, the pos-itive correlation between temperature change and plasma levels of NORFEN supports the argument for a

causal relationship between medication and temperature.In summary, FEN challenge produced a small but significant increase in body temperature which is hy-

pothesized to be mediated by postsynaptic 5-HT2 receptors in the lateral hypothalamus. This body temper-ature increase was inversely correlated with teacher, but not parent, ratings of aggression, supporting a

rapidly emerging literature indicating an association between aggressive behavior and 5-HT function in chil-dren. This study suggests that thermal response to 5-HT agents may provide another index of central 5-HTfunction that can be used in future studies to help elucidate the relationship between central 5-HT and ag-gression in children.

ACKNOWLEDGMENTS

This research was supported by NIMH grant 1 ROI MH46448, The William T. Grant Foundation's Fac-ulty Scholar's Award Program, and grant MOI RR00071 to the Mount Sinai General Clinical ResearchCenter from the National Center for Research Resources, NIH

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Address reprint requests to:

Jeffrey M. Halperin, Ph.D.Department ofPsychologyQueens College of CUNY

65-30 Kissena Blvd.Flushing, NY 11367

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