side effects. Two such studies are now being conducted: asmall, unfunded study by Connor et al. (at the University ofMassachusetts) and a large, NIMH/National Institute of ChildHealth and Human Development-funded study by Kurlanet al. (coordinated at the University of Rochester). Until theresults of these controlled studies are available to guide clini­cal practice, we consider the use of the combination of MPHand clonidine to be ill-advised.

REFERENCESBiederman I. Thisted RA. (;reenhill LL, Rvan ND (199~), Estimation of the

associar"ioll between desipramine and 'the risk for sudden death in 5- to

14-year-old children, J Oill I'sycf,;tltry 56:87-9.'Cantwell DI~ Swanson IS, Connor DP (1')97), Case study: adverse response

to clonidine. J Am Acad ChilrlAdolesc Psycbiatr» Y" 1-6Comings DE, Comings BC, Tacker T, Li SZ (199()), The clonidine patch

and behavior problems (letter). J Am Amd Chilt/ Adolrsc Psvchintrv2'):(,(,7-(,(,8

DEBATE FORUM

Hunt RD (1987), Treatment eHects of oral and rrunsdcrrnal clonidine inrelation to methylphenidate. l'<yc!/(Iph,lrIl1r/col Bul! 2.': 111-114

Hum RD, Minderaa RH, Cohen DJ (1985), Clonidine benefits children

with attention deficit disorder and hyperactivity: report of a double­hlind placebo-crossover therapeutic trial. J Am Acari Child l'svclnatry24:617-(,29

Prince IB, Wi lens TE, Biederman J, Spencer TI, Wozniak IR (19')(1), C1oni­

dine for sleep disturbances associated with arrcntion-dcticir hyperactivitydisorder: a systematic chart review of 62 cases. J Am Amrl ChilrlAdole«I'sychi,Ttry .'~:~99-(,()5

Ruhinsrcin S, Silver LB, l.icamclc WL (1994), Clonidine tilt srimulanr­related sleep problems, JAm ACt,d ChilrlAdolrsr Psvcbi.urv .13:281-282

Steingard R, Biederman J, Spcnccr T, Wi lens T, Con1.ales A (199.'), Com­parison of clonidine response in the treatment of ADH D with and with­out comorhid tic disorders. J Am Acnd Child Adoles« !'rych;rttry .\2:.\~()-.'~.'

Swanson 1M, Flockhart D, Udrea D, Cantwell D'~ Connor D, WiliianlS L(19<)~), Clonidinc in the treatment of ADHD: questions about s"tl·ty

and efficacy. J ChilrlAdolrsr!'rychnpllr/mhlc,,1 5: \() 1-\04Wile", TE, Bicdcrm.m J, Spencer T (19')4), Clonidine tilt sleep disrur­

h.mccs associated with ADl-1D. J Am Am,1 Ch... ld Ad"/"rc Psvrliinrr».\.\:4.~4-426

AFFIRMATIVE REBUTTAL: WI LENS AND SPENCER

In their concise overview on the perils of clonidine alone orin combination with methylphenidate (MPH) or otherstimulants, Swanson er al. reasonably question the efficacydata on this combination. It continues to be important todistinguish controlled trial-derived efficacy from practitioner­derived effectiveness. Although clonidine requires additionalefficacy data, there is substantial clinical evidence for theeffectiveness of clonidine alone or in combination with othermedications. Such is the case within much of child psychi­atry. Despite the paucity of Food and Drug Administration(FDA)-approved psychotropics for youth, the use of med­ications for juvenile psychopathology is an important compo­nent of comprehensive treatment. For example, because oftheir clinical effectiveness, nortriptyline has been used foryears to treat attention-deficit hyperactivity disorder andserotonin reuptake inhibitors to treat depression; however,they have only recently been demonstrated efficacious undercontrolled conditions. While these circumstances are less thandesirable in our field, they nevertheless exist, compelling theclinician to exercise the best judgment in treating individualpatients by extrapolating from available scientific and anec­dotal information.

Our counterparts also raise concerns about the safety ofclonidine alone or in combination with MPH. We would againlike to reiterate our concerns about using the cited cases as thesole basis for the analysis of fatality. The assumptions of ourcolleagues were that these cases were exclusively related to theclonidine. However, in a separate review of these cases by apanel of experts including cardiologists convened by theHeart, Lung, and Blood Section of the National Institutes of

I. AM. ACAIJ. CHII.IJ AIJOI.ESC PSYCHIATRY, .\H:'i, MAY I')')')

Health (NIH) (Diane Atkins, M.D.. Chair, Special EmphasisPanel on Cardiac Arrhythmias in Children, August 29,19%), it was determined that the degree of confoundingfactors made these cases un interpretable. Moreover, questionsarose regarding the autopsy findings in 2 cases in whichcongenital cardiac malformations were found. The panelindicated that unexpected sudden death is an unfortunate,but not so rare cause of death in children, frequently unre­lated to medications. For example, current cardiology dataestimate that 10 to 40 children, adolescents, and young adultsper 1 million die yearly of sudden death. Seventy-five percentof these cases are of demonstrable cardiac origin when meticu­lous autopsies are performed by cardiac pathologists. Routineautopsies can easily miss cardiac pathology.

Moreover, in Swanson and colleagues' analysis of risk, wehad additional concerns. For example, the circularity of usinga speculated mechanism of sudden death as evidence tor"finding" cases prior to the establishment of causality is puz­zling, particularly when not eliminating cases in which ser­ious confounds existed. No attempt was apparently made tocontrol for underlying pathology or populations in which thevarious agents were used. The standardized mortality ratio(reported as odds ratios) is influenced by the base rate, and asstated later, the baseline sudden death rates are substantiallyhigher than those used by our colleagues. In short, we areconcerned about drawing on these hypothetical calculationsto dictate clinical practice.

We again reiterate that the now 2 "opposite" speculatedmechanisms of myocardial interaction between clonidine andMPH put forward by the authors do not explain why more

619

D EBAT E FO RU M

deaths have not routinely occurred between thi s combina­tion. C lonidine continues to be used in card iac intensive care

un its conjointly with p- agon ists in pat ients with markedmyocardial impairm ent: stimulants are ad ministered to treatclonidine overdo se; and clon idin e is routinely used in theamelioration of hyperadrenergic states such as withd rawalfrom drugs of abu se.

We are struck by the convergence o f opin ions on thi s im­portant issue. In addi tion to our co ncerns about th e validityof the assumptions and calculations of clonidine's lethality,independent assessm ents outside of the mental health field

by both a specialized assembly of card iologists and publichealth official s of the NIH, and that of th e card iorenalbran ch of the FD A, all did not co nclude that the cur rentdat a indicate an excess ive risk o f lethality exist s fromclonidine or the combination of clonidine plu s MPH. Gi venthi s state, we believe there is a need for additional evidencepr ior to indi cting the use of thi s co mbinatio n in clin icalpract ice. To this extent, we certai nly agree with Swanso ner al, on the need for furth er monitoring and systematicstu dy of thi s issue from which clinical practice guidelinesmay evolve.

NEGATIVE REBUTTAL: SWANSO N ET AL.

In their scholarly overview of the rationale for the use of thecom bination of clo nid ine and mcth ylphenidarc (M PH) ,Wilens and Spen cer (1) expanded the top ic to address theefficacy of clonidine alone, (2) reviewed the case for the com­bination for the treatment of children with attention-deficithyperactivity disorder (ADHD) and comorbid disorders, (3)emphasized that the combination may have fewer side effectsthan clonidine alone, and (4) reviewed the limitations of anal­ysis of spontaneous report s of adverse events . We restricted thelength and number of references in ou r initial statement , so weexpand ed our response in this rebuttal.

First, we respectfully d isagree wi th Wilens and Spencerabout eviden ce in favor of efficacy of clonidine for treating thetarget symptoms of AD H D . Our d isagreement highl ightsdifferences in our definition of "substant ive body of literature"for evaluation of efficacy. They accept uncontrolled trials asaccept able evidence for efficacy, but we do not. Thus, insteadof relying on "3D studies . . . includin g at least 500 child renand adolescents," we restrict our evaluation to 11 studies ofabo ut 150 subject s. and we submi t even th ese co nt ro lledstud ies to rigorous review. Our impressions are that (1) openstudies are likely to report large effects in almost all subjects(e.g., see Kemph ct al., 1993, or Schvehla et al., 1994), butcontro lled studies do nor . and (2) the reported effect sizes (i.e.,expressed in standard deviation un its) vary by a factor of 10 ormore across controlled studies, from about 5.0 in the Huntet al. (1985) study to about 0.3 in the Leckman er al. (1991)study, with decreasing effect size assoc iated with th e bestmethod ology and largest sample sizes.

We welcome th e challenge put for ward by Wil ens andSpencer and agree that our goal sho uld be "to pro vide clarit yto our task of thoughtfully using medi cations in the treat­ment of ch ild ren and adolescents with psychop ath ology."Stimulated by thi s challenge, we have revived our efforts toperform a rigorous evaluation. Even though our first att emptwa s not suitable for publication in this Journal, we will

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present some of our init ial discoveries that make this a com­plex task. We analyzed 2 of the stud ies we judged to have thebest methodology (Leckrnan et al. , 1991 , and Singer er al.,1995 ), both of wh ich evaluated effects of clon id ine on chil­dren with ADHD and tics. In both studies, we identified sta­tistical ambiguiti es in the data reported on sympto ms ofADHD that suggest that reanalyses may be warranted . A rigor­ous review of the Leckman et al. (1991 ) study (with respect to

effects on AD HD sympto ms. whi ch was not the primarypurpose of thi s stu dy of effects of clonidine on tics) mayprovide addition al support for our point of view, but thi s re­quires clarificat ion by reanalysis. In a parallel- groups designco mparing clo nid ine and placebo, a sign ificant beneficialeffect of clonidine on parent rat ings of impulsive/hyperactivebehavior was reported. Our review suggests th at this maydepend on adjustment for an initial (baseline) differencebetween the placebo and clon idine groups on the impulsive/hype ractive beh avior rat ings. If so, their reported significanteffect may be du e to regression to the mean and considerednon signifi cant, wh ic h would be co nsistent with othermeasure s of AD H D sympto ms in thi s study (e.g. , a non­significant effect on clini cian- rated C linical G lobal Impres­sions of attention deficit d isord er). To be fair, we mu st admitthat our review procedures may offer some suppo rt for theposition of Wi lens and Spencer. For example. in th e Singeret al. (1995) crossover study that reported clonidine and placebodid not differ (and both were inferior to desipramine), someevidence of a sign ificant effect may be d iscern ed (see theirfigure, p. 78). In the last of 3 periods. clon idin e may havebeen superior to placebo. The autho rs were careful to reporttreatment by ord er effects, and since the last period providesa relative rather than an absolute comparison , thi s may justifyreanalysis. Also, in our review of th is study for our meta -an al­ysis. we used the group means and "standard deviat ions" th atwere reported in th eir Tabl e 1 (p, 77). Based on this, wecalculated a large effect size for the clonidine-placebo com-

J. AM . ACAD . C H I I. D A DOI.E SC. PSYCHIATRY. .IX :'; . MA Y 1<) ') ')