BRIEF REPORTDouble-Blind Crossover Study of Chlorpromazine and Lorazepam in the

Treatment of Behavioral Problems During Treatment of Children With AcuteLymphoblastic Leukaemia Receiving Glucocorticoids

Gilles Pelletier, MD,1* Yvon Lacroix, MD,1 Albert Moghrabi, MD,2 andPhilippe Robaey, MD, PhD1

Key words: chlorpromazine; lorazepam; steroids; behavior; children; acutelymphoblastic leukaemia

Corticosteroid treatment in childhood leukemia is as-sociated with behavioral and emotional consequences[1,2]. Numerous symptoms, such as increased irritability,argumentativeness, tiredness, sleep problems, “talks toomuch,” cries for no reason, are reported with intermittenthigh-dose corticosteroid [3]. Such symptoms may inter-fere with family functioning and treatment compliance.There have been no published reports on treatment strat-egies. Chlorpromazine is an antipsychotic, which hasbeen reported to be beneficial in patients with steroid-induced psychosis [4,5]. Lorazepam is a benzodiazepinecommonly used with anxious and agitated children. Thepurpose of this study was to examine the comparativeefficacy and side effects of chlorpromazine and loraze-pam for the short-term treatment of behavior problemsrelated to corticosteroids in children with acute lympho-blastic leukaemia.

Between April, 1996, and June, 1999, 10 subjects(mean age 6.4 years) treated for acute lymphoblastic leu-kemia according to the Dana-Farber Cancer Institute(DFCI 95-001) protocol, and showing moderate to severebehavioral problems on corticosteroids, were referred forthe research protocol. After the parents had given signedinformed consent, the patients were randomized to lor-azepam 0.04–0.08 mg/kg/day or chlorpromazine 1.5–3.0mg/kg/day (standard capsules were prepared by the phar-macist) during the full week during which they receivedcorticosteroids treatment and then were crossed over tothe other drug for the next full week on corticosteroids,after 2 weeks free of corticosteroids. Efficacy and sideeffects were assessed by trained psychiatrists (G.P. andY.L.) before the clinical trial, and at the end of each ofthe 2 weeks of treatment, by means of the Clinical GlobalImpression (CGI) and the Corticosteroid Symptom In-ventory (CSI) and daily by a modified Conners Abbre-viated Questionnaire (CAQ). The code was broken onlyafter the 10 patients had been included and the assess-

ments completed, except for one patient. That individualshowed a severe orthostatic hypotension after a firstsingle dose of chlorpromazine, did not receive any fur-ther medication (neither chlorpromazine nor lorazepam),and was excluded from further statistical analysis. Ninepatients were thus included in the analysis.

CGI SCORES

Severity of illness as evaluated by the CGI variedbetween moderately ill (4) to severely ill (6), with a meanscore of 5.1. Global clinical improvement was rated be-tween very much improved (1) and very much worse (7),with a mean score of 3.1 for chlorpromazine and 3.8 forlorazepam (no statistical difference between drugs). Infact, 5 subjects were rated as improved with lorazepamand 6 with chlorpromazine. However, 4 were rated verydeteriorated with lorazepam but none with chlorproma-zine. The therapeutic index (efficacy/toxicity balance),judged as related to the medication effect only, was alsohigher for chlorpromazine than for lorazepam [1.6 vs. 1.1(n.s.) respectively], although the latter difference was notsignificant. This was due to a higher toxicity rating forlorazepam than for chlorpromazine (2.8 vs. 1.8; Z4−2.04;P 4 0.041) rather than a lower efficacy (2.2 vs.2.4, n.s.).

1Department of Psychiatry, Hoˆpital Ste-Justine, Montre´al, Quebec,Canada2Department of Paediatric Oncology, Hoˆpital Ste-Justine, Montre´al,Quebec, Canada

*Correspondence to: Dr. Gilles Pelletier, MD, De´partement de Psy-chiatrie, Hopital Ste-Justine, 3100 Ellendale, Montre´al, Quebec,Canada H3S 1W3. E-mail: pelletgi@ere.umontreal.ca

Received 20 August 1999; Accepted 7 October 1999

Medical and Pediatric Oncology 34:276–277 (2000)

© 2000 Wiley-Liss, Inc.

CSI SCORES

Parents’ reports were concordant, the mean number ofreported symptoms drop from 16.3 at baseline to 14.0 forlorazepam (n.s.) but to 8.7 for chlorpromazine (Z4−2.39;P 4 0.01). However, the difference between themean number of residual symptoms was not differentbetween lorazepam and chlorpromazine.

CAQ SCORES

Efficacy as assessed by the CAQ showed a significantdecrease with regard to the baseline for lorazepam (from18.5 to 13.6; Z4 −1.99; P 4 0.04) and much moreclearly for chlorpromazine (from 18.5 to 7.85; Z4−2.20; P 4 0.02). However, these ratings (on averagefrom never to sometimes) were not significantly differentbetween the two drugs.

DISCUSSION

Both drugs were active on behavior, but the pharma-cological effect of chlorpromazine appears to be superiorto that of lorazepam with regard to corticosteroid-relatedsymptoms. The most common side effect with chlor-promazine was drowsiness (two cases). In one case weobserved a severe orthostatic hypotension after 5 mg of

chlorpromazine, but we are not sure that this reaction wasrelated to chlorpromazine insofar as the patient presentedthe same reaction with antileukemia medications. Threepatients had a paradoxical agitation with lorazepam, anddrowsiness was also present in three cases.

To summarize, we observed that both chlorpromazineand lorazepam were active on corticosteroid-relatedsymptoms. Chlorpromazine appeared to be more reliableand had fewer side effects than lorazepam and can beused at relatively low dose to obtain a beneficial clinicaleffect.

REFERENCES

1. Drigan R, Shapiro A, Gelber RD. Behavioral effects of cortico-steroids in children with acute lymphoblastic leukaemia. Med Pe-diatr Oncol 1992;20:13–21.

2. Satel SL. Mental status changes in children receiving glucocorti-coids. Review of the literature. Clin Pediatr 1990;29:382–388.

3. Harris JC, Carel CA, Rosenberg LA, et al. Intermittent high dosecorticosteroid treatment in childhood cancer: behavioral and emo-tional consequences. J Am Acad Child Adolesc Psychiatr 1986;25:120–124.

4. Klein JF. Adverse psychiatric effects of systemic glucocorticoidtherapy [review]. Am Fam Physician 1992;46:1469–1474.

5. Bloch M, Gur E, Shalev A. Chlorpromazine prophylaxis of ste-roid-induced psychosis. Gen Hosp Psychiatr 1994;16:42–44.

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