Prog. Neum-Psycllophormocol. & Biol. Rychiut. 199U. Vol. 14. pp. SlGY-S17Y Printed in Goal Britain. All rights reserved

A REVIEW OF PHARMACOLOGICAL AGENTS FOR SELF-INJURIOUS BEHAVIOR

DANIEL J. LUCHINS

Department of Psychiatry, University of Chicago, Chicago, Illinois U.S.A.

(Final Form, May 1990)

Abstract 1. Introduction 2. Antipsychotics 3. Lithium 4. Antidepressants 5. 5-Hydroxytryptophan 6. Beta-blockers 7. Anticonvulsants 8. Minor Tranquilizers 9. Opiate Antagonists

10. Conclusions Acknowledgements References

969

s170 s170 s171 S172 S172 s173 s173 s173 s174 s174 S176 S176

Luchins, Daniel J.: A Review of Pharmacological Agents for Self-Injurious Behavior. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990.& (Supple) : S169-S179

1. The clinical literature regarding the effects of various psychotropic agents on self- injurious behavior is reviewed. Anecdotal reports, open trials and controlled studies are each reviewed.

2. The absence of controlled studies and the failure to distinguish self-injurious behaviors from other forms of aggression are highlighted.

3. However, the review does raise the possibility that a wide range of agents may be useful for treating self-injurious behaviors and these appear to be similar to the agents used to treat other forms of aggression.

Eevwords: anticonvulsants. antidepressants, antipsychotics. beta-blockers. lithium, minor tranquilizers. opiate antagonists, self-injurious behavior.

Abbreviatlo (GTS). self-iny&ious behavior (SIB)

: Corneila de Lange Syndrome (CDL), GiIle de le Tourette’s Syndrome

S169

D. 1. Luchins

Self-injurious behavior (SIB) .is frequently seen in institutionalized retarded populations with estimates of its frequency ranging from lo-35 percent (Singh and Millichamp, 1985). The most frequently observed forms of SIB are self-biting, self- hitting, and head-banging (Rincover, 1986). Psychotropic drugs are widely prescribed for SIB despite the fact that reviews of the pharmacology of SIB (Sir@ and Winston, 1984) stress the paucity of systematic research in this area.

In attempting to review the literature in the area, a major problem is that in presentations of results, SIB is often not differentiated from other forms of aggression. There are several excellent studies of aggression in the retarded which probably would have been relevant to this review except the results do not distinguish between the various forms of aggression (i.e. Craft et al, 1987. Reid et al, 1981). This is unfortunate and could be overcome if more sophisticated rating scales were used such as the Overt Aggression Scale (Yudofsky et al, 1986) which distinguishes between verbal aggression, and aggression against objects, other individuals or self.

Although antipsychotics are widely prescribed in facilities for the mentally retarded

(Intagliata and Rinck. 1985) there are few studies of their behavioral effects and most are vague and uninformative regarding specific symptoms such as SIB (Aman and Singh, 1980). There is reason to believe that high doses of antipsychotics may exacerbate this problem. Vaisanen et al (1981) studied 30 moderately or severely retarded individuals (20 males: age range 17-46) and carried out a double-blind cross-over comparison (6 week for each drug with a 2 week placebo washout between medications) of thioridazine up to 600mg daily (mean serum level at the 6th week=63Oi260ng/ml) and haloperidol up to 60mg daily (mean serum level at the 6th week=29&18ng/ml). They found no difference between the two medications’ effects on SIB and both appeared, if anything to increase its frequency although this was not examined statistically. Using much lower

doses of haloperidol (mean dose = 2.8mg, range 2.5 - 6mgl. Mikkelsen (1986) treated six patients (5 males; age range 19-40) and demonstrated dramatic and presistent (over six months) reductions in SIB. Since low dose haloperidol is used in GiIIes de la Tourette’s syndrome he suggested a parallel between SIB and this disorder. This

suggestion is partially supported by the high rate of SIB seen in Gflles de Ia Tourette’s (Robertson et al, 1989). Antipsychotics have been reported useful in controlling SIB in one case of Lesch-Nyhan syndrome by Goldstein et al (1985). They treated a 20 month old patient in a 6 week single-blind trial of fluphenaxine lmg daily with a one week placebo period at week 5 and noted a cessation of self-biting on medication and a recurrence within 12 hours of beginning placebo. The authors also reported the failure of fluphenazine up to 5mg daily in another 15 year-old with the syndrome. Use of

Agents for self-injurious behavior s171

antipsychotic agents is discussed in greater detail in the section by Gaultieri and

Schroeder in this issue in which they describe an improvement on SIB in 11 of 15

patients on low dose fluphenazine (2.5-6mg dally). Interestingly. higher doses were

often associated with deterioration and some patients only improved when medication

was reduced to doses in the 2.5-3.5mg range.

3. IAtbium

There have been several uncontrolled studies of the effectiveness of lithium for SIB in

mentally retarded populations. Cooper and Fowlie (1972) describe a beneficial response

to lithium 500mg T.I.D. (blood level 0.9mg Eq/l) in an 16 year-old severely retarded girl

who prior to treatment would throw herself down, strike her head against hard objects,

and gnaw at the back of her hands. Over the course of 5 years of lithium treatment SIB

was virtually eliminated. Dale et al (1980) described experience with lithium in 15

aggressive patients at least one of whom had SIB. She was a severely retarded 17 year-

old female who was given 800mg of lithium (blood level 0.5m Eq/l) and showed,

within one month, a reduction in aggression and self- mutilation that persisted over the

more than 3 years of treatment.

Micev and Lynch (1974) used lithium (blood level 0.6 - 1.4mEql) to treat 10 severely

retarded patients (6 males: age 16-58) with aggression and/or SIB. Patients were

assessed every two weeks during the 12 week study. Of the 8 patients with SIB. six

showed a cessation in the behavior and an additional patient showed mild improvement.

This effect on SIB seemed even more dramatic than the reduction of aggression that

was significant in 5 of 9 patients and mild in 3 additional individuals. To determine

whether in fact, antiaggressive drugs such as lithium have a preferential effect on SIB.

Luchins and Dojka (1989) carried out a retrospective analyses to compare the effect of

lithium on SIB and aggression in 11 pattents with both symptoms (6 males, age 23-55).

Patients had been treated for at least three months with blood levels of greater than

5mEq/l and the behavioral data acquired during this period was compared to that of

the three months before lithium treatment. Overall 9 patients showed an absolute

reduction in SIB and 7 showed a reduction in aggression. Mean SIB monthly counts

before treatment were 200 (f283) and afterwards 192 (f376). a 4% reduction which

was not significantly different from the effect on mean aggression counts which were

297 (f504) before and 244 (f507) after treatment, an 18% reduction.

There have also been several indications from controlled studies that lithium may

reduce SIB. but none of these specifIcally looked at SIB per se. Campbell et al (1972) in

a controlled, 7-10 week cqmparison of lithium and chlorpromazine observed cessation of

severe self-mutilation in a 6 year-old autistic child with lithium 6OOmg/day (blood level

.6 - 8mEq/l). Worrall et al (1975) carried out a double-blind cross-over comparison of

lithium (4 weeks) and placebo in 8 aggressive retarded females, one of whom, a 39

year-old postenecephalic also showed SIB. This patlent was one of the .three individuals

S172 D. j. Luchins

to show significantly reduced aggression scores on lithium. Tyrer et al (1984) studies 25

aggressive, mentally retarded individuals (17 males: age range 14-50 years) in a

double-blind, cross-over comparison of lithium (2 months) compared to placebo (2

months). Seventeen patients showed improvement on lithium (0.5 - 08mEq/l) and

improvement was noted in 5 of 6 factors including “self-assault: temper tantrums”, but

difference on this particular scale was not statistically significant from placebo.

4. Antidemessant8

There are no systematic studies of antidepressant effects on SIB. Aman et al (1986)

carried out a double-blind, controlled study of imipramine (3mg/kg. 4 weeks active and

4 weeks placebo) in 10 profoundly retarded individuals. Overall they noted a

deterioration of various measures, including irritability, but SIB was not specifically

addressed. Gaultieri (personal communication) noted from a survey of 138 individuals

with Cornelia deLange syndrome (CDL) that 7 had been treated with antidepressants

primarily for SIB. Three of the 5 on imipramine had improved, a patient on

desipramine did not benefit and a patient treated with the more specific serotonergic

agent, fluoxetine. initially improved but then deteriorated. There is an additional

documented case report to support the use of antidepressants, particularly those with

specific serotonergic effects, in patients with CDL and SIB. O’Neil et al (1986) report on

a 22 year-old retarded man with CDL with disrupted sleep and temper-tantrums

directed towards self and others. Baseline behavior was monitored for three weeks

while on imipramine 150/mg day. Tryptophan up to 3gm was added causing an

improvement in sleep with an increasing of blood serotonin from 34ng/ml to 55ng/ml

but no behavioral change. Imipramine was replaced by trazadone 200mg daily and

during the next month while blood serotonin was 383ng/ml (normal = 161zt473,

tantrums decreased by 75%. Subsequent discontinuation of tryptophan led to a

reduction in whole blood serotonin and an increase ln tantrums.

There have been reports of the utility of 5-hydroxytryptophan (5-HTP) in individuals

with Lesch-Nyhan syndrome as well as Gilles de la Tourette’s syndrome. MIzuno and

Yugari (1975) carried out a prolonged series of trials of 5-HTP I-8mg/Kg in 4 patients

with Lesch-Nyhan syndrome (all male, age range 7-12) and used as control substances

placebo, tryptophan 5Omg/Kg or L-Dopa 15-3Omg/Kg. They noted a dramatic reduction

in self-mutilation (but not choreoathetoid movements) within l-3 days of starting 5-HTP

and a return of symptoms within 12-15 hours of discontinuation. Patients were generally

maintained on 5mg/Kg of SHTP. Placebo and L-tryptophan were ineffective while L-

Dopa (200-400ng daily) produced some temporary and partial effects on SIB.

There has also been the report of SIB in Gille de la Tourette’s (GTS) syndrome

Agents for self-injurious behavior s173

responding to 5HTP. Van Woert (1977) reported on a 15 year-old boy who had shown

symptoms of GTS since age 6 and SIB since age 11 including biting his cheeks and

tongue and punching himself in the face. 5-HTP 1600mg daily was prescribed in

conjunction with carbidopa 300mg daily which produced a reduction in SIB.

Subsequently three periods of placebo substitutions were all followed by a return of

aggression and SIB.

6. Beta Blockers

There are no controlled studies of &blockers for SIB. but at least three open studies

exist. Ratey et al (1986) studied 19 severe to profoundly retarded individuals whom he

treated with propranolol as a measure of last resort. Twelve of the 19 had SIB as a

presenting symptom (8 males, age range 22-49) of whom 8 improved speciflcally on

SIB and in another 3 improvement of a more general nature was noted without specific

mention being made to SIB. These 12 individuals were treated with a mean final propranolol dose of 131mg per day. There were no apparent differences in percentage

of responders or propranolol dosage between those with or without SIB. Ratey et al

(1987) treated with &blockers. eight aggressive autistic patients seven of whom (6

males: age range 25-50) showed SIB as a presenting symptom. All these patients

showed a reduction in SIB on a mean, final propranolol dose of 180mg/day (one patient

was treated with nadolol 120mg/day and another switched to nadolol 120mg/day from

160mg/day of propranolol). Luchins and Dojka (1989) retrospectively reviewed the

records of 6 retarded individuals (3 males, age range 24-45) with both aggression and

SIB who were treated with propranolol for at least 3 months (mean dose = 286mg/day).

Five of the 6 patients showed a reduction in both SIB and aggression. Baseline mean

monthly SIB counts were 137(f200) before treatment and 62(f81) after treatment, a

reduction of 55% while mean aggression counts were 68(f77) before treatment and

25(f34) after treatment. a reduction of 63%. There was no evidence of a statistlcally

significant difference in response to propranolol between symptoms of SIB and

aggression.

7. AntIconvu.lsanta

Although there is an extensive literature suggesting psychotropic benefits with some

anticonvulsants. particularly carbamazepine (DaIby. 1975) my review of most of the

English and French articles failed to identify any in which SIB was specifically

assessed.

8. Minor Tranadlizers

In general, minor tranquilizers might be expected to exacerbate SIB. Baron and

Sandman (1983) studied 100 severly and profoundly mentally retarded individuals (60

s174 D. J. Luchins

males: age range 9-26) who were divided into four groups depending on whether they

showed SIB and stereotypy (N=22) stereotypy alone (N=40). SIB alone (N=18) and

neither SIB or stereotypy (N=20). Patients records were then reviewed to determine

whether large doses of sedative/hypnotic agents had produced “paradoxical responses”,

i.e. decreased sleep and increased restlessness, uncooperativeness. abusiveness. They

found 68% of individuals with both SIB and stereotypy, 35O16 with stereotypy. 39% with

SIB and 0% with neither symptom showed “paradoxical responses”. A confounding

factor in this study is that some patients in this study were receiving chlorpromazine,

and it is uncertain whether it was also classified as a sedative/hypnotic by the authors.

Buspirone. a novel antianxiety agent with serotonergic effects fTraber and Glaser.

1987) may be useful in SIB. Anectodal reports Colenda (1988). suggest an antiaggressive

effect. Ratey and O’DrIscoll (1989) report on 3 mentally retarded individuals (2 males;

ages 23-36) with SIB who responded to between 20-45mg daily of the drug.

8. ODiate An~onists

Since the publication of three reports in 1983 ISandman et aI. 1983, Davidson et al,

1983: Richardson and Zaleski. 1983) there have been many subsequent articles

discussing the effect of the short acting opiate antagonist, naloxone on SIB. More

compelling then the case reports that comprise most of the clinical experience with

naloxone are the more recent and better controlled studies with the long acting

antagonist naltrexone. Herman et al. (1987) originally reported the effects of naltrexone

(5.1.0, - 1.5 and 2mg/Kgl in 3 males, (2 retarded and one with GTS. age range 10-17) and

noted a decrease of SIB relative to placebo at doses of .5 - 1.5mg/Kg and an increase at

2mg/Kg. This effect has been at least partially confirmed by several other groups

(Bernstein et al, 1987; Barrett et al, 1989) although there has been one failure to

replicate in 2 patients studied by Szymanski et al (1987). This area is extensively

reviewed by Herman in this special issue.

10. Conclusions

Aside from demonstrating the paucity of clinical studies of drug treatment for SIB,

what else can this review teach us. As mentioned in the Introduction, our knowledge

in this field would have been greatly increased if previous studies of “aggression” had

distinguished between its various manifestations, so that success or failure of

treatments for SIB would not become submerged in results that lump together SIB,

aggression towards others, verbal abusiveness etc.

Despite this caveat it does appear that a wide variety of agents may have clinical utility

in SIB and these agents are generally useful for other forms of aggression. In fact, there

is increasing evidence that anti-aggressive agents may be equally effective for SIB as for

aggression directed toward others. Micev and Lynch (1974) noted that the effect of

lithium in reducing SIB in 6 of 8 individuals was as great, if not greater than its effect in

Agents for self-injurious behavior 5175

reducing aggression directed towards others in 6 of 9 individuals. We have specifically addressed this issue (Luchins and Dojka, 1989) by examining the effects of lithium (n=ll) and propranolol (n=6) in individuals with both SIB and aggression toward others. (Table

1) The mean number of episodes of aggression and SIB were assessed for three months, prior to beginning these drugs and for three months while on these medications (Table 1). For statistical purposes behavioral data was log transformed and then a mixed model ANOVA of drug type (propranolol and Iitbium), drug treatment (before and during) and behavior (aggression and SIB) with subject effects nested within drug type was carried out.

Table 1

Effect of Medication on Patients With Both Aggremdon and SlB

Medication

propranolol (n=6)

Mean Dose

287mg

Aggression before during

68(f78) ZS(f35)

SIB before during

137(+200) 62(f82)

lithium (n=ll)

1027mg 297(f506) 244(f507) 200(f283) 192(f376)

Although an ANOVA demonstrated signiftcant effect for the drugs, with no significant difference between the two drugs or the two behaviors, retiew of the actual results suggest the possibility that propranolol may have been more effective in both SIB and aggression. Thus from a clinical perspective it may be reasonable to assume that agents useful in one type of aggression might be useful in another. Of course, this does not necessarily imply that all forms of aggression have the same neurochemical basis. Arguing from treatment back to pathophysiology or etiology is always fraught with hazard. The underlying neurochemlcal basis of GTS, Lesch-Nyhan and other syndromes associated with SIB such as CDL may differ, yet the same drugs might still be useful in all these conditions. The search for better understanding of the neurochemical substrate of SIB and the search for better treatment both need to continue. enriching each, but not superceding one another. In this regard, it would be of great interest to examine the utility in the treatment of aggression of drugs so far demonstrated as useful only in SIB (i.e. opiate antagonists) and vice versa (i.e. amantadfne, in SIB, see Gualtieri et al. 1989 ), Determining whether there are drugs that specifically, or at least preferentially are effective in SIB, or a type of SIG. would be a worthwhile clinical enterprise.

D. 1. Luchins

Acknowlcdaements

I would like to thank Denise Dojka, M.S. and the staff of Unit 6 of the Howe

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Inquires and reprlnt requests should be addressed to:

Dr. Daniel J. Luchins

Department of Psychiatry

University of Chicago

5841 S. Maryland Avenue

Chicago, Illinois 60637, U.S.A.