- Email: [email protected]
Fluoxetine Treatment of Severe Self-Injury in Young Adults with Mental Retardation
Case Study I
Fluox!etine Treatment of Severe Self-Injury in Young Adults .I with Mental Retardation I
. I ROBERT W. RICKETTS, M.S., AMANDA B. GOZA, M.S., CYNTHIA R. ELLIS, M.D., YADHU N. SINGH, PH.D., II NIRBHAY N. SINGH, PH.D., AND JOHN C. COOKE III, M.D. I
i
Abstract;
Dysfunction of the serotonergic system has been implicated in the development and maintenance of self-injury In some persons with mental retardation. Several preliminary reports have suggested that f1uoxetine, a drug that bl$cks the reuptake of serotonin, may decrease self-injury in these individuals. Of the 44 cases of selfinjury treated I with f1uoxetine and previously reported in the literature, 42 demonstrated a beneficial response to the drug. welreport four additional cases of adults with mental retardation whose self-injury was treated with f1uoxetine. Each of these individuals benefited from f1uoxetine to some extent, with average decreases in selfinjury ranging from 20% to 88% when compared with baseline levels. These findings, combined with those from previously published case studies, emphasize the need for well-controlled studies to more adequately assess the effects of f1udxetine on self-injury. J. Am. Acad. Child Adolesc. Psychiatry, 1993, 32, 4:865-869. Key Words: I serotonergic dysfunction, f1uoxetine, self-injury, mental retardation.
I I
. Self-injury is among the most common and serious problem behaviors exhibited! by some individuals with mental retardation (Johnson and Day, 1992). It is commonly accepted that there is a combination of behavioral and biological bases to self-injury (Harris, 1992; Luiselli et aI., 1992; S~hroeder et aI., 1986). hpically, the majority of cases of self-injury can be treated with behavioral methods (Luiselli et aI., 1992), and the rem\uning cases are either successfully treated with drugs or arJ intractable to both of these treatment modalities. Although various neuroleptics have been used to control self-injury, their effectiveness is questionable ($ingh et aI., 1992). Hoi.ever, recent psychopharmacological studies based on bi~logical theories have been more sl!Iccessful through the uSf of newer drugs to treat self-injury and other behavior problfms (Aman, 1991). For example, a majority of the studies using the opioid antagonists, naloxone and naltrexone, havJ demonstrated a reduction in selfirljury in persons with q.ental retardation (Ricketts et aI., 1993). Our interest is in the biological hypothesis suggesting a'role of the neurotrans~tter, serotonin (5-hydroxytryptarriine or 5-HT), in the derelopment and maintenance of this behavior. Dysfunctions of the serotonergic system were first implicated in studies thatrUggested self-injury in individuals
Accepted August 11, 1992. Mr. Ricketts is the Direct01 ofResearch and Ms. Goza is a Research ASsistant at the Southwest Institute for Developmental Disabilities at Abilene, Texas; Dr. Ellis is dn Assistant Professor of Pediatrics and Psychiatry at the Medical CJllege of Virginia, Richmond; Dr. Yadhu SiTlgh is an Associate Profe~sor of Pharmacy at South Dakota State Urziversity, Brookings; Dr. N(rbhay Singh is a Professor ofPsychiatry at, the Medical College of Virginia and Director of Research at the Commonwealth Institute fori Child and Family Studies, Richmond, Virginia; and Dr. Cooke is a Staff Psychiatrist at the Abilene State Scho04 Texas. ! .Reprint requests to Dr. G,Ynthia Ellis, Department of Pediatrics, Medical College of Virginia,1 P.O. Box 506, Richmond, VA, 23298. !0890-8567/93/3204-0865$03.00/0©1993 by the American Academy of Child and Adolescent Psychiatry. ! J. Am. Acad. Child Adolesc. !lsychiatry, 32:4, July 1993
with Lesch-Nyhan syndrome could be effectively treated with L-5-hydroxytryptophan (L-5-HTP), the precursor to serotonin (Mizuno and Yugari, 1975). Subsequent studies supported the finding that L-5-HTP, either alone or in combination with carbidopa, could at least temporarily decrease self-injury in these persons (Castells et aI., 1979; Nyhan et aI., 1980). However, other studies that attempted to treat self-injury by increasing serotonin levels through the use of L-5-HTP produced equivocal results (Baumeister et aI., 1984). With the release of fluoxetine as an antidepressant by the FDA in 1988, there has been a resurgent interest in the serotonergic hypotheses of self-injury. As opposed to L-5HTP, which increases 5-HT by stimulating its production, fluoxetine and its major metabolite, norfluoxetine, increase 5-HT by reuptake inhibition (Szymanski, 1991). This renewed interest was further kindled by serotonergic hypotheses that view self-injury as an obsessive-compulsive behavior (Yaryura-Tobias, 1977; Yaryura-Tobias and Neziroglu, 1978) and preliminary reports suggesting that fluoxetine may be an effective treatment for obsessive-compulsive disorders (Jenike et aI., 1989; Stout, 1990). Seven published studies have evaluated the effects of fluoxetine on self-injury in 44 subjects. In the earliest study, Stout (1990) described the case of a 21-year-old female college student who presented with a 7-year history of severe and disfiguring compulsive picking of facial lesions. Within 4 weeks of initiation of fIuoxetine therapy (40 mg/day), she was spending significantly less time picking at her lesions, and within 12 weeks, the lesions had largely cleared. The author described this case as a probable variant of an obsessive-compulsive disorder. In a case of trichotillomania and obsessive-compulsive disorder, Graae et aI. (1992) reported treating a 13-year-old girls with 80 mg/day of fluoxetine over 5 months. Although many symptoms of her obsessivecompulsive disorder showed an improvement, none was noted in her hair pulling.
865
RICKETTS ET AL.
Markowitz (1990) used fluoxetine with eight selfinjurious persons with mental retardation, one of whom also had a diagnosis of chronic schizophrenia. In addition to fluoxetine, all eight also were receiving a neuroleptic, one was concurrently taking both a neuroleptic and lithium, and another was taking a neuroleptic and both phenobarbital and dilantin for a seizure disorder. Within one month of instituting fluoxetine therapy at 20 mg/day, all eight had demonstrated symptomatic improvement both in self-injury and self-stimulatory behaviors (e.g., rocking, twirling, hand flapping). No added benefits were evident in two mild responders when fluoxetine was increased to 40 mg/day. Markovitz et aI. (1991) used 80 mg/day of fluoxetine to treat self-injury in 12 subjects diagnosed as having borderline and/or schizotypal personality disorder. Positive effects were not seen until the ninth week of therapy, at which time their self-injury was reported to be about 25% of the baseline rate. Although two subjects remained self-injurious after 12 weeks of therapy, their self-injury occurred at much lower rates. King (1991) and Bass and Beltis (1991) both reported single case studies of males with severe to profound retardation who had long-standing histories of self-injury refractory to previous pharmacological treatment, including thioridazine for one subject (King, 1991), and propranolol and naltrexone for the other (Bass and Beltis, 1991). Subsequent treatment with 40 mg/day of fluoxetine resulted in an approximate 50% improvement in self-injury in both cases. However, improvement in one of the subjects was maintained only for 60 to 70 days, at which time his self-injury increased to almost baseline levels (King, 1991). In contrast, sustained treatment effects were evident over a 2-year follOW-Up with the other subject. In the most recent study, Markowitz (1992) reported a trial of fluoxetine in 20 self-injurious subjects with severe or profound mental retardation who ranged in age from 17 to 56 years. In addition to their mental retardation, six of the subjects had psychiatric diagnoses that included autism, obsessive-compulsive disorder, atypical psychosis, depression, schizophrenia, and bipolar disorder. All the subjects were on other psychoactive medications throughout the study. After treatment with 20 to 40 mg/day of fluoxetine during a 12-week period, 18 of the 20 subjects showed a decrease in their self-injury, with 12 showing a marked improvement. Adverse effects of fluoxetine were seen in one subject who required discontinuation of the drug secondary to appetite suppression and weight loss. It was noted that one of the two nonresponders to fluoxetine had an atypical psychosis and self-injury that was directly related to exacerbations in her underlying psychosis. We present four additional cases in which fluoxetine was used to treat self-injury in persons with mental retardation. All four subjects lived in a large residential facility for individuals with mental retardation. Their treatment programs were designed and implemented by a multidisciplinary team, and each subject was evaluated by a psychiatrist to determine the presence of any DSM-III-R psychiatric disorders. In each case, their self-injury had proved refractory
866
to numerous behavioral and/or pharmacological interventions before the trial of fluoxetine. Standard behavioral observation techniques were used to measure the rate of self-injury of each subject (Kazdin, 1989). The specific topography of each subject's self-injury was defined, and trained observers were used to collect the data. Initially, data were collected on standard behavioral logs, but this was changed to scatterplots (Touchette et aI., 1985) when a new, facility-wide data collection system was implemented. The observers were aware of the fact that the subjects were being treated with medication for their behavior problems. However, it has been shown that even if observers are aware of the study's hypothesis or informed of the exact medication condition, the data are not compromised through observer bias (Towns et aI., 1984).
Case 1 "Russ" was a 26-year-old white man with profound mental retardation secondary to congenital rubella. Other complications of his congenital rubella included blindness, a severe hearing impairment, congenital heart disease, and a seizure disorder requiring anticonvulsant therapy. In addition, he had been diagnosed with stereotypylhabit disorder and organic mental disorder not otherwise specified (with features of organic mood disorder, depressed type). Russ was ambulatory but required near-total to total assistance with all his daily living needs. He had a 20-year history of institutionalization and intractable self-injury. His self-injury consisted of face slapping with resultant skin redness, swelling, bruising, and bleeding. Numerous behavioral interventions, including differential reinforcement techniques, contingent restraint, restraint fading, and extinction had been found to be unsuccessful in decreasing his self-injury. Behavioral programming was impeded, however, by the rapidity with which he injured himself if left unprotected or unrestrained. As an example of this, an attempt was made to conduct a formal analog functional analysis (Iwata et aI., 1982) but, because of the severity and frequency of his self-injury when released from restraints, the great majority of sessions had to be terminated early and an adequate analysis could not be made. In addition, numerous pharmacological treatments, including imipramine, haloperidol, thorazine, thiothixene, diazepam, chloral hydrate, and clorazepate had been ineffective in reducing his self-injury. Throughout the fluoxetine treatment, Russ received divalproex sodium (500 mg/tid) for seizure control and was involved in behavioral programming that included noncontingent restraint (helmet) to prevent self-injury. His 4-week baseline rate of self-injury was 17 incidents per week. During the first 6 weeks on fluoxetine at 20 mg/day, his rate of self-injury decreased slightly to 15 incidents per week. The dosage of fluoxetine was increased to 40 mg/day and resulted in an average of 2.5 incidents per week over the next 70 weeks. With the exception of a 3-week reduction to 20 mg/day (mean = one incident per week), his fluoxetine dosage was maintained at 40 mg/day. After 12 weeks on this dosage, his self-injury decreased to an average of less than one incident per week, a 95% decrease from baseline. J. Am. Acad. Child Adolesc. Psychiatry, 32:4, July 1993
USE OF FLUOXETINE WITH SELF-INJURY
After 32 weeks, his av6rage weekly rate of self-injury remained 84% below bas~line levels.
;
I Case 2 "Lisa" was a 35-yea~-old African-American woman who l).ad been institutionali~d at the age of 6 years. She had profound mental retardation of unknown origin, and her adaptive functioning wa~ further hampered by cerebral palsy ~nd a mild to moderate ~earing impairment. She had psychiatric diagnoses of stereotypy/habit disorder and organic mental disorder not othetwise specified and, in addition, had experienced symptomsli of depression including insomnia . ~nd weight loss. Lisa had exhibited s~lf-injury for at least 30 years. The tppography of her self-irjury included hitting and slapping her forehead, head banging, biting and scratching herself, and picking at sores and lesions. This had resulted in skin redness, swelling, bruisipg, and bleeding, along with permanent tissue damage con$isting of indention and scarring on her forehead and the bu,ld-up of callouses on her hands. A t?ehavioral program employing differential reinforcement, response cost, extinctio~, and contingent restraint had been only temporarily effective in reducing her self-injury. Subsequently, a variety of oth~r behavioral interventions had been used with no clinically ~ignificant effect. Attempts at controlling her self-injury !with a variety of pharmacological agents, including imipramine, thioridazine, doxepin, nortriptyline, buspirone, and diphenhydramine also had been ineffective. I ; During the 10 week~ before treatment with fluoxetine, l,isa engaged in self-injqry at an average rate of 31 incidents per week. On an initial Idose of 20 mg/day, her self-injury decreased to 11 incide~ts per week. Her dosage was inCreased to 30 mg/day (!tIternating 40 mg and 20 mg daily qoses) during the 13th w¢ek of fluoxetine treatment at which tlme her self-injury incrbased to an average rate of 15 incidents per week. After !another 6 weeks, her dosage was adjusted to 40 mg/day, land her self-injury increased to 17 incidents per week ovet the next 7 weeks. Owing to only limited improvement ori fluoxetine, it was gradually withdrawn over an 8-week pbriod, during which time she exhibi~ed self-injury at an a~erage weekly rate of 13 incidents, 58% lower than baselin~. During a 12-week retum-to-baseline (no medication) ph~se, Lisa exhibited self-injury at an average of eight inciderits per week. i i Case 3 i
1
• "Megan" was a 26-y~ar-old white woman with a 13-year history of institutionaliz~tionas a result of uncontrolled selfinjurious and aggressiv~ behaviors. She had severe mental retardation attributable tb meningitis at the age of 9 months ~lthough her developmertal milestones were somewhat del~yed before that time., Other problems included hearing and visual impairments,! a seizure disorder, and psychiatric diagnoses of organic mehtal disorder not otherwise specified and stereotypylhabit dis~rder. Megan's self-injurious behaviors, which included head Banging, skin picking, hitting self, hitting walls, and picking at or removing fingern~ils and toenails, resulted in black 1
I
.1. Am. Acad. Child Adolesc. rSYChiatry, 32:4, July 1993
eyes, bleeding fingernail beds, and scratch marks on her face. Previous attempts to decrease her self-injury included a variety of behavioral procedures and numerous psychoactive medications, including doxepin, imipramine, nortriptyline, thioridazine, buspirone, and diphenhydramine, none of which produced long-term beneficial effects. Megan was maintained on carbamazepine for seizure control before and during fluoxetine therapy. During the 4-week baseline period she was withdrawn from an unsuccessful trial of nortriptyline and, at that time, exhibited self-injury at an average rate of 20 incidents per week. On a dose of 20 mg/day of fluoxetine, her rate of self-injury increased slightly to an average rate of 23 incidents per week over the next 13 weeks. Fluoxetine was then increased to 40 mg/day and, within 12 weeks, her self-injury decreased to an average weekly rate of eight incidents. After 28 weeks of fluoxetine at 40 mg/day her self-injury occurred at an average rate of six incidents per week. This represented a 70% decrease from baseline levels. Case 4 "Natalie" was a 37-year-old white woman who had been institutionalized for 17 years. She functioned within the profound range of mental retardation resulting from brain damage secondary to perinatal hypoxia and manifested as Angelman syndrome. In addition, she had cerebral palsy and psychiatric diagnoses of organic mental disorder not otherwise specified with possible psychotic-like and bipolarlike features, and stereotypy/habit disorder. Natalie had exhibited self-injurious behaviors for at least 10 years including falling to the floor, biting herself, head banging, and scooting on the floor. She had experienced bruising, bleeding, and sacral swelling as a result of her self-injury. Despite numerous behavioral interventions, her self-injury persisted and, when contingent restraint was added to her program, arm biting emerged. Trials of haloperidol, thioridazine, carbamazepine, and lithium had also proved unsuccessful in controlling her self-injury. During the 8-week baseline period, Natalie was withdrawn from an unsuccessful trial of lithium and her selfinjury occurred at an average rate of 16 incidents per week. She exhibited self-injury at an average rate of seven incidents per week during the first 7 weeks of fluoxetine therapy (20 mg/day). Her fluoxetine was increased to 40 mg/day and, subsequently, increased to 60 mg/day, with no change in her rate of self-injury. When the dosage of fluoxetine was reduced to 40 mg/day, Natalie's self-injury increased to an average weekly rate of 31. After 11 days at 40 mg/day, the dosage was returned to 60 mg/day. During the first 12 weeks at this dose, her average rate of self-injury decreased to 13 incidents per week, and staff reported consistent clinical improvement over her baseline behavior. After 25 weeks of fluoxetine therapy at this dosage, Natalie's self-injury showed a 20% reduction when compared with baseline. Discussion These case reports are based on open trials of fluoxetine in four persons with severe self-injury and mental retardation who lived in a large residential facility for individuals
867
RICKETTS ET AL.
with mental retardation. Throughout the fluoxetine trials, all the subjects were involved in behavioral programming that included a restraint component. In addition, two of the subjects were receiving anticonvulsant medications for seizure control concurrently with the fluoxetine. The data from case 1 must be interpreted with caution because of the confounding programming variables that included the use of noncontingent restraint throughout the baseline and drug phases and the subject's practice of self-restraint. However, despite these caveats, it is clear this subject showed a positive response to fluoxetine. In case 2, the subject's rates of selfinjury while on fluoxetine ranged from 44% to 64% below the baseline rate, with the greatest improvement being noted at 20 mg/day. Her failure to achieve pretreatment rates during the return-to-baseline phase, however, may have been an indication that factors other than fluoxetine were responsible for the apparent reduction in self-injury after the initiation of fluoxetine therapy. It is also likely that this subject's self-injury was related to an underlying depressive disorder that was treated by the fluoxetine. Subject 3 also demonstrated a dramatic decrease in her previously intractable selfinjury in response to an initial dose of fluoxetine at 20 mg/ day. However, there was a clear indication of a dose-related effect with self-injury being optimally controlled on a dose of 40 mg/day. Although only a modest 20% decrease in the rate of self-injury was noted in case 4, staff working with this subject consistently reported clinical improvement on fluoxetine. As with any open-trial uncontrolled study, the findings presented here should be viewed cautiously. Although the rate of self-injury varied within subjects over time, this variability was small enough for the average rates to accurately reflect true symptomatic change. Many phases were less than 12 weeks and, therefore, not of sufficient duration to allow an adequate assessment of drug effects. However, when taken in their best light, the data do suggest that all four individuals benefited from fluoxetine to some extent. Three of the four subjects demonstrated a greater than 50% reduction in self-injury from baseline rates, and two of these subjects have been on maintenance fluoxetine since the trial. It also should be noted that no adverse side effects were reported in any of the four cases. However, clinicians should note that adverse behavioral side effects have been associated with the use of fluoxetine in children and adolescents, including motor restlessness, sleep disturbance, social disinhibition, a subjective sensation of excitation, and mania (Riddle et aI., 19901991; Venkataraman et aI., 1992). Furthermore, in a study of 42 children and adolescents with obsessive-compulsive disorder, treatment with fluoxetine was associated with the emergence or worsening of selfinjurious ideation or behavior in six subjects, 10 to 17 years old (King et aI., 1991). When combined with previously published case studies, it appears that 46 of the 48 individuals administered fluoxetine for the treatment of self-injury in eight studies experienced at least some benefit. However, because no adequately controlled studies have yet been conducted, it cannot be assumed that fluoxetine was responsible for the reported improvement in self-injury. Nevertheless, these case reports
868
do provide sufficient grounds to warrant the initiation of controlled studies. In conducting such studies, it will be important to attempt to differentiate between individuals with disorders associated with impaired functioning of the serotonergic system and those without, as this may be a marker for drug responsiveness. Even if fluoxetine produces dramatic improvements in only some cases of self-injury, it has the potential to be an important pharmacological treatment option for clinicians. Although the exact nature of the mechanisms involved is not entirely clear, the beneficial effects of fluoxetine in the treatment of self-injury may be due in part to its ability to enhance serotonergic neurotransmission and/or reduce adrenergic neurotransmission. Pharmacologic studies indicate that fluoxetine is a potent and selective inhibitor of serotonin reuptake into nerve terminals because of its action on a plasma membrane transporter (Hoffman et aI., 1991). Inhibition of the reuptake system results in elevated levels of serotonin at the synapse leading to activation of postsynaptic receptors and enhanced serotonergic neurotransmission. Activation of these receptors also is believed to increase norepinephrine turnover, resulting in decreased levels of the neurotransmitter (Fuller et aI., 1991) and, hence, an implied reduction in central adrenergic activity. Additional research is needed to elucidate these mechanisms. References Aman, M. G. (1991), Pharmacotherapy in the developmental disabilities: New developments. Aust. N. Z. J. Dev. Disabil., 17:183-199. Bass, J. N. & Beltis, J. (1991), Therapeutic effect of fluoxetine on naltrexone-resistant self-injurious behavior in an adolescent with mental retardation. J. Child Adolesc. Psychopharmacol., 1:331340. Baumeister, A. A., Frye, G. D. & Schroeder, S. R. (1984), Neurochemical correlates of self-injurious behavior. In: Transitions in Mental Retardation: Advocacy, Technology, and Science, Vol. 1, eds. J. A. Mulick & B. L. Mallory. Norwood, NJ: Albex Publishing Corporation, pp. 207-227. Castells, S., Chakrabarti, C., Winsberg, B. G., Hurwic, M., Perel, J. M. & Nyhan, W. L. (1979), Effects of L-5-hydroxytryptophan on monoamine and amino acids turnover in the Lesch-Nyhan Syndrome. J. Autism Dev. Disord., 9:95-103. Fuller, R. W., Wong, D. T. & Robertson, D. W. (1991), Fluoxetine, a selective inhibitor of serotonin uptake. Med. Res. Rev., 11: 17-34. Graae, F., Gitow, A., Piacentini, J., Jaffer, M. & Liebowitz, M. (1992), Response of obsessive-compulsive disorder and trichotillomania to serotonin reuptake blockers. Am. J. Psychiatry, 149:149-150. Harris, J. C. (1992), Neurobiological factors in self-injurious behavior. In: Self-Injury: Analysis, Assessment and Treatment, eds. J. K. Luiselli, J. L. Matson, & N. N. Singh. New York: Springer-Verlag, pp.59-92. Hoffman, B. J., Mezey, E. & Brownstein, M. J. (1991), Cloning of a serotonin transporter affected by antidepressants. Science, 254:579580. Iwata, B. A., Dorsey, M. F., Slifer, K. J., Bauman, K. E. & Richman, G. S. (1982), Toward a functional analysis of self-injury. Anal.
Intervention Dev. Disabil., 2:3-20. Jenike, M. A., Buttolph, L., Baer, L., Ricciardi, J. & Holland, A. (1989), Open trial of fluoxetine in obsessive-compulsive disorder.
Am. J. Psychiatry, 146:909-911. Johnson, W. L. & Day, R. M. (1992), The incidence and prevalence of self-injurious behavior. In: Self-Injury: Analysis, Assessment and Treatment, eds. J. K. Luiselli, J. L. Matson, & N. N. Singh. New York: Springer-Verlag, pp. 21-56. Kazdin, A. E. (1989), Behavior Modification in Applied Settings. Pacific Grove, CA: Brooks/Cole.
J. Am. Acad. Child Adolesc. Psychiatry, 32:4, July 1993
USE OF FLUOXETINE WITH SELF-INJURY
King, B. H. (1991), Fluoxetine reduced self-injurious behavior in an adolescent with mental rdtardation. J. Child Adolesc. Psychophar· macol., 1:321-329. I King, R. A., Riddle, M. A, ~happell, P. B., Hardin, M. T., Anderson, G. M., Lombroso, P. &1 Scahill, L. (1991), Emergence of selfdestructive phenomena ill children and adolescents during fluoxetine treatment. J. Acad. (Jhild Adolesc. Psychiatry, 30: 179-186. Luiselli, J. K., Matson, J. IL. & Singh, N. N. (1992), Self-injury: Analysis, Assessment and, Treatment. New York: Springer-Verlag. Markovitz, P. J., Calabresel J. R., Schulz, S. C. & Meltzer, H. Y. (1991), Fluoxetine in the! treatment of borderline and schizotypal personality disorders. Am~ J. Psychiatry, 148:1064-1067. Markowitz, P. I. (1990), Flupxetine treatment of self-injurious behav• ior in mentally retarded patients. J. Clin. Psychopharmacol., I · 10:299-300. Markowitz, P. I. (1992), Effect of fluoxetine on self-injurious behavior • in the developmentally dibbled: A preliminary study. J. Clin. Psychopharmacol., 12:27-311. Mizuno, T. & Yugari, Y. (1975), Prophylactic effect of L-5-hydroxytryptophan on self-mutilation in the Lesch-Nyhan Syndrome. Neuropttdiatrie, 6:13-23. : Nyhan, W. L., Johnson, H. G., Kaufman, I. A & Jones, K. L. (1980), Serotonergic approaches to the modification of behavior in the , Lesch-Nyhan Syndrome. ',4ppl. Res. Ment. Retard. 1:25-40. Ricketts, R. W., Ellis, C. R., Singh, Y. N. & Singh, N. N. (1993), Opioid antagonists. II: Clinical effects in the treatment of selfinjury in individuals withldevelopmental disabilities. J. Dev. Phys. · Disabil., 5:17-28. ; Riddle, M. A., King, R. A, Hardin, M. T. et al. (1990/1991), Behavioral side effects of fluoxdtine in children and adolescents. J. Child Adolesc. Psychopharmacbl., 3:193-198. 1
Schroeder, S. R., Bickel, W. K. & Richmond, G. (1986), Primary and secondary prevention of self-injurious behavior: A life-long problem. In: Advances in Learning and Behavioral Disabilities, Vol. 5, ed. K. D. Gadow. Greenwich, CT: JAI Press, pp. 63-85. Singh, N. N., Singh, Y. N. & Ellis, C. R. (1992), Psychopharmacology of self-injury. In: Self-Injury: Assessment, Analysis and Treatment, eds. J. K. Luiselli, J. L. Matson, & N. N. Singh. New York: Springer-Verlag, pp. 307-351. Stout, R. J. (1990), Fluoxetine for the treatment of compulsive facial picking. Am. J. Psychiatry, 147:370. Szymanski, L. S. (1991), The search for a single mechanism of selfinjurious behavior. J. Child Adolesc. Psychopharmacol., 1:315317. Touchette, P. E., MacDonald, R. F. & Langer, S. N. (1985), A scatter plot for identifying stimulus control of problem behavior. J. Appl. Behav. Anal., 18:343-351. Towns, A. J., Singh, N. N. & Beale, I. L. (1984), Reliability of observations in a doub1e- and single-blind study: An experimental analysis. In: Advances in learning and behavioral disabilities, Vol. 3, ed. K. D. Gadow. Greenwich, CT: JAI Press, pp. 215-240. Venkataraman, S., Naylor, M. W. & King, C. A. (1992), Mania associated with fluoxetine treatment in adolescents. J. Am. Acad. Child Adolesc. Psychiatry, 31:276--281. Yaryura-Tobias, J. A. (1977), Obsessive-compulsive disorders: A serotonergic hypothesis. J. Orthomolecular Psychiatry, 6:317-326. Yaryura-Tobias, J. A. & Nezirog1u, F. (1978), Compulsions, aggression, and self-mutilation: A hypothalamic disorder? J. Orthomolecular Psychiatry, 7:114-117.
I
J. Am. Acad. Child Adolesc. Psychiatry, 32:4, July 1993
869
Fluox!etine Treatment of Severe Self-Injury in Young Adults .I with Mental Retardation I
. I ROBERT W. RICKETTS, M.S., AMANDA B. GOZA, M.S., CYNTHIA R. ELLIS, M.D., YADHU N. SINGH, PH.D., II NIRBHAY N. SINGH, PH.D., AND JOHN C. COOKE III, M.D. I
i
Abstract;
Dysfunction of the serotonergic system has been implicated in the development and maintenance of self-injury In some persons with mental retardation. Several preliminary reports have suggested that f1uoxetine, a drug that bl$cks the reuptake of serotonin, may decrease self-injury in these individuals. Of the 44 cases of selfinjury treated I with f1uoxetine and previously reported in the literature, 42 demonstrated a beneficial response to the drug. welreport four additional cases of adults with mental retardation whose self-injury was treated with f1uoxetine. Each of these individuals benefited from f1uoxetine to some extent, with average decreases in selfinjury ranging from 20% to 88% when compared with baseline levels. These findings, combined with those from previously published case studies, emphasize the need for well-controlled studies to more adequately assess the effects of f1udxetine on self-injury. J. Am. Acad. Child Adolesc. Psychiatry, 1993, 32, 4:865-869. Key Words: I serotonergic dysfunction, f1uoxetine, self-injury, mental retardation.
I I
. Self-injury is among the most common and serious problem behaviors exhibited! by some individuals with mental retardation (Johnson and Day, 1992). It is commonly accepted that there is a combination of behavioral and biological bases to self-injury (Harris, 1992; Luiselli et aI., 1992; S~hroeder et aI., 1986). hpically, the majority of cases of self-injury can be treated with behavioral methods (Luiselli et aI., 1992), and the rem\uning cases are either successfully treated with drugs or arJ intractable to both of these treatment modalities. Although various neuroleptics have been used to control self-injury, their effectiveness is questionable ($ingh et aI., 1992). Hoi.ever, recent psychopharmacological studies based on bi~logical theories have been more sl!Iccessful through the uSf of newer drugs to treat self-injury and other behavior problfms (Aman, 1991). For example, a majority of the studies using the opioid antagonists, naloxone and naltrexone, havJ demonstrated a reduction in selfirljury in persons with q.ental retardation (Ricketts et aI., 1993). Our interest is in the biological hypothesis suggesting a'role of the neurotrans~tter, serotonin (5-hydroxytryptarriine or 5-HT), in the derelopment and maintenance of this behavior. Dysfunctions of the serotonergic system were first implicated in studies thatrUggested self-injury in individuals
Accepted August 11, 1992. Mr. Ricketts is the Direct01 ofResearch and Ms. Goza is a Research ASsistant at the Southwest Institute for Developmental Disabilities at Abilene, Texas; Dr. Ellis is dn Assistant Professor of Pediatrics and Psychiatry at the Medical CJllege of Virginia, Richmond; Dr. Yadhu SiTlgh is an Associate Profe~sor of Pharmacy at South Dakota State Urziversity, Brookings; Dr. N(rbhay Singh is a Professor ofPsychiatry at, the Medical College of Virginia and Director of Research at the Commonwealth Institute fori Child and Family Studies, Richmond, Virginia; and Dr. Cooke is a Staff Psychiatrist at the Abilene State Scho04 Texas. ! .Reprint requests to Dr. G,Ynthia Ellis, Department of Pediatrics, Medical College of Virginia,1 P.O. Box 506, Richmond, VA, 23298. !0890-8567/93/3204-0865$03.00/0©1993 by the American Academy of Child and Adolescent Psychiatry. ! J. Am. Acad. Child Adolesc. !lsychiatry, 32:4, July 1993
with Lesch-Nyhan syndrome could be effectively treated with L-5-hydroxytryptophan (L-5-HTP), the precursor to serotonin (Mizuno and Yugari, 1975). Subsequent studies supported the finding that L-5-HTP, either alone or in combination with carbidopa, could at least temporarily decrease self-injury in these persons (Castells et aI., 1979; Nyhan et aI., 1980). However, other studies that attempted to treat self-injury by increasing serotonin levels through the use of L-5-HTP produced equivocal results (Baumeister et aI., 1984). With the release of fluoxetine as an antidepressant by the FDA in 1988, there has been a resurgent interest in the serotonergic hypotheses of self-injury. As opposed to L-5HTP, which increases 5-HT by stimulating its production, fluoxetine and its major metabolite, norfluoxetine, increase 5-HT by reuptake inhibition (Szymanski, 1991). This renewed interest was further kindled by serotonergic hypotheses that view self-injury as an obsessive-compulsive behavior (Yaryura-Tobias, 1977; Yaryura-Tobias and Neziroglu, 1978) and preliminary reports suggesting that fluoxetine may be an effective treatment for obsessive-compulsive disorders (Jenike et aI., 1989; Stout, 1990). Seven published studies have evaluated the effects of fluoxetine on self-injury in 44 subjects. In the earliest study, Stout (1990) described the case of a 21-year-old female college student who presented with a 7-year history of severe and disfiguring compulsive picking of facial lesions. Within 4 weeks of initiation of fIuoxetine therapy (40 mg/day), she was spending significantly less time picking at her lesions, and within 12 weeks, the lesions had largely cleared. The author described this case as a probable variant of an obsessive-compulsive disorder. In a case of trichotillomania and obsessive-compulsive disorder, Graae et aI. (1992) reported treating a 13-year-old girls with 80 mg/day of fluoxetine over 5 months. Although many symptoms of her obsessivecompulsive disorder showed an improvement, none was noted in her hair pulling.
865
RICKETTS ET AL.
Markowitz (1990) used fluoxetine with eight selfinjurious persons with mental retardation, one of whom also had a diagnosis of chronic schizophrenia. In addition to fluoxetine, all eight also were receiving a neuroleptic, one was concurrently taking both a neuroleptic and lithium, and another was taking a neuroleptic and both phenobarbital and dilantin for a seizure disorder. Within one month of instituting fluoxetine therapy at 20 mg/day, all eight had demonstrated symptomatic improvement both in self-injury and self-stimulatory behaviors (e.g., rocking, twirling, hand flapping). No added benefits were evident in two mild responders when fluoxetine was increased to 40 mg/day. Markovitz et aI. (1991) used 80 mg/day of fluoxetine to treat self-injury in 12 subjects diagnosed as having borderline and/or schizotypal personality disorder. Positive effects were not seen until the ninth week of therapy, at which time their self-injury was reported to be about 25% of the baseline rate. Although two subjects remained self-injurious after 12 weeks of therapy, their self-injury occurred at much lower rates. King (1991) and Bass and Beltis (1991) both reported single case studies of males with severe to profound retardation who had long-standing histories of self-injury refractory to previous pharmacological treatment, including thioridazine for one subject (King, 1991), and propranolol and naltrexone for the other (Bass and Beltis, 1991). Subsequent treatment with 40 mg/day of fluoxetine resulted in an approximate 50% improvement in self-injury in both cases. However, improvement in one of the subjects was maintained only for 60 to 70 days, at which time his self-injury increased to almost baseline levels (King, 1991). In contrast, sustained treatment effects were evident over a 2-year follOW-Up with the other subject. In the most recent study, Markowitz (1992) reported a trial of fluoxetine in 20 self-injurious subjects with severe or profound mental retardation who ranged in age from 17 to 56 years. In addition to their mental retardation, six of the subjects had psychiatric diagnoses that included autism, obsessive-compulsive disorder, atypical psychosis, depression, schizophrenia, and bipolar disorder. All the subjects were on other psychoactive medications throughout the study. After treatment with 20 to 40 mg/day of fluoxetine during a 12-week period, 18 of the 20 subjects showed a decrease in their self-injury, with 12 showing a marked improvement. Adverse effects of fluoxetine were seen in one subject who required discontinuation of the drug secondary to appetite suppression and weight loss. It was noted that one of the two nonresponders to fluoxetine had an atypical psychosis and self-injury that was directly related to exacerbations in her underlying psychosis. We present four additional cases in which fluoxetine was used to treat self-injury in persons with mental retardation. All four subjects lived in a large residential facility for individuals with mental retardation. Their treatment programs were designed and implemented by a multidisciplinary team, and each subject was evaluated by a psychiatrist to determine the presence of any DSM-III-R psychiatric disorders. In each case, their self-injury had proved refractory
866
to numerous behavioral and/or pharmacological interventions before the trial of fluoxetine. Standard behavioral observation techniques were used to measure the rate of self-injury of each subject (Kazdin, 1989). The specific topography of each subject's self-injury was defined, and trained observers were used to collect the data. Initially, data were collected on standard behavioral logs, but this was changed to scatterplots (Touchette et aI., 1985) when a new, facility-wide data collection system was implemented. The observers were aware of the fact that the subjects were being treated with medication for their behavior problems. However, it has been shown that even if observers are aware of the study's hypothesis or informed of the exact medication condition, the data are not compromised through observer bias (Towns et aI., 1984).
Case 1 "Russ" was a 26-year-old white man with profound mental retardation secondary to congenital rubella. Other complications of his congenital rubella included blindness, a severe hearing impairment, congenital heart disease, and a seizure disorder requiring anticonvulsant therapy. In addition, he had been diagnosed with stereotypylhabit disorder and organic mental disorder not otherwise specified (with features of organic mood disorder, depressed type). Russ was ambulatory but required near-total to total assistance with all his daily living needs. He had a 20-year history of institutionalization and intractable self-injury. His self-injury consisted of face slapping with resultant skin redness, swelling, bruising, and bleeding. Numerous behavioral interventions, including differential reinforcement techniques, contingent restraint, restraint fading, and extinction had been found to be unsuccessful in decreasing his self-injury. Behavioral programming was impeded, however, by the rapidity with which he injured himself if left unprotected or unrestrained. As an example of this, an attempt was made to conduct a formal analog functional analysis (Iwata et aI., 1982) but, because of the severity and frequency of his self-injury when released from restraints, the great majority of sessions had to be terminated early and an adequate analysis could not be made. In addition, numerous pharmacological treatments, including imipramine, haloperidol, thorazine, thiothixene, diazepam, chloral hydrate, and clorazepate had been ineffective in reducing his self-injury. Throughout the fluoxetine treatment, Russ received divalproex sodium (500 mg/tid) for seizure control and was involved in behavioral programming that included noncontingent restraint (helmet) to prevent self-injury. His 4-week baseline rate of self-injury was 17 incidents per week. During the first 6 weeks on fluoxetine at 20 mg/day, his rate of self-injury decreased slightly to 15 incidents per week. The dosage of fluoxetine was increased to 40 mg/day and resulted in an average of 2.5 incidents per week over the next 70 weeks. With the exception of a 3-week reduction to 20 mg/day (mean = one incident per week), his fluoxetine dosage was maintained at 40 mg/day. After 12 weeks on this dosage, his self-injury decreased to an average of less than one incident per week, a 95% decrease from baseline. J. Am. Acad. Child Adolesc. Psychiatry, 32:4, July 1993
USE OF FLUOXETINE WITH SELF-INJURY
After 32 weeks, his av6rage weekly rate of self-injury remained 84% below bas~line levels.
;
I Case 2 "Lisa" was a 35-yea~-old African-American woman who l).ad been institutionali~d at the age of 6 years. She had profound mental retardation of unknown origin, and her adaptive functioning wa~ further hampered by cerebral palsy ~nd a mild to moderate ~earing impairment. She had psychiatric diagnoses of stereotypy/habit disorder and organic mental disorder not othetwise specified and, in addition, had experienced symptomsli of depression including insomnia . ~nd weight loss. Lisa had exhibited s~lf-injury for at least 30 years. The tppography of her self-irjury included hitting and slapping her forehead, head banging, biting and scratching herself, and picking at sores and lesions. This had resulted in skin redness, swelling, bruisipg, and bleeding, along with permanent tissue damage con$isting of indention and scarring on her forehead and the bu,ld-up of callouses on her hands. A t?ehavioral program employing differential reinforcement, response cost, extinctio~, and contingent restraint had been only temporarily effective in reducing her self-injury. Subsequently, a variety of oth~r behavioral interventions had been used with no clinically ~ignificant effect. Attempts at controlling her self-injury !with a variety of pharmacological agents, including imipramine, thioridazine, doxepin, nortriptyline, buspirone, and diphenhydramine also had been ineffective. I ; During the 10 week~ before treatment with fluoxetine, l,isa engaged in self-injqry at an average rate of 31 incidents per week. On an initial Idose of 20 mg/day, her self-injury decreased to 11 incide~ts per week. Her dosage was inCreased to 30 mg/day (!tIternating 40 mg and 20 mg daily qoses) during the 13th w¢ek of fluoxetine treatment at which tlme her self-injury incrbased to an average rate of 15 incidents per week. After !another 6 weeks, her dosage was adjusted to 40 mg/day, land her self-injury increased to 17 incidents per week ovet the next 7 weeks. Owing to only limited improvement ori fluoxetine, it was gradually withdrawn over an 8-week pbriod, during which time she exhibi~ed self-injury at an a~erage weekly rate of 13 incidents, 58% lower than baselin~. During a 12-week retum-to-baseline (no medication) ph~se, Lisa exhibited self-injury at an average of eight inciderits per week. i i Case 3 i
1
• "Megan" was a 26-y~ar-old white woman with a 13-year history of institutionaliz~tionas a result of uncontrolled selfinjurious and aggressiv~ behaviors. She had severe mental retardation attributable tb meningitis at the age of 9 months ~lthough her developmertal milestones were somewhat del~yed before that time., Other problems included hearing and visual impairments,! a seizure disorder, and psychiatric diagnoses of organic mehtal disorder not otherwise specified and stereotypylhabit dis~rder. Megan's self-injurious behaviors, which included head Banging, skin picking, hitting self, hitting walls, and picking at or removing fingern~ils and toenails, resulted in black 1
I
.1. Am. Acad. Child Adolesc. rSYChiatry, 32:4, July 1993
eyes, bleeding fingernail beds, and scratch marks on her face. Previous attempts to decrease her self-injury included a variety of behavioral procedures and numerous psychoactive medications, including doxepin, imipramine, nortriptyline, thioridazine, buspirone, and diphenhydramine, none of which produced long-term beneficial effects. Megan was maintained on carbamazepine for seizure control before and during fluoxetine therapy. During the 4-week baseline period she was withdrawn from an unsuccessful trial of nortriptyline and, at that time, exhibited self-injury at an average rate of 20 incidents per week. On a dose of 20 mg/day of fluoxetine, her rate of self-injury increased slightly to an average rate of 23 incidents per week over the next 13 weeks. Fluoxetine was then increased to 40 mg/day and, within 12 weeks, her self-injury decreased to an average weekly rate of eight incidents. After 28 weeks of fluoxetine at 40 mg/day her self-injury occurred at an average rate of six incidents per week. This represented a 70% decrease from baseline levels. Case 4 "Natalie" was a 37-year-old white woman who had been institutionalized for 17 years. She functioned within the profound range of mental retardation resulting from brain damage secondary to perinatal hypoxia and manifested as Angelman syndrome. In addition, she had cerebral palsy and psychiatric diagnoses of organic mental disorder not otherwise specified with possible psychotic-like and bipolarlike features, and stereotypy/habit disorder. Natalie had exhibited self-injurious behaviors for at least 10 years including falling to the floor, biting herself, head banging, and scooting on the floor. She had experienced bruising, bleeding, and sacral swelling as a result of her self-injury. Despite numerous behavioral interventions, her self-injury persisted and, when contingent restraint was added to her program, arm biting emerged. Trials of haloperidol, thioridazine, carbamazepine, and lithium had also proved unsuccessful in controlling her self-injury. During the 8-week baseline period, Natalie was withdrawn from an unsuccessful trial of lithium and her selfinjury occurred at an average rate of 16 incidents per week. She exhibited self-injury at an average rate of seven incidents per week during the first 7 weeks of fluoxetine therapy (20 mg/day). Her fluoxetine was increased to 40 mg/day and, subsequently, increased to 60 mg/day, with no change in her rate of self-injury. When the dosage of fluoxetine was reduced to 40 mg/day, Natalie's self-injury increased to an average weekly rate of 31. After 11 days at 40 mg/day, the dosage was returned to 60 mg/day. During the first 12 weeks at this dose, her average rate of self-injury decreased to 13 incidents per week, and staff reported consistent clinical improvement over her baseline behavior. After 25 weeks of fluoxetine therapy at this dosage, Natalie's self-injury showed a 20% reduction when compared with baseline. Discussion These case reports are based on open trials of fluoxetine in four persons with severe self-injury and mental retardation who lived in a large residential facility for individuals
867
RICKETTS ET AL.
with mental retardation. Throughout the fluoxetine trials, all the subjects were involved in behavioral programming that included a restraint component. In addition, two of the subjects were receiving anticonvulsant medications for seizure control concurrently with the fluoxetine. The data from case 1 must be interpreted with caution because of the confounding programming variables that included the use of noncontingent restraint throughout the baseline and drug phases and the subject's practice of self-restraint. However, despite these caveats, it is clear this subject showed a positive response to fluoxetine. In case 2, the subject's rates of selfinjury while on fluoxetine ranged from 44% to 64% below the baseline rate, with the greatest improvement being noted at 20 mg/day. Her failure to achieve pretreatment rates during the return-to-baseline phase, however, may have been an indication that factors other than fluoxetine were responsible for the apparent reduction in self-injury after the initiation of fluoxetine therapy. It is also likely that this subject's self-injury was related to an underlying depressive disorder that was treated by the fluoxetine. Subject 3 also demonstrated a dramatic decrease in her previously intractable selfinjury in response to an initial dose of fluoxetine at 20 mg/ day. However, there was a clear indication of a dose-related effect with self-injury being optimally controlled on a dose of 40 mg/day. Although only a modest 20% decrease in the rate of self-injury was noted in case 4, staff working with this subject consistently reported clinical improvement on fluoxetine. As with any open-trial uncontrolled study, the findings presented here should be viewed cautiously. Although the rate of self-injury varied within subjects over time, this variability was small enough for the average rates to accurately reflect true symptomatic change. Many phases were less than 12 weeks and, therefore, not of sufficient duration to allow an adequate assessment of drug effects. However, when taken in their best light, the data do suggest that all four individuals benefited from fluoxetine to some extent. Three of the four subjects demonstrated a greater than 50% reduction in self-injury from baseline rates, and two of these subjects have been on maintenance fluoxetine since the trial. It also should be noted that no adverse side effects were reported in any of the four cases. However, clinicians should note that adverse behavioral side effects have been associated with the use of fluoxetine in children and adolescents, including motor restlessness, sleep disturbance, social disinhibition, a subjective sensation of excitation, and mania (Riddle et aI., 19901991; Venkataraman et aI., 1992). Furthermore, in a study of 42 children and adolescents with obsessive-compulsive disorder, treatment with fluoxetine was associated with the emergence or worsening of selfinjurious ideation or behavior in six subjects, 10 to 17 years old (King et aI., 1991). When combined with previously published case studies, it appears that 46 of the 48 individuals administered fluoxetine for the treatment of self-injury in eight studies experienced at least some benefit. However, because no adequately controlled studies have yet been conducted, it cannot be assumed that fluoxetine was responsible for the reported improvement in self-injury. Nevertheless, these case reports
868
do provide sufficient grounds to warrant the initiation of controlled studies. In conducting such studies, it will be important to attempt to differentiate between individuals with disorders associated with impaired functioning of the serotonergic system and those without, as this may be a marker for drug responsiveness. Even if fluoxetine produces dramatic improvements in only some cases of self-injury, it has the potential to be an important pharmacological treatment option for clinicians. Although the exact nature of the mechanisms involved is not entirely clear, the beneficial effects of fluoxetine in the treatment of self-injury may be due in part to its ability to enhance serotonergic neurotransmission and/or reduce adrenergic neurotransmission. Pharmacologic studies indicate that fluoxetine is a potent and selective inhibitor of serotonin reuptake into nerve terminals because of its action on a plasma membrane transporter (Hoffman et aI., 1991). Inhibition of the reuptake system results in elevated levels of serotonin at the synapse leading to activation of postsynaptic receptors and enhanced serotonergic neurotransmission. Activation of these receptors also is believed to increase norepinephrine turnover, resulting in decreased levels of the neurotransmitter (Fuller et aI., 1991) and, hence, an implied reduction in central adrenergic activity. Additional research is needed to elucidate these mechanisms. References Aman, M. G. (1991), Pharmacotherapy in the developmental disabilities: New developments. Aust. N. Z. J. Dev. Disabil., 17:183-199. Bass, J. N. & Beltis, J. (1991), Therapeutic effect of fluoxetine on naltrexone-resistant self-injurious behavior in an adolescent with mental retardation. J. Child Adolesc. Psychopharmacol., 1:331340. Baumeister, A. A., Frye, G. D. & Schroeder, S. R. (1984), Neurochemical correlates of self-injurious behavior. In: Transitions in Mental Retardation: Advocacy, Technology, and Science, Vol. 1, eds. J. A. Mulick & B. L. Mallory. Norwood, NJ: Albex Publishing Corporation, pp. 207-227. Castells, S., Chakrabarti, C., Winsberg, B. G., Hurwic, M., Perel, J. M. & Nyhan, W. L. (1979), Effects of L-5-hydroxytryptophan on monoamine and amino acids turnover in the Lesch-Nyhan Syndrome. J. Autism Dev. Disord., 9:95-103. Fuller, R. W., Wong, D. T. & Robertson, D. W. (1991), Fluoxetine, a selective inhibitor of serotonin uptake. Med. Res. Rev., 11: 17-34. Graae, F., Gitow, A., Piacentini, J., Jaffer, M. & Liebowitz, M. (1992), Response of obsessive-compulsive disorder and trichotillomania to serotonin reuptake blockers. Am. J. Psychiatry, 149:149-150. Harris, J. C. (1992), Neurobiological factors in self-injurious behavior. In: Self-Injury: Analysis, Assessment and Treatment, eds. J. K. Luiselli, J. L. Matson, & N. N. Singh. New York: Springer-Verlag, pp.59-92. Hoffman, B. J., Mezey, E. & Brownstein, M. J. (1991), Cloning of a serotonin transporter affected by antidepressants. Science, 254:579580. Iwata, B. A., Dorsey, M. F., Slifer, K. J., Bauman, K. E. & Richman, G. S. (1982), Toward a functional analysis of self-injury. Anal.
Intervention Dev. Disabil., 2:3-20. Jenike, M. A., Buttolph, L., Baer, L., Ricciardi, J. & Holland, A. (1989), Open trial of fluoxetine in obsessive-compulsive disorder.
Am. J. Psychiatry, 146:909-911. Johnson, W. L. & Day, R. M. (1992), The incidence and prevalence of self-injurious behavior. In: Self-Injury: Analysis, Assessment and Treatment, eds. J. K. Luiselli, J. L. Matson, & N. N. Singh. New York: Springer-Verlag, pp. 21-56. Kazdin, A. E. (1989), Behavior Modification in Applied Settings. Pacific Grove, CA: Brooks/Cole.
J. Am. Acad. Child Adolesc. Psychiatry, 32:4, July 1993
USE OF FLUOXETINE WITH SELF-INJURY
King, B. H. (1991), Fluoxetine reduced self-injurious behavior in an adolescent with mental rdtardation. J. Child Adolesc. Psychophar· macol., 1:321-329. I King, R. A., Riddle, M. A, ~happell, P. B., Hardin, M. T., Anderson, G. M., Lombroso, P. &1 Scahill, L. (1991), Emergence of selfdestructive phenomena ill children and adolescents during fluoxetine treatment. J. Acad. (Jhild Adolesc. Psychiatry, 30: 179-186. Luiselli, J. K., Matson, J. IL. & Singh, N. N. (1992), Self-injury: Analysis, Assessment and, Treatment. New York: Springer-Verlag. Markovitz, P. J., Calabresel J. R., Schulz, S. C. & Meltzer, H. Y. (1991), Fluoxetine in the! treatment of borderline and schizotypal personality disorders. Am~ J. Psychiatry, 148:1064-1067. Markowitz, P. I. (1990), Flupxetine treatment of self-injurious behav• ior in mentally retarded patients. J. Clin. Psychopharmacol., I · 10:299-300. Markowitz, P. I. (1992), Effect of fluoxetine on self-injurious behavior • in the developmentally dibbled: A preliminary study. J. Clin. Psychopharmacol., 12:27-311. Mizuno, T. & Yugari, Y. (1975), Prophylactic effect of L-5-hydroxytryptophan on self-mutilation in the Lesch-Nyhan Syndrome. Neuropttdiatrie, 6:13-23. : Nyhan, W. L., Johnson, H. G., Kaufman, I. A & Jones, K. L. (1980), Serotonergic approaches to the modification of behavior in the , Lesch-Nyhan Syndrome. ',4ppl. Res. Ment. Retard. 1:25-40. Ricketts, R. W., Ellis, C. R., Singh, Y. N. & Singh, N. N. (1993), Opioid antagonists. II: Clinical effects in the treatment of selfinjury in individuals withldevelopmental disabilities. J. Dev. Phys. · Disabil., 5:17-28. ; Riddle, M. A., King, R. A, Hardin, M. T. et al. (1990/1991), Behavioral side effects of fluoxdtine in children and adolescents. J. Child Adolesc. Psychopharmacbl., 3:193-198. 1
Schroeder, S. R., Bickel, W. K. & Richmond, G. (1986), Primary and secondary prevention of self-injurious behavior: A life-long problem. In: Advances in Learning and Behavioral Disabilities, Vol. 5, ed. K. D. Gadow. Greenwich, CT: JAI Press, pp. 63-85. Singh, N. N., Singh, Y. N. & Ellis, C. R. (1992), Psychopharmacology of self-injury. In: Self-Injury: Assessment, Analysis and Treatment, eds. J. K. Luiselli, J. L. Matson, & N. N. Singh. New York: Springer-Verlag, pp. 307-351. Stout, R. J. (1990), Fluoxetine for the treatment of compulsive facial picking. Am. J. Psychiatry, 147:370. Szymanski, L. S. (1991), The search for a single mechanism of selfinjurious behavior. J. Child Adolesc. Psychopharmacol., 1:315317. Touchette, P. E., MacDonald, R. F. & Langer, S. N. (1985), A scatter plot for identifying stimulus control of problem behavior. J. Appl. Behav. Anal., 18:343-351. Towns, A. J., Singh, N. N. & Beale, I. L. (1984), Reliability of observations in a doub1e- and single-blind study: An experimental analysis. In: Advances in learning and behavioral disabilities, Vol. 3, ed. K. D. Gadow. Greenwich, CT: JAI Press, pp. 215-240. Venkataraman, S., Naylor, M. W. & King, C. A. (1992), Mania associated with fluoxetine treatment in adolescents. J. Am. Acad. Child Adolesc. Psychiatry, 31:276--281. Yaryura-Tobias, J. A. (1977), Obsessive-compulsive disorders: A serotonergic hypothesis. J. Orthomolecular Psychiatry, 6:317-326. Yaryura-Tobias, J. A. & Nezirog1u, F. (1978), Compulsions, aggression, and self-mutilation: A hypothalamic disorder? J. Orthomolecular Psychiatry, 7:114-117.
I
J. Am. Acad. Child Adolesc. Psychiatry, 32:4, July 1993
869