Case Study Clomipramine in Autism: Preliminary Evidence of Efficacy CHRISTOPHER J. McDOUGLE, M.D., LAWRENCE H. PRICE, M.D., FRED R. VOLKMAR, M.D., WAYNE K. GOODMAN, M.D., DEBORAH WARD-O'BRIEN, R.N., JEFFREY NIELSEN, M.S., JOEL BREGMAN, M.D., AND DONALD J. COHEN, M.D.
Abstract. This report provides preliminary evidence for the efficacy of clomipramine in the treatment of young adults with autistic disorder. Four of five outpatients with autistic disorder showed significant improvement in social relatedness, obsessive compulsive symptoms, and aggressive and impulsive behavior with clomipramine treatment. These findings are consistent with previous evidence, suggesting that serotonin neurotransmission may be relevant to the treatment, and possibly the pathophysiology, of some symptoms of autistic disorder. J. Am. Acad. Child Adolesc. Psychiatry, 1992, 31, 4:746-750. Key Words: autism, clomipramine, serotonin. Autistic disorder (AD) is a complex neuropsychiatric syndrome characterized by impaired social relatedness, obsessive compulsive symptoms, and aggressive and impulsive behavior (Kanner, 1943). Despite considerable speculation as to its neurobiological basis (Golden, 1987), little is definitively known regarding the underlying pathophysiology or pathogenesis of the condition. Moreover, no consistently effective pharmacological strategies have been developed for the treatment of persons with AD. Recent preclinical and clinical studies suggest that serotonin (5-hydroxytryptamine [5-HT)) function may be significantly involved in social interactive, obsessive compulsive, and aggressive and impulsive phenomena. Consistent with this finding, patients with AD have been reported to show elevated whole blood serotonin (WBS) levels (Anderson et aI., 1987), antibodies directed against 5-HT neurons (Todd and Ciaranello, 1985), and blunted neuroendocrine responses to pharmacological probes of the 5-HT system (Hoshino et aI., 1984; McBride et aI., 1989). Open-label administration of drugs that affect 5-HT neurotransmission, such as the potent and selective 5-HT reuptake inhibitors fluoxetine (Cook et aI., 1990; Ghaziuddin et aI., 1991; Hamdan-Allen, 1991; Todd, 1991; Meh1inger et aI., 1990), fluvoxamine (McDougle et aI., 1990), and the 5-HT 1A agonist buspirone (Ratey et aI., 1989; Realmuto et aI., 1989), has been reported to produce symptomatic improvement in some patients with AD. Furthermore, clomipramine, a potent 5-HT reuptake inhibitor, was shown to be differentially effective relative to desipramine, a potent norepinephrine reuptake inhibitor, in a 10-week, double-blind crossover study in five children with AD (Gordon et aI., 1991).
Accepted December 4, 1991 From the Department of Psychiatry, Yale University School of Medicine; Clinical Neuroscience Research Unit, Ribicoff Research Facilities, Connecticut Mental Health Center; Yale Child Study Center; Department of Mental Retardation, State of Connecticut. Reprint requests to Dr. McDougle, Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06519. 0890-8567/92/31 04-0746$03.00/0© 1992 by the American Academy of Child and Adolescent Psychiatry.
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This report describes the treatment responses to clomipramine in five outpatient young adults who met DSM-III-R (American Psychiatric Association, 1987) criteria for AD. The patients received no other pharmacological, psychosocial, or behavior therapy during clomipramine treatment.
Case Reports Case I A., a 13-year-old boy who lived with his parents and three siblings, presented with impaired social interaction, extreme ritualistic behavior, and aggression toward others. During his clinical examination, he demonstrated poor eye contact, immediate and delayed echolalia, and inappropriate use of objects. Despite attending a school for autistic children of his age, he developed no friends or social acquaintances. By parental report, he would spontaneously physically assault his older brother and younger sister three to four times per week and destroy their personal possessions. A. hoarded an enormous number of newspaper advertisements and resisted attempts by family members to dispose of them. Ritualistic tapping and touching, as well as symmetrical arranging of household articles, were among other interferring compulsive behaviors. A. met 12 of the 16 DSM-III-R criteria for AD. In addition, he met DSM-III-R criteria for an Axis I diagnosis of obsessive-compulsive disorder (OCD) (except for the apparent egosyntonic nature of the symptoms) and for an Axis II diagnosis of mild mental retardation. He had a score of 96 on the Autism Behavior Checklist (ABC) (Krug et aI., 1980). Other than birth via cesarean section due to posterior presentation, A. had a normal medical history. Physical examination, routine laboratory tests, fragile-X screening, magnetic resonance imaging of the head, and sleep-deprived EEG were normal. Full-scale IQ on the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (Wechsler, 1981) was 58. Speech did not develop until age 3, although motor skills emerged without delay. Family history included a maternal uncle with "mental retardation" who lived alone and a paternal grandfather described as "hyper" who was being treated with a neuroleptic. J. Am. Acad. Child Adolesc. Psychiatry, 31 :4, July 1992
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Previous medication trials included 7.5 mg/day of dextroamphetamine for 8 months and 15 mg/day of methylphenidate for 4 months. Although some improvement in psychomotor hyperactivity was noted with these treatments, his social interaction deteriorated and his compulsive behavior was exacerbated. A course of behavior modification was ineffective. A. was given 25 mg/day of clomipramine for 7 days with an increase to 75 mg/day within 3 weeks. After 6 weeks of clomipramine treatment, a significant improvement in A.'s clinical condition occurred. His total ABC score decreased to 24 and he received a "much improved" on the global improvement item of the Clinical Global Impressions (COl) Scale (Guy, 1976). With family members, he began attending and participating in social outings, such as miniature golf, fishing, and shopping. Numerous large plastic bags filled with newspaper ads were removed from his room and discarded without an increase in anxiety. Repetitive verbalizations, as well as compulsive touching and tapping, were significantly decreased. Aggressive advances toward others were reduced to approximately one episode every 3 weeks. This improvement was maintained over the subsequent 14 months without a further increase in the dosage of clomipramine. A. received no concomitant medications during the treatment with clomipramine.
Case 2 Ms. B., a 33-year-old single woman, presented with persistent social deficits and disabling obsessive compulsive symptoms. Pregnancy and birth were uneventful, and development was reported to be normal until the age of 2.5 years. At that time, coinciding with a fractured wrist, spontaneous speech and other social interaction rapidly deteriorated. Ms. B. attended special education classes until she was 18 years old. At the time of presentation to our clinic, the patient spent only a minimal amount of time with other people. Although she sat with her family at mealtime, she did not interact spontaneously. She had no friends or social acquaintances. Approximately 8 years earlier, Ms. B had developed severe compulsive behavior. This behavior included trichotillomania involving scalp hair, eyelashes, and eyebrows, extensive hoarding of food items, extreme obsessional slowness around dressing and grooming, repetitive hand movements and retracing of steps, and perseverative questioning. Ms. B. met 12 of the 16 DSM-III-R criteria for AD. In addition, she met DSM-III-R criteria for Axis I diagnoses of OCD (except for the apparent egosyntonic nature of the symptoms) and trichotillomania and for an Axis II diagnosis of mild mental retardation. Her total score on the ABC was 102.
Her physical examination, EKG, and routine laboratory tests of blood and urine were normal. Psychological testing revealed a full-scale IQ of 70 on the WAIS-R. There was no family history of neuropsychiatric illness. A previous trial of 2 mg/day of haloperidol resulted in some reduction in anxiety and symptoms of trichotillomania, but no significant change in other compulsive symptoms or in social relatedness. Ms. B. was given 50 mg/day clomipramine, with an inJ. Am. Acad. Child Adolesc. Psychiatry, 31 :4, July 1992
crease in dose to 200 mg/day over 4 weeks. After 8 weeks of treatment, a noticeable change occurred in the patient's social interaction. Her speech became more spontaneous, and she began inquiring about siblings who had moved out of the family home years ago. Ms. B. also expressed a desire to give Christmas presents to staff members at her workshop and to bake a birthday cake for a client at the workshop. Repetitive questioning was significantly reduced and the obsessional slowness around dressing and grooming was markedly improved. The symptoms of trichotillomania resolved, and the hoarding of food items became minimal. The patient's total ABC score decreased to 29, and she received a "much improved" on the global improvement item of the CGl. At follow-up, the improvement in these symptoms had been maintained for 19 months. Ms. B. received no concomitant medications during the clomipramine trial.
Case 3 Mr. C., a 27-year-old single man who lived in a group home for persons with developmental disabilities, presented with compulsive cleaning rituals, inappropriate social interaction, and aggressive behavior directed toward others. The product of a normal pregnancy, labor, and delivery, Mr. C. never developed language skills despite excellent motor coordination. At the age of2 years, he had acquired bronchitis accompanied by febrile seizures. While in the hospital, Mr. C.'s mother requested an auditory evaluation because she believed her son also had a hearing impairment. Subsequent consultation and testing revealed normal hearing. However, psychiatric consultation led to a diagnosis of infantile autism. After the divorce of his parents when he was 2.5 years old, the patient spent the majority of his life in institutions and foster homes. , Mr. C. currently worked in a sheltered workshop. He had rigid routines around housecleaning and dishwashing. He demanded that the furniture in the group home be arranged in an exact manner. If anyone moved the furniture, this would result in an aggressive outburst. When assigned to wash dishes, Mr. C. would proceed in a deliberate, compulsive manner. Each item would have to be washed a certain number of times and a certain order followed, e.g., glasses, then saucers, then bowls, etc. If this routine was interrupted even by another person's voice, violent attacks were often precipitated. Mr. C. did not interact with staff or other clients at the group home or at the workshop. He made essentially no eye contact and never spoke spontaneously. Mr. C. met 10 of the 16 DSM-III-R criteria for AD. He also met DSMIII-R criteria for an Axis I diagnosis of OCD (except for the apparent egosyntonic nature of the symptoms) and for an Axis II diagnosis of severe mental retardation. His total score on the ABC was 90. His physical examination, EKG, EEG, and laboratory tests of blood and urine were normal. His full-scale IQ on the WAIS-R was 29. There was no known family history of neuropsychiatric disorders. Mr. C. was given 50 mg/day clomipramine with subsequent increases in dosage to 250 mg/day over the course of 5 weeks. After 12 weeks of treatment, a marked improve747
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ment in interfering behaviors was evident. Mr. C's total ABC score decreased to 22, and he received a "much improved" on the global improvement item of the COL Although the patient continued to be a meticulous cleaner, he no longer became violent or aggressive toward others when his routine was disrupted. In addition, there was a significant reduction in the amount of time required to complete the cleaning rituals. There were no subsequent aggressive attacks either at home or at work. Mr. C. became an active participant in our social skills training group. At each meeting, he prepared the snacks and made sure that all group members were served. Oroup home staff reported that Mr. C. also began to demonstrate appropriate one- or two-word verbalizations and to greet visitors at the door. These improvements were maintained throughout the 17-month follow-up period. Mr. C. received no medications other than clomipramine during treatment.
Case 4 Ms. D., a 29-year-old single woman who lived in a group home and worked in a sheltered workshop, presented with impairment in reciprocal social interaction, self-injurious behavior, and extreme repetitive questioning. Pregnancy and birth were normal, although her language skills were delayed. Ms. D. received a diagnosis of infantile autism at the age of 2.5 years. Before entering the group home, Ms. D. lived with her parents and attended special education classes. At examination, the patient demonstrated poor eye contact and isolated herself in a corner of the room. She had multiple, recent lacerations, as well as numerous well-healed scars, on both forearms as a result of biting herself. The only verbal exchange consisted of Ms. D. repetitively asking the examiner and others in the room about the color of their garages, the color of the inside of their toasters, and their height and weight. If these questions were not answered immediately and satisfactorily, Ms. D. would begin to scream and bite her arms. These behavioral disturbances had been present for many years. Ms. D. met 12 of the 16 DSMJ1I-R criteria for AD. In addition, Ms. D. met DSM-JII-R criteria for an Axis I diagnosis of OCD (except for the apparent egosyntonic nature of the symptoms) and for an Axis II diagnosis of mild mental retardation. Her total score on the ABC was 118. Other than the forearm lacerations described above, her physical examination, EKO, and routine blood and urine tests were all normal. Ms. D. had no other significant medical history. Her full-scale IQ on the WAIS-R was 66. There was no reported family history of neuropsychiatric illness. A trial of 10 mg/day of haloperidol for 8 weeks was ineffective in alleviating the disabling symptoms. She was then given 50 mg/day clomipramine, and it was increased to ISO mg/day over 4 weeks. After 6 weeks of treatment at this dose, a significant improvement in Ms. D.'s clinical status was apparent. Self-biting was reduced, and only well-healed scars remained on her forearms. Ms. D. began speaking to people in a nonperseverative manner. Although Ms. D. continued to have to ask strangers about the color of their garage and other stereotyped questions, she only asked each question once and a response that did not meet her expecta748
tions no longer resulted in self-injurious behavior. Her total ABC score decreased to 31, and she received a "much improved" on the global improvement item of the COL The improvement in Ms. D.'s condition was maintained through the subsequent 19 months. She received no concomitant medications throughout the clomipramine trial.
Case 5 Mr. E., a 24-year-old single man who lived at home with his parents, presented with a long history of impaired social skills, numerous compulsive rituals, and a preoccupation with television channels and programs. At birth, the patient experienced a 2- to 3-minute period of respiratory distress with Apgar scores of 7. His motor development was delayed and, although his language skills were precocious at 1.5 years of age, these subsequently deteriorated by the age of 2.5 years. Although Mr. E. had a full-scale IQ of 108 on the WAIS-R, he always attended special education classes. He was unemployed, had no friends, and spent inordinate amounts of time in his room, coming out only for meals. His compulsive behaviors included arranging personal belongings in a certain order, repetitive opening and closing of drawers and doors, and extensive nail-biting and fingerpicking. Mr. E. also had approximately 20 years worth of television program guides that he saved and filed in chronological order. Each evening he continuously scanned the channels on his television set, recording the time, date, station of program origin, and specific program. If this process was interrupted, increased anxiety and often aggressive behavior emerged. Mr. E. met 10 of the 16 DSM-JII-R criteria for AD. He also met DSM-III-R criteria for an Axis I diagnosis of OCD. His total score on the ABC was 75. No abnormalities were identified on physical examination, EKO, EEO, or routine laboratory tests of blood and urine. The patient had no history of medical problems other than the respiratory distress at birth. His family history was significant for a maternal male first-cousin with AD. Previous ineffective drug trials included 75 mg/day imipramine alone for 3 months and in combination with 50 mg/day of thioridazine for an additional 2 months, IS mg/day of methylphenidate for 5 months, 80 mg/day of fluoxetine for 4 months, and 30 mg/day hydroxyzine for 2 months. Mr. E. began receiving 50 mg/day clomipramine, with subsequent increases to 250 mg/day over 5 weeks. After 4 months of treatment at 250 mg/day, however, no significant improvement in social relatedness, compulsive behavior, 01'preoccupation with television-related items was observed. Mr. E.'s total ABC score remained essentially unchanged at 77, and he received a "no change" on the global improvement item of the COL He received no medications except clomipramine during the treatment trial. Discussion Four of five young adults with a DSM-III-R diagnosis of AD presenting with disturbances in social relatedness, obsessive compulsive symptoms, and/or aggressive and impulsive behavior had a significant improvement in symptomatology with open-label clomipramine treatment. The fifth patient remained clinically unchanged. Among the four pa· J. Am. A cad. Child Adolesc. Psychiatry, 31 :4, July 1992
CLOMIPIV\:\1INL IN AUTISM
tients who responded. two improved after 6 weeks. one showed a beneficial effect after 8 weeks, and two required up to 12 weeks of treatment with clomipramine before appreciable change occurred, The dose of clomipramine in the four responders ranged from 75 to 250 mg/day. with a mean dose of 185 ::':: 74 mg/day. Although clomipramine blood levels were not obtained during treatment. each patient lived with responsible parents or group home staff who administered the medication as prescribed. Other than mild dry mouth in two cases. the patients tolerated the drug well and had no adverse effects. In particular. Cases I. 2. 3. and 4 showed a significant improvement in social interaction. Cases I. 3 and 4 demonstrated a significant decrease in aggression. and Cases I, 2. 3. and 4 had a significant reduction in obsessive compulsive symptoms with clomipramine treatment. Whether the reduction in social withdrawal and aggressivity was a direct effect of clomipramine or an indirect result of the decrease in obsessive compulsive symptoms requires further study. The four patients who demonstrated clinical improvement are currently being maintained on clomipramine treatment. Clomipramine is a tricyclic antidepressant that has been shown in double-blind. placebo-controlled trials to have clear efficacy in the treatment of OCD (The Clomipramine Collaborative Study Group. 1991). In addition, clomipramine has been reported to be effective in reducing selfinjurious behavior (Lipinski. 1991). Although clomipramine affects noradrenergic and dopaminergic neuronal uptake. its most potent activity is to inhibit 5-HT reuptake. There is strong evidence that clomipramine' s effects on 5-HT reuptake are responsible for the drug's antiobsessive compulsive efficacy (Mavissakalian et aI., 1990). A dysregulation in 5-HT function in patients with AD has been hypothesized. The most consistent biological marker to date in AD is elevated WBS levels. which have been found in 30% to 40Ck of patients studied (Anderson et aI., 1987). In addition. antibodies directed against 5-HT neurons were identified in the blood and cerebrospinal tluid of 7 of 13 patients with AD in one study (Todd and Ciaranello, 1985). Decreased central 5-HT responsivity has been demonstrated in children (Hoshino et al.. 1984) and adults (McBride et aI.. 1989) with AD. as retlected by a decreased prolactin response to L-5-hydroxytryptophan and fentluramine, respectively. Preclinical and clinical evidence indicates that 5-HT function is significantly involved in social interactive. obsessive compulsive, and aggressive and impulsive phenomena. For example. studies of the dominance relationships of adult male vervet monkeys have shown that dominant males have
a peak of approximately 1,100 ng/ml, where they remain indefinitely. Behaviorally. despite WBS levels similar to those of dominant males. these long-term isolated monkeys behave likc subordinate males (McGuirc and Raleigh. 1l)~5). That 5-HT function is critical to the pharmacological treatment and perhaps the pathophysiology of patients with OCD is supported by thc c1car efficacy of 5-HT reuptake inhibitors and by results from some neuroendocrine challenge studies. Drugs that are potent inhibitors of 5-HT reuptake. such as clomipramine (The Clomipramine Collaborative Study Group. 1991). tluoxetine (Pigott et al.. 1990). and tluvoxamine (Goodman et al.. 19R9). have becn shown in double-blind studies to be effectivc in thc treatment of patients with OCD. Investigators have found a blunted prolactin responsc to the 5-HT agonist m-chlorophenylpiperazine in OCD females. suggesting decreased 5-HT responsivity in that patient population (Charney ct al.. 1981\). Although other neurotransmitters, such as dopamine. may also be involved in obsessivc compulsive phenomena (Goodman et aI., 1990). 5-HT function has hecn shown to be critical to the treatment of the disorder. Some investigators have questioned the appropriateness of the terms obsessio/{ and c(impulsio/{ to describe the repetitive activities of patients with autism (Baron-Cohen. 1(89). The improvement in thesc repetitive thoughts and hehaviors during treatment with the antiobsessivc compulsivc agcnt clomipramine in this study suggests that thcse phenomcna may respond similarly to the obsessions and compulsions demonstrated by patients with OCD. A number of clinical studies support a rclationship between a decrease in 5-HT function and aggressivc and impulsive behavior. Postmortem studies of suicide victims have consistently demonstrated a significalH decrcase in 5HT. 5-hydroxyindoleacetic acid (5-HIAA). or both. in suicide victims compared with controls (Stanley and Stanlcy. 1990). One recent postmortem study found that patients with Alzheimer's disease with a history of aggressivity had significantly lower 5-HT cortical levels than either normal controls or Alzhcimcr' s patients without a history of aggrcssive behavior (Palmer et aI., 1988). Preclinical studies have demonstrated that when dominant malc vervet monkeys arc treated with either a 5-HT reuptake inhihitor. a 5-HT rcccptor agonist. or the 5-HT precursor tryptophan. they become more quiescent and less aggressive in thcir social behavior (Raleigh et aI., 1985). Preliminary reports suggest that other medications that facilitate 5-HT neurotransmission may reducc certain disabling symptoms in patients with AD. McDougle et al. (1990) reported that the 5-HT reuptake inhibitor tluvoxamine re-
WI3S Icvds of approximaldy 1.000 ng/ml. whereas slIborui-
ullceu obsessive compulsive allu aggressive behaviors i.lIlU
nate males have WBS levels of about 650 ng/ml. Spontaneous or experimenter-induced changes in the social hierarchy result in corresponding changes in WBS levels (Raleigh et aI., 1984). In related studies in vervets. it has been found that extended isolation from the social group results in significant behavioral and biological changes. Initially, for either dominant or subordinate males, extended isolation results in WBS levels of approximately 650 ng/ml. After 18 weeks of isolation. however. the WBS levels rise and reach
improved social relatedness in a 30-year-old man with AD and comorbid OCD. Cook et al. (1990) found that 20 mg/ day of tluoxetine led to a significant decrease in timc away from a daily workshop placement in a man with a diagnosis of pervasive developmental disorder (not otherwise specified), who demonstrated interpersonal withdrawal and multiple compulsive behaviors. This same group recently reported that 20 mg of fluoxetine every third day to 80 mg/day resulted in a significant improvcment in National Institute
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MCDOUGLE ET AI..
of Mental Health global ratings of illness severity in 15 of 23 patients with AD (Cook ct aI., 1991). Hamdan-Allen (1991) observed that tluoxetine led to a resolution of trichotillomania and improved stereotypic behavior in an 18-yearold man with AD. In a small double-blind, placebo-controlled study, investigators at the Yale Child Study Center found tluoxetine useful in some children and young adults with AD who demonstrated intense patterns of obsessive compulsive behavior 0. Bregman, Pers. Commun., 1991). Investigators have also reported that buspirone, a 5-HTIA agonist, reduces hyperactivity, aggression, and stereotypy in some children (Realmuto et al.. 19&9) and adults (Ratey et al.. 19&9) with AD. In summary, clomipramine was effective in improving social relatedness and in reducing obsessive compulsive and aggressive symptoms in four of five patients with AD. Based on preclinical and clinical research thaI documentes involvement of 5-HT function in social interaction, obsessive compulsive phenomena, and aggressivity and impulsivity, it appears that 5-HT neurotransmission is relevant to the treatment, and possibly the pathophysiology, of some disabling symptoms of AD. However, results of open-label case studies must be viewed with caution. Prospective double-blind, placebo-controlled trials of clomipramine and other drugs that facilitate 5-HT neurotransmission are necessary before definitive conclusions can be drawn about their efficacy in the treatment of patients with AD.
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Tolliver. T. J. & Murphy, D. L. (1990). Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder. Arch. Cen. Psvchiatn-, 47:926-932. Raleigh, M. J., McGuire, M. T .. Brammer. G. L. & Yuwiler, A. ( 1984), Social and cnvironmental influences on blood serotonin concentrations in monkeys. Arch. Cen. Psvchillln·. 41 :405-41 0. - - Brammer. G. L., McGuire, M. T. & Yuwiler, A. (1985), Dominant social status facilitates the behavioral effects of serotonergic agonists. Brain Res., 348:274-282. Ratey, J. J., Sovner. R.. Mikkelsen. E. & Chmielinski, H. E. (1989), Buspirone therapy for maladaptive behavior and anxiety in developmentally disabled persons. 1. Clin. Psvchialn-. 50:382-384. Realmuto, G. M .. August, G. J. & Garfinkel. B. D. (1989). Clinical effect of buspirone in autistic children. 1. Clil/. Psvc!lOpharmacol.. 9: 122-125. Stanley, M. & Stanley, B. (1990). Postmortem evidence for serotonin's role in suicide. 1. Clin. Psychiatry. 51 (Suppl):22-28. Todd. R. D. (1991), Fluoxetine in autism (letter). Am. 1. Psvchialrv. 148: 1089. . . - - Ciaranello, R. D. (1985). Dcmonstration of inter- and intraspecies differences in serotonin binding sites by antibodies from an autistic child. Proc. NlIIl. Acad. Sci. USA. 82:612-616. Wechsler, D. (1981). Manual for Ihe Wecllsler Adult Inlelligence Scale-Revised. San Antonio: Psychological Corporation.
1. Am. A cad. Child Adolesc. Psychiatrv, 3 1:4, July /992
Abstract. This report provides preliminary evidence for the efficacy of clomipramine in the treatment of young adults with autistic disorder. Four of five outpatients with autistic disorder showed significant improvement in social relatedness, obsessive compulsive symptoms, and aggressive and impulsive behavior with clomipramine treatment. These findings are consistent with previous evidence, suggesting that serotonin neurotransmission may be relevant to the treatment, and possibly the pathophysiology, of some symptoms of autistic disorder. J. Am. Acad. Child Adolesc. Psychiatry, 1992, 31, 4:746-750. Key Words: autism, clomipramine, serotonin. Autistic disorder (AD) is a complex neuropsychiatric syndrome characterized by impaired social relatedness, obsessive compulsive symptoms, and aggressive and impulsive behavior (Kanner, 1943). Despite considerable speculation as to its neurobiological basis (Golden, 1987), little is definitively known regarding the underlying pathophysiology or pathogenesis of the condition. Moreover, no consistently effective pharmacological strategies have been developed for the treatment of persons with AD. Recent preclinical and clinical studies suggest that serotonin (5-hydroxytryptamine [5-HT)) function may be significantly involved in social interactive, obsessive compulsive, and aggressive and impulsive phenomena. Consistent with this finding, patients with AD have been reported to show elevated whole blood serotonin (WBS) levels (Anderson et aI., 1987), antibodies directed against 5-HT neurons (Todd and Ciaranello, 1985), and blunted neuroendocrine responses to pharmacological probes of the 5-HT system (Hoshino et aI., 1984; McBride et aI., 1989). Open-label administration of drugs that affect 5-HT neurotransmission, such as the potent and selective 5-HT reuptake inhibitors fluoxetine (Cook et aI., 1990; Ghaziuddin et aI., 1991; Hamdan-Allen, 1991; Todd, 1991; Meh1inger et aI., 1990), fluvoxamine (McDougle et aI., 1990), and the 5-HT 1A agonist buspirone (Ratey et aI., 1989; Realmuto et aI., 1989), has been reported to produce symptomatic improvement in some patients with AD. Furthermore, clomipramine, a potent 5-HT reuptake inhibitor, was shown to be differentially effective relative to desipramine, a potent norepinephrine reuptake inhibitor, in a 10-week, double-blind crossover study in five children with AD (Gordon et aI., 1991).
Accepted December 4, 1991 From the Department of Psychiatry, Yale University School of Medicine; Clinical Neuroscience Research Unit, Ribicoff Research Facilities, Connecticut Mental Health Center; Yale Child Study Center; Department of Mental Retardation, State of Connecticut. Reprint requests to Dr. McDougle, Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06519. 0890-8567/92/31 04-0746$03.00/0© 1992 by the American Academy of Child and Adolescent Psychiatry.
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This report describes the treatment responses to clomipramine in five outpatient young adults who met DSM-III-R (American Psychiatric Association, 1987) criteria for AD. The patients received no other pharmacological, psychosocial, or behavior therapy during clomipramine treatment.
Case Reports Case I A., a 13-year-old boy who lived with his parents and three siblings, presented with impaired social interaction, extreme ritualistic behavior, and aggression toward others. During his clinical examination, he demonstrated poor eye contact, immediate and delayed echolalia, and inappropriate use of objects. Despite attending a school for autistic children of his age, he developed no friends or social acquaintances. By parental report, he would spontaneously physically assault his older brother and younger sister three to four times per week and destroy their personal possessions. A. hoarded an enormous number of newspaper advertisements and resisted attempts by family members to dispose of them. Ritualistic tapping and touching, as well as symmetrical arranging of household articles, were among other interferring compulsive behaviors. A. met 12 of the 16 DSM-III-R criteria for AD. In addition, he met DSM-III-R criteria for an Axis I diagnosis of obsessive-compulsive disorder (OCD) (except for the apparent egosyntonic nature of the symptoms) and for an Axis II diagnosis of mild mental retardation. He had a score of 96 on the Autism Behavior Checklist (ABC) (Krug et aI., 1980). Other than birth via cesarean section due to posterior presentation, A. had a normal medical history. Physical examination, routine laboratory tests, fragile-X screening, magnetic resonance imaging of the head, and sleep-deprived EEG were normal. Full-scale IQ on the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (Wechsler, 1981) was 58. Speech did not develop until age 3, although motor skills emerged without delay. Family history included a maternal uncle with "mental retardation" who lived alone and a paternal grandfather described as "hyper" who was being treated with a neuroleptic. J. Am. Acad. Child Adolesc. Psychiatry, 31 :4, July 1992
CLOMIPRAMINE IN AUTISM
Previous medication trials included 7.5 mg/day of dextroamphetamine for 8 months and 15 mg/day of methylphenidate for 4 months. Although some improvement in psychomotor hyperactivity was noted with these treatments, his social interaction deteriorated and his compulsive behavior was exacerbated. A course of behavior modification was ineffective. A. was given 25 mg/day of clomipramine for 7 days with an increase to 75 mg/day within 3 weeks. After 6 weeks of clomipramine treatment, a significant improvement in A.'s clinical condition occurred. His total ABC score decreased to 24 and he received a "much improved" on the global improvement item of the Clinical Global Impressions (COl) Scale (Guy, 1976). With family members, he began attending and participating in social outings, such as miniature golf, fishing, and shopping. Numerous large plastic bags filled with newspaper ads were removed from his room and discarded without an increase in anxiety. Repetitive verbalizations, as well as compulsive touching and tapping, were significantly decreased. Aggressive advances toward others were reduced to approximately one episode every 3 weeks. This improvement was maintained over the subsequent 14 months without a further increase in the dosage of clomipramine. A. received no concomitant medications during the treatment with clomipramine.
Case 2 Ms. B., a 33-year-old single woman, presented with persistent social deficits and disabling obsessive compulsive symptoms. Pregnancy and birth were uneventful, and development was reported to be normal until the age of 2.5 years. At that time, coinciding with a fractured wrist, spontaneous speech and other social interaction rapidly deteriorated. Ms. B. attended special education classes until she was 18 years old. At the time of presentation to our clinic, the patient spent only a minimal amount of time with other people. Although she sat with her family at mealtime, she did not interact spontaneously. She had no friends or social acquaintances. Approximately 8 years earlier, Ms. B had developed severe compulsive behavior. This behavior included trichotillomania involving scalp hair, eyelashes, and eyebrows, extensive hoarding of food items, extreme obsessional slowness around dressing and grooming, repetitive hand movements and retracing of steps, and perseverative questioning. Ms. B. met 12 of the 16 DSM-III-R criteria for AD. In addition, she met DSM-III-R criteria for Axis I diagnoses of OCD (except for the apparent egosyntonic nature of the symptoms) and trichotillomania and for an Axis II diagnosis of mild mental retardation. Her total score on the ABC was 102.
Her physical examination, EKG, and routine laboratory tests of blood and urine were normal. Psychological testing revealed a full-scale IQ of 70 on the WAIS-R. There was no family history of neuropsychiatric illness. A previous trial of 2 mg/day of haloperidol resulted in some reduction in anxiety and symptoms of trichotillomania, but no significant change in other compulsive symptoms or in social relatedness. Ms. B. was given 50 mg/day clomipramine, with an inJ. Am. Acad. Child Adolesc. Psychiatry, 31 :4, July 1992
crease in dose to 200 mg/day over 4 weeks. After 8 weeks of treatment, a noticeable change occurred in the patient's social interaction. Her speech became more spontaneous, and she began inquiring about siblings who had moved out of the family home years ago. Ms. B. also expressed a desire to give Christmas presents to staff members at her workshop and to bake a birthday cake for a client at the workshop. Repetitive questioning was significantly reduced and the obsessional slowness around dressing and grooming was markedly improved. The symptoms of trichotillomania resolved, and the hoarding of food items became minimal. The patient's total ABC score decreased to 29, and she received a "much improved" on the global improvement item of the CGl. At follow-up, the improvement in these symptoms had been maintained for 19 months. Ms. B. received no concomitant medications during the clomipramine trial.
Case 3 Mr. C., a 27-year-old single man who lived in a group home for persons with developmental disabilities, presented with compulsive cleaning rituals, inappropriate social interaction, and aggressive behavior directed toward others. The product of a normal pregnancy, labor, and delivery, Mr. C. never developed language skills despite excellent motor coordination. At the age of2 years, he had acquired bronchitis accompanied by febrile seizures. While in the hospital, Mr. C.'s mother requested an auditory evaluation because she believed her son also had a hearing impairment. Subsequent consultation and testing revealed normal hearing. However, psychiatric consultation led to a diagnosis of infantile autism. After the divorce of his parents when he was 2.5 years old, the patient spent the majority of his life in institutions and foster homes. , Mr. C. currently worked in a sheltered workshop. He had rigid routines around housecleaning and dishwashing. He demanded that the furniture in the group home be arranged in an exact manner. If anyone moved the furniture, this would result in an aggressive outburst. When assigned to wash dishes, Mr. C. would proceed in a deliberate, compulsive manner. Each item would have to be washed a certain number of times and a certain order followed, e.g., glasses, then saucers, then bowls, etc. If this routine was interrupted even by another person's voice, violent attacks were often precipitated. Mr. C. did not interact with staff or other clients at the group home or at the workshop. He made essentially no eye contact and never spoke spontaneously. Mr. C. met 10 of the 16 DSM-III-R criteria for AD. He also met DSMIII-R criteria for an Axis I diagnosis of OCD (except for the apparent egosyntonic nature of the symptoms) and for an Axis II diagnosis of severe mental retardation. His total score on the ABC was 90. His physical examination, EKG, EEG, and laboratory tests of blood and urine were normal. His full-scale IQ on the WAIS-R was 29. There was no known family history of neuropsychiatric disorders. Mr. C. was given 50 mg/day clomipramine with subsequent increases in dosage to 250 mg/day over the course of 5 weeks. After 12 weeks of treatment, a marked improve747
MCDOUGLE ET AL.
ment in interfering behaviors was evident. Mr. C's total ABC score decreased to 22, and he received a "much improved" on the global improvement item of the COL Although the patient continued to be a meticulous cleaner, he no longer became violent or aggressive toward others when his routine was disrupted. In addition, there was a significant reduction in the amount of time required to complete the cleaning rituals. There were no subsequent aggressive attacks either at home or at work. Mr. C. became an active participant in our social skills training group. At each meeting, he prepared the snacks and made sure that all group members were served. Oroup home staff reported that Mr. C. also began to demonstrate appropriate one- or two-word verbalizations and to greet visitors at the door. These improvements were maintained throughout the 17-month follow-up period. Mr. C. received no medications other than clomipramine during treatment.
Case 4 Ms. D., a 29-year-old single woman who lived in a group home and worked in a sheltered workshop, presented with impairment in reciprocal social interaction, self-injurious behavior, and extreme repetitive questioning. Pregnancy and birth were normal, although her language skills were delayed. Ms. D. received a diagnosis of infantile autism at the age of 2.5 years. Before entering the group home, Ms. D. lived with her parents and attended special education classes. At examination, the patient demonstrated poor eye contact and isolated herself in a corner of the room. She had multiple, recent lacerations, as well as numerous well-healed scars, on both forearms as a result of biting herself. The only verbal exchange consisted of Ms. D. repetitively asking the examiner and others in the room about the color of their garages, the color of the inside of their toasters, and their height and weight. If these questions were not answered immediately and satisfactorily, Ms. D. would begin to scream and bite her arms. These behavioral disturbances had been present for many years. Ms. D. met 12 of the 16 DSMJ1I-R criteria for AD. In addition, Ms. D. met DSM-JII-R criteria for an Axis I diagnosis of OCD (except for the apparent egosyntonic nature of the symptoms) and for an Axis II diagnosis of mild mental retardation. Her total score on the ABC was 118. Other than the forearm lacerations described above, her physical examination, EKO, and routine blood and urine tests were all normal. Ms. D. had no other significant medical history. Her full-scale IQ on the WAIS-R was 66. There was no reported family history of neuropsychiatric illness. A trial of 10 mg/day of haloperidol for 8 weeks was ineffective in alleviating the disabling symptoms. She was then given 50 mg/day clomipramine, and it was increased to ISO mg/day over 4 weeks. After 6 weeks of treatment at this dose, a significant improvement in Ms. D.'s clinical status was apparent. Self-biting was reduced, and only well-healed scars remained on her forearms. Ms. D. began speaking to people in a nonperseverative manner. Although Ms. D. continued to have to ask strangers about the color of their garage and other stereotyped questions, she only asked each question once and a response that did not meet her expecta748
tions no longer resulted in self-injurious behavior. Her total ABC score decreased to 31, and she received a "much improved" on the global improvement item of the COL The improvement in Ms. D.'s condition was maintained through the subsequent 19 months. She received no concomitant medications throughout the clomipramine trial.
Case 5 Mr. E., a 24-year-old single man who lived at home with his parents, presented with a long history of impaired social skills, numerous compulsive rituals, and a preoccupation with television channels and programs. At birth, the patient experienced a 2- to 3-minute period of respiratory distress with Apgar scores of 7. His motor development was delayed and, although his language skills were precocious at 1.5 years of age, these subsequently deteriorated by the age of 2.5 years. Although Mr. E. had a full-scale IQ of 108 on the WAIS-R, he always attended special education classes. He was unemployed, had no friends, and spent inordinate amounts of time in his room, coming out only for meals. His compulsive behaviors included arranging personal belongings in a certain order, repetitive opening and closing of drawers and doors, and extensive nail-biting and fingerpicking. Mr. E. also had approximately 20 years worth of television program guides that he saved and filed in chronological order. Each evening he continuously scanned the channels on his television set, recording the time, date, station of program origin, and specific program. If this process was interrupted, increased anxiety and often aggressive behavior emerged. Mr. E. met 10 of the 16 DSM-JII-R criteria for AD. He also met DSM-III-R criteria for an Axis I diagnosis of OCD. His total score on the ABC was 75. No abnormalities were identified on physical examination, EKO, EEO, or routine laboratory tests of blood and urine. The patient had no history of medical problems other than the respiratory distress at birth. His family history was significant for a maternal male first-cousin with AD. Previous ineffective drug trials included 75 mg/day imipramine alone for 3 months and in combination with 50 mg/day of thioridazine for an additional 2 months, IS mg/day of methylphenidate for 5 months, 80 mg/day of fluoxetine for 4 months, and 30 mg/day hydroxyzine for 2 months. Mr. E. began receiving 50 mg/day clomipramine, with subsequent increases to 250 mg/day over 5 weeks. After 4 months of treatment at 250 mg/day, however, no significant improvement in social relatedness, compulsive behavior, 01'preoccupation with television-related items was observed. Mr. E.'s total ABC score remained essentially unchanged at 77, and he received a "no change" on the global improvement item of the COL He received no medications except clomipramine during the treatment trial. Discussion Four of five young adults with a DSM-III-R diagnosis of AD presenting with disturbances in social relatedness, obsessive compulsive symptoms, and/or aggressive and impulsive behavior had a significant improvement in symptomatology with open-label clomipramine treatment. The fifth patient remained clinically unchanged. Among the four pa· J. Am. A cad. Child Adolesc. Psychiatry, 31 :4, July 1992
CLOMIPIV\:\1INL IN AUTISM
tients who responded. two improved after 6 weeks. one showed a beneficial effect after 8 weeks, and two required up to 12 weeks of treatment with clomipramine before appreciable change occurred, The dose of clomipramine in the four responders ranged from 75 to 250 mg/day. with a mean dose of 185 ::':: 74 mg/day. Although clomipramine blood levels were not obtained during treatment. each patient lived with responsible parents or group home staff who administered the medication as prescribed. Other than mild dry mouth in two cases. the patients tolerated the drug well and had no adverse effects. In particular. Cases I. 2. 3. and 4 showed a significant improvement in social interaction. Cases I. 3 and 4 demonstrated a significant decrease in aggression. and Cases I, 2. 3. and 4 had a significant reduction in obsessive compulsive symptoms with clomipramine treatment. Whether the reduction in social withdrawal and aggressivity was a direct effect of clomipramine or an indirect result of the decrease in obsessive compulsive symptoms requires further study. The four patients who demonstrated clinical improvement are currently being maintained on clomipramine treatment. Clomipramine is a tricyclic antidepressant that has been shown in double-blind. placebo-controlled trials to have clear efficacy in the treatment of OCD (The Clomipramine Collaborative Study Group. 1991). In addition, clomipramine has been reported to be effective in reducing selfinjurious behavior (Lipinski. 1991). Although clomipramine affects noradrenergic and dopaminergic neuronal uptake. its most potent activity is to inhibit 5-HT reuptake. There is strong evidence that clomipramine' s effects on 5-HT reuptake are responsible for the drug's antiobsessive compulsive efficacy (Mavissakalian et aI., 1990). A dysregulation in 5-HT function in patients with AD has been hypothesized. The most consistent biological marker to date in AD is elevated WBS levels. which have been found in 30% to 40Ck of patients studied (Anderson et aI., 1987). In addition. antibodies directed against 5-HT neurons were identified in the blood and cerebrospinal tluid of 7 of 13 patients with AD in one study (Todd and Ciaranello, 1985). Decreased central 5-HT responsivity has been demonstrated in children (Hoshino et al.. 1984) and adults (McBride et aI.. 1989) with AD. as retlected by a decreased prolactin response to L-5-hydroxytryptophan and fentluramine, respectively. Preclinical and clinical evidence indicates that 5-HT function is significantly involved in social interactive. obsessive compulsive, and aggressive and impulsive phenomena. For example. studies of the dominance relationships of adult male vervet monkeys have shown that dominant males have
a peak of approximately 1,100 ng/ml, where they remain indefinitely. Behaviorally. despite WBS levels similar to those of dominant males. these long-term isolated monkeys behave likc subordinate males (McGuirc and Raleigh. 1l)~5). That 5-HT function is critical to the pharmacological treatment and perhaps the pathophysiology of patients with OCD is supported by thc c1car efficacy of 5-HT reuptake inhibitors and by results from some neuroendocrine challenge studies. Drugs that are potent inhibitors of 5-HT reuptake. such as clomipramine (The Clomipramine Collaborative Study Group. 1991). tluoxetine (Pigott et al.. 1990). and tluvoxamine (Goodman et al.. 19R9). have becn shown in double-blind studies to be effectivc in thc treatment of patients with OCD. Investigators have found a blunted prolactin responsc to the 5-HT agonist m-chlorophenylpiperazine in OCD females. suggesting decreased 5-HT responsivity in that patient population (Charney ct al.. 1981\). Although other neurotransmitters, such as dopamine. may also be involved in obsessivc compulsive phenomena (Goodman et aI., 1990). 5-HT function has hecn shown to be critical to the treatment of the disorder. Some investigators have questioned the appropriateness of the terms obsessio/{ and c(impulsio/{ to describe the repetitive activities of patients with autism (Baron-Cohen. 1(89). The improvement in thesc repetitive thoughts and hehaviors during treatment with the antiobsessivc compulsivc agcnt clomipramine in this study suggests that thcse phenomcna may respond similarly to the obsessions and compulsions demonstrated by patients with OCD. A number of clinical studies support a rclationship between a decrease in 5-HT function and aggressivc and impulsive behavior. Postmortem studies of suicide victims have consistently demonstrated a significalH decrcase in 5HT. 5-hydroxyindoleacetic acid (5-HIAA). or both. in suicide victims compared with controls (Stanley and Stanlcy. 1990). One recent postmortem study found that patients with Alzheimer's disease with a history of aggressivity had significantly lower 5-HT cortical levels than either normal controls or Alzhcimcr' s patients without a history of aggrcssive behavior (Palmer et aI., 1988). Preclinical studies have demonstrated that when dominant malc vervet monkeys arc treated with either a 5-HT reuptake inhihitor. a 5-HT rcccptor agonist. or the 5-HT precursor tryptophan. they become more quiescent and less aggressive in thcir social behavior (Raleigh et aI., 1985). Preliminary reports suggest that other medications that facilitate 5-HT neurotransmission may reducc certain disabling symptoms in patients with AD. McDougle et al. (1990) reported that the 5-HT reuptake inhibitor tluvoxamine re-
WI3S Icvds of approximaldy 1.000 ng/ml. whereas slIborui-
ullceu obsessive compulsive allu aggressive behaviors i.lIlU
nate males have WBS levels of about 650 ng/ml. Spontaneous or experimenter-induced changes in the social hierarchy result in corresponding changes in WBS levels (Raleigh et aI., 1984). In related studies in vervets. it has been found that extended isolation from the social group results in significant behavioral and biological changes. Initially, for either dominant or subordinate males, extended isolation results in WBS levels of approximately 650 ng/ml. After 18 weeks of isolation. however. the WBS levels rise and reach
improved social relatedness in a 30-year-old man with AD and comorbid OCD. Cook et al. (1990) found that 20 mg/ day of tluoxetine led to a significant decrease in timc away from a daily workshop placement in a man with a diagnosis of pervasive developmental disorder (not otherwise specified), who demonstrated interpersonal withdrawal and multiple compulsive behaviors. This same group recently reported that 20 mg of fluoxetine every third day to 80 mg/day resulted in a significant improvcment in National Institute
.I. AI/I. Auul. Child Adolesc. Psychiafry. 31 :4. .Iul\' j()1.)2
749
MCDOUGLE ET AI..
of Mental Health global ratings of illness severity in 15 of 23 patients with AD (Cook ct aI., 1991). Hamdan-Allen (1991) observed that tluoxetine led to a resolution of trichotillomania and improved stereotypic behavior in an 18-yearold man with AD. In a small double-blind, placebo-controlled study, investigators at the Yale Child Study Center found tluoxetine useful in some children and young adults with AD who demonstrated intense patterns of obsessive compulsive behavior 0. Bregman, Pers. Commun., 1991). Investigators have also reported that buspirone, a 5-HTIA agonist, reduces hyperactivity, aggression, and stereotypy in some children (Realmuto et al.. 19&9) and adults (Ratey et al.. 19&9) with AD. In summary, clomipramine was effective in improving social relatedness and in reducing obsessive compulsive and aggressive symptoms in four of five patients with AD. Based on preclinical and clinical research thaI documentes involvement of 5-HT function in social interaction, obsessive compulsive phenomena, and aggressivity and impulsivity, it appears that 5-HT neurotransmission is relevant to the treatment, and possibly the pathophysiology, of some disabling symptoms of AD. However, results of open-label case studies must be viewed with caution. Prospective double-blind, placebo-controlled trials of clomipramine and other drugs that facilitate 5-HT neurotransmission are necessary before definitive conclusions can be drawn about their efficacy in the treatment of patients with AD.
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