Fluoxetine Treatment of Children and Adults with Autistic Disorder and Mental Retardation EDWIN H. COOK, JR., M.D., RANDALL ROWLETT, M.D., CATHERINE JASELSKIS, D.O., AND BENNETT L. LEVENTHAL, M.D.
Abstract. An open trial of pharmacological treatment with fluoxetine, ranging from 20 mg every other day to 80 mg per day, led to a significant improvement in Clinical Global Impressions ratings of Clinical Severity in 15 of 23 subjects with autistic disorder and 10 of 16 subjects with mental retardation. Six of 23 patients with autistic disorder and 3 of 16 patients with mental retardation had side effects which significantly interfered with function, consisting predominantly of restlessness, hyperactivity, agitation, decreased appetite, or insomnia. Doubleblind studies of the efficacy of pharmacological agents that potently inhibit 5-HT uptake in the treatment of mental retardation coexisting with Axis I psychiatric disorders (especially obsessive-compulsive disorder) and autistic disorder are warranted. J. Am. Acad. Child Adolesc. Psychiatry, 1992,31,4:739-745. Key Words: autistic disorder, mental retardation, fluoxetine, obsessive compulsive behavior, perseveration. Perseverative behavior has been identified as a frequently associated feature of both mental retardation (MR) and, more specifically, of autistic disorder. In fact, it may be difficult to distinguish autistic disorder from severe and profound mental retardation, in part because of the high frequency of perseverative behavior in both disorders. Although some consider perseverative behavior to be secondary to an underlying incapacity to engage in more functional behaviors, others argue that such ritualistic behavior may be obstructing the autistic individual's innate capacity for more adaptive behavior. It is unclear whether one should view the rituals of autistic and mentally retarded individuals as intrinsic to their disorders, as secondary adaptations, or as evidence for coexisting obsessive-compulsive disorder (OCD). Several authors have recently identified a subgroup of mentally retarded patients whom they consider comorbid for obsessive-compulsive disorder (Matson, 1982; McNally and Calamari, 1989; Vitiello et ai., 1989). Several children with autistic disorder have been reported to develop ritualistic and compulsive behavior for the first time when they are 6 to 7 years old (Rutter et aI., 1967). The objection might be raised that the rituals of OCD are ego-dystonic for its sufferers whereas individuals with developmental disorders usually do not appear to resist
Accepted September 5, 1991. Dr. Cook is Assistant Professor of Psychiatry and Pediatrics; Dr. Rowlett is Clinical Assistant Professor of Psychiatry and Pediatrics; Dr. Jaselskis is an 1nstructor in Psychiatry and Pediatrics; and Dr. Leventhal is Professor of Psychiatry and Pediatrics at the University
their obsessions and compulsions. However, children without developmental disorders with early onset OCD often do not demonstrate ego-dystonicity (Swedo and Rapoport, 1989). In any case, it is very difficult to draw inferences about the subjective emotional states of individuals whose capacities for communication and interpersonal relatedness are severely compromised. Irrespective of the cognitive and psychological representations, autistic and mentally retarded individuals often demonstrate symptoms that are behaviorally indistinguishable from OCD. The advent of some pharmacological agents that potently inhibit the reuptake of serotonin and ameliorate OCD symptoms makes this issue of more than theoretical importance. An open trial was conducted to test the hypothesis that fluoxetine might lead to improvement in clinical ratings of perseverative behaviors in some individuals with autistic disorder and/or mental retardation. Global ratings of severity of autistic disorder or psychopathology in mentally retarded patients without autistic disorder was not expected to significantly improve.
Method Subjects These subjects represent a consecutive series of patients treated with fluoxetine by child and adolescent psychiatrists at the University of Chicago in an outpatient setting between 1988 and 1990. These patients were referred to the clinic by parents and professionals who sought an opinion regarding possible medication treatment. Treating clinicians chose treatment with fluoxetine after clinical assessment and diag-
of Chicago.
nosis according to their personal clinical judgment that flu-
This study was supported in part by the Harris Center for Developmental Studies and N1MH Child and Adolescent Mental Health Academic Award (E.C) MH00822. Patients with autistic disorder and! or mental retardation and their parents have provided assistance individually and through local chapters ofthe Autism Society ofAmerican in 1ndiana and lllinois. Kathlyn E. Fletcher provided assistance in data collection and analysis. Reprint requests to Dr. Cook, Department of Psychiatry, Box 411, 5841 S. Maryland Avenue, Chicago, 1L 60637. 0890-8567/92/31 04-0739$03.0010© 1992 by the American Academy of Child and Adolescent Psychiatry.
oxetine might be of benefit for perseverative behaviors ranging from self-injurious behavior to complex rituals. Many patients referred for assessment during this time were not treated with fluoxetine or other medications. Two groups of patients were studied: autistic (N = 23) and mentally retarded (N = 16). The patients with autistic disorder were diagnosed by DSM-III-R criteria (American Psychiatric Association, 1987) and ranged in age from 7.0 to 28 years (mean ± SO
J. Am. Acad. Child Adolesc. Psychiatly, 31 :4, July 1992
739
COOK ET AL.
= 15.9 ± 6.2). Five patients were female and 18 were male. Concomitant Axis II diagnoses included profound MR (three), severe MR (seven), moderate MR (three), mild MR (six), and borderline intellectual functioning (two). Two patients were in the normal range of intelligence. Concomitant Axis I disorders included OCD (three), impulse control disorder not otherwise specified (NOS) with self-injurious behavior (SIB) (six), impulse control disorder NOS without SIB (five), cyclothymia (one), bipolar disorder NOS (one), and eating disorder NOS (one). Two patients met criteria for attention-deficit hyperactivity disorder except for the presence of a pervasive developmental disorder (Table 1). Oral fluoxetine ranging from 20 mg every other day to 80 mg per day was administered based on open titrati.on. Patients were started at a dosage of 20 mg each mornlllg and increased until side effects emerged or until it appeared that a higher dosage would not lead to therapeutic effects. Dosage was most commonly reduced because of insomni~ a.nd/ or irritability. Patients were discontinued based on chmcal judgment if significant side effects emerged or after at least 2 months treatment without improvement in symptoms. Concomitant psychotropic medication included neuroleptics (eight patients), carbamazepine (one patient), lithium carbonate (two patients), clonidine and alprazolam (one patient), and methylphenidate (one patient). . . The 16 patients with mental retardation without autIstIc disorder had varied comorbid Axis I psychiatric disorders, including attention-deficit hyperactivity disorder (one), impulse control disorder NOS with SIB (two), impulse control disorder without SIB (six), major depression (one), depressive disorder NOS (two), dysthymia (two), bipolar ?isorder NOS (one), psychotic disorder NOS (one), anxIety disorder NOS (one), OCD (one), and trichotillomania (one). This group of patients ranged in age from 7.3 to 52 years (21.0 ± 11.5). Twelve were female and four were male. Three patients had profound MR, four patients had severe MR, three patients had moderate MR, and six patients had mild MR. These subjects received fluoxetine at doses ranging from 20 to 80 mg daily. Concomitant psychotropic ~e.di cation included neuroleptics (six patients), ethosuxImIde (one patient), phenytoin (one patient), desipramine (on~ patient also on thioridazine), lithium carbonate (one patIent), lorazepam (one patient also on haloperidol), and clonidine (one patient). Ratings were performed at baseline and either at the time of discontinuation of fluoxetine or between May and December of 1990 for all subjects being treated with fluoxetine as of December of 1990. Each treating clinician made both the baseline and fluoxetine ratings for each patient. Patients with autistic disorder had been receiving fluoxetine between 11 and 426 days (mean ± SD = 189 ± 153 days) at the time of rating. Patients with mental retardation without autistic disorder had been treated with fluoxetine for 7 to 467 days (183 ± 134) at the time of rating. Subjects were. rated wit.h the Clinical Olobal Impressions scale (COl) (NatIOnal InstItute of Mental Health, 1985) in two areas. The first was an overall rating of severity of illness and therapeutic efficacy. In addition, COl ratings were made that were limited to perseverations, compulsions, or rituals depending on the 740
individual's particular difficulties. COl ratings of severity were made at baseline and during drug treatment. COl ratings of therapeutic efficacy were used as an estimate of si.de effects. COl severity ratings at baseline were compared WIth COl severity ratings after fluoxetine treatment using paired t-tests.
Results Therapeutic Effects
In patients with autistic disorder, fluoxetine led to an improvement in COl ratings of overall clinical severity in 15 of 23 subjects (baseline = 5.7 ± 0.8; fluoxetine = 4.9 ± 1.1; paired t = 4.03; df = 22; p < 0.002~ (Fig. 1)... . Ten of 16 mentally retarded subjects WIthout autIstIC dISorder had an improvement of 1 or more on COl overall severity ratings (baseline = 5.1 ± 1.0; fluoxetine = 4.2 ± 1.3; paired t = 3.57, df = 15, p < 0.004) (Fig. 2). COl ratings of severity of perseverative or compulsive behavior revealed a similar therapeutic response to fluoxetine in patients with autistic disorder (baseline = 5.5 ± 1.5; fluoxetine = 4.7 ± 1.6; paired t = 3.13, df= 22,p < 0.005) and mental retardation (although not significant) (baseline = 3.7 ± 2.1; fluoxetine = 3.1 ± 1.9; df = 14, P < 0.070). Side Effects
Six of 23 subjects with autistic disorder had side effects that significantly interfered with function or outweighed therapeutic effects. Only 1 of the 15 patients who had .an improvement in COl ratings of clinical sev~rity had s~de effects that significantly interfered with functIOn (COl SIde Effects Moderate or Marked; Table 2). Three of 16 subjects with mental retardation without autistic disorder had side effects which significantly interfered with function or would have outweighed therapeutic effects. None of these three subjects had an improvement in CGI ratings of severity of illness (Table 3). There was no relationship between level of mental retardation and response to fluoxetine or between baseline COl "perseveration" ratings and response to fl~oxetine. In addition, dysphoria did not appear to be a predIctor of response to treatment, although this was not specifically measured. Thirteen of the combined group of patients were concomitanty treated with neuroleptics. Four of these I? patients developed significant side effects. Three of the subjects were on haloperidol ranging from 0.25 mg everyday (q.d.) to 0.5 mg three times a day (t.i.d.), and the fourth. patient. was taking trifluoperazine I mg q.d. In contrast, eIght patIents had an improvement in clinical severity ratings .without sid.e effects. Five of these eight responders were takmg halopendol ranging from 0.5 mg q.d. to 2 mg ti.d. Another thre~ of the responders were taking thioridazine at doses rangmg from 25 mg ti.d. to 200 mg daily. The patient being treat~d with 25 mg t.i.d. of chlorpromazine did not respond and dId not have significant side effects.
Case Reports Case 1
Case 1 provides an illustration of a typical patient with J. Am. Acad. Child Adolesc. Psychiatry, 3 J:4, July J992
FLUOXETINE AND DEVELOPMENTAL DISORDERS TABLE 1. Therapeutic Effects of Fluoxetine in Patients with Autistic Disorder and Mental Retardation
Diagnosis Patients with AD Responders
CGI Drug
Comorbid Axis II Disorder
Comorbid Axis I Disorder
Race
Sex
13.8
W
M
40
6
2
None
OCD
27.5
W
M
80
6
5
Mild MR
None
W
M
10
7
6
OCD
15.1
W
M
10
6
5
Borderline intelligence functioning MildMR
7.5
A
M
20
5
4
None
ADHD
12.8
B
M
40
6
5
Severe MR
13.0
W
M
40
5
4
MildMR
Impulse control disorder NOS (and SIB) Impulse control disorder NOS
15.6
H
F
20
6
5
Severe MR
Impulse control disorder NOS
16.1
W
M
20
6
5
Profound MR
16.9
B
M
40
6
5
MildMR
Impulse control disorder, NOS Impulse control disorder NOS
18.2
W
F
40
5
4
21.9
W
F
20
6
5
Borderline intelligence functioning Severe MR
22.4
W
F
20
6
4
Severe MR
28.8
W
M
20
6
5
Profound MR
9.9
W/B
M
40
6
4
Moderate MR
7.0
W
M
30
5
5
Severe MR
23.8 10.1 21.2
W B B
M M M
40 20 20
4 7 4
4 7 4
MildMR Moderate MR MildMR
9.9
H
M
20
5
6
Severe MR
11.2
B
M
20
6
6
Moderate MR
14.3
W
M
20
6
6
Severe MR
8.25
Nonresponders
Optimal COl Dose (mg) Baseline
Age at Trial
J. Am. Acad. Child Adolesc. Psychiatry, 31:4, July 1992
Cyclothymia and OCD (provisional)
None
Bipolar disorder NOS (periodic catatonia) Eating disorder NOS Impulse control disorder NOS (and SIB) Impulse control disorder NOS (and SIB) None None ADHD Impulse control disorder NOS Impulse control disorder NOS (and SIB) Impulse control disorder NOS Impulse control disorder NOS (and SIB)
Type of Improvement Decreased egodystonic, obsessive thoughts Decreased compulsive ordering and rate of aggression Decreased rate of rituals Decreased preoccupation with phone books and open doors More flexible and responsi ve to social cues Less aggressi ve, better mood and sleep Fewer tantrums, more spontaneous and flexible More cheerful, less stubborn, better eye contact Less aggressi ve, better eye contact Decreased aggressi ve and destructive behavior Improved sleep, calmer, more spontaneous Less agitated and irritable Weight gain, decreased vomiting Better mood, more responsive, cessation of SIB Decreased tantrum intensity and severity Less irritable and dysphoric No improvement No improvement No improvement No improvement
No improvement No improvement
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COOK ET AL.
TABLE I. Continued
Diagnosis
Patients with MR (without AD) Responders
Nonresponders
Optimal COl Dose (mg) Baseline
COl Drug
Comorbid Axis II Disorder
Age at Trial
Race
Sex
22.3
H
F
20
7
7
Profound MR
9.6
W
F
20
5
3
MildMR
15.7
W
F
20
6
4
Severe MR
17.0
W
F
20
5
3
Moderate MR
17.6
W
F
20
5
3
Profound MR
17.6
W
M
60
4
3
MildMR
20.5
B
M
40
6
5
Moderate MR
22.7
B
F
40
4
3
Severe MR
23.7
W
F
20
6
5
Severe MR
28.4
B
M
20
5
4
Severe MR
7.3
W
M
20
4
3
MildMR
8.6
W
F
20
4
5
Mild MR
14.6
W
F
20
6
6
Profound MR
17.2
W
F
40
6
6
Profound MR
30.1 37.8
A B
F F
40 20
3 6
3 6
MildMR Moderate MR
52.7
W
F
40
6
6
MildMR
Note: CGI = Clinical Global Impressions scale, NOS = not otherwise specified, SIB tion, OCD = obsessive-compulsive disorder, AD = autistic disorder. autistic disorder who functioned better on fluoxetine treatment than she functioned before fluoxetine treatment. E. met DSM-III-R criteria for autistic disorder because of symptoms including abnormal prosody, perseveration, hypersensitivity to sound, and intolerance of any change in her routines.
742
Comorbid Axis I Disorder Impulse control disorder NOS (& SIB) Impulse control disorder NOS
Type of Improvement No improvement
Calmer, more attentive, less screaming
Impulse control disorder NOS
More spontaneous and flexible, calmer, cheerful, fewer tantrums Major depression, Better mood, more severe, recurconsiderate, less lerent thargic Impulse control Decreased aggression, disorder NOS SIB, and compul(and SIB) sive overeating Dysthymia Smiling, animated, more spontaneous Psychotic disorder Decreased overeating, NOS better mood, less perseverative Anxiety disorder Eliminated self-injuriNOS, impulse ous behavior control disorder NOS (SIB) Impulse control Better eye contact disorder NOS and mood, less aggression "Less hyper," better Impulse control disorder NOS mood Depressive disor- Better mood, more del' NOS (prospontaneous and visional) social ADHD, dysthyNo improvement mia, trichotillomania Impulse control No improvement disorder NOS Less withdrawn, betBipolar disorder NOS (periodic tel' appetite catatonia) and rumination disorder OCD No improvement No improvement Impulse control disorder NOS Chronic schizoNo improvement phrenia and depressive disorder NOS
= self-injurious behavior, MR = mental retarda-
Target symptoms of pharmacological treatment were insomnia, anxiety, and rigidity of response. Her parents preferred not to try neuroleptics because of their awareness of the risk of tardive dyskinesia. After unsuccessful trials with lithium carbonate, cloni-
J. Am. Acad. Child Adolesc. Psychiatry, 31:4, July 1992
FLUOXETINE AND DEVELOPMENTAL DISORDERS TABLE
2. Side Effects of Patients with Autistic Disorder
No. of Patients (%)
Side Effect 8
# of 6 Subjects
-1
0
1
2
3
4
Improvement of Clinical Global Impressions Severity of Illness
FIG. 1. Patients with autistic disorder. Change in Clinical Global
Impression overall clinical severity ratings after treatment with fluoxetine. Ratings after fluoxetine were significantly improved compared with baseline (t = 4.03, df = 22, p < 0.002). 6
Hyperactivity/restlessness/agitation Insomnia Elated affect Decreased appetite Increased rate of screaming Increased socially inappropriate behavior Crying spells Yawning Maculopapular rash COl side effects None Do not significantly interfere with functioning Significantly interferes with functioning Outweighs therapeutic effect Days to onset of side effects 0-[5 16-31
Greater than 31
5 4 4 4 2 1
(22) (17) (17) (17) ( 9) ( 4)
I ( 4) I ( 4) I ( 4)
10 8 4 I
(43) (35) (17) ( 4)
4
5 5
5 4
TABLE
# of 3 Patients
3. Side Effects of Patients with Mental Retardation (without Autistic Disorder)
Side Effect
2
o -1
0
1
2
Improvement of Clinical Global Impressions Severity of Illness
FIG. 2. Patients with mental retardation without autistic disorder.
Change in Clinical Global Impression overall clinical severity ratings after treatment with fluoxetine. Ratings after fluoxetine significantly improved compared with baseline (t = 4.03, df = 22, p < 0.002). dine, and desipramine, E. was treated with diphenhydramine, 50 mg at bedtime, which helped her insomnia but did not lead to an improvement in anxiety or rigidity of response. A year later, when she was 18 years old, fluoxetine was added at an initial dose of20 mg daily. Dosage was increased to 40 mg daily after 3 weeks because of minimal change except an improvement in sleep. After 2 weeks on the higher dosage, E. was said to be " a little more rationaL" However, given the cost of the medication and the apparent modesty of benefit, her parents elected to discontinue the trial. A month later, fluoxetine was restarted at 40 mg g.d. after her parents concluded retrospectively that E. had in fact been much calmer on the drug. Three weeks into the second trial, E.'s teacher reported that she was doing more school work. After 3 months, E.'s father commented enthusiastically that E. was more cooperative, no longer complained of fatigue, was socializing more, and was for the first time speaking spontaneously in school. She no longer required diphenhydramine to fall asleep at night. E. herself stated, "They (the fluoxetine pulvules) make me feel calm, and they make me feel OK, and I never get nervous anymore."
Case 2 G. is an example of a patient who did not respond to l. Am. Acad. Child Adolesc. Psychiatry, 31:4, luly 1992
Hyperacti vity/restlessness/agitation Insomnia Elated affect Decreased appetite Increased socially inappropriate behavior Lethargy Tremor Grimacing Polydipsia COl side effects None Do not significantly interfere with functioning Significantly interferes with functioning Outweighs therapeutic effect Days to onset of side effects
No. of Patients (%) 4 (25) 2 I I I
(12) ( 6) ( 6) ( 6)
I ( 6) I ( 6) I ( 6) j
(
6)
9 (56) 4 (25) 3 (19)
o ( 0)
0-15 16-31
5 2
Greater than 31
4
fluoxetine and developed side effects which significantly interfered with his functioning. He was 14 years old when fluoxetine was initiated. Diagnoses were autistic disorder and severe mental retardation. His mother sought treatment for G. because his symptoms, including continual screeching, touching of others, and repetition of the sound, "geddo-geddo," were prompting abusive behavior by her alcoholic husband. Regrettably, fluoxetine (20 mg g.d.) did not improve matters: G. developed marked insomnia, uncontrollable laughing and was "too hyper to eat." Fluoxetine was discontinued after 11 days. Seven months later, G. was doing reasonably well on propranolol (40 mg ti.d.).
Case 3 A. is an example of a mentally retarded patient without
743
COOK ET AL.
autistic disorder who functioned better during treatment with fluoxetine than before treatment with fluoxetine. She was 9 years old at the time she entered the study. She met DSMllI-R criteria for mild mental retardation (Verbal IQ 63, Performance IQ 74, Full-scale IQ 67) and impulse control disorder. At the time of the referral, A.'s single mother had come reluctantly and guiltily to the conclusion that she would have to place her daughter in a residential facility. Major concerns were A.'s poor impulse control (she would take any pills she found in the medicine cabinet), short attention span, and low frustration tolerance. Behavioral treatments had been undermined by A.' s capacity to scream for hours if she did not get her way and her mother's exhaustion and depression. She began receiving fluoxetine (20 mg q.d.). Nine days later, her mother reported that A. was calmer, less aggressive and screaming less, but that the effect appeared to wear off late in the day. Dosage was increased to 40 mg daily. A week later, her mother reported further improvement. At the end of the 3rd week, the dosage was reduced to 20 mg q.d. because A. was becoming "more obstreperous." At the end of the first month, her mother observed, ''I'm able to think (about how to help my daughter) without anxiety because she's not screaming all the time." Four months after fluoxetine was initiated, A. "continues to do well; we really appreciate her calm." Case 4
D. provides an example of a patient who experienced side effects that significantly interfered with function and functioned worse during treatment with fluoxetine. She was 14 years old when f1uoxetine was introduced. She had a diagnosis of severe to profound mental retardation, Down syndrome, and microcephaly. Her father had bipolar disorder. Target symptoms included impulsive, provocative, and aggressive behavior inadequately controlled on haloperidol (0.5 mg t.i.d.). One week after D. began receiving fluoxetine (20 mg q.d.), the nurse at her residential facility reported the onset of fine tremors in the trunk and upper extremities more than the lower extremities. D. was noted to have a poor appetite, to appear "spacey," and to be "more agitated." Fluoxetine was discontinued. Twenty-four hours later she remained very agitated and fearful, but tremors had been replaced by rigidity. She was given diphenhydramine (50 mg intramuscularly) for an apparent dystonic reaction, and haloperidol was discontinued. Two days later, she had substantially improved and was back to her usual behavior after 5 days. Ten months after her adverse response to combined treatment with fluoxetine and haloperidol, D. was doing well on combined therapy with lithium carbonate and c1onidine.
Discussion Most children, adolescents, and adults with autistic disorder and/or mental retardation had lower CGI severity of illness scores during treatment with fluoxetine than they had immediately before treatment. This open study extends previous case reports of the response of children and adolescents with autistic disorder to pharmacological agents which potently inhibit the reuptake of 5-HT such as fluvoxamine
744
and fluoxetine (Ghaziuddin et aI., 1991; Hamdan-Allen, 1991; McDougle et aI., 1990; Mehlinger et al., 1990; Todd, 1991) and a preliminary report of a double-blind comparison of clomipramine to desipramine (Gordon et aI., 1991). The present study extends our previous report of therapeutic response to f1uoxetine in nonautistic patients (IQ's between 70 and 75) (Cook et aL, 1990) to the mentally retarded range. However, it must be highlighted that this study is limited by being an open trial without placebo control or discontinuation of medication to exclude placebo or order effects. In addition, raters were treating clinicians who were not blind to medication status. Significant aide effects were more common in nonresponders than responders and included restlessness, hyperactivity, agitation, decreased appetite, and insomnia, which remitted after dosage reduction or discontinuation. Responders could not be differentiated from nonresponders on the basis of baseline ratings of perseverative behavior or level of cognitive functioning. Further controlled studies are warranted with more comprehensive baseline assessment to determine whether or not baseline dysphoria or more subtle aspects of cognition or "compulsiveness" predict response. The addition offluoxetine (case 4) may have caused extrapyramidal symptoms because of an increase in serum haloperidol levels or reduction in striatal dopamine synthesis (Baldessarini and Marsh, 1990; Goff et aL, 1991). Interactions between neuroleptics and fluoxetine have been described in some patients without development disorders (Brod, 1989; Tate, 1989), although an open study did not confirm this finding (Goff et aL, 1991). In the current study, there was not an indication of an increased risk of overall side effects when autistic and/or mentally retarded patients were being treated with neuroleptics. Although serotonergic dysfunction has been suggested in autistic and mentally retarded subjects, most studies have revealed heterogeneity in serotonergic measures which may account for the heterogeneity of response seen here (Cook, 1990). Whole blood serotonin (Kremer et al., 1990), platelet serotonin (F1ament et aL, 1987), or plasma prolactin (Hanna et aL, 1991) may be a useful predictor of response or a way of following and determining optimal dose, but this has yet to be confirmed. Although the response to fluoxetine could be the result of an antidepressant rather than antiobsessional effect, a previous open trial with imipramine did not lead to a group improvement in autistic subjects (Campbell et al., 1971). It is notable that avoidant personality disorder without OCD has been reported to respond to treatment with fluoxetine, so that some of the global improvement may have been directed toward a component of social phobia (Deltito and Stam, 1989). Buspirone, an anxiolytic with possible thera- . peutic effects in OeD (Pato et al., 1991), has led to an improvement in both nonautistic developmentally disabled (Ratey et aL, 1989) and autistic individuals (Realmuto et aL, 1989) in open trials. Double-blind placebo controlled studies of fluoxetine (Pigott et al., 1990), sertraline (Chouinard et al., 1990), clomipramine (Katz et al., 1990), or fluvoxamine (Price et al., 1987) are warranted in the treatment of obsessive compulJ. Am. Acad. Child Ado/esc. Psychiatry, 31 :4, Ju/y 1992
FLUOXETINE AND DEVELOPMENTAL DISORDERS
sive symptoms in individuals with autistic disorder and/or mental retardation. These drugs do not address the core symptoms of either cognitive dysfunction or communication, but may be of use in the adjunctive treatment of patients. They may also direct investigations toward a more specific pharmacological treatment of core symptoms. Summary In an open trial, function in a majority of subjects with autistic disorder and mental retardation was improved during treatment with f1uoxetine compared to function immediately preceding treatment. Side effects included hyperactivity, restlessness, insomnia, or decreased appetite in a minority of subjects and remitted within several days of discontinuation or reduction of f1uoxetine. Systematic, double-blind controlled studies of the efficacy of f1uoxetine and other drugs that potently inhibit the uptake of serotonin, such as f1uvoxamine, clomipramine, and sertraline, in the treatment of patients with autistic disorder and with mental retardation and other psychiatric disorders (especially OeD) are warranted. References American Psychiatric Association (1987), Diagnostic and Statistical
Manual of Mental Disorders, 3rd edition-revised (DSM-llI-R). Washington, DC: American Psychiatric Association. Baldessarini, R. J. & Marsh, E. (1990), Fluoxetine and side effects.
Arch. Gen. Psychiatry, 47:[91-192. Brod, T. M. (1989), Fluoxetine and side effects (letter). Am. J. PsychiatlY, 146:1353.
Campbell, M., Fish, B., Shapiro, T. & Floyd, A. (1971), Imipramine in preschool autistic and schizophrenic children. Journal ofAutism and Childhood Schizophrenia, 1:267-282. Chouinard, G., Goodman, W., Greist, J. et a!. (1990), Results of a double-blind placebo controlled trial of a new serotonin reuptake inhibitor, sertraline, in the treatment of obsessive-compulsive disorder. Psychopharmacol. Bull., 26:279-284. Cook, E. H. (1990), Autism: review of neurochemical investigation.
Synapse, 6:292-308. - - Terry, E. J., Heller, W. & Leventhal, B. L. (1990), Fluoxetine treatment of borderline mentally retarded adults with obsessivecompulsive disorder. J. Clin. Psychopharmacol., 10:228-229. Deltito, 1. A. & Stam, M. (1989), Psychopharmacological treatment of avoidant personality disorder. Compr. Psychiatry, 30:498-504. Flament, M. F., Rapoport, J. L., Murphy, D. L., Berg, C. J. & Lake, R. (1987), Biochemical changes during clomipramine treatment of childhood obsessive-compulsive disorder. Arch. Gen. Psychiatry, 44:219-225. Ghaziuddin, M., Tsai, L. & Ghaziuddin, N. (1991), Fluoxetine in autism with depression. J. Am. Acad. Child Adolesc. Psychiatry, 30:508-509. Goff, D. c., Midha, K. K., Brotman, A. W., Waites, M. & Ba[dessarini, R. J. (1991), Elevation of plasma concentrations ofhaloperido[ after the addition of fluoxetine. Am. J. Psychiatry, [48:790-792.
1. Am. Acad. Child Adolesc. Psychiatry, 31:4, July 1992
Gordon, c., Rapoport, J., Hamburger, S. & Mannheim, G. (1991), Differential response of autistic disorder to clomipramine. 1. Am. Acad. Child Adolesc. Psychiatry, 30: [64. Hamdan-Allen, G. (1991), Brief Report: Trichotillomania in an autistic male. J. Autism Dev. Disord., 2 [:79-82. Hanna, G. L., McCracken, 1. T. & Cantwell, D. P. (1991), Prolactin in childhood obsessive-compulsive disorder: clinical correlates and response to clomipramine. 1. Am. Acad. Child Adolesc. Psychiatry, 30: 173-178. Katz, R. J., DeVeaugh-Geiss, J. & Landau, P. (1990), Clomipramine in obsessive-compulsive disorder. BioI. Psychiatry, 28:401-414. Kremer, H. P. H., Goekoop, J. G. & Van Kempen, G. M. J. (1990), Clinical use of the determination of serotonin in whole blood. J. Clin. Psychopharmacol., [0:83-87. Matson, 1. L. (1982), Treatment of obsessive-compulsive behavior in mentally retarded adults. Behav. Modif., 6:551-567. McDougle, C. J., Price, L. H. & Goodman, W. K. (1990), Fluvoxamine treatment of coincident autistic disorder and obsessive-compulsive disorder: a case report. J. Autism. Dev. Disord., 20:537-543. McNally, R. J. & Calamari, J. E. (1989), Obsessive-compulsive disorder in a mentally retarded woman. Br. J. Psychiatry, ISS: [[6-[ 17. Meh[inger, R., Scheftner, W. A. & Poznanski, E. (1990), Fluoxetine and autism. J. Am. Acad. Child Adolesc. Psychiatry, 29:985. National Institute of Mental Health (1985), Special feature: rating scales and assessment instruments for use in pediatric psychopharmacology research. Psychopharmacol. Bull., 21 :839. Pato, M. T., Pigott, T. A., Hill, J. L., Grover, G. N., Bernstein, S. & Murphy, D. L. (1991), Controlled comparison of buspirone and clomipramine in obsessive-compulsive disorder. Am. J. Psychiatry, 148:127-129. Pigott, T. A., Pato, M. T., Bernstein, S. E., Grover, G. N., Hill, J. L., Tolliver, T. J. & Murphy, D. L. (1990), Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder: behavioral and biological results. Arch. Gen. Psychia-
try, 147:926-932. Price, L. H., Goodman, W. K., Charney, D. S., Rasmussen, S. A. & Heninger, G. R. (1987), Treatment of severe obsessive-compulsive disorder with fluvoxamine. Am. 1. Psychiatry, 144: I059-1 06 I. Ratey, J. J., Sovner, R., Mikkelsen, E. & Chmielinski, H. E. (1989), Buspirone therapy for maladaptive behavior and anxiety in developmentally disabled persons. 1. Clin. Psychiatry, 50:382-384. Realmuto, G. M., August, G. 1. & Garfinkel, B. (1989), Clinical effect of buspirone in autistic children. J. Clin. Psychopharmacol., 9:122-125. Rutter, M., Greenfield, D. & Lockyer, L. (1967), A five to fifteen year follow-up study of infantile psychosis. II. Social and behavioural outcome. Br. J. Psychiatry, 113: 1183-1 [99. Swedo, S. E. & Rapoport, J. L. (1989), Phenomenology and differential diagnosis of obsessive-compulsive disorder in children and adolescents. In: Obsessive-Compulsive Disorder in Children and Adolescents, ed. J. L. Rapoport. Washington, DC: American Psychiatric Press, pp. 13-32. Tate, J. L. (1989), Extrapyramidal symptoms in a patient taking haloperidol and fluoxetine. Am. J. Psychiatry, 146:399-400. Todd, R. D. (1991), Fluoxetine in autism. Am. J. Psychiatry, 148: 1089. Vitiello, B., Spreat, S. & Behar, D. (1989), Obsessive-compulsive disorder in mentally retarded patients. J. Nerv. Ment. Dis., 177:232-236.
745
Abstract. An open trial of pharmacological treatment with fluoxetine, ranging from 20 mg every other day to 80 mg per day, led to a significant improvement in Clinical Global Impressions ratings of Clinical Severity in 15 of 23 subjects with autistic disorder and 10 of 16 subjects with mental retardation. Six of 23 patients with autistic disorder and 3 of 16 patients with mental retardation had side effects which significantly interfered with function, consisting predominantly of restlessness, hyperactivity, agitation, decreased appetite, or insomnia. Doubleblind studies of the efficacy of pharmacological agents that potently inhibit 5-HT uptake in the treatment of mental retardation coexisting with Axis I psychiatric disorders (especially obsessive-compulsive disorder) and autistic disorder are warranted. J. Am. Acad. Child Adolesc. Psychiatry, 1992,31,4:739-745. Key Words: autistic disorder, mental retardation, fluoxetine, obsessive compulsive behavior, perseveration. Perseverative behavior has been identified as a frequently associated feature of both mental retardation (MR) and, more specifically, of autistic disorder. In fact, it may be difficult to distinguish autistic disorder from severe and profound mental retardation, in part because of the high frequency of perseverative behavior in both disorders. Although some consider perseverative behavior to be secondary to an underlying incapacity to engage in more functional behaviors, others argue that such ritualistic behavior may be obstructing the autistic individual's innate capacity for more adaptive behavior. It is unclear whether one should view the rituals of autistic and mentally retarded individuals as intrinsic to their disorders, as secondary adaptations, or as evidence for coexisting obsessive-compulsive disorder (OCD). Several authors have recently identified a subgroup of mentally retarded patients whom they consider comorbid for obsessive-compulsive disorder (Matson, 1982; McNally and Calamari, 1989; Vitiello et ai., 1989). Several children with autistic disorder have been reported to develop ritualistic and compulsive behavior for the first time when they are 6 to 7 years old (Rutter et aI., 1967). The objection might be raised that the rituals of OCD are ego-dystonic for its sufferers whereas individuals with developmental disorders usually do not appear to resist
Accepted September 5, 1991. Dr. Cook is Assistant Professor of Psychiatry and Pediatrics; Dr. Rowlett is Clinical Assistant Professor of Psychiatry and Pediatrics; Dr. Jaselskis is an 1nstructor in Psychiatry and Pediatrics; and Dr. Leventhal is Professor of Psychiatry and Pediatrics at the University
their obsessions and compulsions. However, children without developmental disorders with early onset OCD often do not demonstrate ego-dystonicity (Swedo and Rapoport, 1989). In any case, it is very difficult to draw inferences about the subjective emotional states of individuals whose capacities for communication and interpersonal relatedness are severely compromised. Irrespective of the cognitive and psychological representations, autistic and mentally retarded individuals often demonstrate symptoms that are behaviorally indistinguishable from OCD. The advent of some pharmacological agents that potently inhibit the reuptake of serotonin and ameliorate OCD symptoms makes this issue of more than theoretical importance. An open trial was conducted to test the hypothesis that fluoxetine might lead to improvement in clinical ratings of perseverative behaviors in some individuals with autistic disorder and/or mental retardation. Global ratings of severity of autistic disorder or psychopathology in mentally retarded patients without autistic disorder was not expected to significantly improve.
Method Subjects These subjects represent a consecutive series of patients treated with fluoxetine by child and adolescent psychiatrists at the University of Chicago in an outpatient setting between 1988 and 1990. These patients were referred to the clinic by parents and professionals who sought an opinion regarding possible medication treatment. Treating clinicians chose treatment with fluoxetine after clinical assessment and diag-
of Chicago.
nosis according to their personal clinical judgment that flu-
This study was supported in part by the Harris Center for Developmental Studies and N1MH Child and Adolescent Mental Health Academic Award (E.C) MH00822. Patients with autistic disorder and! or mental retardation and their parents have provided assistance individually and through local chapters ofthe Autism Society ofAmerican in 1ndiana and lllinois. Kathlyn E. Fletcher provided assistance in data collection and analysis. Reprint requests to Dr. Cook, Department of Psychiatry, Box 411, 5841 S. Maryland Avenue, Chicago, 1L 60637. 0890-8567/92/31 04-0739$03.0010© 1992 by the American Academy of Child and Adolescent Psychiatry.
oxetine might be of benefit for perseverative behaviors ranging from self-injurious behavior to complex rituals. Many patients referred for assessment during this time were not treated with fluoxetine or other medications. Two groups of patients were studied: autistic (N = 23) and mentally retarded (N = 16). The patients with autistic disorder were diagnosed by DSM-III-R criteria (American Psychiatric Association, 1987) and ranged in age from 7.0 to 28 years (mean ± SO
J. Am. Acad. Child Adolesc. Psychiatly, 31 :4, July 1992
739
COOK ET AL.
= 15.9 ± 6.2). Five patients were female and 18 were male. Concomitant Axis II diagnoses included profound MR (three), severe MR (seven), moderate MR (three), mild MR (six), and borderline intellectual functioning (two). Two patients were in the normal range of intelligence. Concomitant Axis I disorders included OCD (three), impulse control disorder not otherwise specified (NOS) with self-injurious behavior (SIB) (six), impulse control disorder NOS without SIB (five), cyclothymia (one), bipolar disorder NOS (one), and eating disorder NOS (one). Two patients met criteria for attention-deficit hyperactivity disorder except for the presence of a pervasive developmental disorder (Table 1). Oral fluoxetine ranging from 20 mg every other day to 80 mg per day was administered based on open titrati.on. Patients were started at a dosage of 20 mg each mornlllg and increased until side effects emerged or until it appeared that a higher dosage would not lead to therapeutic effects. Dosage was most commonly reduced because of insomni~ a.nd/ or irritability. Patients were discontinued based on chmcal judgment if significant side effects emerged or after at least 2 months treatment without improvement in symptoms. Concomitant psychotropic medication included neuroleptics (eight patients), carbamazepine (one patient), lithium carbonate (two patients), clonidine and alprazolam (one patient), and methylphenidate (one patient). . . The 16 patients with mental retardation without autIstIc disorder had varied comorbid Axis I psychiatric disorders, including attention-deficit hyperactivity disorder (one), impulse control disorder NOS with SIB (two), impulse control disorder without SIB (six), major depression (one), depressive disorder NOS (two), dysthymia (two), bipolar ?isorder NOS (one), psychotic disorder NOS (one), anxIety disorder NOS (one), OCD (one), and trichotillomania (one). This group of patients ranged in age from 7.3 to 52 years (21.0 ± 11.5). Twelve were female and four were male. Three patients had profound MR, four patients had severe MR, three patients had moderate MR, and six patients had mild MR. These subjects received fluoxetine at doses ranging from 20 to 80 mg daily. Concomitant psychotropic ~e.di cation included neuroleptics (six patients), ethosuxImIde (one patient), phenytoin (one patient), desipramine (on~ patient also on thioridazine), lithium carbonate (one patIent), lorazepam (one patient also on haloperidol), and clonidine (one patient). Ratings were performed at baseline and either at the time of discontinuation of fluoxetine or between May and December of 1990 for all subjects being treated with fluoxetine as of December of 1990. Each treating clinician made both the baseline and fluoxetine ratings for each patient. Patients with autistic disorder had been receiving fluoxetine between 11 and 426 days (mean ± SD = 189 ± 153 days) at the time of rating. Patients with mental retardation without autistic disorder had been treated with fluoxetine for 7 to 467 days (183 ± 134) at the time of rating. Subjects were. rated wit.h the Clinical Olobal Impressions scale (COl) (NatIOnal InstItute of Mental Health, 1985) in two areas. The first was an overall rating of severity of illness and therapeutic efficacy. In addition, COl ratings were made that were limited to perseverations, compulsions, or rituals depending on the 740
individual's particular difficulties. COl ratings of severity were made at baseline and during drug treatment. COl ratings of therapeutic efficacy were used as an estimate of si.de effects. COl severity ratings at baseline were compared WIth COl severity ratings after fluoxetine treatment using paired t-tests.
Results Therapeutic Effects
In patients with autistic disorder, fluoxetine led to an improvement in COl ratings of overall clinical severity in 15 of 23 subjects (baseline = 5.7 ± 0.8; fluoxetine = 4.9 ± 1.1; paired t = 4.03; df = 22; p < 0.002~ (Fig. 1)... . Ten of 16 mentally retarded subjects WIthout autIstIC dISorder had an improvement of 1 or more on COl overall severity ratings (baseline = 5.1 ± 1.0; fluoxetine = 4.2 ± 1.3; paired t = 3.57, df = 15, p < 0.004) (Fig. 2). COl ratings of severity of perseverative or compulsive behavior revealed a similar therapeutic response to fluoxetine in patients with autistic disorder (baseline = 5.5 ± 1.5; fluoxetine = 4.7 ± 1.6; paired t = 3.13, df= 22,p < 0.005) and mental retardation (although not significant) (baseline = 3.7 ± 2.1; fluoxetine = 3.1 ± 1.9; df = 14, P < 0.070). Side Effects
Six of 23 subjects with autistic disorder had side effects that significantly interfered with function or outweighed therapeutic effects. Only 1 of the 15 patients who had .an improvement in COl ratings of clinical sev~rity had s~de effects that significantly interfered with functIOn (COl SIde Effects Moderate or Marked; Table 2). Three of 16 subjects with mental retardation without autistic disorder had side effects which significantly interfered with function or would have outweighed therapeutic effects. None of these three subjects had an improvement in CGI ratings of severity of illness (Table 3). There was no relationship between level of mental retardation and response to fluoxetine or between baseline COl "perseveration" ratings and response to fl~oxetine. In addition, dysphoria did not appear to be a predIctor of response to treatment, although this was not specifically measured. Thirteen of the combined group of patients were concomitanty treated with neuroleptics. Four of these I? patients developed significant side effects. Three of the subjects were on haloperidol ranging from 0.25 mg everyday (q.d.) to 0.5 mg three times a day (t.i.d.), and the fourth. patient. was taking trifluoperazine I mg q.d. In contrast, eIght patIents had an improvement in clinical severity ratings .without sid.e effects. Five of these eight responders were takmg halopendol ranging from 0.5 mg q.d. to 2 mg ti.d. Another thre~ of the responders were taking thioridazine at doses rangmg from 25 mg ti.d. to 200 mg daily. The patient being treat~d with 25 mg t.i.d. of chlorpromazine did not respond and dId not have significant side effects.
Case Reports Case 1
Case 1 provides an illustration of a typical patient with J. Am. Acad. Child Adolesc. Psychiatry, 3 J:4, July J992
FLUOXETINE AND DEVELOPMENTAL DISORDERS TABLE 1. Therapeutic Effects of Fluoxetine in Patients with Autistic Disorder and Mental Retardation
Diagnosis Patients with AD Responders
CGI Drug
Comorbid Axis II Disorder
Comorbid Axis I Disorder
Race
Sex
13.8
W
M
40
6
2
None
OCD
27.5
W
M
80
6
5
Mild MR
None
W
M
10
7
6
OCD
15.1
W
M
10
6
5
Borderline intelligence functioning MildMR
7.5
A
M
20
5
4
None
ADHD
12.8
B
M
40
6
5
Severe MR
13.0
W
M
40
5
4
MildMR
Impulse control disorder NOS (and SIB) Impulse control disorder NOS
15.6
H
F
20
6
5
Severe MR
Impulse control disorder NOS
16.1
W
M
20
6
5
Profound MR
16.9
B
M
40
6
5
MildMR
Impulse control disorder, NOS Impulse control disorder NOS
18.2
W
F
40
5
4
21.9
W
F
20
6
5
Borderline intelligence functioning Severe MR
22.4
W
F
20
6
4
Severe MR
28.8
W
M
20
6
5
Profound MR
9.9
W/B
M
40
6
4
Moderate MR
7.0
W
M
30
5
5
Severe MR
23.8 10.1 21.2
W B B
M M M
40 20 20
4 7 4
4 7 4
MildMR Moderate MR MildMR
9.9
H
M
20
5
6
Severe MR
11.2
B
M
20
6
6
Moderate MR
14.3
W
M
20
6
6
Severe MR
8.25
Nonresponders
Optimal COl Dose (mg) Baseline
Age at Trial
J. Am. Acad. Child Adolesc. Psychiatry, 31:4, July 1992
Cyclothymia and OCD (provisional)
None
Bipolar disorder NOS (periodic catatonia) Eating disorder NOS Impulse control disorder NOS (and SIB) Impulse control disorder NOS (and SIB) None None ADHD Impulse control disorder NOS Impulse control disorder NOS (and SIB) Impulse control disorder NOS Impulse control disorder NOS (and SIB)
Type of Improvement Decreased egodystonic, obsessive thoughts Decreased compulsive ordering and rate of aggression Decreased rate of rituals Decreased preoccupation with phone books and open doors More flexible and responsi ve to social cues Less aggressi ve, better mood and sleep Fewer tantrums, more spontaneous and flexible More cheerful, less stubborn, better eye contact Less aggressi ve, better eye contact Decreased aggressi ve and destructive behavior Improved sleep, calmer, more spontaneous Less agitated and irritable Weight gain, decreased vomiting Better mood, more responsive, cessation of SIB Decreased tantrum intensity and severity Less irritable and dysphoric No improvement No improvement No improvement No improvement
No improvement No improvement
741
COOK ET AL.
TABLE I. Continued
Diagnosis
Patients with MR (without AD) Responders
Nonresponders
Optimal COl Dose (mg) Baseline
COl Drug
Comorbid Axis II Disorder
Age at Trial
Race
Sex
22.3
H
F
20
7
7
Profound MR
9.6
W
F
20
5
3
MildMR
15.7
W
F
20
6
4
Severe MR
17.0
W
F
20
5
3
Moderate MR
17.6
W
F
20
5
3
Profound MR
17.6
W
M
60
4
3
MildMR
20.5
B
M
40
6
5
Moderate MR
22.7
B
F
40
4
3
Severe MR
23.7
W
F
20
6
5
Severe MR
28.4
B
M
20
5
4
Severe MR
7.3
W
M
20
4
3
MildMR
8.6
W
F
20
4
5
Mild MR
14.6
W
F
20
6
6
Profound MR
17.2
W
F
40
6
6
Profound MR
30.1 37.8
A B
F F
40 20
3 6
3 6
MildMR Moderate MR
52.7
W
F
40
6
6
MildMR
Note: CGI = Clinical Global Impressions scale, NOS = not otherwise specified, SIB tion, OCD = obsessive-compulsive disorder, AD = autistic disorder. autistic disorder who functioned better on fluoxetine treatment than she functioned before fluoxetine treatment. E. met DSM-III-R criteria for autistic disorder because of symptoms including abnormal prosody, perseveration, hypersensitivity to sound, and intolerance of any change in her routines.
742
Comorbid Axis I Disorder Impulse control disorder NOS (& SIB) Impulse control disorder NOS
Type of Improvement No improvement
Calmer, more attentive, less screaming
Impulse control disorder NOS
More spontaneous and flexible, calmer, cheerful, fewer tantrums Major depression, Better mood, more severe, recurconsiderate, less lerent thargic Impulse control Decreased aggression, disorder NOS SIB, and compul(and SIB) sive overeating Dysthymia Smiling, animated, more spontaneous Psychotic disorder Decreased overeating, NOS better mood, less perseverative Anxiety disorder Eliminated self-injuriNOS, impulse ous behavior control disorder NOS (SIB) Impulse control Better eye contact disorder NOS and mood, less aggression "Less hyper," better Impulse control disorder NOS mood Depressive disor- Better mood, more del' NOS (prospontaneous and visional) social ADHD, dysthyNo improvement mia, trichotillomania Impulse control No improvement disorder NOS Less withdrawn, betBipolar disorder NOS (periodic tel' appetite catatonia) and rumination disorder OCD No improvement No improvement Impulse control disorder NOS Chronic schizoNo improvement phrenia and depressive disorder NOS
= self-injurious behavior, MR = mental retarda-
Target symptoms of pharmacological treatment were insomnia, anxiety, and rigidity of response. Her parents preferred not to try neuroleptics because of their awareness of the risk of tardive dyskinesia. After unsuccessful trials with lithium carbonate, cloni-
J. Am. Acad. Child Adolesc. Psychiatry, 31:4, July 1992
FLUOXETINE AND DEVELOPMENTAL DISORDERS TABLE
2. Side Effects of Patients with Autistic Disorder
No. of Patients (%)
Side Effect 8
# of 6 Subjects
-1
0
1
2
3
4
Improvement of Clinical Global Impressions Severity of Illness
FIG. 1. Patients with autistic disorder. Change in Clinical Global
Impression overall clinical severity ratings after treatment with fluoxetine. Ratings after fluoxetine were significantly improved compared with baseline (t = 4.03, df = 22, p < 0.002). 6
Hyperactivity/restlessness/agitation Insomnia Elated affect Decreased appetite Increased rate of screaming Increased socially inappropriate behavior Crying spells Yawning Maculopapular rash COl side effects None Do not significantly interfere with functioning Significantly interferes with functioning Outweighs therapeutic effect Days to onset of side effects 0-[5 16-31
Greater than 31
5 4 4 4 2 1
(22) (17) (17) (17) ( 9) ( 4)
I ( 4) I ( 4) I ( 4)
10 8 4 I
(43) (35) (17) ( 4)
4
5 5
5 4
TABLE
# of 3 Patients
3. Side Effects of Patients with Mental Retardation (without Autistic Disorder)
Side Effect
2
o -1
0
1
2
Improvement of Clinical Global Impressions Severity of Illness
FIG. 2. Patients with mental retardation without autistic disorder.
Change in Clinical Global Impression overall clinical severity ratings after treatment with fluoxetine. Ratings after fluoxetine significantly improved compared with baseline (t = 4.03, df = 22, p < 0.002). dine, and desipramine, E. was treated with diphenhydramine, 50 mg at bedtime, which helped her insomnia but did not lead to an improvement in anxiety or rigidity of response. A year later, when she was 18 years old, fluoxetine was added at an initial dose of20 mg daily. Dosage was increased to 40 mg daily after 3 weeks because of minimal change except an improvement in sleep. After 2 weeks on the higher dosage, E. was said to be " a little more rationaL" However, given the cost of the medication and the apparent modesty of benefit, her parents elected to discontinue the trial. A month later, fluoxetine was restarted at 40 mg g.d. after her parents concluded retrospectively that E. had in fact been much calmer on the drug. Three weeks into the second trial, E.'s teacher reported that she was doing more school work. After 3 months, E.'s father commented enthusiastically that E. was more cooperative, no longer complained of fatigue, was socializing more, and was for the first time speaking spontaneously in school. She no longer required diphenhydramine to fall asleep at night. E. herself stated, "They (the fluoxetine pulvules) make me feel calm, and they make me feel OK, and I never get nervous anymore."
Case 2 G. is an example of a patient who did not respond to l. Am. Acad. Child Adolesc. Psychiatry, 31:4, luly 1992
Hyperacti vity/restlessness/agitation Insomnia Elated affect Decreased appetite Increased socially inappropriate behavior Lethargy Tremor Grimacing Polydipsia COl side effects None Do not significantly interfere with functioning Significantly interferes with functioning Outweighs therapeutic effect Days to onset of side effects
No. of Patients (%) 4 (25) 2 I I I
(12) ( 6) ( 6) ( 6)
I ( 6) I ( 6) I ( 6) j
(
6)
9 (56) 4 (25) 3 (19)
o ( 0)
0-15 16-31
5 2
Greater than 31
4
fluoxetine and developed side effects which significantly interfered with his functioning. He was 14 years old when fluoxetine was initiated. Diagnoses were autistic disorder and severe mental retardation. His mother sought treatment for G. because his symptoms, including continual screeching, touching of others, and repetition of the sound, "geddo-geddo," were prompting abusive behavior by her alcoholic husband. Regrettably, fluoxetine (20 mg g.d.) did not improve matters: G. developed marked insomnia, uncontrollable laughing and was "too hyper to eat." Fluoxetine was discontinued after 11 days. Seven months later, G. was doing reasonably well on propranolol (40 mg ti.d.).
Case 3 A. is an example of a mentally retarded patient without
743
COOK ET AL.
autistic disorder who functioned better during treatment with fluoxetine than before treatment with fluoxetine. She was 9 years old at the time she entered the study. She met DSMllI-R criteria for mild mental retardation (Verbal IQ 63, Performance IQ 74, Full-scale IQ 67) and impulse control disorder. At the time of the referral, A.'s single mother had come reluctantly and guiltily to the conclusion that she would have to place her daughter in a residential facility. Major concerns were A.'s poor impulse control (she would take any pills she found in the medicine cabinet), short attention span, and low frustration tolerance. Behavioral treatments had been undermined by A.' s capacity to scream for hours if she did not get her way and her mother's exhaustion and depression. She began receiving fluoxetine (20 mg q.d.). Nine days later, her mother reported that A. was calmer, less aggressive and screaming less, but that the effect appeared to wear off late in the day. Dosage was increased to 40 mg daily. A week later, her mother reported further improvement. At the end of the 3rd week, the dosage was reduced to 20 mg q.d. because A. was becoming "more obstreperous." At the end of the first month, her mother observed, ''I'm able to think (about how to help my daughter) without anxiety because she's not screaming all the time." Four months after fluoxetine was initiated, A. "continues to do well; we really appreciate her calm." Case 4
D. provides an example of a patient who experienced side effects that significantly interfered with function and functioned worse during treatment with fluoxetine. She was 14 years old when f1uoxetine was introduced. She had a diagnosis of severe to profound mental retardation, Down syndrome, and microcephaly. Her father had bipolar disorder. Target symptoms included impulsive, provocative, and aggressive behavior inadequately controlled on haloperidol (0.5 mg t.i.d.). One week after D. began receiving fluoxetine (20 mg q.d.), the nurse at her residential facility reported the onset of fine tremors in the trunk and upper extremities more than the lower extremities. D. was noted to have a poor appetite, to appear "spacey," and to be "more agitated." Fluoxetine was discontinued. Twenty-four hours later she remained very agitated and fearful, but tremors had been replaced by rigidity. She was given diphenhydramine (50 mg intramuscularly) for an apparent dystonic reaction, and haloperidol was discontinued. Two days later, she had substantially improved and was back to her usual behavior after 5 days. Ten months after her adverse response to combined treatment with fluoxetine and haloperidol, D. was doing well on combined therapy with lithium carbonate and c1onidine.
Discussion Most children, adolescents, and adults with autistic disorder and/or mental retardation had lower CGI severity of illness scores during treatment with fluoxetine than they had immediately before treatment. This open study extends previous case reports of the response of children and adolescents with autistic disorder to pharmacological agents which potently inhibit the reuptake of 5-HT such as fluvoxamine
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and fluoxetine (Ghaziuddin et aI., 1991; Hamdan-Allen, 1991; McDougle et aI., 1990; Mehlinger et al., 1990; Todd, 1991) and a preliminary report of a double-blind comparison of clomipramine to desipramine (Gordon et aI., 1991). The present study extends our previous report of therapeutic response to f1uoxetine in nonautistic patients (IQ's between 70 and 75) (Cook et aL, 1990) to the mentally retarded range. However, it must be highlighted that this study is limited by being an open trial without placebo control or discontinuation of medication to exclude placebo or order effects. In addition, raters were treating clinicians who were not blind to medication status. Significant aide effects were more common in nonresponders than responders and included restlessness, hyperactivity, agitation, decreased appetite, and insomnia, which remitted after dosage reduction or discontinuation. Responders could not be differentiated from nonresponders on the basis of baseline ratings of perseverative behavior or level of cognitive functioning. Further controlled studies are warranted with more comprehensive baseline assessment to determine whether or not baseline dysphoria or more subtle aspects of cognition or "compulsiveness" predict response. The addition offluoxetine (case 4) may have caused extrapyramidal symptoms because of an increase in serum haloperidol levels or reduction in striatal dopamine synthesis (Baldessarini and Marsh, 1990; Goff et aL, 1991). Interactions between neuroleptics and fluoxetine have been described in some patients without development disorders (Brod, 1989; Tate, 1989), although an open study did not confirm this finding (Goff et aL, 1991). In the current study, there was not an indication of an increased risk of overall side effects when autistic and/or mentally retarded patients were being treated with neuroleptics. Although serotonergic dysfunction has been suggested in autistic and mentally retarded subjects, most studies have revealed heterogeneity in serotonergic measures which may account for the heterogeneity of response seen here (Cook, 1990). Whole blood serotonin (Kremer et al., 1990), platelet serotonin (F1ament et aL, 1987), or plasma prolactin (Hanna et aL, 1991) may be a useful predictor of response or a way of following and determining optimal dose, but this has yet to be confirmed. Although the response to fluoxetine could be the result of an antidepressant rather than antiobsessional effect, a previous open trial with imipramine did not lead to a group improvement in autistic subjects (Campbell et al., 1971). It is notable that avoidant personality disorder without OCD has been reported to respond to treatment with fluoxetine, so that some of the global improvement may have been directed toward a component of social phobia (Deltito and Stam, 1989). Buspirone, an anxiolytic with possible thera- . peutic effects in OeD (Pato et al., 1991), has led to an improvement in both nonautistic developmentally disabled (Ratey et aL, 1989) and autistic individuals (Realmuto et aL, 1989) in open trials. Double-blind placebo controlled studies of fluoxetine (Pigott et al., 1990), sertraline (Chouinard et al., 1990), clomipramine (Katz et al., 1990), or fluvoxamine (Price et al., 1987) are warranted in the treatment of obsessive compulJ. Am. Acad. Child Ado/esc. Psychiatry, 31 :4, Ju/y 1992
FLUOXETINE AND DEVELOPMENTAL DISORDERS
sive symptoms in individuals with autistic disorder and/or mental retardation. These drugs do not address the core symptoms of either cognitive dysfunction or communication, but may be of use in the adjunctive treatment of patients. They may also direct investigations toward a more specific pharmacological treatment of core symptoms. Summary In an open trial, function in a majority of subjects with autistic disorder and mental retardation was improved during treatment with f1uoxetine compared to function immediately preceding treatment. Side effects included hyperactivity, restlessness, insomnia, or decreased appetite in a minority of subjects and remitted within several days of discontinuation or reduction of f1uoxetine. Systematic, double-blind controlled studies of the efficacy of f1uoxetine and other drugs that potently inhibit the uptake of serotonin, such as f1uvoxamine, clomipramine, and sertraline, in the treatment of patients with autistic disorder and with mental retardation and other psychiatric disorders (especially OeD) are warranted. References American Psychiatric Association (1987), Diagnostic and Statistical
Manual of Mental Disorders, 3rd edition-revised (DSM-llI-R). Washington, DC: American Psychiatric Association. Baldessarini, R. J. & Marsh, E. (1990), Fluoxetine and side effects.
Arch. Gen. Psychiatry, 47:[91-192. Brod, T. M. (1989), Fluoxetine and side effects (letter). Am. J. PsychiatlY, 146:1353.
Campbell, M., Fish, B., Shapiro, T. & Floyd, A. (1971), Imipramine in preschool autistic and schizophrenic children. Journal ofAutism and Childhood Schizophrenia, 1:267-282. Chouinard, G., Goodman, W., Greist, J. et a!. (1990), Results of a double-blind placebo controlled trial of a new serotonin reuptake inhibitor, sertraline, in the treatment of obsessive-compulsive disorder. Psychopharmacol. Bull., 26:279-284. Cook, E. H. (1990), Autism: review of neurochemical investigation.
Synapse, 6:292-308. - - Terry, E. J., Heller, W. & Leventhal, B. L. (1990), Fluoxetine treatment of borderline mentally retarded adults with obsessivecompulsive disorder. J. Clin. Psychopharmacol., 10:228-229. Deltito, 1. A. & Stam, M. (1989), Psychopharmacological treatment of avoidant personality disorder. Compr. Psychiatry, 30:498-504. Flament, M. F., Rapoport, J. L., Murphy, D. L., Berg, C. J. & Lake, R. (1987), Biochemical changes during clomipramine treatment of childhood obsessive-compulsive disorder. Arch. Gen. Psychiatry, 44:219-225. Ghaziuddin, M., Tsai, L. & Ghaziuddin, N. (1991), Fluoxetine in autism with depression. J. Am. Acad. Child Adolesc. Psychiatry, 30:508-509. Goff, D. c., Midha, K. K., Brotman, A. W., Waites, M. & Ba[dessarini, R. J. (1991), Elevation of plasma concentrations ofhaloperido[ after the addition of fluoxetine. Am. J. Psychiatry, [48:790-792.
1. Am. Acad. Child Adolesc. Psychiatry, 31:4, July 1992
Gordon, c., Rapoport, J., Hamburger, S. & Mannheim, G. (1991), Differential response of autistic disorder to clomipramine. 1. Am. Acad. Child Adolesc. Psychiatry, 30: [64. Hamdan-Allen, G. (1991), Brief Report: Trichotillomania in an autistic male. J. Autism Dev. Disord., 2 [:79-82. Hanna, G. L., McCracken, 1. T. & Cantwell, D. P. (1991), Prolactin in childhood obsessive-compulsive disorder: clinical correlates and response to clomipramine. 1. Am. Acad. Child Adolesc. Psychiatry, 30: 173-178. Katz, R. J., DeVeaugh-Geiss, J. & Landau, P. (1990), Clomipramine in obsessive-compulsive disorder. BioI. Psychiatry, 28:401-414. Kremer, H. P. H., Goekoop, J. G. & Van Kempen, G. M. J. (1990), Clinical use of the determination of serotonin in whole blood. J. Clin. Psychopharmacol., [0:83-87. Matson, 1. L. (1982), Treatment of obsessive-compulsive behavior in mentally retarded adults. Behav. Modif., 6:551-567. McDougle, C. J., Price, L. H. & Goodman, W. K. (1990), Fluvoxamine treatment of coincident autistic disorder and obsessive-compulsive disorder: a case report. J. Autism. Dev. Disord., 20:537-543. McNally, R. J. & Calamari, J. E. (1989), Obsessive-compulsive disorder in a mentally retarded woman. Br. J. Psychiatry, ISS: [[6-[ 17. Meh[inger, R., Scheftner, W. A. & Poznanski, E. (1990), Fluoxetine and autism. J. Am. Acad. Child Adolesc. Psychiatry, 29:985. National Institute of Mental Health (1985), Special feature: rating scales and assessment instruments for use in pediatric psychopharmacology research. Psychopharmacol. Bull., 21 :839. Pato, M. T., Pigott, T. A., Hill, J. L., Grover, G. N., Bernstein, S. & Murphy, D. L. (1991), Controlled comparison of buspirone and clomipramine in obsessive-compulsive disorder. Am. J. Psychiatry, 148:127-129. Pigott, T. A., Pato, M. T., Bernstein, S. E., Grover, G. N., Hill, J. L., Tolliver, T. J. & Murphy, D. L. (1990), Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder: behavioral and biological results. Arch. Gen. Psychia-
try, 147:926-932. Price, L. H., Goodman, W. K., Charney, D. S., Rasmussen, S. A. & Heninger, G. R. (1987), Treatment of severe obsessive-compulsive disorder with fluvoxamine. Am. 1. Psychiatry, 144: I059-1 06 I. Ratey, J. J., Sovner, R., Mikkelsen, E. & Chmielinski, H. E. (1989), Buspirone therapy for maladaptive behavior and anxiety in developmentally disabled persons. 1. Clin. Psychiatry, 50:382-384. Realmuto, G. M., August, G. 1. & Garfinkel, B. (1989), Clinical effect of buspirone in autistic children. J. Clin. Psychopharmacol., 9:122-125. Rutter, M., Greenfield, D. & Lockyer, L. (1967), A five to fifteen year follow-up study of infantile psychosis. II. Social and behavioural outcome. Br. J. Psychiatry, 113: 1183-1 [99. Swedo, S. E. & Rapoport, J. L. (1989), Phenomenology and differential diagnosis of obsessive-compulsive disorder in children and adolescents. In: Obsessive-Compulsive Disorder in Children and Adolescents, ed. J. L. Rapoport. Washington, DC: American Psychiatric Press, pp. 13-32. Tate, J. L. (1989), Extrapyramidal symptoms in a patient taking haloperidol and fluoxetine. Am. J. Psychiatry, 146:399-400. Todd, R. D. (1991), Fluoxetine in autism. Am. J. Psychiatry, 148: 1089. Vitiello, B., Spreat, S. & Behar, D. (1989), Obsessive-compulsive disorder in mentally retarded patients. J. Nerv. Ment. Dis., 177:232-236.
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