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Psychopharmacological treatment of autistic disorders:
Lofexidine as an useful alternative

Helmut Niederhofer, W Staffen, A Mair

Regional Hospital of Bolzano, Rep. Pediatria, Via L.-Boehler, 5, I-39100 Bolzano, ITALY

and Christian Doppler Klinik, Dep. of Neurology, Salzburg, AUSTRIA

Correspondence adress: Helmut Niederhofer, M.D., Ph.D. Regional Hospital of Bolzano, Rep. Pediatria, Via L.-Boehler, 5, I-39100 Bolzano, ITALY
Tel: 0039 348 936 02 81, E-Mail: helmut.niederhofer@uibk.ac.at

Abstract

Objectives: Many autistic children have problems of eye contact and expressive language that limit the effectiveness of educational and behavioral interventions. Few controlled psychopharmacologic trials have been conducted in autistic children to determine which agents may be effective for these associated features.
Methods: Sixteen male children (6.7 +/- 3.5 years) with autistic disorder, diagnosed by ICD-1O criteria, completed a placebo-controlled, double-blind crossover trial of Lofexidine. Subjects were included in the study if their eye contact and expressive language was inadaequate for their developmental level. Subjects had not tolerated or responded to other psychopharmacologic treatments (neuroleptics, methylphenidate, clonidine or desipramine).
Results: Teacher ratings on the Aberrant Behavior Checklist irritability, stereotypy, and inappropriate speech factors were lower during treatment with Lofexidine than during treatment with placebo. Clinician ratings (Children's Psychiatric Rating Scale Autism, Anger and Speech Deviance factors; Children's Global Assessment Scale; Clinical Global Impressions efficacy) of videotaped sessions were not significantly different between Lofexidine and placebo.
Discussion: Lofexidine was modestly effective in the short-term treatment of irritability in some children with autistic disorder.

Introduction

Autistic disorder is a developmental disorder, characterized by qualitative impairments in reciprocal social interaction, and verbal and nonverbal communication. Additionally, hyperactivity, poor attention span, and impulsivivity are often prominent associated clinical features and have been target symptoms in previous medication trials (Campbell et al., 1951). An adverse response of autistic children to dextroamphetamine has been reported (Campbell et al., 1972). An open trial (Birmaher et al., 1988) suggested that methylphenidate use in autistic hyperactive children may ameliorate hyperactivity, and impulsivity in autistic children. Neuroleptics are somewhat effective in reducing hyperactivity, impulsivity, and inattention in children with autistic disorder (Perry et al., 1959). However, chronic use of neuroleptics may be complicated by cognitive blunting and the often irreversible side effect of tardive dyskinesia (Campbell et al., 1985). Immune system abnormalities have also been associated with autism. These have included decreased natural killer cell activity (Warren et al., 1987), and the demonstration of circulating antibodies to serotonin receptors (Todd et al., 1985).
The Alpha2-receptor agonist clonidine has been used in the treatment of tic disorders and ADHD for more than 20 years (Cohen et al., 1979). The findings from controlled studies, however, have been somewhat inconsistent, with three studies showing benefit (Connor et al., 2000; Hunt et al., 1985; Leckman et al., 1991) and two reporting negative results (Singer et al., 1995; Goetz et al., 1987). Nonetheless, the use of clonidine in children is increasing (Zito et al., 2000), suggesting that clinicians find it useful for a range of behavior problems.
Lofexidine is a newer Alpha2-adrenergic receptor agonist that differs from clonidine in several ways. First, it is less sedating and has a longer duration of action than clonidine (Sorkin et al., 1986). Second, Lofexidine has been shown to improve prefrontal cortical function in nonhuman primates (Jin et al., 1989). For that reason, this placebo-controlled study was conducted to examine the effects of Lofexidine on a variety of target behaviors in young boys with autistic disorder.

Methods

Sixteen outpatient male children (age range 4.8 - 16.4 years; mean=6.7 years; SD=3.5 years) meeting ICD- 10 criteria for autistic disorder were recruited for our study. Full-scale IQs ranged from 38 to 81 (59 +/- 18), and were obtained from several tests, including the Wechsler Intelligence Scale for Children Revised, or the Cattell Infant Intelligence Scale. Agreement of the independent diagnosis of autistic disorder by at least two child and adolescent psychiatrists was obtained. All of the subjects were excessive for their developmental and language levels. Parents provided written informed consent for their children after the procedures and possible side effects were explained to them.
The subjects had no history of identified medical or neurologic illnesses and had been off medications for at least 1 month before the study. All of these children had been treated with either methylphenidate, neuroleptics, or desipramine before entry into the study. In each case, these medications had either not been effective or caused intolerable side effects.

All subjects lived at home with either both parents (13 subjects) or their mothers (3 subjects). Sociooeonomic status for the subjects' families was class I(6 subjects), class II(7 subjects), and class IV (3 subjects) (Hollingshead et al., 1958). Two children's languages consisted of monosyllabic utterances, another two children's languages consisted of single words (10-word vocabulary), and the other children spoke in sentences. However, all children had social and pragmatic language deficits consistent with autistic disorder.
All raters (parents, teachers, and clinicians) were blind to drug order until ratings were completed.
Parent-rated instruments included weekly ratings. Side effects monitored included increased thirst, drowsiness, sleep disturbance, sadness, dizziness, irritability, appetite change, and decreased activity. Parents and teachers responded with "yes" (coded as 0) or "no" (coded as 1) for each item each week. These Symptom Checklist responses were summed over each 6-week treatment period.
Weekly teacher ratings included the Aberrant Behavior (ABC) Checklist (Amman et al., 1985). Clinician ratings (average of both raters) consisted of observations at baseline, 6 weeks, and 13 weeks using the Children's Global Assessment Scale, and Clinical Global Impressions (national Institute of Mental Health, 1985).

This was a double-blind and placbo-controlled crossover study. The dosage we used was 0.8 mg/day (0.4 mg in the morning and 0.4mg in the evening).
The subjects were randomly assigned by a nonrating clinican to begin Lofexidine or placebo. Patients were free of medication for at least 4 weeks before beginning the study but there was no placebo washout phase. Blood pressure and clinical symptoms were monitored via telephone conversations and scheduled visits. School nurses or the family physician measured blood pressure on a weekly basis.

Subjects continued to receive educational and behavioral interventions in school during the course of the study that were not substantially altered for any of the children during their participation in the study.

Parent and teacher ratings were averaged over each 6-week treatment period. Clinician ratings were only made at the end of each treatment period. Ratings during placebo and drug treatment were compared using paired, two-tailed t-tests.

Results

Teacher's ratings on the ABC factors irritability (placebo, 14.9 +/- 5.2; Lofexidine, 11.9 +/- 8.1; p = 0.039), hyperactivity (placebo 21.7 +/- 12.4; Lofexidine 17.8 +/- 12.8; p = 0.042), inadaequate eye contact (placebo, 8.5 +/- 5.0; Lofexidine 7.1 +/- 4.2; p = 0.039), and inappropriate speech (placebo 5.9 +/- 2.2; Lofexidine 4.8 +/- 3.5; p = 0.046) were significantly improved on Lofexidine. The symptom checklist scores combining both parent and teacher scores revealed a significant increase in drowsiness (placebo 1.2 +/- 2.4; Lofexidine 3.5 +/- 3.1; p = 0.038) and decreased activity (placebo, 2.2 +/- 3.4; Lofexidine 4.5 +/- 3.1; p = 0.044). None of the clinician ratings showed significant differences between placebo and Lofexidine. None of the subjects appeared to have headaches or stomachaches, although report of such side effects was limited by the expressive language and social skills of these subjects.

Discussion

This study examined the effects of Lofexidine in male autistic children between the ages of 4 and 17 with inadaequate eye contact and expressive language deficits. Teacher and parent ratings showed a modest symptom improvement while the child was taking Lofexidine. Parents rated significant behavioral changes while their son was on Lofexidine. Clinician rating scales were insensitive to Lofexidine effects. Lofexidine' modest effects in the treatment of a subgroup of children with autistic disorder may be related to noradrenergic dysregulation as indicated by findings such as increased plasma norepinephrine in children with autistic disorder (Lake et al., 1977; Cook et al., 1990).

On the one hand, there are very few specific clinical instruments that target the response of inadaequate eye contact and expressive language deficits to drug treatment in autistic persons, and on the other hand, the failure of the clinician ratings to be sensitive to changes may have been influenced by several factors. Furthermore, 6 weeks may have been an inadequate duration to determine full effect in the current study. Possible ,,unblinding" of parents and teachers because of side effects is another limitation of the study. In addition, a small number of subjects was involved in this study. Although this study revealed a modest therapeutic effect of Lofexidine in the acute management of autistic children in some subjects make it clear that its role in the management of these symptoms in children with autistic disorder may be limited. The role of Lofexidine in acute and chronic treatment of these symptoms requires further investigation. Controlled, chronic pharmacologic trials with clinical observations will be necessary to delineate further the role of Lofexidine in treating this specific population. Such trials should be designed to minimize the development of tolerance.

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First Published June 2003

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