Children with autism spectrum disorders show abnormal conditioned response timing on delay, but not trace, eyeblink conditioning.

Children with autism spectrum disorder (ASD) and age-matched typically-developing (TD) peers were tested on two forms of eyeblink conditioning (EBC), a Pavlovian associative learning paradigm where subjects learn to execute an appropriately-timed eyeblink in response to a previously neutral conditioning stimulus (CS). One version of the task, trace EBC, interposes a stimulus-free interval between the presentation of the CS and the unconditioned stimulus (US), a puff of air to the eye which causes the subjects to blink. In delay EBC, the CS overlaps in time with the delivery of the US, usually with both stimuli terminating simultaneously. ASD children performed normally during trace EBC, exhibiting no differences from TD subjects with regard to the learning rate or the timing of the conditioned response. However, when subsequently tested on delay EBC, subjects with ASD displayed abnormally-timed conditioned eye blinks that began earlier and peaked sooner than those of TD subjects, consistent with previous findings. The results suggest an impaired ability of children with ASD to properly time conditioned eye blinks which appears to be specific to delay EBC. We suggest that this deficit may reflect a dysfunction of the cerebellar cortex in which increases in the intensity or duration of sensory input can temporarily disrupt the accuracy of motor timing over short temporal intervals.

Olanzapine versus haloperidol in children with autistic disorder: an open pilot study.

OBJECTIVES: Conventional neuroleptics ameliorate symptoms in children with autistic disorder; however, they are known to cause dyskinesias. Atypical neuroleptics, including olanzapine, may have less risk for dyskinesia, but their efficacy in autistic disorder is not established. This study was designed to investigate the safety and effectiveness of open-label olanzapine as a treatment for children with autistic disorder by using haloperidol as a standard comparator treatment. METHOD: In a parallel groups design, 12 children with DSM-IV autistic disorder (mean age 7.8+/-2.1 years) were randomized to 6 weeks of open treatment with olanzapine or haloperidol. Mean final dosages were 7.9+/-2.5 mg/day for olanzapine and 1.4+/-0.7 mg/day for haloperidol. Outcome measures included the Clinical Global Impressions (CGI) and the Children's Psychiatric Rating Scale (CPRS). RESULTS: Both groups had symptom reduction. Five of six in the olanzapine group and three of six in the haloperidol group were rated as responders according to the CGI Improvement item. Subjects showed improvement on the CPRS Autism Factor (F1,9 = 24.4, p = .0008). Side effects included drowsiness and weight gain. CONCLUSIONS: The findings suggest that olanzapine is a promising treatment for children with autistic disorder. Further placebo-controlled and long-term studies of olanzapine in autistic disorder are required.

A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder.

BACKGROUND: A subgroup of children and adolescents with conduct disorder are characterized by severe and persistent aggression. Although there is no agreed on treatment for such aggression, lithium carbonate has shown promise in some studies involving children. Our study was designed to critically assess the efficacy of lithium in the treatment of aggression in children and adolescents using a measure specific for aggression. METHODS: Subjects were inpatients with conduct disorder hospitalized because of severe and chronic aggression. A parallel-groups design was used in this double-blind, placebo-controlled trial with randomization to lithium or placebo. Only those who met the aggression criterion during the 2-week placebo-baseline period were randomized to 4 weeks of treatment. Outcome measures included Clinical Global Impressions, the Global Clinical Judgements (Consensus) Scale, and the Overt Aggression Scale. RESULTS: Eighty-six inpatients enrolled in the study; 40 (33 male and 7 female; median age, 12.5 years) entered and completed the treatment phase. Lithium was statistically and clinically superior to placebo. Sixteen of 20 subjects in the lithium group were responders on the Consensus ratings vs 6 of 20 in the placebo group (P=.004). Ratings on the Overt Aggression Scale decreased significantly for the lithium group vs the placebo group (P=.04). More than half of the subjects in the lithium group experienced nausea, vomiting, and urinary frequency. CONCLUSIONS: Lithium is a safe and effective short-term treatment for aggression in inpatients with conduct disorder, although its use is associated with adverse effects.

Aggression classification and treatment response.

This preliminary study investigated whether the aggression subtypes derived from the Aggression Questionnaire (AQ) are related to treatment response. The subjects were 28 aggressive conduct-disordered children (25 males, 3 females), ranging in age from 9.8 to 17.0 years (mean age = 12.69 years), who participated in a double-blind, placebo-controlled study of lithium as a treatment for reducing aggression. We used the Predatory-Affective Index of the AQ to classify subjects into "predatory" (planned) or "affective" (explosive) subtypes of aggression and then related this classification to treatment response. This index did not differentiate placebo baseline responders from nonresponders. However, the Index did significantly differentiate responders and nonresponders during the experimental treatment period, regardless of whether they received lithium or placebo. Treatment response was associated with a more affective and less predatory subtype of aggression. To the best of our knowledge, this is the first study in children to show an association between the aggression subtype and treatment response.

Neuroleptic-related dyskinesias in autistic children: a prospective, longitudinal study.

OBJECTIVE: To report results from a long-term prospective study of safety of haloperidol treatment and prevalence of haloperidol-related dyskinesias. METHOD: Subjects were children with autism requiring pharmacotherapy for target symptoms. After baseline assessments, children received haloperidol treatment; responders requiring further treatment were considered for enrollment into the present study. Six-month haloperidol treatment periods were followed by a 4-week placebo period. The procedure was repeated if further haloperidol treatment was required. At specified times children were evaluated by using multiple instruments. RESULTS: Between 1979 and 1994, 118 children aged 2.3 to 8.2 years participated in the study. The mean dose of haloperidol was 1.75 mg/day. Mainly withdrawal dyskinesias (WD) developed in 40 (33.9%) children; 20 had more than one dyskinetic episode. A subgroup that remained significantly longer in the study and had a significantly higher cumulative dose of haloperidol evidenced a significantly higher incidence of WD. Occurrence rates of tardive dyskinesia (TD) and multiple episodes of TD/WD were higher among girls. CONCLUSION: Female gender and pre- and perinatal complications may be involved in susceptibility to dyskinesias; greater cumulative haloperidol dose and/or longer exposure to haloperidol may increase the risk.

Nonpharmacological response in hospitalized children with conduct disorder.

OBJECTIVE: There is a paucity of research regarding the effects of hospitalization and/or the response to placebo in children with conduct disorder who are hospitalized for chronic and severe aggression. However, many children with this problem are hospitalized and immediately begin pharmacotherapy. In this report, the effects of hospitalization and placebo administration were examined. METHOD: Subjects were forty-four children (37 males, 7 females) with conduct disorder, aged 9.83 to 17.14 years, who were hospitalized for chronic and severe aggression. This was a 4-week double-blind and placebo-controlled study with a 2-week single-blind placebo lead-in period. During the 2-week placebo baseline period, aggression was measured on a 24-hour basis, using the Overt Aggression Scale. Only subjects meeting a specific aggression criterion were randomized to the treatment period of the trial. RESULTS: Of the 44 subjects enrolled, 23 (52.3%) met the aggression criteria for entering the treatment period (baseline nonresponders), while 21 (47.7%) did not (baseline responders). Thus, almost half of the subjects, while taking no active medication, benefited from the inpatient milieu/structure and/or placebo. CONCLUSION: This finding has important treatment and research implications. Medication to treat aggression should not be initiated immediately upon hospitalization because improvements associated with hospitalization may be attributed inaccurately to pharmacotherapy, resulting in unnecessarily medicating children. A placebo baseline period is essential to decrease the risk of a type II error in pharmacological research concerning aggression.

The lithium test dose prediction method in aggressive children.

Cooper and associates (1973) developed a method of ascertaining the lithium dosage required to attain a therapeutic serum level of 0.6 to 1.2 mEq/L. However, reports about the safety and accuracy of their method in children are limited (Geller & Fetner 1989). This study relates our experience with using this method in children. Subjects were 16 conduct-disordered children (13 males, 3 females), ages 8.97 to 17.14 years (mean, 12.73 +/- 2.12), who were treated with lithium to decrease aggressive behavior. Following a lithium 600-mg loading dose, a 24-hour serum lithium level was drawn from which a "predicted" lithium dosage was established. These dosages ranged from 600 to 1,800 mg/day (mean, 1,312.5 +/- 450) and the corresponding serum lithium levels at steady-state ranged from 0.58 to 1.13 mEq/L (mean, 0.87 +/- 0.15). No severe side effects were encountered. This suggests that the method is safe and useful for predicting lithium dosages in children.

The Overt Aggression Scale in a study of lithium in aggressive conduct disorder.

This article describes an open study of lithium carbonate in conduct-disordered children. The objective of the study was to investigate the effectiveness of lithium in reducing aggression and the usefulness of the Overt Aggression Scale (OAS), as a measure of treatment effect. The subjects, 8 children, ages 9.2 to 16.9 years (mean +/- standard deviation [SD] = 12.48 +/- 2.97), were treated for 4 weeks with lithium. Optimal dosages ranged from 1200 to 1800 mg/day (mean = 1350 +/- 227) with corresponding serum lithium levels ranging from 0.86 to 1.39 mEq/L (mean = 1.05 +/- 0.17). OAS results indicated that aggression decreased significantly over time. The findings from the OAS agreed with findings from a more general measure, the Global Clinical Consensus Rating, leading to the conclusion that the OAS is a promising outcome measure for treatment studies of aggression in children. Further placebo-controlled studies of lithium carbonate in reducing aggressive behavior in conduct-disordered children, employing a specific measure such as the OAS, are warranted.

Plasma beta-endorphin levels, naltrexone, and haloperidol in autistic children.

Plasma beta-endorphin levels were measured in 13 autistic children, aged 3.67 to 11.67 years at the end of treatment (naltrexone, haloperidol, pimozide, or placebo) and in 5 of the 13 children also at baseline. Baseline plasma beta-endorphin levels were lower than those reported in the literature. There was a strong correlation between plasma beta-endorphin levels and severity of sterotypies in all children. Naltrexone did not seem to have a specific effect on plasma beta-endorphin levels; short-term haloperidol treatment was associated with an increase, whereas long-term haloperidol treatment seemed to have a depressive effect on plasma beta-endorphin levels, which rose after withdrawal of haloperidol.

Haloperidol withdrawal and weight changes in autistic children.

The long-term effects of haloperidol on weight were assessed in 30 children, 25 males and 5 females, diagnosed with autistic disorder whose ages ranged from 3.08 to 8.42 years. They received haloperidol (0.25-3.50 mg/day; mean 1.26 +/- 0.84) for 6 months followed by a 4-week drug withdrawal period. Weights obtained on the last day of the 6-month haloperidol period were compared to weights obtained following drug withdrawal. There was no significant difference between the mean weights obtained on the last day of haloperidol administration (24.799 +/- 9.741 kg) compared to the mean weights at the end of the fourth week of the placebo period (24.644 +/- 9.833 kg). Weights increased during the first week of drug discontinuation (24.879 +/- 9.855 kg), but decreased during each following week of drug withdrawal. Weight was measured monthly during the 6-month haloperidol treatment period for 8 of the 30 subjects. In this subsample, weight gain was greater during the 1-month period lasting from the end of the 4-week drug withdrawal to the end of the first month after resuming haloperidol treatment than weight gain prior to drug withdrawal, between the fifth and sixth month of haloperidol treatment.

Assessment of therapeutic relationship of community-agency workers.

This article reports on the ratings of the personal and professional characteristics of community-based workers for children and adolescents who had recently been released from a psychiatric inpatient service. The child/adolescent's family members/caregivers and the community workers both responded to the same items of a questionnaire. Families/caregivers rated the community workers with whom they were the most and the least satisfied. Community workers rated themselves in relation to these study children and/or their families. Findings indicate that both family members/caregivers and the community workers themselves saw community workers performing relatively well in the areas of providing information and offering support to families. Likewise, both assessed the service providers as having the greatest deficits in the area of teaching skills for child/adolescent home management. Suggestions for meeting the needs of the families and for ensuring that a system of care for child/adolescents is child-centered and family-focused are discussed.

Diagnostic and assessment issues related to pharmacotherapy for children and adolescents with autism.

Autism involves not only developmental delays but also aberrant behavior, both of which change in nature over time. Rating instruments may be useful to assess maladaptive and adaptive behaviors of autistic children in a standardized way and, perhaps, to measure change due to treatment. With the expansion of basic science, knowledge, and technology, there is increasing evidence that autism is etiologically heterogeneous. Currently, there is no biological marker specific to autism, although hyperserotonemia is a consistent finding in one third of autistic children. An aim of basic science research has been to develop a rational pharmacotherapy based upon the underlying neurochemistry. However, at the present time, this approach has not always been successful. It is expected that the development and use of more restrictive criteria, delineation of subtypes of autism, and interaction of descriptive, behavioral, clinical, and basic research will lead to more effective planning for treatment. The relationship of assessment to treatment response is presented and discussed.

Mental retardation and psychiatric disorders.

Estimates of the prevalence of comorbidity of psychiatric disorders and mental retardation in community and clinical populations range from 14.3 to 67.3 percent. A wide variety of disorders have been reported in this population, including schizophrenia, depression, and, commonly, conduct disorder. The incidence of specific disorders appears to be related to the level of retardation and the concomitant presence of seizure disorder. Accurate assessment of psychiatric disorders in this population is difficult because mentally retarded patients have poor communication skills and because most diagnostic instruments were developed for persons of normal intellectual functioning. Treatment includes educational, behavioral, and pharmacological interventions, but guidelines for safe use of psychotherapeutic drugs are needed.

Factors related to haloperidol response and dyskinesias in autistic children.

A secondary analysis of data pooled from three studies (Anderson et al. 1984, 1989; Campbell et al. 1978) was performed to identify variables predictive of haloperidol response in 125 autistic children, with ages ranging from 2.3 to 8.2 years. Mean behavioral improvement was greater under haloperidol treatment conditions than under placebo. Higher intelligence quotient (IQ) was predictive of reduction in behavioral symptoms under general conditions of haloperidol or placebo treatment, while older children were found to respond favorably to haloperidol itself. Under both haloperidol and placebo conditions, there was also a tendency for greater reduction in symptoms, in terms of raw score and percent change, for those with greater initial severity of illness. Results for initial severity of illness as a predictor of improvement generalized across a wide variety of behavior not specific to autism (e.g., hyperactivity and temper outbursts). However, mean behavioral improvement and its prediction with demographics for individuals tended to be more specific to symptoms related to autism per se. Reduction in symptoms during short-term haloperidol treatment was not found to be related to whether or not children developed dyskinesias in subsequent long-term haloperidol administration.

Repeated episodes of neuroleptic-related dyskinesias in autistic children.

The objective of this study was to examine data from 14 autistic children who developed repeated episodes of haloperidol-related dyskinesias in an ongoing, long-term maintenance clinical trial. The sample consisted of 9 males and 5 females, whose ages ranged from 3.4 to 6.7 years. These 14 children are a subsample of 29 children who developed dyskinesias at least once. In each subsequent episode, the dyskinesias tended to occur increasingly earlier and to last longer. Most of the dyskinesias developed upon haloperidol withdrawal. The topography of dyskinesias, the relationship of behavioral symptoms to severity of dyskinesias, and an attempt to characterize subgroups with dyskinesias are also presented.

Stereotypies and tardive dyskinesia: abnormal movements in autistic children.

Baseline stereotypic movements in 224 autistic children were studied as well as their relationship to certain demographic variables and measures of overall symptomatology and severity of illness. Prediction of haloperidol-related dyskinesias with measures of stereotypies and demographic variables was also attempted. Stereotypies were present in at least mild form in most children, with most showing moderate severity. Most stereotypies were in the orofacial area. I.Q. was found to be negatively related to stereotypies. Furthermore, across methods of assessment, severity and frequency of stereotypies were found to be positively related to overall symptomatology and severity of illness. No significant predictors of development of dyskinesias were found.