Response to stimulant drug treatment in hyperactive children: Prediction from EEG and neurological findings

A study of neurological examinations, EEG findings, and behavioral responses to methylphenidate treatment in 57 hyperactive boys, 5 to 10 years of age, is reported and discussed. The results indicated that subjects with minor neurological abnormalities in 4 or more categories responded with significantly more improvement (p<.01) to methylphenidate treatment than subjects without abnormalities. Subjects with abnormal EEGs had significantly more improvement (p<.001) than those with normal EEGs. A significant correlation was found between the degree of evidence of brain dysfunction (obtained from EEG and neurological examinations) and the probability of response to methylphenidate treatment. It is suggested that both the neurological and the EEG examinations play a significant role in the assessment of hyperactive children.This study was supported in part by NIMH Grant MH17039, a grant from the Andrew Norman Foundation, a grant from the Julius R. Wolf Foundation, and a grant from CIBA Pharmaceutical Company.     

Effects of two doses of methylphenidate on cross-situational and borderline hyperactive children's evoked potentials

This study involved 27 children displaying cross-situational hyperactivity and 14 youngsters with borderline hyperactivity. For all patients, evoked potentials were recorded after receiving 0 (placebo), 0.3 and 0.6 mg/kg methylphenidate. Under each pharmacologic condition, subjects were administered: a photic stimulation procedure; two versions of the Continuous Performance Test (CPT), which varied in difficulty level; and a discrimination ('oddball') test. Under photic stimulation, methylphenidate reduced the impact of increasing brightness levels on the rates of amplitude increment and latency decrease in the P208 component of the visual evoked response. These results are similar to those obtained by Buchsbaum and Wender (1973) for hyperactive patients with a positive clinical response to amphetamine. In CPT and the discrimination test, the two active dosages of methylphenidate brought about a comparable reduction of placebo levels of errors and reaction time. Analogously, in both versions of CPT, the two active dosages resulted in comparable increases in the amplitude of two components of the late positive complex (LPC; P510 and P740). P510 was identified as a classical P300. In the discrimination test, the effect of the stimulant on the response evoked by the visual non-target was to increase the amplitude of a component (P463) previously identified as P300. These pharmacologic results were nearly identical for borderline and cross-situational patients. In general, the results confirmed previous observations that methylphenidate improves hyperactive children's performance and increases the amplitude of their LPC. Further, these findings support previous observations that hyperactive patients' cognitive processing is optimized by a dosage of 0.3 mg/kg methylphenidate. Finally, the similarity between findings for cross-situational and borderline hyperactive patients is consistent with other evidence that stimulant effects are not limited to classically hyperactive children.     

Auditory ERP augmentation-reduction and methylphenidate dosage needs in attention and reading disordered children

From their event related potentials (ERPs) to tones of four intensity levels, a sample of attention disordered and/or reading disabled children, recommended for a trial on methylphenidate, were classified as auditory augmenters or reducers. The augmenters were blindly titrated at significantly lower dosage levels than the reducers. Moreover, the ameliorative effects of the drug, as assessed by teacher ratings, were more evident in hyperactive augmenters. The children diagnosed either as hyperactive or hyperactive and reading disabled had steeper (or more augmenting) gradients than the nonhyperactive reading disabled and attention disordered subjects. The ERP (N1-P2) gradients were not consistently related to reaction time (RT) gradients to the tones or to an RT measure of nervous system sensitivity. It is suggested that ERPs index registration but not response strength, the first being largely automatic and the second purposive.     

Long-term Use and Discontinuation of Methylphenidate with Hyperactive Children

The long-term effects of methylphenidate on the behavior and academic functioning of hyperactive children are described. 36 children having a positive response to methylphenidate entered a three-year follow-up study in which they were closely monitored physically, behaviorally and psychometrically. During this period 13 children spontaneously discontinued medication: there were no statistically significant differences between them and the children who continued medication in terms of age, IQ or ratings at initial interview. The greatest improvement in performance occurred in the early months of treatment, but was only partially maintained during long-term therapy and little further change occurred after medication was discontinued. The findings indicate that sustained improvement is related to factors other than continued medication, and they suggest that drug therapy should be regarded as a short-term intervention until more positive social and school behavior can be established.     

Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes

Objective:To determine the efficacy and safety of clonidine, used alone or in combination with methylphenidate, in treating attention-deficit/hyperactivity disorder (ADHD).Method:A 16-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 122 children, ages 7 to 12, with any subtype of ADHD, randomly assigned to clonidine, methylphenidate, clonidine in combination with methylphenidate, or placebo according to a 2 × 2 factorial design. In two successive 4-week titration periods, clonidine (or matching placebo) and added methylphenidate (or matching placebo) were adjusted to optimal doses and then continued for 8 weeks. The primary efficacy outcome was changed from baseline to week 16 on the Conners Teachers Abbreviated Symptom Questionnaire. Secondary outcomes included the Conners Abbreviated Symptom Questionnaire for Parents and the Children's Global Assessment Scale.Results:On the Conners Teachers Abbreviated Symptom Questionnaire, clonidine was not found to improve ADHD symptoms, whereas subjects treated with methylphenidate showed significant improvement compared to those not treated with methylphenidate. Subjects treated with clonidine had greater improvements on the Conners Abbreviated Symptom Questionnaire for Parents and Children's Global Assessment Scale, but also a higher rate of sedation compared with subjects not treated with clonidine.Conclusions:Based on the Conners Teachers Abbreviated Symptom Questionnaire, methylphenidate offers the best combination of efficacy and tolerability for ADHD. Clonidine was well tolerated despite the frequency of sedation and did offer some benefit.     

The effects of methylphenidate on the mother-child interactions of hyperactive children.

Twenty hyperactive boys were observed while interacting with their mothers during a free play and task period on each of three occasions (no drug, drug, placebo). A triple-blind, drug-placebo crossover design was used to study the effects of methylphenidate on these interactions. A complex objective coding system was used to score the children's responses to various maternal behaviors as well as the mother's responses to a variety of children's behaviors. Results indicated that these children were more compliant with maternal commands during drug treatment. In response, mothers displayed increased attention to compliance while reducing their directiveness toward the boys. However, the hyperactive boys receiving methylphenidate initiated fewer social interactions and tended to show greater nonresponding. Thus, methylphenidate may improve the compliance of hyperactive children but tends to decrease their sociability.     

Methylphenidate and growth in hyperactive children. A controlled withdrawal study

The effect of stimulants on growth has been controversial. Among hyperactive children receiving long-term methylphenidate hydrochloride treatment, we examined the effects of methylphenidate withdrawal on the growth of hyperactive children randomly assigned to be taken off, or remain on, the medication regimen over two consecutive summers. After one summer, no group difference in height was found, but weight was higher in the group that had been taken off methylphenidate therapy. In contrast, two summers of being off methylphenidate treatment had a significant positive effect on height but not on weight. The results document a linkage between exposure to methylphenidate and reduction in growth velocity. However, they do not address whether the medication has long-term effects on height.     

Individual change in methylphenidate use in a national sample of children aged 2 to 11 years.

OBJECTIVES: To determine methylphenidate use in children aged 2 to 13 years. To provide age- and sex-specific estimates of methylphenidate initiation and cessation during a 2-year period. METHOD: Data from 2 cycles of a Canadian household survey yielded a sample of over 10 000 children aged 2 to 11 years at Cycle 1 who continued to participate at Cycle 2. We used logit modelling to estimate Cycle 2 methylphenidate use, methylphenidate use over a 2-year period, and methylphenidate initiation and cessation from Cycles 1 to 2. RESULTS: In 1996 and 1997, methylphenidate use ranged from 0.32% to 6.31% among children aged 4 to 13 years. School-aged boys were more likely than girls to use methylphenidate. Odds were greater for boys aged 6 to 7 years than for boys aged 4 to 5 years; they were also greater for boys aged 10 to 11 years than for boys aged 12 to 13 years. Almost 1% of children used methylphenidate at both data cycles. Odds of Cycle 2 methylphenidate use were 135 times greater for children using methylphenidate at Cycle 1, compared with nonusers. Methylphenidate initiation ranged from 0.20% to 3.34%, and school-aged boys had higher initiation rates than girls. Cessation rates ranged from 18% to78%, and there were no statistically significant differences by age and sex. CONCLUSIONS: Methylphenidate prevalence findings are consistent with past studies. We found an age-by-sex interaction on methylphenidate use. We also found both continuity and discontinuity in methylphenidate use.     

Ineffectiveness of imipramine in children who fail to respond to methylphenidate

Ten hyperactive children who had failed to respond to methylphenidate were treated with imipramine in a placebo-controlled, crossover design. No significant drug effects were obtained either on parent and teacher ratings of the child's behavior or on the child's performance in a laboratory measure of sustained attention. Findings suggest that imipramine has limited clinical usefulness in the treatment of hyperactive children who fail to respond to methylphenidate. This research was supported in part by a grant to Dr. Winsberg from Ciba-Geigy Pharmaceuticals. The authors gratefully acknowledge Dr. Jeffrey Sverd and Dr. Andrew B. Bremness for their assistance in providing drug management.     

Paranoia och alkoholism

The purpose of the present study was to examine growth in children on extended stimulant treatment. Ninety-one hyperactive boys were studied, of whom 68 were treated with amphetamine and 23 with methylphenidate. The age range was 3-10 years. All children were treated with one of these stimulants for a minimum of 1 year. The yearly mean values for height and weight were all between the 25th and 90th percentile of the population norms. During the 1st year of treatment children who used amphetamine showed significantly smaller weight gains than those who used methylphenidate ( F = 6.9, df = 64, P < 0.05). Four patients (17%) in the methylphenidate group and 21 (31%) in the amphetamine group had a weight loss during the 1st year, ranging from 0 to 9.5 kg. Within this group of 25 patients there was a significantly higher number of children with a pretreatment weight greater than that of the 50th percentile group (chi-square = 5.59, P < 0.05). All 25 patients showed sufficient weight gain at later examinations. Multiple regression analyses showed that neither cumulative doses nor age had a significant effect on growth when initial weight and height were controlled for. These findings indicate that, for most children, extended treatments with amphetamine or methylphenidate do not have negative effects on growth. However, some children show weight loss during the 1st year of treatment, more often when amphetamine is used. Among those children who may show reduced weight gain, most are above mean weight before treatment begins.     

Does extended medication with amphetamine or methylphenidate reduce growth in hyperactive children?

The purpose of the present study was to examine growth in children on extended stimulant treatment. Ninety-one hyperactive boys were studied, of whom 68 were treated with amphetamine and 23 with methylphenidate. The age range was 3-10 years. All children were treated with one of these stimulants for a minimum of 1 year. The yearly mean values for height and weight were all between the 25th and 90th percentile of the population norms. During the 1st year of treatment children who used amphetamine showed significantly smaller weight gains than those who used methylphenidate (F = 6.9, df = 64, P < 0.05). Four patients (17%) in the methylphenidate group and 21 (31%) in the amphetamine group had a weight loss during the 1st year, ranging from 0 to 9.5 kg. Within this group of 25 patients there was a significantly higher number of children with a pretreatment weight greater than that of the 50th percentile group (chi-square = 5.59, P < 0.05). All 25 patients showed sufficient weight gain at later examinations. Multiple regression analyses showed that neither cumulative doses nor age had a significant effect on growth when initial weight and height were controlled for. These findings indicate that, for most children, extended treatments with amphetamine or methylphenidate do not have negative effects on growth. However, some children show weight loss during the 1st year of treatment, more often when amphetamine is used. Among those children who may show reduced weight gain, most are above mean weight before treatment begins.     

Hyperactive boys almost grown up. IV. Criminality and its relationship to psychiatric status

Attention-deficit disorder with hyperactivity is believed, by some, to be a developmental antecedent (predisposing factor) to antisocial personality disorder and criminality. However, evidence supporting this association has not been consistent. We report on a prospective follow-up study of 103 males (ages 16 to 23 years), who were diagnosed as hyperactive (attention-deficit disorder with hyperactivity) between ages 6 and 12 years, and 100 normal controls. The official arrest records of all subjects who resided in New York State during the follow-up interval were obtained. Blind diagnoses (based on structured interviews with subjects and their parents) were made on 98% of the initial cohort at follow-up. Although other investigators have reported on the delinquent behavior of hyperactive children in a prospective design, to our knowledge, follow-up mental status has not been studied previously in relation to official arrest records. Significantly more probands than controls had been arrested (39% vs 20%), convicted (28% vs 11%), and incarcerated (9% vs 1%). The presence of an antisocial/conduct disorder in young adulthood almost completely accounted for the increased risk for criminal activities in the former hyperactive children whether or not it was accompanied by a substance use disorder. Continuing attention-deficit disorder with hyperactivity at follow-up, by itself, was not associated with arrest history. The findings support the view that childhood attention-deficit disorder with hyperactivity is a risk factor for later criminality, but that this relationship is almost exclusively mediated by the development of an antisocial disorder in early adulthood.     

State-dependent learning in hyperactive children receiving methylphenidate

State-dependent learning refers to a failure of learning mastered under one drug condition to be remembered when tested under another drug condition. Previous studies of state-dependent learning in hyperactive children receiving stimulants have yielded conflicting results. The authors systematically evaluated learning and transfer of learning in children who were or were not receiving methylphenidate and included several design features intended to optimize the likelihood of demonstrating state-dependent learning. They found no evidence of state-dependent learning. These results diminish concern regarding state-dependent effects in hyperactive children who are positive drug responders and who are clinically administered methylphenidate to control their hyperactivity.     

ADD psychosis: treatment with antipsychotics and methylphenidate?

Two patients with a psychotic disorder who also met the diagnostic criteria for attention deficit hyperactivity disorder ADHD were treated with antipsychotics and methylphenidate. The first patient remained stable for many years with this combination treatment, whereas the second became psychotic several months after he had increased the dose of methylphenidate and had started to use cocaine. In the light of these two case studies, we have reviewed the literature on ADD psychosis, and we formulate recommendations regarding the specialised treatment needed for this uncommon disorder.     

Changes in the electroencephalogram accompanying the use of stimulant drugs (methylphenidate and dextroamphetamine) in hyperactive children

Fifteen hyperactive boys aged 5.6-10.6 years had their electroencephalograms (EEG) recorded during performance of a simple reaction task while on stimulant medication (methylphenidate or d-amphetamine) and after being free of medication for at least 48 hr. Interval histograms were formed from measurements of the duration of 780 half waves taken from predetermined portions of the EEG'S recorded from the left parietal-occipital derivation for both treatment conditions, and the histograms were subjected to a central-moments analysis. Previous evidence showed that, in normal children, smaller-valued 2nd, 3rd, and 4th central moments were associated with greater maturity. The EEG histograms obtained while the hyperactive children were taking stimulant medication had significantly (p less than 0.005) smaller 2nd, 3rd, and 4th central moments than the histograms of the same children obtained when off medication. Age of the group predicted from the means of the 2nd, 3rd, and 4th central moments of the EEG interval histograms was 91 months when the children were off medication--9 months less than the group's actual mean age. Age predicted in the same way when the children were on medication was 97 months. Findings support the concept of a neurophysiological maturational lag in hyperactivity and suggest that this lag is overcome, in part, by the use of stimulant drugs.     

Social functioning in children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment

OBJECTIVE: To test that methylphenidate combined with intensive multimodal psychosocial intervention, which includes social skills training, significantly enhances social functioning in children with attention-deficit/hyperactivity disorder (ADHD) compared with methylphenidate alone and methylphenidate plus nonspecific psychosocial treatment (attention control). METHOD: One hundred three children with ADHD (ages 7-9), free of conduct and learning disorders, who responded to short-term methylphenidate were randomized for 2 years to receive (1) methylphenidate alone, (2) methylphenidate plus multimodal psychosocial treatment that included social skills training, or (3) methylphenidate plus attention control treatment. Assessments included parent, child, and teacher ratings of social function and direct school observations in gym. RESULTS: No advantage was found on any measure of social functioning for the combination treatment over methylphenidate alone or methylphenidate plus attention control. Significant improvement occurred across all treatments and continued over 2 years. CONCLUSIONS: In young children with ADHD, there is no support for clinic-based social skills training as part of a long-term psychosocial intervention to improve social behavior. Significant benefits from methylphenidate were stable over 2 years.     

Executive functions and methylphenidate response in subtypes of attention-deficit/hyperactivity disorder.

BACKGROUND: Oculomotor tasks are a well-established means of studying executive functions and frontal-striatal functioning in both nonhuman primates and humans. Attention-deficit/hyperactivity disorder (ADHD) is thought to implicate frontal-striatal circuitry. We used oculomotor tests to investigate executive functions and methylphenidate response in two subtypes of ADHD. METHODS: Subjects were boys, aged 11.5-14 years, with ADHD-combined (n = 10), ADHD-inattentive (n = 12), and control subjects (n = 10). Executive functions assessed were motor planning (tapped with predictive saccades), response inhibition (antisaccades), and task switching (saccades-antisaccades mixed). RESULTS: The ADHD-combined boys were impaired relative to control subjects in motor planning (p < .003) and response inhibition (p < .007) but not in task switching (p > .92). They were also significantly impaired relative to ADHD-inattentive boys, making fewer predictive saccades (p < .03) and having more subjects with antisaccade performance in the impaired range (p < .04). Methylphenidate significantly improved motor planning and response inhibition in both subtypes. CONCLUSIONS: ADHD-combined but not ADHD-inattentive boys showed impairments on motor planning and response inhibition. These deficits might be mediated by brain structures implicated specifically in the hyperactive/impulsive symptoms. Methylphenidate improved oculomotor performance in both subtypes; thus, it was effective even when initial performance was not impaired.     

Clinical and demographic features of treated first-episode psychotic disorders: a Zambian study

BACKGROUND: There is a relative lack of information about the epidemiology of psychotic disorders in the developing world. The aim of this pragmatic study was to describe the correlates of first-episode psychosis in the central African nation of Zambia. METHOD: Selected clinical and demographic variables were collected on patients with psychotic disorders presenting for the first time at the only psychiatric hospital in Zambia (Chainama Hills College Hospital, Lusaka). RESULTS: During the study period, 160 subjects were admitted to the hospital with the first episode of a psychotic disorder. The male to female sex ratio was 2.5:1, with the median age of first admission for both sexes being 26 years. Half of the subjects had a duration of untreated psychosis one month or less. Recent alcohol and other drug abuse was common in males (56%). Clinical evidence of HIV/AIDs was found in 9% of those admitted. Approximately one-third of the subjects had attended a traditional healer for their psychotic symptoms prior to admission. CONCLUSIONS: Understanding the profile of treated first-episode psychosis in the developing world can help optimize the development of local services. Furthermore, characterizing differences in the epidemiology of psychosis between populations may help generate factors that could influence its cause and course.     

Prevalence of depressive episodes with psychotic features in the general population

OBJECTIVE: The study evaluated the prevalence of major depressive episodes with psychotic features in the general population and sought to determine which depressive symptoms are most frequently associated with psychotic features. METHOD: The sample was composed of 18,980 subjects aged 15-100 years who were representative of the general populations of the United Kingdom, Germany, Italy, Portugal, and Spain. The participants were interviewed by telephone by using the Sleep-EVAL system. The questionnaire included a series of questions about depressive disorders, delusions, and hallucinations. RESULTS: Overall, 16.5% of the sample reported at least one depressive symptom at the time of the interview. Among these subjects, 12.5% had either delusions or hallucinations. More than 10% of the subjects who reported feelings of worthlessness or guilt and suicidal thoughts also had delusions. Feelings of worthlessness or guilt were also associated with high rates of hallucinations (9.7%) and combinations of hallucinations and delusions (4.5%). The current prevalence of major depressive episode with psychotic features was 0.4% (95% CI=0.35%-0.54%), and the prevalence of a current major depressive episode without psychotic features was 2.0% (95% CI=1.9%-2.1%), with higher rates in women than in men. In all, 18.5% of the subjects who fulfilled the criteria for a major depressive episode had psychotic features. Past consultations for treatment of depression were more common in depressed subjects with psychotic features than in depressed subjects with no psychotic features. CONCLUSIONS: Major depressive episodes with psychotic features are relatively frequent in the general population, affecting four of 1,000 individuals. Feelings of worthlessness or guilt can be a good indicator of the presence of psychotic features.     

Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder

OBJECTIVE: Linkage studies of bipolar disorder and schizophrenia have found overlapping evidence for susceptibility genes in four chromosomal regions-10p12-14, 13q32, 18p11.2, and 22q12-13. The authors previously demonstrated familial clustering of psychotic symptoms-defined as hallucinations and/or delusions-in some bipolar disorder pedigrees. In this study they used stratified linkage analysis to test the hypothesis that those bipolar disorder pedigrees most enriched for psychotic symptoms would show greater evidence of linkage to the regions of previous bipolar disorder/schizophrenia linkage overlap. METHOD: Nonparametric linkage analyses using GENEHUNTER and ASPEX were performed on 65 bipolar disorder families. Family subsets were defined by the number of family members with psychotic mood disorder. RESULTS: The 10 families in which three or more members had psychotic mood disorder showed suggestive evidence of linkage to 13q31 (nonparametric linkage score=3.56; LOD score=2.52) and 22q12 (nonparametric linkage score=3.32; LOD score=3.06). These results differed significantly from those for the entire study group of 65 families, which showed little or no linkage evidence in the two regions. The 10 families with three or more psychotic members did not show evidence of linkage to 10p12-14 or 18p11.2. The 95% confidence interval on 22q12 spanned 4.3 centimorgans (2.6 megabases) and was congruent with previous findings. CONCLUSIONS: Bipolar disorder families in which psychotic symptoms cluster may carry susceptibility genes on chromosomal regions 13q31 and 22q12. Replication should be attempted in similar families and perhaps in schizophrenia families in which mood symptoms cluster because these overlapping phenotypes may correlate most closely with the putative susceptibility genes. The localization of the 22q12 finding particularly encourages further study of this region.