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CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing psychiatric disorder that affects both children and adults. There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD; however, little is known about the mechanisms by which these different treatments exert their therapeutic effects. OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylphenidate hydrochloride vs the nonstimulant atomoxetine hydrochloride. DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylphenidate (n = 18) or atomoxetine (n = 18) using a parallel-groups design. SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine, New York, New York. PARTICIPANTS Thirty-six youth with ADHD (mean [SD] age, 11.2 [2.7] years; 27 boys) recruited from randomized clinical trials. MAIN OUTCOME MEASURES Changes in brain activation during a go/no-go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version. RESULTS Treatment with methylphenidate vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean (SD) improvements in ratings of ADHD symptoms (55% [30%] vs 57% [25%]). Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments. Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylphenidate in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex. These findings were not attributable to baseline differences in activation. CONCLUSIONS Treatment with methylphenidate and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic actions in frontoparietal regions that have been implicated in the pathophysiology of ADHD. These results represent a first step in delineating the neurobiological basis of differential response to stimulant and nonstimulant medications for ADHD.

Previous studies have reported hypofunction, structural abnormalities, and biochemical abnormalities of the dorsal anterior midcingulate cortex (daMCC) in attention-deficit/hyperactivity disorder (ADHD). Stimulant medications are effective treatments for ADHD, but their neural effects have not been fully characterized.To determine whether the methylphenidate hydrochloride osmotic-release oral system (OROS) would increase functional magnetic resonance imaging (fMRI) activation, compared with placebo, in the daMCC and other frontoparietal regions subserving attention during the Multi-Source Interference Task (MSIT).Randomized, placebo-controlled, 6-week, before-after fMRI study.Academic medical center ambulatory clinic.Twenty-one adults with ADHD randomized to 6 weeks of treatment with methylphenidate OROS (n = 11) or placebo (n = 10).Patients underwent fMRI twice while performing the MSIT (scan 1 at baseline and scan 2 at 6 weeks).Group-averaged, random-effects, repeated-measures, general linear model analyses were used to compare daMCC (and whole-brain) fMRI activation during the MSIT. Individual-based daMCC volume-of-interest confirmatory analyses and behavioral data are also presented.Performance and baseline fMRI measures in the daMCC and other a priori brain regions did not differ between groups. Group comparisons showed a group x scan interaction and t test confirmation of higher activation in the daMCC at 6 weeks in the methylphenidate OROS group than in the placebo group (P1 x 10(-4), cluster corrected for multiple comparisons). Individual daMCC volume-of-interest analyses confirmed group-averaged findings and suggested that daMCC activity might be related to clinical response. Methylphenidate OROS also produced higher activation in the dorsolateral prefrontal cortex and the parietal cortex at 6 weeks.Methylphenidate OROS increased daMCC activation during the MSIT and may act, in part, by normalizing daMCC hypofunction in ADHD.

Background The duration of action of the immediate-release formulation of methylphenidate hydrochloride is short (3 to 4 hours), and 3 times daily dosing is thought to maximize effectiveness across a 12-hour day. The initial sustained-release formulations of methylphenidate had reduced efficacy compared with immediate-release methylphenidate and were not well accepted. Tachyphylaxis was hypothesized to account for the reduced effects, and an ascending drug delivery pattern was proposed to overcome this acute tolerance. Methods Children with attention-deficit/hyperactivity disorder were evaluated in a laboratory school to characterize onset and duration of the effect of a variety of methylphenidate regimens. In a proof-of-concept study, an experimental ascending profile was established by an initial bolus followed by small increasing doses of immediate-release methylphenidate in capsules administered every 30 minutes for 8 hours. Two proof-of-product studies of a new oral once-a-day formulation to deliver methylphenidate by an osmotic pump process based on OROS (ALZA Corp, Mountain View, Calif) technology (hereafter referred to "OROS-methylphenidate") were conducted: a pharmacokinetic study and a pharmacodynamic study. Results The experimental ascending profile matched the effect of the standard regimen of methylphenidate, 3 times daily. In the pharmacokinetic study, OROS-methylphenidate treatment produced a rapid rise followed by increasing plasma concentrations that peaked 7 to 9 hours after administration. In the pharmacodynamic study, OROS-methylphenidate treatment matched the 3 times daily dosing of methylphenidate for onset and duration of efficacy. Conclusions These studies demonstrate the translation of a basic science finding (acute tolerance to clinical doses of methylphenidate) into clinical application (the selection of a new drug delivery pattern for methylphenidate). This approach produced a new product (OROS-methylphenidate or Concerta), which proved to have the predicted rapid onset (with 1-2 hours) and long duration of efficacy(10-12 hours) after a single administration in the morning.

Background: Stimulants are not considered appropriate for the treatment of children with conduct disorders (CDs). The postulated differences in stimulant effect between children with attention deficit hyperactivity disorder (ADHD) and CD led to the hypothesis that methylphenidate hydrochloride, which is effective in ADHD, would not significantly improve symptoms of CD. Methods: We randomly assigned 84 children with CD, between the ages of 6 and 15 years, to receive methylphenidate hydrochloride (up to 60 mg/d) or placebo for 5 weeks. Behavior was evaluated by parent, teacher, and clinician reports and by direct classroom observations. Two thirds of the children also met criteria for ADHD. Results: Contrary to prediction, ratings of antisocial behaviors specific to CD were significantly reduced by methylphenidate treatment. The magnitude of methylphenidate effect indicated meaningful clinical benefit. Partialling out severity of ADHD did not alter the significant superiority of methylphenidate on CD ratings specifically (P Conclusions: Methylphenidate has short-term positive effects on children and adolescents with CD. Key aspects of antisocial adjustment appear to be treatment responsive. This effect was independent of severity of the children's initial ADHD symptoms.

Background: The findings from case reports and patient questionnaire surveys have been interpreted as indicating that administration of stimulants is ill-advised for the treatment of attention-deficit hyperactivity disorder in children with tic disorder. Methods: Thirty-four prepubertal children with attention-deficit hyperactivity disorder and tic disorder received placebo and three dosages of methylphenidate hydrochloride (0.1, 0.3, and 0.5 mg/kg) twice daily for 2 weeks each, under double-blind conditions. Treatment effects were assessed using direct observations of child behavior in a simulated (clinic-based) classroom and using rating scales completed by the parents, teachers, and physician. Results: Methylphenidate effectively suppressed hyperactive, disruptive, and aggressive behavior. There was no evidence that methylphenidate altered the severity of tic disorder, but it may have a weak effect on the frequency of motor (increase) and vocal (decrease) tics. Conclusion: Methylphenidate appears to be a safe and effective treatment for attention-deficit hyperactivity disorder in the majority of children with comorbid tic disorder.

Objective: To examine the course and potential predictors of treatment response in the early phase of schizophrenia. Design: Prospective study of an inception cohort. Setting: Psychiatric division of an academic medical center with a suburban metropolitan catchment area. Patients and Intervention: Seventy first-episode patients who had undergone four biologic assessment procedures (brain magnetic resonance imaging, behavioral response to methylphenidate hydrochloride, growth hormone levels, eye tracking) were treated with a standardized antipsychotic drug protocol until recovery. Response was measured in terms of psychopathology and degree of remission. Results: Using survival analysis, the proportion of pa- tients remitting by 1 year was estimated at 83%. Mean and median times to remission were 35.7 weeks and 11 weeks, respectively. No baseline demographic or psychopathologic measure significantly predicted time to or level of remission. However, males tended to be nonresponders to treatment and have diagnoses of schizophrenia rather than schizoaffective disorder. Brain pathomorphology and abnormal basal growth hormone significantly predicted time to remission. Conclusions: These results indicate that the antipsychotic treatment response of first-episode schizophrenics is better than chronic multiepisode patients and suggest that specific pathobiologic markers reflect pathophysiologic processes that mediate antipsychotic treatment response.

Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder of childhood. There is considerable evidence that brain dopamine is involved in ADHD, but it is unclear whether dopamine activity is enhanced or depressed.To test the hypotheses that striatal dopamine activity is depressed in ADHD and that this contributes to symptoms of inattention.Clinical (ADHD adult) and comparison (healthy control) subjects were scanned with positron emission tomography and raclopride labeled with carbon 11 (D2/D3 receptor radioligand sensitive to competition with endogenous dopamine) after placebo and after intravenous methylphenidate hydrochloride (stimulant that increases extracellular dopamine by blocking dopamine transporters). The difference in [11C]raclopride's specific binding between placebo and methylphenidate was used as marker of dopamine release. Symptoms were quantified using the Conners Adult ADHD Rating Scales.Outpatient setting.Nineteen adults with ADHD who had never received medication and 24 healthy controls.With the placebo, D2/D3 receptor availability in left caudate was lower (P.05) in subjects with ADHD than in controls. Methylphenidate induced smaller decrements in [11C]raclopride binding in left and right caudate (blunted DA increases) (P.05) and higher scores on self-reports of "drug liking" in ADHD than in control subjects. The blunted response to methylphenidate in caudate was associated with symptoms of inattention (P.05) and with higher self-reports of drug liking (P.01). Exploratory analysis using statistical parametric mapping revealed that methylphenidate also decreased [11C]raclopride binding in hippocampus and amygdala and that these decrements were smaller in subjects with ADHD (P.001).This study reveals depressed dopamine activity in caudate and preliminary evidence in limbic regions in adults with ADHD that was associated with inattention and with enhanced reinforcing responses to intravenous methylphenidate. This suggests that dopamine dysfunction is involved with symptoms of inattention but may also contribute to substance abuse comorbidity in ADHD.

Context Preclinical studies have demonstrated the relevance of adrenergic α2A receptor on the attentional process and the mechanism of action of methylphenidate hydrochloride. Several molecular genetic investigations suggest a role for the adrenergic α2A receptor gene (ADRA2A) in attention-deficit/hyperactivity disorder (ADHD), especially in the inattentive dimension. However, the effect ofADRA2Ain the response to methylphenidate in humans has not been previously investigated, to our knowledge. Objective To evaluate the association between theADRA2A–1291 C>G polymorphism and the clinical response to methylphenidate treatment in children and adolescents with ADHD. Design A pharmacogenomic study was undertaken between November 1, 2002, and May 1, 2004, using a nonrandom assignment, quasi-experimental design. Setting An ADHD outpatient program at a university hospital in Brazil. Patients One hundred six patients consecutively diagnosed as having ADHD were genotyped for theADRA2A–1291 C>G polymorphism and were included in the analyses. Intervention Short-acting methylphenidate administered in increasing dosages until no further clinical improvement was detected or until limited adverse effects occurred. Main Outcome Measures The primary outcome measure was the parent-rated inattentive subscale of the Swanson, Nolan, and Pelham Scale version IV. Secondary outcome measures included the Barkley Side Effect Rating Scale and the parent-rated hyperactivity-impulsivity subscale of the Swanson, Nolan, and Pelham Scale version IV. Scales were applied by child psychiatrists blinded to genotype at baseline and at 1 and 3 months of treatment. Results A significant interaction effect between the presence of the G allele and treatment with methylphenidate over time on inattentive scores was detected during the 3 months of treatment (n = 106; F2,198 = 4.30;P = .02). Conclusions We documented the effect of the G allele at theADRA2A–1291 C>G polymorphism on the improvement of inattentive symptoms with methylphenidate treatment in children and adolescents with ADHD. Our findings provide clinical evidence for the involvement of the noradrenergic system in the modulation of methylphenidate action.

Methylphenidate hydrochloride (Ritalin), the drug of choice for attention-deficit hyperactivity disorder (ADHD), is contraindicated in patients with glaucoma on a theoretical, class-labeling basis. As methylphenidate had been, until recently, primarily prescribed to children, the consideration of prescribing it to patients with glaucoma rarely has arisen. However, as ADHD is being diagnosed and treated in more adults, this is becoming a treatment issue. Moreover, stimulants are being used for the treatment of drug-induced and other sexual dysfunctions on an as-needed basis. 1-3 When used cautiously in conjunction with glaucoma medications and regular ophthalmologic monitoring, methylphenidate and other psychostimulants may be safe in patients with well-controlled, open-angle glaucoma. The following is an example, as well as a practical solution, to this problem. Report of a Case. A 55-year-old male writer with primary open-angle glaucoma was receiving methylphenidate hydrochloride, 25 mg per day, for ADHD. Although his IQ placed him in the gifted

SOME OF the articles appearing in this issue of theArchivesdocument the current interest in the varied applications of methylphenidate hydrochloride in psychiatry. Together, the articles address questions that have been of concern to clinicians and scientists alike. The scope of the clinical use of methylphenidate in adult psychiatry is addressed in the study by Spencer and associates 1 ; a potentially serious side effect (ie, tics) is examined carefully by Gadow et al 2 ; and Volkow and colleagues 3 report on some mechanisms of methylphenidate activity and their contribution to our understanding of the drug's effects. In an excellent review that appeared in theArchivesin 1987, Chiarello and Cole 4 summarize the manifold uses of methylphenidate, as well as those of other psychostimulants. Although the literature consisted mostly of less than See also pages 434, 444, 456, and 464 well-controlled studies conducted in imprecisely identified patient groups, the conclusions pointed to the likely usefulness of psychostimulants

Background: The purposes of this study were to investigate the pharmacokinetics of methylphenidate hydrochloride (Ritalin) in the human brain, to compare them with those of cocaine, and to evaluate whether cocaine and methylphenidate compete for the same binding sites. Methods: We used positron emission tomography to measure the temporal and spatial distribution of carbon 11 (11C)-labeled methylphenidate. These results were compared with those obtained previously for [11C]cocaine. Eight healthy male subjects, 20 to 51 years of age, were scanned with [11C]methylphenidate. Three were tested twice to assess test-retest variability, four were tested at baseline and after administration of methylphenidate, and one was tested with [11C]methylphenidate and [11C]cocaine. Two baboons were scanned to evaluate whether there was competition between cocaine and methylphenidate for the same binding sites in the brain. Results: The uptake of [ 11 C] methylphenidate in the brain was high (mean±SD, 7.5%±1.5%), and the maximal concentration occurred in striatum. Pretreatment with methylphenidate decreased binding only in striatum (40%). Although the regional distribution of [ 11 C]methylphenidate was identical to that of [ 11 C] cocaine and they competed with each other for the same binding sites, these two drugs differed markedly in their pharmacokinetics. Clearance of [ 11 C]methlphenidate from striatum (90 minutes) was significantly slower than that of [ 11 C]cocaine (20 minutes). For both drugs, their fast uptake in striatum paralleled the experience of the "high." For methylphenidate, the high decreased very rapidly despite significant binding of the drug in the brain. In contrast, for cocaine, the decline in the high paralleled its fast rate of clearance from the brain. Conclusion: We speculate that because the experience of the high is associated with the fast uptake of cocaine and methylphenidate in the brain, the slow clearance of methylphenidate from the brain may serve as a limiting factor in promoting its frequent self-administration.

Objective: To characterize the pathophysiology of schizophrenia and to identify biologic markers in first-episode patients with no or little prior treatment exposure. Design: Prospective study of an inception cohort. Setting: Psychiatric division of an academic medical center with a suburban metropolitan catchment area. Patients: 70 patients in their first episode of schizophrenia (77%) or schizoaffective disorder (23%) with no (70%) or limited prior neuroleptic exposure (30%), and 50 healthy volunteer control subjects. Assessment Measures: Demographic and clinical evaluations of natural history and psychopathology; methylphenidate hydrochloride and apomorphine hydrochloride stimulation tests as measures of central nervous system dopamine activity; brain magnetic resonance imaging; eyetracking examinations. Results: Preliminary analyses demonstrate that pathobiologic features previously identified in heterogeneous and primarily chronically ill patients are also present in subgroups during their first episode. These incude psy- chotogenic response to methylphenidate (59%), abnormal growth hormone (GH) secretion (50%), abnormal brain morphology (31%), and eye-tracking dysfunction (51%). An association of pathobiologic variables with increased symptom severity and earlier age of onset was observed but not statistically significant. The strongest associations among biologic variables were for the following: GH secretion and psychotogenic response to methylphenidate, which may reflect increased dopamine agonist neural activity; decreased GH response to apomorphine and thirdventricle enlargement, which may represent a neuropathologic correlate of anterior pituitary abnormalities; and morphologic abnormalities of the medial temporal lobe and third ventricle were associated with normal eye tracking, suggesting that these pathobiologic features are mediated by distinct processes. Conclusions: These phenomena appear to be a consequence of the disease rather than the effects of chronicity, drug treatment, or institutionalization. It remains to be determined if these biologic phenomena will remain stable over time or change with disease progression. A companion article examines the clinical significance of these findings.

Twenty-four hyperactive or unsocialized-aggressive children participated in an exploratory double-blind crossover study comparing the cognitive effects of methylphenidate hydrochloride (0.3 mg/kg), two doses (0.25 and 0.05 mg/kg) of haloperidol, and inert placebo. Each subject received each of four drug conditions, drug order being randomized by a Latin square design. At the end of each 18-day trial period, attention, immediate recognition memory, reaction times, and seat activity were tested. While drug effects were small, methylphenidate and, to a lesser extent, the low dose of haloperidol, facilitated performance, whereas there was some suggestion that the high dose of haloperidol may have caused a slight deterioration In performance. These results are contrasted with effects on social behavior where the latter improved behavior. No differences attributable to diagnosis were found.

• The short-term, dose-response effects of methylphenidate hydrochloride were evaluated on academic and social classroom measures in 29 children with attention deficit disorder. In a double-blind, cross-over design with order randomized, children received a placebo for two weeks and three doses of methylphenidate hydrochloride (0.15 mg/kg, 0.3 mg/kg, and 0.6 mg/kg) for one week each. Dependent measures included the output and accuracy of performance in grade-appropriate reading comprehension workbooks and arithmetic problems, spelling word acquisition, and observations of disruptive and on-task behavior. Beneficial drug effects and linear dose-response curves on all dependent measures were found. The results suggest that beneficial methylphenidate effects on classroom behavior may be accompanied by enhanced academic achievement in some hyperactive children.

— Actively psychotic schizophrenic and nonpsychotic psychiatric inpatients received intravenous methylphenidate hydrochloride (0.5 mg/kg). Each patient was rated for level of psychosis and talkativeness, and each received the Holtzman projective ink blot tests and the Kent-Rosanoff word-association tests before, during, and after methylphenidate infusion. Minnesota Multiphasic Personality Inventory Goldberg Index scores were also obtained as a general measure of psychosis. For the entire patient group, methylphenidate infusion was followed by a significant increase in talkativeness and psychosis ratings and in pathological responses to the Holtzman ink blot test. There was a significant decrease in common word associations. Since neither of the psychological tests allow more than one response per item, it appears that methylphenidate truly effects pathological thought processes and decreases common word associations as such, rather than merely making these processes more evident by increasing verbalization.

• Sixty-one children of average intelligence with appreciable learning lags, but no behavior disorders, received placebo or methylphenidate hydrochloride for a 12-week period. Methylphenidate was instrumental in improving performance on many psychological tests, but did not affect performance on standardized achievement tests. None of the patient characteristics investigated was strongly predictive of drug effect. Methylphenidate seems to have a specific effect on visualmotor processes, which in turn positively affect performance tasks, but not verbal tasks. Under the conditions of this study, methylphenidate treatment alone did not emerge as a useful agent for the amelioration of reading performance, although the data provide evidence for stimulant effects on children's cognitive functions.

• The objectives of this study were (1) to determine whether attention deficit disorder (ADD) is a specific diagnostic entity in adulthood; (2) to evaluate, using a double-blind crossover design, the efficacy of methylphenidate hydrochloride in adults with evidence of residual ADD with hyperactivity (ADD-H) (N = 26); and (3) to evaluate the specificity of drug response by also administering methylphenidate to patients with similar adult symptoms but no childhood history of ADD-H (N = 35). Results indicated success in differentiating relatively distinct groups. However, no overall benefit from methylphenidate was evident, regardless of childhood history of ADD-H. Approximately 25% of the sample appeared clinically to benefit from methylphenidate, but no clear-cut predictors of drug response were identified; history of drug abuse (polydrug) appeared to be the best predictor. Even among the responders, benefit was generally not as marked nor as clinically valuable as in childhood ADD-H.

• To examine the relationship of aminergic overactivity to information processing, we gave methylphenidate hydrochloride, oxazepam, or placebo to 12 nonpsychotic patients in one-week blocks in a double-blind, randomized design. Methylphenidate induced a pattern of information processing dysfunction similar to that seen in schizophrenic patients, strengthening the linkage of the schizophrenia—information processing dysfunction—aminergic overactivity relationship. Further, the time course of the observed deficits in both schizophrenic and methylphenidate-induced states is strikingly compatible with the temporal mapping pattern of monoaminergic neuronal systems. More research is needed to identify definitively the aminergic influences on attentional functioning. A psychophysical task—pharmacologic probe strategy should prove useful.

• The growth in height and weight of 86 hyperactive children receiving methylphenidate hydrochloride (average, 40 mg/day for up to four years) was compared with general population norms on recently updated growth charts. A significant decrease in height percentile was apparent after 2, 3, and 4 years of treatment but not after one year. A significant loss in weight percentile occurred onward from the first year of treatment. Dosage was significantly associated with the decrease in height and weight percentile. Greater initial height and weight were associated with greater growth decrements. The use of adjunctive thioridazine hydrochloride (mean, 87 mg/day) did not influence the growth of children receiving methylphenidate. Although the magnitude of the growth suppressant effect in groups was small (dosage accounted for only 2% of the variance in final height), the results suggest that clinicians should monitor the growth of hyperactive children receiving stimulants and consider dosage reduction in individual cases should evidence of growth suppression occur.

• The height of young adults who were treated with methylphenidate hydrochloride in childhood because of hyperactivity (average daily dose, 45 mg; duration of treatment, six months to five years) was studied. There was no significant difference in height between the treated patients (n =61) and controls (n =99); both groups were at the national US norm in stature. The findings indicated that methylphenidate therapy does not compromise final height, even when it has an adverse impact on children's growth rate during the active treatment phase. A compensatory growth rate, or growth rebound, appears to occur following discontinuation of stimulant therapy.

• Among the evidence supporting the dopamine hypothesis of schizophrenia is the finding that both amphetamine and methylphenidate hydrochloride, potent releasers of dopamine, can cause exacerbation of symptoms in the acute schizophrenic patient. The present report describes three experiments in which the effects of amphetamine in chronic schizophrenic patients were studied. In one of the experiments, orally administered, daily doses of 20 mg of dextroamphetamine sulfate given at 8 PM had little or no effect on the sleep duration of the subjects. In the other two experiments, doses up to 40 mg given orally also had little or no effect on the performance of the subjects on a variety of behavioral tests. There was no evidence of an exacerbation of the disease process in any of the subjects. The most consistent amphetamine effect was a dose-related increase in blood pressure. These results indicate that the chronic schizophrenic patient may be hyporesponsive to amphetamine and suggest that if the dopamine hypothesis is correct, then it must be modified to take into account these findings in the chronic patient.

• The value of neuroendocrine techniques for providing information regarding the pathophysiology of psychotic disorders is largely dependent on clarification of the relationships among psychologic state, neural activity, and neuroendocrine regulation. This study presents a strategy for examining the interface between neurochemical activity, psychologic state, and neuroendocrine regulation. Psychologic state and serum growth hormone (GH) and cortisol were monitored following administration of methylphenidate hydrochloride, a drug that appears to preferentially affect central dopamine regulation. While individuals varied in both their endocrine and psychologic responses to methylphenidate, the general effects were GH elevation, euphoria, and activation with elation, the most pronounced psychologic effect. Subjects who showed GH elevation became elated while those who did not show a GH response did not become elated. Elation and GH release following administration of methylphenidate may be mediated by the same neurochemical events.

• 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.

• This is a study of the growth of 72 hyperactive boys treated continuously with methylphenidate hydrochloride. Major findings were that methylphenidate produces an adverse effect on growth in height and in weight in the first year of treatment, but not in the second year; the first year height deficit is offset in the second year by a greater-than-expected growth rate. No clinical predictors of growth deficits were found; growth in height deficits are not related to total dosage or summer drug holidays, but weight deficits may be related to these factors. Side effects did not correlate with dosage. The temporary growth deficits of the first year are of such minor magnitude as to have little clinical significance.

• A half century after the introduction of amphetamine sulfate (benzedrine), there remains active interest in the use of the major psychostimulants (ie, methylphenidate hydrochloride and pemoline) for the treatment of psychiatric disorders. In the absence of any recent review of the literature on the clinical uses of psychostimulants, we assessed the existing data on the adult psychiatric indications for these agents. Generally, the existing studies are old and inadequate. However, there is some evidence to support the judicious use of psychostimulants in selected clinical instances of several adult psychiatric syndromes.

• The effects of three pharmacological treatments, methylphenidate hydrochloride, thioridazine hydrochloride, a methylphenidate/thioridazine combination, and placebo were studied in outpatient hyperkinetic children rated hyperactive both in school and at home or clinic. Active treatment lasted 12 weeks; placebo lasted four weeks. Significant clinical improvement was obtained in a variety of settings–all treatments were superior to placebo on ratings filled out by parents, teachers, and clinic staff. Though initially the combination of methylphenidate and thioridazine tended to produce greater clinical improvement, it was not superior to methylphenidate alone after 12 weeks of treatment. Methylphenidate alone and the methylphenidate/ thioridazine combination were more effective than thioridazine alone. The salient side effects with methylphenidate treatment were decrease in appetite, difficulty in falling asleep, and increased mood sensitivity. In contrast, thioridazine administration was associated with appetite increase and enuresis.

Double-blind crossover comparison of methylphenidate hydrochloride, dextroamphetamine sulfate, and caffeine after placebo washout in 29 children with minimal brain dysfunction (MBD) showed on six ratings that methylphenidate and dextroamphetamine were significantly (P less than .05 to P less than .001) better than placebo and caffeine, but not significantly (P less than .05) different from each other. Placebo, caffeine, and ratings before drug did not differ significantly. Of 26 drug responders, 12 responded best to dextroamphetamine, ten to methylphenidate, and one to caffeine. The latter child showed no improvement at all with either prescription stimulant. Methylphenidate and dextroamphetamine were each efficacious for six children who did not respond to the other stimulant. All three drugs showed significant (P less than .05) weight loss and cardiovascular side effects, the latter possibly spurious. Dextroamphetamine showed a significant (P less than .05) decrease from placebo in "tummyaches."

• Minimal brain dysfunction (MBD) has long been considered a disorder limited to childhood. A number of longitudinal and adoption studies suggest that MBD may persist into adult life where its existence is concealed by the application of a variety of diagnostic labels. In order to test the hypothesis that MBD does persist into adulthood, 15 putative MBD adults were identified on the basis of current MBD-like complaints, self-description of MBD characteristics in childhood, and a parental rating (on a standardized form) of "hyperactivity" in childhood. Eleven of the 15 subjects were given a double-blind trial of methylphenidate hydrochloride, and all 15 were given an open trial of pemoline, imipramine hydrochloride, or amitryptiline hydrochloride. Eight of the 11 showed a significant response to the double-blind trial of methylphenidate. Of the 15, eight showed a good response to stimulants or tricyclic antidepressants, two showed a moderately favorable response, and five were unresponsive to drug therapy.

• Children with attention deficit disorder with hyperactivity were given either methylphenidate hydrochloride or dextroamphetamine sulfate to compare the effects on urinary excretion of catecholamines, indoleamines, and phenylethylamine (PEA). Methylphenidate's effects were distinctly different from those of dextroamphetamine. After methylphenidate administration, both norepinephrine (NE) and normetanephrine (NMN) concentrations were significantly elevated, and there was a 22% increase in excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG). In contrast, after dextroamphetamine treatment, MHPG excretion was significantly reduced and NE and NMN values were unchanged. Excretion of dopamine and metabolites was unchanged by either drug. Urinary PEA excretion was not significantly changed after methylphenidate treatment, but increased 1,600% in response to dextroamphetamine. Methylphenidate treatment did not significantly alter serotonin or 5-hydroxyindoleacetic acid excretion. Effects of dextroamphetamine were not tested.

A double-blind outpatient study is reported comparing imipramine hydrochloride, methylphenidate hydrochloride, and placebo treatments of 76 hyperactive grade-school boys. In addition, the predrug behavioral evaluation is examined in detail to provide guidelines for clinics examining these children. Base line clinic evaluations showed the usefulness of the psychologist's global estimates of attention and behavior disorder, as these ratings predicted teacher rating of classroom behavior better than did psychiatric playroom observations. Parent four-day diaries of activity and family interaction also predicted teacher ratings and reflected response to stimulant medication. Although the global judgments of psychiatrists, psychologist, and the pediatrician indicated the superiority of both drugs to a placebo, all measures favored the stimulant drug. The significance of these findings may be limited, however, by the dose of imipramine hydrochloride (80 mg) that was lower than in use elsewhere.

• Methylphenidate hydrochloride dextroamphetamine sulfate, and levamfetamine succinate have potential as pharmacologic tools for the indirect evaluation of the role of neurotransmitters in schizophrenia. In actively ill schizophrenic patients, methylphenidate administered intravenously causes a brief but clear intensification of preexisting psychotic symptoms, such as hallucinations and delusions. In our study, methylphenidate, dextroamphetamine, and levamfetamine were administered in equimolar doses to schizophrenic patients. Methylphenidate was a more effective activator of symptoms than dextroamphetamine, which in turn was more effective than levamfetamine. Levodopa (L-dopa) given orally also reportedly produces a temporary worsening of schizophrenic symptoms. While these findings augment a body of information suggesting that dopamine and norepinephrine may play a role in the activation of schizophrenic symptoms, our findings with methylphenidate (reportedly weak in eliciting sterotyped behaviour in rat) and our review of the literature indicate complexities that remain to be resolved. There is some utility of the procedure for differential diagnosis and selective therapy, but this is still of occasional and limited potential.

Sixty-two children from economically deprived urban areas and diagnosed "hyperkinetic reaction of childhood" were studied in order to evaluate the effects of methylphenidate hydrochloride in this population. Methylphenidate was as effective in this population as it has been reported to be in children from different socioeconomic and cultural settings. Improvement was noted in many areas of the child's functioning, and was observed by the parents, the teachers, and the treating physician. Results of the study were further analyzed by dichotomizing the children according to the weekly variability in classroom hyperactivity over the 12-week treatment period. It was found that those children whose variability in weekly ratings of classroom hyperactivity was relatively high were seen as more of a problem by their parents at the base line evaluation than were the children whose treatment response tended to be less variable.