Animal models of self-injurious behaviour: an overview.

Self-injurious behaviour is highly prevalent in neurodevelopmental disorders. Interestingly, it is not restricted to any individual diagnostic group. Rather, it is exhibited in various forms across patient groups with distinct genetic defects and classifications of disorders. This suggests that there may be shared neuropathology that confers vulnerability. Convergent evidence from clinical pharmacotherapy, brain imaging studies, postmortem neurochemical analyses, and animal models indicates that dopaminergic insufficiency is a key culprit. This chapter provides an overview of studies in which animal models have been used to investigate the biochemical basis of self-injury, and highlights the convergence in findings between these models and expression of self-injury in humans.

The pemoline model of self-injurious behaviour.

Traditional models of neuropsychiatric disorders consist of attempts to replicate the broad spectrum of behavioural and neurochemical sequelae that characterize a specific disorder. However, these disorders comprise complex constellations of symptoms, including emotional instability, perseverative thoughts, and aberrant behaviours. Close examination often reveals heterogeneity of symptom expression within patient groups and homogeneity in expression of specific symptoms across diagnostic categories. Accordingly, it may not be possible to model the entire spectrum of characteristics for any one of these disorders in any single animal model. A focus on one or more specific behavioural characteristics (e.g. self-injury) may be a more fruitful strategy. Development of behaviourally focused models yields increased understanding of the genetic basis and biochemical abnormalities that underlie specific psychiatric dysfunctions. Furthermore, by revealing pathophysiology that underlies specific disease characteristics, behaviourally focused models improve translational power and help to identify targets for effective pharmacotherapies. One such behaviourally focused animal model is the pemoline model of self-injurious behaviour.

Eficacia del bupropión en el tratamiento de la dependencia de pemolina / Efficacy of bupropion in the treatment of pemoline dependence

Presentamos el caso de una mujer que solicita evaluación psiquiátrica por llevar 6 meses consumiendo pemolina en unas dosis de entre 100 y 150 mg/día, encontrándose con dificultades para abandonar el consumo de dicha sustancia. La instauración de 300 mg/día de bupropión resuelve la dependencia que tenía la enferma. Proponemos el uso de antidepresivos como el bupropión para el tratamiento de conductas adictivas sobre estimulantes del sistema nervioso central

We present the case of a woman who requested psychiatric evaluation because she had been taking pemoline for six months at a dose between 100-150 mg/day, and was finding it difficult to discontinue taking this substance. Initiation of 300 mg/day of bupropion solved the patient's dependence problem. We propose using antidepressants such as bupropion for the treatment of addictive behaviors due to central nervous system stimulants

Efficacy of bupropion in the treatment of pemoline dependence.

We present the case of a woman who requested psychiatric evaluation because she had been taking pemoline for six months at a dose between 100-150 mg/day, and was finding it difficult to discontinue taking this substance. Initiation of 300 mg/day of bupropion solved the patient's dependence problem. We propose using antidepressants such as bupropion for the treatment of addictive behaviors due to central nervous system stimulants.

Pemoline hepatotoxicity and postmarketing surveillance.

OBJECTIVE: To review the numerous reports of hepatotoxic adverse drug reactions (ADRs) ascribed to pemoline that were sent to the U.S. Food and Drug Administration (FDA) between 1975 and 1996 and to describe the medical community's lack of awareness of these reports. METHOD: All ADR reports from 1975 through 1996 wherein pemoline was the suspect agent were obtained from the FDA MedWatch Internet site, and some details of nine pemoline-related deaths in youths were obtained directly from the FDA. The published literature on this subject was fully reviewed. RESULTS: (1) In premarketing clinical trials with pemoline in the early 1970s, hepatic abnormalities were noted in enzyme levels (1%-3% of youths receiving maintenance treatment), during rechallenges (6 of 6), and in biopsies (2 of 2). (2) Between 1975 and 1989, 12 cases of jaundice and 6 deaths in youths ascribed to pemoline hepatotoxicity were reported to the FDA. (3) The first medical literature report of a serious ADR ascribed to pemoline was in a 1989 letter to the editor. (4) Physicians generally only became aware of serious pemoline hepatotoxicity in December 1996. (5) Pemoline use increased until 1997. CONCLUSION: Limitations in postmarketing surveillance and public reporting in the United States, particularly in the 1980s, largely accounted for delays in an appropriate response to pemoline hepatotoxicity.

Psychotic side effects of psychostimulants: a 5-year review.

OBJECTIVE: To examine the rate of psychotic and mood-congruent psychotic side effects of stimulant medications in children treated for attention-deficit hyperactivity disorder (ADHD). METHOD: A chart review was completed of all children diagnosed with ADHD in an outpatient clinic from January 1989 to March 1995. RESULTS: Over 5 years, 192 children were diagnosed with ADHD. Ninety-eight children received treatment at the clinic with stimulants. Six children developed psychotic or mood-congruent psychotic symptoms during treatment. Children on medication were followed for an average of 1 year and 9 months. CONCLUSIONS: Awareness of the potential for psychotic side effects from stimulant medications is important when prescribing for children. A large prospective study would be useful to predict the frequency and classification of the side effects in children.

Controlled trial of high doses of pemoline for adults with attention-deficit/hyperactivity disorder.

Despite the increasing awareness of attention-deficit/hyperactivity disorder (ADHD) in adults, there are a limited number of controlled pharmacologic studies of this disorder. Because the stimulant medication magnesium pemoline (Cylert, Abbott Laboratories, Abbott Park, IL) has been found effective in treating ADHD in pediatric groups, we tested its efficacy in adults with ADHD using higher daily doses than those previously studied. We conducted a 10-week, double-blind, placebo-controlled, crossover design study of pemoline at a target daily dose of 3 mg/kg per day in 35 adult patients with DSM-III-R and -IV ADHD. We used standardized structured psychiatric instruments for diagnosis. To measure improvement, we used separate assessments of ADHD, depressive, and anxiety symptoms at baseline and at each biweekly visit. ADHD outcome was determined using the ADHD symptom checklist and Clinical Global Impression scales of Severity and Improvement. Of the 35 adults with ADHD who were randomized in the trial, 27 (77%) completed the protocol. Treatment with pemoline in the final week of the 4-week active phase was best tolerated at doses substantially lower than the target dose of 3 mg/kg per day (mean dose, 2.2 mg/kg per day; mean+/-SD, 148+/-95 mg). Pemoline was significantly better at reducing ADHD symptoms compared with placebo (z = 2.4,p < 0.02). Using a predefined 30% reduction in symptoms as an indication of improvement, 50% of pemoline-treated subjects and 17% of subjects in the placebo group were considered positive responders (chi2 = 7.1, p = 0.008). These results indicate that pemoline is moderately effective in the treatment of ADHD in adults. Although robust doses were targeted, most adults preferred more moderate dosing (120-160 mg/day). Given the limited efficacy, tolerability, and concerns of hepatic dysfunction, pemoline should be considered as second-line medication for treating ADHD in adults.

Intensive and sustained air operations: potential use of the stimulant, pemoline.

BACKGROUND: Intensive and sustained military operations involve long periods of overnight work and the occasional use of a stimulant to maintain performance may be beneficial. In this context a dose response study was carried out to investigate the effects of pemoline, a dopamimetic agent, on overnight work and to assess potential residual effects on subsequent sleep. METHODS: Six healthy volunteers participated in a placebo-controlled, double-blind, cross-over trial involving a 12-h period of work during which subjective alertness and performance on a range of tasks were assessed at 1.5 h intervals following ingestion at 2000 hours of pemoline (10, 20, 30 and 40 mg) and, on two occasions, placebo. The work period was preceded by a 6-h sleep period with temazepam 20 mg, and followed by a 4-h recovery sleep with no medication. All sleep periods were recorded electroencephalographically. RESULTS: There was no difference between sleep periods preceding the work period. Subjective alertness and performance on all tasks deteriorated significantly during the work period, with the earliest impairments in performance observed at 0200 hours. Pemoline increased subjective alertness and performance on all but two tasks, compared with placebo. The onset of activity was seen 4.5 h after drug ingestion and alerting effects of 30 and 40 mg pemoline persisted beyond the work period, disturbing morning recovery sleep. Doses of 10 and 20 mg pemoline had no effect on recovery sleep. CONCLUSION: The present studies indicate that a 20 mg dose of pemoline may be suitable for maintaining nocturnal performance without having adverse effects on recovery sleep.

Pemoline in adult attention deficit hyperactivity disorder: predictors of nonresponse.

The psychostimulants are the most widely used treatment modality for attention deficit/hyperactivity disorder (ADHD). Although positive responses to psychostimulants have been demonstrated, 46% of adults with ADHD, on average, are nonresponsive or cannot tolerate the medications because of adverse effects. We reviewed the charts of 43 students treated with pemoline and studied parameters of nonresponse. Sixteen (37%) met the study definition of nonresponse. Of these 5 (12%) were symptom nonresponders and 11 (25%) were nonresponders because of adverse effects. We found a significant relationship between age and nonresponse resulting from adverse effects, yet no other factors predicted nonresponse to pemoline. Clinicians should consider using smaller starting doses of pemoline in adults to minimize adverse effects.

Pemoline-associated hepatic failure: a critical analysis of the literature.

Pemoline is a central nervous system (CNS) stimulant approved for use as part of the comprehensive medical management of attention deficit hyperactivity disorder (ADHD). An increased risk of acute hepatic failure is believed to be associated with pemoline usage, raising concerns about its prescription. A descriptive meta-analysis of the existing scientific literature and drug reporting databases was undertaken to provide more accurate understanding of this possible risk. The analysis appears to indicate that current assumptions of the risk of acute hepatic failure posed by pemoline usage alone are overestimates. Several recommendations regarding hepatic monitoring in the setting of pemoline prescription are provided.

Compliance with stimulant medications in patients with narcolepsy.

The goals of this descriptive study were to determine what percentage of our treated narcoleptic subjects took their stimulant medications as prescribed and to examine the relationship between compliance and response to stimulant medications. Data obtained from a screening questionnaire, sleep diaries, and medical records showed that 22 of our 43 treated narcoleptic subjects reduced their dosage of stimulant medications or had not taken any stimulant medications during a 24-hour monitoring period during which they were expected to be on medication. Although we had expected better compliance among subjects who responded to stimulant medications (day-wake subjects), statistical testing revealed no significant differences between the two groups. Nor were there any significant differences in age, gender, or educational level when compliant and noncompliant subjects were compared. Only the type of drug prescribed (short versus long-acting stimulant) affected compliance; 39.4% of the subjects with prescriptions for dextroamphetamine or methylphenidate took the amount of medication prescribed compared to 87.5% of the subjects with prescriptions for pemoline.

An open trial of pemoline in drug-dependent delinquents with attention-deficit hyperactivity disorder.

OBJECTIVE: Adolescents with conduct disorder and substance use disorders have high rates of comorbid attention-deficit hyperactivity disorder (ADHD); ADHD may contribute to the severity and persistence of substance use disorders and antisocial behaviors. Treatment of ADHD may help patients utilize substance and other behaviorally focused treatment. Yet little is known about the response of ADHD symptoms to psychopharmacological intervention in substance-dependent delinquents. METHOD: Pilot data are presented for 13 male adolescents with conduct disorder, substance use disorders, and ADHD, in a residential substance use treatment program. Patients were treated with pemoline. Scores from the Conners Hyperactivity Index and continuous performance tasks were obtained at baseline and after about 1 month of treatment with pemoline. Physical activity measurements were also assessed at baseline and 1 month. Postmedication assessments were obtained after at least 1 week at maximal dosage (1.2 to 3.3 mg/kg). RESULTS: Mean Conners Hyperactivity Index scores declined 13.9% (p < or = .002) and mean motility declined 7% (p < or = .04) with pemoline treatment. Continuous performance task scores did not change. CONCLUSIONS: Preliminary data indicate that pemoline may be a useful treatment for ADHD in substance-dependent delinquents; the authors propose a controlled trial of pemoline in such youths.

Pemoline effects on children with ADHD: a time-response by dose-response analysis on classroom measures.

OBJECTIVE: To evaluate the dose-response by time-response characteristics of pemoline (Cylert) on dependent measures of behavior and academic performance in a laboratory classroom. METHOD: After a 2-week baseline, a double-blind crossover design was used to compare placebo, 18.75 mg, 37.5 mg, 75 mg, and 112.5 mg of pemoline, q.a.m., with each dose administered for 1 week. Medication was given at 9:00 A.M., and performance was measured beginning immediately and beginning 2, 4, and 6 hours after ingestion. The dependent measures included number of math problems completed correctly, teacher-recorded rates of on-task behavior and noncompliance, and teacher ratings on an Abbreviated Conners Teacher Rating Scale. RESULTS: There were linear effects of medication, with pemoline doses greater than 18.75 mg having an effect beginning 2 hours after ingestion and lasting through the seventh hour after ingestion. CONCLUSIONS: Results are contrasted with widespread misbeliefs regarding pemoline's time course and efficacy.

Evaluation of treatment with stimulants in narcolepsy.

This paper briefly reviews sleep laboratory studies on the treatment efficacy of methylphenidate, pemoline, dextroamphetamine and methamphetamine. The literature indicates that 1) methylphenidate, dextroamphetamine, pemoline and methamphetamine objectively improve somnolence as measured by the Multiple Sleep Latency or Maintenance of Wakefulness Tests (MSLT or MWT); 2) pemoline, at doses up to 112.5 mg, is less effective in controlling somnolence than methylphenidate, dextroamphetamine and methamphetamine; 3) there are dose-dependent improvements in performance that parallel MSLT and MWT data; and 4) at the highest doses of stimulants studied to date, narcoleptics, although improved, still did not function on MSLT or MWT and most performance tests at levels comparable to those of control subjects. Future research designs should address issues of placebo effect, practice effects and the degree to which alertness and performance measures can be pharmacologically brought up to levels comparable to those of normal control subjects.

Pharmacodynamics of pemoline in attention deficit disorder with hyperactivity.

The onset, duration, and offset of pemoline action to improve cognitive performance is examined intensively in 25 prepubescent males suffering from attention-deficit disorder with hyperactivity (ADDH). The purpose was to characterize the pharmacodynamics of pemoline in ADDH patients through correlation of plasma pemoline concentration with psychometric measures of memory search efficiency and paired-associates learning, with the physiological effect of pemoline on dopaminergic transmission concurrently measured by analysis of plasma prolactin response. The effect of pemoline on neuroprocessing is apparent within the first 2 hours after administration with an inverse relationship between plasma pemoline and prolactin concentration present at hour one only (r = 0.84; p = 0.005). Pemoline therapy for 3 weeks does not significantly affect area under the curve for pemoline or prolactin nor did the effect on memory search efficiency decrease, suggesting no apparent tolerance.

Cognitive training in ADHD children: less to it than meets the eye.

This article reviews cognitive training studies that have been carried out with children with attention deficit-hyperactivity disorder (ADHD) during the past decade. The efficacy of cognitive training as a single intervention and as an adjunct to stimulant treatment is discussed. The impact of training on the cognitive, academic, and behavioral functioning of youngsters with ADHD is summarized. Although this treatment modality is inherently appealing, there is little empirical support for its clinical utility with children with hyperactivity.