Bupropion hydrochloride in attention deficit disorder with hyperactivity.

OBJECTIVE: This is a multisite, double-blind, placebo-controlled trial to determine the safety and efficacy of bupropion in the treatment of children with attention deficit disorder with hyperactivity (ADDH). METHOD: In a four-center, double-blind comparison of bupropion (n = 72) and placebo (n = 37), children aged 6 to 12 years meeting DSM-III criteria for ADDH were randomized to receive bupropion 3 to 6 mg/kg per day or placebo, administered twice daily, at 7 A.M. and 7 P.M. Measures of efficacy included the Conners Parent and Teacher Questionnaires (93-item, 39-item, and 10 item), Clinical Global Impressions Scales of Severity and Improvement, the Sternberg Short-Term Memory Task, and the Continuous Performance Test. Screen and posttreatment physical examinations, electrocardiograms, electroencephalograms, and clinical laboratory evaluations were performed. Height, weight, and vital signs were measured and adverse experiences were assessed weekly. RESULTS: A significant treatment effect, apparent as early as day 3, was present for both conduct problems and hyperactivity on the Conners 10-item and 39-item teacher's checklist, and at day 28 for conduct problems and restless-impulsive behavior on the 93-item parent questionnaire. Findings were of smaller magnitude for parent ratings than teacher ratings. Significant treatment effects were present on both the Continuous Performance Test and memory retrieval test. Effect sizes of bupropion/placebo differences for teacher and parent ratings in this study were somewhat smaller than for standard stimulant drugs used to treat ADDH. Bupropion appeared to be well tolerated in most children. Dermatological reactions were twice as frequent in the drug group as the placebo group, with four reactions involving rash and urticaria that were serious enough to require discontinuation of medication. CONCLUSIONS: Bupropion may be a useful addition to available treatments for ADDH. Comparative trials with such standard drugs as methylphenidate are warranted to determine the relative clinical merits of bupropion.

Naltrexone and self-injurious behavior: a retrospective population study.

The results of studies of the opiate antagonist naltrexone (NLTX) in the treatment of self-injurious behavior (SIB) in mentally retarded people have been equivocal. They have relied on small patient samples in short-term trials with varying degrees of scientific rigor. Nor has the clinical efficacy of NLTX for SIB been tested against its wider application in nonresearch settings. The present study is a retrospective, long-term study of the clinical use of NLTX for SIB, drawn from clinical experience in the entire population of the state schools of Texas (population = 8,000). More than 50% of the 56 SIB individuals treated with NLTX were maintained on the drug by virtue of clinical benefit perceived by treating professionals; 25% of the 56 individuals could be classified as unequivocal responders based upon strict objective response criteria. Variables associated with positive response were level of disability and lack of concurrent aggression. Unexpectedly, all of the objective responders displayed a gradual and continuous decrease in SIB over-time, even after 3 years of treatment.

Neurobehavioural performance of adults with closed-head injury, adults with attention deficit, and controls.

The symptoms experienced by people with mild closed-head injury (mCHI) and by people with attention deficit disorder (ADD) are similar in many aspects. We examined the performance of 26 adults with mCHI, 23 adults with ADD, and 25 matched controls on four functional areas: (1) simple motor response, (2) response speed and attention, (3) complex perceptual-motor performance, and (4) memory and learning. Analyses of variance and multivariate analyses of variance were used to compare the performance of the three groups. Test results were also plotted to examine patterns of performance and similarities between the groups. Both groups with mCHI and ADD had significantly more difficulty than controls with sustained attention. However, whereas the group with mCHI was characterized by generalized slowness in their response times, the group with ADD was characterized by impulsivity or an inability to regulate their attention and responses.

Association between patient report of symptoms after mild head injury and neurobehavioural performance.

Patients with closed-head injuries may have physical, affective, behavioural and memory problems that persist for weeks, months or years. Even patients with minor head trauma have been found to exhibit deficits in neurobehavioural performance. However, very little research has been done to examine the association between patient symptoms after minor head injury and neurobehavioural performance. The associations between five sets of symptoms (memory problems, neurological problems, confusion, neurasthenia and co-ordination) and five neurobehavioural areas (simple motor speed, response speed and attention, complex perceptual motor performance, visual memory, and learning) were examined in a group of 32 adults who had suffered mild to moderate head injury. Patients reported their symptoms with a four-point rating scale. Neurobehavioural functioning was assessed using computerized tests. Memory difficulties were the problems most frequently experienced by the patients and most closely associated with performance deficits.

The problem of tardive akathisia.

Akathisia is a disorder characterized by restlessness and dysphoria. Neuroleptic-induced akathisia is one of the acute extrapyramidal reactions caused by neuroleptic drugs, and tardive akathisia (TDAK) is a tardive dyskinesia (TD) variant caused by long-term neuroleptic treatment. Since TDAK is a movement disorder with a psychological dimension, it merits consideration as one of the behavioral variants of TD. TDAK is considered in light of an ongoing, prospective study in mentally retarded people. It is discussed in terms of the "cognitive" functions of the basal ganglia, and the known consequences of other diseases of the basal ganglia that almost invariably cause behavioral and cognitive deterioration.

Clinical and neuropsychological effects of desipramine in children with attention deficit hyperactivity disorder.

Desipramine is a tricyclic antidepressant with demonstrated efficacy for some children with attention deficit hyperactivity disorder (ADHD). In this controlled study, clinical improvement was noted in a group of 12 ADHD children. There also were neuropsychological effects associated with desipramine treatment: a small but significant decline in motor performance and an improvement in long-term verbal memory. The decline in motor performance may be of only limited clinical significance, but it is an effect that desipramine seems to share with other tricyclic antidepressants. The improvement in memory performance is an effect it shares with the psychostimulants.

The functional neuroanatomy of psychiatric treatments.

The attraction of this kind of model-building is its rigor. There is an unhealthy indiscipline to psychiatry as long as it remains purely phenomenologic. Clouds are described, then other clouds; then they are related, one to another; then new clouds form, and they too are described. It is a process that could go on forever, but it is too nebulous to win support for very much longer. In contrast, psychiatry that is based on etiopathogenesis, on brain maps, has rigor. It is either true or untrue, like the three models presented above. If it is true, like the frontal lobe hypothesis of dopamine agonists, it will lead somewhere. If it is only a small part of the truth, like the kindling theory of temporal lobe drugs, it will be supplanted, before long, by a more cogent hypothesis. What is more attractive about this kind of thinking, however, is the practical side of it. The KBS hypothesis of autism is not simply an idle exercise. It is a guide to a specific approach to behavioral treatment and a warning to eschew the mindless search for a pharmacologic "bullet." Theories, like every other living thing, have to do something useful before they are ultimately set aside. At least this one lends some common sense to day-to-day events.

Pharmacotherapy for self-injurious behavior: preliminary tests of the D1 hypothesis.

1. The D1 dopamine hypersensitivity model of self-injurious behavior leads to a testable clinical hypothesis: that the mixed D1/D2 dopamine antagonist fluphenazine may improve the symptoms of self-injurious patients. 2. The hypothesis was tested in an open pilot trial in six patients and a partially controlled trial in nine patients. 3. Some degree of clinical improvement was observed in eleven of the fifteen. 4. The trials represent a partial affirmation of the D1 hypothesis. However, it is also clear that conventional methodology for psychopharmacologic research is inappropriate for the proper clinical evaluation of self-injurious patients. The proper method should include the following elements: i) An epidemiologically representative sample ii) A naturalistic study environment iii) A longitudinal design with long-term follow-up iv) Concurrent behavioral ratings using direct observations and a reliable, treatment-sensitive rating scale. 5. Before subjects enter a clinical trial of an experimental medication, a neuropsychiatric differential diagnosis should be applied to limit the diversity of the sample.

The differential diagnosis of self-injurious behavior in mentally retarded people.

Self-injurious behavior (SIB) is sometimes presented as if it were a unitary behavioral entity. It is this assumption that leads to impunity in clinical trials of SIB patients, who are thought to be a homogeneous group. In fact, nothing could be further from the truth. SIB is no more than the occasion for a neuropsychiatric differential diagnosis; first to consider environmental and medical circumstances that may induce SIB; then specific, diagnosable conditions from neurology and psychiatry; then specific syndromes like Lesch-Nyhan and Cornelia de Lange; and then for "idiopathic" cases, the alternative neuro-chemical hypotheses. The goal of differential diagnosis is not only to guide treatment, but also to improve subject homogeneity in clinical trials.

Pharmacotherapy for self-injurious behavior: preliminary tests of the D1 hypothesis.

The D1 dopamine hypersensitivity model of self-injurious behavior leads to a testable clinical hypothesis: the mixed D1/D2 dopamine antagonist fluphenazine may improve the symptoms of self-injurious patients. The hypothesis was tested in an open pilot trial in six patients and a partially controlled trial in nine patients. Some degree of clinical improvement was observed in 11 of the 15 patients. The trials represent a partial affirmation of the D1 hypothesis. However, it is also clear that conventional methodology for psychopharmacologic research is inappropriate for the proper clinical evaluation of self-injurious patients. The proper method should include the following elements: 1. An epidemiologically representative sample. 2. A naturalistic study environment. 3. A longitudinal design with long-term follow up. 4. Concurrent behavioral ratings using direct observations and a reliable, treatment-sensitive rating scale. Before subjects enter a clinical trial of an experimental medication, a neuropsychiatric differential diagnosis should be applied to limit the diversity of the sample.

Stimulant treatment for the neurobehavioural sequelae of traumatic brain injury.

The subject of stimulant treatment for patients with neurobehavioural sequelae of traumatic brain injury (TBI) has received a good deal of recent attention, although there have to date been no controlled studies published. This is a description of 15 TBI patients who received treatment with the psychostimulant methylphenidate, in a double-blind, placebo-controlled cross-over study, with behavioural and neuropsychological ratings. Three subjects remained on the drug for a year after the acute study, and were subsequently studied in a double-blind, placebo-controlled reversal. The results support the idea that at least some symptomatic improvement may be gained from low-dose stimulant treatment, although the statistical analysis of the data was compromised by the occurrence of carryover effects from one drug condition to another. This, in itself, is an interesting discovery, because such effects have never been observed in stimulant studies of other patient groups. There are clear implications for the design of further studies in this area. The long-term effects of methylphenidate treatment were not at all impressive, however. Although the findings presented below may be subject to differing interpretation, it is conceivable that stimulants act to advance the course of cortical recovery following TBI.

Amantadine for the agitated head-injury patient.

Traumatic brain injury may be associated with agitated aggressive behaviour and the potential for injury to the patient and staff. We report two cases of recovering brain injury patients with difficult-to-treat destructive behaviour, whose agitation and aggression responded to amantadine. Direct-acting dopamine agonists such as amantadine may be the preferred treatment for patients with behaviour problems in the acute stages of recovery from coma.

Motor performance in hyperactive children treated with imipramine.

The effects of the tricyclic antidepressant imipramine were evaluated in a study of 9 children with Attention Deficit-Hyperactivity Disorder. The study was double-blind, placebo-controlled, with three drug conditions, low, medium, and high doses. The focus was on neuropsychological drug effects. Imipramine exerted negative dose-response effects on motor performance (motor speed, motor pursuit), while it improved hyperactive behavior and attention and raised the heart rate slightly.

Pharmacotherapy and the neurobehavioural sequelae of traumatic brain injury.

Recent advances in clinical neuropharmacology are likely to improve the treatment and rehabilitation of traumatic brain injury (TBI) patients. Treatment may be directed to alleviate specific symptoms, to improve function in certain areas, or even to enhance the cortical recovery process. The author reviews pertinent issues in clinical neuropharmacology for the following drug classes: stimulants, other dopamine agonists, antidepressants, lithium, cholinergics, neuroleptics, anticonvulsants, beta-blockers, calcium channel blockers, nootropes, opiates and neuropeptides. Since the relevant research literature in TBI is so sparse, information and recommendations are extrapolated from some other patient groups, especially developmentally handicapped children and adults, and patients with dementia.