Neurotoxic fragrance produces ceroid and myelin disease.

Acetyl ethyl tetramethyl tetralin (AETT), a component of soaps, deodorants, and cosmetics, produces hyperirritability and limb weakness in rats repeatedly exposed to the compound. Brain, spinal cord, and peripheral nerves are discolored blue, show progressive neuronal ceroid degeneration, and develop spectacular myelin bubbling. These neurotoxic properties of AETT provide the basis for industry's decision to withdraw the compound from consumer products. In addition, AETT offers the experimentalist a new probe to explore the etiology and pathogeneses of human ceroid and myelin diseases.

Dyskinesias elicited by methamphetamine: susceptibility of former methadone-consuming monkeys.

Rhesus monkeys with a history of drinking methadone but currently drug-free and control monkeys with no drug history were injected with methamphetamine hydrochloride (2 to 5 milligrams per kilogram of body weight). In six of seven monkeys which had consumed methadone the lowest dose immediately elicited pronounced oral dyskinesias virtually identical to those of human tardive dyskinesia. The control monkeys did not exhibit oral dyskinesias even after prolonged treatment with the highest dose. The clincial implications may be related to the functioning of brain dopaminergic systems.

Motor effects of copper in the caudate nucleus: reversible lesions with ion-exchange resin beads.

A method employing the use of ion-exchange resin beads is described for the punctate introduction of discrete amounts of various anions, cations, or zwitterions into given brain regions. A series of experiments utilizing the method to introduce ionic copper into the caudate nucleus with the resulting motor manifestations are discussed.

Morphine tolerance, physical dependence, and synthesis of brain 5-hydroxytryptamine.

Tolerance and physical dependence development to morphine in mice can be prevented by concomitant administration of cycloheximide. The fact that the rate of synthesis of brain 5-hydroxytryptamine (5HT) increases with tolerance to morphine suggests that the protein involved may be associated with 5HT synthesis. Inhibition of this synthesis with p-chlorophenylalanine markedly decreases tolerance and physical dependence development to morphine.

Melatonin and abnormal movements induced by L-dopa in mice.

Melatonin has blocked adventitious movements induced by L-dopa in intact mice. It has reversed the adventitious turning to the right, and it has induced running to the left in mice receiving L-dopa after a lesion in the right caudate nucleus.

Psychotropic drugs as behavioral teratogens.

Three psychotropic drugs were administered to pregnant rats and were then evaluated for their behavioral and reproductive effects in the offspring. Control rats received either saline or vitamin A. Prochlorperazine had the most disruptive effects on reproduction and growth, but had the least effect on behavior. Propoxyphene had no apparent effects on reproduction or growth, but produced a variety of behavioral changes. Fenfluramine was intermediate in its effects on reproduction and growth and had behavioral effects that were revealed in tests of preweaning development. The data suggest that systematic tests of behavior add important information to evaluations of reproductive toxicity that cannot, at present, be obtained by other means.

Pharmacokinetics of red blood cell phenothiazine and clinical effects. Acute dystonic reactions.

Pharmacokinetics of the phenothiazine, butaperazine, were studied in relationship to acute dystonic reactions. Dystonias appeared on falling drug concentrations, more than one half-life after plasma and red blood cell (RBC) peak butaperazine concentrations. Red blood cell butaperazine kinetics differentiated better than did plasma butaperazine levels those subjects in whom dystonias would develop from those in whom they did not. We conclude that RBC phenothiazine levels may more clearly reflect drug concentration at critical brain sites than do simple plasma drug levels. Furthermore, dystonic reactions may be the result of differential sensitivity of two or more receptor systems to receptor blockade by antischizophrenic agents.

Costs and benefits of two doses of fluphenazine.

The relative costs and benefits of low- and conventional-dose neuroleptic maintenance therapy were evaluated in a double-blind comparison of 5 and 25 mg of fluphenazine decanoate administered every two weeks. Subjects were 50 patients fulfilling DSM-III criteria for schizophrenic disorder who had been successfully maintained with 25 mg or less of fluphenazine decanoate. A one-year survival analysis disclosed that there were no statistically significant differences between the two doses insofar as preventing relapse. Patients receiving the higher dose appeared to feel more uncomfortable, as indicated by higher scores on subscales of the Hopkins Symptom Checklist-90. In addition, patients receiving the higher dose had higher side-effect scores. These findings suggest that a substantial proportion of patients who are presently maintained with 25 mg or less of fluphenazine decanoate every two weeks will do just as well with as little as 5 mg.

The long-acting phenothiazines.

Injected intramuscularly, the enanthane and decanoate esters of the phenothiazine fluphenazine are an effective treatment of the disordered behavior and thinking of schizophrenia. The decanoate preparation is not only slightly longer-acting but also has a smaller incidence of side-effects that the enanthate. The major adverse effect of these medications is the high frequency of extrapyramidal system disturbance. Since the 50% rate of failure of schizophrenic outpatients to take prescribed oral medications decreases treatment failure to about 20% with the use of long-acting injectable phenothiazines, this route of administration offers an advantage in patient management particularly applicable to community mental health systems. Moreover, parenteral administration of long-acting fluphenazine may be useful for patients who do not attain effective serum levels with medication taken orally because of metabolic or absorption difficulties.

Amphetamine-induced dopaminergic hypersensitivity in guinea pigs. Implications in psychosis and human movement disorders.

Following chronic amphetamine pretreatment, guinea pigs demonstrate an increased sensitivity to both d-amphetamine sulfate- and apomorphine hydrochloride-induced stereotyped behavior. This observation suggests that chronic exposure to high doses of a dopamine agonist (d-amphetamine) alters the response of the brain to the subsequent administration of both indirect (d-amphetamine) and direct (apomorphine) dopamine agonists. This altered response may be due to the development of dopamine receptor site hypersensitivity. Clinical evidence suggests that a similar agonist-induced hypersensitivity may play a role in the development of dyskinetic movement disorders and psychoses in humans following the chronic use of such dopamine agonists as amphetamine and levodopa.

Unusual neurotoxicity associated with amiodarone therapy.

One hundred two patients with recurrent, drug-refractory tachyarrhythmias were treated with amiodarone for nine +/- eight months (mean +/- SD) (range, one to 50 months). Forty-five patients exhibited some form of neurotoxic reaction that was severe enough in nine patients to require discontinuation of treatment or reduction in dosage of the drug. The most frequent neurotoxic findings were tremor (44 patients), peripheral neuropathy (ten patients), and ataxia (seven patients). Five patients developed unusual neurotoxic manifestations: brainstem dysfunction characterized by downbeat nystagmus, hemisensory loss and ataxia, severe dyskinesia, jaw tremor, and proximal myopathy. Neurophysiologic studies revealed varying degrees of predominantly demyelinating peripheral neuropathy. Neurotoxic symptoms improved after discontinuing treatment or decreasing the dosage of the drug. Age of the patient and total cumulative dose did not seem to be risk factors for development of neurotoxicity. These neurotoxic findings suggest that amiodarone-induced neurotoxic reactions are not only confined to the peripheral nervous system, but also that parts of the central nervous system (eg, basal ganglia, brain stem, or their connections) may also be involved.

The acute and chronic effect of 5-methoxytryptamine on selected members of a primate social colony.

The acute and chronic effect of 5-methoxytryptamine (5-MeOT), a structural analogue of known tryptamine hallucinogens and a substance found in mammalian brain, on nonhuman primate behavior was studied in a social colony of four Stumptail macaques. In the first study, dose-dependent behavioral changes induced by 5-MeOT were determined with the administration of seven acute doses to each animal. At higher doses, 10-20 mg/kg, 5-MeOT induced two abnormal or "emergent" behaviors, body shakes and limb jerks. 5-MeOT also induced a dose-dependent reduction in normal social and solitary behavior of treated animals suggesting that this drug has sedative properties. The second study examined the effect of once daily administration of 5-MeOT, 10 mg/kg, for 5 days. During this time, tolerance developed to both 5-MeOT-induced body shakes and limb jerks, but failed to develop to the reduction in social and solitary behaviors. Since body shakes and limb jerks are behaviors characteristically induced in this species by hallucinogens, these results suggest that 5-MeOT may possess hallucinogenic properties. However, this effect may be weak and may only occur after large doses since large doses of 5-MeOT were required to induce a relatively small number of body shakes and limb jerks in monkeys when compared to potent hallucinogens such as LSD and 5-MeODMT.

Amphetamine stereotypy: the influence of environmental factors and prepotent behavioral patterns on its topography and development.

This report describes a series of experiments, all of which demonstrate a strong contribution of the behavioral pattern manifested at the time of initial amphetamine injection to the topography and development of the stereotypy that develops with chronic amphetamine intoxication. These initial behavioral patterns reflect (i) learned behaviors, (ii) species-specific behaviors, (iii) behaviors associated with amphetamine arousal, and (iv) novel behaviors reflecting unique environmental circumstances prevailing at the time of administration. In an experiment using eight dogs administered amphetamine in a situation which allowed interaction between the animals, the behavioral stereotypies that developed were comprised of the social interaction patterns ongoing at the time of initial drug effects. Experiments with rats have demonstrated that the configuration of the enclosure in which they are injected influences the initial behavioral reactions to amphetamine and thus modifies the stereotypy. In experiments with cats pressing a lever to self-administer amphetamine, investigatory behavior at the lever-press operandi becomes incorporated as does the learned behavior response into the stereotypy. The behavioral patterns originally associated with amphetamine arousal eventually supersede the learned response component of the stereotypy. Finally, monkeys incorporate components of the initial behaviors associated with amphetamine administration into a wider range of stereotype patterns over months of chronic intoxication, and eventually the stereotypy may evolve into a specific dyskinesia involving movements of the original behavioral component.

Antidepressant withdrawal phenomena.

The authors review the antidepressant withdrawal literature. Withdrawal of tricyclic antidepressants may precipitate the development of discrete syndromes. The most common of these are general somatic or gastrointestinal distress with or without anxiety and agitation, sleep disturbance characterized by excessive and vivid dreaming and initial and middle insomnia, movement disorder, and psychic and behavioral activation extending on a continuum to frank mania. The etiology of these syndromes is discussed. The "cholinergic overdrive hypothesis" explains most antidepressant withdrawal phenomena, including infrequent manifestations. Some antidepressant withdrawal symptomatology may be due to an interaction between cholinergic overdrive and monoaminergic systems. A treatment program useful in ameliorating the distress of patients who develop antidepressant withdrawal symptoms and who cannot continue to take antidepressants is outlined. The theoretical significance of tricyclic withdrawal phenomena and the heuristic value of current hypotheses as to their pathophysiology are discussed.

Drug-related transient dyskinesias.

The ability of some antimalarials, especially chloroquine and amodiaquine, to provoke alarming but transient extrapyramidal movement disorders has been reported. The basis of the reported extrapyramidal symptoms has been the cause of some speculation. This paper reviews case reports and presents some data of the regional uptake of chloroquine in mammalian brain as a factor to consider, along with other factors that could influence the action of chloroquine on the extrapyramidal system. A neuropharmacologic mechanism for the transient extrapyramidal disturbances has been formulated.

Computerized tomography in patients with tardive dyskinesia.

The author reviews the results of computerized tomography performed on eight patients with tardive dyskinesia to determine whether there was permanent structural damage. No significant abnormalities were found. Although it may not be useful in routine workups, this new noninvasive technique might be helpful in differential diagnosis, and its increasing sophistication may suggest further research on tardive dyskinesia.

Maintenance antipsychotic therapy: is the cure worse than the disease?

The serious long-term complications of maintenance antipsychotic therapy led the authors to undertake a critical review of outpatient withdrawal studies. Key findings included the following: 1) for a least 40% of outpatient schizophrenics, drugs seem to be essential for survival in the community; 2) the majority of patients who relapse after drug withdrawal recompensate fairly rapidly upon reinstitution of antipsychotic drug therapy; 3) placebo survivors seem to function as well as drug survivors--thus the benefit of maintenance drug therapy appears to be prevention of relapse; and 4) some cases of early relapse after drug withdrawal may be due to dyskinesia rather than psychotic decompensation. The authors urge clinicians to evaluate each patient on maintenance antipsychotic therapy in terms of feasibility of drug withdrawal and offer practical guidelines for withdrawal and subsequent management.

Atypical tardive dyskinesia.

The author reports an atypical case of tardive dyskinesia in a 19-year-old male who had been given relatively low dosages of neuroleptic medication for less than 6 months. The symptoms cleared within 3 months after the medication was discontinued. The author reviews the literature regarding similar atypical cases and suggests that increased reporting and careful description of such cases might be useful in furthering our understanding of this syndrome.

Deanol in the treatment of tardive dyskinesia.

A patient who developed severe tardive dyskinesia after the termination of long-term phenothiazine therapy was successfully treated with deanol, a possible precursor of acetylcholine. Physiological measurements were obtained to quantify the clinical course. The authors discuss the practical and heuristic implications of these observations and suggest further consideration of therapy directed toward enhancement of cholinergic activity in the central nervous system.

Case report of a toxic reaction from a combination of tryptophan and phenelzine.

The addition of tryptophan to a monoamine oxidase inhibitor (MAOI) has been recommended for patients failing to respond to an MAOI alone. The authors report acute behavioral and neurologic toxicity immediately after tryptophan administration in a patient taking phenelzine.