Severity Of Abnormal Involuntary Movements Research Articles

3H]-NFPS binding to the glycine transporter 1 in the hemi-parkinsonian rat brain.

L-3,4-dihydroxyphenylalanine (L-DOPA) is the main treatment for Parkinson's disease (PD) but with long term administration, motor complications such as dyskinesia are induced. Glycine transporter 1 (GlyT1) inhibition was shown to produce an anti-dyskinetic effect in parkinsonian rats and primates, coupled with an improvement in the anti-parkinsonian action of L-DOPA. The expression of GlyT1 in the brain in the dyskinetic state remains to be investigated. Here, we quantified the levels of GlyT1 across different brain regions using [3H]-NFPS in the presence of Org-25,935. Brain sections were chosen from sham-lesioned rats, L-DOPA-naïve 6-hydroxydopamine (6-OHDA)-lesioned rats and 6-OHDA-lesioned rats exhibiting mild or severe abnormal involuntary movements (AIMs). [3H]-NFPS binding decreased in the ipsilateral and contralateral thalamus, by 28% and 41%, in 6-OHDA-lesioned rats with severe AIMs compared to sham-lesioned animals (P < 0.01 and 0.001). [3H]-NFPS binding increased by 21% in the ipsilateral substantia nigra of 6-OHDA-lesioned rats with severe AIMs compared to 6-OHDA-lesioned rats with mild AIMs (P < 0.05). [3H]-NFPS binding was lower by 19% in the contralateral primary motor cortex and by 20% in the contralateral subthalamic nucleus of 6-OHDA-lesioned rats with mild AIMs animals compared to rats with severe AIMs (both P < 0.05). The severity of AIMs scores positively correlated with [3H]-NFPS binding in the ipsilateral substantia nigra (P < 0.05), ipsilateral entopeduncular nucleus (P < 0.05) and contralateral primary motor cortex (P < 0.05). These data provide an anatomical basis to explain the efficacy of GlyT1 inhibitors in dyskinesia in PD.

Caregiver-Reported Burden in RE-KINECT: Data From a Prospective Real-World Tardive Dyskinesia Screening Study.

RE-KINECT (NCT03062033), a real-world study of possible tardive dyskinesia (TD) in antipsychotic-treated patients, included a questionnaire to assess the effects of patients' abnormal involuntary movements on caregivers. To capture the experiences of caregivers who assisted individuals with abnormal involuntary movements that were confirmed by clinicians as being consistent with TD. Qualified (nonpaid) caregivers were invited to complete a questionnaire that included the following: caregivers' sociodemographic characteristics, their perceptions about the impact of abnormal involuntary movements on patients, and the impact of these movements on themselves (caregivers). Of the 41 participating caregivers, 25 (61.0%) were women, 20 (48.8%) were employed full time or part time, and 35 (85.4%) were family members or friends. Based on responses from caregivers who noticed patients' abnormal involuntary movements and were caring for individuals who also noticed those movements, 48.0% of patients had "a lot" of severity in ≥1 body region and 76.0% had abnormal involuntary movements in ≥2 regions. Caregiver ratings were significantly correlated with patient ratings (but not with clinician ratings) for maximum severity of abnormal involuntary movements and the number of affected regions (both p <.05). Based on their own judgments and perceptions, caregivers reported that the patient's movements had "some" or "a lot" of impact on their (caregiver's) ability to continue usual activities (50.0%), be productive (58.3%), socialize (55.6%), or take care of self (50.0%). Caregivers as well as patients are negatively affected by TD, and the impact of TD on caregivers' lives should be considered when determining treatment options.

Real-world data on paliperidone palmitate for the treatment of schizophrenia and other psychotic disorders: a systematic review of randomized and nonrandomized studies.

The aim of this study was to perform a systematic review of the effects of 1-month paliperidone palmitate (PP1M) for the treatment of schizophrenia and related psychotic disorders in terms of outcomes reported in real-world evidence studies. A systematic review of real-world randomized and nonrandomized studies with PP1M was performed and is reported according to PRISMA guidelines. Comparative effectiveness data with oral antipsychotics indicate that PP1M has a lower likelihood of relapse-related events, including rehospitalization, and these differences are clinically relevant. A randomized, double-blind study showed that PP1M has no advantage over haloperidol decanoate in the time to treatment failure. Although there was a marked variability across studies, PP1M was not superior to other antipsychotics in terms of study completion rates. Pharmacoeconomic data show that, during a follow-up period of 12 months, the mean total healthcare cost was not significantly different in patients treated with PP1M compared with those receiving oral antipsychotics. The mean maximum prolactin levels were significantly higher with PP1M than with haloperidol decanoate; however, neither drug differs in the frequency of prolactin-related adverse events. Results on prolactin-related adverse events were inconsistent in two randomized comparisons with oral antipsychotics and were not reported in a randomized comparison with aripiprazole. There were no significant differences between haloperidol decanoate and PP1M in the severity of abnormal involuntary movements and parkinsonism, or in the incidence of tardive dyskinesia; however, patients treated with haloperidol decanoate showed greater worsening of akathisia and required treatment for parkinsonism and akathisia significantly more frequently than patients who received PP1M. In conclusion, real-world data that originate from both pragmatic randomized clinical trials and observational studies indicate that PP1M is superior to oral antipsychotics in delaying the time to relapse or treatment failure. Furthermore, the pharmacoeconomic data reviewed for this article suggest that the advantages of PP1M compared with oral antipsychotics are not associated with an increased total cost for healthcare providers.

Levodopa infusion does not decrease the onset of abnormal involuntary movements in parkinsonian rats

The short duration of effect of levodopa is linked to pulsatile stimulation of striatal dopamine receptors and dyskinesia induction. However, the recent introduction of intraduodenal (i.d.) infusions and novel oral controlled release formulations of l-dopa may prevent dyskinesia induction and reduce the severity of established involuntary movements. We have compared the effects of twice-daily intraperitoneal (i.p.) administration and daily i.d. infusion of l-dopa on the induction and expression of abnormal involuntary movements in 6-hydroxydopamine (6-OHDA)-lesioned rats. Animals were treated with either twice-daily i.p. administration of l-dopa/carbidopa (7.85/12.5 mg/kg) or an 8-hour i.d. infusion of l-dopa/carbidopa (20/5 mg/mL; infusion rate: 0.04 mL/h) for 14 days, after which treatments were switched between groups and continued for a further 14 days. Pulsatile i.p. administration of l-dopa induced moderate to severe abnormal involuntary movements, which gradually increased in severity over the 14 days, but i.d. infusion of l-dopa induced abnormal involuntary movements of a similar severity. Switching from continuous i.d. to pulsatile i.p. administration of l-dopa continued to provoke severe abnormal involuntary movements expression. Switching from pulsatile i.p. to continuous i.d. l-dopa administration did not alter the peak abnormal involuntary movement severity but tended to reduce their duration. Treatment with less pulsatile l-dopa administration using i.d. infusion does not reduce the risk of the appearance of dyskinesia. By contrast, the duration of established dyskinesia can be reduced by more continuous l-dopa delivery in agreement with clinical experience.

Retigabine, a K V7 (KCNQ) potassium channel opener, attenuates l-DOPA-induced dyskinesias in 6-OHDA-lesioned rats

l-DOPA-induced dyskinesias (LID) represent a severe complication of long-time pharmacotherapy in Parkinson's disease that necessitates novel therapeutics. The acute and chronic effects of K V7.2–7.5 channel openers (retigabine, flupirtine) on the severity of LID and parkinsonian signs were examined in comparison to the glutamate receptor antagonist amantadine (positive control) in a rat model of LID. Acute treatment with retigabine (2.5, 5 mg/kg i.p.) and flupirtine (5, 10 mg/kg i.p.) significantly reduced the severity of abnormal involuntary movements (AIM) to a comparable extent as amantadine (20, 40 mg/kg s.c.), but flupirtine delayed the disappearance of AIM. Chronic treatment with retigabine (daily 5 mg/kg i.p. over 19 days combined with l-DOPA 10 mg i.p.) did not prevent or delay the development of LID, but reduced the severity of AIM, while antidyskinetic effects of amantadine (40 mg/kg i.p.) were restricted to the first day of treatment. Retigabine caused sedation and ataxia which declined during the chronic treatment, but did not reduce the antiparkinsonian effects of l-DOPA in these experiments. Acute co-injections of retigabine (5 mg) together with l-DOPA (10 mg/kg) neither reduced the motor performance in the rotarod test nor exerted negative effects on the antiparkinsonian efficacy of l-DOPA in the block and stepping test. Nevertheless, the sedative effects of retigabine may limit its therapeutic potential for the treatment of LID. The present data indicate that K V7 channels deserve attention in the research of the pathophysiology of dyskinesias. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

Impact of the lesion procedure on the profiles of motor impairment and molecular responsiveness to L-DOPA in the 6-hydroxydopamine mouse model of Parkinson's disease

6-Hydroxydopamine (6-OHDA) lesions are being used in the mouse for basic research on Parkinson's disease and L-DOPA-induced dyskinesia. We set out to compare unilateral lesion models produced by intrastriatal or intramesencephalic injections of a fixed 6-OHDA concentration (3.2μg/μl) in C57BL/6 mice. In the first experiment, toxin injections were performed either at two striatal coordinates (1 or 2μl per site, termed “striatum2×1μl” and “striatum2×2μl” models), in the medial forebrain bundle (MFB), or in the substantia nigra pars compacta (SN) (1μl per site). All the four lesion models produced significant forelimb use asymmetry, but spontaneous turning asymmetry only occurred in the MFB and striatum2×2μl models. After the behavioral studies, the induction of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) by acute L-DOPA (30mg/kg) was used as a marker of post-synaptic supersensitivity. Striatal pERK1/2 expression was sparse in the SN and striatum2×1μl groups, but pronounced in the striatum2×2μl and MFB-lesioned mice. In further experiments, mice with MFB and striatal2×2μl lesions were used to compare behavioral and molecular responses to chronic L-DOPA treatment (12days at 3 and 6mg/kg/day). Maximally severe abnormal involuntary movements (AIMs) occurred in all MFB-lesioned mice, whereas only 35% of the mice with striatal lesions developed dyskinesia. Striatal tissue levels of dopamine were significantly lower in the dyskinetic animals (both MFB and striatum2×2μl groups) in comparison with the non-dyskinetic ones. Noradrenaline levels were significantly reduced only in MFB lesioned animals and did not differ among the dyskinetic and non-dyskinetic cases with striatal lesions. In all groups, the L-DOPA-induced AIM scores correlated closely with the number of cells immunoreactive for tyrosine hydroxylase or FosB/∆FosB in the striatum. In conclusion, among the four lesion procedures examined here, only the MFB and striatum2×2μl models yielded a degree of dopamine denervation sufficient to produce spontaneous postural asymmetry and molecular supersensitivity to L-DOPA. Both lesion models are suitable to reproduce L-DOPA-induced dyskinesia, although only MFB lesions yield a pronounced and widespread expression of post-synaptic supersensitivity markers in the striatum.

An improved model to investigate the efficacy of antidyskinetic agents in hemiparkinsonian rats

A number of experimental models of L-DOPA-induced dyskinesia have been proposed, but these models result in a low to medium rate of dyskinetic animals with mild to severe symptoms. The objective of this study was to combine a model of 6-OHDA-induced parkinsonism and of L-DOPA-induced dyskinesia in rats to establish a reliable preclinical model. Two stereotaxic injections of 6-OHDA were administered in the left striatum. This model led to 90-100% of rats with a marked contralateral circling behaviour, significant limb use asymmetry (20%), a decrease in ipsilateral striatal dopamine content (70%) and degeneration of dopamine neurons in the substantia nigra (70%). Chronic treatment with L-DOPA was administered for 35 days and consisted of three phases with incremental daily doses. The third phase resulted in 83-90% of rats developing severe abnormal involuntary movements (AIMs) which included limb and locomotive dyskinesia, axial dystonia and orolingual dyskinesia. Reproducibility of the model, criteria of strict blinding, placebo-controlled design, randomization of study subjects and pretrial determination of sample size were used to measure efficacy of amantadine and istradefylline and to validate the protocol design. Acute or subchronic post-treatment with amantadine reduced the severity of dyskinesia while istradefylline punctually attenuated AIMs. Our experimental conditions using gradual development of dyskinesia induced by increasing doses of L-DOPA resulted in a reliable model of L-DOPA-induced dyskinesia with a high rate of dyskinetic rats.

Amphetamine-induced abnormal movements occur independently of both transplant- and host-derived serotonin innervation following neural grafting in a rat model of Parkinson's disease

Serotonin has been postulated to play a role in the transplant-induced involuntary movements that occur following intrastriatal grafts of ventral mesencephalic tissue in the treatment of Parkinson's disease. Serotonin innervation of the striatum may be derived from either the donor graft tissue or the normal host projections from the midbrain. In two sets of experiments we study the impact of graft- versus host-derived serotonin innervation. All experiments were performed in l-DOPA treated rats with unilateral 6-hydroxydopamine lesions. As expected, following intrastriatal transplantation of embryonic ventral mesencephalon all the transplanted rats exhibited pronounced contralateral rotation in response to amphetamine and some animals also showed severe abnormal involuntary movements (AIMs). In the first set of experiments, all types of AIMs (axial, limb, orolingual and locomotor) were markedly reduced when amphetamine was co-administered with either the D 2 dopamine receptor antagonist raclopride or the D 1 receptor antagonist SCH23390. Cotreatment with the 5-HT 1A agonist 8-OH-DPAT significantly attenuated the amphetamine-induced axial and limb dyskinesias, whilst locomotor scores remained unchanged. These data point to a major role for dopamine receptors, and to a modulatory role for 5-HT 1A receptors, in post-grafting dyskinesias. In the second experiment, grafted rats exhibiting amphetamine-induced dyskinesia were subjected to 5,7-dihydroxytryptamine injections into the midbrain in order to destroy the host serotonin innervation. This intervention had no effect on either amphetamine-induced AIMs or contralateral rotation. Histological examination of all grafted rats showed similar numbers of dopaminergic neurons and a very low number of serotonin neurons within the transplants, regardless of AIMs expression. Our results suggest that amphetamine-induced AIMs in grafted animals primarily depend on an activation of dopamine receptors, and that serotonin neurons within either the grafts or the host brain play a negligible role.

Result of chronic levodopa therapy and its modification by bromocriptine in Parkinson's disease.

15 years' experience with Parkinson's disease treated with levodopa was compared to the 15 years before the advent of levodopa. Progression to severe disability and death was prolonged, at each stage of severity, by 3 to 5 years. At each duration of illness, the percentage of patients with severe disability was reduced significantly. There was some indication that independence was prolonged by early treatment. Life expectancy was increased to approximately that of the unaffected population. However, especially with patients with onset of disease before the age of 50, fluctuations of therapeutic response and severe abnormal involuntary movements interfered with satisfactory therapeutic results. Supplemental bromocriptine produced a smoother therapeutic response and decreased "off" period dystonia and leg pains in over 70% of patients. At dosages below 20 mg daily, it was not particularly effective in severely affected disabled patients. Adverse reactions prevented the use of bromocriptine in less than 20% of patients.

Manganese superoxide dismutase gene Ala–9Val polymorphism might be related to the severity of abnormal involuntary movements in Korean schizophrenic patients

Objective This study examined whether the manganese superoxide dismutase (MnSOD) gene Ala–9Val single-nucleotide polymorphism (SNP) is associated with neuroleptic-induced tardive dyskinesia (TD) and the severity of the abnormal involuntary movements in Korean schizophrenic patients. Method We investigated whether the MnSOD gene Ala–9Val SNP is associated with TD in Korean schizophrenic patients with ( n = 83) and without ( n = 126) TD who were matched for exposure to antipsychotics and other relevant variables. Results Logistic regression analysis revealed that being older ( p = 0.026) was a risk factor for TD, but that there was no significant association between MnSOD gene and TD. Abnormal involuntary movements were more severe in carriers of the Ala allele than in noncarriers ( p = 0.044). Conclusion These findings do not support that the MnSOD gene Ala–9Val SNP is associated with TD in Korean schizophrenic patients. However, this polymorphism might be related to the severity of abnormal involuntary movements in this population.

Bilateral Deep Brain Stimulation of the Globus Pallidus to Treat Tardive Dyskinesia

Tardive dyskinesia (TD) is a common and potentially disabling disorder induced by use of antipsychotic drugs for which medical treatment often gives disappointing results. To assess the efficacy of bilateral deep brain stimulation of the internal part of the globus pallidus to treat severe TD. Prospective phase 2 multicenter study. Six French university hospitals. Patients Patients with severe TD refractory to medical treatment were studied to evaluate the severity of abnormal involuntary movements before and after 6 months of bilateral globus pallidus deep brain stimulation. A 2-step open Fleming procedure was used to avoid unnecessary accrual of patients. A successful outcome was defined as a decrease of more than 40% in the main outcome measure at 6 months. The early stopping rule was invoked if the number of successful outcomes in 10 patients was fewer than 2, or 5 or more. A double-blind evaluation in the presence and absence of stimulation was performed at 6 months after surgery. Main Outcome Measure Change in score on the Extrapyramidal Symptoms Rating Scale. At 6 months after surgery, the Extrapyramidal Symptoms Rating Scale score had decreased compared with baseline by more than 40% (mean improvement, 61%; range, 44%-75%) in the first 10 patients included. In accord with the 2-step open Fleming procedure, we ended the trial at the first step and concluded that pallidal stimulation is an effective treatment for TD. The efficacy of the treatment was confirmed by a double-blind evaluation, with a mean decrease of 50% (range, 30%-66%) (P = .002) in the Extrapyramidal Symptoms Rating Scale score when stimulation was applied compared with the absence of stimulation. There were no marked changes in the patients' psychiatric status. Although these results need to be confirmed in a larger group of patients with a longer follow-up, bilateral globus pallidus deep brain stimulation seems to offer a much-needed new treatment option for disabling TD.

The impact of graft size on the development of dyskinesia following intrastriatal grafting of embryonic dopamine neurons in the rat

Intrastriatal transplants of embryonic ventral mesencephalon can cause dyskinesia in patients with Parkinson's disease (PD). We assessed the impact of transplant size on the development of graft-induced dyskinesia. Rats with unilateral 6-hydroxydopamine lesions were primed to exhibit L-DOPA-induced dyskinesia. They were then intrastriatally grafted with different quantities of embryonic ventral mesencephalic tissue to give small and large grafts. Without drug treatment, discrete dyskinetic-like movements were observed in most rats with large grafts 2-6 weeks after transplantation, but disappeared later. Amphetamine evoked severe abnormal involuntary movements (AIMs) in grafted animals, which were more striking with large grafts. The AIMs coincided with contralateral rotation, but displayed a different temporal profile and pharmacological properties. Thus, selective dopamine uptake blockade elicited rotational behavior, whereas coadministration of both dopamine and serotonin uptake blockers was required to evoke significant orolingual and limb AIMs. In conclusion, robust and reproducible AIMs were evoked in rats with large grafts by blockade of monoamine reuptake. These AIMs may provide a new tool for assessing dyskinetic effects of neural grafting.

Effectiveness of clozapine in treatment-resistant schizophrenia

Background:Clozapine has been shown to be superior to chlorpromazine in improving the positive and negative symptoms of schizophrenia. However, technical experience with clozapine in Indian patients has not been documented.Aim:To assess the improvement in psychopathology of treatment-resistant schizophrenia with clozapine therapy and to study the relationship between sociodemographic and various psychopathology variables among patients with treatment-resistant schizophrenia.Methods:Twenty-two patients with treatment-resistant schizophrenia were evaluated using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, Calgary Depression Scale, Global Assessment of Functioning (GAF) Scale and Abnormal Involuntary Movement Scale (AIMS). These scales were used to determine the level of psychopathology, depression, overall functioning and severity of abnormal involuntary movements in the patients. The patients were admitted to the hospital for a short time to initiate clozapine therapy. At discharge, patients were stabilized on 300–400 mg/day of clozapine. The patients were re-evaluated after 20 months.Results:The study group showed better global functioning after clozapine therapy. The therapy was well-tolerated though moderate side-effects were seen. Suicidal thoughts declined with clozapine therapy. There was a significant reduction in the negative symptom and general psychopathology scores of PANSS.Conclusion:Clozapine has therapeutic efficacy in some but not all treatment-resistant patients with schizophrenia.

Four-Year Follow-up of Adrenal-to-Brain Transplants in Parkinson's Disease

Evaluate long-term efficacy of autologous adrenal-to-caudate transplants in idiopathic Parkinson's disease refractory to medical treatment. Subjects underwent evaluations several times preoperatively on the University of California-Los Angeles Parkinson's Disease Disability Scale and the Hoehn and Yahr stage of disease. Postoperatively, they were also repeatedly rated on the Unified Parkinson's Disease Rating Scale. Clinical visits and surgery took place at the University of California-Los Angeles Center for the Health Sciences. Three men and one woman, ages 44 to 55 years, were followed up for several years preoperatively. At surgery, disease durations ranged from 7 to 16 years. Originally, all patients had a good response to levodopa, but for several years preoperatively, they had had fluctuating responses and a short duration of drug action. Right adrenalectomy was performed through a midline abdominal incision. Open craniotomy exposed the head of the right caudate into which pieces of adrenal medulla, 1 to 2 mm in size, were implanted. Scores on the three major scales (see "Design") were augmented with the number of hours "off" per day and severity of abnormal involuntary movements. Disease progression of each patient was compared with his own preoperative course and with those of a cohort of patients with Parkinson's disease followed up for 14 years who had received medical treatment without transplant surgery. After 4 years, transplants continued to be beneficial to three patients and had been of brief transient benefit to the fourth. The course of disease was more benign postoperatively than preoperatively and was more slowly progressive than that in the cohort. Improvement was not sufficient to justify adrenal transplants as routine therapy but does point the way to the use of other dopamine tissue transplantation.

On the pathogenesis of abnormal involuntary movements in lithium-treated patients with major affective disorder

Abnormal involuntary movements during long-term lithium treatment were investigated on two occasions, 7 years apart, in 37 outpatients with major affective disorder according to DSM-III. The patients had been on continuous lithium treatment for an average of 8.2 years when entering the study, and all had been exposed to neuroleptics. Psychiatric status and side effects were evaluated, and abnormal involuntary movements were assessed using the Abnormal Involuntary Movement Scale (AIMS). Signs of abnormal involuntary movements were age-dependent and seen in 8% of the patients at the initial investigation in 1980, and the proportion of affected individuals had increased by 16% by the end of the study in 1987. Women above the age of 50 (in which category the frequency of abnormal involuntary movements was 38%) were selected for further analysis. Severe abnormal involuntary movements in this category were associated with the early onset of affective illness, low body weight, the occurrence of dementia among first-degree relatives, and with high 12-h lithium levels.

Monkeys with unilateral ventromedial tegmental lesions of the brain stem: Models for parkinson's disease and lesch-nyhan syndrome

1. Monkeys with surgical unilateral ventromedial tegmental lesions of the brain stem served as models for investigating abnormalities in Parkinson's disease and Lesch-Nyhan syndrome. 2. The animals exhibited some neurological deficits which are similar to those observed in Parkinson's disease or Lesch-Nyhan syndrome. 3. In monkeys with unilateral ventrolateral tegmental lesions, the levels of dopamine and the activities of catecholamine-synthesizing enzymes were reduced on the lesion side of the striatum, and hypokinesia and tremor developed on the contralateral extremities. 4. Dopa or dopamine agonists relieve tremor and evoke abnormal involuntary movements which are similar to the responses observed in patients with Parkinson's disease. 5. The antitremor effect of Dopa is potentiated by catechol-O-methyltransferase inhibition, suggesting a therapeutic potential for these types of agents. 6. Evidence was obtained that stimulation of D 2 dopamine receptors by selective dopamine agonists exerts antitremor activity and evokes abnormal involuntary movements. 7. Combined administration of D 1 and D 2 dopamine agonists seems to enhance the antitremor activity. 8. Partial dopamine agonists exert antitremor activity and produce less severe abnormal involuntary movements than full dopamine agonists. 9. In a group of monkeys with unilateral ventromedial tegmental lesions of the brain stem the administration of mixed D 1/D 2 dopamine agonists results in the occurrence of self-biting behavior of the forelimb digits and spasticrty of the hindlimbs and these symptoms are similar to those observed in patients with Lesch-Nyhan syndrome 10. The self-biting behavior seems to be associated with the stimulation of central D 1 dopamine receptors and therefore the possible involvement of dopamine neuronal abnormalities in Lesch-Nyhan syndrome deserves further investigation.

Relation of neuroleptic dose and tardive dyskinesia to attention, information-processing, and psychophysiology in medicated schizophrenics.

Relationships of neuroleptic dosage and tardive dyskinesia with measures of attentional, information-processing, and psychophysiological dysfunctions in medicated chronic schizophrenics were explored by correlational and stepwise multiple-regression analysis. High neuroleptic dosage was found to be associated with increased reaction time, reduced span of apprehension, low basal skin conductance level, and reduced skin conductance reactivity. Severe abnormal involuntary movements were associated with increased eye-tracking dysfunction, increased scanning eye-movement rate, increased reaction time, and reduced skin conductance reactivity. These findings led to the hypothesis that neuroleptic dosage and tardive dyskinesia may be sources of error variance in the measurement of attentional, information-processing, and psychophysiological functions in schizophrenics.

Therapeutic potentials of centrally acting dopamine and alpha 2-adrenoreceptor agonists.

The antiparkinsonian activity of several dopamine agonists was investigated in an animal model and clinically in parkinsonian patients. The semisynthetic ergoline, pergolide, the partial ergoline, LY 141865 and the 8-alpha-aminoergoline, CU 32-085 were found to be effective antitremor agents in monkeys with ventromedial tegmental lesions. The administration of pergolide or LY 141865 results in a relief of tremor with a concomitant occurrence of severe abnormal involuntary movements, while the administration of CU 32-085 results in a relief of tremor with the occurrence of only minor abnormal involuntary movements. Clinical studies have revealed that pergolide is an effective drug in patients with advanced Parkinson's disease, and it reduces the "on-off" phenomena. The possible regulation of dopamine neurotransmission by the norepinephrine neuronal systems was reviewed. Preliminary data suggest that clonidine may interact with presynaptic dopamine receptors.