George Gardos

A rating scale for tardive dyskinesia

A rating scale for tardive dyskinesia was developed, consisting of nearly all signs seen by two groups of investigators over a 5-year period. Thirty-four items were included in the scale with a possibility of writing in idiosyncratic signs. The scale was shown to have good reliability and validity in studies carried out by both the New York and Boston groups. It is recommended as a suitable instrument for describing the breadth of tardive dyskinesia syndrome and also for quantifying the disorder. A second scale, “the abbreviated dyskinesia scale”, contains 13 items which are more global than the items in the original scale. It also has been shown to be both reliable and valid. Its use is suited to situations requiring less extensively detailed assessments.

ACTH 4-10 in the amelioration of neuropsychological symptomatology associated with senile organic brain syndrome

Eighteen male and female volunteers over the age of sixty who exhibited mild senile organic brain syndrome were administered ACTH 4-10 (Org OI 63) (30 mg, s.c.) or saline in a 2×2 Latin square design. Subjects experienced a reduction in depression and confusion and an increase in vigor. This evidence of an increase in vigor was supported behaviorally by a delay in the onset of increased latency in reaction time. Data also indicated that retrieval from memory may be enhanced by this compound. The electroencephalogram evinced a shift to lower frequencies under ACTH 4-10, but this effect was primarily noted in the females who received drug followed by placebo. These effects of ACTH 4-10 are intriguing and suggest that further work in this area should be encouraged.

The natural history of tardive dyskinesia.

Follow-up data from the first 100 patients with early dyskinesia are presented. After an average of 40.9 months, the cohort showed statistically significant decreases in tardive dyskinesia (TD) ratings. After TD onset, ratings decreased for 4 years, then plateaued and rose during the 7th year. Age was not a negative prognostic factor in this cohort. Improvement in TD correlated significantly with fewer neuroleptic-free periods before and more neuroleptic-free periods after TD onset. Neuroleptic dosage correlated negatively with improvement in trunk and dystonia ratings. Improvement in TD is the usual finding in longitudinal studies of TD cohorts. Follow-up studies of neuroleptic-treated groups with varying proportions of patients showing TD, by contrast, tend to show increased TD because new TD cases more than offset improvement. A naturalistic study with pharmacotherapy tailored to the underlying psychiatric disorder and conducted long-term from TD onset is the ideal design for investigating the natural history of TD.

Drug variables in the etiology of tardive dyskinesia application of discriminant function analysis.

Abstract 1. 1. From the medical records of 50 chronic, hospitalized, psychotic patients, information was obtained on numerous drug and non-drug variables. 2. 2. On the basis of the Simpson Tardive Dyskinesia Rating Scale, the study sample was dichotomized into dyskinesia (N = 23) and no dyskinesia (N = 27) groups. 3. 3. A step-wise multiple discriminant function analysis showed the following variables to discriminate significantly between the two groups: 1) duration of low potency neuroleptic therapy; 2) previous EST; 3) length of neuroleptic therapy; 4) total amount of long-acting fluphenazine; and 5) abnormal EEG. 4. 4. The equation correctly classified 85.2% of “no dyskinesia” and 60.9% of “dyskinesia” patients. 5. 5. The discriminant function analysis appears to be a useful tool in disentangling the relative importance of overlapping etiological factors in dyskinesia.

Are antipsychotic drugs interchangeable

The interchangeability of effective antipsychotic compounds was investigated in a clinical setting. Sixty formerly hospitalized chronic schizophrenics were randomly assigned to chlorpromazine, thiothixene, or continued doctors choice medication groups. Dose of antipsychotic medication and schedule of administration were kept constant. During the 2-year study period 16 patients (44 per cent) in the combined chlorpromazine and thiothixene groups (“switched group”) underwent clinical deterioration to an extent that they had to be terminated from the study. Only two patients (12 per cent) of the control group relapsed during the same period. The significant difference in relapse rates is attributed to the change in antipsychotic medication. Relapses were equal in number during the first and second 6 months of the study. The new antipsychotic (chlorpromazine or thiothixene) may have delayed but did not prevent the relapse of these patients. The study findings imply that for individual schizophrenic patients antipsychotic drugs are not interchangeable. The clinician should be wary of switching drugs in a stabilized chronic schizophrenic, since relapse may be precipitated by the medication change.

The importance of dosage in antipsychotic drug administration--a review of dose-response studies.

Methodologically adequate clinical dose-response studies with antipsychotic compounds are reviewed. A number of consistent findings have emerged. Treatment resistant schizophrenics, and schizophrenics under 40, hospitalized less than 10 years often benefit from high or very high doses of antipsychotics. Low dose treatment is to be considered for apathetic or depressed schizophrenics who are not floridly psychotic. Placebo or no medication is optimal for a hitherto not well defined subgroup. The usual clinical dose range appears to be most therapeutic for the remaining schizophrenic populations, probably including most out-patients. Methodological problems encountered in dose-response studies and clinical problems in posology are discussed.

Membrane depolarization selectively inhibits receptor-operated calcium channels in human T (Jurkat) lymphoblasts

Jurkat lymphoblasts were stimulated by a monoclonal antibody against the CD3 membrane antigen and the evoked calcium signal was followed by the intracellular fluorescent calcium indicator indo-1. The technique applied allowed us to separately investigate the stimulus-induced intracellular calcium release and the calcium-influx pathways, respectively. In the same cells membrane potential was estimated by the fluorescent dye diS-C3-(5). The resting membrane potential of Jurkat lymphoblasts under normal conditions was between -55 and -60 mV. Membrane depolarization, obtained by increasing external K+ concentration, removing external Cl-, or by increasing the Na+/K+ leak permeability with gramicidin or PCMBS, did not induce calcium influx in the resting cells and did not influence the CD3 receptor-mediated internal calcium release, while strongly inhibited the receptor-mediated calcium influx pathway. Half-maximum inhibition of this calcium influx was observed at membrane potential values of about -35 to -40 mV and this inhibition did not depend on the external calcium concentration varied between 5 and 2500 microM. Membrane hyperpolarization by valinomycin did not affect either component of the calcium signal. The observed selective inhibition of the receptor-operated calcium influx pathway by membrane depolarization is probably an important modulator of calcium-dependent cell stimulation.

Quantitative assessment of psychomotor activity in patients with neuroleptic-induced akathisia

1. An ambulatory activity monitor with solid-state memory was employed to obtain 24-hour activity data in 29 neuroleptic-treated hospitalized patients and 9 normal controls. 2. The activity monitor is a piezoelectric device which was strapped to the non-dominant ankle. Activity was recorded in 5-minute epochs throughout the 24-hour period. 3. In contrast to patients with mania (N = 15) and schizophrenia (N = 4), depressed patients (N = 9) had higher clinical ratings of akathisia and lower levels of daytime activity. 4. Manic and depressed patients showed a delay of peak activity (= acrophase). 5. Quantifiable alterations in rest-activity rhythms may occur in neuroleptic-induced akathisia but measurement of activity may be complicated by the patients psychiatric disorder.

Absence of severe tardive dyskinesia in hungarian schizophrenic out-patients

One hundred and twenty-two patients comprising 82% of the non-hospitalized schizophrenic population of a Hungarian town were rated for tardive dyskinesia (TD). Drug histories were also obtained. No severe cases of TD were found. The markedly lower prevalence of TD in the study population in contrast to similar North American samples may be related to differences in treatment styles, in particular to: a) use of EST in place of high-dose neuroleptic therapy; b) extensive exposure to ethopropazine, promethazine, and other antiparkinson drugs. Twenty patients revealed clinically evident fine tremors, mostly of the tongue and eye-lid. Multivariate analysis revealed a positive association of choreiform dyskinesia with duration of low-potency neuroleptic treatment.

Effect of antihistamines and chlorpromazine on the calcium-induced hyperpolarization of the Amphiuma red cell membrane.

1. It has previously been demonstrated that an increase in extracellular Ca2+ conce-tratio- induces a trandient increase in K+ permeability and associated hyperpolarization of the red cell membrane of the giant salamander, Amphiuma meand. This phenomenon is analogous to the Ca2+-induced KCl loss observed in ATP-depleted human red cells and red cell ghosts. 2. Histamine, which enhances the Ca2+-induced K+ loss from depleted human red cells, is without effect on this Ca2+-induced hyperpolarization of Amphiuma red cells. 3. Promethazine (10 muM) and mepyramine (1 mM), which inhibit the Ca2+-induced K+ loss in depleted human red cells, also block the Ca2+-related hyperpolarization of Amphiuma erythrocytes. 4. Chlorpromazine (25 muM), despite being a weak antihistamine, is equally effective in blocking the Ca2+-induced hyperpolarization of Amphiuma red cells. 5. Ionophore A23187 causes a large and sustained Ca2+/K+-dependent hyperpolarization even in the presence of normal (1.8 mM) concentrations of Ca2+. This hyperpolarization is relatively insensitive to chlorpromazine and promethazine. 6. The inhibition of the Ca2+-induced hyperpolarization of the Amphiuma red cell membrane by chlorpromazine and promethazine may berelated to their properties as local anaesthetics.