Lincoln D. Clark

Risperidone dose and blood level variability : Accumulation effects and interindividual and intraindividual variability in the nonresponder patient in the clinical practice setting

Risperidone blood levels were measured every 2 weeks after initiation of therapy in 24 refractory chronic schizophrenic patients referred to a locked, skilled nursing facility for long-term treatment. Blood levels were assessed on 285 occasions over a 1- to 16-month treatment program. Drug plasma level increases peaked by 2 months for risperidone at 334% and by 6 months for 9-hydroxy-risperidone at 104% over the baseline levels. Total blood levels (risperidone plus 9-hydroxy-risperidone) peaked at 111% increase at 6 months and then declined 8% per month to 12 months, stabilizing at a value 31% higher than the initial value. Significant dose to blood level interindividual variation was noted. Considerable blood level variation was evident in single blood level sample determinations. The results suggest the value of risperidone blood levels, consideration of reduction of initial recommended starting dosages, and a need to optimize risperidone dosage approaches individually to patients.

Measurement of social dominance in squirrel monkeys

Several laboratory methods for measuring social dominance in squirrel monkeys are described.

THE EFFECT OF EXPERIMENTALLY-INDUCED STRESS ON PENTYLENETETRAZOL SEIZURE THRESHOLD IN MICE.

SummaryThe effect of 20 min of intermittent foot shock on spontaneous activity and overt behavior was studied in mice. In addition, the effect of a pain-induced conditioned emotional response, and of total body immobilization and postural disequilibrium on the pentylenetetrazol seizure threshold was determined. Foot shock decreased spontaneous motor activity, and induced responses characterized by immobility, crouching, and increased defecation. The pain-induced conditioned emotional response, total body immobilization, and postural disequilibrium all lowered seizure threshold. Data are presented which indicate that there is a direct relation between the reduction in seizure threshold and the intensity of the disturbed emotional state. In addition, it is suggested that the observed increase in brain excitability caused by apprehension and anxiety may result from the effect of endogenouslyreleased catecholamines on the central nervous system. Reference is made to the relation between these findings and the effect of emotional disturbances on seizure frequency in human epileptics.

Effects of chlorpromazine upon psychological development in the puppy.

SummaryPuppies were removed from the mother at three weeks of age and isolated through the seventh week. During the 8th–11th weeks (Phase I) one half received chlorpromazine daily before being removed for a training and observation session in an open arena. One half of each group were always rewarded; the remainder were punished for certain forms of behavior.During Phase II (weeks 12–15) all subjects were reversed on punishment, and half were reversed on drug. Observations in the arena were continued.In Phase III (weeks 16–17) drug was withdrawn and tests were conducted in a runway and in the arena to measure persistent effects. The results were as follows:During Phase I, both drug and punishment depressed the activity level of the animals and did so additively. Chlorpromazine did not impair the ability of the subjects to discriminate safe from dangerous situations in the Arena test and had no delaying effect upon the appearence of new responses; on the other hand, the drug did not alter the “anxieties” of the puppies in such a way as to enable them to enter new situations before non-drugged animals. Differences between drugged and non-drugged puppies were most evident in contacts with inanimate objects. In play with companion puppies, perhaps because of increased stimulus intensity, both groups were highly active and often indistinguishable. This would indicate the importance of stimulus context in interpreting behavioral effects from chlorpromazine.In Phase II, in animals changed from a non-punished regime, it was again evident that chlorpromazine has no deleterious effects upon learning a new avoidance pattern; dangerous versus safe phases of the Arena test were readily discriminated. In groups changed from punishment to non-punishment, the facilitating effect of chlorpromazine on extinction of avoidance behavior was apparent. Whether or not drug had been given to the prior punishment phase was inconsequential; the crucial fact was the presence of drug treatment during extinction.Phase III tests failed to demonstrate any significant differences between groups, either in arena behavior, willingness to run for handler contact, or in the runway dominance test.

The differential effects of chlorpromazine and pentobarbital on two forms of conditioned avoidance behavior in peromyscus maniculatus gracilis

SummaryA series of experiments was designed to compare the conditioned behavior of a subspecies of deermouse (Peromyscus maniculatus gracilis) in two response situations: 1. avoidance of shock by climbing a pole, and 2. avoidance of shock by remaining on a non-electrified pan located at grid level. This subspecies is semi-arboreal in its natural habitat. As was expected, an experimentally-induced response analogous to those to which the animal is phenotypically predisposed is rapidly acquired and resistant to spontaneous extinction. Thus, the pole response was acquired more rapidly, was more resistant to extinction, and was less susceptible to suppression by drugs. The stability of such behavior makes mice exhibiting this type of response advantageous for testing the effects of psychotropic drugs. The fact that chlorpromazine may be differentiated from pentobarbital by means of these technics supports this conclusion.

Some observations on the operant behavior of desert pack rats (Neotoma lepida)

Four desert pack rats (Neotoma lepida) and four Sprague-Dawley rats were maintained in operant chambers continuously for 6 months and exposed to a variety of experimental conditions. Compared to the Sprague-Dawley rats, Neotoma required a lower food intake to maintain its body weight and emitted responses at a more uniform, distributed rate over 24-h periods. The unusual hoarding drive characteristic of Neotoma could be demonstrated in the operant chambers by dispensing glass beads in the pellet dispenser. However, there was no clear evidence that these “nonorganic rewards” were reinforcing.

BEHAVIORAL DEFEAT IN SQUIRREL MONKEYS: AN EXPERIMENTAL MODEL OF REACTIVE DEPRESSION

The combination of a progressive FR schedule of reinforcement and the opportunity to “escape” from this schedule produced a syndrome in the squirrel monkey with prima facie similarity to human reactive depression. This condition was created by a progressive increase in work demanded per reward and a corresponding reduction in density of reinforcement. The syndrome was characterized by progressive reduction of positively reinforced behavior, withdrawal from the environment, task ambivalence, and signs of emotional stress. These behaviors were ameliorated by environmental change which reduced the experientially produced stress and were dramatically reversed by the anti-anxiety agent, chlordiazepoxide.