James V. Hinrichs

DOSE-RESPONSE ANALYSIS OF THE BEHAVIORAL EFFECTS OF DIAZEPAM: I. LEARNING AND MEMORY

A total of 120 healthy volunteers were randomly assigned to four treatments (placebo, 0.1, 0.2, and 0.3 mg/kg) and three testing times (7 AM, 1 PM and 7 PM). Immediate and delayed free recall of word lists revealed consistent decreases in performance as oral diazepam dose increased from 0.1, 0.2, to 0.3 mg/kg. Paradoxically, as the dose increased, the number of predrug list words recalled also increased. A serial number-learning task displayed a pattern of delayed improvement of acquisition as the dose increased. Response times in a semantic-categories task were prolonged as the dose increased. Parallel recovery functions were observed for all doses and tasks. Full recovery after a single administration of 0.1, 0.2, and 0.3 mg/kg doses was estimated to occur after 3.5, 4.5, and 5.5 h, respectively. Several analyses were consistent with the view that acquisition and not retrieval was impaired by diazepam. There were no circadian interactions with the effects of the drug.

Ketamine: behavioral effects of subanesthetic doses

Effects of subanesthetic doses of ketamine (0.25 and 0.5 mg/kg) on memory, cognition, psychomotor function, subjective moods, and incidence of adverse reactions were investigated in 34 healthy young volunteers. The drug caused impairment of immediate and delayed recall. Most of the impairment was du

Caffeine and diazepam: Separate and combined effects on mood, memory, and psychomotor performance

The effects of caffeine and diazepam on several mood, cognitive, learning, memory, and psychomotor tasks were investigated in a double-blind study of 108 young healthy adults who were randomly assigned to nine treatments; oral administration of caffeine (0, 3 and 6 mg/kg), diazepam (0, 0.15, and 0.30 mg/kg) and their combinations. Subjects completed a battery of tasks once before and twice after administration of the drugs. Caffeine alone showed no effects on cognitive, learning, and memory performance, but impaired fine motor coordination and increased anxiety and tenseness. Diazepam alone produced sedation, lowered other ratings of subjective moods, and impaired cognitive, learning, and memory performance. The two drugs did not antagonize the effects of each other, except in the symbol cancellation task.

Memory and performance effects of single and 3-week administration of diazepam

The effects of diazepam on several cognitive and performance tasks were investigated in 30 healthy volunteers randomly assigned to three groups: A chronic group received diazepam for 21 days; an acute group received placebo during the same period, except at session 4 when they received diazepam; and a third group received placebo only at the sessions. Diazepam was given orally in a dose of about 0.2 mg/kg. Behavioral sessions were conducted before treatment (practice), after one administration (session 2), after 19 days (session 3), after 20 days (session 4), and 7 days following withdrawal (session 5). A single administration of diazepam produced significant memory impairment in both immediate and delayed free recall. Reduced memory performance was the result of impaired acquisition rather than reduced retention. Comparison of the chronic and acute groups in sessions 3 and 4 and analysis of the performance of the chronic group over sessions indicated the development of some tolerance to the memory impairment with continued administration. No residual memory effects were apparent following withdrawal. No other cognitive or psychomotor functions differed among the three treatment groups.

Comparison of Psychologic and Cognitive Functions after General or Regional Anesthesia

The behavior of 105 patients randomly assigned to receive cither general or regional anesthesia and who underwent one of three types of surgery (hysterectomy, prostatectomy, or joint replacement) was assessed before, immediately after, and 3 mo after surgery. Psychologic status was assessed by the Sickness Impact Profile, the SCL-90-R, and a Metamemory Questionnaire. Cognitive functioning was measured by a battery of ten psychomotor, memory, and skilled performance tasks. Physical health was scored by the ASA classification of physical status, a health index, postoperative complications ratings, and a self-rated measure of the patients health. There were cognitive differences across surgery groups due to age and gender variability among the patients; however, the type of anesthesia produced no difference in behavior. Both the physical and mental health indices showed improvement from the preoperativc to the postoperative periods. General anesthesia appears to pose no risk to mental function and recovery beyond that associated with regional anesthesia and surgery.

Relationship of free-recall memory to hypertension in the elderly. The Iowa 65+ Rural Health Study

The relationship between hypertension and performance on a test of free recall memory was explored in a geographically-defined population of free-living subjects 65 years and older. Those with diastolic but not isolated systolic hypertension had a significantly lower performance on the memory test, after controlling for general health status, antihypertensive medication use and other factors which might confound or modify this association. These findings from a population study confirm the results of prior investigations in smaller numbers of highly selected subjects and suggest that further study may lead to improved prevention of cognitive decline in the elderly.

Diazepam and memory: Evidence for spared memory function

The effects of diazepam on several tests of memory were investigated in a double-blind study of 24 healthy young adults. Following a single oral administration of 0.3 mg/kg diazepam or placebo, subjects in the diazepam group showed marked impairment in immediate free recall of words as compared to placebo control subjects. However, diazepam-treated subjects demonstrated performance benefits from prior exposure to the same words on tests of memory priming using word completion and category-generation tasks. The two types of memory tests differ in their demand for conscious recollection. Tests of free recall have explicit (declarative) memory demands whereas the priming test places only implicit (procedural) demands upon memory. The results demonstrate that diazepam spares some forms of memory as does amnesia induced by neurological impairment.

The interactions of midazolam and flumazenil on human memory and cognition

BackgroundPrevious research has been unable to show unequivocally whether flumazenil can reverse completely, partially, or not at all the memory effects of benzodiazepines. The effects of midazolam on implicit memory are also unknown. The behavioral effects of flumazenil by itself, and the acute reversal of benzodiazepine effects, are also controversial. The current study was designed to investigate these questions. MethodsUsing a prospective randomized, double-blind crossover study design, memory was assessed using both direct (free recall and recognition) and indirect (word completion) measures. Other cognitive effects were assessed using the digit symbol substitution task. Sedation and other mood effects were assessed using subjective rating scales. Seventy-two healthy subjects were assigned to three equal groups according to the dose of midazolam received (0, 0.05, and 0.1 mg/kg). Each subject received varying doses of flumazenil (0, 1, and 3 mg) in three sessions, at least 1 week apart. After baseline administration of the tasks, midazolam was administered. The assessments were repeated 20 min later, followed by administration of flumazenil. The assessments were repeated 5 and 30 min after administration of flumazenil. After a 2-h recovery period, delayed memory tests were given. ResultsBoth doses of midazolam decreased all scores in the memory and digit symbol substitution tests and mood ratings. Flumazenil reversed both the sedative and the memory effects of the benzodiazepine. The reversal was as complete with the 1-mg dose of flumazenil as with the 3-mg dose. Flumazenil by itself, and the acute reversal of midazolam effects, caused no significant behavioral reactions. ConclusionsMidazolam impairs explicit and implicit memory. Flumazenil reverses both the sedative and memory effects of the drug. Flumazenil, in the doses used, has no intrinsic actions.

Memory complaint and memory performance in the depressed elderly.

Depressed and nondepressed elderly subjects recruited in the context of a large epidemiological study of health were compared on measures of self-reported memory disturbance and an objective index of memory performance (free recall). Three groups were studied including (a) subjects meeting Research Diagnostic Criteria (RDC) for major depression, (b) subjects with high levels of self-reported depressive symptoms who did not meet RDC for major depression, and (c) subjects with low levels of self-reported depressive symptoms. Subjects with high depression symptom levels reported significantly higher levels of memory complaint than did subjects with low symptom levels. However, there were no differences in self-reported memory disturbance as a function of depression diagnosis. Further, there were no significant differences between groups on the free-recall measure, either as a function of symptom level or diagnosis. It is argued that symptom severity rather than diagnosis of depression is important in determining impairment in depressed elderly people.

Diazepam and memory: retrograde facilitation produced by interference reduction

Although diazepam (Valium) reduces learning and memory of information presented after administration (anterograde amnesia), in some cases it improves retention of predrug information (retrograde facilitation). Three experiments examined the magnitude and the conditions for producing retrograde facilitation and tested three hypotheses about the cause of memory enhancement. Differential effort and enhanced consolidation explanations were rejected in favor of a reduced interference interpretation. Improvement in predrug memory occurs because poor postdrug learning reduces the amount of new information available to interfere with prior learning.