The interactions of midazolam and flumazenil on human memory and cognition.

BACKGROUND: Previous 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. METHODS: Using 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. RESULTS: Both 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. CONCLUSIONS: Midazolam 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.

Psychological change following 18 months of cochlear implant use.

Consecutive recipients of multichannel cochlear implants participated in preimplant as well as 9-month and 18-month psychological evaluations. Before receiving a cochlear implant, psychological tests indicated that the implant recipients were more depressed, suspicious, socially isolated, lonely, and socially anxious than was the general population. After 18 months of implant use, there was a significant reduction in depression, loneliness, social anxiety, social isolation, and suspiciousness. These changes in psychological state did not correlate with improved performance on audiological measures. The data suggest that although cochlear implants can have a positive effect on the emotional and behavioral status of persons with acquired postlingual profound deafness, the psychological outcome of implants is not simply a function of the audiological benefit assessed with standardized speech-based audiological tests.

Psychological predictors of audiological outcomes of multichannel cochlear implants: preliminary findings.

The purpose of this research was to determine whether psychological variables were associated with the variability that characterizes the audiological performance of recipients of multichannel cochlear implants. Twenty-nine consecutive recipients of multichannel implants participated in a preoperative psychological assessment and audiological follow-up assessments after 18 months of implant use. Experimental cognitive measures that assess an ability to rapidly detect and respond to features imbedded in sequentially arrayed information accounted for up to 30% of the variance in implant outcome, suggesting the importance of cognitive abilities in implant outcome. Standardized measures of intellectual ability, however, were not predictive of outcome. The Health Opinion Survey, a measure of participatory engagement, was also a significant predictor of audiological outcome. Overall, the results implicated the importance of several specific psychological factors in the audiological outcome of cochlear implants in postlingually deafened adult recipients.

Norms for free associations and five types of constrained associations.

Normative data on verbal free associations and constrained associations of five types (opposites, superordinates, examples of categories, coordinates, and properties) were collected from 72 men and 72 women (mean age, 19.2 yr.). A list of the different responses given by subjects for each of 360 stimuli and the frequency of each response is available.

Psychological consequences of surgery.

The purpose of the present study was to assess changes in psychological distress and memory complaint following a wide variety of surgeries. In addition, variables reflecting type of surgery, demographic characteristics, history of mental illness, and health factors were evaluated as predictors of postoperative psychological distress and memory complaint. Using the Brief Symptom Inventory (BSI), it was found that 10.9% of patients had high levels of psychological distress the day before surgery compared to 13.9% of patients three months after surgery. Complaints of memory disturbance also increased significantly. Only the anxiety subscale of the BSI showed a significant decrease at three months postsurgery. Hierarchical multiple regression revealed that younger age, lower social status, being male, having a history of mental illness, higher presurgery BSI, and poorer postsurgery health were significant predictors of postsurgery psychological distress. The results of the study suggest that, although patients become less anxious after surgery, other forms of emotional distress increase, perhaps due to factors such as slower than anticipated recovery. Results also suggest that medical factors may play an indirect rather than a direct role in psychological consequences of surgery.

Comparison of psychologic and cognitive functions after general or regional anesthesia.

The behavior of 105 patients randomly assigned to receive either 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 patient's 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 preoperative to the postoperative periods. General anesthesia appears to pose no risk to mental function and recovery beyond that associated with regional anesthesia and surgery.

Effects of a subanesthetic concentration of nitrous oxide on overt and covert assessments of memory and associative processes.

Drug effects on human memory are usually assessed by overt recall or recognition tests. Covert tests which do not explicitly assess memory but which indirectly elicit previously presented information may be more sensitive to low levels of learning than overt tests. Three covert tests and corresponding overt recall tests were given to 16 men and 16 women breathing 30% nitrous oxide in oxygen or 100% oxygen to see if the covert tests resisted the memory-impairing effects of nitrous oxide. Nitrous oxide impaired performance on the overt tests. Performance in two covert tests, Constrained Associations and Word Completion, showed resistance to memory impairment. In the least resistant covert test, Free Associations, nitrous oxide altered associative processes. Performance in an additional test involving recognition and preferences for nonsense words repeated with varying frequencies also showed some resistance to memory impairment. The results support the distinction between declarative and procedural memory. Constrained Associations, Word Completion, and Nonsense Words tests may be useful for assessing low levels of learning during drug states.

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.

Diazepam, behavior, and aging: increased sensitivity or lower baseline performance?

Cognitive performance, psychomotor skills, and subjective reactions to diazepam and placebo were compared in 12 healthy, well-educated subjects in three age groups: 19-28, 40-45, and 61-73 years old. With only minor exceptions, the changes in performance caused by diazepam and age differences were statistically additive and noninteracting. Diazepam did not act synergistically in older individuals; the decrements in performance were about the same in all age groups. Baseline performance decreased with increasing age; middle-aged subjects performed more like older than younger subjects. A variety of tasks exhibited similar effects of aging and diazepam, i.e., when performance declined with increasing age, it was also reduced by diazepam.

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.

Comparison of two benzodiazepines with differing accumulation: behavioral changes during and after 3 weeks of dosing.

The effects of diazepam (0.2 mg/kg for 15 days followed by 0.3 mg/kg for 7 days), oxazepam (0.8 mg/kg for 15 days followed by 1.2 mg/kg for 7 days), and placebo were studied in healthy subjects after the first dose, once a week during chronic dosing, and at 48 and 96 hours after withdrawal through a battery of psychologic tests. Diazepam produced quick effects followed by relatively rapid recovery, whereas the effects of oxazepam appeared slowly and lasted longer. Tolerance developed to the effects of both active drugs, so that when the dosages were increased, effects did not. There were no symptoms or signs indicative of withdrawal reactions. There were also no differences between the effects of the two active drugs after repeated dosing, although diazepam is an accumulating drug with active metabolites and oxazepam is a slightly accumulating one with inactive metabolites.

Pharmacokinetic and pharmacodynamic interactions between caffeine and diazepam.

The pharmacokinetic and dynamic interactions of caffeine and diazepam after single doses were investigated in six young healthy adults. Subjects received 6 mg/kg of caffeine, 0.3 mg/kg of diazepam, and their combination at 2-week intervals according to a Latin square design and a double-blind procedure. Subjects had blood samples withdrawn at 0, 5, 10, 20, 30, 45, 60 minutes and every 30 minutes thereafter until 210 minutes after treatment. A battery of behavioral tests were administered before treatment and after each blood sampling, starting with the 20-minute period. The coadministration of caffeine with diazepam resulted in a 22% reduction in diazepam plasma levels. Caffeine produced hand tremors and diazepam produced sedation and impaired memory and cognition. The two drugs did not antagonize the effects of each other except in the symbol cancellation task. There were significant correlations between the caffeine and diazepam plasma levels and performance on several tasks and evidence for the development of acute tolerance to both drugs.

The behavioral actions of diazepam and oxazepam are similar.

In a double-blind and randomized study, we assessed the comparative pharmacodynamic profiles and behavioral effects of diazepam and oxazepam administered to young healthy volunteers. Diazepam 0.3 mg/kg or oxazepam 1.2 mg/kg or placebo were each administered orally to 13 subjects who were tested with tasks which measured learning and memory, cognition, psychomotor performance and mood before and for 9 h after treatment. The two drugs had similar actions, although subjective effects were milder after oxazepam, which also had a slower onset of action. There was no evidence of rebound behavioral impairment.

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 due to interference with retrieval processes. Recovery was virtually complete 60 minutes after administration. The incidence of adverse reactions was high. Benzodiazepines need to be administered even when ketamine is used in subanesthetic doses.

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.

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.

Behavioral effects of oral versus intravenous administration of diazepam.

The behavioral effects of oral versus intravenous administration of diazepam were studied in 50 volunteers using a battery of memory, cognitive, mood and psychomotor tests repeated over a 4.5 hr period. Subjects received diazepam 0.2 mg/kg or placebo as capsules, commercial tablets or intravenous solution in a randomized double blind manner. While a quick onset of effects occurred with intravenous administration followed by the capsule and tablet oral administrations in that order, the recovery rate was similar for the 3 methods of administration. Contrary to many claims in the literature the effects of oral administration were substantial. Behavioral impairment was directly related to the magnitude of the memory component of the task. On many of the tasks the pattern of diazepam impairment was one of delayed improvement of performance, a pattern which would only be apparent with repeated testing. Subjects who received diazepam showed a paradoxical enhancement of recall for material learned before the drug.

Diazepam and propranolol in panic disorder and agoraphobia.

The response to diazepam and propranolol hydrochloride was compared in 21 patients who (with one exception) met DSM-III criteria for panic disorder and agoraphobia. Each drug was administered for two weeks in double-blind fashion according to a crossover design. The response to diazepam was significantly superior on all measures. By observer rating, 18 patients showed at least moderate improvement with diazepam compared with seven receiving propranolol. Panic attacks and phobic symptoms responded to diazepam, but not to propranolol. The results suggest that benzodiazepines constitute effective short-term treatment for these newly defined disorders.