M. W. Van Laar

Therapeutic effects and effects on actual driving performance of chronically administered buspirone and diazepam in anxious outpatients

Two groups of 12 outpatients each (six men and six women) with generalized anxiety disorder, participated in this study. Each patient was treated single-blind with placebo during the first 7 days (baseline), followed by a double-blind drug treatment period of 4 consecutive weeks (active) and ending again with 7 days single-blind placebo treatment (washout). One group received buspirone 5 mg three times a day in the first week and continued with 10 mg in the morning, 5 mg in the afternoon, and 5 mg in the evening during the second, third, and fourth weeks. The other group received diazepam 5 mg three times a day in all 4 weeks. On the evening of the seventh day of each treatment week the Hamilton Rating Scale for Anxiety and the Symptom Check List (90 items) were applied to assess the therapeutic effects, followed by an on-the-road driving test that started 1.5 hours after the last drug or placebo intake. The test consisted of operating an instrumented vehicle over a 100 kilometer highway circuit while attempting to maintain a constant speed and a steady lateral position within the right traffic lane. Two patients in the diazepam group were unable to complete their test after the first and second treatment week, respectively, because of serious sedative reactions. Both buspirone and diazepam were equally effective in reducing overall anxiety symptoms. The specific profiles showed that buspirone also reduced concomitant depressive symptoms and symptoms of interpersonal sensitivity and anger-hostility. In contrast, diazepam was found to be slightly more effective in reducing somatic symptoms and to positively affect sleep disturbances. Moreover, abrupt discontinuation of diazepam resulted in a relapse of psychic anxiety symptoms comparable with the placebo-baseline level and a partial relapse of somatic anxiety symptoms. Chronic treatment with buspirone had no significant effects on lateral position and speed control. In contrast, diazepam significantly impaired control of lateral position in the first 3 weeks of treatment. There was no significant impairment in the fourth treatment week and the placebo-washout week. Speed control was significantly impaired only in the first week. The relevance of the trend toward decreasing performance impairment during chronic treatment remains to be established.

Acute and subchronic effects of nefazodone and imipramine on highway driving, cognitive functions, and daytime sleepiness in healthy adult and elderly subjects

The acute and subchronic effects of two dosages of a new serotonergic antidepressant, nefazodone, and those of the tricyclic imipramine were examined in a double-blind, crossover, placebo-controlled study. Twenty-four healthy subjects from two age groups (12 adults and 12 elderly from both sexes) received the four treatments (nefazodone, 100 and 200 mg twice daily; imipramine, 50 mg twice daily; and placebo) for 7 days with a 7-day washout period. Measurements were performed after the morning doses on day 1 and day 7. These included a standard over-the-road highway driving test, a psychomotor test battery, and sleep latency tests. Blood samples were taken on both days and analyzed to determine concentrations of parent drugs and their major metabolites. The main results showed that the reference drug, imipramine, had a detrimental effect after a single dose on lateral position control in the driving test, primarily in the adult group, that diminished after repeated dosing. Minor impairment on psychomotor test performance was found with both days. On the other hand, a single administration of both doses of nefazodone did not impair highway driving performance (even showed some improvement) and had no or only minor effects on psychomotor performance. After repeated dosing, nefazodone 200 mg twice daily (but not the 100-mg dose) produced slight impairment of lateral position control; dose-related impairment of cognitive and memory functions was found. The effects of nefazodone were generally in the same direction in both age groups. Significant correlations were found between steady-state concentrations of nefazodone in plasma (200-mg, twice-daily condition) as well as imipramine, and reaction time changes in a memory scanning task. Neither drug appeared to induce daytime sleepiness as measured by the sleep latency tests.

Driving and Benzodiazepine Use

Although the data are sparse, epidemiological studies show that benzodiazepine use increases the relative risk of being involved in a traffic accident by a factor of from 1.5 to about 6.5, depending on dose, number of benzodiazepines used and recency of use. These risks are similar to those associated with blood alcohol concentrations of about 0.6 and 1 g/L, respectively. Experimental studies employing on-the-road driving, driving simulation and laboratory tests measuring skills related to driving have clearly established the dose-dependent performance-impairing effects of benzodiazepines.Benzodiazepine hypnotics vary considerably in their potential to produce residual effects in the morning after nocturnal use. The main determinants of the degree and duration of action after a single dose are size of dose, rate and extent of distribution, lipophilicity and receptor affinity. With repeated administration, compounds with a long elimination half-life (t1/2β) are likely to accumulate and produce increased sedation. Diazepam may have a rapid onset of action precipitating the risk of sudden intoxication, but its duration of action is relatively short after a single dose (acute tolerance). The impairing effects of diazepam on driving performance may persist at least during the first 3 weeks of daily administration. The issue of tolerance has not yet been adequately explored and patients should be warned that their performance may not return to the premedication level. Elderly patients may be more sensitive to the sedative and performance-impairing effects than the young, although the evidence is equivocal. Caution is warranted with concomitant use of CNS depressants, such as alcohol, and with drugs interfering with the metabolic pathways of benzodiazepines. Considerable interindividual differences in sensitivity to the behavioural effects of benzodiazepines warrant the careful monitoring of patients. Physicians should educate their patients about the risk of traffic accident during benzodiazepine use

Effects of phentermine and pentobarbital on choice processes during multiple probability learning (MPL) and decision processes manipulated by pay-off conditions

The primary research question in this investigation concerned whether arousal manipulation by a stimulant (phentermine 20 mg) and a depressant (pentobarbital 100 mg) will oppositely affect choice behaviour in a probability learning task and decision processes manipulated by pay‐off. A 3‐source probability learning task was used for this purpose, in that, upon the presentation of a pacing cue (every 2 s) which initiates a sampling response required the subject to predict which source will contain a signal. Three groups of 12 subjects received the drugs or placebo, double‐blind and crossover. One group performed the task under an all‐or‐none pay‐off function (V1), wherein correct responses on the high (0·60), medium (0·30) or low (0·10) probability source were equally paid; the second group performed the task under a pay‐off function, approximately inversely proportional to the signal probability ratio (V2), wherein their gain was maximal on the low probability source when their predictions were correct on this event; while the third group was paid according to a pay‐off function (V3), closely related to the first, in that, the maximum gain could be reached when predictions were correct on the high or medium probability source. The results showed that pentobarbital significantly increased sampling responses on the low probability source in the V1 group, while the effects of phentermine did not reach significance when compared to placebo. In the V2 group, no significant treatment effects were found on sampling responses on the high, medium or low probability source a finding explained in the context of arousal theory. Further, in the V3 group relative to placebo, both phentermine and pentobarbital marginally significantly increased and decreased sampling responses on the medium probability source, respectively. These effects reached significance on the low probability source for both drugs when compared to placebo. It was concluded that: (1) the results generally confirm the expectations regarding the different pay‐off conditions and the general finding that full maximization is hardly ever found in probability learning experiments; (2) the expected effects of the drugs were overall small but consistent and in the hypothesized direction; (3) significant drug effects were mostly found on the low probability source; (4) pentobarbital produced more behavioural changes than phentermine.

Information selection and signal probability in multisource monitoring under the influence of centrally active drugs : Phentermine versus pentobarbital

The present study is concerned with the relationship between drug‐induced arousal shifts and sampling [(monitoring)] behaviour in a three‐source task with ana priori signal occurrence probability of 0·6, 0·3, and 0·1. The multisource monitoring task and procedure was adopted from Hockey (1973) who reported that an arousing treatment, loud noise, produced increased sampling of the course associated with the high signal probability while sleep loss, presumed to decrease arousal level, resulted in a reduction of sampling on this source. Consistent with these findings it was expected that phentermine 20 mg (a stimulant, with a chemical structure related to that of amphetamines) and pentobarbital 100 mg (a barbiturate) would show the same pattern of results, given their opposite effects on brain arousal. Twenty‐four male subjects participated in the study and received the drugs according to a placebo‐controlled double‐blind, three‐way crossover design. In contrast to the results from Hockeys study, neither phentermine nor pentobarbital significantly affected average sampling behaviour on the high probability source. Differential drug effects appeared primarily on the low probability source, in that phentermine significantly reduced sampling on this source and pentobarbital produced the highest number of sampling responses to detect signals on this source. The possible reasons for the discrepancy between Hockeys and the present results are discussed.