Effects of psychotropic drugs on digit substitution: comparison of the computerized symbol-digit substitution and traditional digit-symbol substitution tests.

The digit-symbol substitution test (DSST), performed with paper and pencil or computerized, is widely used to reveal decrements in human attention and cognition. We programmed sets of adjustable tasks (digit-symbol, digit-digit, symbol-digit, symbol-symbol) into a microcomputer and compared the symbol-digit substitution (SDST) and the digit copying test (DDCT) with the traditional DSST in two placebo-controlled double-blind studies of psychotropic drugs with pre-trained young healthy subjects. Performances were measured before drug intake and several times after it; matched, different codes were used at consecutive tests. DSST and SDST substitutions remained at the baseline level after placebo, while the simple DDCT performance improved during the placebo session. The prolonged (3 min) test was not exhaustive because interim counts at 90 s predicted the final performance well. In Trial I, 15 mg diazepam orally reduced DSST and SDST functions in a similar way, but it also impaired simple copying in the DDCT, though to a lesser extent. Ebastine, an H(1)-antihistamine, proved inert alone and failed to increase the effects of diazepam on these variables. In Trial II, 7.5 mg zopiclone, 0.4 mg suriclone and 50 mg chlorpromazine, alone and in combinations, impaired the DSST performance in the manner expected. The drug effects were similar in the SDST, and somewhat less in the DDCT, while the substitution errors were subject related and not altered significantly by any treatment. The simple correlation matrices (Pearson, Spearman), confirmed by analysis of covariance, showed that the results of DSST correlated fairly well with those of SDST after zopiclone, chlorpromazine and their combination, but not after suriclone or its combination with chlorpromazine. The DDCT results correlated with those of the substitution tests when analysing pooled baseline values, but not when analysing the performances after drug intake. Subjective visual analogue variables correlated poorly or not at all with objective performances. Our results suggest that manual dexterity in these computerized tests might contribute significantly to the total impairment of performance in response to different drugs. The DSST and SDST matched each other fairly well in their sensitivity to drug effects, yet this similarity may depend on the drug used.

Caffeine moderately antagonizes the effects of triazolam and zopiclone on the psychomotor performance of healthy subjects.

To determine whether caffeine antagonizes the decremental effects of triazolam and zopiclone on human performance, oral single doses of 0.250 mg triazolam, 7.5 mg zopiclone, or respective placebos, with and without 300 mg caffeine, were given to parallel groups of student volunteers in two double-blind studies. Objective tests and subjective visual analogue ratings were done at baseline and 30 min. and 90 min. after the intake. In Study I, triazolam produced drowsiness at 30 min. but did not differ from the placebo in other tests. Caffeine induced alerting effects in various tests and differed from triazolam in some (digit substitution, drowsiness, calmness, mental slowness) but not all variables measured. Caffeine and triazolam were interpreted as being antagonists. In Study II, zopiclone impaired digit substitution and flicker fusion, produced exophoria and lowered systolic blood pressure. Caffeine differed from zopiclone in several test functions, but it also differed from caffeine + zopiclone whereas zopiclone differed from caffeine + zopiclone only in two tests (Maddox wing, systolic blood pressure). Thus, zopiclone counteracted the effects of caffeine more easily than caffeine counteracted the decremental effects of zopiclone. We conclude that triazolam may not differ importantly from diazepam as regards their antagonism towards caffeine, whereas further research on the antagonism between zopiclone and caffeine needs to be done.

Effect of dexmedetomidine and midazolam on human performance and mood.

The effects of dexmedetomidine (DXM), a novel alpha 2-adrenoceptor agonist, on human performance and mood were studied in a double-blind randomized crossover study in 12 healthy student volunteers. Single IM doses of dexmedetomidine, 0.6 microgram/kg (DXM1) and 1.2 micrograms/kg (DXM2), 80 micrograms/kg midazolam (MID) and saline placebo, were given at one-week intervals. Performance was measured objectively and mood was assessed subjectively with visual analogue scales (VAS) at baseline and 40 min, 2 h, 4 h and 6 h after each injection. Blood pressure and heart rate in the sitting position were measured and venous blood was sampled during each testing round. DXM1 did not significantly impair cognitive (digit symbol substitution), coordinative (tracking) or reactive skills, and at 6 h it shortened reaction time and reduced errors in complex tracking. It produced exophoria, increased body sway with the eyes open and impaired subjective performance on VAS. The higher dose dexmedetomidine also caused impaired cognitive, coordinative and reactive skills (although a trend towards improved coordination was found at 6 h), reduced attention, produced exophoria, increased body sway with the eyes open and caused drowsiness, clumsiness, passiveness and mental slowness on the appropriate VAS scales. MID resembled DXM2 in impaired objective and subjective measures of skilled performance, although the objective effects of MID were of speedier onset and shorter duration. In contrast to MID, DXM caused a significant and dose-dependent decrease in systolic and diastolic blood pressure still detectable 6 h after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Actions of zopiclone and carbamazepine, alone and in combination, on human skilled performance in laboratory and clinical tests.

1. Possible interactions of zopiclone and carbamazepine on human skilled performance were studied in a randomized, double-blind, crossover trial with 12 healthy young subjects. 2. Psychomotor performance (coordination, reactions, attention, cognition) and subjective effects (VAS) were measured and venous blood sampled before and 1.5, 3, 4.5 and 6 h after single oral doses of placebo, 7.5 mg of zopiclone and 600 mg of carbamazepine, which were given alone or combined. Clinical test for drunkenness (CTD) was done 2 and 5 h after drug intake. 3. Both zopiclone and carbamazepine, when administered alone, impaired performance on laboratory tests, the decrements being recorded 1.5 to 6 h after intake. In line with the plasma concentrations, the zopiclone effects peaked earlier (at 1.5 h) and lasted for a shorter time than those of carbamazepine. Zopiclone had a more pronounced effect on perceptual and cognitive functions (digit substitution) and it affected extraocular muscle tone (Maddox wing), whereas carbamazepine had stronger effects on attention. Additive pharmacodynamic actions were found in most tests after the combined treatment with zopiclone and carbamazepine. 4. CTD proved to be less sensitive than the laboratory tests in revealing drug-induced decrement of performance after administration of one agent alone. However, it revealed the combined decremental effects of zopiclone and carbamazepine. 5. When the drugs were given together, the absorption of drugs was retarded. Carbamazepine-10,11-epoxide levels were lower after intake of the drug combination than those measured after intake of carbamazepine alone. 6. The results suggest that the clinical tests developed to detect alcohol effects do not necessarily reveal drug-induced impairment of performance.

Effects of remoxipride on psychomotor performance, alone and in combination with ethanol and diazepam.

The effects of remoxipride, alone and in combination with ethanol and diazepam, on sensory, cognitive, and neuromotor performance were studied in 12 healthy volunteers (7 men, 5 women). The study was of double-blind randomized, crossover design with each subject receiving six different single-dose experimental treatments at six sessions. Tests of sensory, cognitive, and neuromotor functions were carried out, together with subjective assessments. Remoxipride alone seemed to have no effect on the sensory functions measured, but it affected cognitive and neuromotor functions to a limited extent. In general the effects of ethanol and diazepam alone were more pronounced than those of remoxipride. When remoxipride was combined with either ethanol or diazepam, there was a tendency for the effect to be additive.

Objective and subjective effects of remoxipride, alone and in combination with ethanol or diazepam, on performance in healthy subjects.

Effects on human performance of remoxipride (RX), an antipsychotic drug of substituted benzamide structure, were studied in a randomized double-blind crossover trial where 12 young healthy volunteers took at 1 week intervals single oral doses of placebo or remoxipiride 100 mg both alone and in combination with 15 mg diazepam (DZ) or 0.8 g/kg ethanol (EtOH). Objective (digit symbols, tracking, choice reaction, flicker fusion, Maddox wing, body balance, memory) and subjective (visual analogue scales, questionnaire) tests were administered at baseline and 1.5, 3, 4.5 and 6 h post-treatment.

Objective and subjective assessment of hangover during subacute administration of temazepam and nitrazepam to healthy subjects.

Fourteen, healthy students volunteered for a double-blind, cross-over trial of temazepam 20 mg (soft gelatine capsule), nitrazepam 10 mg (uncoated tablet) and placebo in matched formulations, single doses of each being given for 10 nights with a three-week wash-out period between each treatment. Residual drug effects were measured objectively (psychomotor skills) and subjectively (visual analogue scales) in the morning and afternoon of Days 0 (before the first tablet), 1 and 10. The subjects also recorded various events during each treatment period. Serum benzodiazepine concentrations were bioassayed in blood samples taken after the last assessment. Both benzodiazepines shortened sleep latency during the first few nights, and nitrazepam prolonged the duration of sleep. The residual effect of drowsiness was noted during the nitrazepam period, whilst temazepam proved less sedating. The 'morning after' effect was a subjective observation and not an objective measurement. The learning effect interfered with the complex objective assessments, and simple measurement of exophoria with the Maddox wing test provided the clearest objective evidence of drug effects. On Day 10 residual concentrations of nitrazepam were detectable in the serum whereas the level of temazepam was found to be low or negligible. It is concluded, that temazepam 20 mg in a soft gelatine capsule is a suitable hypnotic for subjects whose daily work requires constant alertness.