Effects of sertraline on autonomic and cognitive functions in healthy volunteers

Rationale Though sertraline, a selective serotonin reuptake inhibitor (SSRI), causes autonomic and cognitive adverse events such as dry mouth and somnolence, there is a paucity of appropriately designed studies on the cognitive and autonomic effects of the drug in the literature. Objective To compare the effects of sertraline on cognitive and autonomic functions with those of placebo in healthy humans. Method A randomized, double blind, cross over study of 12 healthy male volunteers aged 24 (21– 32; median; range) years. Subjects orally received 50 mg sertraline and placebo once daily for periods of 14 days each with at least 14 days in between. Heart rate variability (HRV), skin conductance level (SCL) and skin conductance response (SCR) following sudden deep respiration were employed as parameters for autonomic function. Quantitative EEG (qEEG) and psychometric tests served as parameters for cognitive function. Measurements were performed repeatedly before the start of drug administration and on the last treatment day. Results Sertraline caused a significant reduction of heart rate and SCL (P<0.05), whereas HRV and SCR were not changed. Cognitive functions such as flicker fusion frequency, memory, choice reaction time and psychomotor performance were not influenced by sertraline but slow and fast beta power density in the qEEG was increased. Conclusion Cognitive and psychomotor performance are not altered in healthy humans receiving multiple dosing with sertraline. The observed decreases in heart rate and SCL may be due to a sympatho-inhibitory effect of sertraline.     

Effects of reboxetine on Hamilton Depression Rating Scale factors from randomized, placebo-controlled trials in major depression

Reboxetine is the first selective norepinephrine reuptake inhibitor (NRI) approved for the treatment of major depressive disorder (MDD). Although reboxetine has demonstrated efficacy for the treatment of depression, its effects on specific depressive symptoms have not been reported. We evaluated the effects of reboxetine on four Hamilton Depression Rating Scale (HAM-D) factors: psychomotor retardation, anxiety, cognitive disturbance and insomnia. Data were obtained from four short-term (4-8-week), randomized, placebo-controlled trials of reboxetine for the treatment of MDD. For each study, mean changes in HAM-D symptom factor scores from randomization to the study endpoint were compared between reboxetine and placebo. In addition, data from all four studies were pooled to determine the proportions of patients who either improved or worsened with treatment were compared between placebo (n = 353) and reboxetine (n = 350) treatment groups. Compared to placebo, reboxetine significantly improved psychomotor retardation in all four trials. Cognitive disturbance and anxiety were improved in three of four trials, and insomnia was improved in one trial with a positive trend in the second trial. Reboxetine, a selective NRI, improves symptoms of psychomotor retardation, anxiety and cognitive disturbance during treatment of MDD.     

The effects of St John's wort extract on heart rate variability,cognitive function and quantitative EEG: a comparison with amitriptyline and placebo in healthy men

AIMS: To compare the effects of multiple dosing with St John's wort (Hypericum perforatum) extract and amitriptyline on heart rate variability, cognitive function and quantitative EEG (qEEG) with placebo in healthy humans. METHODS: A randomized, double-blind, cross over study of 12 healthy male volunteers. Subjects orally received capsules with 255-285 mg St John's wort extract (900 micro g hypericin content), 25 mg amitriptyline and placebo three times daily for periods of 14 days each with at least 14 days between. The doses of amitriptyline and St John's wort extract are comparable with respect to their antidepressant activity. Compliance was confirmed by coadministration of 10 mg of riboflavin with each capsule and detection of urinary vitamin B2 on treatment day 11 with high performance liquid chromatography. Measurements of heart rate variability, psychometric tests and qEEG were performed before start of medication and repeatedly on the last treatment day. RESULTS: St John's wort extract did not affect heart rate variability (HRV) whereas amitripytline significantly decreased it: the difference in the percentage number of adjacent RR intervals> 50 ms (pNN50) was 8.6 (-2.6, 19.9; mean; 95% confidence interval) between St John's wort extract and placebo and -17.6 (-24.7, -10.4) between amitriptyline and placebo. Neither St John's wort extract nor amitriptyline had an influence on cognitive performance such as choice reaction, psychomotor coordination, short-term memory and responsiveness to distractive stimuli. Amitriptyline but not St John's wort extract decreased self rated activity (P < 0.05). Both drugs caused significant qEEG changes. St John's wort extract increased theta power density. Amitriptyline increased theta as well as fast alpha power density. CONCLUSIONS: Multiple doses of St John's wort extract do not affect heart rate variability nor cognitive function. Chronic administration of amitriptyline causes a decrement of HRV and subjective sedation but it does not impair cognitive performance.     

The effects of reboxetine and amitriptyline, with and without alcohol on cognitive function and psychomotor performance

Reboxetine is a novel antidepressant that has been shown to be effective in the treatment of major depressive disorders. The present experiment was designed to assess whether it affects the cognitive and psychomotor skills necessary for optimum function in everyday life. Ten healthy male volunteers received reboxetine 0.5  mg, 1  mg or 4  mg, amitriptyline 25  mg, or matched placebo with and without alcohol (0.6  mg  kg⁻¹) in a double-blind 10-way crossover study. A psychometric test battery was administered at baseline and at 1, 2.25, 3.5, 6 and 9  h post-dose. The results showed that reboxetine had little or no effect on performance at any dose, compared with placebo. Amitriptyline, however, with and without alcohol, lowered critical flicker fusion threshold compared with placebo and/or reboxetine at all test points (e.g. at 3.5  h: 28.51   vs 30.33  Hz; P <0.05); increased reaction time (e.g. 619   vs 540  ms; P <0.05); increased tracking error (e.g. 16.34 vs 8.54 RMS units; P <0.05); and slowed short-term memory scanning (e.g. 742 vs 590  ms; P <0.05). It is concluded that reboxetine at doses of 4  mg and below is free from disruptive effects on cognitive function and psychomotor performance, and that it does not act synergistically with alcohol, in contrast to amitriptyline.     

Reboxetine versus paroxetine versus placebo: effects on cognitive functioning in depressed patients

Impaired cognitive functioning is often associated with major depressive disorder (MDD). Moreover, a number of agents used to treat MDD are known to have negative effects on cognitive functioning. We report an assessment of the effects of the selective norepinephrine reuptake inhibitor reboxetine, the selective serotonin reuptake inhibitor paroxetine, and placebo on a variety of measures of cognitive functioning in patients with MDD. Cognitive functioning in 74 adult patients (aged 18-65 years) with a confirmed diagnosis of MDD (DSM-IV) was assessed as part of two identical, randomized, double-blind, placebo- and active-treatment-controlled, fixed/flexible dose comparisons of 8 weeks of treatment with reboxetine (8-10 mg/day), paroxetine (20-40 mg/day) and placebo. Cognitive function was assessed at baseline, day 14 and day 56 using a selection of tasks from the Cognitive Drug Research computerized assessment system, including Simple Reaction Time, Digit Vigilance, Choice Reaction Time, Numeric Working Memory, Word Recognition and Critical Flicker Frequency. The results in the 74 patients (reboxetine n = 25, paroxetine n = 23, placebo n = 26) showed that reboxetine significantly improved the ability to sustain attention at day 56 compared with baseline (P = 0.023). In addition, patients who received reboxetine experienced significant improvements in their speed of cognitive functioning when tested at day 56 compared to baseline (P = 0.024). No significant changes or trends in this direction were seen among patients who received either placebo or paroxetine. The results of the present study provide objective data to support the possibility that reboxetine favourably affects cognitive processes in depressed patients.     

Noradrenergic Enhancement of Motor Learning,Attention, and Working Memory in Humans

BackgroundNoradrenaline has an important role as a neuromodulator of the central nervous system. Noradrenergic enhancement was recently shown to enhance glutamate-dependent cortical facilitation and long term potentiation-like plasticity. As cortical excitability and plasticity are closely linked to various cognitive processes, here we aimed to explore whether these alterations are associated with respective cognitive performance changes. Specifically, we assessed the impact of noradrenergic enhancement on motor learning (serial reaction time task), attentional processes (Stroop interference task), and working memory performance (n-back letter task).MethodsThe study was conducted in a cross-over design. Twenty-five healthy humans performed the respective cognitive tasks after a single dose of the noradrenaline reuptake inhibitor reboxetine or placebo administration.ResultsThe results show that motor learning, attentional processes, and working memory performance in healthy participants were improved by reboxetine application compared with placebo.ConclusionsThe results of the present study thus suggest that noradrenergic enhancement can improve memory formation and executive functions in healthy humans. The respective changes are in line with related effects of noradrenaline on cortical excitability and plasticity.     

A double-blind, placebo-controlled investigation of the residual psychomotor and cognitive effects of zolpidem-MR in healthy elderly volunteers

AIM: To assess residual psychomotor and cognitive effects of a modified-release formulation of zolpidem (zolpidem-MR), developed to provide sustained hypnotic efficacy during the whole night, compared with placebo and flurazepam. METHODS: Twenty-four healthy elderly volunteers received four study treatments (zolpidem-MR 6.25 mg and 12.5 mg, placebo and flurazepam 30 mg) using a randomized, cross-over, double-blind design. Residual psychomotor and cognitive effects were assessed with a psychometric test battery. Quality of sleep and residual effects were evaluated subjectively with the Leeds Sleep Evaluation Questionnaire. RESULTS: Psychometric performance was significantly impaired with flurazepam but not with zolpidem-MR at either dose. Ease of falling asleep and sleep quality were significantly improved with both doses of zolpidem-MR and with flurazepam. Neither active drug modified perception of well-being on awakening. CONCLUSION: In elderly subjects, zolpidem-MR showed no residual functional impairment in psychometric or cognitive tests sensitive to flurazepam.     

Comparison of the effects of fengabine,a novel antidepressant,with those of amitriptyline on psychomotor and autonomic functions in healthy volunteers

Two single doses (300 and 600 mg) of fengabine, a novel antidepressant, a single dose (50 mg) of amitriptyline, and a single dose of placebo were taken by sixteen male healthy volunteers (18–30 years), in weekly experimental sessions, according to a balanced double-blind cross-over design. In Part A (eight subjects) subjective mood state, psychomotor performance and some baseline autonomic functions were measured before, and 1, 3 and 5 hours after drug taking. In Part B, cholinoceptor-mediated tissue responses (pilocarpine-evoked miosis and carbachol-evoked sweating) were measured two and a half hours after drug taking. Fengabine and placebo did not affect any of the test results, whereas amitriptyline had effects consistent with the sedative (reduction in alertness, impairment of psychomotor performance) and antimuscarinic (reduction in salivation and carbachol-evoked sweating) properties of the drug.     

A double-blind, placebo-controlled investigation of the effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor function

AIMS: To assess whether fexofenadine in a range of doses from 80 to 180 mg has any disruptive effects on aspects of psychomotor and cognitive function in comparison with placebo, loratadine and promethazine, an antihistamine known to produce psychomotor and cognitive impairment. METHODS: Twenty-four healthy volunteers received fexofenadine 80 mg, 120 mg and 180 mg, loratadine 10 mg, promethazine 30 mg (as a positive internal control) and placebo in a six-way crossover, double-blind study. Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1.5, 3, 6, 9, 12 and 24 h post dose. The test battery included critical flicker fusion (CFF), choice reaction time (CRT) and assessment of subjective sedation (LARS). Overall levels of activity were monitored by means of wrist mounted actigraphs throughout each of the 24 h experimental periods. RESULTS: Fexofenadine at all doses tested was not statistically different from placebo in any of the tests used and loratadine did not cause any significant impairment of cognitive function. Significant impairments were found following promethazine. Promethazine caused a significant reduction in CFF threshold and this effect was evident up to 12 h post dose (P<0.05). There was a significant increase in recognition reaction time at 3 and 6 h post promethazine administration, and the drug caused a significant (P<0. 002) increase in the percentage of 'sleep-like' activity from actigraph records during the daytime. CONCLUSIONS: Fexofenadine at doses up to 180 mg appears free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the verum control promethazine 30 mg.     

Dose-response analysis of the behavioral effects of diazepam: II. Psychomotor performance,cognition and mood

The psychomotor, cognitive, and mood effects of orally administered diazepam and placebo were measured over 3.5 h. A total of 120 volunteers were assigned to 12 groups of 10 each, representing the combination of four treatments (placebo, 0.1, 0.2, and 0.3 mg/kg diazepam) and three testing sessions (7 AM, 1 PM, and 7 PM). A variety of cognitive tasks, tapping and postural stability tests, and a mood evaluation scale were used. Psychomotor and cognitive functions showed consistent dose-response effects, while for subjective evaluations, the only effect of dose level was in the duration of sedation. The pattern of impairment of cognitive functions suggests that the drug affects speed rather than accuracy, and it primarily blocks acquisition of new information or skills. Use of repeated testing may therefore be necessary to detect subtle drug effects. Subjects reported no tranquilization, which suggests that the anxiolytic action of the drug cannot be studied in healthy volunteers. There was no circadian influence on the actions of the drug.     

Cognitive effects of oxybutynin chloride topical gel in older healthy subjects: a 1-week, randomized, double-blind, placebo- and active-controlled study

Background and Objective: Oxybutynin is a common antimuscarinic therapy for overactive bladder. Transdermally administered oxybutynin chloride topical gel 10% (OTG) has a low propensity for anticholinergic adverse effects and possibly also a low risk of cognitive impairment. A randomized, double-blind, placebo- and active-controlled study evaluated the effects of OTG on cognitive and psychomotor functions in older healthy adults. Methods: Healthy adults aged 60-79 years were assigned randomly (1:1:1) to 1-week's treatment with OTG (1?g [100?mg oxybutynin] applied once daily on rotating sites of upper arms/shoulders, abdomen or thighs) plus oral placebo, immediate-release oxybutynin (OXB-IR; 5?mg capsule three times/day) plus placebo gel, or double placebo. Delayed recall Name-Face Association Test (NFAT) score was the primary end point. Treatments were compared by analysis of covariance. Results: Of 152 participants (mean age, 68 years), 49 received OTG, 52 OXB-IR and 51 placebo. NFAT Delayed Recall tests revealed no significant treatment differences (overall, p?=?0.2733; OTG vs placebo, p?=?0.1551; OXB-IR vs placebo, p?=?0.1767). However, a significant effect (p?=?0.0294) was noted for the Misplaced Objects Test, with scores declining only for OXB-IR. Approximately twice as many participants receiving OXB-IR (n?=?10) as those receiving OTG (n?=?5) or placebo (n?=?6) showed a significant decline (≥6 points) in Total Recall score for the Hopkins Verbal Learning Test-Revised. No significant effects on psychomotor reaction time were observed. The most common adverse event, dry mouth, occurred in 6.1%, 73.1% and 7.8% of participants receiving OTG, OXB-IR and placebo, respectively. Conclusions: OTG applied for 1 week had no clinically meaningful effect on recent memory or other cognitive functions in healthy, older adults. Clinical Trial Registration: Registered as NCT00752141 at www.clinicaltrials.gov.     

The effects of acute and repeated doses of moclobemide on psychomotor performance and cognitive function in healthy elderly volunteers

The effects of moclobemide, a new selective and reversible MAO-A inhibitor, on cognitive function and psychomotor performance were measured in 12 healthy elderly male volunteers (with a mean age of 72.5 years). Subjects received moclobemide 200 mg, amitriptyline (positive internal control) 25 mg or placebo twice daily and were assessed on a battery of psychometric tests on the mornings following the first (acute) day and seventh (sub-chronic) day. The tests were: Choice Reaction Time; Tracking; Critical Flicker Fusion Threshold; Memory Scanning; Continuous Attention Task; the Leeds Sleep Evaluation Questionnaire and a Visual Line Analogue Rating Scale. The results show that amitriptyline produced impairment of cognitive and psychomotor functions. Moclobemide, however, did not disrupt sleep or cause daytime sedation, and remained neutral in the assessment of behavioural toxicity.     

The effects of venlafaxine on autonomic functions in healthy volunteers

Antidepressants that block norepinephrine uptake may cause unwanted effects on autonomic functions such as reduction of heart rate variability. This randomized, double-blind, placebo-controlled study examined the effects of venlafaxine on heart rate variability, vasoconstrictory responses (VRs) of cutaneous blood vessels, and pupillary light reflex in humans. Twelve healthy male subjects aged 23 to 32 years (mean +/- SD, 26 +/- 3 years) orally received 37.5 mg of venlafaxine BID for 7 days and subsequently 75 mg BID for another 7 days. After a 14-day washout phase, placebo was administered to the subjects for 14 days under randomized double-blind crossover conditions. Heart rate variability was diminished, and the dilation phase of VR was prolonged during multiple dosing with venlafaxine (P < 0.05). A significant increase in resting pupil diameter, a decrease in amplitude, an increase in latency, and a shortening of the 33% recovery time of the pupillary light reflex were noted with the drug, whereas no changes were observed under placebo condition. Sustained VR and shortening of the recovery time of the pupillary light reflex are consistent with sympathetic potentiation resulting from noradrenaline reuptake blockade in cutaneous blood vessels and iris. The decrease in amplitude and increase in latency of the pupillary light reflex could be indicative of centrally mediated parasympathetic inhibition.     

The effects of St. John's wort extract and amitriptyline on autonomic responses of blood vessels and sweat glands in healthy volunteers

St. John's wort extract is widely used and advertised as a "natural antidepressant" lacking autonomic side effects. This randomized, double-blind, placebo-controlled study compared the effects of St. John's wort extract on autonomic responses of blood vessels and sweat glands with those of amitriptyline and placebo. A randomized, double-blind, crossover study was performed in healthy male volunteers aged 22 to 31 years (25 +/- 3 years; mean +/- SD) years. Subjects orally received capsules with 255 to 285 mg St. John's wort extract (900 microg hypericin content), 25 mg amitriptyline, and placebo 3 times daily for periods of 14 days each with at least 14 days between. Vasoconstrictory response of cutaneous blood flow (VR) and skin conductance response (SR) following a single deep inspiration were employed as parameters of autonomic function. St. John's wort extract had no effect on VR and SR. In contrast, SR was diminished and the dilation phase of VR was prolonged following multiple dosing with amitriptyline (P < 0.05). Decreased electrodermal reactivity observed with amitriptyline reflects inhibition of acetylcholine at peripheral m3-cholinoreceptors, whereas prolongation of VR induced by the tricyclic drug may be due to sustained activation of central and/or peripheral sympathetic neurons.     

The effects of amitriptyline, citalopram and reboxetine on autonomic nervous system

RATIONALE: In therapeutic use, amitriptyline, reboxetine and citalopram have all been associated with apparent anticholinergic-like side effects (dry mouth, constipation, etc.), despite the very low antimuscarinic activity of reboxetine and citalopram in vitro. OBJECTIVES: We hypothesised that the spectral analysis of heart rate variability (HRV) might detect differences between amitriptyline, citalopram and reboxetine in their anticholinergic activities following a single peroral administration. METHODS: In this double-blind, cross-over study, amitriptyline (75 mg), citalopram (20 mg), reboxetine (4 mg) and placebo were randomly given at 1-week intervals to eight healthy male volunteers. Drug and catecholamine concentrations in plasma were determined repeatedly. The drug effect was assessed with periodic recordings of electrocardiogram (ECG) and blood pressure, and with measurements of salivary secretion. The ECG recordings were subjected to spectral analysis of HRV, in which the high frequency (HF) power of R-R interval (RRI) variability was supposed to reflect cardiac parasympathetic tone. RESULTS: Reboxetine increased heart rate and blood pressure and reduced the HF power of RRI and 3,4-dihydroxyphenylglycol (DHPG) plasma concentrations. Amitriptyline diminished salivary secretion and had a prominent sedative action. Measurements after citalopram did not differ significantly from placebo. CONCLUSIONS: Reboxetine, despite its low antimuscarinic activity in vitro, had distinct effects on the HF power of RRI, consistent with anticholinergic activity in vivo. Amitriptyline had a measurable anticholinergic effect in the salivary glands, but, surprisingly, not in the heart. We suggest that the sedative effect of amitriptyline could alter cardiac sympathovagal balance and, therefore, counteract the anticholinergic drug effect.     

Effects of reboxetine on sleep and nocturnal cardiac autonomic activity in patients with dysthymia

Antidepressants may have sleep and autonomic side-effects. The acute and long-term effect of reboxetine (2 mg b.i.d.) on sleep and cardiac autonomic activity was compared with that of placebo in a single-blind study. Twelve patients affected by dysthymia underwent four polysomnographic studies at baseline (placebo); at night 3 (reboxetine; acute effect); at night 9 (reboxetine; intermediate-term effect); and at night 122 (reboxetine; chronic effect). After the first administration, reboxetine increased time awake after sleep onset, number of awakenings, percentage of stages 1 and 2 non-rapid eye movement (REM), and reduced the amount of stages 3-4 non-REM, but all these effects disappeared by continuing treatment. However, reboxetine caused a persistent suppression of REM sleep, which was accompanied by an increase of REM sleep latency. The spectral analysis of heart rate variability showed a trend towards an increase in sympathetic activity with both acute and intermediate reboxetine use. Long-term treatment with 4 mg reboxetine does not cause significant changes in cardiac autonomic function.     

No effects of enhanced central norepinephrine on finger-sequence learning and attention

Rationale When paired with training, substances that increase monoaminergic transmission in the brain support motor and language learning in healthy subjects and in rehabilitation after brain lesions.Objectives To test the hypotheses that enhancement of central norepinephrine by the selective norepinephrine reuptake inhibitor reboxetine (1) improves skilled motor performance, (2) promotes skilled motor learning, and (3) does not exert these effects by modulation of attention.Methods In a double blind, placebo-controlled, crossover study in healthy, adult subjects (n=16), finger-sequence performance and learning was measured after the stimulation of the central noradrenergic system with a single dose (8 mg) of reboxetine and placebo. Effects on attention were assessed by the standardized continuous performance test “CPT-M”.Results No differential effects of reboxetine or placebo on finger-sequence performance, learning and parameters of attention were found.Conclusion Selective stimulation of the central noradrenergic system did not promote skilled motor learning or performance as assessed by finger-sequences. The plasticity-enhancing effect of reboxetine, documented in other studies, appears to be dependent on specific neurophysiological and neuropsychological characteristics of the task, and cannot be generalized to other behavioral paradigms.     

Effects of physostigmine on scopolamine–induced changes in quantitative electroencephalogram and cognitive performance

The effects of physostigmine on scopolamine-induced changes were investigated in a randomized, double-blind cross-over study utilizing quantitative electroencephalogram (qEEG) and cognitive tasks. Ten healthy male volunteers received scopolamine 0·6 mg subcutaneously. After 90 min, single doses of either 0·5, 1·0 and 2·0 mg physostigmine salicylate or placebo were administered subcutaneously in randomized order. qEEG, cognitive function and the visual analogue scale were recorded before and at 1, 2, 3, 4, 6, and 8 h after scopolamine administration; that was 0·5, 1·5, 2·5, 4·5, and 6·5 h after physostigmine administration. Scopolamine produced an increase in delta (1·25–4·50 Hz) and theta power (4·75–6·75 Hz) in qEEG 1 h after administration compared to baseline, while physostigmine decreased the spectral delta power density in qEEG compared to placebo. The maximal effect of physostigmine was seen up to 1·5 h after injection. A dose-dependent reversal of the scopolamine induced decrements in cognitive performance was found 0·5 h after administration of physostigmine. Psychometric tests sensitively discriminated between the doses of physostigmine, and showed dose- and time-dependent effects. The results suggest that physostigmine may reverse the scopolamine-induced changes in both qEEG and cognitive function. This reversal was temporary and of short duration. © 1998 John Wiley & Sons, Ltd.     

A method for determining the magnitude of change across different cognitive functions in clinical trials: the effects of acute administration of two different doses alprazolam

While there is no doubt that benzodiazepine administration leads to transient cognitive impairment in healthy adults, the nature and magnitude of such impairment has not been well described. The cognitive effects of a single dose of alprazolam 0.5 and 1 mg were therefore assessed in 36 healthy adults on measures of psychomotor function, visual attention, working memory, planning and learning in a double-blind parallel-groups study. Measures of these different cognitive functions were selected on the basis of their brevity and because they yielded distributions of performance data that were without skew, floor or ceiling effects of range restriction (i.e. normal distributions). With data satisfying the assumptions for parametric analysis, measures of effect size could be computed in addition to significance testing, thus allowing for direct and meaningful comparison between the different performance measures used. Alprazolam 0.5 mg reduced only the speed of attentional performance although the magnitude of this reduction was large (d = 0.8). At 1.0 mg, impairments in psychomotor function, equivalent to that seen for attentional function at the lower dose, were observed. In addition, moderate (d approx = 0.5) impairments in working memory, and learning also became obvious. When considered together, these results suggest that low-dose alprazolam primarily alters visual attentional function. At the higher dose psychomotor functions also become impaired, and it is likely that the combination of these led to the observed moderate impairments in higher level executive and memory processes. The current study also illustrates a method for directly comparing the magnitude of change in cognitive function between measures with different performance metrics.