The effects of reboxetine on autonomic and cognitive functions in healthy volunteers

RATIONALE: Though reboxetine, a selective noradrenaline reuptake inhibitor, causes autonomic and cognitive adverse events 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 reboxetine on cognitive and autonomic functions with those of placebo in healthy humans. METHOD: A randomised, double-blind, crossover study of 12 healthy male volunteers aged 25 (21-27; median, range) years. Subjects orally received 4 mg reboxetine and placebo twice daily for periods of 14 days each with at least 14 days in between. Vasoconstrictory response of cutaneous vessels (VR) and skin conductance response (SCR) following sudden deep breath were employed as parameters for autonomic function. Quantitative EEG (qEEG) and psychometric tests served as parameters for cognitive function. RESULTS: Reboxetine decreased SCR and prolonged the dilation phase of VR (P<0.05). It did not affect cognitive functions such as flicker fusion frequency, choice reaction, memory and psychomotor coordination but increased slow beta (beta1) power density in the qEEG. Tiredness (n=12), dry mouth (n=9), delayed urination (n=3) and constipation (n=1) were noted with reboxetine. CONCLUSION: Sustained peripheral and/or central sympathetic activation accounts for the prolongation of VR. The decrease of SCR and typical side effects suggest a relevant antimuscarinic drug action. Chronic administration of reboxetine at therapeutic doses causes autonomic dysfunction and subjective sedation but does not impair cognitive and psychomotor abilities in healthy humans.     

Effects of risperidone on psychometric and cognitive functions in healthy elderly volunteers

Abstract Rationale. Dementia includes not only cognitive deficit but may also include psychiatric and behavioral symptoms. These psychological symptoms of dementia require specific treatment without deleterious effects on cognitive functions. Objective. The aim of the present study was to assess the effects of a single dose of risperidone (0.25 or 0.5 mg) on psychomotor performances and cognitive functions compared to a placebo and to a positive control, lorazepam 1 mg, in 12 healthy elderly subjects. Methods. This study was a randomized, double-blind, four-way crossover clinical trial involving four 8-h long treatment periods. The pharmacodynamic assessment criteria included a battery of psychomotor tests, a subjective evaluation and an electroencephalogram. Safety was evaluated by clinical laboratory tests, electrocardiogram and recording of adverse events. Concentrations of risperidone, 9-hydroxy-risperidone and lorazepam were determined before and 2 h after dosing. Results. Few significant effects were observed on psychomotor tests with risperidone at all dosages. Risperidone was devoid of any deleterious effects on speed of reaction, vigilance and sustained attention, working and long-term memory and increased cortical arousal. Risperidone demonstrated minor impairment on motor activity (decreased finger taping), postural stability, and information processing (impaired digit symbol substitution). Contentedness subjective evaluation was decreased with risperidone 0.5 mg, 6 h after dosing. No significant difference was observed on EEG frequencies and no sedative activity was detected with risperidone. At 2 h after dosing, risperidone plasma concentrations were 1.54±0.99 ng/ml and 2.80±1.41 ng/ml; 9-hydroxy-risperidone concentrations were 0.77±0.46 ng/ml and 1.54±0.85 ng/ml after intake of 0.25 mg and 0.5 mg doses, respectively. Well-known detrimental effects of lorazepam on psychomotor performances were observed and sedative effects were confirmed by the EEG findings. At 2 h following lorazepam 1 mg administration, plasma concentrations were 13.40±2.17 ng/ml. None of both compounds induced serious adverse events. Conclusion. The results of this clinical trial conducted on healthy subjects demonstrated that low doses of risperidone, but not low doses of lorazepam, did not disturb the cognitive functions in the elderly. Electronic Publication     

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.     

Dose related effects of trimipramine on psychomotor function,memory, and autonomic nervous system activity in healthy volunteers

The effects of single doses of trimipramine, a tricyclic antidepressant (25, 50 and 100 mg) and placebo on psychomotor performance, memory, haemodynamics, pupil diameter and salivary volume, were assessed in 12 normal volunteers. All subjects received each of the four treatments, at weekly interval, according to a double-blind cross-over Latinsquare design. Treatments effects were monitored using a battery of tests including critical flicker fusion (CFF), choice reaction time (CRT), subjective ratings of mood and memory tasks before, and 3 and 8 hours following medication. Supine standing blood pressure, pupil diameter and salivary volume were recorded at the same times. Compared to placebo, trimipramine impaired both subjective and objective measures in a dose-related manner, with 25 mg affecting some subjective ratings and CFF, and 100 mg impairing most objective and subjective evaluations, except memory and haemodynamic variables. Pupil diameter was reduced by 50 and 100 mg trimipramine, whereas salivary volume was affected only by the highest dose studied. In conclusion, the sedative effects of trimipramine appeared dose-related. No amnesic effect could be evidenced, at the doses studied. Changes in autonomic nervous system activity have been shown on pupil diameter and salivary secretion.     

UV法测定盐酸舍曲林片中间体中盐酸舍曲林的含量

目的 建立UV法测定盐酸舍曲林片中间体中盐酸舍曲林的含量。方法 采用紫外．可见分光光度法，在274nm的波长处测定。结果 线性范围为19．75～296．22μg／ml，r=0．9999；平均回收率为101．3％（n=9）。结论 此法快速、准确，可作为生产工艺监控的有效方法。     

Comparison of diphenhydramine and modafinil on arousal and autonomic functions in healthy volunteers

Arousal is regulated by the interplay between wakefulness- and sleep-promoting nuclei. Major wakefulness-promoting nuclei are the histaminergic tuberomamillary nucleus (TMN) of the hypothalamus and the noradrenergic locus coeruleus (LC) of the pons, which also play a role in autonomic regulation. First generation antihistamines, such as diphenhydramine, are likely to cause sedation by blocking excitatory H1 histamine receptors in the cerebral cortex, and the anti-narcolepsy drug modafinil may promote wakefulness by activating the locus coeruleus. We compared the effects of single doses of diphenhydramine (75 mg) and modafinil (200 mg) on arousal and autonomic functions in 16 healthy male volunteers, using a placebo-controlled, balanced, double-blind design. Arousal was assessed by critical flicker fusion frequency (CFFF), visual analogue scales (VAS) and pupillary fatigue waves (Pupillographic Sleepiness Test (PST)). Autonomic functions measured included resting pupil diameter, light and darkness reflex responses, blood pressure, heart rate and salivation. Data were analysed with ANOVA, with multiple comparisons. Diphenhydramine had sedative effects as shown by reductions in CFFF, VAS alertness ratings and increases of the indices of pupillary fatigue. Modafinil had alerting effects as indicated by reductions in the measures of pupillary fatigue. Comparison of pre-post medication changes in pupil diameter showed a decrease after diphenhydramine and an increase after modafinil. Diphenhydramine reduced salivation, and modafinil increased systolic blood pressure. In conclusion, diphenhydramine and modafinil evoked opposite effects on arousal and sympathetic functions, which are likely to reflect their interaction with the central histaminergic and noradrenergic systems. Hyposalivation by diphenhydramine is likely to be due to its additional anticholinergic property.     

舍曲林对晚期肿瘤患者执行功能和生活质量的影响

目的：探讨舍曲林对恶性肿瘤患者执行功能及生活质量的影响,为更好地治疗晚期肿瘤提供参考。方法122例确诊的Ⅲ期或Ⅳ期恶性肿瘤患者经过医院焦虑抑郁量表（HAD）评估后分入抑郁组（n=86）或非抑郁组（n=36）。所有对象接受对症支持治疗的同时,抑郁组患者口服盐酸舍曲林25～75mg/d抗抑郁治疗,治疗周期为12周。在基线及12周末采用汉密尔顿焦虑量表（HAMA）及汉密尔顿抑郁量表（HAMD）评估焦虑抑郁程度,采用0～10视觉等级模拟（VAS）法进行疼痛评估,用威斯康星卡片分类试验（WSCT）评价执行功能,用健康状况调查表（SF-36）评估生活质量。结果基线时抑郁组与非抑郁组相比,焦虑抑郁程度、执行功能及生活质量下降方面均具有统计学差异。经过抗抑郁治疗,抑郁组焦虑抑郁程度改善,但仍显著高于非抑郁组。WSCT分析表明治疗后抑郁组错误总数平均改善（12.1±4.5）分,而非抑郁组却恶化（-2.3±3.8）分。抑郁组成绩的改善得益于持续错误数的改善[（10.8±3.7）vs（-2.4±3.5）],而非抑郁组成绩恶化的主要原因为非持续错误数显著增加[（-8.1±4.7）vs（1.7±4.2）],差异均达到统计学意义（P＜0.05）。SF-36分析发现基线时抑郁组与非抑郁组相比,生理功能（PF）、生理职能（RP）、躯体疼痛（BP）、总体健康（GH）、活力（VT）、社会功能（SF）、情感职能（RE）及精神健康（MH）各维度均明显下降,差异具有统计学意义（P＜0.01）。经过治疗,抑郁组VT、SF、RE、MH改善程度显著高于非抑郁组,分别为[（19.4±10.8）vs（-8.2±7.9）、（28.8±13.5）vs（-11.3±11.0）、（14.9±11.3）vs（-8.6±8.8）、（25.4±10.5） vs（-4.7±6.3）],差异均具有统计学意义（P＜0.05）。多元回归分析表明HAMA、HAMD、疼痛评分、肿瘤分期与生活质量各个维度均存在显著的相关性。结论抑郁是导致晚期肿瘤患者生活质量和执行功能下降和的重要原因,舍曲林可减轻患者的抑郁症状,改善执行功能障碍,提高生活质量。研究结果对于指导临床实践有一定意义。     

Effects of sibutramine alone and with alcohol on cognitive function in healthy volunteers

AIMS: To investigate the effects of sibutramine in combination with alcohol in a double-blind, randomised, placebo-controlled, four-way crossover study in 20 healthy volunteers. METHODS: On each study day each volunteer received either: sibutramine 20 mg+0.5 g kg-1 alcohol; sibutramine 20 mg+placebo alcohol; placebo capsules+0.5 g kg-1 alcohol; or placebo capsules+placebo alcohol. Alcohol was administered 2 h following ingestion of the study capsules. During each study day, assessments of cognitive performance were made prior to dosing, and at 3, 4.5, 6 and 10 h post dosing. Blood alcohol concentration was estimated using a breath alcometer immediately prior to each cognitive performance test session. Each study day was followed by a minimum 7 day washout period. RESULTS: Alcohol was found to produce statistically significant impairments in tests of attention (maximum impairment to speed of digit vigilance=49 ms) and episodic memory (maximum impairment to speed of word recognition=74 ms). Alcohol also increased body sway (maximum increase 17.4 units) and lowered self rated alertness (maximum decrease 13.6 mm). These effects were produced by an inferred blood alcohol level of 53.2 mg dl-1. Sibutramine was not found to potentiate any of the effects of alcohol. There was a small, yet statistically significant, interaction effect observed on the sensitivity index of the picture recognition task. In this test, the combined effects of sibutramine and alcohol were smaller than the impairments produced by alcohol alone. Sibutramine, when dosed alone, was associated with improved performance on several tasks. Sibutramine improved attention (mean speed of digit vigilance improved by 21 ms), picture recognition speed (improvement at 3=81) and motor control (tracking error at 3 h reduced by 1.58 mm). Also sibutramine improved postural stability (reducing body sway at 3 h by 14.2 units). Adverse events reported were unremarkable and consistent with the known pharmacology of sibutramine and alcohol. CONCLUSIONS: There was little evidence of a clinically relevant interaction of sibutramine with the impairment of cognitive function produced by alcohol in healthy volunteers. The single statistically significant interaction indicated a reduction, rather than a worsening, of alcohol-induced impairment when sibutramine is taken concomitantly. Sibutramine when administered alone is associated with improved performance on several tasks.     

Effects of flunitrazepam on cognitive functions

The effects of various oral doses (1, 2, 4 mg) of flunitrazepam on vigilance, attention, immediate memory, short-term memory, learning, non-consolidated and consolidated long-term memory were determined. Twelve healthy young male volunteers were given placebo or flunitrazepam in a double-blind, random latin-square sequence, crossing over every 2 weeks. Volunteers completed a battery of tests at night, 3.5 h after drug administration, and in the morning, 10 h after drug administration. Flunitrazepam 1 mg did not significantly impair any of the functions tested at night, while 4 mg impaired vigilance, attention, immediate memory, short-term verbal memory and learning. The impairments of immediate and short-term memory seem to be related and proportional to reductions in vigilance and attention. Doses of 2 mg and 4 mg impaired the speed of learning but did not decrease the amount of material learned. Flunitrazepam caused dose-related impairment of long-term memory, both consolidated and not. This reduction of long-term memory does not seem to be related to the impairments of vigilance, attention or learning. The lowest dose did not modify vigilance and learning in any subject, improved attention in half of the subjects but reduced long-term memory in a similar number of subjects. Therefore, our results indicate selective impairment of long-term memory. Since there were no differences between the effects on consolidated and non-consolidated memory, the amnesic effect of flunitrazepam seems to be due to a decrease in the storage of memory traces. There were no clear generalized residual effects in the morning after administration.     

Effects of loprazolam on cognitive functions

The effects of oral loprazolam (1, 2 mg) on vigilance, attention, immediate memory, short-term memory, learning, long-term non-consolidated and long-term consolidated memory were determined. Twelve healthy young male volunteers were given all the treatments, placebo or loprazolam, on three different occasions, in a double-blind, random latin-square sequence, crossing over every 2 weeks. Volunteers completed a battery of tests at night, 3.5 h after drug administration, and in the morning, 10 h after drug administration, to test recall of some of the material presented at night (long-term memory) and residual effects. Loprazolam did not significantly impair any of the functions tested at night. On the other hand, 2 mg loprazolam caused impairment of long-term memory, both consolidated and not. This reduction of long-term memory does not seem to be related to the impairments of vigilance, attention or learning. The 2 mg dose of loprazolam, which did not modify the mean scores and improved vigilance, attention and learning in some of the subjects, reduced long-term memory. Therefore, although caution in interpreting the results should be used, mainly because it is possibile that differences in sensitivity of the tests cannot be overcome and because the relative small number of subjects, our results indicate that loprazolam might induce selective impairment of long-term memory. Since there were no differences between the effects on consolidated and non-consolidated memory, the amnesic effect of loprazolam seems to be due to a decrease in the storage of memory traces. There were no clear generalized residual effects in the morning after administration.     

舍曲林在中国健康志愿者体内的药代动力学研究

目的对中国健康志愿者口服不同剂量盐酸舍曲林片后进行药代动力学研究,探讨舍曲林在国人体内的药代动力学特征。方法12名中国健康男性志愿者按拉丁方设计分别口服3种单剂量盐酸舍曲林片(50、100、150 mg),用固相萃取结合高效液相色谱紫外检测法测定血浆中舍曲林的浓度,采用DAS软件拟合药代动力学参数和统计分析。结果计算所得的药动学参数显示,口服50、100、150 mg盐酸舍曲林片的AUC0-96分别为(437.51±80.78)、(804.19±178.11)和(1154.57±243.92)μg.h.L-1;Cm ax分别为:(11.70±2.40)、(22.84±7.05)和(32.61±7.95)μg.L-1,受试者血药浓度随单剂量给药量的增加呈比例的升高,不同剂量组的AUC0-t/Dose、Cm ax/Dose比值间差异无统计学意义(P>0.05)。结论盐酸舍曲林在中国人体内的过程(剂量范围为50~150 mg)显示线性药代动力学特征。     

Comparison of pramipexole and amisulpride on alertness, autonomic and endocrine functions in healthy volunteers

Rationale In a previous study in healthy volunteers, the anti-Parkinsonian drug pramipexole caused sedation and pupil dilatation, consistent with the stimulation of inhibitory D₂/D₃ autoreceptors on the ventral tegmental area dopaminergic neurones. The sedation may be related to the removal of the dopaminergic excitation of the locus coeruleus (via the meso-coerulear pathway), whereas the pupil dilatation may be due to the removal of the dopaminergic excitation of the Edinger–Westphal nucleus (via a putative meso-pupillomotor pathway).Objectives We investigated the hypothesis that amisulpride, a D₂/D₃ receptor antagonist, would have effects opposite to those of pramipexole on alertness, pupillary and endocrine functions.Materials and methods Pramipexole (0.5 mg), amisulpride (50 mg), and their combination were administered to 16 healthy males in a balanced, cross-over, double-blind design. Tests included measures of alertness (Pupillographic Sleepiness Test, critical flicker fusion frequency, visual analogue scales), pupillary functions (resting pupil diameter, light and darkness reflex responses), non-pupillary autonomic functions (heart rate, blood pressure, salivation, core temperature), and endocrine functions [blood concentrations of prolactin, growth hormone (GH) and thyroid stimulating hormone (TSH)]. Data were analysed by ANOVA.Results Pramipexole reduced alertness and pupillary light reflex response amplitude, tended to reduce core temperature, reduced prolactin levels and increased GH levels. Amisulpride reduced pupil diameter, increased the amplitude of the light reflex response and prolactin and TSH levels.Conclusions The opposite effects of pramipexole and amisulpride on alertness, pupillary function and pituitary hormone levels are consistent with their interactions with inhibitory D₂/D₃ receptors on VTA neurones and in the tuberoinfundibular system.     

Dissociation of autonomic and cognitive effects of THC in man

Intravenous THC, 30–44.8 g/kg, was administered to four subjects. Each received THC on four occasions preceded by either i.v. saline, 0.04 mg/kg atropine sulfate, 0.2 mg/kg propranolol, or both drugs together. Heart rates, subjective intoxication and symptom ratings, time productions, and EEG activity were measured. In the absence of autonomic blocking drugs, THC produced characteristic tachycardia, subjective intoxication, and EEG effects. After combined autonomic blockade, THC had no effect on heart rate, while subjective and EEG changes remained as intense. These findings argue against the hypothesis that the subjective and EEG effects of THC are mediated by autonomic receptors or by interoception of peripheral autonomic actions of THC.To whom offprint requests should be sent     

A comparison of the effects of fluvoxamine and amitriptyline on autonomic functions in healthy volunteers

Summary We have compared the effects of single oral doses of fluvoxamine (50 mg and 100 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced, double-blind, crossover design.Amitriptyline significantly reduced salivation, the miosis evoked by locally applied pilocarpine, and the sweat secretion evoked by locally applied carbachol. Fluvoxamine also significantly attenuated carbachol-evoked sweat gland activity, although to a smaller degree than amitriptyline; fluvoxamine did not significantly alter salivation or pilocarpine-evoked miosis.Neither treatment significantly altered the miotic responses evoked by brief light stimuli. Heart rate and blood pressure were not greatly affected by either treatment, although the fall in heart rate (erect posture) with placebo was significantly reduced by amitriptyline (100 mg).The results suggest that fluvoxamine has some antimuscarinic activity in man, but is considerably less potent in this respect than amitriptyline.     

Effects of single doses of quinapril and atenolol on autonomic nervous function and exercise capacity in healthy volunteers

Summary The effects of single oral doses of the angiotensin converting enzyme (ACE) inhibitor quinapril (CI-906) 40 mg and the cardioselective -adrenoceptor blocker atenolol 100 mg on sympathetic and parasympathetic function and on exercise capacity have been studied in 8 healthy young men. The trial followed a double-blind, placebo controlled, randomized cross-over design, with at least one week between treatments.Blood pressure (BP) and heart rate (HR) at rest were slightly reduced by atenolol but were not affected by quinapril. Atenolol impaired the sympathetically mediated increases in HR and BP caused by standing, immersion of the hand into melting ice, the Valsalva manoeuvre and isometric forearm exercise. Quinapril did not influence those responses nor the vagally mediated bradycardia of the diving reflex. Atenolol, however, augmented the vagal bradycardia, presumably by sympathetic inhibition. In a dynamic bicycle ergometer test with a stepwise increasing work load, exercise performance was decreased by atenolol but not by quinapril. Inhibition of the renin-angiotensin system by quinapril was shown by a marked decrease in serum ACE activity and a several-fold increase in plasma renin activity (PRA). Atenolol produced a moderate reduction in PRA. Before or during exercise, plasma noradrenaline and adrenaline were not influenced by either drug.The results indicate that, unlike the atenolol-induced -adrenoceptor blockade, ACE inhibition by a single dose of quinapril had no clear effect on autonomic nervous function or exercise capacity.Preliminary results from this study were presented at the XX Congress of the Nordic Society of Military Medicine, Helsinki, 14–16 May, 1987, and were published in 1988 in Ann Milit Med Fenn, 63 (1–2)     

Comparison of pramipexole and modafinil on arousal, autonomic, and endocrine functions in healthy volunteers

The noradrenergic locus coeruleus is a major wakefulness-promoting nucleus of the brain, which is also involved in the regulation of autonomic and endocrine functions. The activity of the locus coeruleus is believed to be tonically enhanced by a mesocoerulear dopaminergic pathway arising from the ventral tegmental area of the midbrain. Both modafinil, a wakefulness-promoting drug, and pramipexole, a D(2)/D(3)receptor agonist with sedative properties, may act on this pathway, with modafinil increasing and pramipexole decreasing locus coeruleus activity. The aim of this study was to compare the two drugs on alertness, autonomic and endocrine functions in healthy volunteers. Pramipexole (0.5mg), modafinil (200mg), and their combination were administered to 16 healthy males in a double-blind, placebo-controlled design. Methods included tests of alertness (pupillographic sleepiness test, critical flicker fusion frequency, visual analogue scales), autonomic functions (resting pupil diameter, light and darkness reflex responses, heart rate, blood pressure, salivation, core temperature), and endocrine functions (blood concentrations of prolactin, growth hormone, and thyroid stimulating hormone). Data were analysed by ANOVA. Pramipexole reduced alertness, caused pupil dilatation, increased heart rate, reduced prolactin and thyroid stimulating hormone, and increased growth hormone level. Modafinil caused small increases in blood pressure and core temperature, and reduced prolactin levels. The sedative effect of pramipexole and the autonomic effects of modafinil are consistent with altered activity in the mesocoerulear pathway; the pupil dilatation following pramipexole suggests reduced dopaminergic excitation of the Edinger-Westphal nucleus.     

Psychopharmacological effects of sertraline in normal, healthy volunteers

Summary A double-blind, placebo controlled, cross-over study was carried out in 10 normal healthy volunteers to investigate the effects of sertraline 25 mg, 50 mg, 75 mg and 100 mg on aspects of cognitive functioning.Changes with respect to placebo in objective tests of psychomotor function (critical flicker fusion and choice reaction time) showed that sertraline had an alerting effect. The changes were not consistent with subjective reports of drowsiness.     

The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers

RATIONALE: Cognitive impairment is a common feature of depressive illness. While accumulating evidence suggests that brain serotonin (5-HT) pathways play an important role in the neurobiology of depression, the extent to which altered 5-HT function is responsible for the associated changes in cognition and emotion remains unclear. OBJECTIVE: The present study examined the effects of acute dietary depletion of tryptophan (TRP) on cognitive and affective processing in healthy volunteers and explored the putative role of 5-HT in the neuropsychology of depression. METHODS: We administered computerised cognitive tests to healthy control participants following ingestion of TRP-free and nutritionally balanced amino acid drinks in a double-blind, placebo-controlled, crossover design. RESULTS: The TRP-free amino acid mixture significantly lowered plasma total and free TRP concentrations relative to baseline values and produced selective deficits similar to those observed previously in cases of clinical depression. In particular, TRP depletion increased response times for happy but not sad targets in an affective go/no-go task and slowed responding in a visual discrimination and reversal learning task. These deficits were not due to a global sedative effect, as planning ability was unimpaired. CONCLUSIONS: The present data indicate that serotonergic factors may be more involved in the disrupted inhibitory and emotional processing characteristic of depression than in other aspects of executive function, such as planning ability. These findings support the recent proposal that serotonergic manipulation may have greater effects on tasks mediated by frontal circuitry that includes the orbitofrontal cortex than by dorsolateral prefrontal cortex circuitry.     

Comparison of the effects of binodaline and amitriptyline on peripheral autonomic functions in healthy volunteers.

Twelve healthy male volunteers participated in five experimental sessions separated by weekly intervals. At the beginning of each session the subjects received one single oral dose of the following drugs, according to a double-blind, balanced cross-over design: binodaline hydrochloride (50 mg or 100 mg); amitriptyline hydrochloride (50 mg or 100 mg); lactose placebo. Salivation and resting pupil diameter were assessed before and 2 h after the ingestion of the drugs; baseline sweating, carbachol- or phenylephrine-evoked sweating were measured 2 h following drug taking. Binodaline, like placebo, had little effect on salivary output, whereas amitriptyline caused a dose-dependent decrease in salivation. None of the drugs caused any significant change in resting pupil diameter or in baseline sweating. Carbachol-evoked sweating did not differ significantly following the ingestion of binodaline or placebo; on the other hand responses to carbachol were significantly reduced following amitriptyline. Phenylephrine-evoked sweating was reduced by both binodaline and amitriptyline. The lack of effect of binodaline on salivation, resting pupil diameter, baseline and carbachol-evoked sweating is in agreement with the results of animal experiments indicating the lack of an interaction of this drug with cholinergic mechanisms. The reduction in phenylephrine-evoked sweating would be indicative of an alpha-adrenoceptor blocking property of this drug.     

The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers

RATIONALE: Chronic administration of extracts from the leaves of the tree Ginkgo biloba is known to improve aspects of cognitive performance. However, little is known about the effects of acute doses of Ginkgo on coherent cognitive domains. Recent factor analysis of test measures from subtasks of the Cognitive Drug Research (CDR) computerised assessment battery has revealed that four primary cognitive 'factors' corresponding to speed of attention, accuracy of attention, speed of memory and quality of memory can be useful to describe cognitive function changes. OBJECTIVE: The present study aimed at assessing whether acute administration of Ginkgo biloba had any consistent effect on the four CDR factors. METHODS: The study utilised a placebo-controlled, multi-dose, double-blind, balanced, crossover design. Twenty participants received 120 mg, 240 mg and 360 mg of a standardised extract of Ginkgo (GK501, Pharmaton, SA) or a matching placebo. Cognitive performance was assessed using the CDR computerised test battery immediately prior to dosing and at 1, 2.5, 4 and 6 h thereafter. The primary outcome measures were the four aspects of cognitive performance, which have previously been derived by factor analysis of CDR subtests. RESULTS: Compared with the placebo, administration of Ginkgo produced a number of significant changes on the performance measures. The most striking of these was a dose-dependent improvement of the 'speed of attention' factor following both 240 mg and 360 mg of the extract, which was evident at 2.5 h and was still present at 6 h. Additionally, there were a number of time- and dose-specific changes (both positive and negative) in performance of the other factors. CONCLUSIONS: We conclude that acute administration of Ginkgo biloba is capable of producing a sustained improvement in attention in healthy young volunteers.