Central nervous system effects of the second-generation antihistamines marketed in Japan--review of inter-drug differences using the proportional impairment ratio (PIR)-.

BACKGROUND: Second-generation antihistamines (AHs) have, in general, fewer sedative effects than the first-generation. However, important inter-drug differences remain in the degree of cognitive and/or psychomotor impairment. The extent to which a particular compound causes disruption can be conveniently compared, to all other AHs, using the Proportional Impairment Ratio (PIR). Although the PIR can differentiate the relative impairment caused by individual drugs, there is no indication of the reliability of the ratios obtained. OBJECTIVE: To calculate the PIRs -together with 95% confidence intervals (CIs), as an index of reliability- and compare AHs currently, or soon to be, available in Japan, with respect to their intrinsic capacity to cause impairment. METHODS: Results from studies of cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mequitazine, and olopatadine were included in the PIR calculations. All data utilised came from crossover studies in healthy volunteers which were randomised and placebo and positive-internal controlled. Existing databases from studies reporting the sedative effects of AHs on objective (speed, accuracy, memory) and subjective (feeling) psychometrics were augmented, via results from suitable studies published after the previous reviews. The null value for a PIR was one. RESULTS: A total of 45 studies were finally included for this review. Of the AHs assessed, fexofenadine, ebastine, and levocetirizine showed a PIR for objective tests of 0. However, only fexofenadine (PIR = 0.49) had an upper limit of the 95% CI of less than 1. Fexofenadine, levocetirizine, desloratadine, olopatadine, loratadine, and mequitazine all had a PIR for subjective ratings of 0, but the upper limits of the 95% CIs were all in excess of 1, although fexofenadine (PIR = 2.57) was the lowest. CONCLUSIONS: The results show that there are differences between second-generation AHs in the extent of sedation produced. However, subjective ratings indicate that patients may not necessarily be aware of this.

Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered.

Cognitive impairment is a primary feature of patients with major depressive disorder (MDD) and is characterised by stress-induced neural atrophy. Via alpha-adrenergic, anti-cholinergic and anti-histaminic activities, several antidepressants can cause significant counter-therapeutic cognitive impairment. Evidence is emerging of the involvement of sigma-1 receptor agonism in the mechanism of action of some antidepressants, notably fluvoxamine. Sigma-1 receptors are abundant in areas affected by depression/stress-induced cerebral atrophy and their ligands have a unique pharmacological profile; they may promote neurogenesis and initiate adaptive neural plasticity as a protection/reaction to stress. Fluvoxamine, as a potent sigma-1 receptor agonist, has shown ameliorating effects in animal models of psychosis, depression, stress, anxiety, obsessive-compulsive disorder (OCD) and aggression and has been shown to improve cognitive impairments. In humans, fluvoxamine may repair central nervous system (CNS) atrophy and restore cognitive function. The current review explores the mechanisms through which sigma-1 receptors can modulate cognitive function and examines how antidepressant therapy with fluvoxamine may help improve cognitive outcomes in patients with depression.

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders - first revision.

In this report, which is an update of a guideline published in 2002 (Bandelow et al. 2002, World J Biol Psychiatry 3:171), recommendations for the pharmacological treatment of anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are presented. Since the publication of the first version of this guideline, a substantial number of new randomized controlled studies of anxiolytics have been published. In particular, more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs. The recommendations, developed by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-traumatic Stress Disorders, a consensus panel of 30 international experts, are now based on 510 published randomized, placebo- or comparator-controlled clinical studies (RCTs) and 130 open studies and case reports. First-line treatments for these disorders are selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and the calcium channel modulator pregabalin. Tricyclic antidepressants (TCAs) are equally effective for some disorders, but many are less well tolerated than the SSRIs/SNRIs. In treatment-resistant cases, benzodiazepines may be used when the patient does not have a history of substance abuse disorders. Potential treatment options for patients unresponsive to standard treatments are described in this overview. Although these guidelines focus on medications, non-pharmacological were also considered. Cognitive behavioural therapy (CBT) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders, OCD, and PTSD to support them being recommended either alone or in combination with the above medicines.

Benzodiazepine-induced reduction in activity mirrors decrements in cognitive and psychomotor performance.

OBJECTIVE: To assess whether actigraphy is sensitive to benzodiazepine-induced changes in cognitive and psychomotor performance and sleep. METHODS: Healthy young volunteers (n = 23; 11 males), were randomised to a double-blind, placebo-controlled, crossover trial. Actigraphy was used to record motor activity continuously. Following dosing at 18.00 h with 2.5 mg lorazepam (LZP), psychomotor and cognitive assessments were made at hourly intervals post-dose for 4 h and after sleep at 14.5 h post-dose. RESULTS: Activity levels were significantly reduced after LZP for 5 h post-dose (p = 0.0104), during sleep (5-13 h) (p < 0.02) and the following morning, 13-14.5 h post-dose (p < 0.02). At the same time cognitive and psychomotor performance was also significantly impaired (p < 0.05). LZP also significantly increased actigraphic sleep efficiency and sleep per cent (p < 0.02). CONCLUSION: This study showed that activity levels were significantly reduced following dosing with a benzodiazepine and these changes coincided with impairment of cognitive and psychomotor performance. Actigraphy, therefore, appears to be able to reflect the psychopharmacological effects of a benzodiazepine in changes in daytime function and nocturnal behaviour, which, without waking the subject, is beyond the power of conventional psychometrics.

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.

A double-blind, randomized, parallel-group, flexible-dose study to evaluate the tolerability, efficacy and effects of treatment discontinuation with escitalopram and paroxetine in patients with major depressive disorder.

This multinational, randomized, double-blind, flexible-dose study evaluated the short- and long-term antidepressant tolerability and efficacy of escitalopram and paroxetine. Tolerability was assessed by monitoring adverse events throughout the study, and discontinuation events during brief treatment interruption and tapered withdrawal. Discontinuation-emergent effects were evaluated in two separate double-blind periods. First, to mimic the consequences of non-compliance, patients were randomized to one of two treatment interruption periods (placebo-substitution for 3-5 days). Second, patients were randomized to a 1-2-week tapered withdrawal period randomly scheduled between weeks 28 and 31. The pre-specified primary efficacy endpoint was the mean change from baseline in total Montgomery-Asberg Depression Rating Scale (MADRS) score at week 8, using the principle of last observation carried forward. A total of 323 patients entered 8 weeks of double-blind treatment and received at least one flexible dose of escitalopram (10-20 mg/day) or paroxetine (20-40 mg/day). Patients who demonstrated evidence of a significant clinical improvement (Clinical Global Impression-Improvement of 1 or 2) at week 8 entered a 19-week, double-blind maintenance period during which they were treated with the same dose they received at week 8, followed by a 1-2-week tapered withdrawal period. A total of 89 patients (28%) withdrew during the study; significantly (P<0.01) more patients withdrew from the paroxetine group (34%) than from the escitalopram group (21%), and significantly (P<0.05) more paroxetine patients withdrew due to lack of efficacy. The mean MADRS total score improved for both treatment groups from baseline to week 8, with no statistical difference between groups. In severely depressed patients (baseline MADRS total score >or=30), escitalopram was superior (P<0.05) to paroxetine at week 27 (end of maintenance treatment). There was a high prevalence of sexual dysfunction at baseline: the mean Arizona Sexual Experience Scale (ASEX) score was approximately 20 points in both treatment groups. Mean total ASEX scores increased slightly above baseline values during the acute period and declined slightly below baseline values towards the end of the maintenance period. During taper and cessation of treatment, patients in the paroxetine group demonstrated significantly more discontinuation symptoms relative to escitalopram based on the Discontinuation Emergent Signs and Symptoms scores.

Development of a portable psychometric testing device for use in the field: an alcohol investigation.

Cognitive and psychomotor performance have traditionally been assessed in the laboratory. There is a need for an objective portable assessment tool to assess cognitive and psychomotor performance. This study investigated the viability of a portable psychometric test battery, in a controlled laboratory environment, possibly leading to use in the field. A randomised, double-blind placebo controlled, three-way crossover design was employed. 16 subjects received 50 mg/100 ml and 80 mg/100 ml of alcohol and alcohol placebo. Performance was assessed with a tracking task, and an attention task presented on a small ruggedised handheld computer. The attention task showed no significant training effects; however, an element of the tracking task did. Statistical significance, effect size, and test-retest reliability analyses are presented indicating sensitivity of the portable psychometric test battery to the impairing effects of two separate doses of alcohol. Ability to undertake wide-scale impairment testing in the field with meaningful results in the absence of baseline data collection may have wide reaching implications, particularly in relation to the assessment of drivers impaired by drug use.

Suppression of the histamine-induced wheal and flare response by fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily and placebo in healthy Japanese volunteers.

BACKGROUND: The effects of the selective H1-receptor antagonist fexofenadine have been widely demonstrated in Western populations; however, to date, limited data comparing the effects of fexofenadine with other antihistamines have been reported in Japanese subjects. OBJECTIVE: To investigate the effect of fexofenadine and loratadine on the histamine-induced cutaneous wheal and flare response in healthy Japanese volunteers. METHODS: Eighteen healthy male and female Japanese volunteers aged 20-53 years were randomized to receive fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily or placebo in a 1-day, three-period, double-blind, crossover study. For each treatment, the wheal and flare response to 100 mg/mL histamine was assessed at baseline and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 8, 12 and 24 hours post-dose. Blood samples were taken for pharmacokinetic analysis. RESULTS: Fexofenadine produced significantly greater percentage suppression of the overall wheal response compared with placebo and loratadine (43.1% versus 10.0% and 15.2%, respectively; p < 0.001). Similarly, fexofenadine significantly suppressed the overall flare response compared with placebo and loratadine (43.0% versus 3.5% and -8.9%, respectively; p < 0.01). Loratadine was statistically no different from placebo in terms of both overall wheal and flare suppression. Area under the curve analysis for wheal and flare reduction (0-12 hours post-dose) confirmed these findings. For wheal inhibition, fexofenadine had a significantly faster onset of action (defined as time to > or = 35% inhibition) compared with placebo (p < 0.001) and loratadine (p < 0.01); for flare, fexofenadine had a significantly faster onset of action than loratadine (p < 0.01). Mean maximum inhibition (the mean of the greatest inhibition achieved from baseline for each treatment) for wheal was achieved significantly faster with fexofenadine than loratadine (p < 0.01), and fexofenadine had a significantly longer duration of effect on suppressing wheal and flare compared with placebo and loratadine (p < 0.05 for all). The antihistamine effects of fexofenadine correlated significantly with its Cmax, while loratadine activity did not correlate significantly with its plasma levels. CONCLUSIONS: Fexofenadine is a potent suppressor of the histamine-induced wheal and flare response in healthy Japanese volunteers. These results support findings in Caucasian subjects, and confirm that fexofenadine has greater antihistaminergic activity than loratadine in this human model.

A double-blind, placebo- and positive-internal-controlled (alprazolam) investigation of the cognitive and psychomotor profile of pregabalin in healthy volunteers.

RATIONALE: Pregabalin potently and selectively binds to the alpha(2)-delta subunit of voltage-dependent calcium channels, reducing calcium influx and modulating release of downstream excitatory neurotransmitters, such as glutamate. Pregabalin has demonstrated robust efficacy for several disease states, but its neuropharmacology is still being elucidated. OBJECTIVE: This study was conducted to evaluate the cognitive and psychomotor effects of oral pregabalin (150 mg t.i.d.) using alprazolam (1 mg t.i.d.) as a positive internal control and placebo. METHODS: Twenty-four healthy volunteers were randomised to a double-blind, three-way crossover study. Each period consisted of 3-day double-blind treatment followed by 1 day of single-blind placebo. Psychometrics included tests of Choice Reaction Time (CRT), CNS arousal (Critical Flicker Fusion, CFF), vigilance (Rapid Visual Information Processing, RVIP), serial memory scanning (Sternberg Short-Term Memory Scanning Test, STM), divided attention (Compensatory Tracking Task, CTT), Brake Reaction Time (BRT) in an on-the-road vehicle, and subjective Line Analogue Rating Scales (LARS) for sedation. RESULTS: Pregabalin showed no significant effects on the objective psychometrics-CRT, BRT, RVIP, STM-compared with placebo. Pregabalin produced a limited, significant decrement on CFF and CTT and a significant effect on the LARS. Pregabalin was associated with improvement relative to placebo in BRT. The positive control, alprazolam, produced significant impairment on all objective measures and significant impairment on the LARS, thus establishing the sensitivity of the test battery used in the study. CONCLUSIONS: Pregabalin did not differ on most assessments from placebo, producing only minor, transient impairment on some objective cognitive and psychomotor measures, suggesting a relatively benign CNS side-effect profile.

A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo.

STUDY OBJECTIVES: To assess the effects of pregabalin compared with alprazolam and placebo on aspects of sleep in healthy volunteers. DESIGN: Randomized, double-blind, placebo- and active-controlled, 3-way crossover. SETTING: Single research center. PARTICIPANTS AND INTERVENTIONS: Healthy adult (12 men) volunteers (N=24) received oral pregabalin 150 mg t.i.d., alprazolam 1 mg t.i.d., and placebo t.i.d. for 3 days. MEASUREMENTS AND RESULTS: Objective sleep was measured by an 8-channel polysomnograph; subjective sleep was measured using the Leeds Sleep Evaluation Questionnaire. Compared with placebo, pregabalin significantly increased slow-wave sleep both as a proportion of the total sleep period and the duration of stage 4 sleep. Alprazolam significantly reduced slow-wave sleep. Pregabalin and alprazolam produced modest, but significant, reductions in sleep-onset latency compared with placebo. Rapid eye movement sleep latency after pregabalin was no different than placebo but was significantly shorter than that found with alprazolam. Although there were no differences between the active treatments, both pregabalin and alprazolam reduced rapid eye movement sleep as a proportion of the total sleep period compared with placebo. Pregabalin also significantly reduced the number of awakenings of more than 1 minute in duration. Leeds Sleep Evaluation Questionnaire ratings of the ease of getting to sleep and the perceived quality of sleep were significantly improved following both active treatments, and ratings of behavior following awakening were significantly impaired by both drug treatments. CONCLUSIONS: Pregabalin appears to have an effect on sleep and sleep architecture that distinguishes it from benzodiazepines. Enhancement of slow-wave sleep is intriguing, since reductions in slow-wave sleep have frequently been reported in fibromyalgia and general anxiety disorder.

Effects of fexofenadine and hydroxyzine on brake reaction time during car-driving with cellular phone use.

Antihistamines are a mainstay treatment for allergic rhinitis; however, many older agents cause adverse events, including sedation and central nervous system (CNS) impairment. Research has shown sedating effects of antihistamines on driving; currently, no known study has examined whether cellular phone usage while driving further compounds impairment in individuals administered antihistamines. The aim of this study was to examine this endpoint. In a randomized, double-blind, placebo-controlled, three-way crossover study, healthy volunteers received fexofenadine HCl 120 mg, hydroxyzine HCl 30 mg and placebo. Brake reaction time (BRT) was used to examine driving performance across four conditions: driving only; driving while completing simple calculations; complex calculations; and conversing on a cellular phone. Subjective sedation assessments were also conducted. Brake reaction time with and without cellular phone usage in fexofenadine-treated subjects did not differ significantly from placebo in any condition. In contrast, hydroxyzine-treated subjects were significantly more sedated and had slower BRTs, suggesting slower hazard recognition and brake application, compared with the fexofenadine and placebo groups in all conditions. Importantly, cellular phone operation was an additive factor, increasing BRTs in hydroxyzine-treated volunteers. Fexofenadine did not impair CNS function in subjects involved in a divided attention task of driving and cellular phone operation.

Acute sleep responses in a normobaric hypoxic tent.

PURPOSE: Sleeping in a hypoxic environment is becoming increasingly popular among athletes attempting to simulate a "live high, train low" training regime. The purpose of this study was to investigate the acute effects (one night) of sleeping in a normobaric hypoxic tent (NH) (PO(2) = 110 mm Hg approximately 2500 m) upon markers of sleep physiology and quality, compared with sleep in a normal ambient environment (BL) (PO(2) = 159 mm Hg approximately sea level) and sleep in a normobaric normoxic tent (NN) (PO(2) = 159 mm Hg). METHODS: Eight male recreational athletes (age 34.5 +/- 6.9 yr; stature 169.1 +/- 8.7 cm; mass 69.3 +/- 8.2 kg; VO(2max) 56.4 +/- 8.3 mL.kg(-1).min(-1)) participated in the study using a randomized, double-blind crossover design. Polysomnographic studies were undertaken to measure sleep stages, arterial oxygen saturation (SpO(2)), heart rate (HR), and the Respiratory Disturbance Index (RDI). The Leeds Sleep Evaluation Questionnaire (LSEQ) was used to measure subjective sleep quality. RESULTS: NH (89.9 +/- 4.8%) resulted in a significantly lower (P < 0.05) SpO(2) compared with both BL (95.7 +/- 1.5%) and NN (93.5 +/- 4.0%). Heart rate was significantly higher (P < 0.05) in NH (51.5 +/- 7.6 beats.min(-1)) compared with NN (48.3 +/- 6.9 beats.min(-1)) but was similar versus BL (50.3 +/- 4.3 beats.min(-1)). RDI (counts.h) and RDI (total counts) were lowest in BL (3.5 +/- 2.5; 18.1 +/- 7.9) and highest in NH (36.8 +/- 42.7; 221.9 +/- 254.5). The difference in RDI (counts.h(-1) and total counts) between NH and BL was significant (P < 0.05). The LSEQ revealed that subjects' "behavior following waking" score was significantly (P < 0.05) lower in NH (40.9 +/- 9.2) compared with BL (52.3 +/- 8.3). CONCLUSION: This study presents evidence that sleep in a normobaric hypoxic tent at a simulated altitude of 2500 m may affect sleep parameters in some individuals. This type of analysis may be useful in the early identification of poorly responding individuals to simulated altitude environments.

The effects of Ginkgo biloba extract (LI 1370) supplementation and discontinuation on activities of daily living and mood in free living older volunteers.

The aim of the study was to investigate the effects of continuing treatment with Ginkgo biloba extract (GBE) 120 mg/day on the activities of daily living (ADLs) and mood in healthy older volunteers who had immediately previously participated in a survey of the effects of a 4 month treatment with the drug. Following a prior postal survey investigating the effects of 4 months supplementation with GBE on ADLs and various aspects of mood and sleep, 1570 volunteers continued onto a 6 month follow-up postal survey. Subjects selected their own treatment option for the follow-up survey, which effectively created four groups: a continuation group who received GBE in the initial 4 month study and during the 6 month follow-up (GBE-GBE), a discontinuation group who received GBE in the initial study but not during the follow-up (GBE-NT), a new treatment group who did not receive GBE in the initial 4 month study but who did receive GBE during the 6 month follow-up (NT-GBE), and a no treatment group who received no treatment in either survey (NT-NT). At the end of the 6 month follow-up period each subject completed a line analogue rating scale (LARS) and a self-rating activities of daily living scale (SR-ADL). There were signi fi cant differences in the mean overall LARS and SR-ADL scores between the four treatment combination groups at the end of the follow-up period. A factor analysis of the LARS revealed two factors, 'mood' and 'alertness'. When scores from each of the treatment groups were examined over the whole 10 month period it was evident that the ratings of overall competence in the SR-ADL and both factors of the LARS were diminished on cessation of treatment with GBE, and improved when GBE treatment was initiated. The magnitude of the improvements on all scales was related to the overall duration of GBE supplementation.Signi fi cant differences between the groups of subjects treated with GBE for different periods of time (4-10 months) suggests that the extract has a demonstrable effect in improving mood and the self-assessed performance of the tasks of everyday living.

A double-blind, randomized, 26-week study comparing the cognitive and psychomotor effects and efficacy of 75 mg (37.5 mg b.i.d.) venlafaxine and 75 mg (25 mg mane, 50 mg nocte) dothiepin in elderly patients with moderate major depression being treated in general practice.

To investigate the efficacy and cognitive and psychomotor effects of venlafaxine and dothiepin in elderly patients with moderate major depression. A prospective, randomized, double-blind, parallel-group, active comparator controlled study was conducted. Eighty-eight patients (aged > or = 60 years) were enrolled. Each patient received either venlafaxine (immediate release formulation) 37.5 mg twice per day or dothiepin 25 mg mane followed by 50 mg nocte for 26 weeks. Efficacy was assessed with the Montgomery-Asberg Depression Rating Scale and the Hamilton Depression Rating Scale. A psychometric test battery to assess cognitive function, activities of daily living and sleep consisted of Critical Flicker Fusion (CFF), Short-term Memory--Kim's Game, Cognitive Failures Questionnaire, Milford Epworth Sleepiness Scale, Leeds Sleep Evaluation Questionnaire, and an Accident Scoring Questionnaire. Quality of Life Questionnaires (Short Form 36 and Quality of Life in Depression Scale) were also administered. Venlafaxine significantly (p < 0.05) raised CFF scores compared to baseline but had no effect on any other measure. Dothiepin significantly (p < 0.05) lowered CFF threshold, and increased ratings of both sedation and difficulty in waking. The results showed that venlafaxine at doses of 37.5 mg b.i.d. in elderly depressed patients is free from disruptive effects on cognitive function and psychomotor performance.

Effects of word frequency on recall memory following lorazepam, alcohol, and lorazepam alcohol interaction in healthy volunteers.

Free recall of words has been extensively used in psychopharmacology to assess the effects of CNS-active drugs on memory functions. However, there is a relative lack of information on the impact of word frequency on the subsequent recall of words following the administration of psychoactive drugs. The present double-blind, placebo-controlled, repeated-measures experiment used lorazepam and alcohol to test the effects of word frequency on immediate and delayed word recall in 24 healthy volunteers. One half of the words contained in the lists had a high frequency (HF) of occurrence and the remainder were of low frequency (LF). The results showed that LF words were more sensitive to memory impairment than HF words. However, the more accurate recall of HF words (with respect to LF words) was eliminated when a combination of lorazepam with alcohol was administered. These findings indicate that word frequency has a significant impact on memory and, as such, is a factor to be taken into account when using memory recall tasks to assess the effects of psychoactive drugs on memory.