Statin use among older Finns stratified according to cardiovascular risk

Purpose

Statin use has increased in older age groups, although there is little evidence for the benefits of statin therapy in the elderly, especially in low-risk persons. The aim of this paper is to describe recent trends in the prevalence and incidence of statin use among the Finnish older population, according to the person’s estimated cardiovascular (CV) event risk.

Methods

We conducted a register study covering the whole community-dwelling population of Finland, aged >70 years in 2000–2008 (N?=?883,051). Data on reimbursed purchases of statins, antidiabetic and CV drugs, and pre-existing CV diseases were retrieved from comprehensive national registers. We stratified each person into low, moderate or high CV risk category, and according to age (70–74, 75–79, and >80 years) and sex.

Results

Between 2000 and 2008, the age-sex-standardized prevalence of statin use tripled from 12.2 % to 38.7 % (rate ratio 3.0, 95 % CI 3.0–3.1), and the incidence almost doubled (from 3.7 % to 6.8 %; rate ratio 1.8, 95 % CI 1.8–1.9). The prevalence and incidence of statin use were consistently highest among high-risk persons. The greatest relative increases were observed in persons aged >80 years and in those at low risk; however, the proportion of statin users at low CV risk remained the same (～7 % of all users).

Conclusions

Statin prescribing is shifting towards older age groups. A substantial increase in prevalence and incidence was seen across all risk categories, but the channeling of statin use towards high-risk persons remained unchanged.     

Treatment discontinuation with methylphenidate in adults with attention deficit hyperactivity disorder: a meta-analysis of randomized clinical trials

Background

Attention deficit hyperactivity disorder (ADHD) in adulthood is increasingly diagnosed and treated. Methylphenidate is frequently advocated as a first-line pharmacological treatment.

Purpose

The aim of our study was to compare all-cause discontinuation rate of methylphenidate and its pharmaceutical presentations with placebo in adults with ADHD.

Methods

This was a systematic review and meta-analysis of randomized controlled trials comparing methylphenidate with placebo in adults with ADHD. All-cause treatment discontinuation was the primary endpoint. The efficacy in reducing ADHD symptoms and safety were the secondary endpoints.

Results

Twelve studies (2,496 patients) met the inclusion criteria. Four racemic methylphenidate and one dexmethylphenidate presentations were investigated. The rate of all-cause treatment discontinuation was greater with methylphenidate than with placebo, but this difference was not statistically significant [odds ratio (OR) 1.19, 95 % confidence interval (95 % CI) 0.82–1.74, P?=?0.37, I ²?=?64 %] This finding reached the conventional threshold of statistical significance after one outlier study was excluded (OR?1.44, 95 % CI 1.14–1.82, P?=?0.002, I ²?=?0). Methylphenidate was more efficacious than placebo for reducing ADHD symptoms and it was associated with a higher proportion of patients dropping out due to adverse effects.

Conclusions

Despite reducing ADHD symptoms, methylphenidate showed no advantage over placebo in terms of treatment discontinuation. More attention should be given in the future to the endpoint “all-cause treatment discontinuation” when making regulatory decisions and developing clinical guidelines involving the treatment of ADHD in adulthood.     

A randomized,double-blind,placebo-controlled crossover study of α4β2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder

Rationale

Stimulation of nicotinic cholinergic systems has been shown to alleviate ADHD symptoms and to improve cognitive performance. AZD1446 is a selective α4β2* nicotinic acetylcholine receptor agonist with potential effect on the symptoms of ADHD.

Objectives

The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AZD1446 in adults with ADHD treated for 2 weeks.

Method

This was a randomized, double-blind, placebo-controlled crossover trial. Participants were 79 adults with ADHD, grouped according to their use of nicotine-containing products. Nicotine non-users received placebo and two of three AZD1446 treatment regimens (80 mg tid, 80 mg qd, 10 mg tid). Nicotine users received placebo, AZD1446 80 mg tid and 80 mg qd. Efficacy measures included the Conners' Adult ADHD Rating Scale and cognitive measures of immediate and delayed verbal episodic memory, learning, attention, working memory, executive functioning, and spatial problem solving (CogState computerized test battery).

Results

There was no significant effect of AZD1446 on any of the clinical scores irrespective of dose, schedule, or concomitant use of nicotine products. A statistically significant improvement was seen on the Groton Maze Learning Task, a measure of executive functioning, in nicotine non-users after treatment with AZD1446 80 mg qd.

Conclusions

AZD1446 was well tolerated, but did not significantly improve ADHD symptoms after 2 weeks of treatment compared to placebo. While the present study does not support the therapeutic utility of AZD1446 in ADHD, its potential pro-cognitive effects remain to be explored in other neuropsychiatric disorders.     

Neuropsychological effects associated with recreational cocaine use

Rationale

Recent evidence suggests that recreational cocaine use is on the increase, with the UK reporting one of the highest levels of use in the EU (EMCDDA 2010). Nevertheless, very few studies have addressed the neuropsychological effects associated with non-dependent recreational cocaine use.

Objectives

The current study aimed to assess whether recreational cocaine users show neuropsychological deficits on a battery of tests, previously shown to be sensitive to cocaine-dependent and psychosis-prone individuals. Schizotypal traits were also measured.

Methods

Recreational cocaine users (n?=?17) were compared with controls (n?=?24) on drug use patterns, the General Health Questionnaire, the Brief Schizotypal Personality Questionnaire (SPQ-B) and four neuropsychological tasks: spatial working memory, intra/extra-dimensional set shifting, the Stocking of Cambridge and the rapid visual processing.

Results

Relative to controls, recreational cocaine users produced significantly more errors on the intra/extra-dimensional set shift task and completed fewer stages, made significantly more six box stage errors on the spatial working memory task, and made significantly more errors and fewer hits, with overall poorer detection rates on the rapid visual processing task. Recreational cocaine users reported significantly higher scores on the cognitive perceptual and disorganised thinking SPQ-B subscales and total SPQ-B scores compared to controls.

Conclusions

Recreational cocaine users displayed impairments on tasks tapping sustained attention, attentional shifting and spatial memory and reported higher schizotypal trait expression. These findings are consistent with the emerging literature suggesting subtle cognitive deficits, putatively reflecting underlying dopaminergic dysfunction, in non-dependent, recreational cocaine users.     

Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence,clinical observations,and methodological implications

Purpose

Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a uniform manner, in seven European electronic healthcare databases.

Methods

Annual prevalence per 10,000 person-years (PYs) was calculated for 2001–2009 in databases from Spain, Germany, Denmark, the United Kingdom (UK), and the Netherlands. Prevalence data were stratified according to age, sex, antidepressant type (selective serotonin re-uptake inhibitors [SSRIs] or tricyclic antidepressants [TCAs]) and major indications.

Results

The age- and sex-standardized prevalence was lowest in the two Dutch (391 and 429 users per 10,000 PYs) and highest in the two UK (913 and 936 users per 10,000 PYs) populations in 2008. The prevalence in the Danish, German, and Spanish populations was 637, 618, and 644 users per 10,000 PY respectively. Antidepressants were prescribed most often in 20- to 60-year-olds in the two UK populations compared with the others. SSRIs were prescribed more often than TCAs in all except the German population. In the majority of countries we observed an increasing trend of antidepressant prescribing over time. Two different methods identifying recorded indications yielded different ranges of proportions of patients recorded with the specific indication (15–57 % and 39–69 % for depression respectively).

Conclusion

Despite applying uniform methods, variations in the prevalence of antidepressant prescribing were obvious in the different populations. Database characteristics and clinical factors may both explain these variations.     

Changes in the serum levels of brain-derived neurotrophic factor in adults with attention deficit hyperactivity disorder after treatment with atomoxetine

Rationale

Atomoxetine (ATX) is a non-stimulant drug approved for the treatment of attention deficit hyperactivity disorder (ADHD). Although animal models have provided evidence that brain-derived neurotrophic factor (BDNF) is involved in the effects of ATX in the brain, there are no studies of BDNF in ADHD patients undergoing treatment with ATX.

Objectives

The aim of this study was to evaluate the possible changes in serum levels of BDNF in adults treated with ATX and its relationship with clinical improvement.

Methods

A total of 54 adults with ADHD (age 33.43?±?8.99 years) without any medical or psychiatric comorbidities were treated with ATX for 3 months; 35 of them completed the protocol. The clinical data for ADHD diagnosis, including Conners’ ADHD Rating Scale and blood samples, were collected at baseline (V1) and at the end of the treatment (V2).

Results

Adults with ADHD who completed ATX treatment for 3 months showed a significant improvement in their clinical symptoms. No significant differences were found in BDNF levels before and after treatment with ATX in the whole group of patients (p?=?0.15). The inattentive subgroup of ATX responders showed a decrease of serum BDNF after 3 months of ATX treatment (p?=?0.05) not present in the combined subtype (p?=?0.82).

Conclusions

These results suggest that BDNF is not directly involved in the neurobiological mechanisms of ATX-induced improvement of clinical symptoms of ADHD. The differences between the combined and inattentive subtypes in serum BDNF changes suggest selective ATX-induced effects in the function of brain circuitry.     

Recreational cocaine polydrug use impairs cognitive flexibility but not working memory

Rationale

Chronic use of cocaine is associated with dysfunctions in frontal brain regions and dopamine D2 receptors, with poorer mental flexibility and a reduced ability to inhibit manual and attentional responses. Little is known, however, about cognitive impairments in the upcoming type of recreational cocaine polydrug user (1–4 g monthly consumption).

Objective

We studied whether recreational cocaine polydrug users, who do not meet the criteria for abuse or dependence, showed impairments in working memory (WM) and cognitive flexibility.

Methods

Controls and recreational cocaine polydrug users (who abstained from cocaine and other substances more than 1 week) were matched by sex, age, alcohol consumption, and IQ (Raven’s Standard Progressive Matrices). Groups were tested by using two cognitive tasks measuring cognitive flexibility and three tasks investigating the maintenance and monitoring of information in WM.

Results

Recreational cocaine polydrug users performed significantly worse than controls on tasks tapping cognitive flexibility, but show comparable performance in the active maintenance and monitoring of information in WM.

Conclusions

The findings suggest that recreational use of cocaine selectively impairs cognitive flexibility but not the maintenance of information in WM. The inability to adjust behavior rapidly and flexibly may have repercussions for daily life activities.     

Accuracy of general practitioners’ readings of ECG in primary care

Background

The electrocardiogram (ECG) is a diagnostic test commonly used in daily Primary Care practice. General Practitioners (GP) often feel unsure about their interpretation of ECGs, so they engage external services to provide it.

Aim

To evaluate accuracy of ECG readings done by GPs by comparison with those done by a cardiologist as the gold standard.

Methods

We studied 195 ECGs collected consecutively during first semester of 2010 in an urban Health Centre of Portugal. Each ECG was read by each physician and inter-observer agreement was evaluated. After coding by Novacode, sensitivity and specificity of GP’s readings were calculated.

Results

Inter-observer agreement between GP readings was “good” with an intraclass correlation coefficient of 0.727 (CI 95%: 0.670–0.779). When compared with gold standard, GP achieved a “good” agreement with an intraclass correlation coefficient of 0.712 (CI 95%: 0.659–0.762). The overall accuracy of GP for detecting abnormalities was 81.0% (95%CI: 75.7–85.6%), with a sensitivity of 84.8% (95%CI: 77.3–90.6%) and a specificity of 77.5% (95%CI: 69.7–84.2%). For normal tests, accuracy was 79.9% (95%CI: 74.7–84.3). In the most prevalent classes of abnormalities, accuracy was higher than 90%.

Conclusion

GP showed good skills in reading ECGs in their practice of Primary Care. Better attention should be given to ischemic abnormalities present on ECGs. Key message: General Practitioners demonstrate good skills for reading the ECGs of patients on a primary care centre when compared to the gold standard defined by a cardiologist reading.     

Survey of users of TOPS, an internet-based system to prevent healthy subjects from over-volunteering for clinical trials

Objective

To analyse users’ experience of TOPS, an internet-based system that helps UK clinical research units to prevent healthy volunteers from participating in more than one non-therapeutic trial simultaneously, or starting a second trial too soon after the first.

Methods

We sent to all units that currently use TOPS an anonymous questionnaire comprising 18 questions about the effectiveness and ease of use of the system.

Results

Of 35 units that currently use TOPS, 31 (85.7 %) returned questionnaires. Most users find TOPS easy to use, had increased their detection rate of over-volunteering, and had rejected subjects as a result of using TOPS. A GP reply alone is not enough to prevent over-volunteering. Ethics committees, the MHRA and sponsors know about TOPS and support its use.

Conclusions

The results confirm that TOPS does prevent healthy subjects from over-volunteering. Consequently, the Health Research Authority has agreed to take over the management of TOPS. Ethics committee approval of a phase 1 trial and MHRA accreditation of the unit will henceforth be conditional on consistent and proper use of TOPS. That should enhance its effectiveness and improve the safety of volunteers in non-therapeutic trials in the UK.     

Reduced Acute Recovery from Alcohol Impairment in Adults with ADHD

Rationale

Prior research has found that adults with attention-deficit/hyperactivity disorder (ADHD) show increased sensitivity to the impairing effects of alcohol (Weafer et al., Exp Clin Psychopharmacol 17: 113–121, 2009). However, these studies have focused exclusively on the ascending limb of the blood alcohol concentration (BAC) curve, and it is unclear whether these adults continue to show increased sensitivity during the later phase of the dose as BAC is declining.

Objective

This study tested the hypothesis that those with ADHD would display increased response to alcohol during the ascending limb of the BAC curve and less recovery from the impairing effects during the descending limb.

Methods

Adult social drinkers with ADHD and control adults completed measures of motor coordination, reaction time (RT), and subjective intoxication twice following 0.64 g/kg alcohol and placebo. The measures were administered during the ascending limb of the BAC curve and again during the descending limb.

Results

During the ascending limb, alcohol reduced motor coordination, slowed RT, and increased self-reports of subjective intoxication. Those with ADHD displayed greater impairment of motor coordination compared with controls. During the descending limb, controls reported diminished subjective intoxication and showed recovery from the impairing effects of alcohol on both their motor coordination and their RT. Those with ADHD showed reduced subjective intoxication and faster RT during this time, but they did not recover motor control.

Conclusions

The protracted time course of motor impairment in adults with ADHD despite reductions in subjective intoxication may contribute to poor decision making and diminished behavioral control in this group.     

Effects of ecstasy/polydrug use on memory for associative information

Rationale

Associative learning underpins behaviours that are fundamental to the everyday functioning of the individual. Evidence pointing to learning deficits in recreational drug users merits further examination.

Objectives

A word pair learning task was administered to examine associative learning processes in ecstasy/polydrug users.

Methods

After assignment to either single or divided attention conditions, 44 ecstasy/polydrug users and 48 non-users were presented with 80 word pairs at encoding. Following this, four types of stimuli were presented at the recognition phase: the words as originally paired (old pairs), previously presented words in different pairings (conjunction pairs), old words paired with new words, and pairs of new words (not presented previously). The task was to identify which of the stimuli were intact old pairs.

Results

Ecstasy/ploydrug users produced significantly more false-positive responses overall compared to non-users. Increased long-term frequency of ecstasy use was positively associated with the propensity to produce false-positive responses. It was also associated with a more liberal signal detection theory decision criterion value. Measures of long term and recent cannabis use were also associated with these same word pair learning outcome measures. Conjunction word pairs, irrespective of drug use, generated the highest level of false-positive responses and significantly more false-positive responses were made in the divided attention condition compared to the single attention condition.

Conclusions

Overall, the results suggest that long-term ecstasy exposure may induce a deficit in associative learning and this may be in part a consequence of users adopting a more liberal decision criterion value.     

Altered visual perception in long-term ecstasy (MDMA) users

Rationale

The present study investigated the long-term consequences of ecstasy use on visual processes thought to reflect serotonergic functions in the occipital lobe. Evidence indicates that the main psychoactive ingredient in ecstasy (methylendioxymethamphetamine) causes long-term changes to the serotonin system in human users. Previous research has found that amphetamine-abstinent ecstasy users have disrupted visual processing in the occipital lobe which relies on serotonin, with researchers concluding that ecstasy broadens orientation tuning bandwidths. However, other processes may have accounted for these results.

Objectives

The aim of the present research was to determine if amphetamine-abstinent ecstasy users have changes in occipital lobe functioning, as revealed by two studies: a masking study that directly measured the width of orientation tuning bandwidths and a contour integration task that measured the strength of long-range connections in the visual cortex of drug users compared to controls.

Method

Participants were compared on the width of orientation tuning bandwidths (26 controls, 12 ecstasy users, 10 ecstasy + amphetamine users) and the strength of long-range connections (38 controls, 15 ecstasy user, 12 ecstasy + amphetamine users) in the occipital lobe.

Results

Amphetamine-abstinent ecstasy users had significantly broader orientation tuning bandwidths than controls and significantly lower contour detection thresholds (CDTs), indicating worse performance on the task, than both controls and ecstasy + amphetamine users.

Conclusion

These results extend on previous research, which is consistent with the proposal that ecstasy may damage the serotonin system, resulting in behavioral changes on tests of visual perception processes which are thought to reflect serotonergic functions in the occipital lobe.