Methylphenidate produces selective enhancement of declarative memory consolidation in healthy volunteers

Rationale

Methylphenidate inhibits the reuptake of dopamine and noradrenaline and is used to treat children with attention deficit hyperactivity disorder (ADHD). Besides reducing behavioral symptoms, it improves their cognitive function. There are also observations of methylphenidate-induced cognition enhancement in healthy adults, although studies in this area are relatively sparse. We assessed the possible memory-enhancing properties of methylphenidate.

Objective

In the current study, the possible enhancing effects of three doses of methylphenidate on declarative and working memory, attention, response inhibition and planning were investigated in healthy volunteers.

Methods

In a double blind placebo-controlled crossover study, 19 healthy young male volunteers were tested after a single dose of placebo or 10, 20 or 40?mg of methylphenidate. Cognitive performance testing included a word learning test as a measure of declarative memory, a spatial working memory test, a set-shifting test, a stop signal test and a computerized version of the Tower of London planning test.

Results

Declarative memory consolidation was significantly improved relative to placebo after 20 and 40?mg of methylphenidate. Methylphenidate also improved set shifting and stopped signal task performance but did not affect spatial working memory or planning.

Conclusions

To the best of our knowledge, this is the first study reporting enhanced declarative memory consolidation after methylphenidate in a dose-related fashion over a dose range that is presumed to reflect a wide range of dopamine reuptake inhibition.     

Treatment of first-episode non-affective psychosis: a randomized comparison of aripiprazole, quetiapine and ziprasidone over 1 year

Rationale

Discontinuation of antipsychotic treatment at early phases increases the risk of poor adherence to maintenance drug therapy. Differences among antipsychotics in terms of effectiveness may determine a good adherence to treatment.

Objectives

The aim of this study is to compare the clinical effectiveness of aripiprazole, ziprasidone and quetiapine in the treatment of first-episode schizophrenia spectrum disorders at 1 year.

Method

From October 2005 to January 2011 a prospective, randomized, open-label study was undertaken. Two hundred two first-episode drug-naïve patients were randomly assigned to aripiprazole (N?=?78), ziprasidone (N?=?62), or quetiapine (N?=?62) and followed up for 1 year. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted in the analysis for clinical efficacy.

Results

The overall dropout rate at 1 year was 13.37 %. The treatment discontinuation rate differed significantly between treatment groups (aripiprazole?=?43.6 %, ziprasidone?=?66.1 % and quetiapine?=?82.3 %) (χ ²?=?22.545; p?<?0.001). Insufficient efficacy in the group of quetiapine is the most important reason for differences in discontinuation rates between agents (χ ²?=?19.436; p?<?0.001). The mean time to all-cause discontinuation was significantly different between groups (LogRank?=?30.732 p?<?0.001). The profile of extrapyramidal symptoms varies between treatments. Patients on ziprasidone were more likely to be prescribed antidepressants.

Conclusions

First episode patients treated with quetiapine have a higher risk of treatment discontinuation at midterm due to insufficient efficacy. Establishing differences between SGAs may help clinicians on prescribing decision for treatment of individuals presenting with first-episode non-affective psychosis.     

Methylphenidate increases cigarette smoking in participants with ADHD

Rationale

Methylphenidate (Ritalin®) is commonly prescribed for behavioral problems associated with attention deficit/hyperactivity disorder (ADHD). The results of previous studies suggest that methylphenidate increases cigarette smoking in participants without psychiatric diagnoses. Whether methylphenidate increases cigarette smoking in participants diagnosed with ADHD is unknown.

Objective

In this within-subjects, repeated measures experiment, the acute effects of a range of doses of methylphenidate (10, 20, and 40 mg) and placebo were assessed in nine cigarette smokers who were not attempting to quit and met diagnostic criteria for ADHD but no other Axis I psychiatric disorders other than nicotine dependence.

Methods

Each dose of methylphenidate was tested once while placebo was tested twice. One hour after ingesting drug, participants were allowed to smoke ad libitum for 4 h. Measures of smoking included total cigarettes smoked, total puffs, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum; caloric intake during the 4-h smoking session was calculated.

Results

Methylphenidate increased the total number of cigarettes smoked, total number of puffs, and carbon monoxide levels. Methylphenidate decreased the number of food items consumed and caloric intake.

Conclusions

The results of this experiment suggest that acutely administered methylphenidate increases cigarette smoking in participants with ADHD, which is concordant with findings from previous studies that tested healthy young adults. These data indicate that clinicians may need to consider non-stimulant options or counsel their patients before starting methylphenidate when managing ADHD-diagnosed individuals who smoke.

     

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.     

Adverse effects from antidepressant treatment: randomised controlled trial of 601 depressed individuals

Rationale

Premature discontinuation of antidepressant drugs is a frequent clinical problem. Adverse effects are common, occur early on in treatment and are reported to be one of the main reasons for discontinuation of antidepressant treatment.

Objectives

To investigate the association between adverse effects occurring in the first 2 weeks of antidepressant treatment and discontinuation by 6 weeks as the outcome. To investigate the time profile of adverse effects induced by the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine over 12 weeks of treatment.

Methods

Six hundred and one depressed individuals were randomly allocated to either citalopram (20 mg daily) or reboxetine (4 mg twice daily). A modified version of the Toronto Side Effects Scale was used to measure 14 physical symptoms at baseline (medication free) and at 2, 6 and 12 weeks after randomisation.

Results

Individuals randomised to reboxetine reported a greater number of adverse effects and were more likely to stop treatment than individuals receiving citalopram. Dizziness (OR 1.83; 95% CI 1.09, 3.09; p?=?0.02) and the total number of adverse effects (OR 1.12; 95% CI 1.00, 1.25; p?=?0.06) reported at 2 weeks were associated with discontinuation from overall antidepressant treatment by 6 weeks. Reports of adverse effects tended to reduce throughout the 12 weeks for both antidepressants.

Conclusions

The majority of adverse effects were not individually associated with discontinuation from antidepressant treatment. Reports of physical symptoms tended to reduce over time. The physical symptoms that did not reduce over time may represent symptoms of depression rather than antidepressant-induced adverse effects.     

Differential responses of two related neurosteroids to methylphenidate based on ADHD subtype and the presence of depressive symptomatology

Rationale

Attention deficit with hyperactivity disorder is a neurodevelopmental disorder associated with alterations in the prefrontal cortex via dopaminergic and noradrenergic neurotransmission. Neurosteroids (e.g. allopregnanolone and dehydroepiandrosterone) modulate the release of multiple neurotransmitters.

Objective

This study aims to determine the baseline concentrations and daily variations in allopregnanolone and dehydroepiandrosterone in children with attention deficit hyperactivity disorder (ADHD) and to determine the effect of chronic administration of methylphenidate on clinical symptoms and on the concentrations of these two neurosteroids.

Methods

We included 148 children aged 5 to 14 years, subdivided into two groups: ADHD group (n?=?107, with a diagnosis of ADHD (DSM-IV-TR criteria), further classified in subtypes by an “attention deficit and hyperactivity scale” and subgroups by the “Children’s Depression Inventory”) and a control group (n?=?41). The clinical workup included blood samples that were drawn at 20:00 and 09:00 hours, at inclusion in both groups, and after 4.61?±?2.29 months of treatment only in the ADHD group, for measurements for allopregnanolone and dehydroepiandrosterone. Factorial analysis, adjusted for age and gender, was performed by using Stata 12.0.

Results

Methylphenidate induced the doubling of allopregnanolone levels in the predominantly inattentive ADHD patients without depressive symptoms (27.26?±?12.90 vs. 12.67?±?6.22 ng/ml, morning values). Although without statistical differences, baseline dehydroepiandrosterone levels were higher and slightly increased after methylphenidate in the ADHD subtype with depressive symptoms (7.74?±?11.46 vs. 6.18?±?5.99 ng/ml, in the morning), opposite to the lower baseline levels, and further decrease after methylphenidate in the inattentive subtype with depressive symptoms.

Conclusions

Different neurosteroids may have different baseline concentrations and differential responses to methylphenidate treatment as a function of ADHD subtype and subgroup. These differential responses may be a clinical marker of ADHD subtype and/or co-morbidities.     

Cigarette craving and withdrawal symptoms during temporary abstinence and the effect of nicotine gum

Rationale

It is widely believed that nicotine withdrawal symptoms appear within a few hours of stopping smoking, but few data exist documenting their emergence in naturalistic settings. In several countries, nicotine replacement products are licensed for relief of withdrawal symptoms during temporary abstinence, but again, there are no data supporting this from naturalistic settings.

Objectives

To examine the emergence of cigarette craving and withdrawal symptoms during temporary abstinence in a naturalistic setting while using either nicotine or placebo gum.

Methods

Double-blind, randomised, placebo-controlled study in which 132 dependent smokers abstained for 6 h with the assistance of either nicotine (2 mg, n?=?42 or 4 mg, n?=?24) or placebo (n?=?66) gum while travelling on a non-smoking train. Outcome measures were ratings of craving and mood withdrawal symptoms prior to treatment and at regular intervals during abstinence.

Results

In a multivariate analysis of all symptoms, there was no interaction between treatment and time [F(21,110)?=?1.28, p?=?0.20, $ \eta_{\mathrm{p}}^2 $ ?=?0.20] nor an effect of treatment [F(7,124)?=?0.45, p?=?0.87, $ \eta_{\mathrm{p}}^2 $ ?=?0.03]. There was an effect of time [F(21,110)?=?11.59, p?<?0.001, $ \eta_{\mathrm{p}}^2 $ ?=?0.69) and univariate analyses revealed that the majority of symptoms increased linearly throughout the period of abstinence with detectable onsets typically between the first 60 and 180 min of abstinence.

Conclusions

Smokers who temporarily abstain in naturalistic settings experience craving and withdrawal symptoms that emerge linearly over the first 6 h of abstinence. Changes in craving and several mood withdrawal symptoms can be detected within the first 3 h. Nicotine gum may not have an acute effect on the development of these symptoms.     

Lurasidone in the treatment of schizophrenia: a 6-week, placebo-controlled study

Rationale

There is an unmet need in the treatment of schizophrenia for effective medications with fewer adverse effects.

Objective

This study aims to evaluate the efficacy and safety of lurasidone, an atypical antipsychotic, for the treatment of schizophrenia.

Methods

Patients with an acute exacerbation of schizophrenia were randomized to 6 weeks of double-blind treatment with once-daily, fixed-dose lurasidone 40 mg (N?=?50), lurasidone 120 mg (N?=?49), or placebo (N?=?50). The primary efficacy measure was mean change from baseline to day 42 (last observation carried forward) in the Brief Psychiatric Rating Scale derived (BPRSd) from the Positive and Negative Syndrome Scale (PANSS).

Results

Mean change in BPRSd was significantly greater in patients receiving lurasidone 40 and 120 mg/day versus placebo (?9.4 and ?11.0 versus ?3.8; p?=?0.018 and 0.004, respectively). Treatment with lurasidone 120 mg/day was superior to placebo across all secondary measures, including PANSS total (p?=?0.009), PANSS positive (p?=?0.005), PANSS negative (p?=?0.011), and PANSS general psychopathology (p?=?0.023) subscales and Clinical Global Impression of Severity (CGI-S; p?=?0.001). Treatment with lurasidone 40 mg/day was superior to placebo on the PANSS positive subscale (p?=?0.018) and CGI-S (p?=?0.002). The most common adverse events for patients receiving lurasidone were nausea (16.2 versus 4.0 % for placebo) and sedation (16.2 versus 10.0 % for placebo). Minimal changes in weight, cholesterol, triglyceride, and glucose levels were observed.

Conclusions

In this study, which was limited by a relatively high discontinuation rate, lurasidone provided effective treatment for patients with acute exacerbation of chronic schizophrenia and had minimal effects on weight and metabolic parameters.     

Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial

Rational

It has been suggested that phosphodiesterase 5 inhibitors such as sildenafil may be effective in the treatment of negative symptoms of schizophrenia.

Objective

This study was designed to investigate the effect of sildenafil added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in a double-blind and randomized clinical trial.

Methods

Eligible participants in the study were 40 patients with chronic schizophrenia with ages ranging from 18 to 45?years. All patients were inpatients and were in the active phase of the illness and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion: 20 to risperidone (6?mg/day) plus sildenafil (75?mg/day) and 20 to risperidone (6?mg/day) plus placebo. The principal measure of outcome was Positive and Negative Syndrome Scale (PANSS).

Results

Although both protocols significantly decreased the score of the positive, negative, and general psychopathological symptoms over the trial period, the combination of risperidone and sildenafil showed a significant superiority over risperidone alone in decreasing negative symptoms and PANSS total scores over the 8-week trial (between-subjects factor; F?=?4.77, df?=?1; P?=?0.03; F?=?5.91, df?=?1, P?=?0.02 respectively).

Conclusion

Therapy with 75?mg/day of sildenafil was well tolerated, and no clinically important side effects were observed. The present study indicates sildenafil as a potential adjunctive treatment strategy for treatment of negative symptoms of schizophrenia. This trial is registered with the Iranian Clinical Trials Registry (IRCT1138901151556N11).     

A selective reversible monoamine oxidase B inhibitor in smoking cessation: effects on its own and in association with transdermal nicotine patch

Rationale

Monoamine oxidase B (MAO-B) activity is reduced in smokers. A MAO-B inhibitor alone or co-administered with nicotine may mimic the effects of smoking and be a candidate drug for smoking cessation.

Objective

This study aims to determine the efficacy and safety of EVT302, a selective reversible MAO-B inhibitor, alone and on top of nicotine patch (NP) in smoking cessation.

Methods

This was a randomised, double blind, placebo-controlled phase II, multicentre trial. Smokers (≥10 cigarettes/day) received either EVT302 (N?=?145) or placebo (N?=?145), or EVT302 (N?=?61) or placebo (N?=?61) on top of open label NP 21 mg/day for 8 weeks. The main comparison was between EVT302 and placebo without NP. The primary outcome measure was end-of-treatment 4-week continuous abstinence rate (CAR). Secondary outcome measures: point prevalence abstinence rate, saliva cotinine concentrations in the groups without NP, urge to smoke, nicotine withdrawal symptoms and assessment of subjective effects of cigarettes.

Results

The 4-week CAR was 15.2 % in the placebo, 17.2 % in the EVT302, 26.8 % in the NP?+?placebo and 32.8 % in the NP?+?EVT302 groups, respectively. There was no difference between EVT302 and placebo either alone (adjusted OR: 1.45, 95 % CI: 0.65–3.26) or when co-administered with NP. No statistically significant difference occurred for the secondary outcome measures.

Conclusions

The selective, reversible MAO-B inhibitor EVT302 was not superior to placebo in helping smokers quit, in line with data with selegiline and confirms that MAO-B inhibitors are not effective in smoking cessation. Co-administration of NP does not provide a supplementary benefit.     

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.     

A placebo-controlled study of tropisetron added to risperidone for the treatment of negative symptoms in chronic and stable schizophrenia

Rational

A growing body of evidence illustrates that 5-HT3 receptor antagonist drugs may be of benefit in the treatment of negative symptoms in schizophrenia.

Objective

The objective of this study was to assess the efficacy and tolerability of tropisetron add-on to risperidone on negative symptoms in patients with chronic stable schizophrenia.

Methods

In a double-blind, placebo-controlled 8-week trial, 40 patients with chronic schizophrenia who were stabilized on risperidone were randomized into tropisetron or placebo add-on groups. Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) every 2 weeks. Furthermore, extrapyramidal and depressive symptoms as well as side effects were assessed. The primary outcome measure was the difference in change from baseline of negative subscale scores between the two groups at week 8.

Results

Tropisetron resulted in greater improvement of the total PANSS scores [F(1.860,70.699)?=?37.366, p?<?0.001] as well as negative scores [F(2.439,92.675)?=?16.623, p?<?0.001] and general psychopathology [F(1.767,67.158)?=?4.602, p?=?0.017], but not positive subscale scores [F(1.348, 51.218)?=?0.048, p?=?0.893] compared to placebo. In a multiple regression analysis controlling for positive, extrapyramidal, and depressive symptoms, treatment group (standardized β?=??0.640) significantly predicted changes in primary negative symptoms. The side effect profile did not differ significantly between the two groups.

Conclusion

Tropisetron add-on to risperidone improves the primary negative symptoms of patients with chronic stable schizophrenia.     

Effect of saffron on fluoxetine-induced sexual impairment in men: randomized double-blind placebo-controlled trial

Rationale

Saffron (Crocus sativus L.) has shown aphrodisiac effects in some animal and human studies.

Objectives

To assess the efficacy and tolerability of saffron in fluoxetine-related sexual dysfunction.

Methods

This was a 4-week randomized double-blind placebo-controlled study. Thirty-six married male patients with major depressive disorder whose depressive symptoms had been stabilized on fluoxetine and had subjective complaints of sexual impairment entered the study. The patients were randomly assigned to saffron (15?mg twice per day) or placebo for 4?weeks. International Index of Erectile Function scale was used to assess sexual function at baseline and weeks 2 and 4.

Results

Thirty patients finished the study. Baseline characteristics as well as baseline and final depressive symptoms scores were similar between the two groups. Effect of time?×?treatment interaction on the total score was significant [Greenhouse–Geisser-corrected, F (1.444, 40.434)?=?6.154, P?=?0.009]. By week 4, saffron resulted in significantly greater improvement in erectile function (P?P?=?0.001), and total scores (P?P?=?0.095), overall satisfaction (P?=?0.334), and sexual desire (P?=?0.517) domains scores. Nine patients (60%) in the saffron group and one patient (7%) in the placebo group achieved normal erectile function (score?>?25 on erectile function domain) at the end of the study (P value of Fisher’s exact test?=?0.005). Frequency of side effects were similar between the two groups.

Conclusions

Saffron is a tolerable and efficacious treatment for fluoxetine-related erectile dysfunction.     

Neural correlates of free T3 alteration after catecholamine depletion in subjects with remitted major depressive disorder and in controls

Rationale

Thyroid hormones and their interactions with catecholamines play a potentially important role in alterations of mood and cognition.

Objectives

This study aimed to examine the neurobiological effects of catecholamine depletion on thyroid hormones by measuring endocrine and cerebral metabolic function in unmedicated subjects with remitted major depressive disorder (RMDD) and in healthy controls.

Methods

This was a randomized, placebo-controlled, and double-blind crossover trial that included 15 unmedicated RMDD subjects and 13 healthy control subjects. The participants underwent two 3-day-long sessions at 1-week intervals; each participant was randomly administered oral α-methyl-para-tyrosine in one session (catecholamine depletion) and an identical capsule containing hydrous lactose (sham depletion) in the other session prior to a [¹⁸F]-fluorodeoxyglucose positron emission tomography scan.

Results

Serum concentrations of free T3 (FT3), free T4 (FT4), and TSH were obtained and assessed with respect to their relationship to regional cerebral glucose metabolism. Both serum FT3 (P?=?0.002) and FT4 (P?=?0.0009) levels were less suppressed after catecholamine depletion compared with placebo treatment in the entire study sample. There was a positive association between both FT3 (P?=?0.0005) and FT4 (P?=?0.002) and depressive symptoms measured using the Montgomery–Åsberg Depression Rating Scale. The relative elevation in FT3 level was correlated with a decrease in regional glucose metabolism in the right dorsolateral prefrontal cortex (rDLPFC; P?<?0.05, corrected).

Conclusions

This study provided evidence of an association between a thyroid–catecholamine interaction and mood regulation in the rDLPFC.     

Methylphenidate and impulsivity: a comparison of effects of methylphenidate enantiomers on delay discounting in rats

Rationale

Current formulations of methylphenidate (MPH) used in treatment of attention-deficit/hyperactivity disorder (ADHD) result in significantly different bioavailability of MPH enantiomers. Daytrana^®, a dl-MPH transdermal patch system, produces higher levels of l-MPH than when dl-MPH is administered orally (e.g., Ritalin^®). One potential limitation of increased l-MPH was indicated in a preclinical study showing l-MPH may attenuate effects of d-MPH.

Objectives

The objective of the study was to investigate the interactive effects of MPH enantiomers by (1) assessing drug effects via a preclinical model of “impulsivity” and (2) performing a quantitative dose equivalence analysis of MPH enantiomer interactions.

Methods

Sprague–Dawley rats were trained to emit either of two responses, one producing an immediate food pellet, the other producing four pellets delivered at increasing delays (0, 8, and 32 s). The percent selection of the larger food amount was graphed as a function of delay with the area under the curve (AUC) assessed. Increases in AUC are consistent with decreases in “impulsivity” (i.e., selection of the smaller, immediate over the larger, delayed reinforcer).

Results

Systemic administration of dl-MPH and d-MPH dose-dependently increased AUC, while l-MPH, morphine, and pentobarbital did not alter AUC. An analysis based upon dose equivalence indicated that dl-MPH produced additive effects that were not different from that predicted from effects of the enantiomers administered alone.

Conclusions

The present results indicate pharmacologically selective effects in that only drugs prescribed for the treatment of ADHD symptoms decreased a measure of “impulsivity” and that l-MPH likely does not attenuate or enhance the effects of d-MPH in the current delay-discounting task.     

Feasibility of discontinuing chronic benzodiazepine use in nursing home residents: a pilot study

Purpose

Guidelines discourage chronic benzodiazepines and related Z drugs (BZD/Zs) for sleep problems. However, prevalence among nursing home residents remains high. Discontinuing these drugs is widely recommended but seems difficult to implement. The aim of our study was to evaluate the overall feasibility in the nursing home, in terms of willingness towards discontinuation and success rate at 8 months, together with the impact on withdrawal symptoms, change in sleep quality, quality of life and medication use.

Methods

In a convenience sample of five nursing homes (823 residents), we included cognitively competent residents with chronic BZD/Z use for insomnia. We investigated sleep quality [with Pittsburgh Sleep Quality Index (PSQI)], quality of life (EQ-5D) and withdrawal symptoms [Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ)]. Success rate was analysed with survival analysis.

Results

Of the 135 eligible residents, both general physician (GP) and resident were willing to initiate discontinuation in 38 residents. Reasons for refusing to initiate discontinuation among GPs was the unmotivated patient and among residents the reluctance towards change. At 8 months, 66.0 % were successful discontinuers, with the subjective PSQI component evolving favourably (p?=?0.013) and a decreasing number of midnight awakenings (p?=?0.041). In the relapse group (n?=?13), the quality of life decreased (p?=?0.012), with mainly an increase of problems with activities and pain/discomfort. In both groups, the withdrawal symptoms, functionality and medication use did not change.

Conclusion

Discontinuation of chronic BZD/Z use is feasible in the nursing home setting without noticeable withdrawal symptoms, without a switch in medication use, without detrimental effect on quality of life and with a positive effect on the self-perceived sleep quality.     

Monoaminergic modulation of behavioural and electrophysiological indices of error processing

Rationale

Error processing is a critical executive function that is impaired in a large number of clinical populations. Although the neural underpinnings of this function have been investigated for decades and critical error-related components in the human electroencephalogram (EEG), such as the error-related negativity (ERN) and the error positivity (Pe), have been characterised, our understanding of the relative contributions of key neurotransmitters to the generation of these components remains limited.

Objectives

The current study sought to determine the effects of pharmacological manipulation of the dopamine, noradrenaline and serotonin neurotransmitter systems on key behavioural and event-related potential correlates of error processing.

Methods

A randomised, double-blinded, placebo-controlled, crossover design was employed. Monoamine levels were manipulated using the clinically relevant drugs methylphenidate, atomoxetine and citalopram, in comparison to placebo. Under each of the four drug conditions, participants underwent EEG recording while performing a flanker task.

Results

Only methylphenidate produced significant improvement in performance accuracy, which was without concomitant slowing of reaction time. Methylphenidate also increased the amplitude of an early electrophysiological index of error processing, the ERN. Citalopram increased the amplitude of the correct-response negativity, another component associated with response processing.

Conclusions

The effects of methylphenidate in this study are consistent with theoretical accounts positing catecholamine modulation of error monitoring. Our data suggest that enhancing catecholamine function has the potential to remediate the error-monitoring deficits that are seen in a wide range of psychiatric conditions.     

Impact of Release Mechanism on the Pharmacokinetic Performance of PAUC Metrics for Three Methylphenidate Products with Complex Absorption

Purpose

Investigate the performance of partial area under the drug concentration-time curve (PAUC) metrics (0–3 h) and (3–24 h), for Concerta, Ritalin LA and Focalin XR (different Methylphenidate modified-release formulations). The metrics have been chosen as additional BE metrics for Ritalin LA by the FDA to establish BE for these products due to the early and late peak concentrations critical for treatment of morning and afternoon symptoms of attention deficit hyperactivity disorder (ADHD).

Methods

Two-stage analysis was performed on plasma data for the methylphenidate modified-release products. Simulations using the fitted parameters determined how changes in fast absorption rate constant k0fast, and slow absorption rate constant KAslow affected curve shape and BE determination using Cmax, AUCINF and PAUC.

Results

Sensitivity of the mean PAUC(test)/PAUC(reference) ratios to changes in k0fast and Kaslow were product dependent. Focalin XR mean PAUC(test)/PAUC(reference) ratios for PAUC0–3 h and PAUC3–24 h were most responsive to changes in k0Fast and Kaslow than Concerta and Ritalin LA. The PAUC(test)/PAUC(reference) ratios for (0–3 h) were not responsive to changes to Kaslow. Concerta PAUC (3–24 h) ratios were responsive to changes in Kaslow at ratios less than 1.

Conclusions

Response to PAUC(0–3 h) in the formulations was greater for k0fast than was PAUC(3–24) to changes in KAslow.     

Efficacy and safety evaluation of intensive statin therapy in older patients with coronary heart disease: a systematic review and meta-analysis

Purpose

To reveal and evaluate the efficacy and safety of intensive statin therapy in older patients (age ≥ 65 years) with coronary heart disease (CHD).

Methods

Electronic databases were searched for randomized controlled trials (RCTs) that involved intensive statin therapy use in older patients with CHD. Data was extracted and used to calculate risk ratios (RR) by software Revman 5.1.

Results

Five RCTs and 11,132 patients were included in. Compared with non-intensive statin therapy, intensive statin therapy had significant effect on reducing low density lipoprotein cholesterol (LDL-C) levels (55.4 %) and total cholesterol (TC) and triglyceride (Tg). Although the results showed that intensive statin therapy had no superior effect on reduction of mortality (both all-cause mortality [RR?=?0.97, p?=?0.65] and cardiac death [RR?=?0.95, p?=?0.57]) and cardiac arrest (RR?=?1.09, p?=?0.81), it possessed significant effects on prevention of nonfatal myocardial infarction (MI) (RR?=?0.78, p?=?0.008), stroke (RR?=?0.72, p?=?0.02) and coronary revascularization (RR?=?0.69, p?=?0.007). In terms of side effects, intensive statin therapy was associated with small absolute increase in incidence of drug discontinuation, due to adverse events (3.9 %) and liver enzymes abnormalities (1.7 %). And the occurrence rates of myopathy, rhabdomyolysis and creatine kinase (CK) elevation were very low.

Conclusions

This results show that intensive statin therapy has excellent effects on reduction of serum lipid level including LDL-C, TC, Tg, and also on prevention of nonfatal MI, stroke and coronary revascularization with small absolute increased risk of side effects. Our analysis supports the use of intensive statin therapy in patients ≥?65 years old with CHD.