Metabolic effects of adjunctive aripiprazole in clozapine‐treated patients with schizophrenia

Fan X, Borba CPC, Copeland P, Hayden D, Freudenreich O, Goff DC, Henderson DC. Metabolic effects of adjunctive aripiprazole in clozapine‐treated patients with schizophrenia. Objective: This study examined the effects of adjunctive aripiprazole therapy on metabolism in clozapine‐treated patients with schizophrenia. Method: In an 8‐week randomized, double‐blind, placebo‐controlled study, subjects received either aripiprazole (15 mg/day) or placebo. At baseline and week 8, metabolic parameters were assessed by the frequently sampled intravenous glucose tolerance test, nuclear magnetic resonance spectroscopy and whole‐body dual‐energy X‐ray absorptiometry (DXA). Results: Thirty subjects completed the study (16 in the aripiprazole group and 14 in the placebo group). Glucose effectiveness measured by the frequently sampled intravenous glucose tolerance test improved significantly in the aripiprazole group (0.003 ± 0.006 vs. ?0.005 ± 0.007/min, P = 0.010). The aripiprazole group showed significant reductions in both plasma low‐density lipoprotein (LDL) levels (?15.1 ± 19.8 vs. 4.4 ± 22.5 mg/dl, P = 0.019) and LDL particle numbers (?376 ± 632 vs. ?36 ± 301 nm , P = 0.035). Further, there was a significant reduction in the lean mass (?1125 ± 1620 vs. 607 ± 1578 g, P = 0.011) measured by whole‐body DXA scan in the aripiprazole group. All values were expressed as mean ± standard deviation, aripiprazole vs. placebo. Conclusion: Adjunctive therapy with aripiprazole may have some metabolic benefits in clozapine‐treated patients with schizophrenia.     

Randomized,placebo‐controlled trial of incobotulinumtoxina for upper‐limb post‐stroke spasticity

Introduction: Efficacy and safety of incobotulinumtoxinA in post‐stroke upper‐limb spasticity were studied. Methods: Subjects randomized 2:1 to incobotulinumtoxinA (fixed dose 400 U) or placebo, with fixed doses for the primary target clinical pattern (PTCP; flexed elbow, 200 U; flexed wrist, 150 U; clenched fist, 100 U). Doses for non‐primary patterns were flexible within predefined ranges. Results: At week 4, incobotulinumtoxinA led to larger improvements in PTCP Ashworth scale (AS) scores than placebo [least‐squares mean change ± standard error: –0.9 ± 0.06 (n = 171) vs. –0.5 ± 0.08 (n = 88); P < 0.001], and more subjects were PTCP AS responders (≥1‐point improvement) with incobotulinumtoxinA (69.6%) than with placebo (37.5%; P < 0.001). Investigator's Global Impression of Change confirmed superiority of incobotulinumtoxinA vs. placebo (P = 0.003). IncobotulinumtoxinA was associated with functional improvements, as demonstrated in responder rates for Disability Assessment Scale principal target at week 4 (P = 0.007). Adverse events were mainly mild/moderate, and were reported by 22.4% (incobotulinumtoxinA) and 16.8% (placebo) of subjects. Conclusions: IncobotulinumtoxinA significantly improved upper‐limb spasticity and associated disability, and was well‐tolerated. Muscle Nerve 53: 415–421, 2016     

Atomoxetine treatment in adults with attention‐deficit/hyperactivity disorder and comorbid social anxiety disorder

Background: To evaluate the effect of atomoxetine (ATX) on attention‐deficit/hyperactivity disorder (ADHD) and comorbid social anxiety disorder in adults. Methods: Randomized, double‐blind, placebo‐controlled, conducted in adults with ADHD and social anxiety disorder. Patients received 40–100 mg ATX (n=224) or placebo (n=218) for 14 weeks following a 2‐week placebo lead‐in period. Efficacy measures included the Conners' Adult ADHD Rating Scale: Investigator‐Rated: Screening Version (CAARS:Inv:SV), Liebowitz Social Anxiety Scale (LSAS), Clinical Global Impression‐Overall‐Severity (CGI‐O‐S), State‐Trait Anxiety Inventory (STAI), Social Adjustment Scale‐Self Report (SAS), and Adult ADHD Quality of Life Scale‐29 (AAQoL). Safety and tolerability were also assessed. Results: ATX mean change (?8.7±10.0) from baseline (29.6±10.4) on CAARS:Inv:SV Total ADHD Symptoms score was significantly greater than placebo mean change (?5.6±10.2) from baseline (31.2±9.4; P<.001). ATX mean change (?22.9±25.3) from baseline (85.3±23.6) on LSAS Total score was significant compared to placebo mean change (?14.4±20.3) from baseline (82.1±21.3; P<.001). The visit‐wise analysis revealed greater improvement on the CAARS:Inv:SV Total ADHD Symptoms score and LSAS Total score for ATX at every time point throughout the study (P values ≤.012). Mean changes in CGI‐O‐S, STAI‐Trait Anxiety scores, and AAQoL Total score were significantly greater for ATX compared to placebo. Mean change for both groups on STAI‐State Anxiety scores was comparable. Improvement on SAS for ATX compared to placebo was not significant. Rates of insomnia, nausea, dry mouth, and dizziness were higher with ATX than with placebo. Discontinuation rates due to treatment‐emergent adverse events were similar between groups. Conclusions: ATX monotherapy effectively improved symptoms of ADHD and comorbid social anxiety disorder in adults and was well tolerated. Depression and Anxiety, 2009. Published 2009 Wiley‐Liss, Inc.     

Duodenal levodopa/carbidopa infusion therapy in patients with advanced Parkinson’s disease leads to improvement in caregivers’ stress and burden

Background: Continuous duodenal levodopa infusion (DLI) is an effective therapy that improves quality of life (QoL) in advanced Parkinson’s disease (PD). However, the impact of DLI on caregivers’ stress and burden has not been reported. Methods: We evaluated prospectively open‐label seven advanced PD patients (65.7 ± 9.6 years, 71.4% men) treated with DLI. Schwab & England Activities of Daily Living Scale (ADLS), 39‐item Parkinson’s disease QoL Questionnaire Summary Index score (PDQ‐39SI), Zarit Caregiver Burden Interview (ZCBI), and Caregiver Strain Index (CSI) were used. Comparisons were made between scores obtained at baseline and those at a mean follow‐up of 31.4 ± 7.9 months (range, 23–42). Results: In patients, mean ± SD ADLS was increased from 50 ± 8.2 to 80 ± 11.6 (P = 0.014), and mean ± SD PDQ‐39SI was decreased from 53.7 ± 11.9 to 33.6 ± 12.8 (P = 0.018). In caregivers, ZCBI decreased from 43 ± 13.3 to 20.7 ± 12.1 (P = 0.018) and CSI from 6.3 ± 2.5 to 1.6 ± 0.9 (P = 0.018). At baseline, 57.1% of caregivers reported moderate to severe burden (ZCBI 41–88) compared to 28.6% at the end of the follow‐up (P = 0.015); at that time, no caregiver reported high level of stress (CSI ≥ 7) compared to 57.1% at baseline (P = 0.046). There were significant correlations between ZCBI and CSI improvement (r = 0.813, P = 0.026), ZCBI and PDQ‐39SI (r = 0.875, P = 0.01), and ZCBI and ADLS (r = 0.813, P = 0.026). Conclusions: Duodenal levodopa infusion‐related clinical improvement in patients with advanced PD leads to substantial reductions in caregivers’ stress and burden.     

Augmentation of clozapine with a second antipsychotic – a meta‐analysis of randomized,placebo‐controlled studies

Objective: Inadequate response to clozapine treatment is frequently encountered in practice and augmentation strategies have been developed in an attempt to improve response. Aims of the study were to evaluate the therapeutic effect of adding an antipsychotic drug to clozapine treatment. Method: Meta‐analysis of randomized, placebo‐controlled studies of antipsychotic augmentation of clozapine treatment. Results: Ten studies (including 522 subjects) met inclusion criteria. Antipsychotic augmentation showed significant benefit over the addition of placebo on only one outcome measure examined [mean effect size for rating scale score (BPRS/PANSS) ?0.180, 95% CI ?0.356 to ?0.004]. Antipsychotic augmentation showed no advantage on withdrawals from trials (risk ratio 1.261, 95% CI 0.679–2.345) or on CGI scores (effect size ?0.661, 95% CI ?1.475 to 0.151). Duration of study was not associated with outcome (P = 0.95). There was no evidence of publication bias. Conclusion: In studies lasting up to 16 weeks, the addition of an antipsychotic to clozapine treatment has marginal therapeutic benefit. Longer and larger trials are necessary to demonstrate the precise therapeutic utility of antipsychotic co‐therapy with clozapine.     

Clinical Evaluation of the Daily Assessment of Symptoms‐Anxiety (DAS‐A): A New Instrument to Assess the Onset of Symptomatic Improvement in Generalized Anxiety Disorder

Introduction: Rapid onset of symptomatic improvement is a desirable characteristic of new generalized anxiety disorder (GAD) treatments. A validated rating scale is needed to assess GAD symptoms during the first days of treatment. Aims: To provide clinical data to support the validation of the Daily Assessment of Symptoms‐Anxiety (DAS‐A), a new instrument to assess onset of symptomatic improvement in GAD. Methods: We assessed the ability of the DAS‐A to detect onset of symptomatic improvement during the first week of therapy in 169 GAD patients randomized to paroxetine 20 mg/day, lorazepam 4.5 mg/day, or placebo for 4 weeks. Results: On the primary outcome measure, average change from baseline over the first 6 days of DAS‐A assessments, lorazepam (?14.5 ± 1.8 [LS mean, SE]; P= 0.006 vs. placebo) showed a significant improvement versus placebo (?7.85 ± 1.7), whereas paroxetine (?8.3 ± 1.7; P= 0.83 vs. placebo) did not. Lorazepam produced a significant treatment effect on the DAS‐A at 24 h (P= 0.0004), whereas paroxetine did not (P= 0.5666). Both active drugs produced statistically significant improvement versus placebo on the DAS‐A total change score (last‐observation carried forward method; LOCF, endpoint). On the DAS‐A total change score (observed cases analysis), lorazepam produced statistically significant improvement versus placebo at weeks 1, 2, and 4 (P < 0.05; no week 3 visit), whereas paroxetine, separated from placebo at weeks 2 and 4 (P < 0.05). Both active drugs produced results on the Hamilton Anxiety Rating Scale (HAM‐A) at weeks 1 through 4 that were similar to those found on the DAS‐A. Conclusions: These data indicate that the DAS‐A can detect symptomatic improvement in GAD patients treated with lorazepam during the first week of treatment, and, in a secondary analysis, as early as 24 h.     

A randomized,double‐blind,placebo‐controlled trial evaluating cysteamine in Huntington's disease

Background : Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington's disease. Methods : Ninety‐six patients with early‐stage Huntington's disease were randomized to 1200 mg delayed‐release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed‐effects model for repeated measures was used to assess treatment effect, expressed as the least‐squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo. Results : At 18 months, the treatment effect was not statistically significant — least‐squares mean difference, ‐1.5 ± 1.71 (P = 0.385) — although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated. Conclusions : Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington's disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society     

Randomized,controlled trial of rasagiline as an add‐on to dopamine agonists in Parkinson's disease

Dopamine agonists (DA) are often used as first‐line monotherapy for the symptomatic control of Parkinson's disease (PD). However, DA monotherapy typically becomes inadequate within a few years, at which time the DA dosage must be increased or other antiparkinsonian medications added. Adding a monoamine oxidase‐B (MAO‐B) inhibitor to DA monotherapy might improve symptomatic control while maintaining good safety and tolerability. We conducted an 18‐week, randomized, double‐blind, placebo‐controlled trial of rasagiline 1 mg/d as an add‐on to DA therapy (ropinirole ≥ 6 mg/d or pramipexole ≥ 1.0 mg/d) in early PD patients whose conditions were not adequately controlled on their current treatment regimen. The primary efficacy variable was the change in total Unified Parkinson Disease Rating Scale (UPDRS) score (sum of parts I, II, and III) from baseline to week 18, comparing rasagiline and placebo groups. The modified intent‐to‐treat (ITT) population included 321 subjects whose mean ± SD age was 62.6 ± 9.7, and duration of PD was 2.1 ± 2.1 years. Results demonstrated a significantly greater improvement in total UPDRS scores from baseline to week 18 in the rasagiline group compared with the placebo group (least squares [LS] mean difference ± SE, ?2.4 ± 0.95; 95% confidence interval [CI], ?4.3, ?0.5; P = 0.012). Mean improvement (LS mean ± SE) was ?3.6 ± 0.68 in the rasagiline group and ?1.2 ± 0.68 in the placebo group. Rasagiline was well tolerated, and the most common adverse events (AEs; rasagiline vs. placebo) were dizziness (7.4% vs. 6.1%), somnolence (6.8% vs. 6.7%), and headache (6.2% vs. 4.3%). Rasagiline 1 mg/d provided statistically significant improvement when added to dopamine agonist therapy and was well tolerated. © 2014 International Parkinson and Movement Disorder Society     

Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized,placebo‐controlled and dose‐finding study

Background Lubiprostone is a prostone analog with a novel mechanism of action involving type‐2 chloride channel activation. The aim of this work was to perform a dose‐finding study for lubiprostone for the treatment of constipation with or without irritable bowel syndrome (IBS) in Japan. Methods A total of 170 patients (128 without IBS and 42 with IBS) with chronic idiopathic constipation (CIC) randomly received a placebo (n = 42) or 16 μg (n = 41), 32 μg (n = 43), or 48 μg (n = 44) of lubiprostone daily for 2 weeks. Key Results There was a statistically significant and dose‐dependent increase in change from baseline in the weekly average number of spontaneous bowel movements at week 1 (placebo: 1.5 ± 0.4; 16 μg: 2.3 ± 0.4, 32 μg: 3.5 ± 0.5; and 48 μg: 6.8 ± 1.1, per week, mean ± SE; P < 0.0001). These primary endpoint results were significant on stratified analysis when patients were limited to those without IBS (P < 0.0001). The primary endpoint in patients with IBS treated with 48 μg of lubiprostone was significantly better than those given placebo (P = 0.0086). Dose dependency was also seen for the secondary efficacy endpoints. Lubiprostone produced no serious side effects. Conclusions & Inferences Our results suggest that lubiprostone produced a steady and effective improvement in the symptoms of CIC with or without IBS in a dose‐dependent manner with a good safety profile and tolerability in a Japanese population.     

Riluzole in augmentation of fluvoxamine for moderate to severe obsessive–compulsive disorder: Randomized,double‐blind,placebo‐controlled study

Aim

The aim of the present randomized, double‐blind, placebo‐controlled, 8‐week trial was to assess the efficacy and tolerability of riluzole augmentation of fluvoxamine in treatment of patients with moderate to severe obsessive–compulsive disorder.

Methods

Patients were randomized into two parallel groups to receive fluvoxamine plus placebo or fluvoxamine plus riluzole (50 mg twice daily). All patients, regardless of their treatment group, received fluvoxamine at 100 mg/day for the initial 4 weeks of the study followed by 200 mg/day of fluvoxamine for the rest of the trial course. A total of 50 patients (25 in each group) were evaluated for response to treatment using the Yale–Brown Obsessive Compulsive Scale (Y‐BOCS) at baseline and at weeks 4, 8 and 10. Side‐effects were recorded using predesigned checklists in each visit. Repeated‐measure analysis of variance showed a significant effect for time × treatment interaction in the Y‐BOCS total score and a significant effect for time × treatment interaction in the Y‐BOCS Compulsive subscale score between the two groups.

Results

Repeated‐measure analysis of variance showed a significant effect for time × treatment interaction (Greenhouse–Geisser corrected: F = 4.07, d.f. = 1.22, P = 0.04) in the Y‐BOCS total score and a significant effect for time × treatment interaction (Greenhouse–Geisser corrected: F = 4.45, d.f. = 1.33, P = 0.028) in the Y‐BOCS Compulsive subscale score between the two groups. Riluzole augmentation therapy demonstrated higher, partial or complete treatment response according to the Y‐BOCS total scores.

Conclusion

Riluzole may be of clinical use as an adjuvant agent to fluvoxamine in treatment of moderate to severe obsessive–compulsive disorder.     

Randomized,double‐blind,multicenter evaluation of pramipexole extended release once daily in early Parkinson's disease

The objective of this study was to evaluate the efficacy and safety of pramipexole extended release (ER) administered once daily in early Parkinson's disease (PD). Pramipexole immediate release (IR) administered three times daily (TID) is an efficacious and generally well‐tolerated treatment for PD. A pramipexole ER formulation is now available. We performed a randomized, double‐blind, placebo and active comparator–controlled trial in subjects with early PD. The primary efficacy and safety evaluation of pramipexole ER compared with placebo took place at week 18. Two hundred fifty‐nine subjects were randomized 2:2:1 to treatment with pramipexole ER once daily, pramipexole IR TID, or placebo. Levodopa rescue was required by 7 subjects in the placebo group (14%), 3 subjects in the pramipexole ER group (2.9%, P = 0.0160), and 1 subject in the pramipexole IR group (1.0%, P = 0.0017). Adjusted mean [standard error (SE)] change in Unified Parkinson Disease Rating Scale (UPDRS) II [activities of daily living (ADL)] + III (motor) scores from baseline to week 18, including post‐levodopa rescue evaluations, was ?5.1 (1.3) in the placebo group, ?8.1 (1.1) in the pramipexole ER group (P = 0.0282), and ?8.4 (1.1) in the pramipexole IR group (P = 0.0153). Adjusted mean (SE) change in UPDRS ADL + motor scores, censoring post‐levodopa rescue data, was ?2.7 (1.3) in the placebo group, ?7.4 (1.1) in the pramipexole ER group (P = 0.0010), and ?7.5 (1.1) in the pramipexole IR group (P = 0.0006). Adverse events more common with pramipexole ER than placebo included somnolence, nausea, constipation, and fatigue. Pramipexole ER administered once daily was demonstrated to be efficacious compared with placebo and provided similar efficacy and tolerability as pramipexole IR administered TID. © 2010 Movement Disorder Society     

Orodispersible sublingual piribedil to abort OFF episodes: A single dose placebo‐controlled,randomized, double‐blind,cross‐over study

S90049, a novel sublingual formulation of the non‐ergoline D₂‐D₃ agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single‐dose double‐blind double‐placebo 3 × 3 cross‐over study. Optimal tested doses were determined during a previous open‐label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (ΔUPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 ± 8 years, PD duration: 12 ± 6 years, UPDRS III OFF: 37 ± 15) participated. S90049 wassuperior to placebo on ΔUPDRS III (?13 ± 12 versus ?7 ± 9 respectively; estimated difference ?5.2, 95% Confidence Interval (CI)[?10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, ΔUPDRS III was similar on S90049 (?21.2 ± 10.1) and apomorphine (?23.6 ± 14.1) (estimated difference: 4.0 95% CI [?2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate. © 2009 Movement Disorder Society     

Electrophysiology in chronic inflammatory demyelinating polyneuropathy with IGIV

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) received immune globulin intravenous, 10% caprylate/chromatography purified (IGIV‐C, Gamunex; n = 59) or placebo (n = 58) every 3 weeks for up to 24 weeks (first period) in a randomized, double‐blind, parallel‐group, response‐conditional, crossover study. Motor and sensory nerves were assessed at baseline and endpoint/week 24. A nonsignificant trend toward improvement in the proximal amplitude of the most severely affected motor nerve was observed with IGIV‐C (0.69 ± 1.86 mV) versus placebo (0.47 ± 2.29 mV), and a greater improvement of 1.08 ± 2.15 mV with IGIV‐C versus 0.46 ± 2.03 mV with placebo (P = 0.089) was observed with exclusion of data from Erb's point stimulation. Greater improvements from baseline favoring IGIV‐C were observed for 127/142 electrophysiologic parameters. The averaged motor amplitudes from all motor nerves significantly improved with IGIV‐C versus placebo [treatment difference, 0.62 mV; 95% confidence interval (CI), 0.05, 1.20; P = 0.035], and conduction block decreased significantly (treatment difference, ?5.54%; 95% CI, ?10.43, ?0.64; P = 0.027), particularly in the lower limbs. Overall, the data suggest that IGIV‐C improves electrophysiologic parameters in CIDP. Muscle Nerve, 2009     

Muscular adaptations and insulin‐like growth factor‐1 responses to resistance training are stretch‐mediated

Introduction: Modulation of muscle characteristics was attempted through altering muscle stretch during resistance training. We hypothesized that stretch would enhance muscle responses. Methods: Participants trained for 8 weeks, loading the quadriceps in a shortened (SL, 0–50° knee flexion; n = 10) or lengthened (LL, 40–90°; n = 11) position, followed by 4 weeks of detraining. Controls (CON; n = 10) were untrained. Quadriceps strength, vastus lateralis architecture, anatomical cross‐sectional area (aCSA), and serum insulin‐like growth factor‐1 (IGF‐1) were measured at weeks 0, 8, 10, and 12. Results: Increases in fascicle length (29 ± 4% vs. 14 ± 4%), distal aCSA (53 ± 12% vs. 18 ± 8%), strength (26 ± 6% vs. 7 ± 3%), and IGF‐1 (31 ± 6% vs. 7 ± 6%) were greater in LL compared with SL muscles (P < 0.05). No changes occurred in CON. Detraining decrements in strength and aCSA were greater in SL than LL muscles (P < 0.05). Conclusions: Enhanced muscle in vivo (and somewhat IGF‐1) adaptations to resistance training are concurrent with muscle stretch, which warrants its inclusion within training. Muscle Nerve 49 : 108–119, 2014     

Pregabalin in the treatment of post‐traumatic peripheral neuropathic pain: a randomized double‐blind trial

Background: Pregabalin is effective in the treatment of peripheral and central neuropathic pain. This study evaluated pregabalin in the treatment of post‐traumatic peripheral neuropathic pain (including post‐surgical). Methods: Patients with a pain score ≥4 (0–10 scale) were randomized and treated with either flexible‐dose pregabalin 150–600 mg/day (n = 127) or placebo (n = 127) in an 8‐week double‐blind treatment period preceded by a 2‐week placebo run‐in. Results: Pregabalin was associated with a significantly greater improvement in the mean end‐point pain score vs. placebo; mean treatment difference was ?0.62 (95% CI ?1.09 to ?0.15) (P = 0.01). The average pregabalin dose at end‐point was ～326 mg/day. Pregabalin was also associated with significant improvements from baseline in pain‐related sleep interference, and the Medical Outcomes Study sleep scale sleep problems index and sleep disturbance subscale (all P < 0.001). In the all‐patient group (ITT), pregabalin was associated with a statistically significant improvement in the Hospital Anxiety and Depression Scale anxiety subscale (P < 0.05). In total, 29% of patients had moderate/severe baseline anxiety; treatment with pregabalin in this subset did not significantly improve anxiety. More patients reported global improvement at end‐point with pregabalin than with placebo (68% vs. 43%; overall P < 0.01). Adverse events led to discontinuation of 20% of patients from pregabalin and 7% from placebo. Mild or moderate dizziness and somnolence were the most common adverse events in the pregabalin group. Conclusion: Flexible‐dose pregabalin 150–600 mg/day was effective in relieving neuropathic pain, improving disturbed sleep, improving overall patient status, and was generally well tolerated in patients with post‐traumatic peripheral neuropathic pain.     

Long‐term antidyskinetic efficacy of amantadine in Parkinson's disease

Several randomized placebo‐controlled trials have consistently shown antidyskinetic effects of amantadine in levodopa treated patients with advanced Parkinson's disease (PD). However, all of these were of short duration and there have been claims that the effect of amantadine on levodopa induced dyskinesias (LID's) wear off after about 9 months of treatment. This randomized placebo‐controlled parallel‐group study was performed to assess the long‐term antidyskinetic effect of amantadine in 32 PD patients, who after having been on stable amantadine therapy for LID over at least one year‐ were switched in a double blind manner to amantadine or placebo and followed for 3 weeks. Dyskinesia duration and intensity were assessed by UPDRS IV items 32 and 33 as well as by patient's diaries. The primary outcome was the score change of UPDRS IV items 32 + 33 between baseline and 3 weeks after treatment as well as the between treatment group comparison of the score change of UPDRS IV items 32 + 33. There was a significant increase of UPDRS IV items 32 + 33 in patients treated with placebo from 3.06 (95% CI, 2.1–4.03) at baseline to 4.28 (95% CI, 3.1–5.4) at three‐week follow‐up (P = 0.02) compared with no significant change between baseline 3.2 (95% CI, 2.1–4.4) to follow‐up 3.6 (95% CI, 2.3–4.8) in patients staying on amantadine. These findings argue for long‐term antidyskinetic efficacy of amantadine in PD patients with LID's. © 2010 Movement Disorder Society     

Augmentation of clozapine with a second antipsychotic - a meta-analysis

Taylor DM, Smith L, Gee SH, Nielsen J. Augmentation of clozapine with a second antipsychotic – a meta‐analysis. Objective: To examine using meta‐analysis the effect of adding a second antipsychotic to established clozapine monotherapy. Method: A literature search was conducted in April 2011, and randomised placebo‐controlled double‐blind studies were identified. We performed a meta‐analysis of efficacy (as standardised mean difference) and tolerability (withdrawals from trials) and a regression analysis of duration of study versus effect size. We also examined publication bias using funnel‐plot analysis. Results: Overall, 14 studies were included (734 subjects). Individual study numbers ranged from 10 to 207 (mean 52.6, median 40). Augmentation of clozapine with a second antipsychotic conferred a small benefit over placebo (effect size ?0.239 (95% CI: ?0.452, ?0.026); P = 0.028). Meta‐regression of the effect of length of treatment on effect size showed no relationship (P = 0.254). The risk of discontinuing antipsychotic augmentation was no greater than the risk of discontinuing placebo (RR = 1.20, 95% CI 0.80–1.82). There was no evidence of publication bias. Conclusion: Augmentation with a second antipsychotic is modestly beneficial in patients not responding fully to clozapine. Tolerability seems not to be adversely affected, at least in the short term. Longer studies do not appear to increase the probability of showing positive effects for augmentation.     

Donepezil in Parkinson's disease dementia: A randomized,double‐blind efficacy and safety study

Parkinson's disease dementia (PDD) is associated with cholinergic deficits. This report presents an efficacy and safety study of the acetylcholinesterase inhibitor donepezil hydrochloride in PDD. PDD patients (n = 550) were randomized to donepezil (5 or 10 mg) or placebo for 24 weeks. Coprimary end points were the Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS‐cog) and Clinician's Interview‐Based Impression of Change plus caregiver input (CIBIC+; global function). Secondary end points measured executive function, attention, activities of daily living (ADLs), and behavioral symptoms. Safety and tolerability were assessed. ADAS‐cog mean changes from baseline to week 24 (end point) were not significant for donepezil in the intent‐to‐treat population by the predefined statistical model (difference from placebo: ?1.45, P = .050, for 5 mg; ?1.45, P = .076, for 10 mg). Alternative ADAS‐cog analysis, removing the treatment‐by‐country interaction term from the model, revealed significant, dose‐dependent benefit with donepezil (difference from placebo: ?2.08, P = .002, for 5 mg; ?3.31, P < .001, for 10 mg). The 10‐mg group, but not the 5‐mg group, had significantly better CIBIC+ scores compared with placebo (3.7 vs 3.9, P = .113, for 5 mg; 3.6 vs 3.9, P = .040, for 10 mg). Secondary end points—Mini–Mental State Exam; Delis–Kaplan Executive Function System; Brief Test of Attention, representing cognitive functions particularly relevant to PDD—showed significant benefit for both donepezil doses (P ≤ .007). There were no significant differences in ADLs or behavior. Adverse events were more common with donepezil but mostly mild/moderate in severity. Although the study did not achieve its predefined primary end points, it presents evidence suggesting that donepezil can improve cognition, executive function, and global status in PDD. Tolerability was consistent with the known safety profile of donepezil. © 2012 Movement Disorder Society     

Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized,placebo‐controlled study

Perampanel, a novel, noncompetitive, selective AMPA‐receptor antagonist demonstrated evidence of efficacy in reducing motor symptoms in animal models of Parkinson's disease (PD). We assessed the safety and efficacy of perampanel for treatment of “wearing off” motor fluctuations in patients with PD. Patients (N = 263) were randomly assigned to once‐daily add‐on 0.5, 1, or 2 mg of perampanel or placebo. The primary objective was to determine whether there was a dose‐response relationship for efficacy among the 3 perampanel doses and placebo. The primary efficacy endpoint for each treatment was measured as the least‐squares (LS) mean change from baseline to week 12 in percent “off” time reduction during the waking day, as recorded by patient diaries. The primary efficacy analysis was a 1‐sided Williams test for dose‐response trend at the 0.025 level of significance. At week 12, dose‐response trends, as determined by the Williams test, were not statistically significant for LS mean reduction in percent “off” time during the waking day (P = 0.061, with significance defined as P ≤ 0.025). The 2 higher perampanel doses (ITT population; n = 258) produced nonsignificant reductions from baseline to week 12 in percent “off” time during the waking day versus placebo (7.59%, P= 0.421 [1 mg], 8.60%, P = 0.257 [2 mg] versus 5.05% [placebo]; significance for pairwise comparisons defined as P ≤ 0.05). There were no significant changes in dyskinesia or cognitive function in any perampanel group versus placebo. Adverse events were similar across treatment groups. Perampanel treatment was well tolerated and safe, but failed to achieve statistical significance in primary and secondary endpoints. © 2010 Movement Disorder Society     

A double‐blind,placebo‐controlled study of prucalopride in elderly patients with chronic constipation

Background Constipation affects up to 50% of the elderly; this study evaluates the efficacy, safety, and tolerability of the selective 5‐HT₄ agonist prucalopride in chronically constipated elderly patients. Methods Three hundred chronic constipation patients aged ≥65 years were randomized to prucalopride (1, 2, or 4 mg once daily) or placebo for 4 weeks. The primary endpoint was the percentage of patients with ≥3 spontaneous complete bowel movements (SCBM) per week. Secondary endpoints included the percentage with an increase of ≥1 SCBM per week, BM frequency, constipation‐related symptoms, quality of life (QoL), safety, and tolerability. Key Results More patients achieved ≥3 SCBM per week with prucalopride than with placebo. This difference was largest and significant during the first week of 4 mg prucalopride (P ≤ 0.05). Significantly more patients in each prucalopride group achieved an increase of ≥1 SCBM per week from baseline vs placebo (e.g. 60% with 1 mg prucalopride vs 34% with placebo at week 4; P ≤ 0.05). More patients had improvement in PAC‐QOL satisfaction score of ≥1 with 1 mg prucalopride than with placebo (P ≤ 0.05); the same was true for PAC‐SYM stool symptoms (1 and 4 mg prucalopride; P ≤ 0.05). Treatment‐emergent adverse events were similar between groups: the most frequently reported with prucalopride were headache and gastrointestinal events. There were no clinically significant differences between prucalopride and placebo for vital signs, laboratory assessments, or ECG variables. Conclusions & Inferences Prucalopride, in the dose‐range tested (1–4 mg once daily), has beneficial effects on bowel movements, symptoms, and QoL, and is safe and well‐tolerated in elderly patients with chronic constipation.