Efficacy and safety of pregabalin in generalised anxiety disorder: A critical review of the literature.

The aim of this review is to summarise the literature on the efficacy and safety of pregabalin for the treatment of generalised anxiety disorder (GAD). Of 241 literature citations, 13 clinical trials were identified that were specifically designed to evaluate the efficacy and safety of pregabalin in GAD, including 11 randomised double-blind trials and two open-label studies. Pregabalin efficacy has been consistently demonstrated across the licensed dose range of 150-600 mg/day. Efficacy has been reported for pregabalin monotherapy in elderly patients with GAD, patients with severe anxiety, and for adjunctive therapy when added to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor in patients who have failed to respond to an initial course of antidepressant therapy. The two most common adverse events with pregabalin are somnolence and dizziness, both of which appear to be dose-related. Pregabalin appears to have a low potential for causing withdrawal symptoms when long-term therapy is discontinued; however, tapering over the course of at least one week is recommended. A review of available evidence indicates that pregabalin is a well-tolerated and consistently effective treatment for GAD, with a unique mechanism of action that makes it a useful addition to the therapeutic armamentarium.

A review of the pharmacoeconomics of eletriptan for the acute treatment of migraine.

Migraine is a commonly occurring, chronic disorder that can cause significant disability. Eletriptan, a selective serotonin 5-hydroxytryptamine 1 receptor subtype B/D (5-HT1B/1D) agonist, is a clinically effective treatment for moderate to severe migraine. The objective of this literature review was to summarize the available data on the pharmacoeconomics of eletriptan relative to other triptans. Articles meeting the following three criteria were included in the review: 1) contained pharmacoeconomic data on a marketed dose of eletriptan; 2) included data on at least one other comparator triptan; and 3) was in English. A MEDLINE(®) search yielded a total of eight studies (from the European Union [n=5] and from the USA [n=3]) across multiple regions. Seven of the studies examined the pharmacoeconomics of eletriptan relative to other triptans, and a further study examined the health care costs of eletriptan 40 mg versus sumatriptan 100 mg. Eletriptan 40 mg was among a group of triptans, including rizatriptan 10 mg and almotriptan 12.5 mg, demonstrating the greatest cost-effectiveness. This result held across different definitions of efficacy (2 hours pain-free, sustained pain-free, and sustained pain-free with no adverse events) and also held when cost-effectiveness models accounted for second doses and use of rescue medication, management of adverse events, and productivity loss, in addition to drug acquisition costs. Only limited head-to-head comparator data were available. The majority of pharmacoeconomic studies utilized the same set of efficacy and/or tolerability data, and indirect costs were rarely included despite the fact that the majority of per capita migraine costs are attributable to indirect costs. In summary, although the market is now dominated by generics, eletriptan 40 mg is among the most clinically and cost-effective oral triptans available for the management of acute migraine. Increased effectiveness/efficacy of eletriptan may necessitate a lesser need for other migraine treatments and/or switching to other triptans.

Outcome for headache and pain-free nonresponders to treatment of the first attack: a pooled post-hoc analysis of four randomized trials of eletriptan 40 mg.

OBJECTIVE: The objective of this article is to evaluate, in first attack eletriptan headache and pain-free nonresponders, the efficacy of treating a second and third attack with the same dose of eletriptan 40 mg (ELE-40). METHODS: Data were pooled from four randomized, double-blind, placebo-controlled, multiple attack studies of eletriptan in the treatment of migraine. The first-attack eletriptan headache (HNR) and pain-free (PFNR) nonresponder samples consisted of patients who did not achieve headache or pain-free responses at two hours, or sustained headache or pain-free responses at 24 hours. The efficacy of the same dose of eletriptan (vs placebo; PBO) in treating the second and third attacks was evaluated using a logistic regression model. RESULTS: Among Attack 1 eletriptan HNRs, treatment with ELE-40 (vs PBO) was associated with significantly higher two-hour headache response and pain-free rates, respectively, on both Attack 2 (48.8% vs 20.2%; 17.0% vs 3.9%; P < 0.0001 for both comparisons) and Attack 3 (37.4% vs 15.5%; 18.8% vs 3.2%; P < 0.0001 for both comparisons). Significantly higher sustained headache response and pain-free rates at 24 hours were also observed on both Attack 2 and Attack 3. CONCLUSIONS: The results of this pooled analysis suggest that patients who have HNR or PFNR to an initial dose of eletriptan may respond when a second and third attack is treated with the same dose.

Consistency of eletriptan in treating migraine: Results of a randomized, within-patient multiple-dose study.

OBJECTIVE: The current study evaluated the consistency of eletriptan response. METHODS: Using a within-patient crossover design, patients with migraine completed a three-attack, open-label, lead-in period, before being treated, double-blind for four attacks, with either eletriptan 40 mg (ELE-40; N = 539) or eletriptan 80 mg (ELE-80; N = 432); placebo was randomly substituted for the treatment of one attack. RESULTS: On an A PRIORI analysis of within-patient consistency, double-blind treatment was associated with similar 2 hour headache response rates using a ≥2/3 response criterion for ELE-40 (77%) and ELE-80 (73%), and using a 3/3 response criterion for ELE-40 (46%) and ELE-80 (47%). Within-patient consistency in achieving pain-free status at 2 hours using a ≥2/3 criterion was slightly higher on ELE-40 (42%) compared with ELE-80 (38%), and was similar using the 3/3 criterion (18% on ELE-40, 17% on ELE-80). On a repeated measures logistic regression analysis across all treated attacks, the probability of achieving a headache response at 2 hours ranged from 71% to 74% on ELE-40 vs. 17% to 28% on placebo ( P < 0.0001), and from 66% to 74% on ELE-80 vs. 21% to 27% on placebo ( P < 0.0001). The incidence, per attack, of adverse events was low for both ELE-40 and ELE-80. Few adverse events occurred with incidence ≥10% on ELE-40 (asthenia, 5.0%) or ELE-80 (asthenia, 10%; nausea, 5.8%). Discontinuations because of adverse events were 0.2% on ELE-40, and 1.6% on ELE-80 CONCLUSION: In this multiple attack study, eletriptan was well-tolerated and demonstrated consistent and significant efficacy in the treatment of migraine.

How well do randomized controlled trial data generalize to 'real-world' clinical practice settings? A comparison of two generalized anxiety disorder studies.

The aim of this post-hoc comparison is to compare efficacy and tolerability results from two generalized anxiety disorder (GAD) studies: a placebo-controlled, randomized controlled trial (RCT) and a study conducted in the clinical practice setting, and to evaluate the extent to which results from RCTs in GAD patients can be generalized to clinical practice. In the clinical practice study, GAD outpatients (n=578) were treated with 4 weeks of pregabalin 150-600mg/day. In the double-blind placebo-controlled RCT, GAD outpatients (n=249) were randomized to 8 weeks of pregabalin (300-600mg/day), or placebo (only the first 4 weeks are included in the current analysis). Efficacy measures included the Hospital Anxiety and Depression Scale - Anxiety and Depression subscales (HADS-A; HADS-D), a visual analogue anxiety scale (VAS-Anxiety), and the Medical Outcomes Study Sleep Problems Index (MOS-SPI). Baseline HADS-A and HADS-D scores were both higher in the clinical practice study vs. the RCT. In the RCT, treatment with pregabalin resulted in significantly greater Week 4 change vs. placebo in the HADS-A (-5.3 vs. -3.9; P<0.005), VAS-Anxiety (-24.0 vs. -13.3; P<0.02), MOS-SPI (-19.1 vs. -9.5; P<0.01), and HADS-D (-2.7 vs. -1.4; P<0.05). The magnitude of Week 4 improvement on pregabalin in the clinical practice study was numerically larger on the HADS-A (-5.9), VAS-Anxiety (-36.0), MOS-SPI (-22.7), and HADS-D (-5.1), despite use of lower doses. These results suggest that clinical practice patients with GAD may achieve comparable efficacy on lower doses of pregabalin than tested in RCTs, despite having comparable levels of anxiety symptom severity at baseline. The current exploratory comparison also suggests that results from RCTs in patients with GAD may not be directly generalizable to clinical practice.

Pregabalin long-term treatment and assessment of discontinuation in patients with generalized anxiety disorder.

Discontinuation effects following cessation of 12 and 24 wk of pregabalin treatment for generalized anxiety disorder (GAD) were evaluated in a placebo- and lorazepam-controlled, randomized, double-blind, multicentre trial conducted in 16 countries. The study design consisted of two 12-wk treatment periods (periods 1 and 2), each followed by a 1-wk taper and two post-discontinuation assessments, one immediately following the taper and one 1-wk post-taper. Patients were assigned to receive an initially flexible dose of pregabalin 450-600 mg/d, pregabalin 150-300 mg/d, or lorazepam 3-4 mg/d for 6 wk; responders continued fixed-dose therapy for 6 additional weeks. Patients entering period 2 continued on the same fixed dose or switched to placebo. Discontinuation effects were evaluated with the Physician Withdrawal Checklist (PWC) and reported discontinuation-emergent signs and symptoms. Rebound anxiety was measured with the Hamilton Anxiety Rating Scale. GAD symptoms improved with all treatments and improvements were maintained over 12 and 24 wk. Low levels of discontinuation symptoms were evident in all treatment groups. For patients who received active treatment during both periods, mean (95% confidence interval) increases on the PWC from last visit on active treatment to the second post-discontinuation assessment were: pregabalin 450-600 mg/d: 2.8 (1.6-3.9), pregabalin 150-300 mg/d: 1.7 (0.7-2.8), lorazepam 3-4 mg/d: 2.2 (1.0-3.5). Rates of rebound anxiety were also low at both 12 and 24 wk (0-6%). This suggests that risk of discontinuation symptoms and rebound anxiety are low for pregabalin after 12 and 24 wk of treatment.

An open-label trial of a sumatriptan auto-injector for migraine in patients currently treated with subcutaneous sumatriptan.

OBJECTIVE: To assess the ability of patients, during an acute migraine attack, to successfully self-inject a single dose of sumatriptan using a novel sumatriptan auto-injector (Alsuma(®)), and to evaluate the safety, tolerability, and effectiveness of this sumatriptan auto-injector during an acute migraine attack. BACKGROUND: This sumatriptan auto-injector is a single-use system for the rapid subcutaneous delivery of 6 mg of sumatriptan succinate in the acute management of migraine pain. This auto-injector was developed to address the clinical need for an easy-to-use and rapid-to-administer system that did not require any assembly during the time of an ongoing attack. METHODS: This was an open-label, phase 3 trial conducted at 10 sites in the USA. Male or female adults, ages 18-60 years old, were eligible for study entry if they met International Headache Society criteria for migraine with or without aura, with at least 2 attacks per month, and if they reported use of subcutaneous injectable sumatriptan on at least 2 occasions within the previous 2 months. During the onset of a migraine attack of moderate-to-severe intensity, patients were asked to administer a 6-mg subcutaneous dose of sumatriptan using the auto-injector. Patients returned to the study site within 72 hours of the migraine for the post-treatment assessment visit. RESULTS: A total of 63 patients met entry criteria and received a dose of study medication (the intent-to-treat sample). Sixty-one patients (96.8%) reported injection in the thigh, and 2 patients (3.2%) reported injection in the arm. On the patient questionnaire, 100% of patients (95% confidence interval [CI] 94.3-100%) "agreed" or "agreed strongly" that the written instructions for the auto-injector were clear and easy to follow (30.2% "agreed"; 69.8% "agreed strongly"); 95.2% of patients (95% CI 86.7-99.0%) found that the auto-injector was easy to use (36.5% "agreed"; 58.7% "agreed strongly"), and 65.1% of patients (95% CI 52.0-76.7%) stated that they preferred the new auto-injector to the traditional auto-injector that they were using prior to study entry (42.9% "agreed"; 22.2% "agreed strongly"). Headache response rate at 2 hours was 93.7% (95% CI 84.5-98.2%), and pain-free rate at 2 hours was 60.3% (95% CI 47.2-72.4%). Pain-free rates at 2 hours were similarly high (58.3%; 95% CI 36.6-77.9%) in the subgroup of patients reporting severe baseline headache pain. Only 1 patient reported use of rescue medication after use of the auto-injector, a single oral dose of sumatriptan 100 mg on the same day. The most frequent adverse event was injection site bruising, reported by 15.9% of patients, and rated in all instance as mild in intensity. The second most frequent adverse event was injection site pain, reported by 6.3% of patients, and rated as mild by all patients except 1, who rated it as moderate in intensity. CONCLUSION: The majority of injection-experienced patients reported the pre-assembled, single-use sumatriptan auto-injector to be an easy-to-use, preferred treatment for an acute migraine attack. The study found the auto-injector to be safe and well tolerated, with levels of injection site reactions that were mild and infrequent.

Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial.

To evaluate the efficacy of pregabalin in facilitating taper off chronic benzodiazepines, outpatients (N = 106) with a lifetime diagnosis of generalized anxiety disorder (current diagnosis could be subthreshold) who had been treated with a benzodiazepine for 8-52 weeks were stabilized for 2-4 weeks on alprazolam in the range of 1-4 mg/day. Patients were then randomized to 12 weeks of double-blind treatment with either pregabalin 300-600 mg/day or placebo while undergoing a gradual benzodiazepine taper at a rate of 25% per week, followed by a 6-week benzodiazepine-free phase during which they continued double-blind study treatment. Outcome measures included ability to remain benzodiazepine-free (primary) as well as changes in Hamilton Anxiety Rating Scale (HAM)-A and Physician Withdrawal Checklist (PWC). At endpoint, a non-significant higher proportion of patients remained benzodiazepine-free receiving pregabalin compared with placebo (51.4% vs 37.0%). Treatment with pregabalin was associated with significantly greater endpoint reduction in the HAM-A total score versus placebo (-2.5 vs +1.3; p < 0.001), and lower endpoint mean PWC scores (6.5 vs 10.3; p = 0.012). Thirty patients (53%) in the pregabalin group and 19 patients (37%) in the placebo group completed the study, reducing the power to detect a significant difference on the primary outcome. The results on the anxiety and withdrawal severity measures suggest that switching to pregabalin may be a safe and effective method for discontinuing long-term benzodiazepine therapy.

Does early improvement predict endpoint response in patients with generalized anxiety disorder (GAD) treated with pregabalin or venlafaxine XR?

Many patients with generalized anxiety disorder (GAD) only respond to pharmacological treatment after a delay of some weeks, and approximately 35% of patients do not respond. Therefore, early identification of potential responders may have important implications for clinical decision-making. In order to identify early improvement criteria that optimally predict eventual response during short-term treatment of GAD with pregabalin or venlafaxine XR, data were pooled from four double-blind, placebo-controlled GAD treatment studies. A range of measures were analyzed using logistic regression models and receiver operator characteristic (ROC) curve analysis, to predict endpoint response. Results showed that early improvement (≥ 20% reduction from baseline score) on the Hamilton Anxiety Scale (HAM-A) was associated with a high probability of achieving an endpoint response at Weeks 1 and 2 among patients treated with pregabalin (~67%), and at Week 2 with venlafaxine XR (60%). A Clinical Global Impression - Improvement (CGI-I) score ≤ 3 at Week 2 was a reliable predictor of achieving endpoint response for pregabalin and venlafaxine XR (odds ratio [OR], 5.33 and 2.47, respectively) with high sensitivity (pregabalin, 0.91; venlafaxine XR, 0.86) and relatively low specificity (pregabalin, 0.33; venlafaxine XR, 0.29), indicating a high true positive rate, but relatively low true negative rate. These findings indicate that improvement by Week 2 on the single item CGI may be a simple and reliable way to predict treatment response with pregabalin or venlafaxine XR in patients with GAD, but a less reliable way to predict non-responders.

Efficacy of pregabalin in preventing relapse in patients with generalized social anxiety disorder: results of a double-blind, placebo-controlled 26-week study.

The objective of this study was to evaluate the efficacy and safety of pregabalin in preventing relapse in generalized social anxiety disorder (SAD). Patients with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) generalized SAD, who met responder criteria after 10 weeks of open-label treatment with fixed-dose pregabalin (450 mg/day; n=153), were randomly assigned to 26 weeks of double-blind treatment with pregabalin (450 mg/day) or placebo. The primary a-priori outcome of time to relapse was analyzed using the Kaplan-Meier method and the log-rank test. Double-blind treatment with pregabalin was associated with significant delay in time to relapse versus placebo (P=0.035), and with significantly greater maintenance of symptomatic improvement over 26 weeks on the Liebowitz Social Anxiety Scale total (P=0.012) and subscale scores and on the Marks Fear Questionnaire total phobia (P=0.010) and social phobia (P=0.014) subscales. Pregabalin was generally well tolerated. During the double-blind phase, the adverse events that occurred more frequently with pregabalin compared with placebo were dizziness (11.3 vs. 4.1%) and infection (21.3 vs. 16.4%). The results of this study suggest that pregabalin (450 mg/day) is safe, well tolerated, and has significant relapse-prevention efficacy over 26 weeks in patients with SAD who responded to an initial course of the pregabalin treatment.

Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study.

OBJECTIVE: The study was designed to evaluate the short-term efficacy and safety of lurasidone in the treatment of acute schizophrenia. METHOD: Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of double-blind treatment with 40 mg of lurasidone, 120 mg of lurasidone, 15 mg of olanzapine (included to test for assay sensitivity), or placebo, dosed once daily. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score (as the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (as the key secondary efficacy measure). RESULTS: Treatment with both doses of lurasidone or with olanzapine was associated with significantly greater improvement at week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. There was no statistically significant difference in mean PANSS total or CGI-S change scores for the lurasidone groups compared with the olanzapine group. With responders defined as those with an improvement of at least 20% on the PANSS, endpoint responder rates were significant compared with placebo for olanzapine only. The incidence of akathisia was higher with 120 mg of lurasidone (22.9%) than with 40 mg of lurasidone (11.8%), olanzapine (7.4%), or placebo (0.9%). The proportion of patients experiencing ≥ 7% weight gain was 5.9% for the lurasidone groups combined, 34.4% for the olanzapine group, and 7.0% for the placebo group. CONCLUSIONS: Lurasidone was an effective treatment for patients with acute schizophrenia. Safety assessments indicated a higher frequency of adverse events associated with 120 mg/day of lurasidone compared with 40 mg/day.

Efficacy of extended-release naltrexone in patients with relatively higher severity of alcohol dependence.

BACKGROUND: Because some literature reviews have suggested that naltrexone's benefit may be limited to less-severe alcohol dependence, and exclusively to reduction in heavy drinking rather than abstinence, we examined the efficacy of once per month, injectable extended-release naltrexone (XR-NTX 380 mg) in patients with relatively higher severity alcohol dependence. METHODS: Post hoc analyses examined data from a multicenter, placebo-controlled, 24-week randomized trial of XR-NTX for alcohol dependence (N = 624). We analyzed treatment effects in alcohol-dependent patients who had higher baseline severity, as measured by: (i) the Alcohol Dependence Scale (ADS) or (ii) having been medically detoxified in the week before randomization. Efficacy was also examined via the relationship between pretreatment severity indices and reporting at least 4 days of lead-in abstinence prior to treatment-a major predictor of good outcome in the original study. RESULTS: Higher severity alcohol-dependent patients, defined by the ADS, when receiving XR-NTX 380 mg (n = 50) compared with placebo (n = 47), had significantly fewer heavy-drinking days in-trial (hazard ratio=0.583; p = 0.0049) and showed an average reduction of 37.3% in heavy-drinking days compared with 27.4% for placebo-treated patients (p = 0.039). Among those who had a detoxification just prior to randomization, these reductions were 48.9% (XR-NTX 380 mg; n = 11) and 30.9% (placebo; n = 15) (p = 0.004). Subjects with at least 4 days of pretreatment abstinence (n = 82) versus those without (n = 542) had significantly higher pretreatment ADS scores (p = 0.002) and were more likely to require detoxification prior to randomization (p < 0.001). Patients with lead-in abstinence experienced significantly better maintenance of initial and 6-month abstinence. CONCLUSIONS: These secondary analyses support the efficacy of XR-NTX 380 mg in relatively higher severity alcohol dependence for both reduction in heavy drinking and maintenance of abstinence, with implications for the role of adherence pharmacotherapy.

Efficacy of pregabalin in generalized social anxiety disorder: results of a double-blind, placebo-controlled, fixed-dose study.

The objective of this study was to evaluate the efficacy and tolerability of pregabalin for the treatment of generalized social anxiety disorder (SAD). Patients with generalized SAD, who met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) criteria (total N=329), were randomly assigned to 11 weeks of double-blind treatment with fixed daily doses of either pregabalin (300, 450, and 600(mg) or placebo. The treatment with pregabalin (600(mg) was associated with a significantly greater mean reduction in the Liebowitz Social Anxiety Scale total score, from baseline to endpoint, compared with placebo (-29.8 vs. -19.7; P= 0.0099), whereas reduction on pregabalin (300(mg, -20.2) and pregabalin (450(mg, -25.5) was not significant Treatment with pregabalin (600(mg) was also associated with a significantly greater improvement than placebo on the fear and avoidance subscales of the Liebowitz Social Anxiety Scale, as well as the majority of other secondary measures. Onset of improvement occurred by week 1 in the pregabalin 600-mg dose group. The most common adverse events on all three doses of pregabalin were somnolence and dizziness. Consistent with a previous study, the results of this study suggest that the 600-mg dose of pregabalin per day may be efficacious in the treatment of SAD.

Long-term opioid blockade and hedonic response: preliminary data from two open-label extension studies with extended-release naltrexone.

The emergence of extended-release naltrexone (XR-NTX) raises the opportunity to explore the role of endorphin blockade on hedonic response during long-term alcohol dependence treatment. A hedonic survey was administered to 74 alcohol dependent patients treated for an average of 3.5 years with nearly continuous month-long intramuscular XR-NTX. The paper-and-pencil, one-time survey asked patients about the degree of pleasure they experienced in the past 90 days with drinking alcohol, sex, exercise and other daily activities. The data revealed lower pleasure ratings for alcohol than for sex, exercise and 10 other common activities. Mean responses to drinking alcohol and gambling were significantly lower than to listening to music, sex, reading, being with friends, eating good food, eating spicy food, and playing video/card games. This effect was independent of XR-NTX dose or duration. Although this exploratory study lacked baseline data, a comparison group or control for the impact of patient discontinuation, the data indicate the feasibility of examining long-term hedonic response in recovery. The differential hedonic ratings suggest that, in patients who persist with long-term continuous therapy, XR-NTX may selectively inhibit the pleasure associated with drinking alcohol, compared to a variety of other activities.

PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease.

OBJECTIVE: To evaluate the safety and tolerability of PF-04494700, an oral inhibitor of receptor for advanced glycation end products, in patients with mild-to-moderate dementia of the Alzheimer type. METHODS: Patients aged 50 years and older who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria for Alzheimer disease with an Mini-Mental State Examination (MMSE) score between 12 and 26 (inclusive) were randomized to 10 weeks of double-blind treatment with either a 10 mg "low dose" of PF-04494700 (after a 6-d loading dose of 30 mg/d), a 20 mg "high dose" of PF-04494700 (after a loading dose of 60 mg/d), or placebo. Safety measures included adverse events, laboratory tests, vital signs, and 12-lead electrocardiogram. RESULTS: Twenty-seven patients received PF-04494700 30/co mg (female: 63%; mean age: 74.6 y; mean MMSE: 21.1), 28 patients received PF-04494700 60/20 mg (female: 57%; mean age: 76.6 y; mean MMSE: 21.6), and 12 patients received placebo (female: 67%; mean age: 74.1 y; mean MMSE: 19.2). A higher proportion of patients completed 10 weeks of double-blind treatment on both the "low-dose" regimen of PF-04494700 (88.9%) and the "high-dose" regimen (85.7%) than patients who were on placebo (66.7%). Discontinuation owing to adverse events and incidence of severe adverse events, respectively, were lower in the "low-dose" regimen (7.4%, 11.1%) and the "high-dose" regimen (3.6%, 10.7%) compared with placebo (25.0%, 16.7%). There were no clinically meaningful differences in vital signs, laboratory test results, or mean electrocardiogram parameters in patients treated with PF-04494700. PF-04494700 had no consistent effect on plasma levels of ß-amyloid, inflammatory biomarkers, or secondary cognitive outcomes. CONCLUSIONS: Ten weeks of treatment with PF-04494700 was safe and well tolerated in patients with mild-to-moderate Alzheimer disease, indicating the feasibility of a larger long-term efficacy trial.

Lurasidone: a new drug in development for schizophrenia.

BACKGROUND: Lurasidone is a novel psychotropic agent in development for the treatment of schizophrenia and bipolar disorder. OBJECTIVES: This paper describes the development of lurasidone, including its receptor binding affinities, pharmacokinetics, CNS activity in rodent models and results of early clinical efficacy and safety studies in humans. METHODS: The available literature on lurasidone was reviewed, including abstracts from medical congresses supplemented by data on file with the sponsor. RESULTS/CONCLUSIONS: Lurasidone has a high affinity for dopamine D(2) and serotonin 5-HT(2A) receptors as well as for receptors implicated in enhancement of cognitive function (e.g., 5-HT(7,) 5-HT(1A), alpha(2c)). Lurasidone has no affinity for muscarinic M(1) and histamine H(1) receptors and minimal affinity for alpha(1) adrenoceptors, dopamine D(1) and D(3) receptors, serotonin 5-HT(2C) receptors and alpha(2A) adrenoceptors. Phase II efficacy data indicate that lurasidone doses from 40 to 120 mg/day are effective in the treatment of schizophrenia, with positive symptom reduction exceeding that for negative symptoms, as seen with other antipsychotics. Preclinical data indicate that lurasidone reverses MK-801 induced learning and memory impairment in rodents, and active comparator data from a Phase Ib study of lurasidone 120 mg/day versus ziprasidone 160 mg/day also found a signal for effects on cognition. Phase II studies suggest that lurasidone has no significant QTc prolongation and a benign metabolic profile.

The efficacy of pregabalin and benzodiazepines in generalized anxiety disorder presenting with high levels of insomnia.

The objective of this study was to assess the impact of high levels of insomnia on response to pregabalin (PGB) in patients with generalized anxiety disorder (GAD). Pooled data were analyzed from six double-blind, placebo-controlled, 4- to 6-week trials of outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) criteria for GAD with a minimum Hamilton Rating Scale for Anxiety (HAM-A) score = 18. Response was evaluated for three fixed-dose PGB groups (150, 300-450, 600 mg/day), and for a benzodiazepine group (alprazolam or lorazepam). A 'high-insomnia' subgroup was defined by a baseline HAM for Depression (HAM-D) insomnia factor score greater than 3 (maximum = 6). At baseline, 1002 (54%) patients met the criteria for the high-insomnia subgroup, and 852 (46%) for the low-insomnia subgroup. Mean baseline HAM-A scores were 1-2 points higher in high-insomnia versus low-insomnia patients. In high-insomnia patients, PGB produced significantly greater improvement in HAM-A total scores at last observation carried forward endpoint on 300-450 mg (-13.1+/-0.6) and 600 mg (-11.2+/-0.5) dose groups compared with placebo (-8.3+/-0.5; P<0.0001 for both comparisons); the improvement on PGB 150 mg was not significant (-9.9+/-0.7; P = 0.051). Improvement was significant in the benzodiazepine group (-11.0+/-0.6; P<0.0001). In the high-insomnia subgroup, treatment with PGB significantly (P<0.001) improved the HAM-D insomnia factor scores on both the 300-450 mg (-2.73) and 600 mg (-2.35) doses, and on benzodiazepines (-2.52) compared with placebo (-1.51); improvement on PGB 150 mg (-1.69) was not significant. Rates of treatment-emergent insomnia were lower on PGB compared with placebo in both the high- and low-insomnia subgroups. In conclusion, PGB was well tolerated, and improved overall anxiety symptoms, while specifically improving insomnia in patients with GAD presenting with high levels of concurrent insomnia.

Imipramine and buspirone in patients with panic disorder who are discontinuing long-term benzodiazepine therapy.

Pretreatment with imipramine, buspirone, or placebo was compared in 40 patients meeting the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria for panic disorder and in patients who were discontinuing long-term benzodiazepine use. The average duration of benzodiazepine use was 75 +/- 64 months, and the average benzodiazepine intake expressed as diazepam equivalents was 25.7 +/- 19 mg/d. We hypothesized that pretreatment with either imipramine or buspirone, in contrast to pretreatment with placebo, would lead to a significant decrease of symptoms of anxiety and depression before tapering benzodiazepines, thus making the taper process easier to complete. All 3 treatments (imipramine, buspirone, and placebo) caused a reduction in anxiety and depression symptoms as measured by changes in the Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale. Neither discontinuation severity nor taper-free status 12 weeks posttaper differed between the 3 treatment groups.