Addition of an NK1 receptor antagonist to an SSRI did not enhance the antidepressant effects of SSRI monotherapy: results from a randomized clinical trial in patients with major depressive disorder.

OBJECTIVE: Aprepitant is a neurokinin 1 receptor antagonist approved for prevention of chemotherapy-induced and post-operative nausea and vomiting. Early studies demonstrated promising antidepressant activity as monotherapy, although this was unsupported by subsequent phase 3 trials. This phase 2 study evaluated whether aprepitant potentiated the antidepressant effects of paroxetine. METHODS: Outpatients with major depressive disorder were randomized to aprepitant 200 mg + paroxetine 20 mg, paroxetine + placebo, or aprepitant + placebo for 6 weeks. The primary endpoint was change in HAMD-17 total score. Secondary/exploratory endpoints included changes in HAMA, CGI-S, CGI-I, and HAMD Item-1 scores at week 6. RESULTS: A total of 79, 78, and 79 patients received aprepitant + paroxetine, paroxetine + placebo, and aprepitant + placebo, respectively. At week 6, mean changes in HAMD-17 were -11.0 (95% confidence interval [CI]: -12.7, -9.4), -11.7 (95% CI: -13.3, -10.0), and -9.5 (95% CI: -10.9, -8.1), respectively. Pairwise comparisons of HAMD-17 change with combination therapy versus paroxetine alone demonstrated no significant difference (p = 0.567). Changes in CGI-S, CGI-I, and HAMD Item-1 scores were also comparable, although there was a greater reduction in anxiety (HAMA) with paroxetine alone than aprepitant + paroxetine (p = 0.045). Adverse events were generally more common with the combination than either monotherapy. CONCLUSION: Concomitant use of aprepitant + paroxetine for 6 weeks did not provide greater antidepressant benefit compared with paroxetine + placebo in patients with major depression.

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile x syndrome.

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5' untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics (PK) and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding in period 1 of the study, participants who received BPN14770 in the period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

Lack of efficacy of L-759274, a novel neurokinin 1 (substance P) receptor antagonist, for the treatment of generalized anxiety disorder.

Preclinical studies suggest that substance P acting at neurokinin 1 (NK1) receptors may be involved in stress responses and NK1 receptor antagonists show activity in tests of anxiety. These data raise the possibility that NK1 receptor antagonists could be potential anxiolytic treatments in humans. We evaluated this hypothesis clinically using the NK1 antagonist L-759274. This is a randomized, double-blind, placebo- and active-controlled, multicentre, proof-of-concept trial. Patients with generalized anxiety disorder were randomized 1:1:1 to 6 wk of treatment with 40 mg L-759274 (n = 73), 1-6 mg lorazepam (n = 69) or placebo (n = 71). Efficacy was assessed using the Hamilton Anxiety Scale (HAMA). A positron emission tomography (PET) study was also performed in 16 healthy subjects to determine the relationship between NK1 receptor occupancy and plasma levels of L-759274 to verify adequate target engagement by the doses tested during the clinical trial. No statistically significant difference in mean change from baseline HAMA score at 6 wk was seen for L-759274 vs. placebo [difference = 1.0 (95% confidence intervals (CI) -1.2 to 3.2), p = 0.359] whereas the lorazepam group did show a significant improvement vs. placebo (difference = -2.7, 95% CI -5.0 to -0.4, p = 0.020) and L-759274 (difference = 3.7, 95% CI 1.5-6.0, p = 0.001]. Results from the PET study indicated that the L-759274 dosing regimen used in the clinical trial likely provided high levels of NK1 receptor occupancy (>90%), supporting the view that it was an adequate proof-of-concept trial. The NK1 receptor antagonist L-759274 does not appear to be efficacious for the treatment of generalized anxiety disorder.

Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial.

The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18-41 years) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631 ). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342) and Cognition Crystallized Composite score (+5.31, P = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.

IV tramadol: A novel option for US patients with acute pain-A review of its pharmacokinetics, abuse potential and clinical safety record.

Tramadol is a centrally acting dual-mechanism (opioid and monoamine reuptake inhibition) analgesic that has been noted to have a lower risk of abuse compared to conventional opioids such as morphine. Oral tramadol has been ap-proved in the United States since 1995 and intravenous (IV) tramadol has been widely prescribed outside the United States (OUS); nevertheless, IV tramadol has not yet been approved for use in the United States. This paper provides a review of the pharmacokinetics (PK) of the IV tramadol dosing regimen being developed in the United States, its abuse potential as documented in the literature, and its safety record in clinical practice, and discusses how IV tramadol may become a useful option for patients in the United States with acute pain.

Misuse of Tramadol in the United States: An Analysis of the National Survey of Drug Use and Health 2002-2017.

OBJECTIVE: To analyze the rates of misuse - that is, use in any way not directed by a doctor - of products containing oral tramadol, a Schedule IV opioid, from the National Survey of Drug Use and Health (NSDUH), as compared to comparator Schedule II opioids (morphine, oxycodone, and hydrocodone) and alprazolam, a commonly prescribed Schedule IV controlled substance in the U.S. METHODS: The NSDUH is a congressionally mandated household survey that collects information on tobacco, alcohol, and drug use, mental health and other health-related issues in the US. A cross-sectional surveillance study design was used to examine lifetime and past year misuse of oral tramadol and comparators of interest among NSHUH respondents aged 12 years or older. Based on when particular data were available, the past-year misuse analysis includes NSDUH data from 2015 to 2017, and the lifetime misuse analysis includes NSDUH data from 2002 to 2014. RESULTS: In 2015 to 2017, past-year misuse of oral tramadol was approximately 4% of the total number of prescriptions, versus 7% to 8% for all of the comparators when adjusted for drug availability. In 2002 to 2014, lifetime misuse of oral tramadol remained at 1.5% or less over the 13-year period, and was lower than reported for hydrocodone (6%) and oxycodone (4%), respectively. Comparison of oral tramadol and alprazolam showed misuse of tramadol was also much lower than alprazolam. Too few reports of tramadol misuse by injection (n = 7) were reported, versus 570, 1096, and 32 reports of injection of morphine, oxycodone, and hydrocodone, respectively, during the 16-year analysis period to allow for any population-based estimation. Only morphine has an intravenous formulation available and tramadol was not available as an intravenous formulation in the U.S. during that time period. CONCLUSIONS: This analysis shows a low prevalence of oral tramadol misuse, relative to other commonly prescribed opioids, in a nationally representative sample of noninstitutionalized US residents. Estimates of reported oral tramadol misuse have remained relatively stable over time and are substantially lower than those reported for comparators when adjusted for prescription volume. Reports of oral tramadol misuse are also much less than alprazolam, another Schedule IV drug.

Comparing the Pharmacokinetics of 2 Novel Intravenous Tramadol Dosing Regimens to Oral Tramadol: A Randomized 3-Arm Crossover Study.

Tramadol is a dual-mechanism (opiate and monoamine reuptake inhibition) analgesic. Intravenous (IV) tramadol has been widely prescribed outside the United States. However, there have not been studies comparing the pharmacokinetics (PK) of IV dosing regimens to that of oral tramadol. In this phase 1, open-label, single investigational center, 3-treatment, 3-period, multidose crossover study, we compared 2 novel IV dosing regimens (IV tramadol 75 mg and IV tramadol 50 mg) to oral tramadol 100 mg given every 6 hours (the highest approved oral dosage in the United States) Compared to the oral regimen, IV tramadol 50 mg administered at hours 0, 2, and 4 and every 4 hours thereafter reached initial tramadol peak serum concentration (Cmax ) more rapidly, while resulting in similar overall steady-state Cmax and area under the plasma concentration-time curve. IV tramadol 75 mg administered at hours 0, 3, and 6 and every 6 hours thereafter had higher Cmax and greater fluctuation in peak to trough tramadol concentration. The primary metabolite M1 (a potent µ agonist) had lower area under the plasma concentration-time curve and Cmax for both IV regimens than for the oral regimen. IV tramadol at both doses was well tolerated, with adverse event profiles consistent with the known pharmacological effects of tramadol. IV tramadol 50 mg is now in phase 3 development in patients with postsurgical pain.

IV Tramadol - A New Treatment Option for Management of Post-Operative Pain in the US: An Open-Label, Single-Arm, Safety Trial Including Various Types of Surgery.

PURPOSE: There is a need to reduce exposure to Schedule II opioids in the United States (US) due to the ongoing opioid epidemic. Schedule II opioids have higher potential for abuse and misuse than Schedule IV opioids. This Phase 3, multicenter, single-arm, open-label, multiple-dose US trial evaluated the safety and tolerability of intravenous tramadol 50 mg, a Schedule IV opioid, in the management of postoperative pain in a real-world setting, where intravenous tramadol is not yet approved for use. PATIENTS AND METHODS: Patients undergoing a range of soft-tissue and orthopedic surgeries were enrolled. Intravenous tramadol 50 mg was given at hours 0, 2, 4, and every 4 h thereafter through up to 7 days of treatment. Non-opioid medications per treating physicians' discretion were allowed if additional pain relief was needed. Endpoints included treatment-emergent adverse events (TEAEs), laboratories, vital signs, electrocardiograms (ECGs), and patient global assessment (PGA) of effectiveness. RESULTS: A total of 251 patients were enrolled, with 4% discontinuing due to TEAE; no patient discontinued due to a lack of efficacy. Patients averaged 13 doses, resulting in average 48 h of exposure. Intravenous tramadol was well tolerated, with TEAEs consistent with known tramadol pharmacology. No unexpected findings were observed, with 95% of patients reporting study medication was good, very good, or excellent for controlling pain. CONCLUSION: Outcomes from this real world use study demonstrated intravenous tramadol 50 mg was safe and well tolerated in the management of postoperative pain where intravenous conventional opioids are often used. Intravenous tramadol alone or coadministered with non-opioid medication (when needed) as a multimodal combination analgesia approach resulted in high patient satisfaction with their pain relief. In light of the US opioid epidemic, reducing the exposure to conventional opioids in these patients via use of IV tramadol may be possible.

Intravenous Tramadol is Effective in the Management of Postoperative Pain Following Abdominoplasty: A Three-Arm Randomized Placebo- and Active-Controlled Trial.

BACKGROUND AND OBJECTIVE: Oral tramadol, an atypical opioid approved in the United States (US) since 1995 and a Schedule IV controlled substance, has less abuse liability compared to Schedule II conventional opioids. Intravenous (IV) tramadol is not available in the US, but has the potential to fill a gap between non-opioid medications and conventional opioids for treatment of acute pain. This study evaluates IV tramadol in the management of postoperative pain compared to placebo and standard-of-care active control. METHODS: A phase 3, multicenter, double-blind, three-arm, randomized, placebo- and active-controlled, multiple-dose, parallel-group study was conducted to evaluate the efficacy and safety of 50 mg IV tramadol versus placebo and 4 mg IV morphine over 48 h in patients with postoperative pain following abdominoplasty surgery. RESULTS: IV tramadol was statistically superior (p < 0.05) to placebo and comparable to IV morphine for the primary and all key secondary efficacy outcomes and demonstrated numerically lower rates for the incidence of most common treatment-emergent adverse events (TEAEs) compared to morphine. No unexpected findings were observed for TEAEs, laboratory tests, vital signs, or electrocardiograms (ECGs). Over 90% of patients completed the study. CONCLUSION: The study demonstrated that IV tramadol 50 mg is highly effective in the management of postoperative pain following abdominoplasty. The consistency of effects between tramadol and morphine (as compared to placebo) for primary and key secondary endpoints validates the efficacy of tramadol observed. The study also provided direct evidence of improved tolerability of IV tramadol over a standard-of-care conventional Schedule II opioid. IV tramadol may become a useful option in patients where exposure to conventional opioids is not desired.

Efficacy and Safety of Intravenously Administered Tramadol in Patients with Moderate to Severe Pain Following Bunionectomy: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study.

INTRODUCTION: This study is part of the registrational program for intravenously administered (IV) tramadol in the USA and compared the analgesic benefit and tolerability of two doses of IV tramadol (50 mg and 25 mg) to placebo in adult patients undergoing bunionectomy, an orthopedic surgical model. METHODS: This was a phase 3, multicenter, double-blind, three-arm, randomized, placebo-controlled, multiple-dose, parallel-group trial to evaluate IV tramadol in the management of postoperative pain following bunionectomy. Eligible patients were randomized (1:1:1 ratio) to IV tramadol 50 mg, 25 mg, or placebo. Primary endpoint was summary of pain intensity differences over 48 h (SPID48). Key secondary endpoints included SPID24, total consumption of rescue analgesia, and patient global assessment of efficacy (PGA). Safety assessments included treatment emergent adverse events (TEAEs), clinical laboratory tests, vital signs, and electrocardiograms (ECGs). Assessment of the dose-response was an important objective of the study. RESULTS: The study established a dose response, with IV tramadol 50 mg demonstrating statistically significant benefit (p < 0.05) over placebo for primary and all key secondary efficacy endpoints, whereas tramadol 25 mg demonstrated intermediate results between the 50 mg and placebo arms. IV tramadol 50 mg was well tolerated; most common TEAEs were nausea and vomiting; and there were no meaningful differences among treatments for vital signs, ECG, and laboratory assessments. The largest proportion of patients completed tramadol 50 mg (98.6%) compared to tramadol 25 mg (91.8%) and placebo (88.2%). CONCLUSION: IV tramadol 50 mg was effective and well tolerated as treatment for postoperative pain following bunionectomy surgery, while IV tramadol 25 mg, although well tolerated, was judged an ineffective dose for the treatment of pain in this setting. IV tramadol 50 mg was further developed in the registrational program for the USA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03290378.

Is bigger better for depression trials?

OBJECTIVE: A key assumption underlying the principle that power increases with sample size is that the standardized effect size is fixed over time. In therapeutic areas where it may be difficult to continually recruit from a homogeneous population, this assumption may not be valid; patients randomized toward the end of enrollment may derive from a more heterogeneous population and negatively impact the power of a study. Post hoc analyses were performed on clinical data from four phase III depression trials with paroxetine to evaluate this possibility. METHODS: Each study used a randomized, double-blind, placebo-controlled design and enrolled approximately 150 patients per treatment arm. Plots of observed p-values for the treatment difference between paroxetine and placebo (on the HAM-D17 change from baseline score at week 8) by cumulative enrollment were made for each study. RESULTS: As previously reported, three of the four studies showed an overall significant treatment effect and one did not. In each study, a significant treatment effect was observed before approximately 100 patients had been enrolled per treatment arm. Continuing to enroll additional patients did not maintain the achieved level of significance in most instances, and in one case appeared to alter a potentially positive study into a failed study. Plots of p-values versus cumulative enrollment by patient quarters using combined data from all four studies suggested that late-enrolling patients were more likely to be placebo responders than early-enrolling patients. Hypothesized explanations for this finding include a depleted pool of depressed patients and the rush for patient recruitment at the end of a study in order to meet completion timelines. However, no corroborative evidence could be found to support either possibility. CONCLUSIONS: This analysis demonstrates that bigger is not necessarily better for depression trials.

Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder.

BACKGROUND: An early clinical trial suggested that the substance P (neurokinin(1) receptor) antagonist, aprepitant, might provide a unique mechanism of antidepressant activity. Phase III trials were conducted to confirm these findings. METHODS: Five 8-week, randomized, double-blind, parallel-groups, placebo-controlled, multicenter trials in outpatients with Major Depressive Disorder were performed. Aprepitant 160 mg and placebo were included in all trials. Aprepitant 80 mg and paroxetine 20 mg (active comparator) were included in three trials. Approximately 150 patients were enrolled per treatment group in each trial. The primary end point was the mean change-from-baseline of the first 17 items of the Hamilton Rating Scale for Depression (HAM-D(17)) score at 8 weeks. A positron emission tomography (PET) study was also performed in normal subjects to determine the relationship between neurokinin(1) receptor occupancy and aprepitant plasma concentrations in dosing regimens relevant to the trials. RESULTS: No statistically significant differences from placebo on the HAM-D(17) were observed at week 8 for either dose of aprepitant in any of the trials, whereas paroxetine 20 mg was significantly (p

The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group.

PURPOSE: In early clinical trials with patients receiving highly emetogenic chemotherapy, the neurokinin antagonist aprepitant significantly enhanced the efficacy of a standard antiemetic regimen consisting of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV). PATIENTS AND METHODS: Patients receiving cisplatin > or = 70 mg/m2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments. RESULTS: The percentage of patients with complete response on days 1 to 5 was significantly higher in the aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]), as were the percentages on day 1, and especially on days 2 to 5 (P <.001 for all three comparisons). CONCLUSION: Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy.

A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment.

Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and might be mediated via the COX-2 enzyme. Previous studies with the selective COX-2 inhibitors, rofecoxib and celecoxib, have shown that they do not alter the progression of AD. We conducted a double-blind study to investigate whether rofecoxib could delay a diagnosis of AD in patients with mild cognitive impairment (MCI), a group with an expected annual AD diagnosis rate of 10-15%. MCI patients > or =65 years were randomized to rofecoxib 25 mg (N=725) or placebo (N=732) daily for up to 4 years. The primary end point was the percentage of patients with a clinical diagnosis of AD. The estimated annual AD diagnosis rate was lower than the anticipated 10-15%: 6.4% in the rofecoxib group vs 4.5% in the placebo group (rofecoxib : placebo hazard ratio=1.46 (95% CI: 1.09, 1.94), p=0.011). Analyses of secondary end points, including measures of cognition (eg the cognitive subscale of the AD Assessment Scale (ADAS-Cog)) and global function (eg the Clinical Dementia Rating (CDR)), did not demonstrate differences between treatment groups. There was also no consistent evidence that rofecoxib differed from placebo in post hoc analyses comparing ADAS-Cog and CDR-sum of boxes scores in overlapping subgroups of patients who had Mini Mental State Exam scores of 24-26 in the present MCI study and in a previous AD treatment study with a similar design. The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD. In conjunction with the lack of effects observed in previous AD studies, the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD.

Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant.

BACKGROUND: Aprepitant is a highly selective substance P (neurokinin 1 [NK(1)] receptor) antagonist that significantly improves the pharmacotherapy of acute and delayed highly emetogenic chemotherapy-induced nausea and vomiting, probably through an action in the brain stem region of the central nervous system. Here, we report the use of positron emission tomography imaging with the NK(1) receptor binding-selective tracer [(18)F]SPA-RQC to determine the levels of central NK(1) receptor occupancy achieved by therapeutically relevant doses of aprepitant in healthy humans. METHODS: Two single-blind, randomized, placebo-controlled studies in healthy subjects were performed. The first study evaluated the plasma concentration-occupancy relationships for aprepitant dosed orally at 10, 30, 100, or 300 mg, or placebo (n = 12). The second study similarly evaluated oral aprepitant 30 mg and placebo (n = 4). In each study, dosing was once daily for 14 consecutive days. Data from both studies were combined for analyses. The ratio of striatal/cerebellar [(18)F]SPA-RQ (high receptor density region/reference region lacking receptors) was used to calculate trough receptor occupancy 24 hours after the last dose of aprepitant. RESULTS: Brain NK(1) receptor occupancy increased after oral aprepitant dosing in both a plasma concentration-related (r =.97; 95% confidence interval [CI] =.94-1.00, p <.001) and a dose-related (r =.94; 95% CI =.86-1.00, p <.001) fashion. High (> or =90%) receptor occupancy was achieved at doses of 100 mg/day or greater. The plasma concentrations of aprepitant that achieved 50% and 90% occupancy were estimated as approximately 10 ng/mL and approximately 100 ng/mL, respectively. CONCLUSIONS: Positron emission tomography imaging with [(18)F]SPA-RQ allows brain NK(1) receptor occupancy by aprepitant to be predicted from plasma drug concentrations and can be used to guide dose selection for clinical trials of NK(1) receptor antagonists in central therapeutic indications.

Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression.

The efficacy and safety of a selective NK(1) antagonist, L-759274, was investigated in outpatients with diagnosis of major depressive disorder with melancholic features, following evidence obtained with the novel compound aprepitant that Substance P (NK(1)) antagonists may provide a unique mechanism of antidepressant activity. A randomized, double-blind placebo-controlled study was carried out. Patients, male or female, aged 18-60, scoring >/=25 points on total of first 17 items of 21-item Hamilton Depression Scale (HAMD), and scoring >/=4 (moderately ill) on Clinical Global Impressions-Severity Scale were randomized to oral L-759274 40 mg daily (n=66) or placebo (n=62) for 6 weeks. For patients receiving L-759274, improvement (mean decrease from baseline) in HAMD-17 total score was 10.7 points, compared with a mean 7.8 point improvement in patients receiving placebo (p<0.009). Mean scores for item 1 of HAMD-17 (depressed mood) also improved to a greater extent in the active group compared with the placebo group (0.3 points, p<0.058). Compared with placebo, mean scores on Clinical Global Impressions-Improvement Scale improved significantly by the end of the trial (p=0.009). L-759274 was generally safe and well-tolerated. The incidence of sexual side effects was on par with that observed in patients receiving placebo, and the incidences of gastrointestinal effects were low. Antidepressant actions have now been observed with two different highly selective NK(1) antagonists (aprepitant and L-759274). NK(1) antagonism is a replicated and generally well-tolerated antidepressant mechanism.

Rofecoxib in the acute treatment of migraine: a randomized controlled clinical trial.

OBJECTIVE: To investigate the efficacy, tolerability, and safety of rofecoxib and ibuprofen for acute migraine treatment. BACKGROUND: Rofecoxib was effective and well tolerated in a previous study of treatment of a single migraine attack. We sought to replicate these findings for a single attack and also study the clinical profile of rofecoxib in the acute treatment of multiple migraine attacks. Ibuprofen was included as a reference nonselective NSAID. METHODS: Adult migraineurs (n = 783) treated one migraine attack with either rofecoxib (25 or 50 mg), ibuprofen 400 mg, or placebo in a randomized, double-blind study. Patients could elect to enroll in a 3-month double-blind extension phase. RESULTS: In the single-attack phase, headache relief at 2 hours postdose was reported by 59.4%, 62.2%, and 57.7% of patients who took rofecoxib 25 mg, rofecoxib 50 mg, and ibuprofen 400 mg, respectively, versus 30.5% for placebo (all P < .001 vs placebo). The active drugs were statistically superior to placebo on a variety of additional measures. In the extension phase, the mean percentage of patients' attacks with headache relief at 2 hours postdose was 61.8% for rofecoxib 25 mg, 65.4% for rofecoxib 50 mg, and 59.3% for ibuprofen 400 mg. The mean percentage of patients' attacks with 24-hour sustained headache relief was greater for rofecoxib 50 mg (52.0%) than for rofecoxib 25 mg (47.8%, P < .050) or ibuprofen (39.0%, P < .010). In the single-attack phase, the adverse event rate was higher for rofecoxib 50 mg (37.8%) than placebo (27.8%, P < .050); rates were similar to placebo for rofecoxib 25 mg (32.0%, n.s.) and ibuprofen 400 mg (28.1%, n.s.). In the extension phase, treatment groups had similar adverse event rates. CONCLUSIONS: Rofecoxib 25 and 50 mg and ibuprofen 400 mg were effective and generally well tolerated in the acute treatment of migraine.

Montelukast for migraine prophylaxis: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of montelukast 20 mg in the prophylactic treatment of migraine. BACKGROUND: A previous small open-label study in migraine patients suggested prophylactic efficacy for montelukast, an antagonist of the cysteinyl leukotriene receptor that is used in the treatment of asthma. We sought to confirm these findings in a randomized controlled trial. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-groups study enrolled adult migraine outpatients who experienced > or =3 and < or =8 migraine attacks per month for the last 6 months. Patients were entered into a 2-month, single-blind, placebo run-in phase. Only patients who experienced > or =3 migraine attacks in the second month were eligible to enter the subsequent 3-month, double-blind treatment phase of the study. The primary efficacy endpoint was the percentage of patients reporting at least a 50% decrease in migraine attack frequency per month during the double-blind treatment period (months 3-5) compared to baseline (run-in month 2). RESULTS: A total of 93 patients were randomized to montelukast 20 mg and 84 patients to placebo at the end of the placebo run-in month 2; 76 patients on montelukast and 72 patients on placebo completed the double-blind treatment period. Over 3 months of treatment, there was no significant difference between the two groups in the percentage of patients who reported at least a 50% decrease in migraine attack frequency per month: 15.4% for montelukast versus 10.3% for placebo (P= .304). In addition, montelukast 20 mg was not significantly superior to placebo on any of the secondary endpoints. There were no differences between treatment groups for adverse events. CONCLUSION: Montelukast 20 mg was well tolerated in migraine patients but was not an effective prophylactic for prevention of migraine.