S A Reines

Brown University, Providence, RI, United States

Are you S A Reines?

Claim your profile

Publications (37)288.68 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    The International Journal of Neuropsychopharmacology 03/2012; · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the efficacy, safety, and tolerability of carisbamate (CRS), an investigational drug, as adjunctive treatment for partial-onset seizures in adults. A randomized, double-blind, placebo-controlled, multicenter, dose-ranging study was conducted in 12 countries. Patients counted seizures during an 8-week baseline period, and then, if eligible, entered a double-blind phase consisting of a 4-week dose-titration period (target CRS doses: 100, 300, 800, or 1,600 mg/d or placebo in two divided doses) and a 12-week maintenance period. The primary efficacy variable was percent reduction in partial-onset seizure frequency during the double-blind phase compared with pretreatment baseline. Safety data and responder rates were also assessed. Five hundred thirty-seven patients were randomized, and 82% completed the study. In the intent-to-treat population (n = 533), CRS at doses of > or =300 mg/d (p < or = 0.006) reduced the frequency of partial-onset seizures vs placebo: 6% (placebo) vs 24% (300 mg/d), 21% (800 mg/d), and 29% (1,600 mg/d) for CRS. Adverse events consisted primarily of CNS effects, and led to discontinuation of drug in 8% of the placebo group vs 5% (100 mg/d), 6% (300 mg/d), 12% (800 mg/d), and 19% (1,600 mg/d) of the CRS groups. Carisbamate at doses of 300, 800, and 1,600 mg/d was effective as adjunctive therapy for reducing the frequency of partial-onset seizures.
    Neurology 11/2008; 71(20):1586-93. · 8.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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. 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. This analysis demonstrates that bigger is not necessarily better for depression trials.
    Journal of Psychiatric Research 08/2008; 42(8):622-30. · 4.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the efficacy, tolerability, and safety of rofecoxib and ibuprofen for acute migraine treatment. 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. 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. 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. Rofecoxib 25 and 50 mg and ibuprofen 400 mg were effective and generally well tolerated in the acute treatment of migraine.
    Headache The Journal of Head and Face Pain 03/2006; 46(2):264-75. · 2.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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. 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 <or= .05) more effective than placebo at week 8 in each of the three trials in which it was included. Results from the PET study indicated that the aprepitant dosing regimens provided continuously high levels of neurokinin(1) receptor blockade over 8 weeks. Because the methodology employed confirmed the antidepressant efficacy of paroxetine, the absence of an effect for aprepitant indicates that it was not an effective treatment for depression. The concept of neurokinin(1) receptor antagonism as an antidepressant mechanism was not supported.
    Biological Psychiatry 03/2006; 59(3):216-23. · 9.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Neuropsychopharmacology 07/2005; 30(6):1204-15. · 8.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the efficacy and tolerability of montelukast 20 mg in the prophylactic treatment of migraine. 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. 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). 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. Montelukast 20 mg was well tolerated in migraine patients but was not an effective prophylactic for prevention of migraine.
    Headache The Journal of Head and Face Pain 06/2004; 44(6):581-6. · 2.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the clinical profile of rofecoxib, a long-acting (approximately 17-hour half-life) selective cyclo-oxygenase-2 inhibitor, for the acute treatment of migraine. A randomized, double-blind, placebo-controlled, parallel-group study was conducted. Patients age > or =18 treated a moderate or severe migraine headache with placebo (n = 182), rofecoxib 25 mg (n = 183), or rofecoxib 50 mg (n = 192). The primary efficacy measure was headache relief (mild or no pain) 2 hours after dose. The proportions of patients with migraine headache relief at 2 hours after dose were 34.3% for placebo, 54.0% for rofecoxib 25 mg (p < 0.001 vs placebo), and 56.7% for rofecoxib 50 mg (p < 0.001 vs placebo). Rofecoxib 25 and 50 mg were superior to placebo in providing pain freedom at 2 hours, 24-hour sustained headache relief, and 24-hour sustained pain freedom; in reducing photophobia, phonophobia, nausea (50 mg only), and functional disability at 2 hours after dose; and in improving some quality-of-life scores over 24 hours. More patients on rofecoxib 50 mg reported adverse events (39.6%) than patients on rofecoxib 25 mg (26.8%) or placebo (23.6%) regardless of drug relatedness; however, the incidences of drug-related adverse events were similar between treatment groups. These adverse events were generally mild or moderate in severity. The most commonly reported adverse events were dry mouth, dizziness, somnolence, nausea, dyspepsia, paresthesia, and asthenia, with similar incidences between treatment groups. Rofecoxib 25 and 50 mg were effective and generally well tolerated for the acute treatment of migraine attacks.
    Neurology 06/2004; 62(9):1552-7. · 8.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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. 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. 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.
    Biological Psychiatry 06/2004; 55(10):1007-12. · 9.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Neuropsychopharmacology 03/2004; 29(2):385-92. · 8.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inflammatory mechanisms have been implicated in the pathogenesis of Alzheimer's disease (AD) and may be mediated via the cyclo-oxygenase-2 enzyme. This study sought to evaluate the effect of rofecoxib, a nonsteroidal anti-inflammatory drug that selectively inhibits cyclo-oxygenase-2, in slowing the progression of dementia in patients with established AD. A double-blinded, multicenter trial was conducted in which 692 patients with mild or moderate AD aged 50 years or older were randomly assigned to receive 25 mg rofecoxib or placebo daily for 12 months. The key efficacy measures were mean change from baseline at month 12 on the cognitive subscale of the AD Assessment Scale (ADAS-cog) and score on the Clinician's Interview Based Impression of Change with caregiver input (CIBIC+). Four hundred eighty-one patients (70%) completed assessments and remained on treatment at 12 months. No significant differences between treatments were found on the mean change from baseline error score for the ADAS-cog (rofecoxib = 4.84; placebo = 5.44; difference = -0.60) or mean score on the CIBIC+ (rofecoxib = 4.90; placebo = 4.87; difference = 0.03) over 12 months. This result persisted after adjusting for severity of dementia at baseline, presence of the APOE-epsilon4 allele, and donepezil use. Secondary analyses did not reveal any significant differences on any other measures. The failure of selective cyclo-oxygenase-2 inhibition to slow the progression of AD may indicate either that the disease process is too advanced to modify in patients with established dementia or that cyclo-oxygenase-2 does not play a significant role in the pathogenesis of the disorder.
    Neurology 02/2004; 62(1):66-71. · 8.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 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. 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). 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.
    Journal of Clinical Oncology 11/2003; 21(22):4112-9. · 18.04 Impact Factor
  • American Journal of Cancer. 01/2003; 2(5):391-392.
  • Psychoneuroendocrinology 01/2000; 25. · 5.59 Impact Factor
  • Biological Psychiatry - BIOL PSYCHIAT. 01/2000; 47(8).
  • [Show abstract] [Hide abstract]
    ABSTRACT: To examine the safety and efficacy of rizatriptan 10 mg PO in the treatment of multiple migraine attacks. Rizatriptan is a potent and rapidly absorbed 5-HT1B/1D receptor agonist. Efficacy and general safety have been examined in controlled trials treating single migraine attacks. In the current placebo-controlled study, we report constancy of safety and efficacy of rizatriptan for patients treating four discrete migraine attacks. Patients with moderate or severe migraine (n = 473) were randomized to one of five sequence groups, in which each patient was to treat four migraine attacks. Patients in four groups received rizatriptan 10 mg for three of four attacks and placebo for the remaining attack. Patients in the fifth group received rizatriptan 10 mg for four attacks. Headache severity, functional disability, and migraine symptoms were measured immediately before dosing and at 0.5, 1, 1.5, 2, 3, and 4 hours postdose. After the first attack, response rates were 77% for rizatriptan and 37% for placebo (p < 0.001). Similar efficacy of rizatriptan, ranging from a 75 to 80% response, was observed in each of the subsequent attacks with no evidence of tolerance to therapeutic effects. Most patients (93%) responded to rizatriptan 10 mg during the first or second attack. Adverse experiences were generally mild and transient, the most common being dizziness and somnolence. Incidence of adverse experiences per attack decreased after the first attack. Rizatriptan 10 mg PO is efficacious and generally well tolerated in acute migraine. Its efficacy is maintained throughout the treatment of multiple, discrete migraine attacks.
    Neurology 10/1998; 51(3):773-81. · 8.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.
    Science 10/1998; 281(5383):1640-5. · 31.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rizatriptan is a novel, selective 5-HT1B/1D receptor agonist with a rapid onset of action after oral dosing for the acute treatment of migraine. We conducted a long-term (up to 1 year), multicenter, randomized study in 1831 patients treating more than 46,000 attacks to compare the efficacy and tolerability of rizatriptan 5 mg and 10 mg to standard care medications routinely used for the acute treatment of migraine attacks. Both doses of rizatriptan were highly effective, without evidence of tachyphylaxis. Rizatriptan 10 mg was consistently superior (P < 0.05), both to the 5-mg dose and to standard care, in providing relief in 90% of attacks, with 50% pain-free by 2 hours after dosing. The most common dose-related adverse events were nausea, somnolence, and asthenia/fatigue. Based on this large, multicenter, long-term trial, rizatriptan is an important new oral agent for the acute treatment of migraine.
    Headache The Journal of Head and Face Pain 01/1998; 38(10):764-71. · 2.94 Impact Factor
  • M S Kramer, B Last, A Getson, S A Reines
    [Show abstract] [Hide abstract]
    ABSTRACT: Based mainly on the selective antagonism of clozapine at D4 compared with D2 dopamine receptors, hopes have run high that a selective D4 dopamine receptor antagonist might improve the pharmacological treatment of patients with schizophrenia. We report, to our knowledge, the first multicenter study of the antipsychotic potential of a highly specific D4 dopamine receptor antagonist (ie, L-745,870) in patients with acute schizophrenia. Thirty-eight acutely psychotic and neuroleptic responsive (by history) newly admitted inpatients with schizophrenia were randomized to 4 weeks of double-blind treatment (2:1) with either L-745,870 (n = 26), 15 mg/d, or placebo (n = 12) after a 3- to 5-day placebo run-in period. Overall, a greater percentage of patients receiving L-745,870 compared with patients receiving placebo discontinued the study for insufficient therapeutic response (32% vs 16%). At the end of 4 weeks by last observation carried forward analysis, the mean change from baseline to week 4 on the total Brief Psychiatric Rating Scale favored placebo (i.e., -8 points [-15% change from baseline] vs -1 point [-2% change from baseline] for placebo vs L-745,870, P = .09). Similar differences in favor of placebo in changes from baseline mean scores were observed for the not carried forward analysis on the total Brief Psychiatric Rating Scale (P < .03), for not carried forward and last observation carried forward analyses on the sum of selected positive symptom items of the Brief Psychiatric Rating Scale, and for the Clinical Global Impression analysis (P = .03, last observation carried forward). A greater percentage of patients receiving L-745,870 had scores indicative of some level of worsening (compared with baseline) on the total Brief Psychiatric Rating Scale and the Clinical Global Impressions' Severity of Illness Scale as well as positive symptoms compared with those receiving placebo. The selective D4 dopamine receptor antagonist L-745,870 was ineffective as an antipsychotic for the treatment of neuroleptic responsive inpatients with acute schizophrenia.
    Archives of General Psychiatry 06/1997; 54(6):567-72. · 13.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A double-blind, in-clinic, placebo-controlled, randomized, three-period crossover study was undertaken to investigate the potential sedative and cognitive effects of diphenhydramine 50 mg, p.o. and cyclobenzaprine 5 mg, p.o. in elderly volunteers. Subjects were given 10 doses of each treatment over a 4-day period according to a t.i.d. schedule. A battery of cognitive tests was administered 2 h after the first and last dose of each treatment period and subjects also completed visual analogue scale subjective ratings at regular intervals. There was no evidence that either drug caused drowsiness or affected cognitive test performance. These findings contrast with previous data using similar assessments in young volunteers, which indicated clear diphenhydramine-induced impairments. Contrary to commonly held belief, the elderly appear to be less sensitive than the young to the central nervous system effects of oral diphenhydramine.
    Journal of Psychopharmacology 02/1997; 11(4):325-9. · 3.37 Impact Factor

Publication Stats

2k Citations
288.68 Total Impact Points

Institutions

  • 2006
    • Brown University
      • Department of Psychiatry and Human Behavior
      Providence, RI, United States
  • 2005
    • University of California, San Diego
      San Diego, California, United States
  • 1997
    • Merck
      Whitehouse Station, New Jersey, United States
  • 1989
    • Texas Tech University Health Sciences Center
      El Paso, Texas, United States