Development of an integrated conceptual model of multiple sclerosis spasticity.

PURPOSE: Spasticity is common in multiple sclerosis (MS), often leading to functional limitations and disability. We developed a conceptual model of spasticity in MS integrating expert opinion, recent literature, and experiences of clinicians and people with MS spasticity. METHODS: A conceptual model was developed based on a targeted literature review of articles published between 2014 and 2019, followed by input from clinicians, then input from participants with MS spasticity. Multidisciplinary experts on spasticity provided guidance at each step. RESULTS: Key concepts of the integrated spasticity conceptual model included: moderators; triggers; modifiers; treatment; objective manifestations; subjective experience; physical, functional, social, and emotional/psychological impacts; and long-term consequences. Participants with MS spasticity most frequently endorsed spasms, tightness, and pain as descriptors of spasticity. Some participants with MS spasticity had difficulty distinguishing spasticity from other MS symptoms (e.g. muscle weakness). Some triggers, emotional/psychological impacts, and long-term consequences of spasticity reported by participants with MS spasticity were not previously identified in the published literature. CONCLUSIONS: This conceptual model of spasticity, integrating published literature with the experience of clinicians, people with MS spasticity, and experts, demonstrates the complex, multidimensional nature of MS spasticity. This model may be used to improve clinician-patient dialogue, research, and patient care.

Many people with multiple sclerosis (MS) have spasticity, generally in the lower limbs, but this symptom is complex and multidimensional and therefore difficult to characterize.MS spasticity may be influenced by moderators, triggers, modifiers, and treatment, all of which can affect objective measures and the subjective experience of spasticity.MS spasticity can have physical, functional, social, and emotional/psychological impacts as well as long-term consequences that can affect rehabilitation and ultimately reduce health-related quality of life for people with MS.Given that people with MS may view spasticity differently than their rehabilitation providers, providers should ask patients about their spasticity, including their moderators, triggers, modifiers, experience, impacts, long-term consequences, and effects on quality of life.This conceptual model provides a framework to improve clinician-patient dialogue, research, and rehabilitation for MS spasticity.

Pharmacokinetic Drug-Drug Interaction With Coadministration of Cannabidiol and Everolimus in a Phase 1 Healthy Volunteer Trial.

When highly purified cannabidiol (CBD; Epidiolex) and the mammalian target of rapamycin inhibitor everolimus are used concomitantly in the treatment of tuberous sclerosis complex, there is evidence of a pharmacokinetic (PK) interaction, leading to increased everolimus systemic exposure. We evaluated the effect of steady-state CBD exposure following multiple clinically relevant CBD doses on everolimus PK in healthy adult participants in a single-center, fixed-sequence, open-label, phase 1 study. All participants received oral everolimus 5 mg on day 1, followed by a 7-day washout. On days 9-17, participants received CBD (100 mg/mL oral solution) at 12.5 mg/kg in the morning and evening. On the morning of day 13, participants also received a single dose of oral everolimus 5 mg. Medications were taken 30 or 45 minutes (morning or evening dose) after starting a standardized meal. Maximum concentration and area under the concentration-time curve (AUC) from time of dosing to the last measurable concentration and extrapolated to infinity, of everolimus in whole blood were estimated using noncompartmental analysis, with geometric mean ratios and 90% confidence intervals for the ratios of everolimus dosed with CBD to everolimus dosed alone. A single dose of everolimus 5 mg was well tolerated when administered with multiple doses of CBD. Log-transformed everolimus maximum concentration, AUC from time of dosing to the last measurable concentration, and AUC extrapolated to infinity values increased by ≈2.5-fold, and everolimus half-life remained largely unchanged in the presence of steady-state CBD relative to everolimus dosed alone. Everolimus blood concentration monitoring should be strongly advised with appropriate dose reduction when coadministered with CBD.

Efficacy of nabiximols oromucosal spray on spasticity in people with multiple sclerosis: Treatment effects on Spasticity Numeric Rating Scale, muscle spasm count, and spastic muscle tone in two randomized clinical trials.

BACKGROUND: To provide a comprehensive assessment of the treatment effects of nabiximols oromucosal spray on multiple sclerosis spasticity in two clinical trials, GWSP0604 and SAVANT. METHODS: Both studies enriched for responders before randomization, defined by a ≥20% improvement in Spasticity 0-10 numeric rating scale (NRS) score. Additionally, SAVANT used randomized re-titration following washout. Spasticity NRS outcomes, spasm count, and modified Ashworth scale (MAS) scores were analyzed. RESULTS: Mean change from baseline in average daily Spasticity NRS scores was significantly larger for nabiximols than placebo at all postbaseline timepoints, ranging from -0.36 to -0.89 in GWSP0604 and -0.52 to -1.96 in SAVANT. Percent reduction in geometric mean change from baseline in average daily spasm count for nabiximols ranged from 19-35% versus placebo. A treatment difference favoring nabiximols was observed in overall MAS scores during the randomized part of each study. Treatment effect was larger for combinations of lower limb muscle groups (ranging between -0.16 and -0.37). CONCLUSIONS: Nabiximols leads to improvement in spasticity that was sustained over the 12-week treatment period as measured by average daily Spasticity NRS scores, daily spasm counts, and MAS scores for combinations of muscle groups, especially the combination of the 6 key muscle groups in the lower limbs in NRS responders to nabiximols treatment.

Metabolism and disposition of JNJ-10450232 (NTM-006) in rats, dogs, monkeys and humans.

JNJ-10450232 (NTM-006), a novel non-opioid, non-nonsteroidal anti-inflammatory drug with structural similarities to acetaminophen, demonstrated anti-pyretic and/or analgesic activities in preclinical models and humans and reduced potential to cause hepatotoxicity in preclinical species. Metabolism and disposition of JNJ-10450232 (NTM-006) following oral administration to rats, dogs, monkeys and humans are reported. Urinary excretion was the major route of elimination based on recovery of 88.6% (rats) and 73.7% (dogs) of oral dose. The compound was extensively metabolized based on low recovery of unchanged drug in excreta from rats (11.3%) and dogs (18.4%). Clearance is driven by O-glucuronidation, amide hydrolysis, O-sulfation and methyl oxidation pathways. The combination of metabolic pathways driving clearance in human is covered in at least one preclinical species despite a few species-dependent pathways. O-Glucuronidation was the major primary metabolic pathway of JNJ-10450232 (NTM-006) in dogs, monkeys and humans, although amide hydrolysis was another major primary metabolic pathway in rats and dogs. A minor bioactivation pathway to quinone-imine is observed only in monkeys and humans. Unchanged drug was the major circulatory component in all species investigated. Except for metabolic pathways unique to the 5-methyl-1H-pyrazole-3-carboxamide moiety, metabolism and disposition of JNJ-10450232 (NTM-006) are similar to acetaminophen across species.

First-in-human study to evaluate the safety, tolerability and pharmacokinetics of a novel analgesic and antipyretic drug with structural similarity to acetaminophen.

JNJ-10450232 (NTM-006) is a new molecular entity that comprises structural similarities to acetaminophen and provides comparable analgesia in animals and humans without causing the hepatotoxicity associated with acetaminophen overdose in preclinical models. This double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of JNJ-10450232 (NTM-006) following single (50-6000 mg) and multiple (250-2500 mg twice daily for 8 days) doses in healthy male volunteers. JNJ-10450232 (NTM-006) was absorbed within 1-3 h, except at high doses at which Cmax was delayed and bimodal, while increases in AUC were more than dose proportional. CL/F and Vd/F decreased approximately 3-fold with increasing single doses up to 6000 mg and multiple doses up to 1000 mg, resulting in similar t½ values that ranged from 8 to 10 h across doses. JNJ-10450232 (NTM-006) was generally safe and well tolerated, and no dose-limiting toxicities were observed. Transient increases in indirect bilirubin were noted at post-baseline timepoints due to UGT1A1 inhibition, without any evidence of adverse hepatic effects. Macular rash and generalized erythema were the most common drug-related adverse events after multiple doses.

A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects.

OBJECTIVE: The pharmacokinetics (PK) and safety of single oral 750-mg doses of a plant-derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the USA and Epidyolex in Europe; 100-mg/mL oral solution) were assessed in healthy adults following a high-fat/calorie meal (n = 15), a low-fat/calorie meal (n = 14), whole milk (n = 15), or alcohol (n = 14), relative to the fasted state (n = 29). METHODS: Blood samples were collected until 96 hours postdose in each period and evaluated by liquid chromatography and tandem mass spectrometry. PK parameters (maximum observed plasma concentration [Cmax ], area under the plasma concentration-time curve from time zero to the last observed quantifiable concentration, area under the concentration-time curve from time zero to infinity [AUC0-∞ ], and time to maximum plasma concentration [tmax ]) of CBD and its major metabolites were derived using noncompartmental analysis. RESULTS: CBD exposure increased by 3.8-fold for AUC0-∞ and 5.2-fold for Cmax when CBD was administered with a high-fat/calorie meal versus fasted. To a lesser extent, a low-fat/calorie meal enhanced CBD exposure versus fasted with a 2.7-fold increase in AUC0-∞ and a 3.8-fold increase in Cmax . Similarly, when dosed with whole milk, CBD exposure increased versus fasted by 2.4-fold for AUC0-∞ and 3.1-fold for Cmax . Modest elevations in CBD exposure occurred when it was dosed with alcohol: 1.6-fold for AUC0-∞ and 1.9-fold for Cmax . No clinically relevant effect of any test condition on CBD tmax or t½ versus the fasted state was apparent. The same trend was seen for the CBD metabolites, except that 7-carboxy-cannabidiol tmax was considerably longer when CBD was administered with alcohol (14 vs 4 hours fasted). Inter- and intrasubject variability in PK parameters was moderate to high during the trial. SIGNIFICANCE: CBD and metabolite exposures were most affected by a high-fat/calorie meal. CBD exposures also increased with a low-fat/calorie meal, whole milk, or alcohol, but to a lesser extent. CBD was tolerated, and there were no severe or serious adverse events during the trial.

Does Half-Life Matter After Antipsychotic Discontinuation? A Relapse Comparison in Schizophrenia With 3 Different Formulations of Paliperidone.

OBJECTIVE: To evaluate the effect of 1 oral and 2 distinct long-acting injectable (LAI) formulations of the same antipsychotic on times to relapse following medication discontinuation. METHODS: Data were drawn from 3 similarly designed, multicenter, double-blind, placebo-controlled, randomized-withdrawal studies of paliperidone in adults with a schizophrenia diagnosis (according to DSM-IV criteria for ≥ 1 year before screening): once-daily extended-release oral paliperidone (ORAL paliperidone), once-monthly paliperidone palmitate (PP1M), and once-every-3-months paliperidone palmitate (PP3M). In a post hoc analysis, we compared median time to relapse across the treatment-withdrawal arms of the 3 studies using final analysis datasets. Time to relapse in the withdrawal arm of each study was examined using log-rank tests and Cox proportional hazards models. RESULTS: Four hundred forty-nine patients were withdrawn from 3 paliperidone formulations: 101 from ORAL paliperidone, 203 from PP1M, and 145 from PP3M. Postwithdrawal median (95% confidence interval [CI]) days to relapse were 58 days (42-114 days) for ORAL paliperidone, 172 days (134-222 days) for PP1M, and 395 days (274 days-not reached) for PP3M (P < .0001, pairwise comparisons). Relapse risk was significantly lower (P < .001) for patients who withdrew from either PP formulation relative to ORAL paliperidone and additionally for patients who withdrew from PP3M relative to PP1M. CONCLUSIONS: Results demonstrate that 50% of patients who withdrew treatment from ORAL paliperidone, PP1M, or PP3M remained relapse free for approximately 2 months, 6 months, and 13 months, respectively. This may be relevant for risk mitigation strategies in schizophrenia, a condition in which interruptions in maintenance antipsychotic treatment are commonplace and unpredictable. LAI antipsychotic formulations may provide substantial delays over oral equivalents in times to relapse when patients discontinue therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00086320, NCT00111189, and NCT01529515.

Drug-Drug Interaction Studies of Paliperidone and Divalproex Sodium Extended-Release Tablets in Healthy Participants and Patients with Psychiatric Disorders.

The objective of these 2 phase 1, open-label, 2-treatment, single-sequence studies was to evaluate the effect of repeated oral doses of divalproex sodium extended-release (ER) on the pharmacokinetics (PK) of a single dose of paliperidone ER in healthy participants (study 1), and the effect of multiple doses of paliperidone ER on the steady-state PK of valproic acid (VPA) in patients with psychiatric disorders (study 2), respectively. In study 1 healthy participants received, in a fixed sequential order, treatment A, paliperidone ER 12 mg (day 1); treatment B, VPA 1000 mg (2 × 500 mg divalproex sodium ER) once daily (days 5 to 18) and paliperidone ER 12 mg (day 15). In study 2 patients received treatment A, VPA (days 1-7); treatment B, VPA + paliperidone ER 12 mg (days 8-12). Divalproex sodium ER doses (study 2) were individualized such that systemic therapeutic VPA exposure from prior treatment was maintained on entry into the study. PK assessments were performed at prespecified time points (paliperidone days 1 and 15 [study 1]; VPA days 7 and 12 [study 2]). The oral bioavailability of paliperidone was increased by an estimated 51% (Cmax ) and 51%-52% (AUCs) when coadministered with divalproex sodium ER. No effect on the steady-state plasma concentration of VPA was observed following repeated coadministration with paliperidone ER: the 90%CI around the VPA exposure ratios for the 2 treatments was within the 80%-125% bioequivalence criteria for Cmax,ss and AUCτ . Both VPA and paliperidone ER were well tolerated, and no new safety concerns were identified.

Practical guidance for dosing and switching from paliperidone palmitate 1 monthly to 3 monthly formulation in schizophrenia.

OBJECTIVE: This commentary summarizes recommended dosing strategies for a recently developed 3 monthly long-acting injectable 1 (LAI) formulation of paliperidone palmitate (PP3M) for the treatment of schizophrenia in adults. METHODS: Recommendations for different dosing scenarios are based on the pharmacokinetic, efficacy and safety outcomes from phase 1 and phase 3 studies, population pharmacokinetic models, and model based simulations. RESULTS: Switching to PP3M treatment is recommended only in patients previously treated with once monthly paliperidone palmitate LAI (PP1M) for at least 4 months. The first injection of PP3M (175 to 525 mg equivalent [eq.]) should be given at the time of next scheduled injection of PP1M as a 3.5-fold multiple of the last PP1M dose (50-150 mg eq.), with a dosing window of ± 1 week. Following that first injection of PP3M, once-every-three-months maintenance injections with PP3M are recommended, with a dosing window of ± 2 weeks. The doses of PP3M can be administered in either deltoid (≥ 90 kg: 1.5 inch 22 G needle; <90 kg: 1.0 inch 22 G needle) or gluteal muscles (1.5 inch 22 G needle regardless of weight). In patients with mild renal impairment (creatinine clearance: 50-80 mL/min), a 25% dose reduction in PP1M and subsequent switching to a corresponding 3.5-dose multiple of PP3M (but not exceeding 350 mg eq.) is recommended. Appropriate dosing is recommended in elderly patients with diminished renal function not exceeding mild renal impairment. Similarly to PP1M, PP3M is not recommended in patients with moderate/severe renal impairment. Like PP1M, no dosage adjustment is required in patients with mild or moderate hepatic impairment or elderly patients with normal renal function. CONCLUSIONS: These data provide clinical guidelines for the optimum use of PP3M in patients with schizophrenia previously treated with PP1M for at least 4 months. REGISTRATION: ClinicalTrials.gov identifier: NCT01559272 and NCT01529515.

Doctor shopping for medications used in the treatment of attention deficit hyperactivity disorder: shoppers often pay in cash and cross state lines.

BACKGROUND: Doctor shopping, defined by filling overlapping prescriptions from more than one prescriber at more than two pharmacies, is a way to obtain scheduled medications for diversion or abuse. Little is known about how far attention deficit hyperactivity disorder (ADHD) medication shoppers travel, how often they cross state lines to fill their ADHD prescriptions and how often they pay for their medication in cash, i.e. entirely out of pocket. OBJECTIVE: We sought to describe the pattern of doctor shopping for ADHD medications: how far shoppers travel, how often they cross state lines to fill their prescriptions, and how often they pay in cash. METHODS: Retrospective cohort study using LRx, a large US retail prescription database. We included subjects with any ADHD medication dispensed between 2011 and 2012. Subjects were followed for 18 months. RESULTS: Of a total of 4 402 464 subjects exposed to ADHD medications, 0.4% developed shopping behavior. Women were more likely to become shoppers. Shoppers travelled a median of 91.9 miles and non-shoppers 0.2 miles to fill their ADHD prescriptions. Almost 28% of the shoppers filled prescriptions in >1 state compared with 4.3% of non-shoppers. Of the shoppers, 27.3% paid at least one prescription in cash compared to 14.4% of the non-shoppers. CONCLUSIONS: Shoppers travelled larger distances, visited more states and paid in cash for ADHD medications more often than non-shoppers. Data sharing among prescriptions monitoring programs can improve their effectiveness and drug utilization studies should take account of cash purchases.

Efficacy and Safety of the 3-Month Formulation of Paliperidone Palmitate vs Placebo for Relapse Prevention of Schizophrenia: A Randomized Clinical Trial.

IMPORTANCE: Treatment nonadherence and relapse are common problems in patients with schizophrenia. The long-acting 3-month formulation of paliperidone palmitate, owing to its extended elimination half-life, may offer a valuable therapeutic option for these patients. OBJECTIVE: To evaluate the efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo in delaying time to relapse of schizophrenia symptoms. DESIGN, SETTING, AND PARTICIPANTS: This randomized, multicenter trial conducted from April 26, 2012, through April 9, 2014, in 8 countries consisted of 4 phases: 3-week screening phase, flexible-dose 17-week open-label transition phase, 12-week open-label maintenance phase, and open-ended double-blind (DB) phase. Of the 506 patients enrolled (aged 18-70 years; DSM-IV-TR diagnosis of schizophrenia), 305 were randomized to 3-month paliperidone palmitate (n = 160) or placebo (n = 145) in the DB phase. INTERVENTIONS: Patients received once-monthly doses of the 1-month formulation of paliperidone palmitate (50, 75, 100, or 150 mg eq) during the transition phase, followed by a single dose of the 3-month formulation (3.5 times the stabilized dose of once-monthly paliperidone palmitate) during the maintenance phase. Stabilized patients were randomized to receive either a fixed dose of 3-month paliperidone palmitate (175, 263, 350, or 525 mg eq) or placebo once every 3 months during the DB phase. MAIN OUTCOMES AND MEASURES: Time from randomization to the first relapse event (time to relapse) in the DB phase. RESULTS: In the interim analysis, time to first relapse was significantly different in favor of the paliperidone palmitate group vs the placebo group (hazard ratio = 3.45; 95% CI, 1.73-6.88; P < .001); median time to relapse was 274 days for placebo but not estimable for 3-month paliperidone palmitate. An independent data monitoring committee recommended early study termination due to efficacy. In the DB phase, 183 of 305 patients (62% with 3-month paliperidone palmitate; 58% with placebo) had at least 1 treatment-emergent adverse event; those noted more frequently in the group receiving paliperidone palmitate than in the placebo group were headache (9% vs 4%), weight increased (9% vs 3%), nasopharyngitis (6% vs 1%), and akathisia (4% vs 1%). CONCLUSIONS AND RELEVANCE: Compared with placebo, the 3-month formulation of paliperidone palmitate administered 4 times yearly significantly delayed time to relapse in patients with schizophrenia. The 3-month formulation was generally tolerable and has a safety profile consistent with other marketed paliperidone formulations. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01529515.

Pharmacokinetic profile after multiple deltoid or gluteal intramuscular injections of paliperidone palmitate in patients with schizophrenia.

Paliperidone palmitate (PP) is a once-monthly long-acting injectable antipsychotic approved for the treatment of schizophrenia in many countries. To evaluate the different injection-site options, we compared the pharmacokinetic profile of paliperidone after multiple injections of PP 100 mg eq. (156 mg of PP, equivalent to 100 mg of paliperidone) on days 1, 8, 36, and 64 into the deltoid (n = 24) or gluteal muscle (n = 25) in patients with schizophrenia. After four injections in the deltoid muscle, paliperidone exposure was higher for AUCτ and Cmax , compared with the gluteal muscle (geometric mean AUCτ -based ratio: 120% [90% CI: 93.1-154.7%], and geometric mean Cmax -based ratio: 130% [90% CI: 100.6-168.9%]). The mean [SD] fluctuation index was higher, with a larger interpatient variability, after deltoid-injections (75.9% [30.9%]) than gluteal-injections (58.5% [14.3%]). The median tmax was similar for both sites. PP was generally tolerable in patients, with more favorable local-site tolerability for gluteal-injection. In conclusion, to achieve therapeutic-concentrations quickly, the first-two injections of PP are best administered into the deltoid muscle, whereas thereafter maintenance-injections can be administered either in the deltoid or gluteal muscle.

Shopping behavior for ADHD drugs: results of a cohort study in a pharmacy database.

OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) medications are subject to abuse, misuse, and diversion. Obtaining ADHD prescriptions from multiple prescribers or filled across multiple pharmacies, known as 'doctor shopping', may reflect such unsanctioned use. We sought to create a definition of shopping behavior that differentiated ADHD medications from medications with low risk of diversion, i.e. asthma medications, and describe the incidence, frequency, and demography of shopping behavior. METHODS: This was a retrospective cohort study in a pharmacy database-LRx-covering 65 % of US retail pharmacies. Subjects had ADHD or asthma medication dispensed between February 2011 and January 2012. We followed subjects for 18 months to assess the number with overlapping dispensings from different prescribers, and the number of prescribers and pharmacies involved in those dispensings. RESULTS: We included 4,402,464 subjects who were dispensed ADHD medications, and 6,128,025 subjects who were dispensed asthma medications. Overlapping prescriptions from two or more prescribers dispensed by three or more pharmacies was four times more frequent in the ADHD cohort than in the asthma cohort. Using this definition, ADHD medication shopping behavior was more common among experienced users than naïve users, and was most common in subjects aged 10-39 years. Among subjects who shopped, 57.4 % shopped only once (accounting for 22.4 % of episodes), and 9.2 % shopped six or more times (accounting for 42.0 % of episodes). Shoppers more often received stimulant ADHD drugs than non-stimulants. CONCLUSIONS: Overlapping prescriptions by different prescribers and filled at three or more pharmacies defines ADHD medication shopping. Shopping behavior is most common in adolescents and younger adults. A small proportion of shoppers is responsible for a large number of shopping episodes.

A single-dose, open-label, parallel, randomized, dose-proportionality study of paliperidone after intramuscular injections of paliperidone palmitate in the deltoid or gluteal muscle in patients with schizophrenia.

Paliperidone palmitate (PP) is a long-acting injectable (LAI) antipsychotic, developed for monthly intramuscular (i.m.) administration into deltoid/gluteal muscle, approved for the treatment of schizophrenia in many countries. To assess the options for i.m. injection sites, dose-proportionality of PP was investigated after injection of a single dose (25-150 mg eq.) of PP in either gluteal (n = 106) or deltoid (n = 95) muscle of schizophrenic patients. Overall, mean (geometric) area under plasma concentration-time curve from time zero to infinity (AUC∞ ) of paliperidone increased proportionally with increasing PP doses, regardless of injection site. Mean maximum plasma concentration (Cmax ) was slightly less than dose-proportional for both injection sites at PP doses >50 mg eq. Mean Cmax was higher after injection in the deltoid compared with the gluteal muscle, except for the 100 mg eq. dose, while AUC∞ for both injection sites was comparable at all doses. Median time to reach Cmax (tmax ) ranged from 13-14 days after deltoid and 13-17 days after gluteal injection across all doses. Single PP injections in deltoid and gluteal muscles in the dose range of 25-150 mg eq. were generally tolerable both locally and systemically.

Effect of carbamazepine on the pharmacokinetics of paliperidone extended-release tablets at steady-state.

Given the potential concomitant use of carbamazepine and paliperidone extended-release (ER) in the treatment of schizophrenia or schizoaffective disorder, this open-label, two-treatment sequential study investigated the effect of repeated administration of carbamazepine on the steady-state pharmacokinetics of paliperidone. Sixty-four patients with a diagnosis of schizophrenia or bipolar-I disorder received the following treatments in a fixed sequential order, without washout between treatments: (i) paliperidone ER 6 mg tablet once daily for 7 days, and (ii) paliperidone ER 6 mg once daily concomitantly with carbamazepine 200 mg twice daily for the subsequent 21 days. Upon coadministration with carbamazepine, paliperidone steady-state total exposure (AUC24 h ) and peak plasma concentrations (Cmax ) decreased by approximately 37% [LSM ratio-AUC24 h : 63.4 (90% CI: 57.19; 70.29); Cmax : 62.47 (90% CI: 55.77; 69.98)]. This decrease is accounted for to a substantial degree by a 35% increase in renal clearance of paliperidone, likely as a result of induction of renal P-glycoprotein by carbamazepine. A 14% decrease in the amount of drug excreted unchanged in the urine suggests that carbamazepine coadministration has a limited effect on the intestinal absorption or cytochrome metabolism of paliperidone.

Limited utility of number needed to treat and the polarity index for bipolar disorder to characterize treatment response.

The medical community increasingly supports the use of simplifying constructs or ratios to facilitate incorporation of evidence-based medicine into clinical practice such as number needed to treat (NNT) and polarity index (PI). Clinicians and teachers find them to be an appealing, easy-to remember integer that can be readily translated into clinical practice. However, serious questions have been raised with respect to the validity, reliability and value of these descriptors of response. This commentary identifies some of the specific limitations of the NNT and PI constructs when applied to treatments of bipolar disorder.

Efficacy and safety of prolonged-release OROS methylphenidate in adults with attention deficit/hyperactivity disorder: a 13-week, randomized, double-blind, placebo-controlled, fixed-dose study.

OBJECTIVES: Methylphenidate (MPH) is effective for adults with attention-deficit/hyperactivity disorder (ADHD). This study aimed to evaluate the efficacy and safety of OROS MPH in adults with ADHD. METHODS: Randomized, double-blind study; 279 subjects received OROS MPH 54 or 72 mg/day, or placebo, for 13 weeks. Primary endpoint was the Conners' Adult ADHD Rating Scale - Screening Version (CAARS-O:SV). Secondary outcomes included CAARS Self Report - Short Version (CAARS-S:S), Sheehan Disability Scale (SDS) and ADHD Impact Module - Adult (AIM-A). RESULTS: Improvements in CAARS-O:SV were significantly greater with OROS MPH 72 mg vs. placebo (P = 0.0024). CAARS-S:S scores decreased significantly vs. placebo in both OROS MPH arms (P < 0.05). There was no significant change in SDS score from baseline in either treatment arm, although significant benefit vs. placebo was observed on several AIM-A subscales. Treatment was well tolerated. CONCLUSIONS: OROS MPH provided overall benefits in the treatment of adults with ADHD.

A randomized, placebo- and active-controlled study of paliperidone extended-release as maintenance treatment in patients with bipolar I disorder after an acute manic or mixed episode.

BACKGROUND: Paliperidone ER monotherapy was efficacious in treating acute mania in two 3-week studies in patients with bipolar I disorder. We assessed its efficacy in a study investigating maintenance treatment of clinically stable patients with this disorder. METHODS: Patients (n=766), aged 18 to 65 years inclusive, with current manic or mixed episodes were initially randomized (4:1) to flexibly-dosed paliperidone ER (3-12 mg/day) or olanzapine (5-20 mg/day; 3-week acute treatment phase); responders continued the same treatment (12-week continuation phase). Patients on paliperidone ER who achieved remission during this phase were randomized (1:1) to fixed-dose paliperidone ER (n=152) or placebo (n=148); those on olanzapine continued to receive that at fixed dose (n=83) (maintenance phase). RESULTS: Median time to recurrence of any mood symptoms (primary endpoint) was: 558 days (paliperidone ER), 283 days (placebo) and not observed with olanzapine (<50% of patients experienced recurrence). Time to recurrence of any mood symptoms was significantly longer with paliperidone ER than placebo (p=0.017; based on weighted Z-test at 0.0198 significance level; hazard ratio [placebo: paliperidone ER; unweighted 95% confidence interval]: 1.43 [1.03; 1.98]); the difference was significant for preventing recurrence of manic, but not depressive, symptoms. Treatment-emergent adverse events (maintenance phase) occurred more often in olanzapine group (64%) than placebo (59%) or paliperidone ER groups (55%). LIMITATIONS: Responder-enriched design prevents extrapolation of data to patients not previously stabilized on paliperidone ER. CONCLUSIONS: Paliperidone ER significantly delayed the time to recurrence of any mood symptoms, versus placebo, in patients with bipolar I disorder. No new safety concerns emerged.