The effect of esketamine in patients with treatment-resistant depression with and without comorbid anxiety symptoms or disorder.

BACKGROUND: Comorbid anxiety is generally associated with poorer response to antidepressant treatment. This post hoc analysis explored the efficacy of esketamine plus an antidepressant in patients with treatment-resistant depression (TRD) with or without comorbid anxiety. METHODS: TRANSFORM-2, a double-blind, flexible-dose, 4-week study (NCT02418585), randomized adults with TRD to placebo or esketamine nasal spray, each with a newly-initiated oral antidepressant. Comorbid anxiety was defined as clinically noteworthy anxiety symptoms (7-item Generalized Anxiety Disorder scale [GAD-7] score ≥10) at screening and baseline or comorbid anxiety disorder diagnosis at screening. Treatment effect based on change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and response and remission were examined by presence/absence of comorbid anxiety using analysis of covariance and logistic regression models. RESULTS: Approximately 72% (162/223) of patients had baseline comorbid anxiety. Esketamine-treated patients with and without anxiety demonstrated significant reductions in MADRS (mean [SD] change from baseline at day 28: -21.0 [12.51] and -22.7 [11.98], respectively). Higher rates of response and remission, and a significantly greater decrease in MADRS score at day 28 were observed compared to antidepressant/placebo, regardless of comorbid anxiety (with anxiety: difference in LS means [95% CI] -4.2 [-8.1, -0.3]; without anxiety: -7.5 [-13.7, -1.3]). There was no significant interaction of treatment and comorbid anxiety (p = .371). Notably, in the antidepressant/placebo group improvement was similar in those with and without comorbid anxiety. CONCLUSION: Post hoc data support efficacy of esketamine plus an oral antidepressant in patients with TRD, regardless of comorbid anxiety.

Once-monthly paliperidone palmitate compared with conventional and atypical daily oral antipsychotic treatment in patients with schizophrenia.

OBJECTIVE: This analysis of the Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study (NCT01157351) compared outcomes after administration of once-monthly paliperidone palmitate (PP) vs conventional oral antipsychotics (COAs) or atypical oral antipsychotics (AOAs). METHODS: PRIDE was a 15-month study of 444 individuals with schizophrenia and a history of incarceration. They were randomly assigned to PP or to 1 of 7 commonly prescribed OAs. Primary endpoint was time to first treatment failure (TF). Event-free probabilities were estimated using the Kaplan-Meier method; treatment group differences (PP vs COAs, PP vs AOAs, and PP vs oral paliperidone/risperidone) were assessed using a log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. No adjustment was made for multiplicity. RESULTS: Compared with PP, risk for first TF was 34% higher with COAs (HR: 1.34; 95% CI: 0.80-2.25), 41% higher with AOAs (HR: 1.41; 95% CI: 1.06-1.88), and 39% higher with paliperidone/risperidone (HR: 1.39; 95% CI: 0.97-1.99). Incidences of extrapyramidal symptom-related adverse events (AEs) were 45.7%, 13.7%, and 10.6% in the COA, AOA, and oral paliperidone/risperidone groups vs 23.9% in the PP group. Incidences of prolactin-related AEs were 5.7%, 3.8%, and 3.5% vs 23.5%, and incidences of ≥7% weight increase were 11.4%, 14.9%, and 16.0% vs 32.4%. CONCLUSIONS: Results suggest a lower risk of TF but a higher rate of some AEs after treatment with PP vs COAs, AOAs, and paliperidone/risperidone. Deselection of specific OAs and low patient-compliance rates with OAs likely biased the safety results.

Earlier Use of Long-Acting Injectable Paliperidone Palmitate Versus Oral Antipsychotics in Patients With Schizophrenia: An Integrated Patient-Level Post Hoc Analysis.

Objective: To assess the efficacy and safety of paliperidone palmitate (PP) long-acting injectable antipsychotic (LAI) versus oral antipsychotic (OAP) treatment in adult patients diagnosed with schizophrenia (per DSM-IV or DSM-5 criteria) and varying duration of illness (0-3 years and > 3 years).Methods: Patient-level data from the PRIDE, PROSIPAL, and DREaM studies were included in a post hoc analysis. Efficacy and safety outcomes, including relapse assessments, Personal and Social Performance scale scores, Medication Satisfaction Questionnaire total scores, and treatment-emergent adverse events (TEAEs), were measured systematically. Treatment failure (TF) included relapses due to psychiatric hospitalizations, arrest or incarceration, suicidal or homicidal ideation or behavior, discontinuation due to inadequate efficacy and/or safety or tolerability, treatment supplementation due to inadequate efficacy, and significant worsening of symptoms.Results: Fewer TFs were observed with PP versus OAP in both the 0-3 years group (17.7% and 25.3%, respectively) and the > 3 years group (32.3% and 42.4%, respectively). Time to first TF was significantly longer with PP versus OAP treatment in both duration of illness groups. TEAE rates were similar between the PP and OAP groups, with no new safety signals identified.Conclusions: This post hoc analysis suggests that PP provides significant benefit in reducing TF or relapse compared with OAPs regardless of duration of illness and highlights the potential benefit of implementing PP earlier in the course of schizophrenia.Trial Registration: ClinicalTrials.gov identifiers NCT01157351 (PRIDE), NCT01081769 (PROSIPAL), and NCT02431702 (DREaM).

Population pharmacodynamic modeling of various extended-release formulations of methylphenidate in children with attention deficit hyperactivity disorder via meta-analysis.

Placebo and pharmacodynamic (PD) models were developed which link temporal measures of efficacy in children with attention deficit hyperactivity disorder (ADHD) and methylphenidate (MPH) plasma concentrations from adults. These models can be used to predict daily pediatric clinical measure profiles following administration of different MPH formulations in children without conducting pediatric pharmacokinetic (PK) or PD studies by using more easily obtained adult PK data. Mean PK data from various extended-release MPH formulations studied in adults and mean PD data from nine pediatric efficacy studies were obtained from the literature. The individual time-course of the clinical measures from three pediatric trials were also analyzed after being combined with the meta-analysis data. The clinical measure profiles following placebo administration were described by indirect response models with time-varying elimination rates. MPH pharmacodynamic effect was described by E(max) models, which included time-dependent tolerance. Internal and external evaluations using a visual predictive check technique confirmed the prediction capability of the models. This modeling exercise demonstrated that time courses of MPH concentrations in adults with different drug release patterns can be used to predict time courses of clinical efficacy parameters in pediatrics by employing the models developed by meta-analysis.

Telehealth-Based Psychoeducation for Caregivers: The Family Intervention in Recent-Onset Schizophrenia Treatment Study.

BACKGROUND: Schizophrenia is a lifelong illness that requires long-term treatment and caregiving. Family psychoeducation (FP) has been shown to lessen caregiver burden, improve caregiver functioning, and improve outcomes in patients. However, the impact of FP delivered specifically to caregivers on patient outcomes has not been well explored, particularly for early schizophrenia. Furthermore, there is a lack of research examining the benefits of telehealth-based psychoeducation for caregivers on either patient or caregiver outcomes. OBJECTIVE: The Family Intervention in Recent-Onset Schizophrenia Treatment (FIRST) study is a randomized controlled trial of patients with schizophrenia spectrum disorders and their caregivers, which is designed to evaluate the effect of telehealth-based, caregiver-focused, study-provided psychoeducation versus usual care (UC) on patient treatment failure (TF). The impact of study-provided psychoeducation on caregiver burden is also investigated. METHODS: Eligible patients and their designated caregivers were randomly assigned to either the study-provided psychoeducation (≤16 sessions of telehealth-based psychoeducation over 6 months) or UC group, stratified by antipsychotic treatment (paliperidone palmitate or oral antipsychotic). The major TF events (ie, psychiatric hospitalization or intervention, arrest or incarceration, and suicide attempts) were assessed at 3, 6, and 12 months after baseline. A proportional means model using mean cumulative function was used to assess between-group differences in the mean cumulative number of TF events over 12 months. Caregiver burden was assessed using the Involvement Evaluation Questionnaire and 12-item Short Form Health Survey. RESULTS: A total of 148 pairs of participants were enrolled in the study, of whom 96 (64.9%) patients and 94 (63.5%) caregivers completed the 12-month follow-up. The mean number of sessions in the study-provided psychoeducation group was 7.7 (SD 5.9). No differences were observed between the study-provided psychoeducation and UC groups in patient outcomes (rates of TF: 70% vs 67%; P=.90) or measures of caregiver burden (assessment of caregiver distress and physical and mental health). However, post hoc analyses revealed lower relapse rates in patients who received paliperidone palmitate than in those who received oral antipsychotics at all time points. Although the FIRST study did not meet the primary end point, several key lessons were identified to inform future caregiver-focused, telehealth-based FP interventions. Lack of study-provided psychoeducation, focus on caregiver-only intervention, difficulties with enrollment, and caregiver-treatment team coordination may have affected the outcomes of the FIRST study. CONCLUSIONS: Key insights from the FIRST study suggest the potential importance of supporting sufficient caregiver engagement; communication between clinicians, patients, and family members regarding treatment plans; and solidifying the relationship between clinicians providing psychoeducation to the caregiver and patient treatment team. TRIAL REGISTRATION: ClinicalTrials.gov NCT02600741; http://clinicaltrials.gov/ct2/show/NCT02600741.

Impact of COVID-19 Pandemic on Prescribing of Long-Acting Injectable Antipsychotics for Schizophrenia: Results from a United States Prescriber Survey.

Purpose: To describe changes due to the COVID-19 pandemic in the prescribing of long-acting antipsychotics (LAI) for schizophrenia, patient outcomes, and patient and healthcare provider (HCP) attitudes regarding COVID-19 vaccination in the United States (US). Methods: An anonymous online survey was administered to US-based LAI prescribers with a psychiatry specialty in May 2021. Information on prescriber and clinical practice characteristics, LAI prescribing, patient outcomes, and attitudes toward COVID-19 vaccination was collected and described. Results: Of the 401 LAI prescribers meeting survey criteria, 64.6% reported that LAI prescribing remained unchanged (increase: 19.2%, decrease: 14.0%). The majority did not switch patients from LAIs to oral antipsychotics (OAP; 63.3%) or to LAI formulations with lower frequency of administration (68.1%); most prescribers switched the same number of patients from OAPs to LAIs during the pandemic as in previous practice (65.1%). Half of LAI prescribers (50.1%) reported antipsychotic adherence as unchanged among most patients; 44.6% reported symptom control/relapse frequency as unchanged. Most prescribers believed their patients with schizophrenia should be prioritized for COVID-19 vaccination (74.1%) and encouraged all patients to obtain a COVID-19 vaccine (84.0%). However, 64.1% of prescribers reported hesitancy among some patients about vaccines' safety; 51.4% reported that some patients were willing to be vaccinated despite the hesitancy, 48.6% indicated that some patients perceived COVID-19 vaccines as safe, effective, and important. Conclusion: LAI prescribing and prescriber-reported antipsychotic adherence in patients with schizophrenia remained largely unchanged approximately one year after the start of COVID-19. Focused efforts to overcome patients' COVID-19 vaccine hesitancy are warranted.

Understanding the Health System Conditions Affecting the Use of Long-Acting Injectable Antipsychotics in the Treatment of Schizophrenia in Clinical Practice: A US Healthcare Provider Survey.

Purpose: To describe factors that enable the routine use of long-acting injectable antipsychotics (LAIs) for appropriate patients in the current clinical practice, including changes in LAI prescribing due to the COVID-19 pandemic and expectations for prescribing in 2021 in the United States (US). Methods: Frequent LAI prescribers recruited from a nationwide panel in 2020 completed an online survey regarding practice characteristics, perspectives on healthcare system conditions enabling routine use of LAIs, and prescribing patterns and changes in patterns during the COVID-19 pandemic. Results: Of 408 prescribers who completed the survey, 77.7% were physicians and 59.1% had ≥10 years of psychiatry practice. More than half of frequent prescribers (57.1%) reported treating >20% of their patients with schizophrenia with LAIs. The American Psychiatric Association (APA) guideline was followed by 64.0% of prescribers. Most prescribers identified poor adherence to antipsychotics as a circumstance when LAIs are recommended (94.9%) and patient/caregiver involvement in treatment decisions as a key factor impacting the decision to prescribe LAIs (97.3%). Most prescribers reported that LAI prescribing rates were unchanged in 2020 (59.8%). Similar proportions of prescribers expected no change (44.1%) or an increase (42.9%) in LAI prescribing rates in 2021. The number of patients followed, cost of treatment, and availability of staff to administer LAIs were the main driving factors identified by prescribers expecting an increase in LAI prescribing rates. Conclusion: LAIs were commonly recommended to patients with poor adherence, and patient/caregiver involvement was an important factor affecting prescribers' treatment decisions. LAI prescribing rates remained unchanged during the COVID-19 pandemic in 2020.

Comparing Relapse Rates in Real-World Patients with Schizophrenia Who Were Adequately versus Not Adequately Treated with Paliperidone Palmitate Once-Monthly Injections Before Transitioning to Once-Every-3-Months Injections.

Purpose: This retrospective cohort study evaluated real-world data on relapses in adult patients with schizophrenia who transitioned to long-acting injectable paliperidone palmitate once-every-3-months (PP3M) following treatment with once-monthly paliperidone palmitate (PP1M). Patients and Methods: Data derived from the IBM® MarketScan® Multi-State Medicaid Database were analyzed. Adults aged ≥18 years with ≥1 schizophrenia diagnosis claim and ≥12 months of continuous medical and prescription enrollment before and/or at index date of PP3M were eligible for inclusion. Patients were matched on propensity score to 2 PP3M cohorts: (1) adequately treated (AT), defined as patients treated with PP1M for ≥4 months, with the last 2 doses the same and a PP3M initiation dose meeting the corresponding PP1M-to-PP3M dose conversion, or (2) not adequately treated (NAT), defined as patients who received ≤2 or no PP1M doses. Relapse rates and time to relapse distributions based on the first occurrence of a qualifying event during the 2-year follow-up period were compared between PP3M cohorts using Kaplan-Meier survival curves and log rank test statistics. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Two sensitivity analyses using different matched populations were performed to assess the robustness of the primary findings. Results: Propensity score matching yielded a sample of 1314 patients (657 per group). Most patients were male (68.9%) and aged 25-64 years (90.1%). The relapse rate was significantly lower in the AT (18.4%) versus NAT cohort (26.8%), P = 0.0002. Risk of relapse decreased by 35% for AT versus NAT (HR: 0.65 [95% CI: 0.51-0.81]). Relapse reductions favored the AT cohort in both sensitivity analyses (HR: 0.67 [95% CI: 0.54-0.83] and HR: 0.74 [95% CI: 0.56-0.97]). Conclusion: In this analysis of Medicaid claims data, patients adequately treated with PP1M before transitioning to PP3M demonstrated significantly lower relapse rates and delayed time to relapse.

Longitudinal Course of Adverse Events With Esketamine Nasal Spray: A Post Hoc Analysis of Pooled Data From Phase 3 Trials in Patients With Treatment-Resistant Depression.

Objective: To describe the tolerability of esketamine nasal spray based on the adverse event profile observed during treatment sessions occurring early and later over the course of treatment.Methods: In 2 long-term, phase 3 studies (NCT02493868, October 1, 2015-February 16, 2018; NCT02497287, September 30, 2015-October 28, 2017), patients with treatment-resistant major depressive disorder (per DSM-5) and nonresponse to ≥ 2 oral antidepressants received esketamine nasal spray (56 or 84 mg) twice weekly during a 4-week induction phase, weekly for weeks 5-8, and weekly or every 2 weeks thereafter as maintenance treatment, in conjunction with a new oral antidepressant. A post hoc analysis using descriptive statistics evaluated occurrence (incidence, frequency, severity) and recurrence (incidence and severity) of events of specific interest.Results: In patients treated with esketamine nasal spray plus a newly initiated oral antidepressant (n = 928), spontaneously reported adverse events of dizziness, nausea, sedation, vertigo, and increased blood pressure were more likely to recur after the first week of treatment if they occurred more frequently (twice > once > none) during the first week. The same pattern was observed when these events were assessed by structured instruments. Incidences of dizziness, dissociation, increased blood pressure, nausea, vertigo, and sedation were highest in week 1 of treatment (20.6%, 16.7%, 4.3%, 14.0%, 12.1%, and 3.8%, respectively) and decreased thereafter. Initial occurrences and subsequent recurrences of events were mostly mild or moderate in severity.Conclusions: Adverse events during treatment with esketamine nasal spray plus an oral antidepressant generally become less frequent with ongoing treatment, and the majority are mild or moderate in severity.Trial Registration: ClinicalTrials.gov identifiers: NCT02493868; NCT02497287.

Long-term safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: an open-label, dose-titration, 1-year study.

OBJECTIVE: To evaluate the long-term safety of OROS methylphenidate in the management of attention-deficit/hyperactivity disorder (ADHD) in adults. METHODS: This multicenter, open-label, dose-titration, flexible dose study enrolled adults with ADHD for 6 or 12 months of treatment with OROS methylphenidate. Dosing began at 36 mg/d, with titration in 18-mg increments every 7 days until a predefined outcome (efficacy threshold, maximum dosage of 108 mg/d, or limiting adverse event). Dose reduction occurred for prespecified reasons, and the subjects discontinued if unable to tolerate 36 mg/d. Assessments included ADHD symptoms, adverse events, vital signs, and laboratory results. RESULTS: A total of 550 subjects received treatment (52% were men; mean age, 39 years; range, 18-65 years), and 57% (146/258) and 44% (129/292) completed their 6 or 12 months of treatment with mean durations of 128 and 213 days, respectively. The final prescribed dosages were 36 mg/d (22.4%), 54 mg/d (25.1%), 72 mg/d (22.0%), 90 mg/d (17.1%), and 108 mg/d (13.5%). Modest increases from baseline to final visit were observed in mean systolic (2.6 mm Hg) and diastolic (1.9 mm Hg) blood pressure and pulse (4.1 beats per minute). The mean weight decreased by 2.3 kg. No clinically meaningful changes in laboratory values or electrocardiogram parameters were observed other than increased heart rate. Most common adverse events included decreased appetite (26.7%), headache (24.0%), and insomnia (20.7%). No serious adverse event was considered related to study medication. Several measures of efficacy indicated improvement during the study. CONCLUSIONS: OROS methylphenidate, in the flexible dosage range from 36 to 108 mg/d, was well tolerated for up to 1 year in adults with ADHD.

Direct and Indirect Costs Among Caregivers of Patients With Major Depressive Disorder and Suicidal Ideation or Suicidal Attempt.

Objective: To compare direct and indirect costs among caregivers of patients with major depressive disorder (MDD) and suicidal ideation and/or suicide attempts (MDSI) versus caregivers of patients with MDD alone versus caregivers of patients without MDD or suicidal ideation and/or suicide attempts (controls).Methods: Cohorts were based on caregivers of adult patients with MDSI, MDD alone, and controls. Patients were identified by Workpartners employer database ICD-9/ICD-10 codes (January 2010 to July 2019) and were spouses or domestic partners of employees (caregivers). Twenty controls and 20 MDD-alone caregivers were matched to each MDSI caregiver on sex, age, and index year. All caregiver-patient pairs had 6 months pre/postindex information and met additional inclusion/exclusion criteria. Patient and caregiver medical and prescription claims and caregiver absenteeism (payment/time) were analyzed. Direct costs (medical, prescription) and indirect costs (absence payments by benefit type) were analyzed using separate, 2-part stepwise regression models and controlling for demographics, job-related variables, region, index year, and Charlson Comorbidity Index score.Results: 570 MDSI caregiver-patient pairs and 11,400 matched MDD-alone and control pairs were identified. MDSI and MDD-alone caregivers had higher medical costs compared with controls ($5,131 and $4,548 versus $3,885, respectively; P < .0001). Prescription costs were highest among MDSI caregivers, followed by MDD-alone and control caregivers ($1,852, $1,425, and $1,005, respectively; P < .001). MDSI caregivers had the highest total indirect costs. MDSI patient medical and prescription costs were highest, followed by MDD-alone and control patients.Conclusion: MDSI caregivers had significantly greater direct and indirect costs compared with MDD-alone and non-MDD caregivers.

Self-reported review of the value of esketamine in patients with treatment-resistant depression: Understanding the patient experience in the STRIVE Study.

Esketamine nasal spray (ESK) is indicated, in conjunction with an oral antidepressant (OAD), for the management of treatment-resistant depression (TRD) in adults. Select US-based patients from an open-label, long-term extension safety study of ESK (NCT02782104) participated in this study through semi-structured interviews. The study evaluated patient-reported early health changes related to emotional health, daily functioning, and social functioning in adults with TRD treated with ESK plus OAD. Eligible patients were responders to ESK who had begun initial ESK treatment ≤30 months before enrollment and were currently receiving ESK plus OAD. Results from 23 patients (9 men, 14 women; mean age, 46 years) were analyzed. Patients described the degree to which ESK treatment changed the effects of depression on aspects of health as either being much improved or improved (91.8%, 156/170). Key characteristics noted regarding treatment with ESK plus OAD included degree of effectiveness (n = 11), rapid onset of action (n = 7), and side-effect profile (n = 5). All patients reported being either satisfied (52%) or very satisfied (48%) with ESK plus OAD treatment. Adverse events were consistent with the known safety profile of ESK. Study insights may help prepare patients with TRD and their clinicians to anticipate potential health changes experienced with ESK.

Efficacy and safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, double-blind, parallel group, dose-escalation study.

OBJECTIVE: To assess the efficacy and safety of OROS methylphenidate (Concerta; McNeil Pediatrics Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc, Titusville, NJ) in the management of attention-deficit/hyperactivity disorder (ADHD) in adults. METHODS: A randomized, 7-week, double-blind, placebo-controlled, dose-escalation, parallel-group study of OROS methylphenidate 36, 54, 72, 90, or 108 mg/d versus placebo was conducted in adults with ADHD. The primary end point was the Adult ADHD Investigator Symptom Report Scale. Other assessments included the Clinical Global Impressions-Improvement scale, a post hoc responder analysis, adverse events, and vital signs. RESULTS: Two hundred twenty-six subjects (56.2% male; mean age, 39.0 years; range, 18-65 years) were included in the intention-to-treat population (110 subjects on OROS methylphenidate; 116 subjects on placebo). OROS methylphenidate resulted in greater ADHD symptom improvement than placebo as demonstrated by a statistically significantly lower least squares mean change from baseline in Adult ADHD Investigator Symptom Report Scale total score at the final visit (last observation carried forward [LOCF]; P = 0.012). Subjects on OROS methylphenidate also had a significantly lower least squares mean Clinical Global Impressions-Improvement score at the final visit (LOCF; P = 0.008). A significantly greater proportion of subjects on OROS methylphenidate (36.9%, 38/103 subjects) were responders at the final visit (LOCF) compared with placebo (20.9%, 24/115 subjects; P = 0.009). OROS methylphenidate was well tolerated. Adverse events were reported by 93 (84.5%) of the 110 OROS methylphenidate-treated subjects versus 74 (63.8%) of the 116 placebo-treated subjects. No serious treatment-emergent adverse events and no deaths were reported. Similar mean changes from baseline to final visit (LOCF) for systolic and diastolic blood pressures for the OROS methylphenidate and placebo groups were observed. CONCLUSIONS: In a dose escalation ranging from 36 to 108 mg/d, OROS methylphenidate is effective and well tolerated in the management of ADHD in adults.

Treatment effect with paliperidone palmitate compared with oral antipsychotics in patients with recent-onset versus more chronic schizophrenia and a history of criminal justice system involvement.

AIM: Long-acting injectable antipsychotics (APs) are not well studied in recent-onset schizophrenia. This exploratory analysis of a study designed to reflect real-world schizophrenia, as defined by patients, interventions and outcomes, compared relative treatment effect between once-monthly paliperidone palmitate (PP) and daily oral APs in patients with recent-onset or chronic illness METHODS: This randomized, open-label, event monitoring board-blinded study compared treatment response in subjects with schizophrenia and a history of criminal justice system involvement following treatment with PP or oral APs for 15 months (ClinicalTrials.gov identifier, NCT01157351). Event-free probabilities were estimated using Kaplan-Meier method; hazard ratios (HRs) were estimated using Cox proportional hazard models. This subgroup analysis analysed data by disease duration (≤5 (recent-onset) or >5 years (chronic illness) since first psychiatric diagnosis). RESULTS: Seventy-seven subjects met the criteria for recent-onset illness; 365 for chronic illness. HRs (95% CI) for treatment failure for oral APs versus PP were 1.73 (0.87-3.45; P = 0.121) for recent-onset and 1.37 (1.02-1.85; P = 0.039) for chronic illness. Most common adverse events for PP versus oral APs were injection site pain (recent-onset, 26% vs. 0%; chronic, 17% vs. 0%), increased weight (14% vs. 6%; 12% vs. 6%), akathisia (14% vs. 9%; 10% vs. 7%), insomnia (12% vs. 17%; 18% vs. 10%) and anxiety (12% vs. 6%; 10% vs. 8%). CONCLUSIONS: Although neither pre-planned nor adequately powered, the estimated HRs suggest that the relative advantage of PP over oral APs for reducing the risk for treatment failure may be greater in patients with recent-onset schizophrenia than in those with more chronic illness.

Medication changes after switching from CONCERTA® brand methylphenidate HCl to a generic long-acting formulation: A retrospective database study.

BACKGROUND: Observational studies of switching from branded to generic formulations of the same drug substance often lack appropriate comparators for the subjects who switched. Three generic formulations were deemed equivalent to Concerta: an authorized generic (AG) identical except for external packaging, and two other generics (EG). OBJECTIVE: Compare the incidence of a combined endpoint (switching back to Concerta, changing the use of immediate release methylphenidate (MPH), stopping all long-acting methylphenidate, or starting a new medication) among people switched from Concerta to the AG versus the EG. METHODS: Cohort study from the Truven CCAE database of people aged 6 to 65 diagnosed with ADHD, treated with Concerta, and switched to the EG or to the AG formulation. RESULTS: In the EG arm 24.6% and in the AG arm 19.7% of subjects switched back to Concerta. The proportion of subjects meeting the combined endpoint was 39.5% in the EG arm, 32.9% in the AG arm, a crude risk ratio of 1.20 (95% CI 0.94, 1.54). After adjustment by propensity score stratification, the adjusted odds ratio (OR) was 1.23 (95% CI 0.90, 1.70). In an unplanned analysis using a different method of adjustment, the adjusted OR was 1.00 (95% CI 0.69, 1.44). DISCUSSION: This study did not detect a difference between the proportion of people who met the study endpoint in the two study arms, i.e. between those who switched to a generic formulation that was identical to Concerta except for external packaging and those who switched to the comparison generics. The high incidence of the combined endpoint in the AG arm demonstrates the need for an appropriate comparator in studies of this type. TRIAL REGISTRATION: ClinicalTrials.gov NCT02730572.

Randomized, 6-Week, Placebo-Controlled Study of Treatment for Adult Attention-Deficit/Hyperactivity Disorder: Individualized Dosing of Osmotic-Release Oral System (OROS) Methylphenidate With a Goal of Symptom Remission.

OBJECTIVE: To evaluate the efficacy and safety of individualized dosing within the approved dose range for osmotic-release oral system (OROS) methylphenidate hydrochloride in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: A double-blind, 6-week trial was conducted between July 2009 and February 2010 at 35 US sites. Adults with ADHD (DSM-IV diagnostic criteria) and a screening ADHD Investigator Symptom Rating Scale (AISRS) score > 24 were randomly assigned to OROS methylphenidate 18 mg or matching placebo. Treatment dose could be increased at 18 mg increments, up to 72 mg/d, until an optimal dose was achieved. AISRS score changes from baseline to end point (primary outcome) were analyzed using analysis of covariance. RESULTS: At baseline, the intent-to-treat population of 169 OROS methylphenidate and 172 placebo subjects (mean age = 35.8 years) had mean (standard deviation [SD]) AISRS scores of 37.8 (6.94) and 37.0 (7.51), respectively. OROS methylphenidate-treated subjects exhibited a significantly greater mean (SD) AISRS score improvement than placebo subjects (-17.1 [12.44] vs -11.7 [13.30]; P < .001). In general, OROS methylphenidate-treated subjects experienced greater improvements than placebo subjects in secondary measures of symptom frequency, cognitive function, work productivity, and quality-of-life. Little effect of OROS methylphenidate was observed in exploratory sleep assessments. The adverse event pattern was similar to previous reports of stimulants in adults with ADHD. CONCLUSIONS: OROS methylphenidate treatment with individualized doses titrated to achieve symptom remission demonstrated greater ADHD symptom reduction than placebo treatment. These data support the overall efficacy of OROS methylphenidate treatment in the management of adults with ADHD and provide new possibilities for additional intervention. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00937040.

Multicenter, randomized, open-label study of OROS methylphenidate versus atomoxetine: treatment outcomes in African-American children with ADHD.

The Formal Observation of Concerta versUs Strattera (FOCUS) study was conducted to assess, in children with ADHD, treatment outcomes with Concerta [OROS methylphenidate (MPH)], a once-daily controlled-release medication, and Strattera, (atomoxetine), a selective noradrenaline reuptake inhibitor, Because of the lack of data in minority groups treated for ADHD, the present subgroup analysis was conducted to determine the effectiveness and tolerability of ADHD treatments in African-American patients who were randomized to OROS MPH (n=125) or atomoxetine (n=58) during the FOCUS study. At the end of the study, the mean dose of OROS MPH was 32.8 +/- 10.9 mg and that of atomoxetine was 1.1 +/- 0.4 mg/kg. The results demonstrated that both treatments were associated with significant improvements in ADHD symptoms from baseline; however, patients who received OROS MPH demonstrated significantly greater improvements in total ADHD symptoms, inattentiveness and global improvement. The incidence of adverse events was similar in both treatment groups. OROS MPH and atomoxetine are effective and tolerable in the treatment of African Americans with ADHD, and significantly greater treatment responses were observed in patients receiving OROS MPH compared with those receiving atomoxetine over three weeks. Additional studies are needed to evaluate treatment response in this population.

Outcomes of OROS methylphenidate compared with atomoxetine in children with ADHD: a multicenter, randomized prospective study.

This community-based study was designed to evaluate treatment outcomes with OROS methylphenidate (MPH) and atomoxetine in children with attentiondeficit/hyperactivity disorder (ADHD), as assessed by physicians and parents in a setting that resembles clinical practice. In a multicenter, prospective, open-label study, children 6 to 12 years of age with ADHD were randomized (2:1, respectively) to 3 weeks of treatment with once-daily OROS MPH or atomoxetine. Investigatorrated measures of symptoms included the ADHD Rating Scale (ADHD-RS) and the Clinical Global Impression-Improvement of Illness scale (CGI-I). Assessments were made at baseline and during a telephone interview in week 1, a clinic visit in week 2, and a final clinic visit in week 3. In total, 1323 patients received OROS MPH (n = 850) or atomoxetine (n = 473). Significant reductions from baseline in investigator-evaluated ADHD-RS scores were observed among patients receiving OROS MPH and those receiving atomoxetine. At the end of the study, mean decreases from baseline ADHD-RS scores were 20.24 for OROS MPH and 16 for atomoxetine (P < .001). Between-treatment differences appeared to increase over time (2.77, 3.44, and 4.24 at weeks 1, 2, and 3, respectively; P < .001). Treatment response (ie, 25% reduction from baseline ADHD-RS scores) was significantly greater at each evaluation for patients taking OROS MPH than for those taking atomoxetine (P < .001). Similar percentages of patients taking OROS MPH (4.8%) and atomoxetine (5.5%) withdrew because of adverse events. Although community-based studies often lack the control of randomized, placebo-controlled trials, these results nevertheless suggest greater ADHD symptom improvement with OROS MPH compared with atomoxetine.

Real-world outcomes of paliperidone palmitate compared to daily oral antipsychotic therapy in schizophrenia: a randomized, open-label, review board-blinded 15-month study.

OBJECTIVE: The Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study compared the effects of once-monthly paliperidone palmitate with daily oral antipsychotics on treatment failure in adults with schizophrenia. METHOD: The PRIDE study is a 15-month, randomized, multicenter study (May 5, 2010, to December 9, 2013) of adult subjects with a DSM-IV diagnosis of schizophrenia and a history of incarceration. Subjects were randomly assigned to once-monthly paliperidone palmitate injections or daily oral antipsychotics (randomly assigned from 7 acceptable, prespecified oral antipsychotics) for 15 months. The primary end point was time to first treatment failure, defined as arrest/incarceration; psychiatric hospitalization; suicide; treatment discontinuation or supplementation due to inadequate efficacy, safety, or tolerability; or increased psychiatric services to prevent hospitalization. Time to first treatment failure was determined by a blinded event-monitoring board and analyzed with the Kaplan-Meier method. RESULTS: In this study, 450 patients were randomly assigned, and 444 were included in the intent-to-treat population. Paliperidone palmitate was associated with significant delay in time to first treatment failure versus oral antipsychotics (hazard ratio, 1.43; 95% CI, 1.09-1.88; log rank P = .011). Observed treatment failure rates over 15 months were 39.8% and 53.7%, respectively. Arrest/incarceration and psychiatric hospitalization were the most common reasons for treatment failure in the paliperidone palmitate and oral antipsychotic groups (21.2% vs 29.4% and 8.0% vs 11.9%, respectively). The 5 most common treatment-emergent adverse events for the paliperidone palmitate treatment group were injection site pain (18.6% of subjects), insomnia (16.8%), weight increased (11.9%), akathisia (11.1%), and anxiety (10.6%). CONCLUSIONS: In a trial designed to reflect real-world management of schizophrenia, once-monthly paliperidone palmitate demonstrated superiority compared to oral antipsychotics in delaying time to treatment failure. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01157351.

Cost effectiveness of paliperidone palmitate versus oral antipsychotics in patients with schizophrenia and a history of criminal justice involvement.

OBJECTIVE: Conduct a cost effectiveness analysis for the Paliperidone palmitate Research In Demonstrating Effectiveness (PRIDE) trial. RESEARCH DESIGN AND METHODS: PRIDE was a 15 month, prospective, randomized, open-label study in which once monthly paliperidone palmitate significantly delayed the time to first treatment failure (healthcare or criminal justice system [HC/CJS] events) versus oral antipsychotics in recently incarcerated adults with schizophrenia. The present analysis used a state government perspective and HC/CJS event data that were collected on a resource use questionnaire (RUQ) every 3 months. MAIN OUTCOME MEASURES: Since cost information was not collected in the trial, cost estimates from published literature and an analysis of multistate Medicaid data for CJS and HC events, respectively, were applied to RUQ event data. Effectiveness and costs were adjusted to 456 days (trial duration). Incremental cost effectiveness was calculated as the adjusted cost difference divided by the adjusted effectiveness difference. RESULTS: Adjusted costs (in US dollars) in the paliperidone palmitate group (n = 198) and the oral antipsychotic group (n = 193), respectively, were: non-drug costs $22,331 and $25,027; drug costs $18,592 and $7833; and total costs $40,923 and $32,860. Adjusted effectiveness differences and corresponding incremental cost effectiveness per event avoided (in parentheses) for paliperidone palmitate versus oral antipsychotics were as follows: 0.33 fewer CJS events ($24,409), 0.13 fewer psychiatric hospitalizations ($60,484), 0.46 fewer psychiatric hospitalizations or CJS events combined ($17,391), and 0.30 fewer incarcerations ($26,754). CONCLUSIONS: Costs for HC/CJS events avoided offset 25% of the greater drug cost for the paliperidone palmitate versus oral antipsychotic treatment group in this vulnerable population. Use of a recall-dependent RUQ for event rates and cost estimates instead of actual costs are potential limitations and may make the results conservative from a state government perspective. Indirect costs are likely to be substantial for this population, but were not considered in the analysis.