The Role of Norepinephrine and Its α-Adrenergic Receptors in the Pathophysiology and Treatment of Major Depressive Disorder and Schizophrenia: A Systematic Review.

Norepinephrine (NE) is recognized as having a key role in the pathophysiology of major depressive disorder (MDD) and schizophrenia, although its distinct actions via α-adrenergic receptors (α-ARs) are not well defined. We performed a systematic review examining the roles of NE and α-ARs in MDD and schizophrenia. PubMed and ProQuest database searches were performed to identify English language papers published between 2008 and 2015. In total, 2,427 publications (PubMed, n = 669; ProQuest, n = 1,758) were identified. Duplicates, articles deemed not relevant, case studies, reviews, meta-analyses, preclinical reports, or articles on non-target indications were excluded. To limit the review to the most recent data representative of the literature, the review further focused on publications from 2010 to 2015, which were screened independently by all authors. A total of 16 research reports were identified: six clinical trial reports, six genetic studies, two biomarker studies, and two receptor studies. Overall, the studies provided indirect evidence that α-AR activity may play an important role in aberrant regulation of cognition, arousal, and valence systems associated with MDD and schizophrenia. Characterization of the NE pathway in patients may provide clinicians with information for more personalized therapy of these heterogeneous diseases. Current clinical studies do not provide direct evidence to support the role of NE α-ARs in the pathophysiology of MDD and schizophrenia and in the treatment response of patients with these diseases, in particular with relation to specific valence systems. Clinical studies that attempt to define associations between specific receptor binding profiles of psychotropics and particular clinical outcomes are needed.

Inpatient resource use and costs associated with switching from oral antipsychotics to aripiprazole once-monthly for the treatment of schizophrenia.

BACKGROUND: Schizophrenia is associated with high direct healthcare costs due to progression of disease and frequent occurrence of relapses. Aripiprazole once-monthly (AOM) has been shown to reduce total psychiatric hospitalizations among patients who switched from oral standard of care (SOC) therapy to AOM in a multicenter, open-label, mirror-image study of patients with schizophrenia. Because of the increasing need to improve patient outcomes while containing costs, it is important to understand the impact of AOM treatment initiation on medical costs associated with psychiatric hospitalizations and antipsychotic pharmacy costs. METHODS: In the current study, an economic model was developed using data from the AOM mirror-image study to evaluate the psychiatric hospitalization-related medical costs and antipsychotic pharmacy costs during a 6-month period before (retrospective period) and after (prospective period) the AOM treatment initiation. The economic model evaluated cost-saving potential of AOM among all patients (n=433) as well as a subset of patients with ≥1 prior hospitalization (n=165) who switched from oral SOC to AOM. Unit cost data were obtained from publicly available sources. RESULTS: Both hospitalizations and hospital days were reduced following a switch from oral SOC to AOM. As a result, psychiatric hospitalization-related costs were lower during the prospective period when compared with the retrospective period. Furthermore, the increase in antipsychotic pharmacy costs due to switching from oral SOC to AOM was offset by a reduction in psychiatric hospitalization-related medical costs. Per-patient costs were reduced by $1,046 (USD) in the overall population and by $20,353 in a subset of patients who had at least 1 psychiatric hospitalization during the retrospective period. Results were most sensitive to changes in hospitalization costs. CONCLUSIONS: AOM is associated with reducing the risk of relapse among patients with schizophrenia. The increase in antipsychotic pharmacy costs due to switching from oral SOC to AOM was offset by a reduction in costs associated with psychiatric hospitalizations, thereby presenting a cost-saving opportunity for health plans.

Long-term outcomes of antipsychotic treatment in patients with first-episode schizophrenia: a systematic review.

BACKGROUND: Treatment during first-episode psychosis (FEP) or early schizophrenia may affect the rates of relapse and remission, as well as cognitive functioning, over time. Prolonged duration of psychosis is associated with a poor prognosis, but the effects of treatment in patients with FEP or early schizophrenia on the long-term outcomes are not well defined. OBJECTIVE: To understand the long-term effects of treatment with antipsychotic agents on remission, relapse, and cognition in patients with FEP or early schizophrenia. METHODS: Using PubMed and Scopus databases, a systematic review was undertaken of articles published between January 1, 2000, and May 20, 2015, that reported randomized and nonrandomized prospective clinical trials on the long-term effects of oral or long-acting injectable antipsychotics on measures of relapse, remission, or cognition in patients with FEP or early schizophrenia. For comparative purposes, trials reporting the effects of later intervention with antipsychotics in patients with longer disease history were also evaluated. Titles, abstracts, and full-text articles were independently screened for eligibility by all the authors based on the predefined criteria. RESULTS: Nineteen studies met inclusion criteria: 13 reported long-term outcomes of relapse, remission, or cognition following antipsychotic treatment in patients with FEP and six reported on patients with a longer disease history. Antipsychotic treatment in patients with FEP produced high rates of remission in the year following treatment initiation, and untreated FEP reduced the odds of later achieving remission. Maintenance therapy was more effective than treatment discontinuation or intermittent/guided discontinuation in preventing relapse. Initiating antipsychotic treatment in patients with FEP also produced sustained cognitive improvement for up to 2 years. Antipsychotic therapy also reduced the risk or rate of relapse in patients with a longer disease history, with outcomes in one study favoring a long-acting injectable formulation over an oral antipsychotic. CONCLUSION: Treatment of patients with FEP is associated with benefits in the long-term outcomes of remission, relapse, and cognition. More long-term studies of treatment in patients with FEP are needed to confirm these findings.

Racial differences in antipsychotic use: Claims database analysis of Medicaid-insured patients with schizophrenia.

BACKGROUND: Database analyses have indicated that medical treatment for schizophrenia varies among racial groups. This study assessed antipsychotic use and healthcare utilization across races in Medicaid-insured patients with schizophrenia. METHODS: A Medicaid database of inpatient/outpatient medical claims and outpatient prescription claims for more than 28 million enrollees in 11 geographically diverse states was analyzed. The primary outcome, racial differences in antipsychotic use in 2012, was examined in 5 multivariable logistic regression models: (1) any antipsychotic, (2) first-generation (FG) long-acting injectables (LAIs), (3) FG oral antipsychotics, (4) second-generation (SG) LAIs, and (5) SG oral antipsychotics. RESULTS: Odds ratios and adjusted predicted probabilities were comparable for any antipsychotic use between black and white patients. Black patients were less likely to receive SG oral antipsychotics (P < .001) and more likely to receive SG or FG LAIs (P = .001 and P < .001, respectively) and FG oral antipsychotics (P = .003) vs white patients. Further, black patients had a higher mean number of emergency room visits (P < .001) and a lower mean number of hospitalizations (P < .05) vs white patients; the mean number of physician visits was comparable. CONCLUSIONS: Disparities in antipsychotic use and healthcare utilization across races in patients with schizophrenia warrant further investigation and elimination of these disparities should be a national goal.

Reduction in inpatient resource utilization and costs associated with long-acting injectable antipsychotics across different age groups of Medicaid-insured schizophrenia patients.

OBJECTIVE: Evaluate utilization of inpatient healthcare resources and associated costs after 12 months of treatment using long-acting injectable (LAI) antipsychotic medications among a large sample of Medicaid-insured patients categorized by different age groups. METHOD: Adult patients with schizophrenia were identified from the Thomson Reuters MarketScan Research database (1/1/2006-12/31/2010) before initiation of treatment using LAI antipsychotic agents. Utilization of inpatient healthcare resources and associated direct medical costs were compared for 12-month baseline and 12-month follow-up periods. RESULTS: Among 3,094 Medicaid-insured patients with schizophrenia initiating treatment with LAIs, the mean number of all-cause hospitalizations and hospitalization days were reduced by 24% and 31% (p<0.0001) compared with baseline, respectively, with similar significant reductions among all age groups (18-30, 31-40, 41-50, and 51-60 years). During 12-month follow-up with LAIs, mean reductions in all-cause costs were $4,369 (18-30 years, p<0.0001), $3,681 (31-40 years, p<0.0001), $2,051 (41-50 years, p=0.1332), and $4,492 (51-60 years, p=0.0107). Subanalyses separating first-generation and second-generation medication groups resulted in mean reduction in all-cause costs of $3,561 and $3,645, respectively. CONCLUSIONS: Results from this large cohort study provide naturalistic real-world evidence of the utility of LAIs in patients with schizophrenia and suggest that these agents may help to reduce the risk of relapse across all age groups (especially among younger patients). Given that relapse prevention is the ultimate goal of antipsychotic treatment, results from this large Medicaid patient population establish the value of LAIs for the management of schizophrenia.

Lack of tolerable treatment options for patients with schizophrenia.

PURPOSE: Atypical antipsychotics (AAs), an effective treatment for schizophrenia, have a range of pharmacologic properties leading to differences in tolerability as well as heterogeneity in treatment response. Individual patient characteristics must be considered when making treatment choices, especially from an adverse event (AE) or tolerability perspective. Despite the availability of numerous AAs, after appraising patient characteristics at the time of treatment selection, physicians may quickly run out of tolerable treatment options. PATIENTS AND METHODS: AE risk factors, defined as having either a prior history of an AE or a risk factor for that AE, were determined for Medicaid-insured and Commercially insured patients using database analysis. Patients receiving AA treatment between January 1, 2010 and December 31, 2012 defined the index date of first observed AA prescription during this period. Nine AAs were evaluated for association with AE risk factors as informed by drug prescribing information from the different manufacturers and published meta-analyses. The proportion of patients with pre-index AE risk factors prescribed an AA associated with that risk factor was then determined. RESULTS: A high proportion of patients (>80%) were prescribed an AA associated with extrapyramidal symptoms or akathisia despite experiencing extrapyramidal symptoms or akathisia prior to AA treatment initiation. Similar trends were observed among patients with diabetes (>60%) and obesity (>40%). From the nine treatment options available, the number of optimal choices for individual patient segments were limited based on their prior history, including those with cardiometabolic and cardiovascular comorbidities (four); experiencing prolactin elevation-related problems (seven); needing to avoid excessive sedation (four); or at risk of extrapyramidal symptoms or akathisia (two). Options were then further restricted among patients in more than one segment when multiple pre-index AE risk factors were combined. CONCLUSION: When combining patient risk profile with antipsychotic AE profile, physicians may quickly run out of tolerable treatment options for individual patients, despite the availability of many AAs, suggesting a need for additional treatment options with better tolerability and without compromising efficacy.

Hospitalization resource utilization and costs among Medicaid insured patients with schizophrenia with different treatment durations of long-acting injectable antipsychotic therapy.

This study evaluated the impact of using long-acting injectable (LAI) antipsychotics for a longer treatment duration versus a short duration on health care resource utilization among Medicaid-insured schizophrenia patients. Schizophrenia patients 13 years or older initiating LAI antipsychotics were identified from the Truven Health Analytics MarketScan Research Medicaid database between July 1, 2005, and June 30, 2010. The study population was grouped into 2 study cohorts (longer-usage-duration cohort: ≥ 180 days of supply and short-usage-duration cohort: <180 days of supply). Hospitalization-related resource utilization and costs were determined during a variable follow-up period and compared at the unadjusted and adjusted levels. Of the 5694 patients identified, 2838 patients were treated with LAI antipsychotics for a mean duration of 604 (SD, 432) days (mean age, 38.91 years), and 2856 were treated for 86 (SD, 43) days (mean age, 39.96 days). Total hospital lengths of stay, all cause (6.56 [SD, 18.63] vs 4.93 [SD, 13.40] days, P < 0.001) and schizophrenia related (5.18 [SD, 14.96] vs 4.16 [SD, 11.94] days, P = 0.005), and the mean number of hospitalizations, all cause (0.79 [SD, 1.78] vs 0.61 [SD, 1.41], P < 0.001) and schizophrenia related (0.63 [SD, 1.55] vs 0.51 [SD, 1.26], P = 0.001), were lower for the longer-usage-duration cohort. Cox regression results showed that using LAI antipsychotics for a longer duration was correlated with longer time to the first hospitalization for any cause and for schizophrenia. After multivariate regression, longer usage duration of LAI antipsychotics was associated with a decreased number of hospitalizations (-0.15 per year, P < 0.001), a decreased hospital length of stay (-1.50 days, P < 0.001), and reduced hospital payment (-26%, P < 0.001). Patients who are treated with LAI antipsychotics for a longer versus shorter duration use hospital resources less.

Impact of oral antipsychotic medication adherence on healthcare resource utilization among schizophrenia patients with Medicare coverage.

Nonadherence to antipsychotic medications is widespread and compromises the outcome of patients with schizophrenia. Using the MarketScan Medicare claims database, this study examined the impact of medication adherence on healthcare utilization among Medicare insured schizophrenia patients. The study population was separated into two cohorts defined by medication adherence, one with a medication possession ratio (MPR) ≥0.7 (high adherence) and the other with a MPR <0.7(low adherence). Of the 354 patients identified, 126 (36 %) had high adherence (mean ± SD MPR 0.94 ± 0.09) and 228 (64 %) had low adherence (MPR 0.24 ± 0.19). All cause hospitalizations (0.68 vs. 0.44; p = 0.015) and length of stay (LOS) (7.0 vs. 2.6 days; p = 0.005), and relapse hospitalizations (0.22 vs. 0.11; p = 0.028) and LOS (3.2 vs. 0.7 days; p = 0.027) were greater among patients with low adherence. Low adherent Medicare insured patients with schizophrenia require significantly more inpatient care and represent a patient population in which effective interventions are needed to improve disease management.

Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: synthesizing results across different research designs.

OBJECTIVE: Nonadherence is a major challenge in schizophrenia treatment. While long-acting (depot) antipsychotic medications are often recommended to address adherence problems, evidence on the comparative effectiveness of depot versus oral antipsychotics is inconsistent. We hypothesize that this inconsistency could be due to systematic differences in study design. This review evaluates the effect of study design on the comparative effectiveness of antipsychotic formulations. The optimal use of different antipsychotic formulations in a general clinical setting depends on better understanding of the underlying reasons for differences in effectiveness across research designs. DATA SOURCES: A PubMed literature review targeted English-language studies (2000-2011) with information on relapse, hospitalization, or all-cause discontinuation for depot and oral antipsychotic treatment arms in schizophrenia. The time frame was chosen to reflect research focused on the newer generation of antipsychotic agents. The search required at least 1 term from each of the following categories: (1) schizophrenia; (2) inject, injection, injectable, injectables, injected, depot, long-acting; and (3) iloperidone, fluphenazine, haloperidol, paliperidone, risperidone, olanzapine, asenapine, flupentixol, flupenthixol, lurasidone, clopenthixol, fluspirilene, zuclopentixol, zuclopenthixol. STUDY SELECTION: Thirteen relevant studies were identified by 2 independent reviewers; these studies included information on 19 depot-oral comparisons. DATA EXTRACTION: Age- and gender-adjusted risk ratios (RRs) (depot/oral) were calculated for the identified endpoints and pooled by study design (randomized controlled trial [RCT], prospective observational, and retrospective observational). Meta-analysis with random effects was used to estimate the pooled RRs, by study design. Average conversion factors between study designs were calculated as the ratios of pooled RRs. RESULTS: Meta-analysis of adjusted endpoints showed no apparent benefit of depot over oral formulations in RCTs, with an RR of 0.89 (P = .416). In contrast, there was a significant advantage for depot formulations in other study designs (prospective RR = 0.62 [P < .001]; retrospective RR = 0.56 [P < .001]). These imply conversion factors of 1.43 and 1.59 between RCTs and prospective and retrospective designs, respectively. CONCLUSIONS: The comparative effectiveness of antipsychotic formulations is sensitive to research design. Depot formulations displayed significant advantages in nonrandomized observational studies, whereas in RCTs no difference was observed. The estimated conversion factors may facilitate comparison across studies.

Healthcare cost reductions associated with the use of LAI formulations of antipsychotic medications versus oral among patients with schizophrenia.

Real-world medication adherence and healthcare costs of patients with schizophrenia initiating long-acting injectable (LAI) vs. oral antipsychotics were compared. Patients with schizophrenia initiating LAI or oral antipsychotics (index event) were identified from MarketScan Commercial and Medicare claims databases and their medication possession ratios (MPR), pre- and post-index costs for inpatient/outpatient care were compared. Of 3,004 patients, 394 initiated LAI antipsychotics and 2,610 oral antipsychotics. Post-index, the mean MPR was greater for the LAI cohort (0.67 ± 0.34 vs. 0.56 ± 0.35; p < 0.001). Schizophrenia-related hospital costs for LAI users were reduced during the follow-up period in comparison to the pre-index period, but were increased for patients using oral antipsychotics (-$5,981 ± $16,554 vs. 758 ± 14,328, p < 0.001). The change in costs of outpatient care also favored LAI medications ($134 ± 8,280 vs. 658 ± 3,260, p = 0.023). Drug costs of LAI antipsychotics were higher ($4,132 ± 4,533 vs. 2,562 ± 2,714, p < 0.001). Schizophrenia patients initiating LAI antipsychotics incur less healthcare costs in comparison to patients initiating oral antipsychotics.

Impact of early nonadherence to oral antipsychotics on clinical and economic outcomes among patients with schizophrenia.

INTRODUCTION: To quantify early nonadherence to antipsychotic medications in patients with schizophrenia and its impact on short-term antipsychotic adherence, healthcare utilization, and costs. METHODS: Patients who initiated oral antipsychotic treatment between January 1, 2006 to September 30, 2009 were identified from the MarketScan® Commercial Claims and Encounters (CCE) database (Truven Health Analytics, Ann Arbor, Michigan, USA). Patients were required to have a diagnosis of schizophrenia determined by the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) code 295.x, be 13-65 years of age, and have ≥ 12 months of continuous coverage prior to and after (follow-up) the earliest antipsychotic usage (index event). Medication discontinuation was defined as a gap of 30 days in available therapy; early nonadherence was defined as having the gap 90 days from the index event. During the follow-up period, medication adherence was estimated with quarterly medication possession ratios (MPR), and all-cause and schizophrenia-related healthcare resource utilization and costs were determined. RESULTS: The mean time to discontinuation (TTD) was 39.5 ± 20.1 days for early nonadherence patients (n = 873) and 250.7 ± 103.3 days for patients who were adherent early (n = 589). Early nonadherence resulted in more hospitalizations (0.57 vs. 0.38; P = 0.0006) with longer length of stay (LOS, 5.0 vs. 3.0 days; P = 0.0013) and higher costs ($5,850 vs. $4,211; P = 0.0244); schizophrenia-related hospitalizations, LOS, and costs were also greater. Patients that were adherent used more schizophrenia-related medications (10.4 vs. 4.7; P < 0.0001), increasing pharmacy costs ($3,684 vs. $1,549; P < 0.0001). Early nonadherence was correlated with lower drug adherence at each quarter of the follow-up period. CONCLUSION: Approximately 60% of patients with schizophrenia are nonadherent to antipsychotic medication early in treatment and are less likely to be adherent later. Early nonadherence resulted in more all-cause and schizophrenia-related hospitalizations with a greater LOS and cost of care.

Impact on healthcare resource usage and costs among Medicaid-insured schizophrenia patients after initiation of treatment with long-acting injectable antipsychotics.

OBJECTIVE: This study compared healthcare resource usage and costs before and after initiating LAI antipsychotics among Medicaid-insured schizophrenia patients. METHODS: Schizophrenia patients ≥13 years of age initiating LAI antipsychotics were identified from the Thomson Reuters MarketScan® Research Medicaid database between 7/1/2005 and 6/30/2010. Patients were required to have 6 months of continuous medical/prescription drug coverage prior to LAI initiation (baseline period) and during a variable follow-up period. Annualized healthcare resource usage and costs for the baseline and follow-up periods were determined and compared. RESULTS: Among 5694 eligible patients, 55% were male and 45% were female, and the majority of the population was between the ages of 18-55 (86%). The study population had low general comorbidity, as assessed by the Charlson Comorbidity Index (CCI). Diabetes (17%) and chronic pulmonary disease (14%) were the most prevalent comorbidities. In comparison to the baseline period, during the follow-up period (mean duration = 25.7 months) the mean number of hospitalizations, all cause (1.52 ± 2.41 vs 0.70 ± 1.61, p < 0.001) and schizophrenia-related (1.21 ± 2.04 vs 0.57 ± 1.41, p < 0.001) declined as well as hospital lengths of stay (all cause: 14.77 ± 28.61 vs 5.75 ± 16.26 days, p < 0.001; schizophrenia-related: 12.39 ± 25.86 vs 4.67 ± 13.54 days, p < 0.001). As a result, annualized hospital payments were much lower (all cause: $16,249 ± $36,404 vs $7380 ± $21,087, p < 0.001; schizophrenia-related: $13,388 ± $31,614 vs $5645 ± $15,767, p < 0.001). LIMITATIONS: This study attempted to minimize the impact of differences in patient characteristics by having patients serve as their own controls in the before vs after comparison, however one still may not be able to account for all confounders in this non-randomized study population. CONCLUSION: For patients with schizophrenia who initiate LAI antipsychotic therapy, there is an improvement in disease management based on fewer hospitalizations for relapses, which is also associated with a marked reduction in healthcare costs.

Healthcare resource usage of schizophrenia patients initiating long-acting injectable antipsychotics vs oral.

OBJECTIVE: To compare hospitalizations and incidence of relapses among patients with schizophrenia initiating long-acting injectable (LAI) antipsychotics vs oral antipsychotics. METHODS: Patients with schizophrenia initiating LAI antipsychotics or oral antipsychotics (index events) were identified from large databases (MarketScan; Truven Health Analytics, CA), containing commercial and Medicare healthcare claims and their pre-index (12-month baseline period) and post-index (12-month follow-up period) hospitalizations and relapse rates were compared. Descriptive and bivariate statistics were utilized to compare demographics, clinical characteristics, and hospital resource usage among cohorts. Multivariate analysis was used to evaluate the impact of initiating LAI vs oral antipsychotics on differences in the number of hospitalizations and length of stay (LOS) between follow-up and baseline periods. RESULTS: Commercially insured patients initiating LAI antipsychotics (n = 394) had significant reductions in inpatient healthcare usage after initiating antipsychotic therapy: mean number (±standard deviation) of all cause hospitalizations (1.60 ± 1.66 vs 0.70 ± 1.20, p < 0.001), LOS (16.9 ± 20.7 vs 6.6 ± 14.4 days, p < 0.001), schizophrenia-related hospitalizations (1.03 ± 1.26 vs 0.43 ± 0.86, p < 0.001), associated LOS (12.3 ± 17.7 vs 4.8 ± 12.8 days, p < 0.001). Patients initiating LAI vs oral antipsychotics (n = 2610) had significantly greater reductions during the follow-up period vs baseline period in the mean number of all cause hospitalizations (-0.90 ± 1.77 vs 0.02 ± 1.49, p < 0.001), LOS (-10.3 ± 23.2 vs 0.7 ± 16.7 days, p < 0.001), schizophrenia-related hospitalizations (-0.60 ± 1.37 vs 0.05 ± 0.99, p < 0.001) and associated LOS (-7.5 ± 20.7 vs 0.6 ± 12.5 days, p < 0.001). These results were further supported by multivariate analyses in which patient characteristics were taken into consideration. LIMITATIONS: This study attempted to minimize the impact of differences in patient characteristics by having patients serve as their own controls in the before vs after comparison followed by multivariate regressions, however one still may not be able to account for all confounders in this non-randomized study population. CONCLUSION: Patients with schizophrenia who initiated LAI vs oral antipsychotics experienced reductions in hospitalizations and schizophrenia relapses after drug initiation, which may be indicative of improved disease management.