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.

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.

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.