Longitudinal study of inflammation and relapse in schizophrenia.

INTRODUCTION: The clinical course of schizophrenia is often characterized by recurrent relapses. Blood inflammatory markers are altered in acute psychosis, and may be state markers for illness relapse in schizophrenia. Few studies have investigated longitudinal, intra-individual changes in inflammatory markers as a predictor of relapse. In the present study, we explored this association in a relapse prevention trial in patients with schizophrenia. METHODS: We analyzed blood inflammatory markers in 200 subjects, with a mean 11 samples per subject, during the 30 month Preventing Relapse in schizophrenia: Oral Antipsychotics Compared to Injectable: eValuating Efficacy (PROACTIVE) trial. Associations between longitudinal changes in inflammatory markers and relapse were analyzed using a within-subjects design. RESULTS: 70 (35 %) of subjects relapsed during the study period. There were no significant differences in mean inflammatory marker levels based on relapse status (yes/no). Baseline levels of inflammatory markers did not predict incident relapse. Among subjects who relapsed, there was a significant decrease in mean blood IL-6 (n = 38, p = 0.019) and IFN-γ (n = 44, p = 0.012) levels from the visit before the relapse to the visit after relapse. CONCLUSION: Although there was some evidence for inflammation as a potential state marker for acute psychosis, we did not find significant evidence for its utility as a relapse-predictive marker.

Sublingual Dexmedetomidine for the Treatment of Acute Agitation in Adults With Schizophrenia or Schizoaffective Disorder: A Randomized Placebo-Controlled Trial.

Objective: Determine if sublingual dexmedetomidine, a selective α2 adrenergic receptor agonist, reduces symptoms of acute agitation associated with schizophrenia or schizoaffective disorder.Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults diagnosed with schizophrenia or schizoaffective disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The study was conducted at 15 US sites between January 23, 2020, and May 8, 2020. Participants were randomized to sublingual dexmedetomidine 180 µg, 120 µg, or matching placebo. The primary efficacy endpoint was mean change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC) total score at 2 hours postdose.Results: Altogether, 380 participants (mean age 45.6 years, 63.4% identifying as male, 77.9% identifying as Black or African American) were randomized; 380 (100%) self-administered study medication, and 372 (97.9%) completed the study. The mean PEC total score at baseline (17.6) indicated mild to moderate agitation. At 2 hours postdose, the least squares mean changes (SE) from baseline were -10.3 (0.4) for sublingual dexmedetomidine 180 µg, -8.5 (0.4) for 120 µg, and -4.8 (0.4) for placebo. Least squares mean differences (97.5% confidence intervals) in the sublingual dexmedetomidine groups were -5.5 (-6.7 to -4.3) for 180 µg and -3.7 (-4.9 to -2.5) for 120 µg (both P < .001 vs placebo). The most commonly encountered adverse events with dexmedetomidine (incidence ≥ 5% and ≥ 2× rate observed with placebo) were somnolence, dry mouth, and hypotension for the 120 µg dose, and somnolence, dizziness, orthostatic hypotension, and oral hypoesthesia for the 180 µg dose.Conclusions: Treatment with sublingual dexmedetomidine 180 µg or 120 µg was more efficacious than placebo in reducing acute agitation associated with schizophrenia as measured by PEC scores at 2 hours postdose.Trial Registration: ClinicalTrials.gov identifier: NCT04268303.

Real-World Outcomes and Costs Following 6 Months of Treatment with the Long-Acting Injectable (LAI) Aripiprazole Lauroxil for the Treatment of Schizophrenia.

BACKGROUND: Continuous antipsychotic therapy is recommended as part of long-term maintenance treatment of schizophrenia, and gaps in antipsychotic treatment have been associated with increased risks of relapse and rehospitalization. Because the use of long-acting injectable (LAI) antipsychotics may reduce the likelihood of undetected medication gaps, initiating an LAI medication may affect resource utilization and costs. The LAI aripiprazole lauroxil (AL) was approved in the United States (US) in 2015 for the treatment of schizophrenia in adults. OBJECTIVE: The objective of this retrospective observational cohort study was to examine treatment patterns, resource utilization, and costs following initiation of AL for the treatment of schizophrenia in adults. METHODS: A retrospective analysis of Medicaid claims data identified a cohort of patients (N = 485) starting AL shortly after Food and Drug Administration approval in October 2015. Treatment patterns, resource utilization, and costs were compared 6 months before and after treatment initiation. Subgroup analyses were conducted based on the type of antipsychotic (LAI, oral, or none) received before initiation of AL. RESULTS: Over 6 months of follow-up, patients received an average of 4.6 injections out of a maximum of six (77%). After initiating AL, all-cause inpatient admissions decreased by 22.4%; other significant reductions were observed in mental health-related admissions and emergency room (ER) visits. All-cause inpatient costs decreased by an average of US$2836 per patient (p < 0.05) in the 6-month post-AL period, whereas outpatient pharmacy costs increased by US$4121 (p < 0.05), resulting in no significant difference in overall costs between the pre- and post-AL periods. The subgroup of patients who had been prescribed an oral antipsychotic before starting AL had significant reductions in proportion of patients with inpatient and ER visits and costs, but also reported a significant increase in pharmacy costs. CONCLUSIONS: AL was associated with a significant reduction in inpatient costs and an increase in outpatient pharmacy costs, resulting in no changes in total healthcare costs over 6 months. The adherence rate and reductions in inpatient use may indicate the potential for greater clinical stability among patients initiated on AL compared with their previous treatment.

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level: A Mega-analysis of Individual Participant-Level Data.

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection: In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose. Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

Beyond 52-Week Long-Term Safety: Long-Term Outcomes of Aripiprazole Lauroxil for Patients With Schizophrenia Continuing in an Extension Study.

OBJECTIVE: To describe the long-term safety, tolerability, and symptom trajectory with the long-acting injectable antipsychotic aripiprazole lauroxil (AL) in patients with DSM-5-diagnosed schizophrenia followed for up to 180 weeks (3.5 years). METHODS: Long-term safety of 2 fixed doses of AL (441 or 882 mg every 4 weeks) was assessed during up to 180 weeks (3.5 years) of continuous AL exposure using data from 2 sequential long-term safety studies. Safety metrics included adverse events (AEs), AEs leading to study discontinuations, physical examinations, laboratory parameters, and extrapyramidal symptom (EPS) rating scales. Symptom trajectory was assessed in post hoc analyses using Positive and Negative Syndrome Scale total (PANSST) and Clinical Global Impressions-Severity of Illness scale (CGI-S) scores. RESULTS: A total of 478 patients entered the 52-week study and were included in the safety analysis. After the first 52 weeks, safety assessments revealed no new safety concerns and were consistent with the known safety profile of aripiprazole. AEs were reported by 57.5% of patients (441 mg, 52.7%; 882 mg, 59.0%). EPS-related AEs occurred in 12.8% of patients (441 mg, 9.1%; 882 mg, 13.9%). In the post hoc analysis (n = 432), least-squares mean (SE) PANSST scores improved significantly from weeks 12 to 124 with AL 441 mg (-5.5 [0.9]) and 882 mg (-5.0 [0.5]; both P < .0001). CGI-S scores followed a similar pattern of improvement. CONCLUSIONS: The AL safety profile over 180 weeks (3.5 years) of follow-up was consistent with prior 52-week results. Continued therapeutic efficacy, based on PANSST and CGI-S scores, was observed throughout the post hoc analysis period. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01626456; ClinicalTrials.gov identifier: NCT01895452.

Using Long-Acting Injectable Antipsychotics to Enhance the Potential for Recovery in Schizophrenia.

The goals of schizophrenia treatment are to control symptoms, prevent relapse, and improve functioning and quality of life. For many patients, these goals are not being met. This report highlights information provided by experts on the reasons for, impact of, and means to reduce relapse in patients with schizophrenia; on patient-centered and patient-reported assessment; on the benefits and risks of medication options, including long-acting injectable (LAI) antipsychotics; and on psychosocial interventions that may improve adherence and help prevent relapse in individuals living with schizophrenia. Modifiable risk factors for poor outcomes in patients with schizophrenia include longer duration of untreated illness, comorbid substance abuse, early nonresponse to an antipsychotic, and the number of relapses that are related to nonadherence. Recommendations include 1) adopting a patient-centered approach that incorporates the use of patient-reported outcome measures; 2) selecting medications based on a balanced risk-benefit assessment, including a focus on addressing symptoms for which the agents were superior to placebo and/or active controls; 3) considering LAIs as an alternative to oral medications, as they offer benefits such as reliable drug delivery, uncovering nonadherence and pseudo-resistance, and reduced relapse risk and mortality; and 4) implementing psychosocial interventions that have been proven to be effective in improving adherence and overall outcomes.

Patient-Centered Psychopharmacology and Psychosocial Interventions: Treatment Selection and Shared Decision-Making to Enhance Chances for Recovery.

Individuals with schizophrenia can achieve the ultimate goal of treatment-recovery. However, patients are often nonadherent to prescribed medication regimens, leading to relapses and significantly decreasing their chances of ever reaching this goal. By implementing patient-centered assessment and evidence-based pharmacologic and psychosocial interventions, such as LAI antipsychotics, cognitive-behavioral therapy, and motivational interviewing, clinicians can improve medication adherence and enhance the potential for functional recovery.

Prevalence and Impact of Relapse in Patients With Schizophrenia.

Many individuals with schizophrenia experience multiple relapses, which are associated with serious and potentially fatal outcomes. Nonadherence to antipsychotic medications is a major contributor to relapse. By using reliable strategies to measure adherence and identify patients who are not taking their medications as prescribed, clinicians can intervene to possibly prevent relapse or decrease its severity.

Managing Transitions in Care and Adherence to Improve Outcomes in Schizophrenia.

With effective, continuous care, individuals with schizophrenia can experience long periods of wellness, but, unfortunately, many patients end up repeating a cycle of treatment interruptions leading to relapses. In this webcast, Dr John Lauriello and Dr Diana Perkins explore all dimensions of this topic, from the many causes of treatment interruptions to the steps clinicians can take to prevent them. Interviews with actual patients and caregivers are also presented.

Enhancing the Treatment of Patients With Schizophrenia Through Continuous Care.

Schizophrenia is a chronic disorder that can be effectively controlled but will likely require lifelong treatment. Unfortunately, most patients experience numerous relapses, ongoing symptoms, and impairment, often because of treatment interruptions. Continuous treatment is imperative to prevent relapse and the potentially devastating consequences that can follow a return of psychotic symptoms. Clinicians must better monitor a common cause of relapse, nonadherence, and offer strategies to improve adherence. Strategies can target the patient, the environment, or treatment. One treatment-related strategy is the use of long-acting injectable (LAI) antipsychotics, which have the potential to reduce relapse and rehospitalization for many patients with schizophrenia.

Psychosis.

PURPOSE OF REVIEW: Psychosis is a psychiatric condition that has significant overlap with neurologic disease. This article is intended to educate the neurologist on the psychiatric manifestations of psychosis and its evaluation, diagnosis, and treatment. How to differentiate a primary psychiatric cause of psychosis from psychosis secondary to a medical or neurologic condition is also reviewed. RECENT FINDINGS: Current research in psychotic disorders has focused increasingly on negative symptoms and cognitive impairment in psychotic illness, as it is now recognized that these cause the greatest impact on functional deficits for patients. A number of new medications have also been introduced to target negative symptoms and cognitive deficits in psychotic illness. These have new implications in terms of treatment overlap with medications being prescribed by providers in psychiatry, neurology, and general practice. SUMMARY: This article discusses the current methods for evaluating, diagnosing, and treating psychosis. Psychosis as a primary mental health disorder is a diagnosis of exclusion, as psychosis can be a direct symptom of underlying medical or neurologic disease. Delirium and dementia are the two most important disorders to rule out. This article will help readers be more prepared to assess and treat the patient with psychosis.

Long-Acting Injectable Antipsychotics: Where Do They Fit in the Treatment Plan?

Long-acting injectable (LAI) antipsychotics have the potential to improve adherence and outcomes for patients with serious mental illness but are underused. Watch this Webcast to learn how to identify patients who may benefit from using LAIs, monitor treatment adherence, and use LAIs safely and effectively in patients with schizophrenia and related disorders.

Aripiprazole Long-Acting Injectable for Maintenance Treatment of Bipolar I Disorder in Adults.

Bipolar I disorder is a serious and disabling psychiatric illness. It is associated with a significant reduction in quality of life and an increased risk for suicide. Pharmacotherapy is essential for both the acute and maintenance treatment of bi-polar I disorder. While multiple oral medications are recommended for the maintenance treatment, there are not many long-acting injectable medications approved for this indication. New treatments that would improve patient adherence have the potential for decreasing relapses and improving patients' ability to remain functional members of society. In this paper we discuss the available data for safety and efficacy of aripiprazole long-acting injectable in bipolar disorder.

Predicting relapse in schizophrenia: Is BDNF a plausible biological marker?

Understanding the biological processes that underlie why patients relapse is an issue of fundamental importance to the detection and prevention of relapse in schizophrenia. Brain Derived Neurotrophic Factor (BDNF), a facilitator of brain plasticity, is reduced in patients with schizophrenia. In the present study, we examined whether decreases in plasma BDNF levels could be used as a biological predictor of relapse in schizophrenia. A total of 221 patients were prospectively evaluated for relapse over 30months in the Preventing Relapse in Schizophrenia: Oral Antipsychotics Compared to Injectables: eValuating Efficacy (PROACTIVE) study. Serial blood samples were collected at a maximum of 23 time points during the 30-month trial and BDNF levels were measured in plasma samples by ELISA. Receiver Operating Characteristic (ROC) curve analysis indicated that BDNF was not a significant predictor of relapse, hospitalization or exacerbation. Regardless of treatment group (oral second generation antipsychotic vs. long-acting injectable risperidone microspheres), baseline BDNF value did not differ significantly between those who experienced any of the adverse outcomes and those who did not. While contrary to the study hypothesis, these robust results offer little support for the use of plasma BDNF alone as a biomarker to predict relapse in schizophrenia.

Combination Antipsychotic Therapies: An Analysis From a Longitudinal Pragmatic Trial.

BACKGROUND: Combination antipsychotics (CAs) are prescribed in schizophrenia despite limited evidence of efficacy. To explore the effect of switching from CA to monotherapy, we performed an exploratory analysis of the PROACTIVE (Preventing Relapse in Schizophrenia: Oral Antipsychotics Compared with Injectables: Evaluating Efficacy) study data, in which 305 patients with schizophrenia and schizoaffective disorder were followed for 30 months after randomization to long-acting injectable (LAI) risperidone or second-generation oral antipsychotic (OA). METHODS: Patients who entered the PROACTIVE study on CA (n = 50), LAI (n = 20), or OA (n = 206) were compared in terms of time to relapse and clinical measures. FINDINGS: The OA group had significantly fewer hospitalizations than the CA group (P = 0.009) at baseline. In the CA group, 68% patients relapsed versus 53% in the LAI, and 52% in the OA groups. Although there was no significant difference in the relapse rate among groups on χ test (χ = 3.85, P = 0.146), the log-rank test showed a significant difference among the groups in time to first relapse (χ = 6.81, P = 0.033), with significantly longer time to relapse in the OA group (mean, 562.8 days) than in the CA group (mean, 409.5; P = 0.011). The LAI group's mean time to first relapse (594 days) was not significantly different from the other groups. However, after adjusting for number of hospitalizations, group was no longer significant (hazard ratio, 1.541; P = 0.052). IMPLICATIONS: Based on our exploratory analysis, taking antipsychotic combinations predicts earlier relapse and calls for additional treatment guidance in schizophrenia.

The Use of Long-Acting Injectable Antipsychotics in Schizophrenia: Evaluating the Evidence.

Long-acting injectable antipsychotics (LAIs) are among the most effective treatments in psychiatry, yet they remain underutilized in clinical practice. Although LAIs are typically used to maintain treatment adherence in patients with chronic schizophrenia, recent research has suggested that they may also provide an effective treatment strategy for patients with early-phase or first-episode disease. In October 2015, a group of 8 experts on the management of schizophrenia and LAIs met to evaluate the evidence surrounding the efficacy, safety, and cost-effectiveness of LAIs and to develop practical recommendations regarding the clinical use, education, and unmet needs related to LAIs. Participants were also asked to rate the importance of several patient characteristics when choosing an LAI versus an oral antipsychotic, from the perspectives of 4 different stakeholder groups: patients, health care professionals, families, and payers. The evidence review demonstrated that LAIs are superior to placebo for acute and maintenance treatment of schizophrenia and, in general, appear to be similar to one another in terms of schizophrenia relapse prevention. Study design impacts the demonstrated efficacy of LAIs versus oral antipsychotics, but recent database and randomized controlled studies favor the use of LAIs in early-phase schizophrenia patients. LAIs vary considerably in their propensity to cause certain adverse effects, including weight gain, metabolic effects, extrapyramidal symptoms, and prolactin elevation, and these differences can be used to help guide LAI selection. Some studies, but not all, have demonstrated significant reductions in health care utilization or overall costs with LAIs. The expert panel identified several barriers to LAI use in current practice, including clinician lack of knowledge, negative attitudes about LAIs, and resource and cost issues. The participants also identified a number of additional factors that should be considered when weighing the use of LAI therapy, including medication adherence, relapse risk and severity, cognitive impairment, ease of use, substance misuse, access and cost, stigma, social support, patient autonomy, control over medication dosing, fear of needles, and the potential for patient harm due to relapses and associated loss of functioning. This evidence review, discussion, and summary recommendations may help clinicians, patients, families, payers, and other stakeholders to better characterize the role of LAIs in the treatment of schizophrenia.

Comparison of Injectable and Oral Antipsychotics in Relapse Rates in a Pragmatic 30-Month Schizophrenia Relapse Prevention Study.

OBJECTIVE: In a pragmatic clinical trial, this study sought to compare relapses among patients receiving either long-acting injectable or oral second-generation antipsychotics. METHODS: PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy), a prior 30-month relapse prevention study, compared use of a long-acting injectable second-generation antipsychotic with use of an oral second-generation antipsychotic by 305 patients with schizophrenia or schizoaffective disorder and found similar rates of first relapse between groups (42% with injectable medication, 32% with oral medication). This study examined subsequent relapses among patients who had relapsed in PROACTIVE and who continued in treatment, follow-up, or both. RESULTS: Thirty-two patients (11%) experienced two relapses, and 13 patients (4%) had three relapses. Neither rate of relapse nor time to successive relapses differed between treatment groups. CONCLUSIONS: There was an impressively low rate of subsequent relapses in this pragmatic clinical trial. Because all patients had a clinic visit according to the biweekly long-acting injectable medication administration schedule, frequent contact may have contributed to low relapse rates. Maintaining frequent clinical contact may be a valid psychosocial relapse prevention treatment.