Publications by authors named "Joseph P McEvoy"

133 Publications

Controversies Surrounding the Use of Long-Acting Injectable Antipsychotic Medications for the Treatment of Patients with Schizophrenia.

CNS Drugs 2021 Oct 11. Epub 2021 Oct 11.

Fondation FondaMental, Créteil, France.

Schizophrenia is a serious mental illness that requires continuous and effective long-term management to reduce symptoms, improve quality of life, and prevent relapse. Oral antipsychotic medications have proven efficacy for many patients taking these medications; however, a considerable number of patients continue to experience ongoing symptoms and relapse, often due to lack of adherence. The advent of long-acting injectable (LAI) formulations of antipsychotic medications provided an opportunity to improve treatment adherence and overall patient outcomes. Despite data to support LAI efficacy, safety, and improved adherence over oral formulations, there are several misconceptions about and barriers to LAI implementation within a standard of care for patients with schizophrenia. Areas of resistance around LAIs include (1) doubts regarding their benefits outside of improved adherence, (2) questions regarding their prescribing to a broader population of patients with schizophrenia, (3) when to initiate LAIs, (4) concerns regarding the safety of LAIs in comparison with oral medication, and (5) the most effective ways to educate healthcare providers, patients, and caretakers to enable appropriate LAI consideration and acceptance. Here, we discuss these key controversies associated with LAIs and provide supportive evidence to facilitate LAI use in a manner that is constructive to the clinician-patient relationship and successful treatment.
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http://dx.doi.org/10.1007/s40263-021-00861-6DOI Listing
October 2021

Insomnia and inflammation in phase 1 of the clinical antipsychotic trials of intervention effectiveness study.

Psychiatry Res 2021 Aug 29;305:114195. Epub 2021 Aug 29.

Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA, United States.

Insomnia and inflammation are both common in schizophrenia. In the general population, insomnia is associated with inflammation. In n=519 subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, terminal insomnia was investigated as an indicator of inflammation using non-parametric ANCOVA. After controlling for potential confounders, insomnia was significantly associated with higher blood IL-6 (F=4.12, p=0.007) and leptin (F=9.67, p<0.001) with large effect sizes (d=1.03 and d=0.79, respectively). Findings suggest that the assessment of insomnia is relevant to studies of inflammation in schizophrenia, and germane to trials of adjunctive hypnotics and anti-inflammatory agents in these patients.
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http://dx.doi.org/10.1016/j.psychres.2021.114195DOI Listing
August 2021

Insomnia and inflammation in phase 1 of the clinical antipsychotic trials of intervention effectiveness study.

Psychiatry Res 2021 Aug 29;305:114195. Epub 2021 Aug 29.

Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA, United States.

Insomnia and inflammation are both common in schizophrenia. In the general population, insomnia is associated with inflammation. In n=519 subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, terminal insomnia was investigated as an indicator of inflammation using non-parametric ANCOVA. After controlling for potential confounders, insomnia was significantly associated with higher blood IL-6 (F=4.12, p=0.007) and leptin (F=9.67, p<0.001) with large effect sizes (d=1.03 and d=0.79, respectively). Findings suggest that the assessment of insomnia is relevant to studies of inflammation in schizophrenia, and germane to trials of adjunctive hypnotics and anti-inflammatory agents in these patients.
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http://dx.doi.org/10.1016/j.psychres.2021.114195DOI Listing
August 2021

Monitoring for myocarditis during treatment initiation with clozapine.

Acta Psychiatr Scand 2021 08 3;144(2):194-200. Epub 2021 Jun 3.

Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Objective: Clozapine use is associated with myocarditis. In this study, we investigated what clinical signs and symptoms, and/or laboratory test(s), alert clinicians to presumptive myocarditis (PrMy) most accurately and at the earliest time point. We also investigated the incidence of PrMy during the initial exposure to clozapine versus in patients restarted on clozapine after extended interruption of prior prolonged treatment.

Methods: 100 patients admitted to state psychiatric hospital started on clozapine were recruited into the study. 76 patients were treated with clozapine for the first time and 24 patients were restarts. Creatine kinase (CK), troponin I (TROP), eosinophil count (EOS), and C-reactive protein (CRP) were obtained at baseline and weeks 1, 2, 3, and 4. Descriptive statistics were calculated for demographic and clinical variables. Student's t test and chi-squared test were used to compare means and proportions between initial exposure and restart groups.

Results: Clinical features and laboratory tests suggestive of PrMy were seen in 4 patients (5.3%) in initial exposure group and none in restart group. 3.5% of TROP levels were abnormal in initial exposure group and no abnormal levels were found in the restart group. 30% and 46% of CK, 23% and 39% of CRP, and 14% and 23% of EOS were abnormal in initial exposure group and restart groups, respectively.

Conclusions: PrMy was common (5.3%) during clozapine initiation. Prospective management through serial laboratory monitoring with weekly TROP levels was sensitive enough to allow for timely clozapine discontinuation.
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http://dx.doi.org/10.1111/acps.13328DOI Listing
August 2021

How to Evaluate Patients and Educate Them About Self-Examinations for Tardive Dyskinesia Between Appointments.

J Clin Psychiatry 2021 03 9;82(1). Epub 2021 Mar 9.

Dauten Family Center for Bipolar Treatment Innovation and the Depression Clinical and Research Program, Massachusetts General Hospital, and Department of Psychiatry, Harvard Medical School, Boston.

Patients taking dopamine-blocking agents such as antipsychotics are at risk for developing tardive dyskinesia. In this webcast, Drs McEvoy and Nierenberg discuss symptoms of tardive dyskinesia, how to observe patients (whether in person or via telemedicine), and how to educate patients and families about TD.
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http://dx.doi.org/10.4088/JCP.NU19047WC6CDOI Listing
March 2021

Long-term effect of aripiprazole lauroxil on health-related quality of life in patients with schizophrenia.

BMC Psychiatry 2021 03 24;21(1):164. Epub 2021 Mar 24.

Alkermes, Inc., Waltham, MA, USA.

Background: This post hoc analysis of clinical trial data evaluated long-term, self-reported mental and physical health-related quality of life (HRQoL) scores in schizophrenia patients receiving aripiprazole lauroxil (AL), an atypical long-acting injectable (LAI) antipsychotic approved for the treatment of schizophrenia in adults.

Methods: The study population included 291 stable schizophrenia outpatients enrolled in 2 consecutive long-term safety studies of AL given every 4 weeks for up to 124 weeks. HRQoL was measured using the SF-36v2® Health Survey (SF-36v2) over the course of the follow-up. The primary outcome was change in SF-36v2 mental component summary (MCS) and physical component summary (PCS) scores from baseline to 124 weeks. To contextualize these scores, descriptive analyses were conducted to compare the scores with available scores for the general population as well as for other populations with chronic medical (ie, hypertension and type 2 diabetes) or psychiatric (ie, depression) conditions.

Results: Results from this post hoc analysis indicated that the mean MCS score for patients continuing AL improved significantly from baseline over 124 weeks (P < .05, all timepoints), while mean PCS score showed little change over 124 weeks. At baseline, patients had lower (worse) MCS scores than the normed general population, but by week 124, patients had MCS scores comparable to those in the general population. This pattern of change was not observed with PCS scores. Comparison of study MCS scores with those associated with other diseases showed that this schizophrenia cohort had lower scores than those with chronic medical conditions but higher scores than those with depression. PCS scores were higher in the study population than published scores for all reference populations at baseline and week 124.

Conclusions: In this post hoc analysis, outpatients with schizophrenia who continued the LAI antipsychotic AL showed gradual and sustained improvement in self-reported mental HRQoL over several years of follow-up, whereas self-reported physical HRQoL did not change. By the end of follow-up, mental health scores of study patients with schizophrenia were comparable to those of the general population and better than those of patients with depression.

Trial Registration: ClinicalTrials.gov (NCT01626456 [trial registration date: June 15, 2012] and NCT01895452 [trial registration date: July 5, 2013]).
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http://dx.doi.org/10.1186/s12888-021-03124-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992347PMC
March 2021

Longitudinal study of inflammatory markers and psychopathology in schizophrenia.

Schizophr Res 2020 10 22;224:58-66. Epub 2020 Oct 22.

Department of Psychiatry, Augusta University, Augusta, GA, United States. Electronic address:

Objective: Schizophrenia is associated with abnormal levels of blood inflammatory markers, which may be correlated with levels of psychopathology. Few previous studies have explored whether baseline inflammatory marker levels predict longitudinal changes in psychopathology. In the present study, we explored this association in a cohort of patients with schizophrenia.

Method: We investigated inflammatory markers and psychopathology after 3, 6, and 12 months of antipsychotic treatment for subjects with baseline and follow-up data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. Linear regression models, controlling for multiple potential confounding factors, were used to investigate these associations.

Results: There was a significant decrease in monocyte, ICAM, and adiponectin levels between baseline and 12 months. Higher baseline blood interleukin-6 (IL-6) predicted greater reduction in PANSS total and general subscale scores at 3 and 6 months, and PANSS negative subscale scores at 3 months (β = -0.10 to -0.16, p < 0.05 for each). Higher baseline blood leptin levels predicted greater reduction in PANSS total, negative and general subscale scores at 6 months (β = -0.09 to -0.11, p < 0.05 for each). In post-hoc analyses, associations between baseline IL-6 levels and symptom reduction were strongest in patients treated with either ziprasidone or quetiapine. Changes in blood inflammatory markers were generally not associated with changes in psychopathology.

Conclusions: Our findings provide additional support that measuring blood inflammatory markers may be relevant to the clinical care of patients with schizophrenia. Specifically, these markers may help guide selection of antipsychotic treatment towards more personalized medicine approaches for patients with schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2020.10.003DOI Listing
October 2020

How to Assess Tardive Dyskinesia Symptom Improvement With Measurement-Based Care.

Authors:
Joseph P McEvoy

J Clin Psychiatry 2020 11 3;81(6). Epub 2020 Nov 3.

Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Georgia

​​​​​​ Clinicians now have 2 effective and well-tolerated vesicular monoamine transporter 2 (VMAT2) inhibitors-valbenazine and deutetrabenazine-for the treatment of patients with tardive dyskinesia (TD), a severe and potentially irreversible side effect associated with dopamine receptor blocking agents. Clinicians should use measurement-based care, eg, the Abnormal Involuntary Movement Scale with activation maneuvers, to assess and document TD symptoms and treatment progress. Each follow-up visit should be personalized with questions related to patients' functioning and level of distress regarding their specific TD symptoms. Family members, if available, can provide information on symptom changes and assistance with medication adherence. With continued treatment and measurement-based care, patients can experience improvement in their TD symptoms.
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http://dx.doi.org/10.4088/JCP.NU19047BR4CDOI Listing
November 2020

Selecting Treatment for Patients With Tardive Dyskinesia Using Safety and Efficacy Evidence.

Authors:
Joseph P McEvoy

J Clin Psychiatry 2020 09 29;81(6). Epub 2020 Sep 29.

Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Georgia

​​ Tardive dyskinesia (TD) is a condition of potentially irreversible abnormal involuntary movements associated with dopamine receptor blocking agents, such as antipsychotics. While prevention is the best strategy, it is not always possible. This report outlines strategies to reduce TD symptoms, including the use of the FDA-approved treatment options (valbenazine and deutetrabenazine).
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http://dx.doi.org/10.4088/JCP.NU19047BR3CDOI Listing
September 2020

A single assessment with the Brief Adherence Rating Scale (BARS) discriminates responders to long-acting injectable antipsychotic treatment in patients with schizophrenia.

Schizophr Res 2020 06 5;220:92-97. Epub 2020 Apr 5.

Department of Psychiatry, University of Arizona and Southern Arizona VA Health Care System, Tucson, AZ 85723, USA.

Objective: To determine if a single baseline adherence assessment (Brief Adherence Rating Scale [BARS]) could identify patients who are likely to respond to long-acting injectable (LAI) antipsychotic treatment.

Method: The current secondary analysis included a sub-sample of adult outpatients (N = 176) with schizophrenia or schizoaffective disorder who participated in the "A Comparison of Long-Acting Injectable Medications for Schizophrenia (ACLAIMS)" trial and had a baseline BARS assessment and a baseline and month 3 Positive and Negative Syndrome Scale (PANSS) rating. The main outcome was LAI treatment response, defined as a ≥ 20% decrease (baseline to month 3) on the PANSS total score. Receiver Operating Characteristic (ROC) and Area Under the Curve (AUC) analysis was conducted to determine the optimal cutpoint of baseline BARS adherence in discriminating LAI treatment response at month 3. A logistic mixed model estimated the odds of response to LAI treatment at month 3 from the optimal baseline BARS cutpoint.

Results: The ROC analysis determined that the single baseline BARS rating (cutoff ≤66%), indicating low adherence, best discriminated patients likely to respond to LAI treatment (AUC = 0.603, SE = 0.046, 95% binomial exact CI = 0.527 to 0.676, p = 0.025), with 38% sensitivity and 85% specificity. The logistic mixed model analysis revealed that patients with ≤66% BARS adherence had 3.464 times the predicted odds (95% CI = 1.604 to 7.480, p = 0.001) of responding to LAI treatment than those who were >66% BARS adherent.

Conclusion: A single baseline BARS assessment discriminated response to LAI treatment suggesting it is a reasonable tool to identify candidates for LAI antipsychotic treatment.
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http://dx.doi.org/10.1016/j.schres.2020.03.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306424PMC
June 2020

A Modified Delphi Consensus Study of the Screening, Diagnosis, and Treatment of Tardive Dyskinesia.

J Clin Psychiatry 2020 Jan 28;81(2). Epub 2020 Jan 28.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA.

Objective: A nominal group process followed by a modified Delphi method was used to survey expert opinions on best practices for tardive dyskinesia (TD) screening, diagnosis, and treatment and to identify areas lacking in clinical evidence.

Participants: A steering committee of 11 TD experts met in nominal group format to prioritize questions to be addressed and identify core bibliographic materials and criteria for survey panelists. Of 60 invited experts, 29 (23 psychiatrists and 6 neurologists) agreed to participate.

Evidence: A targeted literature search of PubMed (search term: tardive dyskinesia) and recommendations of the steering committee were used to generate core bibliographic material. Inclusion criteria were as follows: (1) review articles, meta-analyses, guidelines, or clinical trials; (2) publication in English between 2007 and 2017; (3) > 3 pages in length; and (4) publication in key clinical journals with impact factors ≥ 2.0. Of 29 references that met these criteria, 18 achieved a score ≥ 5 (calculated as the number of steering committee votes multiplied by journal impact factor and number of citations divided by years since publication) and were included.

Consensus Process: Two survey rounds were conducted anonymously through electronic media from November 2017 to January 2018; responses were collected, collated, and analyzed. Respondent agreement was defined a priori as unanimous (100%), consensus (75%-99%), or majority (50%-74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥ 4 ("agree completely" or "agree"). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with < 25% agreement and > 75% agreement (unless feedback suggested further investigation).

Conclusions: Consensus was reached that (1) a brief, clinical assessment for TD should be performed at every clinical encounter in patients taking antipsychotics; (2) even mild movements in 1 body area may represent possible TD; (3) management requires an overall evaluation of treatment, including reassessment of antipsychotics and anticholinergics as well as consideration of vesicular monoamine transporter 2 (VMAT2) inhibitors; and (4) informed discussions with patients/caregivers are essential.
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http://dx.doi.org/10.4088/JCP.19cs12983DOI Listing
January 2020

Early Recognition and Treatment of Tardive Dyskinesia in Patients With Mood Disorders and Schizophrenia.

J Clin Psychiatry 2020 Jan 28;81(1). Epub 2020 Jan 28.

​​​​Early Recognition and Treatment of Tardive Dyskinesia in Patients With Mood Disorders and Schizophrenia Click to enlarge page​​.
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http://dx.doi.org/10.4088/JCP.NU18041AH5CDOI Listing
January 2020

FDA-Approved Medications to Treat Tardive Dyskinesia.

Authors:
Joseph P McEvoy

J Clin Psychiatry 2019 12 17;81(1). Epub 2019 Dec 17.

Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.

Tardive dyskinesia (TD), a condition characterized by involuntary movements, is found in patients taking antipsychotics or other agents that block dopamine receptors. Symptoms of TD are associated with reduced quality of life, psychosocial problems, and medication nonadherence. Few agents tested in the treatment of TD had sufficient data to support or refute their use, until recently. A review of new evidence was combined with the existing guideline to provide new treatment recommendations. This activity provides an overview of treatments for patients with TD, including valbenazine and deutetrabenazine, which both received FDA approval for the treatment of TD.
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http://dx.doi.org/10.4088/JCP.NU18041BR3CDOI Listing
December 2019

Psychosocial Implications of Tardive Dyskinesia in Patients With Mood Disorders Versus Schizophrenia.

Authors:
Joseph P McEvoy

J Clin Psychiatry 2019 12 3;80(6). Epub 2019 Dec 3.

Medical College of Georgia, Augusta, Georgia, USA.

Dopamine receptor blocking agents-including antipsychotics-can produce tardive dyskinesia (TD). First-generation antipsychotics were effective in treating schizophrenia and severe forms of bipolar disorder; however, they were associated with substantial extrapyramidal effects, especially at high doses. Second-generation antipsychotics are effective and produce fewer adverse movement effects; nevertheless, the risk for TD was not eliminated. Tardive dyskinesia can be distressing to patients with good insight into their illness and the movements, especially if they are working and in relationships, and should be treated to improve psychosocial outcomes. In patients with poor insight into their illness and lack of awareness of their TD symptoms, clinicians should treat TD if it causes severe impairment.
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http://dx.doi.org/10.4088/JCP.NU18041BR2CDOI Listing
December 2019

The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

Schizophr Res Cogn 2020 Mar 31;19:100161. Epub 2019 Oct 31.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, United States of America.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests.
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http://dx.doi.org/10.1016/j.scog.2019.100161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889798PMC
March 2020

Urinary tract infection, inflammation, and cognition in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness Study.

Ann Clin Psychiatry 2019 11;31(4):242-248

Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA USA. E-MAIL:

Background: Schizophrenia is associated with an increased prevalence of infections throughout the life span. Previous studies have found an association between urinary tract infection (UTI) and acute psychosis. We investigated the prevalence and correlates of UTI in a large cohort of patients with schizophrenia.

Methods: We estimated the prevalence of UTI at the baseline visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. We then investigated associations between UTI and inflammatory markers, psychopathology, and cognition, controlling for potential confounding factors.

Results: The prevalence of probable UTI at baseline in the CATIE trial was 1.2% (n = 13 of 1,061 participants). Compared with participants with a normal urinalysis (n = 387), after controlling for potential confounders, UTI was a significant predictor of greater impairments (approximately 1 standard deviation difference) in the cognition composite score (beta = -0.153, P = .002), and poorer working memory (beta = -0.190, P < .001). There were no differences in psychopathology scores between participants with probable UTI and those with a normal urinalysis.

Conclusions: Urinary tract infections in patients with schizophrenia may have an impact on cognition. Findings provide additional evidence regarding infectious disease comorbidity, which may be clinically relevant in the treatment of patients with schizophrenia.
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November 2019

A commentary on the efficacy of olanzapine for the treatment of schizophrenia: the past, present, and future.

Neuropsychiatr Dis Treat 2019 5;15:2559-2569. Epub 2019 Sep 5.

Alkermes, Inc., Waltham, MA, USA.

Olanzapine is a second-generation atypical antipsychotic with proven efficacy for the treatment of schizophrenia. Approved in 1996, olanzapine is one of the most studied antipsychotics, resulting in a considerable amount of clinical data across diverse patient populations. Despite the fact that olanzapine is associated with a known risk of metabolic side effects, including weight gain, many clinicians continue to prescribe olanzapine for the treatment of schizophrenia with the expectation of additional therapeutic antipsychotic efficacy relative to other first-line atypical antipsychotics. The goal of this narrative is to revisit the role of oral olanzapine in the management of patients with schizophrenia, including those with recently diagnosed schizophrenia ("first-episode"), those with an established schizophrenia diagnosis who experience acute exacerbations, those receiving long-term antipsychotic treatment as a maintenance intervention, and those with suboptimal response to antipsychotic treatment, including treatment resistance. Collectively, data from published literature support the favorable efficacy of olanzapine compared with other first- and second-generation antipsychotics, including lower rates of treatment discontinuation and clinically meaningful improvements in the symptoms of schizophrenia. The development of antipsychotic medications with the favorable efficacy of olanzapine, but with reduced weight gain, could address a major unmet need in the treatment of schizophrenia.
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http://dx.doi.org/10.2147/NDT.S209284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733343PMC
September 2019

Total and differential white blood cell counts, inflammatory markers, adipokines, and incident metabolic syndrome in phase 1 of the clinical antipsychotic trials of intervention effectiveness study.

Schizophr Res 2019 07 19;209:193-197. Epub 2019 May 19.

Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA, United States. Electronic address:

Objective: The metabolic syndrome is highly prevalent in patients with schizophrenia. We previously found that blood C-reactive protein (CRP), interleukin-6 (IL-6), and leptin levels were predictors of current metabolic syndrome in schizophrenia. In the present study, we investigated whether baseline levels of total and differential white blood cell (WBC) counts, inflammatory markers, and adipokines predicted incident metabolic syndrome in schizophrenia.

Method: For subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial who did not have metabolic syndrome at baseline (n = 726), WBC counts, inflammatory markers, and adipokines were investigated as predictors of incident metabolic syndrome over 12 months of antipsychotic treatment. Cox proportional hazards regression models, controlling for multiple potential confounding factors, were used to investigate these associations.

Results: 39% of subjects (n = 280) had incident metabolic syndrome over 12 months. After controlling for potential confounders, baseline blood IL-6 (HR = 1.12, 95% CI 1.01-1.24, p = 0.031) and leptin (HR = 1.12, 95% CI 1.01-1.24, p = 0.038) were significant predictors of incident metabolic syndrome, and there was a trend-level association with CRP (HR = 1.09, 95% CI 1.00-1.19, p = 0.059).

Conclusions: Our findings provide additional evidence that measurement of inflammatory markers and adipokines are germane to the clinical care of patients with schizophrenia. Specifically, these markers may identify-prior to treatment-patients with schizophrenia at heightened risk for incident adverse cardiometabolic effects of antipsychotics. Given the tremendous burden of cardiovascular disease morbidity and mortality in schizophrenia, vigilant screening for and treatment of metabolic risk factors in this patient population are warranted.
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http://dx.doi.org/10.1016/j.schres.2019.04.021DOI Listing
July 2019

Characterizing Treatment Effects of Valbenazine for Tardive Dyskinesia: Additional Results From the KINECT 3 Study.

J Clin Psychiatry 2018 12 18;80(1). Epub 2018 Dec 18.

Neurocrine Biosciences, Inc, San Diego, California, USA.

Background: In the KINECT 3 (NCT02274558; October 2014 to September 2015) study, valbenazine efficacy in tardive dyskinesia (TD) was demonstrated based on mean changes from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7). Data from this study were analyzed further to provide a more clinically meaningful interpretation of the primary AIMS results.

Methods: The study included adults who had a DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or any mood disorder and also met DSM-IV criteria for neuroleptic-induced TD. Study participants received 6 weeks of double-blind treatment with valbenazine (40 or 80 mg/d) or placebo. Post hoc AIMS analyses, based on available data, included Cohen d effect sizes, response analyses with odds ratios (ORs) and numbers needed to treat (NNTs), and shift analyses.

Results: At week 6 (N = 202), medium-to-high effect sizes were found for mean improvements in AIMS total score (40 mg/d, d = 0.52; 80 mg/d, d = 0.89). For AIMS total score responses of ≥ 10% to ≥ 70% improvement from baseline, statistical significance was found for valbenazine 80 mg/d versus placebo (P ≤ .01), with ORs (range, 3.0-10.3) and NNTs (range, 3-9) indicating clinical relevance. For response per AIMS item (score ≤ 1 at week 6), significant differences between valbenazine (both doses or 80 mg/d) and placebo were found in the lips, jaw, tongue, and upper extremities. In participants who had an AIMS item score ≥ 1 at baseline, the percentage with a ≥ 1-point improvement at week 6 (shift) was significantly higher with valbenazine (40 and/or 80 mg/d) versus placebo in all 7 body regions.

Conclusions: Consistent with primary published results for KINECT 3, these supplemental analyses indicate that participants treated with valbenazine (40 or 80 mg/d) had statistically significant and clinically relevant improvements in TD severity both overall and in specific body regions.

Trial Registration: ClinicalTrials.gov identifier: NCT02274558.
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http://dx.doi.org/10.4088/JCP.18m12278DOI Listing
December 2018

Heterogeneity of Treatment Effects of Long-Acting Injectable Antipsychotic Medications.

J Clin Psychiatry 2018 11 27;80(1). Epub 2018 Nov 27.

Department of Psychiatry and Health Behaviors, Augusta University Health, Augusta, Georgia, USA.

Objective: To investigate subgroup responses to long-acting injectable (LAI) medications haloperidol decanoate (HD) and paliperidone palmitate (PP) in a randomized controlled trial that found no difference between the treatments on the primary outcome of efficacy failure.

Methods: A Comparison of Long-Acting Injectable Medications for Schizophrenia (ACLAIMS) enrolled 311 participants from March 2011 to July 2013 meeting DSM-IV-TR criteria for diagnoses of schizophrenia or schizoaffective disorder at risk of relapse due to medication nonadherence or substance abuse. Participants were randomly assigned to double-blinded treatment with HD or PP and followed for up to 2 years. A committee blinded to treatment assignment adjudicated efficacy failure on the basis of participants' meeting at least 1 of these criteria: psychiatric hospitalization, crisis stabilization, increased outpatient visits, could not discontinue oral antipsychotic, discontinued assigned LAI due to inadequate therapeutic benefit, or ongoing or repeated need for adjunctive oral antipsychotic medication. Survival analyses examined modification of treatment effects on efficacy failure by age, sex, race, substance abuse, baseline symptom severity, and baseline adherence. Mixed-effect linear models and analysis of covariance examined this modification on safety outcomes.

Results: An interaction between age and treatment (P = .009) revealed younger participants assigned HD had longer time to efficacy failure than those assigned PP. Interactions were not significant between treatment group and sex, race, substance use disorder, baseline symptom severity, or baseline adherence. An interaction of treatment and age on akathisia (P = .047) found an advantage for PP that was larger among younger persons. An advantage for HD on serum prolactin levels was larger among younger women (P = .033).

Conclusions: Among younger persons, HD was associated with lower rates of efficacy failure than PP. Age effects on adverse effects were mixed. Age-related heterogeneity of antipsychotic treatment effects warrants further investigation and consideration in clinical practice.

Trial Registration: ClinicalTrials.gov identifier: NCT01136772.
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http://dx.doi.org/10.4088/JCP.18m12109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296243PMC
November 2018

Adjunct Aripiprazole Reduces Prolactin and Prolactin-Related Adverse Effects in Premenopausal Women With Psychosis: Results From the DAAMSEL Clinical Trial.

J Clin Psychopharmacol 2018 Aug;38(4):317-326

Department of Psychiatry, Georgia Regents University, Augusta, GA.

Purpose/background: Prolactin-related adverse effects contribute to nonadherence and adverse health consequences, particularly in women with severe mental illness. Treating these adverse effects may improve treatment acceptability, adherence, and long-term outcomes.

Methods/procedures: Premenopausal women with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were recruited for a randomized, double-blind, placebo-controlled 16-week trial of adjunct aripiprazole (5-15 mg/d). Participants had elevated prolactin (>24 ng/mL) and were experiencing galactorrhea, amenorrhea, oligomenorrhea, or sexual dysfunction on a prolactin-elevating antipsychotic. Participants were evaluated biweekly for prolactin elevation and galactorrhea and completed a menstrual diary review. Psychiatric symptoms and adverse effects were closely monitored.

Findings/results: Forty-six women were randomized (n = 25 aripiprazole, n = 21 placebo). Thirty-seven completed at least 8 weeks of the study (n = 20 [80%] aripiprazole and n = 17 [81%] placebo). Aripiprazole (mean dose, 11.7 ± 2.4 mg/d) was effective for lowering prolactin relative to placebo (P = 0.04). In addition, 45% (9/20) of the aripiprazole group had a normalized prolactin (<24 mg/mL) compared with 12% (2/17) of the placebo group (P = 0.028). Galactorrhea resolved in 77% (10/13) of the aripiprazole-treated participants compared with 33% (4/12) in the placebo group (P = 0.028). Normalization of sexual function (<16 on the Arizona Sexual Experience Scale) occurred in 50% on aripiprazole (7/14) versus 9% (1/11) on placebo (P = 0.030). No differences between groups in symptoms or adverse effects were noted. Overall, women rated a mean score of 4.6 ± 0.6 on a 5-point Likert scale for sexual function improvement, suggesting their particular satisfaction with improvement in this domain.

Implications/conclusions: Building upon prior studies, this rigorous evaluation confirms the utility of adjunctive aripiprazole as a strategy for improving prolactin and managing prolactin-related adverse effects in premenopausal women with psychosis.
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http://dx.doi.org/10.1097/JCP.0000000000000898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103648PMC
August 2018

What You Should Know About Tardive Dyskinesia: Screening, Causes, and New Treatment Options.

J Clin Psychiatry 2018 Jan/Feb;79(1)

Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.

Do you know which of your patients are at risk for developing tardive dyskinesia? Watch this Webcast to learn about how to prevent tardive dyskinesia in your patients and new treatment strategies for your patients who have already been diagnosed.
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http://dx.doi.org/10.4088/JCP.NU16048WC3CDOI Listing
June 2019

Evidence-Based Strategies for Managing Tardive Dyskinesia.

Authors:
Joseph P McEvoy

J Clin Psychiatry 2018 Jan/Feb;79(1)

Medical College of Georgia, Augusta University, Augusta, Georgia, USA.

Do you know how to manage tardive dyskinesia symptoms? In this Case and Comment activity, consider the case of John, a 25-year-old project manager diagnosed with bipolar disorder who has begun exhibiting symptoms of uncontrollable movement.
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http://dx.doi.org/10.4088/JCP.NU16048CC2CDOI Listing
June 2019

Durability of Therapeutic Response With Long-Term Aripiprazole Lauroxil Treatment Following Successful Resolution of an Acute Episode of Schizophrenia.

J Clin Psychiatry 2017 Sep/Oct;78(8):1103-1109

Clinical Development, Alkermes, Inc., Waltham, Massachusetts, USA.

Objective: To evaluate durability of therapeutic effect of long-term treatment with aripiprazole lauroxil in patients with schizophrenia following successful treatment of an acute psychotic episode.

Methods: This post hoc analysis assessed long-term outcomes for a subgroup of patients who entered a 52-week extension study after being successfully stabilized with one of 2 doses of aripiprazole lauroxil (441 or 882 mg) in a pivotal 12-week, placebo-controlled, randomized clinical trial. Durability of therapeutic effect was measured by the proportion of patients completing the 1-year course of aripiprazole lauroxil, the trajectories of the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression-Severity (CGI-S) item scores beyond the first 12 weeks, and the likelihood of remission at any follow-up point.

Results: In total, 181 patients treated with aripiprazole lauroxil entered the extension study; 73% and 66% of patients from the 441 mg and 882 mg groups, respectively, completed all 13 aripiprazole lauroxil treatments scheduled every 4 weeks over 52 weeks. Both groups continued on a positive trajectory of symptom improvements (P < .0001 for reductions in PANSS total and CGI-S scores from week 12 to end of follow-up). Most patients (74% and 68% in the aripiprazole lauroxil 441 mg and 882 mg groups, respectively) achieved remission during follow-up.

Conclusions: These post hoc analyses of a subgroup of patients demonstrate the continued therapeutic efficacy of aripiprazole lauroxil after successful treatment of an acute episode of schizophrenia. Both the 441 mg and 882 mg groups had similar retention rates, degree of symptom improvement, and likelihood of remission.

Trial Registration: ClinicalTrials.gov identifier: NCT01469039; European Clinical Trials Database (EudraCT) numbers: 2012-003445-15 and 2012-003996-20​​​​.
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http://dx.doi.org/10.4088/JCP.17m11625DOI Listing
November 2017

Inflammation, substance use, psychopathology, and cognition in phase 1 of the clinical antipsychotic trials of intervention effectiveness study.

Schizophr Res 2018 05 24;195:275-282. Epub 2017 Aug 24.

Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA, United States.

Introduction: Schizophrenia has been associated with aberrant blood levels of inflammatory markers. However, patients with comorbid illicit drug use have been inadequately studied with respect to immune function. Furthermore, associations between inflammatory markers, psychopathology, and cognition have been inconsistently considered. We investigated relationships between inflammatory markers, comorbid marijuana and cocaine use, and psychopathology and cognition in patients with schizophrenia.

Method: For subjects with available fasting data from the baseline visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, inflammatory markers were investigated as predictors of psychopathology and cognition in patients with and without comorbid marijuana or cocaine use, using linear regression models controlling for potential confounding factors.

Results: Compared to subjects with a negative urine drug screen (UDS), marijuana use was a predictor of higher lymphocytes and E-selectin, and lower leptin (p≤0.04 for each); cocaine use was a predictor of higher adiponectin (p=0.04). In subjects with marijuana use, lower WBC and higher IL-6 were predictors of higher PANSS total score (p<0.05 for each). In subjects with cocaine use, lower total and differential WBC were predictors of higher PANSS total score (p<0.04 for each). In younger, non-obese subjects with a negative UDS, higher monocytes and IL-6 were predictors of PANSS total score (p<0.04 for each).

Conclusions: Our findings provide additional evidence that inflammation may be associated with psychopathology and cognition in some patients with schizophrenia. Furthermore, there is preliminary evidence for differential effects of comorbid marijuana and cocaine use on these relationships.
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http://dx.doi.org/10.1016/j.schres.2017.08.027DOI Listing
May 2018

Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial.

Lancet Psychiatry 2017 08 28;4(8):595-604. Epub 2017 Jun 28.

Center for Neurological Restoration, Cleveland Clinic, Cleveland, OH, USA.

Background: Tardive dyskinesia results from exposure to dopamine receptor antagonists, such as typical and atypical antipsychotics. If clinically appropriate, clinicians often manage this disorder by lowering the dose of, or discontinuing, the causative drug. There is a significant unmet need for a treatment option that does not disrupt treatment regimens for underlying psychiatric illnesses. We aimed to assess the efficacy, safety, and tolerability of fixed doses of deutetrabenazine-a novel vesicular monoamine transporter-2 inhibitor-in patients with tardive dyskinesia.

Methods: We did this double-blind, randomised, placebo-controlled, phase 3 trial at 75 centres in the USA and Europe. Patients aged 18-80 years with tardive dyskinesia (≥3 months before screening) were randomly assigned centrally (1:1:1:1), via interactive response technology, to receive one of three fixed doses of deutetrabenazine (12 mg/day, 24 mg/day, or 36 mg/day) or matching placebo. Randomisation was stratified by baseline use of dopamine receptor antagonists. Patients were started on oral deutetrabenazine 12 mg/day, and this dose was increased through week 4 until the randomised dose was achieved, then maintained over 8 weeks. During the treatment period, patients, investigators, their site personnel, and sponsor were masked to group assignment. The primary efficacy endpoint was change in Abnormal Involuntary Movement Scale (AIMS) score from baseline to week 12 in patients with at least one post-baseline rating. The primary efficacy analysis was done in the modified intention-to-treat population (baseline AIMS score ≥6 and at least one post-baseline rating). The safety analysis was done in patients who received any study drug. This trial is registered with ClinicalTrials.gov, number NCT02291861.

Findings: Between Oct 29, 2014, and Aug 19, 2016, we randomly assigned 298 patients to receive at least one dose of placebo (n=74), deutetrabenazine 12 mg/day (n=75), 24 mg/day (n=74), or 36 mg/day (n=75); 222 patients comprised the modified intention-to-treat population and 293 patients comprised the safety population. From baseline to week 12, the least-squares mean AIMS score improved by -3·3 points (SE 0·42) in the deutetrabenazine 36 mg/day group, -3·2 points (0·45) in the 24 mg/day group, and -2·1 points (0·42) in the 12 mg/day group, with a treatment difference of -1·9 points (SE 0·58, 95% CI -3·09 to -0·79; p=0·001), -1·8 points (0·60, -3·00 to -0·63; p=0·003), and -0·7 points (0·57, -1·84 to 0·42; p=0·217), respectively, versus -1·4 points (0·41) in the placebo group. The rate of adverse events was similar between patients in the deutetrabenazine 36 mg/day group (n=38/74 [51%]), 24 mg/day group (n=32/73 [44%]), and 12 mg/day group (n=36/74 [49%]), and those in the placebo group (n=34/72 [47%]). Serious adverse events were reported in four (5%) patients given deutetrabenazine 36 mg/day, six (8%) patients given 24 mg/day, and two (3%) patients given 12 mg/day, compared with four (6%) patients given placebo. Two (1%) patients in the safety population died, one each in the deutetrabenazine 24 mg/day and 36 mg/day groups; neither death was deemed related to study drug by the investigator or sponsor.

Interpretation: Deutetrabenazine 24 mg/day and 36 mg/day provided a significant reduction in tardive dyskinesia, with favourable safety and tolerability. These findings suggest that dosing regimens could be individualised and tailored for patients on the basis of dyskinesia control and tolerability.

Funding: Teva Pharmaceutical Industries.
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http://dx.doi.org/10.1016/S2215-0366(17)30236-5DOI Listing
August 2017

Adjunctive Minocycline in Clozapine-Treated Patients with Schizophrenia: Analyzing the Effects of Minocycline on Clozapine Plasma Levels.

Psychiatr Q 2018 03;89(1):73-80

Maryland Psychiatric Research Center, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD, 21228, USA.

Clozapine is the sole antipsychotic agent effective for the treatment of refractory schizophrenia. Sixty percent of clozapine-treated patients, however, fail to adequately respond. Minocycline, a tetracycline antibiotic, possesses antiinflammatory and neuroprotective properties that may play a role in schizophrenia. Clozapine is mainly metabolized by CYP1A2 enzymes, and minocycline may potentially inhibit CYP1A2 as hypothesized by case report data. To date, no pharmacokinetic interaction has been reported between minocycline and clozapine. This is a secondary analysis of a 10-week controlled study of adjunctive minocycline to clozapine in treatment refractory schizophrenia. Clozapine plasma levels were collected every two weeks during the study. 28 participants assigned to receive minocycline and 22 assigned to placebo were included. No differences existed in baseline demographics, clozapine dose or plasma levels. Average changes from baseline in clozapine plasma level (p = 0.033) were significantly higher in the minocycline group despite maintenance of stable doses. No statistically significant treatment differences were found in the norclozapine (p = 0.754) or total clozapine (p = 0.053) changes in plasma levels, although possible changes in total clozapine levels require further investigation. This analysis suggests that minocycline administration may lead to increased clozapine plasma levels. Further study is needed to examine possible explanations.
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http://dx.doi.org/10.1007/s11126-017-9515-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670021PMC
March 2018

Adjunctive Minocycline in Clozapine-Treated Patients with Schizophrenia: Analyzing the Effects of Minocycline on Clozapine Plasma Levels.

Psychiatr Q 2018 03;89(1):73-80

Maryland Psychiatric Research Center, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD, 21228, USA.

Clozapine is the sole antipsychotic agent effective for the treatment of refractory schizophrenia. Sixty percent of clozapine-treated patients, however, fail to adequately respond. Minocycline, a tetracycline antibiotic, possesses antiinflammatory and neuroprotective properties that may play a role in schizophrenia. Clozapine is mainly metabolized by CYP1A2 enzymes, and minocycline may potentially inhibit CYP1A2 as hypothesized by case report data. To date, no pharmacokinetic interaction has been reported between minocycline and clozapine. This is a secondary analysis of a 10-week controlled study of adjunctive minocycline to clozapine in treatment refractory schizophrenia. Clozapine plasma levels were collected every two weeks during the study. 28 participants assigned to receive minocycline and 22 assigned to placebo were included. No differences existed in baseline demographics, clozapine dose or plasma levels. Average changes from baseline in clozapine plasma level (p = 0.033) were significantly higher in the minocycline group despite maintenance of stable doses. No statistically significant treatment differences were found in the norclozapine (p = 0.754) or total clozapine (p = 0.053) changes in plasma levels, although possible changes in total clozapine levels require further investigation. This analysis suggests that minocycline administration may lead to increased clozapine plasma levels. Further study is needed to examine possible explanations.
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http://dx.doi.org/10.1007/s11126-017-9515-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670021PMC
March 2018
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