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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., Plain Language Summary Schizophrenia is a mental condition that affects how a person acts, thinks, sees, and interprets their surroundings and expresses how they feel. Relapse can lead to hospitalization and other poor outcomes. Almost half of patients with schizophrenia tend to start and stop treatment, which can cause more relapses and make symptoms worse over time. Using antipsychotic drugs long term can reduce impairing illness symptoms and improve patient quality of life. Consistent use of antipsychotic drugs can help prevent relapse. Available antipsychotic drugs can be taken by mouth (oral) or by an injection. Oral drugs have to be taken every day, whereas long-acting injections (LAIs) of antipsychotic drugs can be given less often, such as every 2 weeks, monthly, and up to once every 3 months. In the past, LAIs were used only when oral antipsychotic drugs did not work, which was usually because patients did not take them every day. However, LAIs also work as an early treatment, which can be better for the patient. Patients taking LAIs skip fewer doses and so may have fewer relapses and hospitalizations. Because LAIs have to be given at the clinic, patients get more regular medical care and tend to keep taking their medicine for longer. Most LAI side effects are similar to those of oral antipsychotic drugs. Despite this, some clinicians hesitate to prescribe LAIs. More education for clinicians and patients about LAIs could increase interest and use. Recovery and relapse prevention are the main treatment goals for patients and their care team, and LAIs can improve both.

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 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]).

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.

Purpose Tardive dyskinesia (TD) is a common but serious hyperkinetic movement disorder and side effect of antipsychotic medications used to treat bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SZ). The purpose of this study was to evaluate health-related quality of life (HRQoL) in a population with diagnoses for BD, MDD, or SZ by comparing patients with TD (n = 197) with those without TD (n = 219). HRQoL in each group was also compared with HRQoL of the general population. Methods This study employed a cross-sectional web-based survey. HRQoL was assessed by four instruments: the SF-12 Health Survey, Version 2 (SF-12v2), the Quality of Life Enjoyment and Satisfaction Questionnaire, Short Form (Q-LES-Q-SF), the Social Withdrawal subscale of the Internalized Stigma of Mental Illness Scale (SW-ISMI); and two questions on movement disorders. Results Patients with TD had significantly worse HRQoL and social withdrawal than those without. The differences were more pronounced for physical HRQoL domains than for mental health domains. Patients with more-severe TD, assessed through either self-rating or clinician rating, experienced significantly worse HRQoL than did those with less-severe TD. The impact of TD was substantially greater in patients with SZ than in those with BD or MDD. Compared with the general population, patients with BD, MDD, or SZ experienced significantly worse HRQoL regardless of TD status, although this deficit in HRQoL was greater among those with TD. Conclusions The presence of TD is associated with worse HRQoL and social withdrawal. The most severe impact of TD is on physical aspects of patients’ HRQoL.

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.

Objective: Insomnia occurs frequently in the clinical course of schizophrenia. There is a robust association between insomnia and suicide in other psychiatric disorders. Several previous studies found associations between insomnia and suicidal ideation, suicide attempt, and psychopathology in schizophrenia. We explored these associations in a cross-sectional study of a large sample of patients with schizophrenia. Methods: In February 2020, we investigated relationships between current insomnia, suicidal ideation over the past 2 weeks, suicide attempt in the past 6 months (assessed by either the Calgary Depression Scale for Schizophrenia or self-report), and current psychopathology for subjects with baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (DSM-IV schizophrenia trial conducted 2001-2004) using regression models. Results: After controlling for multiple potential confounding factors, terminal insomnia was associated with significant, 2.7-fold increased odds of current suicidal ideation (OR = 2.7, 95% CI = 2.0-3.6, P

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.

​​​​​​ 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.

BackgroundSuicide risk among individuals with schizophrenia (SZ) is intractably high, with over 40% of individuals attempting to take their own lives during their lifetime and an estimated 5–10% completing suicide. At present, available pharmacological and psychotherapeutic treatments offer limited risk reduction benefits, and thus, there remains an urgent need to explore novel interventions that will ameliorate this risk. Aerobic exercise (AE) has been shown to improve a number of predictors of suicide risk (e.g., depressed mood, sleeping difficulties). As individuals with SZ display a highly sedentary lifestyle, AE may reduce suicide risk.MethodsEmploying a multi-site, single-blind, randomized clinical trial design, we will examine the impact of AE on risk for suicide and related variables in individuals with SZ. Participants will be randomized to one of two 12-week exercise interventions: AE or a stretching and toning (ST) control intervention. Primary outcome measures will include suicide risk (Columbia Suicide Severity Rating Scale, C-SSRS) and aerobic fitness (VO2max), along with additional measures of suicide risk, mood, emotion regulation, sleep, cognition, and physical activity, with assessments completed at baseline and after 6 and 12 weeks of interventions.DiscussionIt is hypothesized that AE will reduce suicide risk among individuals with SZ. This study may offer support for a more efficacious treatment method for this population in addition to the pre-existing pharmacological and psychotherapeutic treatment regimens.Trial registrationClinicaltrials.gov,NCT03270098. Registered on September 1, 2017.

​​ 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).

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.

In schizophrenia, the years before psychosis are morbid, not premorbid. Widespread, low-grade corruption of circuitry (brain damage) occurs, resulting in enduring deficits in cognitive, social, and motor functioning and motivation. These deficits persist during patients’ lifetime and do not respond to medication or talking. Expectations of patients’ functioning must be modified (reduced); interactions and environments must be accommodated to support best residual functioning, and prostheses (mechanical or actions of others) must replace functions no longer available. One of the deficits—anosognosia—interferes with treatment efforts. When the circuits managing dopamine neurons in the ventral tegmental area are corrupted, storms of dopamine imbue random items of sensory experience and intrapsychic life with salience—psychosis appears. Early and uninterrupted dopamine antagonist medication results in sustained remission of psychosis but is rarely achieved because of the inadequacies of standard care. Enduring engagement by multi-disciplinary teams is the necessary response to the neurobiology of schizophrenia.

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.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.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.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.

​​​​Early Recognition and Treatment of Tardive Dyskinesia in Patients With Mood Disorders and Schizophrenia Click to enlarge page​​.

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.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.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.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.

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, p0.001) 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.

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​​​​.

Summary 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.

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.

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.

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.

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 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.

BACKGROUND: Women with serious mental illnesses like bipolar disorder and schizophrenia are more likely to be tobacco smokers as compared to women without mental illness. Antipsychotic medications may impact craving and nicotine’s rewarding effects via dopaminergic neurotransmitter activity. Differences in pharmacologic profiles and receptor affinity among antipsychotic agents may lead to variability in impact on craving and/or substance use. Aripiprazole, a partial dopamine agonist antipsychotic, may impact tobacco craving. To our knowledge, no one has specifically examined tobacco craving/usage patterns in women with psychotic disorders treated with adjunctive aripiprazole. METHODS: We report baseline and endpoint tobacco use/craving data for cigarette smokers completing a 16-week randomized double-blind placebo-controlled trial of adjunct aripiprazole vs placebo. Participants recruited were all women with high prolactin levels and not reporting any desire to change smoking behaviors, which provides the opportunity to look at a naturalistic population. Assessments included the Fagerstrom Test for Nicotine Dependence (FTND) Scale, the Tobacco Craving Questionnaire-Short Form (TCQ-SF), the Drug and Alcohol Use Summary, expired carbon monoxide (CO), and all answered questions about smoking habits at baseline, 8 weeks, and 16 weeks (endpoint). Between-group changes from baseline to endpoint were measured by Effect size (Cohen’s D) due to the underpowered pilot nature of the data. RESULTS: Of the 16 women smokers included, 9 were assigned to aripiprazole and 7 to placebo. The average age of participants was 38.5 years (SD=9.9) and mean age at onset of illness was 20.9 (SD=8). The average number of cigarettes smoked daily was 10.6 (SD=7.6) and the average years of smoking was 20.9 (SD=10.4). Of the 16 participants, 2 (12.5%) were diagnosed with bipolar disorder, 4 (25%) had schizoaffective disorder, and 10 (62.5%) had schizophrenia. There were no baseline differences in demographic or smoking measures between groups. During the 16-week study the FTND scores were moderately decreased with aripiprazole relative to placebo with an effect size (ES) of -0.49. The ES for expired CO favoring aripiprazole was -0.86, however there wasn’t a decrease in the aripiprazole group, only an increase noted in the study with placebo. Aripiprazole, compared to placebo, did not appear to affect the number of cigarettes smoked daily (ES= -0.22) or the TCQ-SF scores (ES= 0.20). DISCUSSION: This pilot study is the first to evaluate the effect of adjunct aripiprazole on measures of tobacco and use and craving in women smokers with psychotic disorders. In this small sample there were moderate effect size favoring adjunct aripiprazole on a decrease in dependency scores but not in craving and cigarette smoking. Future research should investigate the impact of aripiprazole on tobacco craving in a larger sample. Additionally, both men and women should be included for a representative sample and to examine potential sex differences. This study was funded by NIMH R01 (MH090071-04) (Kelly PI) and NIDA K23 (DA034034-01A1) (Wehring PI). Aripiprazole and matching placebo were supplied by Bristol-Myers Squibb/Otsuka.

Objective: To assess the impact of developing tardive dyskinesia (TD), both with and without other pre-existing extrapyramidal symptoms (EPS), on healthcare resource utilization (HRU) among patient...

Individuals with schizophrenia (SZ) display cognitive deficits that have been identified as major determinants of poor functioning and disability, representing a serious public health concern and an important target for interventions. At present, available treatments offer only minimal to moderate benefits to ameliorate cognitive deficits. Thus, there remains an urgent need to identify novel interventions to improve cognition in people with SZ. Emerging evidence from animal and basic human research suggests aerobic exercise training (AE) has beneficial effects on cognition. Preliminary findings suggest that AE is efficacious in improving cognitive functioning in SZ, however the extant studies have been limited by small samples, a dearth of information on biologically-relevant covariates, and limited information on impact on daily functioning. Additionally, while AE-related cognitive benefits have been linked to Brain-Derived Neurotrophic Factor (BDNF) upregulation, this putative mechanism needs confirmation. The present report describes a study protocol designed to address these limitations—we review and summarize the current literature on treatment of cognitive deficits in SZ, state the rationale for employing AE to target these deficits, and describe the current protocol—a multi-site, single-blind, randomized clinical trial aiming to recruit 200 community-dwelling individuals with SZ. Participants are randomized to one of two 12-week interventions: AE using active-play video games (i.e., Xbox Kinect) and traditional cardiovascular exercise equipment or a stretching-and-toning (ST) control intervention. Participants undergo assessments of aerobic fitness, cognition, and daily functioning, as well as BDNF and other biomarkers of cognitive change, at baseline and after 6- and 12-weeks.

Clozapine is a highly effective antipsychotic medication, which provides a range of significant benefits for patients with schizophrenia, and is the standard of care for treatment-resistant schizophrenia as well as for reducing the risk of suicidal behaviors in schizophrenia and schizoaffective disorder. However, clozapine is widely underutilized, largely because prescribing clinicians lack experience in prescribing it and managing its adverse events (AEs). Clozapine is associated with three uncommon but immediately dangerous AEs-agranulocytosis, myocarditis/cardiomyopathy, and seizures-as well as AEs that may become dangerous if neglected, including weight gain, metabolic syndrome and constipation, and others that are annoying or distressing such as sedation, nighttime enuresis and hypersalivation. Because of the risk of agranulocytosis, clozapine formulations are available only through restricted distribution via a patient registry, with mandatory, systematized monitoring for absolute neutrophil count using a specific algorithm. We identified articles on managing clozapine-associated AEs by searching PubMed using appropriate key words and search techniques for each topic. A review of the prevalence and clinical characteristics of clozapine-associated AEs shows that these risks can be managed efficiently and effectively. The absolute risks for both agranulocytosis and myocarditis/cardiomyopathy are low, diminish after the first six months, and are further reduced with appropriate monitoring. Weight gain/metabolic disorders and constipation, which develop more gradually, can be mitigated with regular monitoring and timely interventions. Sedation, hypersalivation, and enuresis are common but manageable with ameliorative measures and/or medications.

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.

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.

OBJECTIVE: To investigate subgroup responses to long-acting injectable (LAI) 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. METHOD: A Comparison of Long-Acting Injectable Medications for Schizophrenia (ACLAIMS) enrolled 311 participants from March 2011 to July 2013 meeting DSM-VI-TR criteria for diagnoses of schizophrenia or schizoaffective disorder at risk of relapse due to medication non-adherence 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 based on meeting at least one of these criteria: psychiatric hospitalization, crisis stabilization, increased outpatient visits, could not discontinue oral antipsychotic, discontinued assigned LAI due to inadequate therapeutic benefit, or prolonged need for adjunctive oral antipsychotic medication. Survival analyses examined modification of treatment effects on efficacy failure by age, gender, 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=0.009) revealed younger participants assigned HD had longer time to efficacy failure than those assigned PP. Interactions were not significant between treatment group and gender, race, substance use disorder, baseline symptom severity, or baseline adherence. An interaction of treatment and age on akathisia (p=0.047) 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=0.033). CONCLUSION: 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. CLINICAL TRIALS REGISTRATION: A Comparison of Long-acting Injectable Medications for Schizophrenia (ACLAIMS) https://clinicaltrials.gov/ct2/show/NCT01136772?term=ACLAIMS&rank=1, NCT01136772

BackgroundTardive dyskinesia (TD) is an often-irreversible movement disorder that may intensify the stigma of patients with psychiatric disorders and worsen quality of life. In two randomized, double-blind, placebo (PBO)-controlled, 12-week trials, ARM-TD and AIM-TD (‘parent studies’), deutetrabenazine (DTB) demonstrated statistically significant improvements in centrally read Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with PBO and was generally well tolerated.Study ObjectiveTo evaluate the long-term efficacy of DTB in an open-label safety study following double-blind treatment using site-rated efficacy measures: AIMS, the Clinical Global Impression of Change (CGIC) and the Patient Global Impression of Change (PGIC), which may be used in real-world clinical practice settings.MethodPatients with TD who completed the parent studies were eligible to enter this open-label, long-term extension (OLE) after completing the 1-week washout period and final evaluation in the blinded portion of the trial. This extension comprised a 6-week titration period followed by a long-term maintenance phase. Patients began DTB at 12mg/day, titrating up to a maximum total dose of 48mg/day based on dyskinesia control and tolerability. Efficacy endpoints included in this analysis are the change in site-rated AIMS score (items 1–7) from parent study baseline, and the proportion of patients who were “Much Improved” or “Very Much Improved” (treatment success) on the CGIC and PGIC from OLE baseline.ResultsAt the end of the parent studies (Week 12), patients treated with DTB had experienced greater mean (standard error) improvements in site-rated AIMS score (–5.0[0.40]) than patients given PBO (–3.2[0.47]). With long-term DTB treatment, both groups experienced improvements in site-rated AIMS scores (prior DTB, –7.9[0.62]; prior placebo, –6.6[0.64]) compared with parent study baseline. Similarly, at the end of the parent studies, a greater proportion of patients treated with DTB had treatment success on the CGIC (DTB, 51%; PBO, 32%) and the PGIC (DTB, 46%; PBO: 33%); whereas at Week 54 of the OLE study, treatment success on CGIC and PGIC were similar in both the CGIC (prior DTB: 66%; prior PBO: 68%) and PGIC (prior DTB: 62%; prior PBO: 62%) groups. DTB was generally well tolerated.ConclusionsPatients treated with DTB showed improvements in abnormal movements, as measured by site-rated AIMS, CGIC, and PGIC scores, which may be used in real-world clinical practice settings. These results corroborate the previously reported efficacy of DTB as observed in the 12-week, double-blind ARM-TD and AIM-TD trials, in which central raters were used to evaluate AIMS scores.Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USAFunding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.

The metabolic syndrome is highly prevalent in patients with schizophrenia, and is associated with a state of chronic, low-grade inflammation. We investigated relationships between total and differential white blood cell (WBC) counts, inflammatory markers, adipokines and the metabolic syndrome in patients with schizophrenia.For subjects with available data from the baseline/screening visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, WBC counts, inflammatory markers, and adipokines were investigated as predictors of the metabolic syndrome (and its components), using linear and binary logistic regression models, controlling for potential confounding effects of age, sex, race, smoking, fasting status, alcohol, and illicit drug use.After controlling for potential confounders, blood CRP, interleukin-6, and leptin were significant predictors of all five individual components of the metabolic syndrome (as both continuous and categorical outcome measures). Furthermore, total WBC (OR=2.31, 95% CI 1.58-3.41, p0.01) and lymphocyte (OR=2.51, 95% CI 1.75-3.60, p0.01) counts were the strongest predictors of current metabolic syndrome.Our findings provide the strongest evidence to date that measurement of total and differential WBC counts are germane to the clinical care of patients with schizophrenia, and that inflammation and adipokines are associated with metabolic disturbance in these patients.

Women have been largely underrepresented in clinical trials in schizophrenia yet have a different presentation of symptoms, such as higher affective symptoms compared to men. Thus, adjunctive antipsychotic treatment, particularly low-dose aripiprazole, in women may be an effective strategy, particularly for its effects on anxious or depressive symptoms. Premenopausal women with schizophrenia or bipolar disorder were recruited for a randomized double-blind, 16-week trial of adjunct aripriprazole (5 to 15 mg day). The primary study population was those with symptomatic hyperprolactinemia (these results reported elsewhere). Stable participants were evaluated biweekly for psychiatric symptoms using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the Calgary Depression Rating Scale (CDS), and the Clinical Global Improvement (CGI). The Psychological General Well Being Index (PGWB) and the Repeatable Battery for Assessment of Neurological Symptoms (RBANS) were performed monthly and end of study, respectively. Forty-four women were randomized and received medication (N = 24 aripiprazole and N = 20 placebo). Four aripiprazole participants discontinued (2 clinical worsening, 1 patient choice, and 1 nonadherence) and 3 discontinued in the placebo group (patient choice, medication nonadherence and administrative pharmacy error). There were no significant treatment differences in BPRS, SANS, CDS, or CGI scores between the aripiprazole and placebo groups ( > .05). Robust response on the total BPRS (>30% response) was noted in (12%) in the aripiprazole group vs. none in the placebo group ( = .12). There were no differences in RBANS or PGWB index scores and no differences in side effects noted. This clinical trial suggests that adjunct treatment aripiprazole to treat symptomatic hyperprolactinemia in clinically stable women does not significantly improve psychiatric symptoms in most patients. However, 12% of women had robust symptom improvements (>30%) in BPRS scores, and 10% had worsening of BPRS scores leading to discontinuation. No significant improvements were noted in any other clinical ratings such as anxiety, depression or cognition. Nonetheless, adjunct aripriprazole is a safe strategy for stable patients when added for symptomatic hyperprolatinemia, and future work should help distinguish which factors may predict robust symptoms improvements and which women may have clinical worsening that occur in about 10%–12% of patients using this strategy.

IntroductionExtrapyramidal symptoms (EPS), including tardive dyskinesia (TD), may result from exposure to antipsychotics. TD is often irreversible, may be debilitating, and cause additional burden to patients with underlying psychiatric conditions.ObjectiveTo assess the impact of developing TD, both with and without other EPS, on healthcare resource utilization (HRU).MethodsData on patients receiving antipsychotics who had schizophrenia, major depressive disorder, or bipolar disorder were extracted from a Medicaid claims database. Patients from the TD cohorts (TD+EPS and TD non-EPS) were matched to those in the non-TD/EPS cohort at ∼1:5 ratio. HRU outcomes associated with TD were assessed.ResultsTD+EPS (n=289) and TD non-EPS (n=394) cohorts were matched with 1398 and 1922 control patients, respectively. The percentage of patients with all-cause and mental disorder-related inpatient admissions increased from baseline to follow-up in the TD+EPS (12.8% and 12.5%, respectively) and TD non-EPS (16.0% and 13.5%) cohorts, in contrast with slight decreases (∼3%) in matched controls. A higher percentage of patients in the TD cohorts had medical admissions/visits and claims for drugs that might be used to address TD or EPS than their matched controls at baseline and follow-up. The within-cohort change from baseline to follow-up in the use of potential drugs for TD or EPS was similar between the TD cohorts and their matched controls; however, both TD cohorts exhibited a larger increase in crisis–non-specific psychotherapy services versus matched controls.ConclusionsResults demonstrated increased HRU in TD patients with or without other pre-existing EPS, compared with matched controls.Presented at: Psych Congress; September 16–19, 2017; New Orleans, Louisiana, USA.Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.

BACKGROUND: Morbidity and premature mortality is high in schizophrenia. Poor diets, low rates of physical activity, substance use, and lack of preventative care predispose patients to poor physical health and comorbid medical diseases. Women with schizophrenia have distinct preventative and physical health needs which poses and even greater burden on disease risk. We evaluated laboratory measures and health indices in women with schizophrenia having antipsychotic-induced hyperprolactinemia. METHODS: This study includes data from a one-time fasting laboratory screening visit in women treated with prolactin elevating antipsychotics (N=43). Laboratories were drawn in the follicular phase of the menstrual cycle if possible. Women were between the ages of 18–50 years and had a known high prolactin level (

BackgroundTardive dyskinesia (TD) results from exposure to dopamine-receptor antagonists (DRAs), such as typical and atypical antipsychotics. Clinicians commonly manage TD by reducing the dose of or stopping the causative agent; however, this may cause psychiatric relapse and worsen quality of life. In the 12-week ARM-TD and AIM-TD trials, deutetrabenazine demonstrated statistically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores versus placebo and was generally well tolerated, regardless of baseline DRA use or comorbidities.Study ObjectiveTo evaluate the impact of underlying disease and current DRA use on efficacy and safety of long-term therapy of deutetrabenazine in patients with TD.MethodPatients with TD who completed ARM-TD or AIM-TD were eligible to enter this open-label, single-arm, long-term extension after completing the 1-week washout period and final evaluation in the blinded portion of the trial. Change in AIMS scores from baseline to Week 54 and patients “Much Improved” or “Very Much Improved” (treatment success) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) at Week 54 were analyzed by baseline psychiatric illness type, including mood disorders (bipolar disorder/depression/other) or psychotic disorders (schizophrenia/schizoaffective disorder), and presence or absence of current DRA use.ResultsAt Week 54, meaningful improvements from baseline in mean (standard error) AIMS scores were observed for patients with baseline mood disorders (–5.2[0.93]) and psychotic disorders (–5.0[0.63]), and in patients currently using DRAs (–4.6[0.54]) or not using DRAs (–6.4[1.27]). Most patients with mood disorders (73%) and psychotic disorders (71%) were “Much Improved” or “Very Much Improved” on CGIC at Week 54, similar to patients currently using (71%) or not using (74%) DRAs. The majority of patients with mood disorders (62%) and psychotic disorders (57%), as well as patients currently using (58%) or not using (63%) DRAs, were also “Much Improved” or “Very Much Improved” on PGIC at Week 54. Prior treatment in ARM-TD and AIM-TD did not impact the long-term treatment response. Underlying psychiatric disorder and concomitant DRA use did not impact the occurrence of adverse events (AEs). The frequencies of dose reductions, dose suspensions, and withdrawals due to AEs were low, regardless of baseline psychiatric comorbidities and DRAuse.ConclusionsLong-term deutetrabenazine treatment demonstrated meaningful improvements in abnormal movements in TD patients, which were recognized by clinicians and patients, regardless of underlying psychiatric illness or DRAuse.Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USAFunding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.

ObjectiveTo evaluate the long-term safety and tolerability of lurasidone in schizophrenia and schizoaffective disorder patients switched to lurasidone.MethodPatients in this multicenter, 6-month open-label, flexible-dose, extension study had completed a core 6-week randomized trial in which clinically stable, but symptomatic, outpatients with schizophrenia or schizoaffective disorder were switched to lurasidone. Patients started the extension study on treatment with the same dose of lurasidone taken at study endpoint of the 6-week core study; following this, lurasidone was flexibly dosed (40–120 mg/day), if clinically indicated, starting on Day 7 of the extension study. The primary safety endpoints were the proportion of patients with treatment emergent adverse events (AEs), serious AEs, or who discontinued due to AEs. Secondary endpoints included metabolic variables and measures of extrapyramidal symptoms and akathisia, as well as the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), and the Calgary Depression Scale for Schizophrenia (CDSS). The study was conducted from August 2010 to November 2011.ResultsOf the 198 patients who completed the 6-week core study, 149 (75.3%) entered the extension study and 148 received study medication. A total of 98 patients (65.8%) completed the 6-month extension study. Lurasidone 40, 80, and 120 mg were the modal daily doses for 19 (12.8%), 65 (43.9%), and 64 (43.2%) of patients, respectively. Overall mean (SD) daily lurasidone dose was 102.0 mg (77.1). The most commonly reported AEs were insomnia (13 patients [8.8%]), nausea (13 patients [8.8%]), akathisia (12 patients [8.1%]), and anxiety (9 patients [6.1%]). A total of 16 patients (10.8%) had at least one AE leading to discontinuation from the study. Consistent with prior studies of lurasidone, there was no signal for clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin. Movement disorder rating scales did not demonstrate meaningful changes. Treatment failure (defined as any occurrence of discontinuation due to insufficient clinical response, exacerbation of underlying disease, or AE) was observed for 19 patients (12.8% of patients entering) and median time to treatment failure was 58 days (95% CI 22–86). The discontinuation rate due to any cause was 50/148 (33.8%), and median time to discontinuation was 62 days (95% CI 30–75). The mean PANSS total score, mean CGI-S score, and mean CDSS score decreased consistently from core study baseline across extension visits, indicating an improvement in overall condition.ConclusionsIn this 6-month, open-label extension study, treatment with lurasidone was generally well-tolerated with sustained improvement in efficacy measures observed in outpatients with schizophrenia or schizoaffective disorder who had switched to lurasidone from a broad range of antipsychotic agents.

Uncontrolled studies have suggested that increasing the dose of ziprasidone above the standard maximum daily dose of 160 mg may be more effective for some patients with schizophrenia. To test this hypothesis, we conducted an 8-week, placebo-controlled, fixed-dose escalation trial comparing ziprasidone 160 versus 320 mg/d in individuals with schizophrenia or schizoaffective disorder who remained symptomatic despite treatment with ziprasidone 160 mg/d for at least 3 weeks. Of 75 randomized patients, 42 completed the study. Serum ziprasidone concentrations increased significantly in the high-dose group compared with the standard-dose group at week 4 but did not differ between groups at week 8. Both treatment groups exhibited significant symptomatic improvement. Response did not differ between treatment groups; however, in the high-dose group, higher ziprasidone serum concentrations were associated with better response at a trend level. Higher ziprasidone concentrations were also associated with reductions in diastolic blood pressure and, at a trend level, with more prominent negative symptoms and greater QTc prolongation. In summary, increasing the ziprasidone dose to 320 mg/d did not produce a sustained elevation in serum concentrations or symptomatic improvement compared with a standard ziprasidone dose of 160 mg/d.

This study examined the clinical significance of switching from olanzapine, quetiapine, or risperidone to aripiprazole by examining changes in predicted risk of cardiovascular disease (CVD) according to the Framingham Risk Score (FRS) and metabolic syndrome status. FRS estimates 10-year risk of "hard" coronary heart disease (CHD) outcomes (myocardial infarction and coronary death) while metabolic syndrome is associated with increased risk of CVD, stroke, and diabetes mellitus.Changes in FRS and metabolic syndrome status were compared between patients with BMI ≥ 27 and non-HDL-C ≥ 130 mg/dL randomly assigned to stay on stable current treatment (olanzapine, quetiapine, or risperidone) or switch to treatment with aripiprazole with 24 weeks of follow-up. All study participants were enrolled in a behavioral program that promoted healthy diet and exercise.The pre-specified analyses included 89 switchers and 98 stayers who had post-baseline measurements needed to assess changes. Least squares mean estimates of 10-year CHD risk decreased more for the switch (from 7.0% to 5.2%) than the stay group (from 7.4% to 6.4%) (p = 0.0429). The odds ratio for having metabolic syndrome (stay vs. switch) at the last observation was 1.748 (95% CI 0.919, 3.324, p = 0.0885).Switching from olanzapine, quetiapine, or risperidone to aripiprazole was associated with larger reductions in predicted 10-year risk of CHD than the behavioral program alone. The advantage of switching on metabolic syndrome was not statistically significant. The benefits of switching must be balanced against its risks, which in this study included more discontinuations of the study treatment but no significant increase in symptoms or hospitalizations.

Objective To examine the effectiveness of switching patients to lurasidone using 3 different dosing strategies. Method Adults with DSM-IV-defined schizophrenia or schizoaffective disorder in a nonacute phase of illness were randomized to 1 of 3 lurasidone dosing regimens for the initial 2 weeks of the study: (1) 40 mg/d for 2 weeks; (2) 40 mg/d for 1 week, increased to 80 mg/d on day 8 for week 2 (up-titration group); and (3) 80 mg/d for 2 weeks. Lurasidone was then flexibly dosed (40-120 mg/d) for the subsequent 4 weeks of the study. The preswitch antipsychotic agent was tapered by day 7 to 50% of the original dose and discontinued by the end of week 2. Subjects were stratified on the basis of whether the primary preswitch antipsychotic medication was classified as "sedating" (olanzapine or quetiapine) or "nonsedating" (all other antipsychotics). The primary outcome measure was time to treatment failure, defined as any occurrence of insufficient clinical response, exacerbation of underlying disease, or discontinuation due to an adverse event. The study was conducted from June 2010 to May 2011. Results Of 240 subjects treated in this study, 86 (35.8%) were treated with an antecedent sedating antipsychotic, and 154 (64.2%) were treated with an antecedent nonsedating antipsychotic. Nineteen (7.9%) of the 240 patients experienced treatment failure. No clinically relevant differences were observed when the 3 randomized switch groups were compared. Treatment failure rates were 10/86 (11.6%) versus 9/154 (5.8%) among subjects who had been receiving a preswitch sedating versus nonsedating antipsychotic medication, respectively. Consistent with prior studies of lurasidone, there was no signal for clinically relevant adverse changes in body weight, glucose, insulin, lipids, or prolactin; mean improvements in weight and lipids were observed. Movement disorder rating scales did not demonstrate meaningful changes. The incidence of akathisia as an adverse event was 12.5%; only 1 subject (0.4%) discontinued due to akathisia. Conclusions Switching patients to lurasidone can be successfully accomplished by starting at 40 mg/d for 2 weeks, or 80 mg/d for 2 weeks, or 40 mg/d for 1 week followed by 80 mg/d the second week. Trial registration ClinicalTrials.gov identifier: NCT01143077.

This study assessed the relative cost-effectiveness of haloperidol decanoate (HD), a first-generation long-acting injectable (LAI) antipsychotic, and paliperidone palmitate (PP), a second-generation LAI antipsychotic.A double-blind, randomized 18-month clinical trial conducted at 22 clinical research sites in the United States compared the cost-effectiveness of HD and PP among 311 adults with schizophrenia or schizoaffective disorder who had been clinically assessed as likely to benefit from an LAI antipsychotic. Patients were randomly assigned to monthly intramuscular injections of HD (25-200 mg) or PP (39-234 mg) for up to 24 months. Quality-adjusted life years (QALYs) were measured by a schizophrenia-specific algorithm based on the Positive and Negative Syndrome Scale and side-effect assessments; total health care costs were assessed from the perspective of the health system.Mixed-model analysis showed that PP was associated with .0297 greater QALYs over 18 months (p=.03) and with $2,100 more in average costs per quarter for inpatient and outpatient services and medication compared with HD (p.001). Bootstrap analysis with 5,000 replications showed an incremental cost-effectiveness ratio for PP of $508,241 per QALY (95% confidence interval=$122,390-$1,582,711). Net health benefits analysis showed a .98 probability of greater cost-effectiveness for HD compared with PP at an estimated value of $150,000 per QALY and a .50 probability of greater cost-effectiveness at $500,000 per QALY.HD was more cost-effective than PP, suggesting that PP's slightly greater benefits did not justify its markedly higher costs, which are likely to fall once the medication's patent expires.

Robin Emsley and colleagues question the use of placebos when established treatment is effective and lack of harm has not been proved

Objective This multisite randomized trial addressed risks and benefits of staying on long-acting injectable haloperidol or fluphenazine versus switching to long-acting injectable risperidone microspheres.

Background: Accumulating evidence suggests minocycline (MINO) is effective as an adjunct treatment in schizophrenia. We previously reported significant improvement in avolition, anxiety/depression and working memory and a trend for positive symptoms and total Brief Psychiatric Rating Scale (BPRS) scores with MINO in a double-blind, placebo-controlled trial. We also found a >30% reduction in total BPRS scores in 25% of the MINO group compared to 4% in placebo (P = .04). Here we examine variables associated with symptom improvements.

This randomized trial addressed the risks and benefits of staying on antipsychotic polypharmacy or switching to monotherapy.Adult outpatients with schizophrenia taking two antipsychotics (127 participants across 19 sites) were randomly assigned to stay on polypharmacy or switch to monotherapy by discontinuing one antipsychotic. The trial lasted 6 months, with a 6-month naturalistic follow-up. Kaplan-Meier and Cox regression analyses examined time to discontinuation of assigned antipsychotic treatment, and random regression models examined additional outcomes over time.Patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy. By month 6, 86% (N=48) of those assigned to stay on polypharmacy were still taking both medications, whereas 69% (N=40) of those assigned to switch to monotherapy were still taking the same medication. Most monotherapy discontinuations entailed returning to the original polypharmacy. The two groups did not differ with respect to psychiatric symptoms or hospitalizations. On average, the monotherapy group lost weight, whereas the polypharmacy group gained weight.Discontinuing one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued. However, two-thirds of participants successfully switched, the groups did not differ with respect to symptom control, and switching to monotherapy resulted in weight loss. These results support the reasonableness of prescribing guidelines encouraging trials of antipsychotic monotherapy for individuals receiving antipsychotic polypharmacy, with the caveat that patients should be free to return to polypharmacy if an adequate trial on antipsychotic monotherapy proves unsatisfactory.

There is growing concern that people with schizophrenia and other severe mental illnesses are increasingly at risk for unnecessary criminal justice system (CJS) involvement. There has been limited examination, however, of which individual characteristics predict future CJS involvement. This study uses data from the Clinical Antipsychotic Trials of Intervention Effectiveness on sociodemograhic characteristics, baseline clinical status, and service use among patients diagnosed with schizophrenia to prospectively identify predictors of CJS involvement during the following year. A series of bivariate chi-square and F tests were conducted to examine whether significant relationships existed between CJS involvement during the first 12 months of the trial and baseline measures of sociodemographic characteristics, psychiatric status, substance abuse, and other patient characteristics. Multivariate logistic regression analysis was then used to identify the independent strength of the relationship between 12-month CJS involvement and potential risk factors that were found to be significant in bivariate analyses. Multivariate logistic regression analyses indicated that past adolescent conduct disorder, being younger and male, symptoms of Akathisia (movement disorder, most often develops as a side effect of antipsychotic medications), and particularly drug abuse increase the risk for CJS involvement. Since CJS involvement among people with schizophrenia was most strongly associated with drug abuse, treatment of co-morbid drug abuse could reduce the risk of stigma, pain, and other adverse consequences of CJS involvement as well as save CJS expenditures.