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Leslie Citrome1, Joseph P McEvoy2, Mark S Todtenkopf3, David McDonnell4, Peter J Weiden3 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA, USA; 3Alkermes, Inc., Waltham, MA, USA; 4Alkermes Pharma Ireland Ltd., Dublin, IrelandCorrespondence: Leslie Citrome 11 Medical Park Drive, Suite 106, Pomona, NY 10970, USATel +1 845 362 2081Email citrome@cnsconsultant.comAbstract: 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.Keywords: antipsychotic, efficacy, metabolic dysregulation, weight gain

Objective: The authors conducted a multisite randomized controlled trial examining the strategy of switching from olanzapine, quetiapine, or risperidone to aripiprazole to ameliorate metabolic risk factors for cardiovascular disease.Method: Patients with schizophrenia or schizoaffective disorder with a body mass index ≥ 27 and non-high-density lipoprotein (non-HDL) cholesterol ≥ 130 mg/dl who were on a stable treatment dosage of olanzapine, quetiapine, or risperidone were randomly assigned to switch to ari-piprazole (N=109) for 24 weeks or stay on their current medication (N=106). All participants were enrolled in a behaviorally oriented diet and exercise program. Clinical raters were blinded to treatment assignment. The primary and key secondary outcomes were change in non-HDL cholesterol and efficacy failure, respectively.Results: The prespecified primary analysis included 89 switchers and 98 stayers who had at least one postbaseline non-HDL cholesterol measurement. The least squares mean estimates of non-HDL cholesterol decreased more for the switch group than for the stay group (-20.2 mg/dl and -10.8 mg/dl, respectively). Switching was associated with larger weight reductions (least squares mean=2.9 kg) and a net reduction of serum triglycerides of 32.7 mg/dl. Twenty-two switchers (20.6%) and 18 stayers (17.0%) experienced protocol-defined efficacy failure. Forty-seven switchers (43.9%) and 26 stayers (24.5%) discontinued the assigned antipsychotic medication before 24 weeks.Conclusions: Switching to aripiprazole led to improvement of non-HDL cholesterol levels and other metabolic parameters. Rates of efficacy failure were similar between groups, but switching to aripiprazole was associated with a higher rate of treatment discontinuation. In the context of close clinical monitoring, switching from an antipsychotic with high metabolic risk to one with lower risk to improve metabolic parameters is an effective strategy. [ABSTRACT FROM AUTHOR]

Objective: This randomized trial addressed the risks and benefits of staying on antipsychotic polypharmacy or switching to monotherapy.Method: 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.Results: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

The authors provide an overview of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) sponsored by the National Institute of Mental Health. CATIE was designed to compare a proxy first-generation antipsychotic, perphenazine, to several newer drugs. In phase 1 of the trial, consenting patients were randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months on a double-blind basis. Patients with tardive dyskinesia were excluded from being randomly assigned to perphenazine and were assigned to one of the four second-generation antipsychotics in phase 1A. Clozapine was included in phase 2 of the study. Overall, olanzapine had the longest time to discontinuation in phase 1, but it was associated with significant weight and metabolic concerns. Perphenazine was not significantly different in overall effectiveness, compared with quetiapine, risperidone, and ziprasidone. Also, perphenazine was found to be the most cost-effective drug. Clozapine was confirmed as the most effective drug for individuals with a poor symptom response to previous antipsychotic drug trials, although clozapine was also associated with troublesome adverse effects. There were no differences in neurocognitive or psychosocial functioning in response to medications. Subsequent randomizations suggest that a poor response to an initial medication may mean that a different medication will be more effective or better tolerated. Although the CATIE results are controversial, they are broadly consistent with most previous antipsychotic drug trials and meta-analyses; however, the results may not generalize well to patients at high risk of tardive dyskinesia. Patient characteristics and clinical circumstances affected drug effectiveness; these patient factors are important in making treatment choices. [ABSTRACT FROM AUTHOR]

Objective: This 52-week randomized, double-blind, flexible-dose, multicenter study evaluated the overall effectiveness (as measured by treatment discontinuation rates) of olanzapine, quetiapine, and risperidone in patients early in the course of psychotic illness.Method: Patients were randomly assigned to treatment with olanzapine (2.5-20 mg/day), quetiapine (100-800 mg/day), or risperidone (0.5-4 mg/day) administered in twice-daily doses. Statistical analyses tested for noninferiority in all-cause treatment discontinuation rates up to 52 weeks (primary outcome measure) based on a prespecified noninferiority margin of 20%.Results: A total of 400 patients were randomly assigned to treatment with olanzapine (N=133), quetiapine (N=134), or risperidone (N=133). The mean modal prescribed daily doses were 11.7 mg for olanzapine, 506 mg for quetiapine, and 2.4 mg for risperidone. At week 52, all-cause treatment discontinuation rates were 68.4%, 70.9%, and 71.4% for olanzapine, quetiapine, and risperidone, respectively. Reductions in total score on the Positive and Negative Syndrome Scale (PANSS) were similar for the three treatment groups, but reductions in PANSS positive subscale scores were greater in the olanzapine group (at 12 weeks and at 52 weeks or withdrawal from study) and the risperidone group (at 12 weeks). The most common elicited adverse events for olanzapine were drowsiness (53%), weight gain (51%), and insomnia (38%); for quetiapine, drowsiness (58%), increased sleep hours (42%), and weight gain (40%); and for risperidone, drowsiness (50%), menstrual irregularities in women (47%), and weight gain (41%).Conclusions: Olanzapine, quetiapine, and risperidone demonstrated comparable effectiveness in early-psychosis patients, as indicated by similar rates of all-cause treatment discontinuation. [ABSTRACT FROM AUTHOR]

Objective: The relative effectiveness of newly started antipsychotic drugs for individuals with schizophrenia may depend on multiple factors, including each patient's previous treatment response and the reason for a new medication trial. This randomized, double-blind study compared olanzapine, quetiapine, and risperidone in patients who had just discontinued the older antipsychotic perphenazine.Method: Subjects with schizophrenia (N=114) who had been randomly assigned to and then discontinued perphenazine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study were reassigned randomly to double-blinded treatment with olanzapine, 7.5-30.0 mg/day (N=38); quetiapine, 200-800 mg/day (N=38); or risperidone, 1.5-6.0 mg/day (N=38). The primary aim was to determine whether there were differences among these three treatments in effectiveness, as measured by time to treatment discontinuation for any reason. Secondary outcomes included reasons for treatment discontinuation and measures of drug tolerability.Results: The time to treatment discontinuation was longer for patients treated with quetiapine (median, 9.9 months) and olanzapine (7.1 months) than with risperidone (3.6 months). There were no significant differences between treatments on discontinuation due to inefficacy, intolerability, or patient decision.Conclusions: Among this group of patients with chronic schizophrenia who had just discontinued the older antipsychotic perphenazine, quetiapine and olanzapine were more effective than risperidone, as reflected by longer time to discontinuation for any reason. In the context of other results from the CATIE study, the effectiveness and acceptability of antipsychotic drugs appears to vary considerably according to clinical circumstances. [ABSTRACT FROM AUTHOR]

Objective: This study examined the relative effects of the second-generation antipsychotic drugs and an older representative agent on psychosocial functioning in patients with chronic schizophrenia.Method: Consenting patients were enrolled in the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project. In phase 1, patients were randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months. Clozapine was included for patients who chose this pathway after discontinuing phase 1 due to inefficacy; all other patients received another second-generation antipsychotic. Psychosocial functioning was assessed using the Quality of Life Scale.Results: Psychosocial functioning modestly improved for the one-third of phase 1 patients who reached the primary Quality of Life Scale analysis endpoint of 12 months (average effect size 0.19 SD units). Although for several of the drugs individually there were significant changes from baseline, overall there were no significant differences between the different agents. Results were similar at 6 and 18 months. There were no significant differences among the treatment groups in the amount of change in the Quality of Life Scale total score or subscale scores at 6, 12, or 18 months. Patients treated with clozapine in the efficacy pathway made comparable gains. Early treatment discontinuations, especially among patients most impaired at baseline, limited the ability to achieve more substantial functional gains.Conclusions: All antipsychotic treatment groups in all phases made modest improvements in psychosocial functioning. There were no differences among them after 6, 12, or 18 months. More substantial improvements would likely require more intensive adjunctive psychosocial rehabilitation interventions. [ABSTRACT FROM AUTHOR]

Background. We report here a study examining the relationships between insight and psychopathology, cognitive performance, brain volume and co-morbid depression in 251 patients experiencing a first episode of psychosis, who were then randomly assigned to 2 years of double-blind treatment with either olanzapine or haloperidol.Method. Repeated measures of insight were obtained at baseline and 12, 24, 52 and 104 weeks by the Insight and Treatment Attitudes Questionnaire (ITAQ).Results. Older age, female gender and white ethnicity were associated with more insight. Higher total, positive, negative and general psychopathology scores on the Positive and Negative Syndromes Scale (PANSS) were associated with less insight. Higher depression scores were associated with more insight. Better neurocognitive function and large brain volumes were associated with more insight. More insight throughout the study was associated with longer time to medication non-adherence. However, baseline insight was not significantly related to the probability of discontinuing the study before 2 years. Insight improved significantly over the course of the study, but the improvement in insight was not significantly different between the two antipsychotic treatment groups.Conclusions. Multiple factors contribute to insight. Patients experiencing a first episode of psychosis who have little insight are at increased risk of discontinuing their medication. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study examined the relationship between substance use and psychosocial functioning in schizophrenia. METHODS: Participants were enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness. This study used baseline assessments and examined psychosocial functioning assessed by the Quality of Life Scale. Participants were classified as being abstinent, using substances, or having a substance use disorder. RESULTS: Of the 1,460 participants, 23 percent used substances and 37 percent had a substance use disorder. Of the 544 with a substance use disorder, 87 percent used alcohol, 44 percent used marijuana, and 36 percent used cocaine. Compared with participants who used substances, those with a substance use disorder had higher rates of polysubstance use. Compared with those who were abstinent, those who used substances had higher overall psychosocial functioning, and those with a substance use disorder had similar overall functioning but lower scores on the common objects and activities subscales. Among participants with a substance use disorder, those who used cocaine had lower overall functioning. CONCLUSIONS: Compared with abstinence, substance use and substance use disorder, unless they involved cocaine use, were generally associated with higher or equivalent overall psychosocial functioning. Patterns of substance use were similar to those in the community, suggesting that treatment of substance use disorders in schizophrenia should focus on reconnecting substance users to nonusing peer groups. [ABSTRACT FROM AUTHOR]

Objective: This cross-sectional study aimed to evaluate the interrelationships of psychiatric symptom severity, medical comorbidity, and psychosocial functioning in a sample of patients with schizophrenia by utilizing the baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).Methods: This study utilized baseline data from a multisite trial of antipsychotic pharmacotherapy, which collected data from 1,460 patients with schizophrenia at more than 50 sites in the United States between 2001 and 2003. Bivariate correlations were used to evaluate associations between schizophrenia symptoms and medical comorbidity, and multivariate regression models were used to determine the independent association between medical comorbidity and psychosocial functioning.Results: Of the 1,424 participants in the study sample, 58 percent had at least one medical condition: 20 percent had hypertension, 11 percent had diabetes mellitus, and 9 percent had four or more medical conditions. Medical comorbidity was associated with poorer neurocognitive functioning and greater depressive symptoms. The number of medical conditions was not associated with more severe schizophrenia symptoms. Both the number of medical conditions and physical health status were only weak correlates of psychosocial functioning.Conclusions: In this sample of persons with schizophrenia, medical comorbidity was associated with depression and neurocognitive impairment but was a weaker correlate of psychosocial functioning or employment status than psychotic symptoms, depression, and neurocognitive impairment. [ABSTRACT FROM AUTHOR]

Background: In the treatment of schizophrenia, changing antipsychotics is common when one treatment is suboptimally effective, but the relative effectiveness of drugs used in this strategy is unknown. This randomized, double-blind study compared olanzapine, quetiapine, risperidone, and ziprasidone in patients who had just discontinued a different atypical antipsychotic.Method: Subjects with schizophrenia (N=444) who had discontinued the atypical antipsychotic randomly assigned during phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) investigation were randomly reassigned to double-blind treatment with a different antipsychotic (olanzapine, 7.5-30 mg/day [N=66]; quetiapine, 200-800 mg/day [N=63]; risperidone, 1.5-6.0 mg/day [N=69]; or ziprasidone, 40-160 mg/day [N=135]). The primary aim was to determine if there were differences between these four treatments in effectiveness measured by time until discontinuation for any reason.Results: The time to treatment discontinuation was longer for patients treated with risperidone (median: 7.0 months) and olanzapine (6.3 months) than with quetiapine (4.0 months) and ziprasidone (2.8 months). Among patients who discontinued their previous antipsychotic because of inefficacy (N=184), olanzapine was more effective than quetiapine and ziprasidone, and risperidone was more effective than quetiapine. There were no significant differences between antipsychotics among those who discontinued their previous treatment because of intolerability (N=168).Conclusions: Among this group of patients with chronic schizophrenia who had just discontinued treatment with an atypical antipsychotic, risperidone and olanzapine were more effective than quetiapine and ziprasidone as reflected by longer time until discontinuation for any reason. [ABSTRACT FROM AUTHOR]

Objective: The authors compared the efficacy and safety of three atypical antipsychotics (clozapine, olanzapine, and risperidone) with one another and with haloperidol in the treatment of patients with chronic schizophrenia or schizoaffective disorder.Method: In a double-blind trial, 157 inpatients with a history of suboptimal treatment response were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol for 14 weeks (an 8-week escalation and fixed-dose period followed by a 6-week variable-dose period).Results: Clozapine, risperidone, and olanzapine (but not haloperidol) resulted in statistically significant improvements in total score on the Positive and Negative Syndrome Scale. Improvements seen in total and negative symptom scores with clozapine and olanzapine were superior to haloperidol. The atypical drugs, particularly olanzapine and clozapine, were associated with weight gain.Conclusions: The effects of atypical antipsychotics in this population were statistically significant but clinically modest. The overall pattern of results suggests that clozapine and olanzapine have similar general antipsychotic efficacy and that risperidone may be somewhat less effective. Clozapine was the most effective treatment for negative symptoms. However, the differences among treatments were small. [ABSTRACT FROM AUTHOR]

Background: The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study.Methods: A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments.Results: Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects.Conclusions: The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism. [ABSTRACT FROM AUTHOR]

Background: Insomnia is common in schizophrenia and associated with suicide. Clozapine has anti-suicidal properties and beneficial effects on sleep. Whether effects on insomnia mediate the anti-suicidal properties of clozapine remains unclear., Methods: In n = 76 patients from the Clinical Antipsychotic Trials of intervention effectiveness schizophrenia trial using a within-subjects design, we investigated whether improvement in terminal insomnia was associated with improvement in suicidal ideation (SI) after treatment with non-clozapine antipsychotics, and then after treatment with clozapine, using binary logistic regression. Terminal insomnia and SI over the past 2 weeks were assessed before and after both non-clozapine antipsychotic and clozapine treatment with the Calgary Depression Scale for Schizophrenia., Results: There was no association between improved terminal insomnia and resolution of SI after treatment with non-clozapine antipsychotics (OR = 0.2, 95% CI 0.0-9.0, p = 0.41). In the same patients, improved terminal insomnia was associated with resolution of SI after clozapine treatment (OR = 14.6, 95% CI 1.7-129.2, p = 0.02)., Conclusions: Improved terminal insomnia is associated with improved SI following clozapine treatment. Findings warrant replication in a larger sample with standard instruments in the assessment of insomnia and suicide, but suggest beneficial effects on sleep as a mediator of the anti-suicidal properties of clozapine. Future mechanistic studies are also needed., (© 2024 American Association of Suicidology.)

Introduction: Insomnia commonly occurs in schizophrenia, and insomnia is associated with suicide risk. Clozapine has anti-suicidal properties and beneficial effects on sleep. We performed a meta-analysis of insomnia in randomized controlled trials (RCTs) of patients with schizophrenia treated with clozapine. We hypothesized that compared to clozapine there is an increased odds of insomnia in patients treated with other antipsychotics., Methods: We systematically searched PubMed, PsycINFO, and Web of Science databases. We included RCTs, in English, with data on insomnia in patients with schizophrenia treated with clozapine versus other antipsychotics. Data were pooled using a random effects model., Results: Eight RCTs (1952 patients: 922 on clozapine and 1030 on other antipsychotics) met inclusion criteria. Patients treated with other antipsychotics versus clozapine had a significant increased odds of insomnia (22.3 % versus 12.4 %, OR = 2.20, 95 % CI = 1.64-2.94, p < 0.01). Olanzapine, quetiapine, risperidone, and ziprasidone were each associated with significant increased odds of insomnia compared to clozapine. In meta-regression analyses, clozapine dose, publication year, sex, trial duration, and study quality score were unrelated to the association; however, there was a significant association with age. The observed ORs for insomnia from RCTs were almost perfectly correlated with reported ORs from pharmacovigilance data., Conclusion: Clozapine is associated with significantly less insomnia compared to other antipsychotics. Findings provide additional evidence for improvement in sleep as a potential pathway underlying clozapine's anti-suicidal properties. A greater mechanistic understanding of this association is needed., Competing Interests: Declaration of competing interest Dr. Miller has no disclosures relevant to the present work. In the past year, Dr. Miller received research support from NIMH, SMRI, and Augusta University; and Honoraria from Carlat Psychiatry and Psychiatric Times. Dr. McEvoy has no disclosures relevant to the present work. In the past year, Dr. McEvoy participated in Advisory Boards for Ameritox, Forum, Merck, and Otsuka; and has received research grants from Alkermes, Auspex, Avenir, and Otsuka. Dr. McCall has no disclosures relevant to the present work. In the past year, Dr. McCall has received honoraria from Anthem Inc. and Wolters Kluwer Publishing; and research support from MECTA Corp, and Merck; and is a scientific advisor for Eisai, Idorsia, and Janssen., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Impaired insight poses a challenge in the treatment of patients with schizophrenia because of its potential to jeopardize therapeutic engagement and medication adherence. This study explored how insight impairment, graded from none to extreme, is related to patient-reported mental health status, depression, and neurocognition in schizophrenia., Methods: In a post hoc analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (NCT00014001), insight was measured using the Positive and Negative Syndrome Scale (PANSS) Item G12 (lack of insight). Additional assessments for this analysis included the 12-Item Short-Form Health Survey (SF-12) Mental Component Summary (MCS), physician- and patient-reported Clinical Global Impression-Severity (CGI-S), MATRICS Consensus Cognitive Battery, and Calgary Depression Scale for Schizophrenia. Relationships between patient-reported outcomes and PANSS total and Item G12 ratings were evaluated., Results: Among 1431 CATIE study participants in this analysis, increasingly impaired insight at baseline was significantly associated with better patient-reported quality of life (QoL), lower baseline depression, and greater divergence between physician- and patient-reported illness severity. Patients with more severely impaired insight reported milder illness compared with physician reports, particularly those with moderate-severe to extreme impairment (PANSS Item G12 rating ≥ 5), approximately 10% (138/1431) of CATIE participants. For the 90% of patients with PANSS Item G12 ratings < 5, patient-reported QoL decreased with increasing symptoms. SF-12 MCS scores were linearly related to baseline PANSS total score only in patients with PANSS total score < 90 (moderately ill or better), and better symptom scores were associated with higher QoL. No significant relationship between insight and neurocognition was observed., Conclusions: In the small subgroup (10%) of CATIE study patients with schizophrenia and PANSS Item G12 ratings ≥5, moderate-severe-severe/extreme insight impairment was associated with significantly more positive perception of QoL and illness severity by the patient versus the treating physician. This was not observed in the remaining 90% of patients with normal to moderately impaired insight, suggesting that poor insight as a threat to the validity of self-report is uncommon., (© 2022. The Author(s).)

Schizophrenia is a severe mental disorder with various medical comorbidities and early mortality. Hyperprolactinemia is common in women and its impact on sexual function, galactorrhea and amenorrhea is well known. This paper evaluates the risk of 25-hydroxy vitamin D deficiency and other metabolic related laboratory abnormalities in women with schizophrenia having hyperprolactinemia (N = 43). The mean prolactin level in these women was 88.5 ± 56.0 ng/mL. We found that 100% of women were overweight of which 74% (32/43) of the women were obese, 56% (23/41) had abnormal total cholesterol levels and 30% (13/43) had high fasting blood glucose. Vitamin D levels were considered deficient or inadequate in 37% of women. We did not see significant correlations of prolactin with laboratory measures, however all female patients had elevated and high prolactin levels, leading to low variability in a small sample, which may have precluded seeing any direct relationships. Recognizing prolactin related side effects and understanding the role of other health measures seen in women with antipsychotic induced hyperprolactinemia in our female patients are critical steps toward better personalization of their care and recovery., (Copyright © 2022. Published by Elsevier Ltd.)

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., (© 2021. The Author(s).)

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., (Copyright © 2021. Published by Elsevier B.V.)

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., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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]).

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  < .001). Initial/middle insomnia was associated with a significant, 5.5-fold increased odds of suicide attempt in the past 6 months (OR = 5.5, 95% CI = 1.4-21.1, P  = .013). Terminal insomnia was also a significant indicator of higher Positive and Negative Syndrome Scale total (β = 0.12, P  < .001), positive subscale (β = 0.11, P  < .001), and general psychopathology subscale (β = 0.14, P  < .001) scores. There were no other significant associations between insomnia, suicidal thinking or behavior, and psychopathology., Conclusions: Insomnia is associated with suicidal ideation, recent suicide attempt, and greater psychopathology in schizophrenia. Findings provide additional evidence that formal assessment of insomnia is relevant to the clinical care of patients with schizophrenia as an indicator of suicidal ideation and behavior, as well as symptom severity., Trial Registration: ClinicalTrials.gov identifier: NCT00014001., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

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., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

​​​​​​ 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., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

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., Competing Interests: Declaration of competing interest Ms. Feng declares no conflict of interest. Dr. McEvoy has nothing to disclose for the present work. In the past 12 months, Dr. McEvoy participated in Advisory Boards for Otsuka, Merck, Forum, and Ameritox; and has received research grants from Otsuka, Avenir, Auspex, and Alkermes. Dr. Miller has nothing to disclose for the present work. In the past 12 months, Dr. Miller received research support from Alkermes, Augusta University, NARSAD, the National Institute of Mental Health, and the Stanley Medical Research Institute; and Honoraria from Psychiatric Times., (Copyright © 2020 Elsevier B.V. All rights reserved.)

​​ 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)., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

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., Competing Interests: Declaration of competing interest PAN and MJB have received research grant funding from Otsuka Pharmaceutical. TSS was an investigator in a clinical trial sponsored by Auspex Pharmaceuticals (now Teva Pharmaceutical Industries) and participated in a continuing medical education presentation supported by an independent educational grant from Intra-Cellular Therapies Inc. All other authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Undergraduate biochemistry students frequently find the quantitative treatment of weak acids and bases troublesome. Given the pK a of a weak acid HA, for instance, many students struggle to calculate the pH of a solution of the conjugate base A - at concentration C, pH(A - , C). The traditional method involves calculating the base dissociation constant K b and the artificial quantity pOH before reaching pH, but these steps increase the risk of mistakes and provide little insight into acid-base equilibria. The alternative method presented here allows students to calculate the pH of a weak base solution from the pK a of its conjugate acid without calculating K b and pOH, using a memorable relationship: pH(HA, C) + pH(A - , C) = pK a  + 7., (© 2020 International Union of Biochemistry and Molecular Biology.)

​​​​Early Recognition and Treatment of Tardive Dyskinesia in Patients With Mood Disorders and Schizophrenia Click to enlarge page​​., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

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., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Bacterial biofilms can cause problems in various arenas, from the fouling of water processing equipment to persistent in vivo infections. Silver nanoparticles are promising antimicrobial agents with activity against biofilm bacteria. Here we describe the synthesis of antimicrobial silver nanoparticles and the measurement of their antimicrobial activity against E. coli colony biofilms, which is a popular in vitro biofilm model for antibiotic assays.

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., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

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., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

Gram-negative bacteria such as Escherichia coli commonly resist β-lactam antibiotics using plasmid-encoded β-lactamase enzymes. Bacterial strains that express β-lactamases have been found to detoxify liquid cultures and thus to protect genetically susceptible strains, constituting a clear laboratory example of social protection. These results are not necessarily general; on solid media, for instance, the rapid bactericidal action of β-lactams largely prevents social protection. Here, we tested the hypothesis that the greater tolerance of biofilm bacteria for β-lactams would facilitate social interactions. We used a recently isolated E. coli strain, capable of strong biofilm formation, to compare how cooperation and exploitation in colony biofilms and broth culture drives the dynamics of a non-conjugative plasmid encoding a clinically important β-lactamase. Susceptible cells in biofilms were tolerant of ampicillin-high doses and several days of exposure were required to kill them. In support of our hypothesis, we found robust social protection of susceptible E. coli in biofilms, despite fine-scale physical separation of resistant and susceptible cells and lower rates of production of extracellular β-lactamase. In contrast, social interactions in broth were restricted to a relatively narrow range of ampicillin doses. Our results show that β-lactam selection pressure on Gram-negative biofilms leads to cooperative resistance characterized by a low equilibrium frequency of resistance plasmids, sufficient to protect all cells., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2019.)

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.

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., Competing Interests: Dr. Buchanan in the past 3 years has served on advisory boards for Avanir, Astellas Pharma, ITI, Inc., and Roche and has served as a consultant for Takeda, and Upsher-Smith Laboratories, Inc. Dr. Csernansky in the last 3 years has served as a consultant for Indivior Pharmaceuticals and Aptinyx, Inc. Dr. Goff has received research support from Avanir Pharmaceuticals. Dr. Green has been a consultant to AiCure, Lundbeck, and Takeda, and he is on the scientific board ofCadent. He has received research funds from FORUM. In the past 3 years, Dr. Jarskog has received research grant funding from Auspex/Teva, Boehringer-Ingelheim and Otsuka. In the past 3 years, Dr. Kimhy has served as a consultant for Neurocog Trials. Dr. Lieberman neither accepts nor receives any personal financial remuneration for consulting, speaking or research activities from any pharmaceutical, biotechnology or medical device companies. He receives support administered through Columbia University and the Research Foundation for Mental Hygiene in the form of funding and medication supplies for investigator initiated research from Denovo, Taisho, Pfizer, Sunovion, and Genentech, and for company sponsored phase II, III and IV studies from Alkermes, Allergan and Boehringer Ingelheim, and is a consultant to or member of the advisory board of Intracellular Therapies, Lilly, Pierre Fabre, Pear Therapeutics and Psychogenics for which he receives no remuneration. He is a paid consultant for Clintara, a clinical research services organization, and holds a patent from Repligen that yields no royalties. Dr. McEvoy has received research grant funding from Alkermes, BoehringerIngelheim, Neurocrine, Takeda, and TEVA and has given disease state talks for Neurocrine. Dr. Marder has served as a consultant for Abbvie, Roche, Otsuka, Teva, Neurocrine, Newron, and Lundbeck. Dr. Marder has received research support from Neurocrine, Takeda, and Boeringer-Ingelheim. Dr. Richard Keefe currently or in the past 3 years has received honoraria, served as a consultant, speaker, or advisory board member for Abbvie, Acadia, Aeglea, Akebia, Akili, Alkermes, Allergan, ArmaGen, Astellas, Avanir, AviNeuro/ChemRar, Axovant, Biogen, Boehringer-Ingelheim, Cerecor, CoMentis, Critical Path Institute, FORUM, Gammon Howard & Zeszotarski, Global Medical Education (GME), GW Pharmaceuticals, Intracellular Therapeutics, Janssen, Kempharm, Lundbeck, Lysogene, MedScape, Mentis Cura, Merck, Merrakris Therapetics, Minerva Neurosciences Inc., Mitsubishi, Montana State University, Monteris, Moscow Research Institute of Psychiatry, Neuralstem, Neuronix, Novartis, NY State Office of Mental Health, Orygen, Otsuka, Paradigm Testing, Percept Solutions, Pfizer, Pharm-Olam, Regenix Bio, Reviva, Roche, Sangamo, Sanofi, SOBI, Six Degrees Medical, Sunovion, Takeda, Targacept, Teague Rotenstreich Stanaland Fox & Holt, Thrombosis Research Institute, University of Moscow, University of Southern California, University of Texas Southwest Medical Center, WebMD, and Wilson Therapeutics. Dr. Keefe has currently or in the past 3 years received research funding from the National Institute of Mental Health and Boehringer-Ingelheim. Dr. Keefe receives royalties from versions of the BAC testing battery, the MATRICS Battery (BACS Symbol Coding), and the Virtual Reality Functional Capacity Assessment Tool (VRFCAT). He is also a shareholder in NeuroCog Trials, Inc. and Sengenix. Mr. Kraus, Dr. Gold, Dr. Barch, Ms. Walker, Dr. Chun, Dr. Javitt, Dr. Mesholam-Gately, Dr. Seidman, Ms. Ball, Dr. Kern, Dr. McMahon and Dr. Robinson report no competing interests., (© 2019 Published by Elsevier Inc.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: External fixation surgery is frequently complicated by percutaneous pin site infection focused on the surface of the fixator pin. The primary aim of this study was to compare biofilm growth of clinically isolated pin site bacteria on Kirschner wires of different materials., Materials and Methods: Two commonly infecting species, Staphylococcus epidermidis and Proteus mirabilis , were isolated from patients' pin sites. A stirred batch bioreactor was used to grow these bacteria as single culture and co-cultured biofilms on Kirschner wires made of three different materials: stainless steel, hydroxyapatite-coated steel and titanium alloy., Results: We found that the surface density of viable cells within these biofilms was 3x higher on stainless steel and 4.5x higher on hydroxyapatite-coated wires than on the titanium wires., Conclusion: Our results suggest that the lower rates of clinical pin site infection seen with titanium Kirschner wires are due to, at least in part, titanium's better bacterial biofilm resistance., Clinical Significance: Our results are consistent with clinical studies which have found that pin site infection rates are reduced by the use of titanium relative to stainless steel or hydroxyapatite-coated pins., How to Cite This Article: McEvoy JP, Martin P, Khaleel A, et al. Titanium Kirschner Wires Resist Biofilms Better Than Stainless Steel and Hydroxyapatite-coated Wires: An In Vitro Study. Strategies Trauma Limb Reconstr 2019;14(2):57-64., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2019; Jaypee Brothers Medical Publishers (P) Ltd.)

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., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

The electrochemistry of aryl diazonium salts is usually dominated by one-electron reduction, loss of dinitrogen, and the grafting of aryl radicals onto the electrode. In contrast, p -nitro- and p -cyanobenzene diazonium salts dissolved in mixed aqueous-acetonitrile solvents showed diffusion-limited, quasi-reversible, two-electron cyclic voltammetry. Voltammetric pH-dependence and spectrophotometric kinetic studies suggest that the basicity and low polarity of the aqueous solvent mixture has revealed the biologically-significant interconversion of diazohydroxide and diazene., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

This study compared plastic ingestion between pelagic and benthic fish populations from two UK watersheds: the Thames Estuary and the Firth of Clyde. The alimentary canals of 876 individuals were examined. Of twenty-one estuarine species investigated, fourteen ingested plastics, including predator (fish) and prey (shrimp) species. Overall, 32% of organisms ingested plastic, mostly fibres (88% of total plastics). More flatfish (38%) ingested plastics than other benthic species (17%). In the Thames, more plastic was ingested by pelagic species (average number of plastic pieces ingested: 3.2) and flatfish (average number of plastic pieces ingested: 2.9) than by shrimp (average number of plastic pieces ingested: 1). More fish from the Clyde ingested plastic than similar Thames species (39% compared to 28% respectively); however, the average amount of plastic ingested did not differ between the sites., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

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., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

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.

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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.