Improved insomnia is one pathway underlying the anti-suicidal properties of clozapine.

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.

Meta-analysis of clozapine and insomnia in schizophrenia.

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.

Impaired insight in schizophrenia: impact on patient-reported and physician-reported outcome measures in a randomized controlled trial.

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.

25-Hydroxyvitamin D and metabolic-related laboratory values in women with schizophrenia and hyperprolactinemia.

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.

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

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.

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.

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

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.

Insomnia, Suicidal Ideation, and Suicide Attempts in the Clinical Antipsychotic Trials of Intervention Effectiveness.

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 (ß = 0.12, P < .001), positive subscale (ß = 0.11, P < .001), and general psychopathology subscale (ß = 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.

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

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.

Monitoring for myocarditis during treatment initiation with clozapine.

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.

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

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]).

Longitudinal study of inflammatory markers and psychopathology in schizophrenia.

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 (ß = -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 (ß = -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.

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

​​​​​​ 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.

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

​​ 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).

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

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.

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

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

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

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.

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

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.

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

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.