Recognition and management of clozapine adverse effects: A systematic review and qualitative synthesis.

OBJECTIVE: Clozapine is substantially underutilized in most countries and clinician factors including lack of knowledge and concerns about adverse drug effects (ADEs) contribute strongly to treatment reluctance. The aim of this systematic review was to provide clinicians with a comprehensive information source regarding clozapine ADEs. METHODS: PubMed and Embase databases were searched for English language reviews concerned with clozapine ADEs; publications identified by the automated search were manually searched for additional relevant citations. Following exclusion of redundant and irrelevant reports, pertinent information was summarized in evidence tables corresponding to each of six major ADE domains; two authors reviewed all citations for each ADE domain and summarized their content by consensus in the corresponding evidence table. This study was conducted in accordance with PRISMA principles. RESULTS: Primary and secondary searches identified a total of 305 unique reports, of which 152 were included in the qualitative synthesis. Most clozapine ADEs emerge within 3 months, and almost all appear within 6 months, after initiation. Notable exceptions are weight gain, diabetic ketoacidosis (DKA), severe clozapine-induced gastrointestinal hypomotility (CIGH), clozapine-induced cardiomyopathy (CICM), seizures, and clozapine-induced neutropenia (CIN). Most clozapine ADEs subside gradually or respond to dose reduction; those that prompt discontinuation generally do not preclude rechallenge. Rechallenge is generally inadvisable for clozapine-induced myocarditis (CIM), CICM, and clozapine-induced agranulocytosis (CIA). Clozapine plasma levels >600-1000 µg/L appear more likely to cause certain ADEs (e.g., seizures) and, although there is no clear toxicity threshold, risk/benefit ratios are generally unfavorable above 1000 µg/L. CONCLUSION: Clozapine ADEs rarely require discontinuation.

Treatment Bed Utilization Following Placement in a Foster Care Program for Veterans with Serious Mental Illness.

Hospital and residential treatment bed utilization rates were measured before and after foster home placement in individuals with serious mental illness. Medical records of all Veterans consecutively enrolled in a Department of Veterans Affairs Community Residential Care (CRC) program during a 6 year period (N = 140) were reviewed retrospectively. Treatment bed days were tabulated by bed type (psychiatric hospital, inpatient detoxification, medical hospital, physical rehabilitation, and psychosocial residential treatment) for each patient during symmetric pre- and post-placement time intervals. Pre- and post-placement bed days were compared using the paired-sample t test in a naturalistic one-group pretest-posttest analytic design. Psychiatric hospital and residential treatment bed days were significantly reduced post-placement (-77.5% and -99.8%, respectively). Most patients (89.0%) had fewer psychiatric hospital bed days post-placement, and all patients with pre-placement residential treatment program bed days had fewer of those days post-placement. Longer CRC placements were associated with greater reductions in bed utilization.

A COMMENTARY ON IMPROVING CLOZAPINE ACCESSIBILITY AND REDUCING TREATMENT COST.

Clozapine is vastly underutilized in the United States and many other countries. The most commonly cited reason for this is the requirement for frequent blood monitoring, which continues for the duration of treatment. Despite the notoriety clozapine achieved early in its development, accumulated evidence has demonstrated that close blood monitoring beyond the first year of treatment yields minimal safety benefits. Many health care systems have relaxed clozapine blood monitoring requirements during the COVID-19 pandemic for practical reasons, and this presents an opportunity to implement permanent, long overdue changes in mandated monitoring that reflect what has been learned about the real risk for blood dyscrasias with clozapine.

Recognizing psychiatric presentations of anti-NMDA receptor encephalitis in children and adolescents: A synthesis of published reports.

AIM: The aim of this study was to improve early recognition of anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDArE) in children and adolescents by identifying characteristic temporal patterns of clinical features in patients likely to be referred for psychiatric evaluation. In this form of autoimmune encephalitis, NMDAr hypofunction is caused by autoantibodies to receptor surface components. Clinical outcomes following prompt immunotherapy are usually good, but delayed treatment often results in a protracted course with significant residual disability or death. Anti-NMDArE frequently mimics psychiatric disorders, so most patients are referred initially to a psychiatrist and treated for days or weeks before being correctly diagnosed. METHODS: A systematic search of PubMed and EMBASE electronic databases identified all published reports of antibody-confirmed anti-NMDArE associated with psychiatric symptoms in patients <19 years old. Redundant reports were eliminated manually. For each patient, the order in which each feature was first observed was ranked relative to others. Median temporal ranks were used to compare the sequencing of individual features and major symptom domains. RESULTS: One hundred and sixty seven cases (121 females) met the inclusion criteria. The most common features were dyskinesias (77.8%), seizures (72.5%), mutism or staring (40.7%), insomnia (39.5%), language dysfunction (36.5%), fever (31.1%), disorientation/confusion (28.7%), reduced arousal (28.1%), and memory disturbance (26.9%). The configuration and temporal sequencing of features were highly variable between individuals. CONCLUSION: Clinicians need to suspect this disorder: if new behavioral symptoms arise in the context of a recent viral prodrome; if they are accompanied by dyskinesias, seizures or insomnia; or if psychiatric symptoms are unusual (e.g., non-verbal auditory hallucinations).

Frequency and temporal sequence of clinical features in adults with anti-NMDA receptor encephalitis presenting with psychiatric symptoms.

BACKGROUND: Anti-NMDA receptor (NMDAr) encephalitis is the most common autoimmune encephalitis in adults. It mimics psychiatric disorders so often that most patients are initially referred to a psychiatrist, and many are misdiagnosed. Without prompt and effective treatment, patients are likely to suffer a protracted course with significant residual disability, or death. This study focuses on the frequency and chronology of salient clinical features in adults with anti-NMDAr encephalitis who are likely to be first evaluated by a psychiatrist because their presentation suggests a primary psychiatric disorder. METHODS: A systematic search of PubMed and EMBASE databases identified published reports of anti-NMDAr encephalitis associated with prominent behavioral or psychiatric symptoms. After eliminating redundancies, the frequencies and relative timing of clinical features were tabulated. Signs and symptoms were assigned temporal ranks based on the timing of their first appearance relative to the first appearance of other signs and symptoms in each patient; median ranks were used to compare temporal sequencing of both individual features and major symptom domains. RESULTS: Two hundred thirty unique cases (185 female) met study inclusion criteria. The most common features were seizures (60.4%), disorientation/confusion (42.6%), orofacial dyskinesias (39.1%), and mutism/staring (37.4%). Seizures, fever, and cognitive dysfunction were often the earliest features to emerge, but psychiatric features predominated and sequencing varied greatly between individuals. CONCLUSIONS: Clinicians should consider anti-NMDAr encephalitis when new psychiatric symptoms are accompanied by a recent viral prodrome, seizures or unexplained fever, or when the quality of the psychiatric symptoms is unusual (e.g. non-verbal auditory hallucinations).

Potentially fatal outcomes associated with clozapine.

Clozapine has been shown to be the most efficacious therapy for treatment resistant schizophrenia, estimated at one third of all schizophrenia cases. There is significant morbidity and mortality associated with clozapine including risk of agranulocytosis, aspiration pneumonia, bowel ischemia, myocarditis, seizures, and weight gain. Here we present a case of a 62-year-old man with chronic paranoid schizophrenia refractory to numerous antipsychotics who was started on clozapine therapy during an acute inpatient psychiatric admission. Within three weeks of starting clozapine, the patient developed flu-like symptoms, pleuritic chest pain, and was sent to a medical hospital for evaluation. After transfer, the patient had a rapidly deteriorating course with newly developed congestive heart failure, acute respiratory failure requiring intubation, and cardiovascular collapse requiring vasopressors. The patient expired within two days of transfer and four days after initial symptoms developed. The underlying etiology in this case is likely clozapine induced myocarditis leading to rapid cardiovascular collapse and death. Mortality with clozapine induced myocarditis has been estimated up to 24%. Given that 90% of clozapine cardiotoxic sequelae are seen in the first month post-initiation, more rigorous post-initiation surveillance is recommended for the first four weeks of clozapine with weekly cardiac enzymes (troponins, creatinine kinase-MB), EKG, and acute inflammatory markers (C-reactive protein, and erythrocyte sedimentation rate).

A systematic review of sex and age factors in neuroleptic malignant syndrome diagnosis frequency.

OBJECTIVE: To examine sex and age distributions in neuroleptic malignant syndrome (NMS) patients based on a systematic literature review. METHOD: EMBASE and PubMed databases were searched to identify any observation of NMS published from January 1, 1998 through November 1, 2014 that was accessible and interpretable (using language translation software). Redundant and equivocal reports were excluded. Sex ratio and age distributions were examined using standard graphical techniques and measures of association. RESULTS: Twenty-eight independent sex ratio estimates were included. Males predominated in most (75%) estimates with an overall median sex ratio of 1.47 (95% CI, 1.20-1.80). NMS incidence peaked at age 20-25 years and declined steadily thereafter, with males consistently outnumbering females at all but the oldest age intervals. CONCLUSION: NMS patients are 50% more likely to be males, and NMS is most likely to occur in young adulthood.

A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome.

BACKGROUND: Neuroleptic malignant syndrome requires prompt recognition for effective management, but there are no established diagnostic criteria. This is the first validation study of recently published international expert consensus (IEC) diagnostic criteria, which include priority points assigned on the basis of the importance of each criterion for making a diagnosis of neuroleptic malignant syndrome. METHODS: Data were extracted from 221 archived telephone contact reports of clinician-initiated calls to a national telephone consultation service from 1997 to 2009; each case was given a total priority point score on the basis of the IEC criteria. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (DSM-IV-TR) research criteria, in original form and modified to accept less than "severe" rigidity, served as the primary diagnostic reference standard. Consultants' diagnostic impressions were used as a secondary reference standard. Receiver operating characteristic curve analysis was used to optimize the priority point cutoff score with respect to the reference standards. RESULTS: Area under the receiver operating characteristic curve ranged from 0.715 (95% confidence interval, 0.645-0.785; P = 1.62 × 10) for consultant diagnoses to 0.857 (95% confidence interval, 0.808-0.907; P < 5 × 10) for modified DSM-IV-TR criteria. The latter was associated with 69.6% sensitivity and 90.7% specificity. CONCLUSIONS: Agreement was best between IEC criteria with a cutoff score of 74 and modified DSM-IV-TR criteria (sensitivity, 69.6%; specificity, 90.7%); this cutoff score demonstrated the highest agreement in all comparisons. Consultant diagnoses showed much better agreement with modified, compared with original, DSM-IV-TR criteria, suggesting that the DSM-IV-TR criterion of "severe" rigidity may be more restrictive than what most knowledgeable clinicians use in practice.

Preparing residents in training to become health-care leaders: a pilot project.

OBJECTIVE: The aim of this study is to describe a successful and exportable training module that addresses Next Accreditation System (NAS) behavioral milestones for leadership competencies. METHODS: A novel leadership training module, which required the creation of original business plans by teams of residents, was incorporated into a psychiatry PGY-2 training curriculum. RESULTS: In the creation and presentation of their business plans, the residents demonstrated competencies in the NAS functional domains of interpersonal and communication skills, professionalism, practice-based learning and improvement, and systems-based practice. Residents who responded with feedback after completing the course were very positive about their experience. CONCLUSIONS: The leadership training module described here allowed residents to acquire and demonstrate many of the competencies specified in leadership-oriented NAS milestones. The module did not require additional funding or a formal rotation or "track," is scalable to accommodate any number of residents and can be modified based on available local teaching resources.

Cognitive task performance and symptoms contribute to personality abnormalities in first hospitalized schizophrenia.

Chronic schizophrenia patients have personality abnormalities and cognitive deficits that are associated with poor clinical, social, and vocational outcomes. Very few studies have examined relationships between personality and cognitive function, and chronic illness effects may have confounded those studies. In this study personality traits in clinically stable first episode schizophrenia patients (21M, 9F) and psychiatrically healthy controls (38M, 24F) were measured with the NEO-FFI, a self-report measure of neuroticism, extraversion, openness, agreeableness, and conscientiousness. All subjects completed the Information, Digit Span, Vocabulary, and Digit Symbol subtests of the Wechsler Adult Intelligence Scale; and Trails A and B. Standard statistical techniques were used to quantify relationships between personality and symptom levels and/or task performance, and relative contributions of diagnosis and task performance to personality variance. Patients showed elevated mean neuroticism and openness, and reduced mean extraversion, agreeableness and conscientiousness. Task performance and negative symptoms contributed significantly and uniquely to most personality dimensions in patients. Task performance accounted for significant amounts of personality variance even after accounting for diagnosis, and it also contributed to personality variance in controls. These results suggest that cognitive deficits and negative symptoms contribute to consistently observed personality abnormalities in this disorder, and that the contribution of neuropsychological performance to personality variance may be independent of diagnostic classification. Personality abnormalities in schizophrenia may stem from the neurocognitive deficits associated with this disorder, and add to their adverse effects on social and vocational functioning.

Neuropsychological performance within-person variability is associated with reduced treatment consent capacity.

OBJECTIVE: The capacity of older adults to make healthcare decisions is often impaired in dementia and has been linked to performance on specific neuropsychological tasks. Within-person across-test neuropsychological performance variability has been shown to predict future dementia. This study examined the relationship of within-person across-test neuropsychological performance variability to a current construct of treatment decision (consent) capacity. METHODS: Participants completed a neuropsychological test battery and a standardized capacity assessment. Standard scores were used to compute mean neuropsychological performance and within-person across-test variability. Assessments were performed in the participant's preferred location (e.g., outpatient clinic office, senior center, or home). Participants were recruited from the community with fliers and advertisements and consisted of men (N = 79) and women (N = 80) with (N = 83) or without (N = 76) significant cognitive impairment. Participants completed the MacArthur Competence Assessment Tool-Treatment and 11 neuropsychological tests commonly used in the cognitive assessment of older individuals. RESULTS: Neuropsychological performance and within-person variability were independently associated with continuous and dichotomous measures of capacity, and within-person neuropsychological variability was significantly associated with within-person decisional ability variability. Prevalence of incapacity was greater than expected in participants with and without significant cognitive impairment when decisional abilities were considered separately. CONCLUSION: These findings are consistent with an emerging construct of consent capacity in which discrete decisional abilities are differentially associated with cognitive processes and indicate that the sensitivity and accuracy of consent capacity assessments can be improved by evaluating decisional abilities separately.

WITHDRAWN:A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome.

Ahead of Print article withdrawn by publisher.

An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method.

OBJECTIVE: The lack of generally accepted diagnostic criteria for neuroleptic malignant syndrome (NMS) impedes research and clinical management of patients receiving antipsychotic medications. The purpose of this study was to develop NMS diagnostic criteria reflecting a broad consensus among clinical knowledge experts, represented by an international multispecialty physician panel. PARTICIPANTS: Eleven psychiatrists, 2 neurologists, 2 anesthesiologists, and 2 emergency medicine specialists participated in a formal Delphi consensus procedure. EVIDENCE: A core bibliography consisting of 12 prominent, current reviews of the NMS literature was identified by an objective, comprehensive electronic search strategy. Each panel member was given a copy of these references and asked to examine them before commencing the survey process. CONSENSUS PROCESS: After reviewing the core bibliography, panel members were asked to list any clinical signs or symptoms or diagnostic studies that they believed, on the basis of their knowledge and clinical experience, were useful in making a diagnosis of NMS. In subsequent survey rounds, panel members assigned priority points to these items, and items that failed to receive a minimum priority score were eliminated from the next round. Information about individual panel member responses was fed back to the group anonymously in the form of the group median or mean and the number of members who had ranked or scored each survey item. The a priori consensus endpoint was defined operationally as a change of 10% or less in the mean priority score for any individual item, and an average absolute value change of 5% or less across all items, between consecutive rounds. The survey was conducted from January 2009 through September 2009. RESULTS: Consensus was reached on the fifth round regarding the following criteria: recent dopamine antagonist exposure, or dopamine agonist withdrawal; hyperthermia; rigidity; mental status alteration; creatine kinase elevation; sympathetic nervous system lability; tachycardia plus tachypnea; and a negative work-up for other causes. The panel also reached a consensus on the relative importance of these criteria and on the following critical values for quantitative criteria: hyperthermia, > 100.4°F or > 38.0°C on at least 2 occasions; creatine kinase elevation, at least 4 times the upper limit of normal; blood pressure elevation, ≥ 25% above baseline; blood pressure fluctuation, ≥ 20 mm Hg (diastolic) or ≥ 25 mm Hg (systolic) change within 24 hours; tachycardia, ≥ 25% above baseline; and tachypnea, ≥ 50% above baseline. CONCLUSIONS: These diagnostic criteria significantly advance the field because they represent the consensus of an international multispecialty expert panel, include critical values, provide guidance regarding the relative importance of individual elements, and are less influenced by particular theoretical biases than most previously published criteria. They require validation before being applied in clinical settings.

Reasoning in the capacity to make medical decisions: the consideration of values.

PURPOSE: To examine the contribution of "values-based reasoning" in evaluating older adults' capacity to make medical decisions. DESIGN AND METHODS: Older men with schizophrenia (n=20) or dementia (n=20), and a primary care comparison group (n=19), completed cognitive and psychiatric screening and an interview to determine their capacity to make medical decisions, which included a component on values. All of the participants were receiving treatment at Veterans Administration (VA) outpatient clinics. RESULTS: Participants varied widely in the activities and relationships they most valued, the extent to which religious beliefs would influence healthcare decisions, and in ratings of the importance of preserving quality versus length of life. Most participants preferred shared decision making with doctor, family, or both. Individuals with schizophrenia or dementia performed worse than a primary care comparison group in reasoning measured by the ability to list risks and benefits and compare choices. Individuals with dementia performed comparably to the primary care group in reasoning measured by the ability to justify choices in terms of valued abilities or activities, whereas individuals with schizophrenia performed relatively worse compared to the other two groups. Compared to primary care patients, participants with schizophrenia and with dementia were impaired on the ability to explain treatment choices in terms of valued relationships. CONCLUSION: Medical decision making may be influenced by strongly held values and beliefs, emotions, and long life experience. To date, these issues have not been explicitly included in structured evaluations of medical decision-making capacity. This study demonstrated that it is possible to inquire of and elicit a range of healthcare related values and preferences from older adults with dementia or schizophrenia, and individuals with mild to moderate dementia may be able to discuss healthcare options in relation to their values. However, how best to incorporate a values assessment into a structured capacity evaluation deserves further research attention.

Neuropsychological disturbance in schizophrenia: a diffusion tensor imaging study.

Patients with schizophrenia and healthy control subjects underwent both neuropsychological evaluation and magnetic resonance diffusion tensor imaging, during which the cingulum bundle (CB) and the uncinate fasciculus (UF) were defined with fiber tractography and their integrity was quantified. On the basis of prior findings, it was hypothesized that neuropsychological disturbance in schizophrenia may be characterized, in part, by 2 dissociable functional neuroanatomical relationships: (a) executive functioning-CB integrity and (b) episodic memory-UF integrity. In support of the hypothesis, hierarchical regression results indicated that reduced white matter of the CB and the UF differentially and specifically predicted deficits in executive functioning and memory, respectively. Neuropsychological correlates of the CB also extended to lower generalized intelligence, as well as to reduced visual memory that may be related to failures of contextual monitoring of to-be-remembered scenes. Reduced white matter of the CB and the UF may each make distinct contributions to neuropsychological disturbance in schizophrenia.

Episodic memory and neuroimaging of hippocampus and fornix in chronic schizophrenia.

A group of 44 patients with schizophrenia and 43 age-matched controls completed psychometrically-matched tasks of recall and recognition. The patients showed similarly depressed scores across both recall and recognition matched tasks, independent of their reduced IQ and executive functioning scores. In addition, reduced memory scores correlated in the expected direction with magnetic resonance imaging (MRI) of the hippocampus and diffusion tension imaging (DTI) of the fornix for subsets of both patients and controls that had available these structural imaging measures. Reduced executive functioning also correlated with lower fornix integrity for the patient subset. However, increased hippocampal volume correlated, in the negative direction, with lower scores for executive functioning and IQ in the control subset. Implications of these results are discussed.