Electroconvulsive Therapy Anesthetic Choice and Clinical Outcomes.

OBJECTIVE: Etomidate and methohexital are the 2 commonly used anesthetics for electroconvulsive therapy (ECT) in the United States. The objective of this study was to examine how anesthetic choice between etomidate and methohexital is associated with real-world clinical outcomes. METHODS: This naturalistic retrospective cohort study examined longitudinal electronic health records for 495 adult patients who received 2 or more ECT treatments from 2010 to 2019 in Kaiser Permanente North California, a large integrated health care system. Study outcomes included 12-month posttreatment depression remission as measured by the 9-item Patient Health Questionnaire, psychiatric and all-cause emergency department visits, and psychiatric and all-cause hospitalizations. RESULTS: Anesthetic choice was not significantly related to depression severity, emergency department visits, or psychiatric hospitalizations at 12 months after completing ECT. In exploratory analyses, we found that etomidate compared with methohexital was associated with higher rates of patient discomfort adverse effects-postictal agitation, phlebitis, and myoclonus (2.4% vs 0.4%; P < 0.001). CONCLUSIONS: We present the first large comparison of etomidate and methohexital as anesthetics for ECT and their associations with real-world outcomes. Our study showed no significant difference on depression remission, emergency department visits, or hospitalizations 12-months posttreatment. Thus, clinicians should focus on other patient or treatment characteristics when deciding on anesthetics for ECT. Further investigation is needed to confirm our exploratory findings that etomidate use was correlated with a higher rate of patient discomfort adverse effects relative to methohexital.

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.

A Retrospective 4-year Outcome Study of Veterans Admitted to an Acute Inpatient Detoxification Unit for Opioid Use Disorder.

BACKGROUND AND OBJECTIVES: With 47 600 opioid-related deaths in 2017, the yearly deaths have surpassed the HIV/AIDS peak yearly death rates. Residential rehabilitation (RR) and medication-assisted treatments (MAT) are commonly utilized treatments for opioid use disorder (OUD). METHODS: All patients (n = 182) who were admitted to the Boston Veterans Health Administration for inpatient admission for medically supervised opioid withdrawal in 2015 were included. Deceased patients were matched 1:1, based on age and sex to living patients from the 182-patient cohort. Nationwide electronic medical records were analyzed from 2015 through 2018. Via multilinear regression, risk factor correlation to all-cause mortality (the dependent variable) was our main outcome. Primary risk factors included recurrent admissions for medically supervised withdrawals and exposure to RR or MAT. Secondary risk factors were opioid use traits, nonopioid drug use, partner support, education level, homelessness, and employment. RESULTS: 18.4% (n = 34) were deceased by the time of follow-up-equivalent to 4760 deaths per 100 000 person-years. A total of 61.8% (n = 21) of these deaths were directly related to opioid use. Completion of RR correlated with lower predicted mortality (ß = -8.21, P = 0.03). In contrast, attending RR but not completing correlated with higher predicted mortality rate (ß = 6.51, P = 0.046). Concurrent benzodiazepine use (ß = 8.99, P = 0.047), generalized anxiety disorder (ß = 7.13, P = 0.03) and major depressive disorder (ß = 5.44, P = 0.04) increased risk of death. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: OUD carries a shockingly high lethality in Veterans requiring inpatient admission for opioid withdrawal, particularly when there are untreated comorbid psychiatric conditions. RR and MAT are correlated to lower all-cause mortality in this population and should be highly utilized. Given the extremely high mortality, intensive system-wide interventions are needed for the care of Veterans with OUD. On the basis of the reduced predicted mortality with RR and MAT, further research into novel MATs as well as refining RR programs should be a major focus. (Am J Addict 2019;28:318-323).

Opioid use and schizophrenia.

PURPOSE OF REVIEW: To summarize the current literature regarding comorbid schizophrenia and opioid use disorder (OUD). RECENT FINDINGS: Epidemiological evidence is unclear on whether patients with schizophrenia have a higher rate of OUD. Patients with OUD have been shown to have a higher risk of developing schizophrenia. However, it is clear that patients with both schizophrenia and OUD are less likely to receive standard of care including medication-assisted treatment (MAT) for opiate use disorder and have worse outcomes compared with patients with schizophrenia who do not abuse opioids. OUD significantly increases the risk of converting patients from prodromal schizophrenia states to schizophrenia or schizoaffective disorder. Shared pathophysiology involving the kappa opioid receptor may help explain the relationships between schizophrenia and OUD. Second-generation antipsychotics, long-acting injectables, and MAT for OUD should be utilized in a dual-diagnosis and treatment approach for patients with schizophrenia and OUD. SUMMARY: Exploration into the relationship between schizophrenia and opiate abuse is still in its infancy and requires a significant amount of future attention to clarify the epidemiology of this comorbidity, neurobiological relationship, shared genetic underpinnings, and possible treatments for both the psychotic symptoms and substance abuse.

Antipsychotics and the microbiota.

PURPOSE OF REVIEW: The gut microbiota has been speculated to underpin metabolic changes associated with chronic antipsychotic use. The change in the gut microbiota can also cause abnormal absorbtion from the gut into the blood stream (leaky gut syndrome) that can lead to inflammatory reactions, and thus, secondary damage to the brain and central nervous system. Our article aims to highlight relevant research on antipsychotic's effect on the microbiota and to point out future directions. RECENT FINDINGS: Antipsychtoic use can result in specific microbiota changes, and it is important to differentiate this from the innate microbiota of the patient. It is important to treat these microbiota changes, as they are correlated with obesity, which is a negative contributor to the cardiovascular health of those suffering with schizophrenia. Ways to prevent antipsychotic-induced side-effects include antibiotic treatment, histamine 3 receptor blockade and metformin use. SUMMARY: Given the dearth of current literature, more research is needed, however, to determine, which comes first in people with schizophrenia--an abnormal gut microbiota that elevates one's risk for schizophrenia or psychopharmacologic treatment of schizophrenia leading to secondary microbiota abnormalities or the negative symptoms of schizophrenia leading to obesity and its associated microbiota changes.

Does obtaining CYP2D6 and CYP2C19 pharmacogenetic testing predict antidepressant response or adverse drug reactions?

Treatment non-response and adverse reactions are common in patients receiving antidepressants. Personalizing psychiatric treatment based on pharmacogenetic testing has been proposed to help clinicians guide antidepressant selection and dosing. This systematic literature review assesses the two most robustly studied drug-metabolizing enzymes, CYP2D6 and CYP2C19, and examines whether obtaining CYP2D6 and CYP2C19 testing can be used to predict antidepressant response or adverse drug reactions in order to improve clinical outcomes. In general, literature reviews published prior to 2013 indicated that results have been inconsistent linking CYP2D6 and CYP2C19 to antidepressant treatment outcomes, suggesting that more evidence is required to support the clinical implementation of genotyping to predict outcomes. We thus performed an extensive and systematic literature review, focusing on studies published from 2013 through 2018. Sixteen studies were found to be relevant. The results yielded inconsistent findings, suggesting that CYP2D6 and CYP2C19 testing may predict response in certain individuals, but it remains unclear if this will translate to improved clinical outcomes. Further research is required to determine when pharmacogenetic testing should be utilized and in which populations it is indicated. Randomized, controlled, prospective trials with adequate sample sizes would best clarify whether genotype-guided antidepressant selection will ultimately improve clinical outcomes.

Meloxicam-desmopressin drug-drug interaction producing hyponatremia.

BACKGROUND: People with schizophrenia and medical comorbidities are often on multiple medications to manage their symptoms. Herein we present a case of drug-drug interaction (meloxicam and desmopressin), in a patient also on clozapine, that ultimately resulted in hyponatremia and seizure. METHODS: The patient provided consent to have his case published. We searched PubMed and after reviewing 321 articles, 11 were chosen for relevance. RESULTS: Meloxicam enhanced the adverse effect (hyponatremia) of desmopressin and was the likely culprit. CONCLUSIONS: In a patient with higher ADH levels, as in our patient taking desmopressin, the addition of an NSAID could further increase water retention and worsen hyponatremia; indeed, meloxicam was the only new medication added to the patient's regimen, and a drug interaction calculator supports the desmopressin-meloxicam drug-drug interaction as the culprit. We urge clinicians to avoid the use of desmopressin in patients with schizophrenia as this can lead to water intoxication. As meloxicam may worsen desmopressin-induced hyponatremia and could result in seizure, one should avoid using NSAIDs in patients with schizophrenia whom are also prescribed vasopressin/desmopressin. Serum sodium levels should be closely monitored in patients with schizophrenia whose regimen includes desmopressin.

Sudden death in schizophrenia.

PURPOSE OF REVIEW: To examine the recent literature regarding sudden death in patients with schizophrenia and synthesize salient conclusions based on this evidence. RECENT FINDINGS: Sudden cardiac death (SCD) is the largest subset of sudden unexpected death (SUD), with up to 40% of SUD from cardiovascular causes. SCD has been associated with exposure to both first and second-generation antipsychotics. Clozapine [odds ratio (OR) 3.67, 95% confidence interval (CI) 1.94-6.94] confers the highest risk of SCD followed by risperidone (OR 3.04, 95% CI 2.39-3.86) then olanzapine (OR 2.04, 95% CI 1.52-2.74). SCD not associated with antipsychotic use has been correlated to several modifiable and nonmodifiable risk factors - obesity, smoking, dyslipidemia, diabetes, hypertension, age, sex, and history of cardiovascular disease. Other subsets of SUD include hematological and pulmonary causes, including agranulocytosis leading to sepsis, deep vein thrombosis leading to pulmonary embolisms, and aspiration pneumonia leading to sepsis. SUMMARY: There is a huge paucity in genetic and pharmacogenetic data focused on SUD in schizophrenia. Future studies should emphasize the genetic aspects as well as clarify the underlying molecular mechanisms of these pathways. Additionally, early detection of those patients at high risk for SUD and discovery of preventive measures should also be emphasized.

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).

Clozapine pharmacogenomics: a review of efficacy, pharmacokinetics, and agranulocytosis.

PURPOSE OF REVIEW: To examine recent literature regarding the pharmacogenomics of clozapine (CLZ) efficacy, pharmacokinetics, and agranulocytosis. RECENT FINDINGS: Several genetic loci (FKBP5, NR3C1, BDNF, NTRK2) along the hypothalamic pituitary adrenal axis have been investigated as targets for CLZ response. Homozygous FKBP5-rs1360780, homozygous NTRK2-rs1778929, and homozygous NTRK2-rs10465180 conferred significant risks for CLZ nonresponse - 2.11x risk [95% confidence interval (CI) 1.22-3.64], 1.7x risk (95% CI 1.13-2.59), and 2.15x risk (95% CI 1.3-3.55), respectively. BDNF and NR3C1 had no significant associations with CLZ response. Candidate genes within neurotransmitter pathways continue to be explored including dopaminergic (DRD1-4, COMT) and glutamatergic pathways (GRIN2B, SLC1A2, SLC6A9, GRIA1, GAD1). Despite promising trending data, no significant associations between CLZ response and glutamatergic system variants have been found. Synergistic effect of catecholamine O-methyltransferase (COMT) Met and dopamine receptor-4 (DRD4) single 120 bp duplicate associated with improved CLZ response odds ratio (OR) 0.15 (95% CI 0.03-0.62) while COMT Val/Val confer a risk of CLZ nonresponse OR 4.34 (95% CI 0.98-23.9). Diagnostic performance testing continues through human leukocyte antigen (HLA) and other genetic loci but have yet to find statistically or clinically meaningful results. SUMMARY: Current landscape of pharmacogenomic research in CLZ continues to be limited by small sample sizes and low power. However, many promising candidate genes have been discovered and should be further investigated with larger cohorts.

First-Episode of Synthetic Cannabinoid-Induced Psychosis in a Young Adult, Successfully Managed with Hospitalization and Risperidone.

Synthetic cannabinoids- (SCs-) induced psychosis is a growing public health concern. It leads to significant impairment, including emotional distress, difficulty communicating, and other debilitating symptoms. In this case report, we discuss a patient with no previous history of psychotic symptoms, presenting with first-episode psychosis in the context of progressive, acutely worsening, disorganized, psychotic thoughts and behaviors following prolonged use of SCs. We also discuss relevant literature on SCs-induced psychosis, highlighting its prevalence, presentation, diagnosis, and recommended management. It is important to diagnose and treat SCs-induced psychosis as early and efficiently as possible, in order to alleviate symptoms while limiting functional impairment and emotional distress to the patient.