Valproate: Not All Boxed Warnings Are Created Equal.

OBJECTIVE: Valproate has undergone significant changes in labeling to the boxed warnings associated with it. This review will analyze evidence regarding the valproate-boxed warnings for teratogenicity, hepatotoxicity, and pancreatitis, with a particular emphasis on the fetal risk. DATA SOURCES: A review of Pubmed, Cochrane Central Register, Google Scholar, manufacturer websites, and product labeling was performed from 1963 to February 2022, using the following search terms: valproate, valproic acid, depakote, teratogenicity, birth defects, fetal risk, hepatotoxicity, and pancreatitis. Relevant English-language studies and those conduced in humans were considered. Product labeling was also reviewed. DATA SYNTHESIS: There is a significant fetal risk following in utero valproate exposure (risk of malformation development: 8.6% in 360 women in North America). Current labeling in the United States recommends co-prescribing effective contraception for women of childbearing age. The risk of hepatotoxicity and pancreatitis is much lower in the general population (1/20 000 and 1/40 000 patients, respectively) compared with those patients with certain risk factors who are taking valproate (1/500). CONCLUSIONS: Overstated monitoring recommendations for the potential risk of hepatotoxicity and pancreatitis distracts from a much more common and severe risk of fetal harm. Clinicians must be diligent about discussing this risk with patients and documenting when this discussion occurs. Changes to the current recommendations for monitoring of the boxed warnings associated with valproate therapy should be considered, such as more stringent monitoring requirements for the inherent fetal risk. This could be accomplished through a Risk Evaluation and Mitigation Strategy program or through institution-based policies and procedures. In addition, monitoring recommendations for the risk of hepatotoxicity and pancreatitis should account for contributing risk factors.

Clinical Management of Bleeding Risk With Antidepressants.

OBJECTIVE: This nonsystematic review describes risk of bleeding in treatment with serotonin reuptake inhibitors (SRIs) and provide recommendations for the management of patients at risk of bleeding. DATA SOURCES: Articles were identified by English-language MEDLINE search published prior to June 2018 using the terms SRI, serotonin and noradrenaline reuptake inhibitors, OR antidepressive agents, AND hemorrhage OR stroke. STUDY SELECTION AND DATA EXTRACTION: Meta-analyses were utilized to identify information regarding risk of bleeding with antidepressants. Individual studies were included if they had information regarding bleeding risk with specific SRIs, timing of risk, or risk with medications of interest. DATA SYNTHESIS: SRIs increase risk of bleeding by 1.16- to 2.36-fold. The risk is synergistic between SRIs and nonsteroidal anti-inflammatory drugs (NSAIDs; odds ratio [OR] range between studies 3.17-10.9). Acid-reducing medications may mitigate risk of gastrointestinal bleeds in chronic NSAIDs and SRI users (OR range between studies 0.98-1.1). Antidepressants with low or no affinity for the serotonin transporter, such as bupropion or mirtazapine, may be appropriate alternatives for patients at risk of bleeding. Relevance to Patient Care and Clinical Practice: This review includes data regarding bleeding risk for specific antidepressants, concomitant medications, and risk related to duration of SRI use. Considerations and evidence-based recommendations are provided for management of SRI users at high bleeding risk. CONCLUSIONS: Clinicians must be aware of the risk of bleeding with SRI use, especially for patients taking NSAIDs. Patient education is prudent for those prescribed NSAIDs and SRIs concurrently.

Relative exposure to psychiatric conditions and medications in pharmacy education.

INTRODUCTION: Common psychiatric conditions occur at rates similar to chronic medical conditions. This study aimed to evaluate the exposure to psychiatric disease states as comorbidities in relation to other common chronic conditions within the curriculum at one college of pharmacy. METHODS: Researchers reviewed course activities for instances of specific conditions as comorbidities. The comorbidities evaluated fell into two categories: psychiatric and non-psychiatric. The primary outcome was the frequency each comorbidity appeared within course content. Secondary outcomes included characterization of instances of comorbidities, including the semester, course topic, and corresponding step of the Pharmacists' Patient Care Process. Prevalence data were analyzed for the health system where students conducted experiential learning. RESULTS: Overall, hypertension, diabetes, and hyperlipidemia appeared as comorbidities more frequently in the curriculum than depression and anxiety, despite similar prevalence patterns between these conditions. Students received the most exposure to these conditions as comorbidities during team-based learning case activities in therapeutics courses taught during the second professional year. CONCLUSIONS: This study found that psychiatric conditions were represented as comorbidities less frequently in the curriculum, despite similar prevalence patterns with other common comorbid disease states. With this knowledge, educators may identify potential opportunities for enhancing the curriculum around psychiatric illnesses.

Myasthenia gravis: What does a pharmacist need to know?

PURPOSE: Myasthenia gravis (MG) is not commonly covered in pharmacy school curricula. However, many medications that have been reported to cause exacerbations of MG are among the top 200 most prescribed drugs. The purpose of this therapeutic update is to provide pharmacists with a general understanding of the pathophysiology and treatment of MG and describe common medications with the potential to cause new onset or acute worsening of this disease. SUMMARY: MG is an autoimmune disorder in which patients develop autoantibodies to a component of the neuromuscular junction, most frequently the acetylcholine receptor, resulting in impairment of skeletal muscle contraction. Although MG is not highly prevalent, there are up to 60,000 individuals with MG in the US, making it a disease that many pharmacists will likely encounter at least once in their career. Immunosuppressant medications and acetylcholinesterase inhibitors are the mainstays of treatment, although there is limited evidence as to which agents are most efficacious. Medications that activate the immune system, such as immune checkpoint inhibitors, may cause new onset of disease, while those with actions on the neuromuscular junction, such as macrolides and fluoroquinolones, can cause acute worsening of disease. CONCLUSION: MG, although not frequently covered in pharmacy school curricula, is a disease state for which it is not uncommon for pharmacists to provide care. Treatment tends to be patient specific, and evidence is often weak. Many medications that cause new onset or worsening of MG are among the most prescribed. Key classes of medications to use with caution include macrolides, fluoroquinolones, ß-blockers, and magnesium.

Loxapine in the Treatment of Manic and Psychotic Symptoms in an Individual Intolerant to Multiple Mood-Stabilizing and Antipsychotic Medications.

First-line treatments for schizophrenia and schizoaffective disorder include antipsychotics and mood stabilizers, but their use may at times be limited due to severe adverse events. This case describes a 41-year-old male with a history of schizoaffective disorder and polysubstance use who was admitted to an inpatient psychiatry unit for acute manic and psychotic symptoms in the setting of absconding from his residential home and noncompliance with prescribed psychiatric medications. During his inpatient psychiatric hospitalization, he experienced DRESS (drug reaction with eosinophilia and systemic symptoms) with valproate, nephrogenic diabetes insipidus with lithium, potential neuroleptic malignant syndrome with risperidone, and orthostasis/tachycardia with clozapine. He ultimately achieved stabilization of manic and psychotic symptoms with loxapine without experiencing adverse events. This report highlights the potential utility of loxapine in individuals with schizoaffective disorder intolerant to standard mood-stabilizing and antipsychotic medications.

An update on recently approved long-acting injectable second-generation antipsychotics: Knowns and unknowns regarding their use.

There are now 9 available FDA-approved second-generation long-acting injectable antipsychotics including aripiprazole (3), olanzapine (1), paliperidone (3), and risperidone (2). These high-cost medications are commonly used with the goal of improving adherence and patient outcomes. With almost 2 decades of use, key aspects have been well studied, including population pharmacokinetics, CYP interactions and various clinical and economic outcomes. However, there are still unknowns with these medications. Issues including adherence, transition from oral antipsychotics, renal dosing, pharmacogenomics, and managing missed doses will be addressed in the context of 4 patient cases.

Identifying olanzapine induced liver injury in the setting of acute hepatitis C: A case report.

Olanzapine is linked to asymptomatic, transient elevations of liver aminotransferases but is historically thought to rarely cause significant hepatotoxicity. Underlying liver disease is a risk factor for drug-induced liver injury and may complicate the differential diagnosis of acute transaminitis in patients taking medications associated with hepatotoxicity. Ms L presented with 2 months of new psychotic symptoms resulting in hospitalizations. Although psychosis previously improved with haloperidol, she reported symptoms concerning for akathisia. Restlessness improved and psychotic symptoms resolved after initiation of olanzapine. Concurrently, her alanine aminotransferase (ALT) was elevated, prompting further workup and new diagnosis of acute hepatitis C. Over the course of hospitalization, her ALT increased exponentially. Initially attributed solely to acute hepatitis C infection, ALT rapidly decreased after holding olanzapine, implying it was contributing to her liver injury. Subsequently, given her prior response, haloperidol was retrialed with close monitoring for adverse effects. Her subjective restlessness was treated with additional agents, and she was then transitioned to monthly haloperidol decanoate injections to further assist her adherence. Prior to discharge, she had resolution of psychosis and transaminitis. Olanzapine may contribute to hepatotoxicity with concurrent viral hepatitis, and clarity can be obtained by a trial of stopping the suspected medication. Furthermore, olanzapine, when combined with underlying liver disease, may have an additive effect on liver injury, resulting in accelerated elevations in liver aminotransferases.

Cannabinoids and solid organ transplantation: Psychiatric perspectives and recommendations.

Cannabinoid use in patients seeking solid organ transplantation (SOT) is an important and unsettled matter which all transplantation clinicians regularly encounter. It is also a multifaceted, interprofessional issue, difficult for any specialty alone to adequately address in a research article or during clinical care. Such uncertainty lends itself to bias for or against cannabinoid use accompanied by inconsistent policies and procedures. Scientific literature in SOT regarding cannabinoids often narrowly examines the issue and exists mostly in liver and kidney transplantation. Published recommendations from professional societies are mosaics of vagueness and specificity mirroring the ongoing dilemma. The cannabinoid information SOT clinicians need for clinical care may require data and perspectives from diverse medical literature which are rarely synthesized. SOT teams may not be adequately staffed or trained to address various neuropsychiatric cannabinoid effects and risks in patients. In this article, authors from US transplantation centers conduct a systematized review of the few existing studies regarding clinician perceptions, use rates, and clinical impact of cannabinoid use in SOT patients; collate representative professional society guidance on the topic; draw from diverse medical literature bases to detail facets of cannabinoid use in psychiatry and addiction pertinent to all transplantation clinicians; provide basic clinical and policy recommendations; and indicate areas of future study.

Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action.

INTRODUCTION: MDD represents a significant burden worldwide, and while a number of approved treatments exist, there are high rates of treatment resistance and refractoriness. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, is a novel, rapid-acting antidepressant, however the mechanisms underlying the efficacy of ketamine are not well understood and many other mechanisms outside of NMDAR antagonism have been postulated based on preclinical data. This focused review aims to present a summary of the proposed mechanisms of action by which ketamine functions in depressive disorders supported by preclinical data and clinical studies in humans. METHODS: A literature search was completed using the PubMed and Google Scholar databases. Results were limited to clinical trials and case studies in humans that were published in English. The findings were used to compile this article. RESULTS: The antidepressant effects associated with ketamine are mediated via a complex interplay of mechanisms; key steps include NMDAR blockade on γ-aminobutyric acid interneurons, glutamate surge, and subsequent activation and upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. DISCUSSION: Coadministration of ketamine for MDD with other psychotropic agents, for example benzodiazepines, may attenuate antidepressant effects. Limited evidence exists for these effects and should be evaluated on a case-by-case basis.

Loxapine in patient with clozapine-resistant psychosis.

Clozapine is recognized as the drug of choice for treatment-refractory schizophrenia, but use may be limited because of strict monitoring requirements and adverse effects including severe neutropenia, seizures, and myocarditis. Loxapine is a first-generation antipsychotic with similarities to clozapine in both structure and receptor binding. This case describes a 57-year-old male with a history of severe paranoid schizophrenia despite treatment with clozapine and other psychotropic agents, who experienced clinical improvement after a cross titration from clozapine to loxapine. Loxapine may be a reasonable alternative in patients with treatment-refractory schizophrenia who do not tolerate or respond to clozapine.

Vertigoheel induced psychosis: A patient case report.

OBJECTIVE: To describe a case of a patient who developed psychosis after ingestion of Vertigoheel for treatment of dizziness. CASE SUMMARY: A 28-year-old male with no psychiatric history presented with 5 days of worsening depression and psychosis. He denied current use of prescription medications, alcohol, or illicit substances. Approximately 2 weeks prior, while visiting family in Germany, he developed dizziness. A provider in Germany prescribed Vertigoheel, 1 tablet to be taken every hour until symptom improvement. This did not improve his dizziness but did cause him to feel as if he were "in a dream." He stopped taking the medication after 2 days but continued to feel amotivated with decreased appetite and insomnia. Several days later, he developed ego-dystonic auditory hallucinations. He returned to the United States; was admitted to an inpatient psychiatric unit for 4 days; and given olanzapine 5 mg at bedtime, lorazepam 1 mg every evening, and melatonin 6 mg every evening. He experienced gradual improvement in symptoms and was discharged with olanzapine 5 mg daily and outpatient follow-up. DISCUSSION: Vertigoheel is a homeopathic preparation containing ambra grisea, Cocculus indicus, Conium maculatum, and petroleum. Psychosis was not reported in any of the randomized controlled trials evaluating the use of Vertigoheel for treatment of vertigo. A literature search revealed no published reports of psychosis as a result of administration of any components of Vertigoheel. CONCLUSION: A possible causal relationship was observed between the homeopathic supplement Vertigoheel and an acute episode of psychosis in a young male patient with no comorbidities.

Review of Allopregnanolone Agonist Therapy for the Treatment of Depressive Disorders.

OBJECTIVE: This paper reviews the current literature available for the efficacy and safety of allopregnanolone agonists and discusses considerations for their place in therapy. LITERATURE SEARCH: A literature search was conducted utilizing PubMed, clinicaltrials.gov, and the manufacturer's website. DATA SYNTHESIS: One phase II trial and two phase III trials evaluating the efficacy and safety of brexanolone were identified. Brexanolone demonstrated efficacy through significantly reduced Hamilton Depression Rating Scale (HAM-D) scores compared to placebo in the treatment of postpartum depression (PPD). Noted adverse effects were somnolence and dizziness, excessive sedation, and loss of consciousness. One published phase II study and the interim results of two phase III trials and one phase II trial on zuranolone were included in this review. Zuranolone, an oral allopregnanolone agonist, is given as a single, 14-day course. A significant reduction in HAM-D scores was demonstrated in patients with major depressive disorder (MDD) at 15 and 28 days compared to placebo. Interim results for zuranolone in PPD and bipolar disorder (BPD) show promising reductions in HAM-D scores. Adverse effects included sedation, dizziness, and headache. PLACE IN THERAPY: Allopregnanolone agonists seem to have a role in PPD when weighing the quick onset of action and potential risks of untreated PPD. The class of medications is limited by the single course for this indication and may fit as a bridge to maintenance therapy with selective serotonin reuptake inhibitors (SSRIs). Brexanolone, specifically, is hindered by the long infusion time, hospitalization associated with administration, and risk evaluation and mitigation strategy program. Zuranolone may also have a role in MDD or BPD, but more data are needed. CONCLUSION: Allopregnanolone agonists present a novel mechanism of action in the treatment of depressive disorders. Clinical trials and interim results support significant reductions in depression scores for brexanolone in PPD, and for zuranolone in PPD, MDD, and BPD.

Symptomatic bradycardia with oral aripiprazole and oral ziprasidone.

OBJECTIVE: To describe the case of a patient who developed symptomatic bradycardia upon initiation of oral ziprasidone and later with oral aripiprazole, both of which resolved shortly after discontinuation of therapy. CASE SUMMARY: An 18-year-old female with bipolar disorder was started on oral ziprasidone 80 mg at night and the dose was subsequently increased to 120 mg for management of acute mania and delusions. The patient developed symptomatic bradycardia (heart rate 31-35 beats/min), which resolved after ziprasidone was decreased to 80 mg. Three months later, the patient was readmitted for treatment of bipolar mania with psychotic features in the context of medication nonadherence. She was started on oral aripiprazole 15 mg daily (subsequently increased to 20 mg) in conjunction with 600 mg lithium carbonate twice daily. The patient again developed symptomatic bradycardia that resolved after discontinuation of aripiprazole. DISCUSSION: This is the first case report of symptomatic bradycardia associated with the use of ziprasidone or aripiprazole. The Naranjo probability scale suggests that the likelihood of the atypical antipsychotic as the cause of bradycardia is probable for both ziprasidone and aripiprazole. Symptomatic bradycardia with the use of other atypical antipsychotics has been reported in the literature. Little is known about the mechanisms that contribute to the antipsychotic-associated bradycardic response. CONCLUSIONS: Further studies are needed to better determine the relationship between antipsychotics and reflex bradycardia. Although bradycardia remains a relatively uncommon phenomenon seen with the use of these medications, the severity of this potential adverse effect warrants consideration when initiating antipsychotic therapy.

Long-acting injectable antipsychotics and their use in court-ordered treatment: A cross-sectional survey of psychiatric pharmacists' perceptions.

INTRODUCTION: People with serious mental illness may be subjected to "court-ordered treatment" (COT), per the mental health statutes of their respective state. COT enforces adherence to a psychiatric treatment regimen and may involve involuntary medication administration. Long-acting injectable (LAI) antipsychotics are frequently used in this setting, although little is known about the clinical effectiveness or patterns of use of these agents in the context of COT. Because psychiatric pharmacists are medication experts, we sought to characterize their perceptions and experiences on this topic. METHODS: A cross-sectional, electronic, 14-item survey was administered via the College of Psychiatric and Neurologic Pharmacists listserv from October 9, 2018, to November 9, 2018. The survey collected demographic information, experience and use of LAI antipsychotics at each practice site, and perception of LAI antipsychotics. RESULTS: Of 843 possible respondents, 72 completed the survey, yielding an 8.5% response rate. LAIs were perceived as underused or adequately used as a whole, with a significant difference in perception favoring the opinion that LAIs are underused versus overused for those respondents who perceived an adherence benefit (P = .042). We also found that LAIs were used disproportionately in the context of COT versus oral formulations (P = .03). DISCUSSION: The use of LAIs in the context of COT has not been studied, and it may expose this vulnerable population to adverse effects from medications they are legally compelled to take. Further research on the perceptions of other interdisciplinary team members and the clinical impact of LAI use in COT is needed.

Akathisia and Newer Second-Generation Antipsychotic Drugs: A Review of Current Evidence.

Akathisia continues to present a significant challenge in clinical practice. As a class, so-called atypical, or second-generation, antipsychotics (SGAs) are the mainstay of treatment for schizophrenia and are commonly used to treat mood disorders. These medications have traditionally been distinguished from first-generation antipsychotics by their lowered risk of extrapyramidal side effects (EPS) such as dystonia, dyskinesia, akathisia, and pseudoparkinsonism. However, the occurrence of EPS, particularly akathisia, has been demonstrated to some degree in all commercially available SGAs. This review examines the incidence of akathisia in nine newer SGAs in patients with schizophrenia, bipolar disorder, and major depressive disorder (MDD). We performed a search of PubMed, ClinicalTrials.gov, Cochrane Central Register, and Google Scholar, as well as manufacturer websites and product labeling for published and unpublished clinical trials, meta-analyses, and systematic reviews. Studies evaluating adult patients with schizophrenia, bipolar disorder, or MDD were eligible for inclusion. Data on treatment-emergent akathisia rates were gathered from each study, and potential dose-response relationships were explored. A total of 177 studies were included in this review, comprising 58,069 patients across 414 treatment arms. Compared with placebo with a composite 3.7% incidence of akathisia, individual SGAs produced akathisia at total composite rates ranging from 2.9-13.0% across the included studies. High doses of an SGA were generally associated with an increased risk of akathisia. Clinicians should consider the risk of akathisia when choosing a treatment option and monitor for akathisia in patients beginning therapy with an SGA or following a dose increase of the SGA.