Therapeutic drug monitoring in anticancer agents: perspectives of Australian medical oncologists.

BACKGROUND: In the development of anticancer agents for solid tumours, body surface area continues to be used to personalise dosing despite minimal evidence for its use over other dosing strategies. With the development of tyrosine kinase inhibitors and other oral targeted anticancer agents, dosing using therapeutic drug monitoring (TDM) is now utilised in many health systems but has had limited uptake in Australia. AIM: To determine attitudes and barriers to the implementation of TDM among Australian oncologists. METHODS: A comprehensive questionnaire was developed by the Dutch Pharmacology Oncology Group from semistructured interviews of stakeholders. Seventy-nine questions across seven domains were developed with three free-text responses. This was rationalised to 17 questions with three free-text responses for Australian medical oncologists who identified limited experience with TDM. RESULTS: Fifty-seven responses were received, with 49 clinicians (86%) identifying limited experience of performing TDM in daily practice. Clinicians were positive (62-91% agree/strongly agree across seven questions) about the advantages of TDM. There was a mixed response for cost-effectiveness and scientific evidence being a barrier to implementation, but strong agreement that prospective studies were needed (75% agreed or strongly agreed); that national treatment guidelines would enable practice (80%) and that a 'pharmacology of oncolytics' education programme would be useful (96%) to provide knowledge for dose individualisation. CONCLUSION: Despite the limited experience of TDM in oncology in Australia, medical oncologists appear positive about the potential benefit to their patients. We have identified three barriers to implementation that could be targeted for increased adoption of TDM in oncology in Australia.

Tardive Dyskinesia: A Historical Perspective.

The goal of this column is to provide historical context on tardive dyskinesia (TD) to help the reader understand how the concept was studied and evolved over time. Psychiatrists today should understand this history and consider it in combination with more recent data on the neurobiology of TD, including data from animal studies. This combination of classic data with modern science can help readers develop a more complete understanding and lead to a more judicious use of the term TD, after consideration of all of the alternative causes of abnormal movements, including spontaneous dyskinesia (SD). We advocate that clinicians use the term SD when in doubt about the cause of a movement disorder in a given patient, as TD is never distinguishable from SD in a given patient but is instead an issue of a statistical odds ratio.

Student Evaluation of the Yellow Ribbon Suicide Prevention Program in Midwest Schools.

OBJECTIVE: Yellow Ribbon is a gatekeeper-type suicide prevention program that is widely used in public schools. However, data on its effectiveness are limited. The purpose of our study was to evaluate self-reported changes in knowledge and comfort level communicating about suicide following Yellow Ribbon training for a large, representative sample of students from a public school system in the midwestern United States. METHODS: The program was administered to students within the same school district during 2006 through 2009. A pre-post survey using a 4-point Likert scale was administered to rate students' knowledge of risk factors and available resources, comfort level communicating about suicide, estimate of friends at risk for suicide, and behavioral intent toward help-seeking. RESULTS: Aggregate responses from 3,257 students, aged 11 to 18 years, were collected by the schools; 51% were female, 33% were Hispanic, and 30% were white. Suicide-related knowledge of risk factors, where to go for help, and resources, along with comfort level in asking for help, all significantly improved following program participation (Cramer's V = 0.243 to 0.376, P < .001). Responses were associated with age and gender, indicating that younger males may benefit more than older males. CONCLUSIONS: Implementation of the Yellow Ribbon school-based suicide prevention program appears to be beneficial for students in the midwestern United States. We observed significant improvement in knowledge, comfort level, and behavioral intent for help-seeking if suicidal thoughts occur. Findings also suggested that Yellow Ribbon training administered during middle school may be especially helpful for males.

Homicidality and Psychosis Caused by an Over-the-Counter Performance-Enhancing Supplement Containing Dendrobium Extract and L-Dopa.

The authors examine the role that unregulated dietary supplements may have had in a young man who presented with psychotic and homicidal ideations.

Determining Whether a Definitive Causal Relationship Exists Between Aripiprazole and Tardive Dyskinesia and/or Dystonia in Patients With Major Depressive Disorder, Part 4: Case Report Data.

This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients who develop abnormal movements during treatment with antipsychotics. The first column in the series presented a patient who developed abnormal movements while being treated with aripiprazole as an augmentation strategy for major depressive disorder and reviewed data concerning the historical background, incidence, prevalence, and risk factors for tardive and spontaneous dyskinesias, the clinical presentations of which closely resemble each other. The second column in the series reviewed the unique mechanism of action of aripiprazole and reviewed preclinical studies and an early-phase human translational study that suggest a low, if not absent, risk of TD with aripiprazole. The third column in this series reviewed the registration trial data for aripiprazole across all of its indications and found a raw incidence of TD ranging from 0.004 (4 out of 987) in long-term studies of the drug as an augmentation strategy for major depressive disorder to 0.0016 (19 out of 11,897) based on all short-term (ie, weeks to <6 mo) and long-term (6 mo to 1 y) studies combined. This fourth column in the series reviews the "real-world" data on aripiprazole and assesses whether these data also support the conclusion that aripiprazole has a low to absent risk of causing TD. The "real-world" data consist of case reports from the medical literature and the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We found 37 cases in the medical literature reporting what was termed TD in association with aripiprazole treatment as well as 27 case reports suggesting improvement in preexisting TD with aripiprazole treatment. On the basis of the case reports from the medical literature, the potential or raw incidence of TD during "real-world" treatment with aripiprazole was 0.0000062 (37 out of the 6 million individuals who had been treated with aripiprazole in the United States as of 2013 according to a report from Otsuka). A query of the FAERS yielded 312 cases of TD in which aripiprazole was the primary suspect. On the basis of the FAERS data and again assuming 6 million individuals exposed to aripiprazole, this yields a raw incidence of 0.000052 (312 out of 6 million) for TD in patients treated with aripiprazole. However, these estimates have limitations because they are based on anecdotal reports and pharmacovigilance data and, thus, the events themselves were not confirmed or verified in a systematic way. Further, the figure of 6 million people exposed to aripiprazole was based on data reported to the authors by the drug's manufacturer and only applies to exposure in the United States. The final column in this 5-part series will discuss the types of prohibitively expensive and logistically difficult studies that would be needed to determine whether a definitive causal relationship between aripiprazole and TD exists.

Determining Whether a Definitive Causal Relationship Exists Between Aripiprazole and Tardive Dyskinesia and/or Dystonia in Patients With Major Depressive Disorder, Part 2: Preclinical and Early Phase Human Proof of Concept Studies.

This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients treated with antipsychotics. The first column in this series began with the case of a 76-year-old man with major depressive disorder who developed orofacial dyskinesias while being treated with aripiprazole as an antidepressant augmentation strategy. It was alleged that a higher than intended dose of aripiprazole (ie, 20 mg/d for 2 wk followed by 10 mg/d for 4 wk instead of the intended dose of 2 mg/d) was the cause of the dyskinetic movements in this man, and the authors were asked to review the case and give their opinion. The principal basis for this theory of causation was the class warning about TD in the package insert for aripiprazole. The rationale for concluding aripiprazole caused TD in the 76-year-old man led to this series of columns about aripiprazole, its potential--if any--to cause TD, and the presence of a class warning about TD in its package insert. The central point is to illustrate why class warnings exist and their implications for practice. The first column in this series focused on the historical background, incidence, prevalence, risk factors, and clinical presentations of tardive and spontaneous dyskinesias and concluded with a discussion of diagnostic considerations explaining why clinicians should avoid making a diagnosis of TD until a thorough differential diagnosis has been considered. This second column in the series reviews the pharmacology of aripiprazole and the preclinical and phase I translational human studies that suggest aripiprazole should have a low to nonexistent risk of causing TD compared with other antipsychotics. The third column in the series will review the systematic clinical trial data and "real-world" data on TD and the use of aripiprazole as adjunctive treatment with antidepressants for major depressive disorder to see whether these data support the conclusion of a low to nonexistent relationship between aripiprazole treatment and the development of TD. The fourth and final column in the series will consider the type of study that would need to be performed to avoid a specific class warning, focusing on the TD class warning as an example and discussing why such studies are rarely done.

Wernicke's Encephalopathy: Increasing Clinician Awareness of This Serious, Enigmatic, Yet Treatable Disease.

OBJECTIVE: Undiagnosed and/or undertreated Wernicke's encephalopathy can result in permanent brain damage, long-term institutionalization, and death. The purpose of this article is to heighten clinical awareness of Wernicke's encephalopathy and shed light on its diagnosis and treatment, which are often inconsistent due to unclear diagnostic criteria and limited practice guidelines. An update on the management of Wernicke's encephalopathy is presented and several case reports and a quality improvement project from our hospital are described. DATA SOURCES: PubMed, the Cochrane Database of Systematic Reviews, and PsycINFO were searched for English-language articles published between January 1991 and January 2014 using combinations of the following keywords: Wernicke's encephalopathy, diagnosis, treatment/guideline(s), and thiamine. STUDY SELECTION: The automated search identified over 500 articles. A manual review of the related citations and reference lists from articles of interest was also conducted. The articles reviewed were chosen on the basis of author consensus and because they represented expert opinion or the highest quality of evidence available. RESULTS: Diagnostic criteria are reviewed in this article and should be used to diagnose Wernicke's encephalopathy with high sensitivity and specificity. The European Federation of Neurologic Societies and the Royal College of Physicians issued national guidelines for the diagnosis, prevention, and treatment of Wernicke's encephalopathy. No benchmark national guidelines for treating Wernicke's encephalopathy exist in the United States. CONCLUSIONS: Whenever Wernicke's encephalopathy is suspected, treatment should be initiated immediately with intravenous thiamine because oral thiamine is inadequate for preventing permanent brain damage. An adequate dose of intravenous thiamine administrated in a timely manner is a safe and life-saving treatment for Wernicke's encephalopathy that could preserve brain cells and function.

Determining Whether a Definitive Causal Relationship Exists Between Aripiprazole and Tardive Dyskinesia and/or Dystonia in Patients With Major Depressive Disorder: Part 1.

This series of columns has 2 main goals: (1) to explain the use of class warnings by the US Food and Drug Administration and (2) to increase clinicians' awareness of movement disorders that may occur in patients being treated with antipsychotic medications and why it is appropriate and good practice to refrain from immediately assuming the diagnosis is tardive dyskinesia/dystonia (TD). This first column in the series will focus on the second goal, which will then serve as a case example for the first goal. Clinicians should refrain from jumping to a diagnosis of TD because a host of other causes need to be ruled out first before inferring iatrogenic causation. The causal relationship between chronic treatment with dopamine antagonists and TD is based on pharmacoepidemiology (ie, the prevalence of such movement disorders is higher in individuals receiving chronic treatment with such agents than in a control group). There is nothing pathognomonic about movement disorders, nor is there any test that can currently prove a drug caused a movement disorder in a specific individual. Another goal of this series is to describe the types of research that would be needed to establish whether a specific agent has a meaningful risk of causing TD. In this first column of the series, we present the case of a patient who developed orofacial dyskinesia while being treated with aripiprazole. In this case, the movement disorder was prematurely called TD, which led to a malpractice lawsuit. This case highlights a number of key questions clinicians are likely to encounter in day-to-day practice. We then review data concerning the historical background, incidence, prevalence, and risk factors for 2 movement disorders, TD and spontaneous dyskinesia. Subsequent columns in this series will review: (1) unique aspects of the psychopharmacology of aripiprazole, (2) the limited and inconsistent data in the literature concerning the causal relationship between aripiprazole and TD, (3) the use of class warnings by the US Food and Drug Administration, which are automatically applied to a drug if it belongs to a specific therapeutic or pharmacological class unless the manufacturer provides convincing data that it does not warrant such a class label, and (4) the types of prohibitively expensive studies that would be needed to determine whether a meaningful causal relationship between aripiprazole and TD exists.

Attitudes towards Lung Cancer Screening in an Australian High-Risk Population.

Objectives. To determine whether persons at high risk of lung cancer would participate in lung cancer screening test if available in Australia and to elicit general attitudes towards cancer screening and factors that might affect participation in a screening program. Methods. We developed a 20-item written questionnaire, based on two published telephone interview scripts, addressing attitudes towards cancer screening, perceived risk of lung cancer, and willingness to be screened for lung cancer and to undertake surgery if lung cancer were detected. The questionnaire was given to 102 current and former smokers attending the respiratory clinic and pulmonary rehabilitation programmes. Results. We gained 90 eligible responses (M:F, 69:21). Mean [SD] age was 63 [11] and smoking history was 32 [21] pack years. 95% of subjects would participate in a lung cancer screening test, and 91% of these would consider surgery if lung cancer was detected. 44% of subjects considered that they were at risk of lung cancer. This was lower in ex-smokers than in current smokers. Conclusions. There is high willingness for lung cancer screening and surgical treatment. There is underrecognition of risk among ex-smokers. This misperception could be a barrier to a successful screening or case-finding programme in Australia.