Pharmacists' Knowledge and Perceptions of FDA Approval Standards and the Breakthrough Therapy Designation.

The "breakthrough therapy" designation (BTD) is a recent mechanism implemented by the United States Food and Drug Administration (FDA) to expedite access to drugs that address unmet needs. The purpose of this study is to describe pharmacists' knowledge of FDA drug-approval standards and knowledge and perceptions of the BTD. Pharmacists engaged in advanced clinical practice were identified through membership profiles of a professional pharmacy organization. Eligible participants were then sent a questionnaire to assess knowledge of FDA approval standards and the BTD. A total of 226 pharmacists responded. The majority of respondents were women (70.2%) and had completed post-graduate training (85.8%). Over half correctly answered at least two of three questions on FDA approval standards (58.1%) and the BTD (78.1%). Only 24.1% of respondents identified as being familiar with the BTD. The majority of pharmacists (62.8%) were certain that FDA-approved "breakthrough" drugs represented a major advance over currently approved therapies and most (88.5%) preferred the drug designated as "breakthrough" in a hypothetical scenario. In conclusion, pharmacists were able to correctly answer questions about FDA approval standards and the BTD. However, they were unfamiliar with the implications of a BTD and may overestimate the benefit demonstrated by these drugs. Future research should identify knowledge gaps in pharmacist understanding of regulatory mechanisms designed to expedite drug approval.

Differential impact of lipopolysaccharide defects caused by loss of RfaH in Yersinia pseudotuberculosis and Yersinia pestis.

RfaH enhances transcription of a select group of operons controlling bacterial surface features such as lipopolysaccharide (LPS). Previous studies have suggested that rfaH may be required for Yersinia pseudotuberculosis resistance to antimicrobial chemokines and survival during mouse infections. In order to further investigate the role of RfaH in LPS synthesis, resistance to host defense peptides, and virulence of Yersinia, we constructed ΔrfaH mutants of Y. pseudotuberculosis IP32953 and Y. pestis KIM6+. Loss of rfaH affected LPS synthesis in both species, resulting in a shorter core oligosaccharide. Susceptibility to polymyxin and the antimicrobial chemokine CCL28 was increased by loss of rfaH in Y. pseudotuberculosis but not in Y. pestis. Transcription of genes in the ddhD-wzz O-antigen gene cluster, but not core oligosaccharide genes, was reduced in ΔrfaH mutants. In addition, mutants with disruptions in specific ddhD-wzz O-antigen cluster genes produced LPS that was indistinguishable from the ΔrfaH mutant. This suggests that both Y. pseudotuberculosis and Y. pestis produce an oligosaccharide core with a single O-antigen unit attached in an RfaH-dependent fashion. Despite enhanced sensitivity to host defense peptides, the Y. pseudotuberculosis ΔrfaH strain was not attenuated in mice, suggesting that rfaH is not required for acute infection.

Lipopolysaccharide Biosynthesis Genes of Yersinia pseudotuberculosis Promote Resistance to Antimicrobial Chemokines.

Antimicrobial chemokines (AMCs) are a recently described family of host defense peptides that play an important role in protecting a wide variety of organisms from bacterial infection. Very little is known about the bacterial targets of AMCs or factors that influence bacterial susceptibility to AMCs. In an effort to understand how bacterial pathogens resist killing by AMCs, we screened Yersinia pseudotuberculosis transposon mutants for those with increased binding to the AMCs CCL28 and CCL25. Mutants exhibiting increased binding to AMCs were subjected to AMC killing assays, which revealed their increased sensitivity to chemokine-mediated cell death. The majority of the mutants exhibiting increased binding to AMCs contained transposon insertions in genes related to lipopolysaccharide biosynthesis. A particularly strong effect on susceptibility to AMC mediated killing was observed by disruption of the hldD/waaF/waaC operon, necessary for ADP-L-glycero-D-manno-heptose synthesis and a complete lipopolysaccharide core oligosaccharide. Periodate oxidation of surface carbohydrates also enhanced AMC binding, whereas enzymatic removal of surface proteins significantly reduced binding. These results suggest that the structure of Y. pseudotuberculosis LPS greatly affects the antimicrobial activity of AMCs by shielding a protein ligand on the bacterial cell surface.

Environmental cadmium and lead exposures and age-related macular degeneration in U.S. adults: the National Health and Nutrition Examination Survey 2005 to 2008.

Age-related macular degeneration (AMD) is a complex disease resulting from the interplay of genetic predisposition and environmental exposures, and has been linked to oxidative stress and inflammatory mechanisms. Lead and cadmium can accumulate in human retinal tissues and may damage the retina through oxidative stress, and may thereby play a role in the development of AMD. We examined associations between blood lead, blood cadmium, and urinary cadmium concentrations and the presence of AMD in 5390 participants aged 40 years and older with blood lead and blood cadmium measures and a subsample of 1548 with urinary cadmium measures in the 2005-2008 National Health and Nutrition Examination Surveys. AMD was identified by grading retinal photographs with a modification of the Wisconsin Age-Related Maculopathy Grading System. The weighted prevalence of AMD was 6.6% (n=426). Controlling for age, gender, race/ethnicity, education and body mass index, adults in the highest blood cadmium quartile had higher odds of AMD compared to the lowest quartile (odds ratio [OR], 1.56; 95% CI, 1.02-2.40), with a significant trend across quartiles (p-trend=0.02). After further adjustment for pack-years of cigarette smoking, estimates were somewhat attenuated (OR, 1.43; 95% CI, 0.91-2.27; p-trend=0.08). Similar associations were found with urinary cadmium. The association between urinary cadmium and AMD was stronger in non-Hispanic whites (NHW) than in non-Hispanic blacks (NHB) (OR, 3.31; 95% CI, 1.37-8.01 for levels above versus below the median among NHW; OR,1.45; 95% CI, 0.40-5.32 for levels above versus below the median among NHB; p-interaction=0.03). We found no association between blood lead levels and AMD. Higher cadmium body burden may increase risk of AMD, particularly among non-Hispanic white individuals; however, additional studies are needed before firm conclusions can be drawn.

Increased risk of developing dementia in patients with bipolar disorder: a nested matched case-control study.

OBJECTIVE: The association between bipolar disorder and subsequent dementia risk is not well established. The objective of this study was to investigate whether patients with bipolar disorder were at an increased risk for developing dementia. METHODS: A conditional logistic regression model was performed using data from the National Health Insurance Research Database, a nationwide dataset in Taiwan. The study sample included 9,304 patients with incident dementia first diagnosed between 2000 and 2009, and 55,500 gender-, age-, and index date-matched subjects without dementia. Cerebrovascular disease, diabetes, hypertension, head injury, chronic pulmonary disease, alcohol-related disorders, substance use disorders, and health system utilization were treated as covariates in the analyses. RESULTS: After controlling for the covariates, bipolar disorder was significantly associated with an increased risk of subsequent dementia [adjusted odds ratio (aOR) = 4.32, 95% confidence interval (CI): 3.21-5.82]. An increased risk of developing dementia was observed in males and females alike (aOR = 4.01, 95% CI: 2.53-6.35 in males; aOR = 4.55, 95% CI: 3.07-6.73 in females). Moreover, a significantly increased risk was observed in subjects diagnosed with dementia before the age of 65 years (aOR = 3.77, 95% CI: 1.78-8.01). CONCLUSIONS: Findings from this study suggest a positive association between the presence of a lifetime history of bipolar disorder and an increased risk of developing dementia. Furthermore, our results also suggest that subjects with bipolar disorder tend to develop dementia in middle age. Going forward, it will be of importance to confirm our findings in different populations.

Association between antidepressants and venous thromboembolism in Taiwan.

OBJECTIVE: To investigate the association between venous thromboembolism (VTE) and antidepressant use in an Asian population. METHODS: The authors conducted a nested case-control study of 1888 patients with VTE and 11,222 matched controls enrolled in the National Health Insurance Research Database in Taiwan from 2001 to 2009. The antidepressant exposure status and potential confounding factors were measured and included in the analyses. Conditional logistic regressions were applied to determine the effect of antidepressant use on VTE. RESULTS: We found a significant association of current antidepressant use with VTE in the total study sample (adjusted odds ratio [aOR], 1.59; 95% confidence interval (CI), 1.27-2.00). With regard to antidepressant classes and potency, we found that tricyclic antidepressants (aOR, 1.56; 95% CI, 1.11-2.18), serotonin 5-HT2A receptor blockers (aOR, 2.03; 95% CI, 1.27-3.24), and antidepressants with a low potency of serotonin reuptake inhibition (aOR, 1.57; 95% CI, 1.18-2.08) were associated with a significantly increased risk of VTE. When further stratifying by age, sex, and comorbid conditions, the VTE risk with antidepressant use was elevated among young and middle-aged adults, but not among the elderly. In addition, an elevated risk of VTE was observed in women and subjects without severe comorbid conditions, but not in men and subjects with severe comorbid conditions. CONCLUSIONS: There was a small increase in VTE risk with antidepressant use. The prescription of antidepressant drugs should be cautious, and especially, should be based on clinical evaluations of benefits and risks. The underlying mechanisms of the interaction between antidepressants and VTE warrant further investigation.

Psychotropic drugs and risk of motor vehicle accidents: a population-based case-control study.

AIM: To examine comprehensively the relationship between exposure to four classes of psychotropic drugs including antipsychotics, antidepressants, benzodiazepines (BZDs) and Z-drugs, and motor vehicle accidents (MVAs). METHOD: The authors conducted a matched case-control study of 5183 subjects with MVAs and 31 093 matched controls, identified from the claims records of outpatient service visits during the period from 2000 to 2009. Inclusion criteria were defined as subjects aged equal to or more than 18 years and involved in MVAs. Conditional logistic regressions with covariates adjustment (including urbanity, psychiatric and non-psychiatric outpatient visits and Charlson comorbidity score) were applied to examine the effect of four classes of psychotropic drugs on MVAs. RESULTS: Significant increased risk of MVAs was found in subjects taking antidepressants within 1 month (adjusted odds ratio (AOR) 1.73, 95% confidence interval (CI) 1.34, 2.22), 1 week (AOR 1.71, 95% CI 1.29, 2.26), and 1 day (AOR 1.70, 95% CI 1.26, 2.29) before MVAs occurred. Similar results were observed in subjects taking benzodiazepines (BZDs) (AOR 1.56, 95% CI 1.38, 1.75 for 1 month; AOR 1.64, 95% CI 1.43, 1.88 for 1 week, and AOR 1.62, 95% CI 1.39, 1.88 for 1 day) and Z-drugs (AOR 1.42, 95% CI 1.14, 1.76 for 1 month, AOR 1.37, 95% CI 1.06, 1.75 for 1 week, AOR 1.34, 95% CI 1.03, 1.75 for 1 day), but not antipsychotics. Moreover, significant dose effects of antidepressants (equal to or more than 0.6-1.0 DDD), BZDs (equal to or more than 0.1-0.5 DDD) and Z-drugs (more than 1 DDD) were observed, respectively, on the risk of experiencing an MVA. CONCLUSION: Taken together, subjects taking antidepressants, BZDs and Z-drugs, separately, should be particularly cautioned for their increasing risk of MVAs.

Overlapping Prescriptions of Stimulants for Children and Adolescents With Attention-Deficit Hyperactivity Disorder.

OBJECTIVES: The study aimed to assess the occurrence of overlapping prescriptions for methylphenidate among children and adolescents with newly diagnosed attention-deficit hyperactivity disorder (ADHD) and to evaluate the extent to which physician-level and patient-level characteristics affected the risk of prescription overlap during a one-year treatment period. METHODS: The analytic sample comprised 3,081 incident cases of ADHD in 2002 involving children aged 17 years or younger from a retrospective cohort study in Taiwan. Medical and pharmacy claims data from 1999 to 2002 were retrieved from the National Health Insurance Program. All records of methylphenidate prescriptions within a year of treatment initiation were retrieved for each patient, and the number of overlapping days for any two successive prescriptions (new, renewal, or refill) was measured. Multilevel analyses were performed to identify predictors of methylphenidate prescription overlap. RESULTS: Within a year of treatment initiation, approximately 3% to 4% individuals with a new diagnosis of ADHD had experienced methylphenidate prescription overlap. Youngsters who resided in a rural region (adjusted odds ratio [AOR]=2.68) or who had ever changed prescribing doctors (AOR=3.04) were more likely to have visits with a methylphenidate prescription overlap. Receiving methylphenidate from physicians aged 46 or older was associated with 3.6-fold increased odds of prescription overlap. CONCLUSIONS: In an effort to improve the quality and safety of prescription of controlled substances in younger populations, interventions or policies should be devised to target both the service providers and the patients.

Adherence patterns with first- versus second-generation antipsychotics for newly diagnosed schizophrenia in Taiwan.

OBJECTIVE: The aim of this study was to compare the early adherence patterns for first-generation antipsychotics and second-generation antipsychotics during the first month of treatment for patients newly diagnosed as having schizophrenia. METHODS: With a random sample from the Taiwan national health insurance database, persons with a schizophrenia diagnosis (ICD-9-CM code 295.X) and a concurrent initial antipsychotic prescription from 1998 to 2006 were defined as being newly treated for schizophrenia. Adherence patterns within one month of diagnosis were categorized into four independent groups: refill, switch, admission, and discontinuation. RESULTS: Treatment initiated with first-generation or second-generation antipsychotics resulted in similar rates of refill (57% versus 59%). However, patients who started with first-generation antipsychotics were significantly less likely to switch (9% versus 14%) but more likely to discontinue (34% versus 26%) medications than those whose treatment was initiated with second-generation antipsychotics. CONCLUSIONS: The data substantiated previous observations of the magnitude of adherence problems in Asian populations and highlight the importance of developing new strategies for intervention.

Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study.

BACKGROUND: The association between autoimmune diseases and schizophrenia has rarely been systematically investigated. AIMS: To investigate the association between schizophrenia and a variety of autoimmune diseases and to explore possible gender variation in any such association. METHOD: Taiwan's National Health Insurance Research Database was used to identify 10 811 hospital in-patients with schizophrenia and 108 110 age-matched controls. Univariate and multiple logistic regression analyses were performed, separately, to evaluate the association between autoimmune diseases and schizophrenia. We applied the false discovery rate to correct for multiple testing. RESULTS: When compared with the control group, the in-patients with schizophrenia had an increased risk of Graves' disease (odds ratio (OR) = 1.32, 95% CI 1.04-1.67), psoriasis (OR = 1.48, 95% CI 1.07-2.04), pernicious anaemia (OR = 1.71, 95% CI 1.04-2.80), celiac disease (OR = 2.43, 95% CI 1.12-5.27) and hypersensitivity vasculitis (OR = 5.00, 95% CI 1.64-15.26), whereas a reverse association with rheumatoid arthritis (OR = 0.52, 95% CI 0.35-0.76) was also observed. Gender-specific variation was found for Sjögren syndrome, hereditary haemolytic anaemia, myasthenia gravis, polymyalgia rheumatica and dermatomyositis. CONCLUSIONS: Schizophrenia was associated with a greater variety of autoimmune diseases than was anticipated. Further investigation is needed to gain a better understanding of the aetiology of schizophrenia and autoimmune diseases.

Five-year trajectories of long-term benzodiazepine use by adolescents: patient, provider, and medication factors.

OBJECTIVES: This study sought to understand the stability of and change in benzodiazepine use among incident long-term benzodiazepine users over a five-year period and to investigate predictors of variation in use patterns from adolescence into adulthood. METHODS: Long-term use was defined as receipt of benzodiazepine prescriptions for 31 or more cumulative days in a calendar year. Data for 1999-2005 were obtained from the National Health Insurance Research Database in Taiwan. Two age groups of incident long-term users in 2000 were identified--1,758 aged 12-15 and 5,265 aged 16-19-and their benzodiazepine prescription records from 2001 to 2005 were retrieved. Group-based trajectory analyses and polytomous logistic regression were performed to evaluate differential risk of benzodiazepine use over time. RESULTS: From 3% to 5% of the incident benzodiazepine users were long-term users. Four distinct groups of users emerged from the five years of study data: occasional, decelerating, accelerating, and chronic users. Overall, one-quarter were accelerating or chronic users. A history of psychosis or epilepsy, prescription by providers from multiple specialties, and receipt of benzodiazepines with a long half-life or mixed indications significantly increased one's risk of becoming a chronic or accelerating user (range of adjusted odds ratios from 2 to 6). CONCLUSIONS: Patient characteristics and attributes of service providers and pharmacological agents played significant roles in benzodiazepine use patterns. Prescribers can reduce the risk of long-term use by assessing whether pediatric patients have received benzodiazepines from multiple doctors for various medical conditions.

Differential effects of predictors on methylphenidate initiation and discontinuation among young people with newly diagnosed attention-deficit/hyperactivity disorder.

OBJECTIVE: Previous population-based studies have identified factors accounting for differential utilization of psychotropic medications among young patients with attention-deficit/hyperactivity disorders (ADHDs); yet, few analyses have addressed changes in such factors that can occur in the help-seeking process. The aim of this study was to examine patient- and service provider-level predictors for methylphenidate (MPH) initiation and discontinuation. METHOD: This cohort study included 10,153 newly diagnosed ADHD patients under 18 years of age in 2000, identified from the National Health Insurance Research Database. The risk association was estimated by time-dependent survival analyses, as indexed by hazard ratio. RESULTS: Approximately 30% of young people received MPH treatment within the year of their ADHD diagnosis, and virtually none remained in treatment beyond 12 months. Regardless of co-morbidity status, the following were significantly associated with earlier initiation of MPH treatment: older age (e.g., adjusted hazard ratio [aHR] for age 12-17 = 4.5-7.6), lower socioeconomic status (aHR = 1.2-1.4), southern residence (aHR = 1.4-1.6), receiving the diagnosis while school was in session (aHR = 1.3-1.4), receiving the diagnosis from a physician specializing in pediatrics or psychiatry (aHR = 7.3-16.8), and receiving the diagnosis in a district hospital/clinic (aHR = 1.3-1.7). However, once treatment started, older ages appeared to increase the risk of early discontinuation by 15%, and the corresponding estimates for receiving initial MPH in a regional hospital or district hospital/clinic were 27% and 32%, respectively. Change in treatment location upon subsequent visit was associated with a 58% reduction in early discontinuation. CONCLUSIONS: This information about time-varying predictors for MPH utilization throughout treatment may provide insight into the delivery of pediatric mental health services and has important implications for the design of clinical treatment programs.

Multidimensional assessments of impulsivity in subjects with history of suicidal attempts.

OBJECTIVE: This study aimed to examine whether subjects with history of suicidal attempts had higher impulsivity as measured by neurocognitive tests and self-report questionnaires. The interrelationships among different impulsivity measures were also explored. METHODS: Fifty-four nonpsychotic psychiatric inpatients, including 24 subjects with previous history of suicidal attempts and 30 comparison subjects without previous suicidal attempts, completed the self-report Barratt Impulsiveness Scale-11-Chinese version (BIS-11-CH) and 2 neuropsychologic tests of impulsivity: the immediate memory task/delayed memory task (IMT/DMT) and the single key impulsivity paradigm (SKIP). RESULTS: The results indicated that subjects with previous suicidal attempts exhibited higher BIS-11-CH factor 2 (lack of self-control/attentional impulsivity) subscore (P = .02) and more commission errors in IMT (P = .03). However, BIS-11-CH scores and performance indices of IMT/DMT and of SKIP did not correlate with each other. CONCLUSIONS: Our findings supported that subjects with previous suicidal attempts had higher impulsivity, which could be revealed by both self-report and neurocognitive measures. However, there is no correlation among self-report, IMT/DMT, and SKIP measures, indicating that they might be measuring different dimensions of impulsivity.

Predictors of the incidence and discontinuation of long-term use of benzodiazepines: a population-based study.

Long-term use of benzodiazepines (BZDs) has been linked with an array of negative health consequences and increased medical costs and social burden. In this study, we sought to investigate the factors accounting for differential risks in the process from incident BZD use to long-term use and discontinuation in the general population. On the basis of a random sample of 187,413 people enrolled in Taiwan's National Health Insurance program on January 1, 2000, data of 2000-2002 healthcare and pharmacological services utilization were retrieved. Long-term use (LTU) was defined by having received BZD prescriptions for 180 or more days within any given calendar year. Multivariate logistic regression analyses were carried out to assess the strength of associations while adjusting for the effects of individual sociodemographics, service providers, and pharmacological agents simultaneously. Results indicated that males, elderly, and those with physical or mental disorders were more likely to become long-term users of BZDs. Having received BZD prescriptions in multiple pharmacological agents, short-acting or mixed-type agents, and hypnotic indication were associated with a roughly 2- to 5-fold increased risk of BZD LTU soon after prescription initiation. With respect to discontinuation, the effects of pharmacological characteristics seem more salient as compared to those of individual and service-provider factors. Future strategies targeting individual factors and modifying service-provider prescription behaviors may be considered to reduce possible negative consequences of BZD LTU.

Benzodiazepine and risk of hip fractures in older people: a nested case-control study in Taiwan.

OBJECTIVE: To examine the characteristics of benzodiazepines usage and their associations with hip fractures. METHOD: All subjects were aged 65 and older and enrolled in the National Health Insurance program in Taiwan, 2001-2004. Cases (N = 217) were elderly patients who were identified with hip fractures for the first time in their outpatient claims. They were individually matched to 1,214 comparison patients based on age, gender, and index year. Benzodiazepine usage (doses, duration, half-life) and the other covariates including comorbidities, health care utilization, and psychotropic medications used in the 180 days before index events were constructed. RESULTS: Using nonusers as reference group, use of benzodiazepines was significantly associated with hip fractures (adjusted odds ratio [AOR] = 1.7, 95% confidence interval [CI] = 1.2-2.5). Such risks appear to be particularly high during the first month (AOR = 5.6, 95% CI = 2.7-11.8) of exposure, doses higher than 3.0 mg/day in diazepam equivalents (AOR = 1.8, 95% CI = 1.1-3.1), and using short-acting benzodiazepines (AOR = 1.8, 95% CI = 1.3-2.7). CONCLUSIONS: Benzodiazepine exposure in the elderly increases the risk of hip fractures. This is true even with modest dosage, short-acting agents and short-term exposures. Clinicians should prescribe benzodiazepines judiciously with the elderly to minimize drug-related hip fractures.