The use of off-label medications in substance abuse treatment programs.

Background: Substance use disorder (SUD) treatment centers serve a population of clients who have diverse needs, and may desire or require access to varied treatments while seeking care for their SUDs. While pharmacotherapies have increased in popularity for the treatment of SUDs, adoption rates do remain quite low. But a wider array of pharmacotherapies has become available in recent years which may shift the trend. This article helps shed light on how variations in SUD treatment centers develop and persist with regard to the adoption and delivery of off-label medications. Methods: We use a nationally representative and longitudinal sample of SUD treatment centers in the US (N = 196). We use a logistic regression to analyze the relationship between organizational characteristics and offering any medications, off-label. We also use a negative binomial regression to analyze the relationship between organizational characteristics and the number of medications that were used off-label. Results: Our findings reveal that older centers, accredited centers, and centers that offer mental health screenings are all positively associated with the provision of off-label medication in SUD treatment. We also find a positive relationship between private funding and offering a greater number of off-label medications. Conclusions: Our results suggest that SUD clients who seek treatment from centers that offer medications off-label, may have access to a greater number of medication-assisted treatment options.

Scientific Issues Relevant to Improving the Diagnosis, Risk Assessment, and Treatment of Major Depression.

Over the past two decades, research in the biology and treatment of major depression has led to advances in our understanding of the biology of the disorder and to the development of novel treatments. While progress has been made, a number of key issues have emerged regarding diagnosis of the disorder and how we develop and test new therapies. Among these are the potential need to include new dimensions in the diagnostic criteria, the limited utility of clinical predictors of response, the moving away from traditional blinded trials in major depression, and whether preclinical models tell us much about novel drug development. These issues need to be addressed to avoid the field's embarking on trails of research and treatment development that could actually mislead or misdirect our efforts to develop better diagnostic tools and more effective treatments. Possible solutions to these problems are proposed.

Assessment of Use of Combined Dextromethorphan and Quinidine in Patients With Dementia or Parkinson Disease After US Food and Drug Administration Approval for Pseudobulbar Affect.

Importance: In 2010, the US Food and Drug Administration (FDA) approved a combination of dextromethorphan hydrobromide and quinidine sulfate for the treatment of pseudobulbar affect after studies in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This medication, however, may be commonly prescribed in patients with dementia and/or Parkinson disease (PD). Objective: To investigate the prescribing patterns of dextromethorphan-quinidine, including trends in associated costs. Design, Setting, and Participants: This population-based cohort study of patients prescribed dextromethorphan-quinidine used data from 2 commercial insurance databases, Optum Clinformatics Data Mart and Truven Health MarketScan. The Medicare Part D Prescription Drug Program data set was used to evaluate numbers of prescriptions and total reported spending by the Centers for Medicare & Medicaid Services. Patients were included if they were prescribed dextromethorphan-quinidine from October 29, 2010, when the drug was approved, through March 1, 2017, for Optum and December 31, 2015, for Truven. Data were analyzed from December 1, 2017, through August 1, 2018. Main Outcomes and Measures: The proportion of patients prescribed dextromethorphan-quinidine with a diagnosis of MS, ALS, or dementia and/or PD, as well as the number of patients with a history of heart failure (a contraindication for the drug). Results: In the commercial health care databases, 12 858 patients filled a prescription for dextromethorphan-quinidine during the study period. Mean (SD) age was 66.0 (18.5) years, 66.7% were women, and 13.3% had a history of heart failure. Combining results from both databases, few patients had a diagnosis of MS (8.4%) or ALS (6.8%); most (57.0%) had a diagnosis of dementia and/or PD. In the Medicare Part D database, the number of patients prescribed dextromethorphan-quinidine increased 15.3-fold, from 3296 in 2011 to 50 402 in 2016. Reported spending by Centers for Medicare & Medicaid Services on this medication increased from $3.9 million in 2011 to $200.4 million in 2016. Conclusions and Relevance: Despite approval by the FDA for pseudobulbar affect based on studies of patients with ALS or MS, dextromethorphan-quinidine appears to be primarily prescribed for patients with dementia and/or PD.

Perioperative use of gabapentinoids in France. Mismatch between clinical practice and scientific evidence.

BACKGROUND: Gabapentinoids have governmental health agency approval for "chronic neuropathic pain." Over the last decade, however, the perioperative prescription of gabapentinoids has become more popular among anaesthesiologists due to their anxiolytic and antihyperalgesic proprieties, despite weak scientific evidence supporting the risk/benefit ratio for this indication. METHODS: Our aim was to extensively describe the use of perioperative gabapentinoids by French anaesthesiologists. An online questionnaire was sent to the French Society of Anaesthesiology members. The questionnaire, focusing on gabapentinoid prescriptions, included questions on demographic data, patient conditions and types of surgeries, mode of prescription, motives and presumed side effects (dizziness, confusion, desaturation and visual disorders). RESULTS: Five hundred and eight questionnaires were analysed, among which 70% reported gabapentinoid use. Twenty-five percent of prescribers stated using gabapentinoids in all types of surgeries, 30% in outpatient surgeries and 46% in combination with regional anaesthesia. In 66% of the cases, preoperative and postoperative prescriptions were combined. Sedation, dizziness and visual disturbance were expected side effects according to 68%, 45% and 20% of anaesthesiologists, respectively. Reported reasons in favor of gabapentinoid prescription were prevention of chronic pain (93%), expected high postoperative acute pain, i.e. painful surgeries (91%), a history of chronic pain (72%) and patient opioid dependence (72%). DISCUSSION: French anaesthesiologists have recently included gabapentinoids in the multimodal management of postoperative pain but they are unaware of certain frequent side effects. Moreover, their expectations about the prevention of chronic pain are not validated. Our survey is a call to moderate the systematic prescription of these drugs in the perioperative period.

[Changes in drug management of Alzheimer's disease in nursing homes: Impact of the media campaign against specific drugs for Alzheimer's disease]. / Évolution de la prise en charge médicamenteuse de la maladie d'Alzheimer en EHPAD : impact de la campagne médiatique contre les médicaments spécifiques de la maladie d'Alzheimer.

CONTEXT: Alzheimer's disease is a common disease in nursing homes. Evolution is constantly negative and specific treatments, which are only symptomatic, are subject to controversy. In a context of media exposure, the Transparency Committee of the Haute Autorité de santé (HAS) downgraded their medical service in October 2011, seeing it as weak. AIM: Assess the evolution of the consumption of specific treatments for Alzheimer's disease; assess changes in the quality of monitoring in specific consultation. METHODS: This is a retrospective and descriptive study, cross-sectional in three times (T0 January 2011, T1 October 2011 and T2 June 2012), in 6 nursing homes of Lille and its surroundings. RESULTS: In total, 262 residents with dementia and present at least once during the three times of the study were included. Their mean age was 85.8 years. Among them, 40 % had Alzheimer's disease clearly identified. At T0, 76.7 % of patients present who were supposed to receive a specific treatment of Alzheimer's disease were actually receiving such treatment, 73.6 % at T1 and 71.6 % at T2. After 17 months of observation, the discontinuation rate of anticholinesterase was 34 %, 24 % for anti-glutamate. The monitoring in specific consultations decreased slightly between the three stages. CONCLUSION: Our work did not show major impact of the media campaign against specific drugs for Alzheimer's disease. There is however a trend towards a decrease of their consumption in people with dementia living in nursing homes with no obvious link between monitoring in specific consultation and specific prescription. This trend would ask to be confirmed by a study on a larger scale.

Suicide risk assessment and intervention in people with mental illness.

Suicide is the 15th most common cause of death worldwide. Although relatively uncommon in the general population, suicide rates are much higher in people with mental health problems. Clinicians often have to assess and manage suicide risk. Risk assessment is challenging for several reasons, not least because conventional approaches to risk assessment rely on patient self reporting and suicidal patients may wish to conceal their plans. Accurate methods of predicting suicide therefore remain elusive and are actively being studied. Novel approaches to risk assessment have shown promise, including empirically derived tools and implicit association tests. Service provision for suicidal patients is often substandard, particularly at times of highest need, such as after discharge from hospital or the emergency department. Although several drug based and psychotherapy based treatments exist, the best approaches to reducing the risk of suicide are still unclear. Some of the most compelling evidence supports long established treatments such as lithium and cognitive behavioral therapy. Emerging options include ketamine and internet based psychotherapies. This review summarizes the current science in suicide risk assessment and provides an overview of the interventions shown to reduce the risk of suicide, with a focus on the clinical management of people with mental disorders.

Memantine for treatment of moderate or severe Alzheimer's disease patients in urban China: clinical and economic outcomes from a health economic model.

OBJECTIVE: To estimate the clinical and economic benefits of memantine treatment initiated in moderate Alzheimer's disease (AD) in China, compared with initiation in severe AD only. METHODS: A Markov model with a 5-year time horizon simulated moderate patients' progression through health states. Two groups were compared: patients receiving memantine from the moderate stage (i.e., at model entry), continuing treatment when reaching the severe stage; patients initiating memantine only when they developed severe disease. RESULTS: After 5 years, fewer patients receiving memantine from the moderate stage were severe (49%), dependent (59%) or aggressive (47%) compared with moderate patients who initiated treatment from severe stage only (58, 67 and 55%, respectively). Total cost of care was lower for treatment from moderate stage (67 billion RMB) when compared with treatment from severe stage (73 billion RMB). CONCLUSIONS: In China, AD treatment with memantine from the moderate stage could result in substantial cost savings.

Novel metabotropic glutamate receptor 2/3 antagonists and their therapeutic applications: a patent review (2005 - present).

INTRODUCTION: This review focuses on the medicinal chemistry efforts directed toward the identification of competitive and noncompetitive antagonists of glutamate at group II metabotropic glutamate receptors (mGluRII: mGlu2/3 and mGlu2). This class of compounds holds promise for the treatment of CNS disorders such as major depression, cognitive deficits and sleep-wake disorders, and several pharmaceutical companies are advancing mGluRII antagonists from discovery research into clinical development. AREA COVERED: This review article covers for the first time the patent applications that were published on mGlu2/3 orthosteric and allosteric antagonists between January 2005 and September 2014, with support from the primary literature, posters and oral communications from international congresses. Patent applications published prior to 2005 for which compositions of matter were largely described in peer review articles are briefly discussed with main findings. EXPERT OPINION: Recent advances in the prodrug approach of novel mGlu2/3 orthosteric antagonists combined with the design of novel mGlu2/3 and mGlu2 negative allosteric modulators provide new therapeutic opportunities for neurologic and psychiatric disorders.

Consumption trends for specific drugs used to treat dementia in the region of Madrid (Spain) from 2002 to 2012.

INTRODUCTION: Analysing drug consumption in large population groups lets us observe consumption trends and compare them between different settings. OBJECTIVE: to analyse the time trends for consumption and costs of specific drugs used to treat dementia in the region of Madrid (Spain) and compare trends by sex and age cohort. METHODS: Descriptive study of cholinesterase inhibitors (N06DA) and memantine (N06DX01) dispensed in Madrid between 2002 and 2012 and covered by the Spain's national health system. Consumption was calculated by analysing changes in DDD (defined daily doses) to find total and yearly increases. The cost was estimated based on DDD price. To compare consumption rates by age and sex, we calculated DDD per 100 inhabitants/day. RESULTS: Between 2002 and 2012, consumption of drugs used to treat dementia increased sixfold. During this period, cholinesterase inhibitors accounted for 76.70% of the drugs consumed and memantine, 23.30%. The estimated cost rose by a by a factor of 5.7 over 11 years (or by a factor of 4 taking into account the use of generic drugs). In 2012, 2.42% of the patients aged 65 or over consumed cholinesterase inhibitors (women 2.82%, men 1.83%) and 0.90% consumed memantine (women 1.10%, men 0.61%). Consumption increased in age cohorts up to 86 to 90 (5.84% for cholinesterase inhibitors and 2.33% for memantine) and declined thereafter. CONCLUSIONS: Consumption of cholinesterase inhibitors and memantine gradually increased, but consumption in 2012 did not reach levels equivalent to dementia prevalence figures. Pharmaceutical expenditure restraint measures may temporarily slow the cost increase temporarily but if the same trend of consumption persists, costs will rise.

Antidementia drug use among community-dwelling individuals with Alzheimer's disease in Finland: a nationwide register-based study.

The objective of this study was to investigate the prevalence of acetylcholinesterase inhibitor (AChEI) and memantine use, duration of treatment, concomitant use of these drugs, and factors associated with the discontinuation of AChEI therapy during 2006-2009. We utilized data from a nationwide sample of community-dwelling individuals with a clinically verified Alzheimer's disease diagnosed during the year 2005 (n=6858) as a part of the MEDALZ-2005 study. During the 4-year follow-up, 84% used AChEI and 47% used memantine. Altogether, 22% of the sample used both drugs concomitantly. The median duration of the first AChEI use period was 860 (interquartile range 295-1458) days and 1103 (interquartile range 489-1487) days for the total duration of AChEI use. Although 20% of the AChEI users discontinued the use during the first year, over half of them restarted later. The risk of discontinuation was higher for rivastigmine [hazard ratio 1.34 (confidence interval 1.22-1.48)] and galantamine users [hazard ratio 1.23 (confidence interval 1.15-1.37)] compared with donepezil users in the adjusted model. In conclusion, median time for AChEI use was over 3 years and every fifth Alzheimer's disease patient used AChEI and memantine concomitantly during the follow-up. The low rate of discontinuation is consistent with the Finnish Care Guideline but in contrast to the results reported from many other countries.

Multiple sclerosis spasticity daily management: retrospective data from Europe.

Multiple sclerosis (MS) is a distressing and debilitating disease, which often leads to a state of progressive deterioration for the individual. Spasticity is a common and disabling neurological feature with increasing presence and severity throughout the progression of MS. Management of this spasticity is a key component of day-to-day care for patients with MS. Data from recent epidemiological studies in Spain (the '6E' and '5E' studies) and Germany (the 'MOVE 1' study) confirm the frequent occurrence of spasticity symptoms in patients with MS. Despite the difficulties experienced by MS patients with spasticity, the condition is largely undertreated because current treatment options do not provide adequate control of MS spasticity. With worsening MS spasticity there is an increase in individual patient symptoms, worsening of quality of life and impairment of daily living. From a healthcare/societal perspective, MS spasticity has been shown to be associated with substantial costs. Many of these costs relate to the increased disability (and consequent need for rehabilitation and caregiver support) that are associated with moderate-to-severe spasticity. Consequently, newer drugs that can provide better symptomatic relief and may slow progression to more severe forms of disability will be a step forward in the level of care that we can provide for MS patients.

Cognitive assessment: a guide for community nurses.

Ageing increases the risks of dementia and there are an estimated 667,000 people in England living with dementia. Less than half have a formal diagnosis. Community nurses are now being asked to screen older people for dementia under the Commissioning for Quality and Innovation framework. This article provides a brief explanation of common screening tools and explains the community nurse's role in identifying people who may have undiagnosed dementia.

[Assessment of benefits of drug therapies: memantine for Alzheimer's disease as an example]. / Zur Bewertung des Nutzens medikamentöser Therapieoptionen am Beispiel von Memantin bei Alzheimer Demenz.

After the approval of a drug, which represents a first assessment, independent institutions and medical professional associations provide further evaluations. Here, the question is to be asked whether common or diverging evaluation methods exist that can have an impact on the result. In principle, two methods are used: meta-analyses and responder analyses. Meta-analyses and the resulting effect sizes have to be interpreted according to the field of application (for example, the type and severity degree of a disease) with medical expertise. Omitting this can lead to incorrect evaluations and to a discrepancy of evaluation results. In the case of memantine, the merely biometric evaluation of meta-analyses performed by the IQWiG led to a denial of the benefit, while the same data, considering clinical routine, led professional associations to recommend memantine for moderate to severe Alzheimer´s disease. In contrast to meta-analyses, responder analyses directly show the benefit of a therapy option in the presence of significant group differences, as the selected responder criteria are based on the indication. The corresponding results of the responder analyses on memantine were also acknowledged by the IQWiG and led to a positive evaluation of memantine. This discrepancy of evaluation results illustrates the fact that statistical procedures are necessary when evaluating drug and non-drug therapy options but, that the interpretation of the results with medical expertise is essential.

Racial and ethnic disparities in Alzheimer's disease pharmacotherapy exposure: an analysis across four state Medicaid populations.

BACKGROUND: Treatment disparities in Alzheimer's disease (AD) have received little attention. Determining whether disparities exist in this subpopulation is an important health policy issue. OBJECTIVE: The aim was to determine whether an association existed between race/ethnicity and exposure to AD pharmacotherapy across 4 state Medicaid populations. METHODS: Data from the Centers for Medicare and Medicaid Services (CMS) were used in this retrospective study. Persons with AD enrolled in California, Florida, New Jersey, or New York Medicaid programs on January 1, 2004, and remained in that program for 1 year. Individuals had an AD diagnosis based on the ICD-9-CM code 331.0. Outcomes of interest were exposure to a cholinesterase inhibitor (ChEI) or memantine. Multivariate logistic regression was used to test for the association between race/ethnicity and exposure to a ChEI or memantine. Variables of interest included demographic characteristics and resource utilization factors. The Oaxaca-Blinder decomposition method was used to test for disparities to determine whether exposure to AD pharmacotherapy was influenced by race. RESULTS: Race, age, long-term care admittance, inpatient care admittance, state of residence, and sex were significant predictors of AD pharmacotherapy exposure (P < 0.0001 for all variables). Racial/ethnic disparities were observed with respect to exposure to a ChEI or memantine between non-Hispanic whites and Hispanics (in favor of Hispanics) in Florida (P < 0.0001), between non-Hispanic blacks and Hispanics (in favor of Hispanics) in California (P < 0.0001) and Florida (P < 0.0001), between non-Hispanic blacks and non-Hispanic others (in favor of non-Hispanic others) in California (P < 0.0001) and New York (P < 0.0001), and between Hispanics and non-Hispanic others (in favor of non-Hispanic others) in California (P = 0.001) and New York (P < 0.0001). CONCLUSIONS: Disparities in AD pharmacotherapy exposure among minority populations are just as prevalent, if not of greater magnitude, than minority/white disparities.

Memantine in Alzheimer's disease: experience in an Alzheimer's disease assessment unit.

BACKGROUND AND AIMS: Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist. Clinical and observational studies have demonstrated its efficacy on both cognitive and behavioral symptoms of moderate-to-severe Alzheimer's disease (AD) and described its good safety and tolerability profile. We report here our experience with memantine in patients with AD during a two-year follow-up. METHODS: From June 2005 to May 2010, memantine was given to 201 outpatients with moderate-to-severe AD: 93 patients were concomitantly receiving treatment with acetyl cholinesterase inhibitors (AChEIs) (Group 1) and the other 108 were prescribed memantine as monotherapy (Group 2). All patients were administered the following scales: Mini Mental State Examination, Activities of Daily Living, Instrumental Activities of Daily Living, Neuropsychiatric Inventory. We report the results of followup assessments conducted at six months and 1, 2 and 3 years. RESULTS: Sixteen patients (8%) stopped treatment within the first month because of side-effects. In each group, about 20% of subjects showed no deterioration at six months and 1 year, and this proportion decreased only slightly at 2 years. Higher NPI scores at baseline and psychotropic drug use emerged as factors significantly related to reduced response to treatment (p<0.01). CONCLUSIONS: Results confirmed the short-term effect of memantine, both in monotherapy and in combination with AchEIs in moderate-to-severe AD. This efficacy, albeit slight, was found to persist in the longer term.

Cost-effectiveness of memantine in moderate and severe Alzheimer's disease in Norway.

BACKGROUND: The cost-effectiveness of memantine for the treatment of moderate and severe Alzheimer's disease has been assessed in several European countries. Objective of the study was to assess it in Norwegian settings. METHODS: This cost-utility analysis used a Markov modelling approach to simulate the evolution of patients until their need for full-time care (FTC) over a 5-year period. FTC was defined as a patient becoming either dependent or institutionalised. Transition probabilities were estimated using a newly developed predictive equation of time to FTC. Health resource use and utilities were obtained from the Scandinavian Study of Cost and Quality of Life in Alzheimer's Disease study, and mortality was obtained from the Oslo study. Memantine efficacy was based on a meta-analysis of six large trials. The model compared memantine with its alternative in this population, that is no pharmacological treatment or background therapy with acetylcholinesterase inhibitors. The model underwent extensive sensitivity analyses. RESULTS: In Norway, memantine was found to delay the need for FTC by 4.4 weeks compared with standard care and was associated with increased quality-adjusted life years. Memantine was the dominant strategy with cost savings of €3739 (30 041 NOK) per patient. The probability of being the dominant strategy was 98.8%. This result was confirmed across multiple sensitivity analyses. CONCLUSIONS: The model suggests that memantine prolongs time to FTC for no additional cost to the healthcare system and society. It can be regarded as a cost-effective choice in the management of moderate and severe Alzheimer's disease.

MR spectroscopy for assessment of memantine treatment in mild to moderate Alzheimer dementia.

OBJECTIVES: Magnetic Resonance Spectroscopy (MRS) may provide a precise and reliable assessment of the extent and severity of neural tissue loss caused by various diseases. In particular, the N-Acetyl Aspartate (NAA) and Creatine (Cr) ratio has been found to be an indicator of the degree of neuronal loss in Alzheimer's disease (AD). Memantine is thought to benefit the AD brain by stabilizing the NMDA receptors on neurons in turn reducing excitotoxicity. Despite its effectiveness in treating moderate to severe AD, memantine has not had similar success in the treatment of mildly demented AD patients. The objective of this study was to test whether memantine would slow or prevent the loss of neurons in mild to moderate AD patients. METHODS: A double-blind placebo-controlled study was designed to measure the effect of a year-long course of memantine in patients with a probable AD diagnosis with mild to moderate dementia. The primary outcome measure was stipulated to be change in MRS NAA/Cr ratio in inferior parietal cortex in memantine relative to the placebo treatment condition. The secondary outcome measures were changes in cognitive and function scale scores. RESULTS: This pilot study failed to demonstrate a benefit of memantine on the primary outcome measure, the inferior parietal NAA/Cr ratio, or the secondary outcome measures. CONCLUSIONS: More studies are needed to determine the effect of memantine on regions of the brain significantly affected by AD pathology.