Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies.

BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable. METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study. RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11). CONCLUSION: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).

Clinical Pharmacy in Psychiatry: Towards Promoting Clinical Expertise in Psychopharmacology.

Although clinical pharmacy is a discipline that emerged in the 1960s, the question of precisely how pharmacists can play a role in therapeutic optimization remains unanswered. In the field of mental health, psychiatric pharmacists are increasingly involved in medication reconciliation and therapeutic patient education (or psychoeducation) to improve medication management and enhance medication adherence, respectively. However, psychiatric pharmacists must now assume a growing role in team-based models of care and engage in shared expertise in psychopharmacology in order to truly invest in therapeutic optimization of psychotropics. The increased skills in psychopharmacology and expertise in psychotherapeutic drug monitoring can contribute to future strengthening of the partnership between psychiatrists and psychiatric pharmacists. We propose a narrative review of the literature in order to show the relevance of a clinical pharmacist specializing in psychiatry. With this in mind, herein we will address: (i) briefly, the areas considered the basis of the deployment of clinical pharmacy in mental health, with medication reconciliation, therapeutic education of the patient, as well as the growing involvement of clinical pharmacists in the multidisciplinary reflection on pharmacotherapeutic decisions; (ii) in more depth, we present data concerning the use of therapeutic drug monitoring and shared expertise in psychopharmacology between psychiatric pharmacists and psychiatrists. These last two points are currently in full development in France through the deployment of Resource and Expertise Centers in PsychoPharmacology (CREPP in French).

One year mirror-image study using paliperidone palmitate for relapse prevention of schizophrenia in four university hospitals in Canada.

BACKGROUND: Superiority of long acting injectable antipsychotics (LAI) over oral antipsychotics remains controversial and dependent on study design and inclusion criteria. Meta-analysis of 21 RCTs demonstrated no difference in their effectiveness, but meta-analysis of 25 mirror-image studies did. None of these included paliperidone palmitate (PP). METHODS: We challenged efficiency of PP in a multicentric mirror-image study. Primary outcome was total hospitalization days. Mirror periods were 365days either side of the first injection in model-1, and either side of index admission in model-2. Inclusion criteria were: 18 to 65years, schizophrenia spectrum disorder, ≥3 injections received, and oral antipsychotic prescriptions before PP trial. Exclusion criteria were: prior clozapine or LAI trial. Cost-effectiveness was calculated from a public payer's perspective. RESULTS: 114 patients were recruited (77% males, mean 37years, mean disease duration 10years). Oral antipsychotics adherence was 43%. Mean PP treatment lasted 297days (adherence 81%). Mean annual hospitalization days weren't significantly different in model-1 (45.8days vs 38.5days, p=0.058), but were significantly lower in model-2, (14.4days vs 24.2days, p=0.003). 1.9 admissions per patient-year fell to 0.64 on PP (p<0.0001). PP was approximately cost-neutral: differences were -$326 and $1788 for model-1 and model-2. DISCUSSION: PP as a first LAI improved adherence, decreased hospital visits and duration was cost neutral. Drawbacks are the retrospective design and lack of comparator and safety data. Strengths are naturalistic design and adherence calculation. A subset of patients responds well to LAI, leading to meaningful reductions in hospital services requirements.

Suicide prevention in pharmaceutical education: Raising awareness with inspiring stories.

Suicide rates are high in high-income countries like Canada and the United States, where 10 to 12 people per 100 000 commit suicide every year. In the United States, in 2011 there were 73.3 emergency room visits per 100 000 people for suicide attempts with prescription drugs. The latter were also involved in 13% of completed suicides between 1999 and 2013. In most cases, these drugs were distributed by members of our profession who could not predict this outcome. This led us to create an initiative to teach pharmacy students how to prevent suicide. A literature review and online search were performed to find documentation about pharmacists' commitment to the cause, but very little information exists. Thus, a training session was developed for third-year pharmacy students that includes basic statistics, arguments for involving pharmacists in suicide prevention, role-playing, tools to evaluate suicide risk, thoughtful verbatims of interview techniques, and case studies. It is delivered during the mental health theme of the psychiatry course. In 5 years, around 1150 students have participated in the course, of whom approximately 950 are now practicing pharmacists. This intervention may have prevented some suicides, although the impact is impossible to measure. The objective of this paper is to describe the creative process of designing a suicide prevention training session for pharmacy students, while inspiring a mental health sensitive readership to this noble cause. This article does not provide guidelines on how to replicate this initiative, nor does this article replace proper training on suicide prevention.

A randomized controlled trial with a Canadian electronic pill dispenser used to measure and improve medication adherence in patients with schizophrenia.

OBJECTIVE: Medication adherence is extremely important in preventing relapse and lowering symptoms in schizophrenic patients. However, estimates show that nearly half of these patients have poor adherence. The Brief Adherence Rating Scale (BARS) seems to be the most reliable tool assessing adherence in schizophrenia and shows that the antipsychotic adherence ratio (AAR) is about 49.5% in schizophrenia. The aim of the study was to test if an electronic pill dispenser named DoPill(®) improved AAR of schizophrenic patients. Furthermore, we compared AAR obtained by the DoPill(®) and the BARS, in order to verify whether the DoPill(®) provides reliable assessment of medication adherence. METHODS: The DoPill(®) is a smart pill dispenser that beeps and flashes at the appropriate time of the day. Each of its 28 compartments is covered by a plastic lamina that, when taken off, sends a signal to the pharmacist. Patients were randomized to the DoPill(®) or treatment as usual groups for 6 weeks. The BARS was used as a reference measure. RESULTS: Forty-six percent of patients were deemed to be non-adherent with antipsychotic medication. The mean AAR was 67% after 6 weeks. DoPill(®) recorded better AAR than some of those found in the literature and were lower than the BARS estimate we found. CONCLUSION: These results suggest that DoPill(®) is a valid tool that provides more reliable and objective data for the clinician about their patient's adherence, than existing assessment tools like the BARS. Furthermore, the device may help patients successfully manage their medication regimen.

Therapeutic drug monitoring for drugs used in the treatment of substance-related disorders: literature review using a therapeutic drug monitoring appropriateness rating scale.

BACKGROUND: The efficacy of drugs for the treatment of substance-related disorders is moderate at best. Therapeutic drug monitoring (TDM) could be an instrument to improve outcomes. Because TDM for most of those drugs is not established, the authors reviewed the literature and built a rating scale to detect the potential added value of TDM for these pharmacologic agents. METHODS: A literature search was performed for acamprosate, bupropion, buprenorphine, clomethiazole, disulfiram, methadone, naltrexone, and varenicline. The rating scale included 22 items and was divided in five categories: efficacy, toxicity, pharmacokinetics, patient characteristics, and cost-effectiveness. Three reference substances with established TDM were similarly assessed for comparison: clozapine, lithium, and nortriptyline. The three reference substances achieved scores of 15, 12, and 14 points, respectively. RESULTS: Drugs for treatment of substance-related disorders achieved 3 to 17 points, 17 for methadone, 11 for buprenorphine, 10 for disulfiram, also 10 for naltrexone for the indication opioid-dependence and 9 for the indication alcohol dependence as well as bupropion, 7 points for acamprosate, 6 points for clomethiazole, and 3 for varenicline. CONCLUSIONS: It is concluded that systematic evaluation of drug- and patient-related variables with the new rating scale can estimate the appropriateness of TDM. Because their rating revealed similar scores as the three reference drugs, it is proposed that TDM should be established for bupropion, buprenorphine, disulfiram or a metabolite, methadone, and naltrexone. An objective rating of drug- and patient-related characteristics could help laboratories focus their method development on the most likely drugs to require TDM along with a thorough drug use evaluation.

Factors influencing enoxaparin anti-Xa activity in surgical critically ill patients.

STUDY OBJECTIVE: The objectives of the present study were to describe the incidence of low anti-Xa levels defined as below 0.1 IU/mL in a general surgical intensive care unit population and to evaluate factors independently influencing anti-Xa activity. DESIGN: A prospective study was undertaken. SETTING: Thirty-six patients admitted to a general intensive care unit and receiving subcutaneous (SC) enoxaparin 30 mg twice daily for thromboprophylaxis between November 2003 and August 2005 were included in the study. MEASUREMENTS AND MAIN RESULTS: After reaching steady state, anti-Xa activity was determined by chromogenic assay at 0, 3, 6, and 9 hours after injection. Anti-Xa levels below 0.1 IU/mL at any time were considered subtherapeutic. Areas under the curve (AUCs) for a 12-hour dosing interval were estimated. Factors influencing anti-Xa AUC were evaluated using linear regression. Two patients (5.6%) did not attain therapeutic levels defined as anti-Xa more than 0.1 IU/mL at 3 hours post dose. Median AUC was 1.84 IU·h/mL (interquartile range, 1.47 IU·h/mL). In the linear regression analysis, sex and creatinine clearance were significant predictors of anti-Xa AUC(0-12h) levels. CONCLUSION: In the study, prophylactic SC enoxaparin in critically ill patients at the current 30 mg SC twice daily dosage attained an anti-Xa level more than 0.1 U/mL in nearly all patients. In addition, low creatinine clearances and female sex are associated with higher anti-Xa activity AUC(0-12h).