Predicting clozapine dose required to achieve a therapeutic plasma concentration - A comparison of a population algorithm and three algorithms based on gene variant models.

BACKGROUND: Clozapine is the most effective antipsychotic but requires careful titration to therapeutic blood levels. Methods to predict therapeutic doses are based on population data. AIMS: We aimed to construct a model based on genetic variants which accurately predicted plasma levels for clozapine. METHOD: We measured clozapine plasma levels in patients on a stable dose of clozapine who were known to be fully compliant. Measured plasma levels were adjusted for sampling time and dose. Hepatic enzyme variants were analysed and models were constructed to predict the required dose. These predictions were compared with a standard population-based algorithm. RESULTS: We measured plasma clozapine concentrations in 18 adherent patients on stable doses of clozapine and recorded the exact timing of sampling. For the algorithm-predicted dose, the mean difference was -49.9 mg/day ((SD 155.9), r = 0.36) from the actual dose required to give a plasma concentration of 0.35 ng/ml. The gene variant activity score predicted a dose for which the mean difference was -43.5 mg/day ((SD 140.1), r = 0.55). For the gene variant activity score with omeprazole correction predicted dose, the mean difference was -31.0 mg/day ((SD 140.8), r = 0.54), and with the gene variant CYP1A2 inducibility predicted dose the mean difference was 44.9 mg/day ((SD 160.8), r = 0.32). CONCLUSION: Our gene variant activity score with omeprazole correction gave the best estimate of the clozapine dose required to achieve a minimum therapeutic plasma concentration. The use of this model will allow safer titration of clozapine and may reduce the need for plasma-level monitoring during titration.

Introduction of a Single Electronic Health Record for Maternity Units in Ireland: Outline of the Experiences of the Project Management Team.

Electronic health records (EHRs) are being introduced worldwide. The change from paper to electronic records has not always been a seamless or quick process; however, EHRs are viewed as central to updating modern health care, especially organization structures and delivery of sustainable care with the potential for joint decision-making with the patient. The objective of this viewpoint paper is to outline how an EHR is being developed in Ireland. The focus of the Maternal & Newborn Clinical Management System project is the design and implementation of an EHR for all women and babies in the maternity services in the Republic of Ireland. The paper also outlines the lessons learned from the planning to the optimization stage of the project. The paper was developed through discussions with the project management team and their completed reports that outline the lessons they acquired from each project stage. Key lessons learned from each stage of the project are highlighted. This viewpoint paper explains how the national project management team is implementing the EHR and outlines the experiences and lessons learned and the challenges ahead following the phase one introduction. The Maternal & Newborn Clinical Management System is an example of a clinician-led, patient-focused, change management project from its inception to implementation. The introduction of EHRs is essential in modernizing health care and optimizing patient outcomes through the accurate and appropriate use of data.

Pharmacological interventions for clozapine-induced hypersalivation.

BACKGROUND: Clozapine is widely used for people with schizophrenia. Although agranulocytosis, weight gain, and cardiac problems are serious problems associated with its use, hypersalivation, sometimes of a gross and socially unacceptable quantity, is also common (30-80%). OBJECTIVES: To determine the clinical effects of pharmacological interventions for clozapine-induced hypersalivation. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (March 2007), inspected references of all identified studies for further trials, contacted relevant pharmaceutical companies, drug approval agencies and authors of trials. SELECTION CRITERIA: We included randomised controlled trials comparing pharmacological interventions, at any dose and by any route of administration, for clozapine-induced hypersalivation. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data (homogenous) we calculated relative risk (RR) with 95% confidence intervals (CI) and numbers needed to treat (NNT) on an intention-to-treat basis. We calculated weighted mean difference (WMD) for continuous data. MAIN RESULTS: Of the 15 trials identified, 14 were conducted in China and 14 in hospitals. The quality of reporting was poor with no studies clearly describing allocation concealment and much data were missing or unusable. All results are vulnerable to considerable bias. Most frequently the primary outcome was the diameter of the wet patch on the pillow. Antimuscarinics (astemizole, diphenhydramine, propantheline, doxepin) were the most commonly evaluated drugs. For the outcome of 'no clinically important improvement' astemizole and diphenhydramine were more effective than placebo (astemizole: n=97, 2 RCTs, RR 0.61 CI 0.47 to 0.81 NNT 3 CI 2 to 5; diphenhydramine: n=131, 2 RCTs, RR 0.43 CI 0.31 to 0.58, NNT 2 CI 1.5 to 2.5), but the doses of astemizole used were those that can cause toxicity. Data involving propantheline were heterogeneous (I2= 86.6%), but both studies showed benefit over placebo. Adverse effects were poorly recorded. Of the other interventions, oryzanol (rice bran oil and rice embryo oil extract) showed benefit over the antimuscarinic doxepin in terms of 'no clinically important change' (n=104, 1 RCT, RR 0.45 CI 0.27 to 0.75, NNT 4 CI 2 to 7). The Chinese medicine suo quo wan (comprises spicebush root, Chinese yam and bitter cardamom) showed benefit over doxepin (n=70, 1 RCT, RR 'no clinically important change' 0.31 CI 0.16 to 0.59, NNT 3 CI 1.5 to 3.7). AUTHORS' CONCLUSIONS: There are currently insufficient data to confidently inform clinical practice. The limitations of these studies are plentiful and the risk of bias is high. These trials, however, are invaluable guides for current and future study design. Well conducted randomised trials are possible. Some may be underway. Current practice outside of well designed randomised trials should be clearly justified.

A systematic review: the effects of podiatrical deviations on nonspecific chronic low back pain.

Lower back pain (LBP) is a widespread, expensive, and debilitating problem in Western industrialized countries. Though LBP can be caused by acute injuries, biomechanical discrepancies have also been indicated to cause chronic LBP. A possible link between podiatrical deviations and LBP has been established in the literature; yet, no comprehensive review investigating the effects of foot and ankle deviations on low back pain has been published. The aim of this study was to assess the relevant literature concerning the effects of foot and ankle deviations on LBP. After review, it was determined that there is limited research regarding ankle and foot deviations and their connection to LBP. Reviewed studies have linked flat feet, ankle instability, sagittal plane blockage and excessive pronation to LBP. Specifically, excessive pronation has been shown to cause leg length discrepancies leading to pelvic tilts and LBP. Based on these results, ankle and foot deviations can be considered a potential cause for LBP due to the disruption of the kinetic chain from the foot to the back. Clinicians should consider the foot and ankle when addressing LBP, especially if more conventional etiologies fail to describe the condition.

Clozapine treatment of adolescents with posttraumatic stress disorder and psychotic symptoms.

This study investigates the efficacy of clozapine in treatment-resistant abused adolescents detained in a secure environment who present with chronic posttraumatic stress disorder and psychotic symptoms. All participants had received at least 2 trials of conventional neuroleptic medication prior to starting clozapine. Efficacy was assessed by using single case methodology across 6 participants employing predependent and postdependent measures of psychiatric symptoms and behavioral observations. Subjective self-reports were also sought after treatment had been established. Evaluation of the data suggests that 4 of the participants demonstrated substantial improvements in psychiatric symptoms and behavioral presentation once a therapeutic dose of clozapine had been achieved. Questionnaire responses from 5 participants indicated that clozapine treatment was associated with a reduction in hallucinatory experiences. The most troubling side effects were those of excessive salivation, dizziness, and weight gain. These findings indicate that clozapine may be effective in decreasing psychiatric symptoms and risk behaviors in traumatized adolescents presenting with psychotic symptoms.