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Background identifying drug-related hospital admissions (DRAs) in older people is difficult. A standardised chart review procedure has recently been developed. It includes an adjudication team (physician and pharmacist) screening using 26 triggers and then performing causality assessment to determine whether an adverse drug event (ADE) occurred (secondary to an adverse drug reaction, overuse, misuse or underuse) and whether the ADE contributed to hospital admission (DRA). Objective to assess the performance of those triggers in detecting DRA. Design retrospective study using data from the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people) trial. Settings four European medical centres. Subjects multimorbid (≥ 3 chronic medical conditions) older (≥ 70 years) inpatients with polypharmacy (≥ 5 chronic medications) were enrolled in the OPERAM trial (N = 2,008) and followed for 12 months. We included patients with ≥1 adjudicated hospitalisation during the follow-up. Methods the positive predictive value (PPV; number of DRAs identified by trigger/number of triggers) was calculated for each trigger and for the tool as a whole. Results of 1,235 hospitalisations adjudicated for 832 patients, 716 (58%) had at least one trigger; an ADE was identified in 673 (54%) and 518 (42%) were adjudicated as DRAs. The overall PPV of the trigger tool for detecting DRAs was 0.66 [0.62–0.69]. Conclusions this tool performs well for identifying DRAs in older people. Based on our results, a revised version of the tool was proposed but will require external validation before it can be incorporated into research and clinical practice.

Contains fulltext : 244715.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Immune dysregulation may be involved in the pathophysiology of schizophrenia. Given the need for new treatment options in schizophrenia, anti-inflammatory medication could be a potential treatment in this illness. METHODS: In this double-blind, placebo-controlled clinical trial, patients with schizophrenia, schizoaffective disorder or psychosis NOS were randomized 1:1 to either prednisolone or placebo, in addition to their regular antipsychotic medication. Patients diagnosed with schizophrenia for less than 7 years and on antipsychotics, were treated with prednisolone or placebo, tapered-off within six weeks in the following schedule: 40 mg/day for 3 days and 30 mg/day for 4 days, followed by a decrease of 5 mg/day per week during the remaining 5 weeks. Change in symptom severity relative to baseline was compared between treatment arms, as measured through the Positive and Negative Syndrome Scale total score. RESULTS: In total, 68 patients signed informed consent and were screened on eligibility criteria, of whom 42 patients were randomized to either prednisolone or placebo, with 39 patients completing the treatment and tapering phase. Due to recruitment difficulties, the study was terminated prematurely. Symptom severity decreased significantly in both the prednisone and placebo treatment arm (p

Aims We aimed to develop a standardized chart review method to identify drug-related hospital admissions (DRA) in older people caused by non-preventable adverse drug reactions and preventable medication errors including overuse, underuse and misuse of medications: the DRA adjudication guide. Methods The DRA adjudication guide was developed based on design and test iterations with international and multidisciplinary input in four subsequent steps: literature review; evaluation of content validity using a Delphi consensus technique; a pilot test; and a reliability study. Results The DRA adjudication guide provides definitions, examples and step-by-step instructions to measure DRA. A three-step standardized chart review method was elaborated including: (i) data abstraction; (ii) explicit screening with a newly developed trigger tool for DRA in older people; and (iii) consensus adjudication for causality by a pharmacist and a physician using the World Health Organization-Uppsala Monitoring Centre and Hallas criteria. A 15-member international Delphi panel reached consensus agreement on 26 triggers for DRA in older people. The DRA adjudication guide showed good feasibility of use and achieved moderate inter-rater reliability for the evaluation of 16 cases by four European adjudication pairs (71% agreement, κ = 0.41). Disagreements arose mainly for cases with potential underuse. Conclusions The DRA adjudication guide is the first standardized chart review method to identify DRA in older persons. Content validity, feasibility of use and inter-rater reliability were found to be satisfactory. The method can be used as an outcome measure for interventions targeted at improving quality and safety of medication use in older people.

Non-adherence to medication is a major issue in the treatment of schizophrenia in general and in particular for those treated with clozapine. A reliable tool to quantify patients long-term adherence to clozapine is currently unavailable. Enhanced FL3 neutrophil granulocyte fluorescence was serendipitously observed in a small population of schizophrenic patients treated with clozapine. The present study was aimed at assessing the association between clozapine use and FL3-fluorescence. A cross-sectional study was performed using data from the Utrecht Patient Oriented Database (UPOD). A total of 38,390 inpatients were included, of which 124 (0.33%) used clozapine. FL3-fluorescence was significantly higher (U=240,179, P

Age-dependent changes in lithium pharmacokinetic and pharmacodynamic properties can influence lithium use in an aging population, especially as newer treatment options are available.We compared lithium use patterns between middle-aged and elderly outpatients in the Netherlands.Data for this study were obtained from the Dutch PHARMO Record Linkage System. Incident lithium users 40 years or older were identified in the period 1996-2008. The following lithium use patterns were defined: continuation, add on, switch, and discontinuation. Differences were assessed for the following age groups: 40 to 49 years, 50 to 59 years, 60 to 69 years, and 70 years or older. The youngest group was the reference group. Patient baseline characteristics and potential determinants of changes in lithium use patterns were assessed.We identified 2081 incident lithium users. Use of antidepressants was not different at baseline between age groups, but elderly patients starting lithium treatment used baseline antipsychotics less frequently (P0.05). Older patients were less likely to receive psychotropic drugs as add on to ongoing lithium therapy (P0.05). Frequency of discontinuation and switch events did not differ between the age groups. In the whole study group, age was associated with any change in lithium use patterns.Older patients are less likely to receive psychotropic drugs as add on to ongoing lithium therapy. Despite pharmacokinetic and pharmacodynamic changes in the elderly, lithium is not more often discontinued and not more often switched in older patients.

To assess the association between mood state and the prevalence and the severity of lithium adverse drug reactions (ADRs).A 26-year follow-up study was conducted among patients >= 18 years treated at the outpatient lithium clinic of the University Medical Center Groningen, The Netherlands, between November 1973 and December 2000. At each monthly scheduled visit, patients were questioned by a research nurse in a standardized manner about the presence and the severity of nine specific ADRs that frequently occur as a consequence of lithium treatment and that can be identified by the patients themselves. In addition, lithium serum level was measured and mood state was rated at each visit.A total of 186 patients participated and the median duration of follow-up was 5.7 years (interquartile range 2.2-11.8 years). We observed an increased prevalence and severity of ADRs with increased lithium serum level (p Both physicians and researchers need to be aware that lithium serum level and mood state are independently associated with patient reporting and severity scoring of ADRs, which may complicate objective assessment of ADRs.

Intoxications with lithium carry considerable risk for long-term morbidity and even mortality. Consequently, any patient suspected of lithium intoxication requires immediate and appropriate care. The objectives of this study were to assess the completeness and the applicability of generally available treatment guidelines for the management of patients with a lithium intoxication and, hence, to provide general recommendations for improvement of existing treatment guidelines. Nineteen treatment guidelines originating from 7 different countries were gathered by searching the Internet, online databases, and textbooks and by contacting different poison information centers and university medical centers. A list of items was composed from the retrieved treatment guidelines and a further literature search. Most relevant items were present in the various guidelines. However, in some guidelines, essential information was missing or potentially hazardous information was provided. Clarity, presentation, and applicability of the guidelines, as assessed using parts of the Appraisal of Guidelines Research and Evaluation instrument, were relatively poor. Regular updates of treatment guidelines should be performed to incorporate new essential information. To improve applicability of guidelines, unambiguous key recommendations, alternative treatments, and special care requirements should be provided and authors are recommended to test treatment guidelines using a panel of less experienced caregivers in a hypothetical case scenario.

Background: The objectives of the present study were to investigate in outpatients in the Netherlands between 1996 and 2005, changes in 1) the incidence and prevalence of lithium use and 2) lithium use patterns (discontinuation, add-on, and switch).Methods: Incidence and prevalence of lithium use were determined for each year between 1996 and 2005. In addition, we determined cumulative changes in lithium use (discontinuation, add-on, and switching) at three, six, 12 and 24 months for three separate time-cohorts (1998-1999, 2000-2001 and 2002-2003). Lastly, concomitant use of other drugs used in the treatment of bipolar disorders next to lithium during the 24 months after the first lithium prescription was determined for the three time-cohorts.Results: Incidence of lithium use was constant at approximately 0.2 per 1000 person-years, prevalence increased with 26% from 0.95 to 1.2 per 1000 persons. The percentage of patients receiving an add-on drug used in the treatment of bipolar disorders was constant over the three time-cohorts, with a significant decrease in use of tricyclic antidepressants. Within the patient group that stopped using lithium, more patients switched from lithium to another agent used in the treatment of bipolar disorders over calendar time, and fewer patients discontinued lithium. There was a significant increase in the use of atypical antipsychotics and valproic acid next to lithium.Limitations: We did not know the specific diagnosis for which lithium treatment was instituted.Conclusion: The changes were in line with the increase in alternatives during the last decade and in line with Dutch guidelines. (C) 2008 Elsevier B.V All rights reserved.

Lithium is the drug that is most frequently associated with acquired nephrogenic diabetes insipidus (NDI). The exact mechanism of lithium-induced NDI in man is unknown. The aim of the present study was to investigate the kidney response to minimal and maximal stimulation of the kidney urine concentrating mechanism by measuring urine osmolality, and urine levels of cAMP and AQP-2 in urine of patients under long-term lithium treatment.Twenty patients under long-term lithium treatment were included. The kidney urinary 3',5'-cyclic adenosine monophosphate (cyclic AMP), aquaporin-2 levels and urine osmolality were determined during a situation of minimal kidney urine concentrating activity (induced by water loading) and during a situation following maximal stimulation of kidney urine concentrating activity (induced by 1-desamino-8-D-arginine-vasopressin).Patients were classified as NDI, partial NDI and non-NDI based on maximal reached urine osmolality. The partial correlation (r) between urinary cyclic AMP levels (mol/l) and urine osmolality was 0.94 (P In conclusion we found that in lithium-induced kidney urine concentrating deficit in man, the cyclic AMP generation in response to 1-desamino-8-D-arginine-vasopressin administration after water loading, is impaired. It remains to be elucidated whether principal cells, G-proteins or adenylate cyclase e.g. are the major targets for the mechanism underlying lithium-induced NDI in man. (c) 2007 Elsevier B.V. All rights reserved.

BACKGROUND Lithium is used both in bipolar disorder and as augmentation in treatment-resistant unipolar depression. Long-term treatment is often indicated. Pharmacokinetic and pharmacodynamic changes in older age, as well as increasing comorbidities and polypharmacy, could result in instability of serum lithium concentrations. In this study, several parameters, considered proxy for instability, were compared between age groups. These parameters were derived from studies involving oral anticoagulants. METHODS A retrospective study (1995-2004) was conducted using serum lithium concentrations from the laboratories of 3 hospitals in the Netherlands; 759 patients treated with lithium, 40 years or older, with at least 2 years' follow-up were identified. They were divided into 4 age groups: 40-49, 50-59, 60-69, and 70+ years; the youngest group was used as a reference group. The variance growth rate and percentage of time below, in, and above treatment range are all proxies for instability. They were analyzed between the age categories. RESULTS There was no significant difference for these variables between the reference group and the older age groups. In a subgroup of 454 patients, the parameters considered as proxy for instability during titration, number of days and number of serum lithium concentration measurements during titration, were evaluated; no significant difference was found between the age groups. In a small group of 117 patients, titration and maintenance treatment for at least 2 years could be analyzed separately. Also in this group, there was no difference between the age groups. CONCLUSIONS Age is not a determinant of serum lithium concentration instability. Therefore, age is not a reason to not initiate or discontinue lithium therapy.

Administration to rats of mood stabilizers approved for bipolar disorder (BD) downregulates markers of the brain arachidonic acid (AA, 20:4n-6) metabolic cascade, including phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) expression. We hypothesized that other agents that target the brain AA cascade, nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, also would ameliorate BD symptoms.Medication histories on subjects who had been prescribed lithium were collected from the Netherlands PHARMO Record Linkage System. Data were stratified according to drug classes that inhibit PLA(2) and/or COX enzymes, and duration of use. Incidence density (ID) of medication events (dose increase or substance change) was used as a proxy for clinical worsening. ID ratios in patients with the inhibitors plus lithium were compared to ratios in patients using lithium alone.Low-dose acetylsalicylic acid (aspirin) significantly reduced the ID ratio of medication events, independent of use duration. The ID ratios of NSAIDs and glucocorticoids did not differ significantly from 1.0 if prescribed foror =180 oror =90 days, but exceeded 1.0 with shorter use. Selective COX-2 inhibitors had no significant effect and multiagent administration increased the ID ratio above 1.0.Low-dose aspirin produced a statistically significant duration-independent reduction in the relative risk of clinical deterioration in subjects on lithium, whereas other NSAIDs and glucocorticoids did not. These tentative findings could be tested on larger databases containing detailed information about diagnosis and disease course, as well as by controlled clinical trials.

Objectives: Safety monitoring is an important aspect of bipolar disorder treatment, as mood-stabilising medications have potentially serious side effects, some of which may also aggravate existing medical comorbidities. This paper sets out the International Society for Bipolar Disorders (ISBD) guidelines for the safety monitoring of widely used agents in the treatment of bipolar disorder. These guidelines aim to provide recommendations that take into consideration the balance between safety and cost-effectiveness, to highlight iatrogenic and preventive clinical issues, and to facilitate the broad implementation of therapeutic safety monitoring as a standard component of treatment for bipolar disorder. Methods: These guidelines were developed by an ISBD workgroup, headed by the senior author (MB), through an iterative process of serial consensus-based revisions. After this, feedback from a multidisciplinary group of health professionals on the applicability of these guidelines was sought to develop the final recommendations. Results: General safety monitoring recommendations for all bipolar disorder patients receiving treatment and specific monitoring recommendations for individual agents are outlined. Conclusions: These guidelines are derived from evolving and often indirect data, with minimal empirical cost-effectiveness data available to provide guidance. These guidelines will therefore need to be modified to adapt to different clinical settings and health resources. Clinical acumen and vigilance remain critical ingredients for safe treatment practice.

Background: A previous Study aimed at revealing the prevalence and determinants Of lithium induced polyuria Suggested an increased risk of polyuria (urine volume >= 3L/24h) in those using serotonergic antidepressants next to lithium.Objective: The objective of our study was to re-evaluate this secondary finding in another study population.Methods: We performed a multicenter medical chart review study in patients using lithium in whom a 24-hour urine volume had been determined.Results: We included 116 patients, twelve (26 %) of the 46 patients with polyuria used serotonergic antidepressants compared to ten (14%) of the 70 patients without polyuria. We found an increased risk of polyuria in lithium users concurrently using serotonergic antidepressants (odds ratio 2.86; 95 % confidence interval 1.00-8.21), adjusted for age, gender, use of antiepileptics and thyreomimetics.Conclusion: Our results Confirm the previous secondary finding of an increased risk of polyuria in patients using serotonergic antidepressants next to lithium. Physicians should take this into account when evaluating polytiria in patients using lithium and when choosing an antidepressant in patients using lithium.

A 12-year-old boy developed pancreatitis, complicated by a pancreatic pseudocyst, as an adverse reaction to valproic acid (VPA) treatment for epilepsy. Pancreatitis subsided within three weeks after discontinuation of VPA. The pancreatic pseudocyst was managed without surgery and resolved spontaneously in four weeks. Valproic acid was concluded to be the most probable cause, since no other explanation was found. According to the literature VPA is a rare but known cause of pancreatitis. A computer-assisted literature search revealed seven previously reported cases of VPA-induced pancreatitis complicated by a pancreatic pseudocyst. Six of these patients were under 20 years of age. Four patients were treated conservatively; three needed cystostomy or external drainage. All patients recovered. Patients using VPA, especially children, presenting with acute abdominal pain should be suspected of valproic acid-induced pancreatitis. If VPA induced pancreatitis is complicated by a pseudocyst, conservative treatment should be the first line of treatment.