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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

Background Antipsychotic-induced Weight Gain (AiWG) is a debilitating and common adverse effect of antipsychotics. AiWG negatively impacts life expectancy, quality of life, treatment adherence, likelihood of developing type-2 diabetes and readmission. Treatment of AiWG is currently challenging, and there is no consensus on the optimal management strategy. In this study, we aim to evaluate the use of metformin for the treatment of AiWG by comparing metformin with placebo in those receiving treatment as usual, which includes a lifestyle intervention. Methods In this randomized, double-blind, multicenter, placebo-controlled, pragmatic trial with a follow-up of 52 weeks, we aim to include 256 overweight participants (Body Mass Index (BMI) > 25 kg/m2) of at least 16 years of age. Patients are eligible if they have been diagnosed with schizophrenia spectrum disorder and if they have been using an antipsychotic for at least three months. Participants will be randomized with a 1:1 allocation to placebo or metformin, and will be treated for a total of 26 weeks. Metformin will be started at 500 mg b.i.d. and escalated to 1000 mg b.i.d. 2 weeks thereafter (up to a maximum of 2000 mg daily). In addition, all participants will undergo a lifestyle intervention as part of the usual treatment consisting of a combination of an exercise program and dietary consultations. The primary outcome measure is difference in body weight as a continuous trait between the two arms from treatment inception until 26 weeks of treatment, compared to baseline. Secondary outcome measures include: 1) Any element of metabolic syndrome (MetS); 2) Response, defined as ≥5% body weight loss at 26 weeks relative to treatment inception; 3) Quality of life; 4) General mental and physical health; and 5) Cost-effectiveness. Finally, we aim to assess whether genetic liability to BMI and MetS may help estimate the amount of weight reduction following initiation of metformin treatment. Discussion The pragmatic design of the current trial allows for a comparison of the efficacy and safety of metformin in combination with a lifestyle intervention in the treatment of AiWG, facilitating the development of guidelines on the interventions for this major health problem. Trial registration This trial was registered in the Netherlands Trial Register (NTR) at https://www.trialregister.nl/trial/8440 as NTR NL8840 on March 8, 2020.

Aims: Previously, we have reported an association between clozapine use and elevated FL3 neutrophil fluorescence, a flow-cytometric parameter for cell viability. Here, we developed and evaluated a pharmacokinetic-pharmacodynamic model relating FL3-fluorescence to clozapine exposure and derived a nomogram for estimation of long-term adherence. Methods: Data from 27 patients initiating clozapine were analysed using nonlinear mixed effects modelling. A previously described pharmacokinetic model for clozapine was coupled to a FL3 fluorescence model. For this, an effect compartment with clozapine concentrations as input and a first order decay rate as output was linked with an Emax model to FL3-fluorescence. FL3-fluorescence was simulated for clozapine doses of 50, 150 and 400 mg daily (n = 10 000) to establish the nomogram. Finally, true simulated adherence (% of daily doses taken over 100 days) was compared to nomogram-estimated adherence to evaluate the performance of the nomogram. Results: The half-life of FL3-fluorescence was estimated at 228 h (coefficient of variation 35%). Median absolute prediction errors of the nomogram in case of fully random adherence for 50, 150 and 400 mg ranged from -0.193% to -0.525%. The nomogram performed slightly worse in case of nonrandom adherence (median prediction error up to 5.19%), but was still clinically acceptable. Compliance patterns containing longer drug holidays revealed that the nomogram adequately estimates compliance over approximately the last 3 weeks prior to FL3-measurement. Conclusion: Our nomogram could provide information regarding long-term adherence based on prescribed clozapine dose and FL3-fluorescence. Future studies should further explore the clinical value of this biomarker and nomogram.

BACKGROUND: Lithium can influence calcium homeostasis resulting in changes in parathormone set point and renal calcium handling. The clinical significance of these changes in older patients is unknown. The objective of this study was to investigate the possible association between duration of lithium treatment and corrected calcium, parathormone and 24-h urinary calcium excretion in older psychiatric patients corrected for renal function and vitamin 25OH D and also to estimate the point prevalence of hypercalcemia and raised parathormone. METHODS: A cross-sectional study of psychiatric outpatients visiting a specialized facility for older patients treated with lithium was performed. Patients underwent a comprehensive assessment and blood and urine testing. Potential confounders of calcium homeostasis were recorded. On the basis of the duration of lithium treatment, patients were divided into four groups. RESULTS: One hundred eleven patients were included, mean age 75.2 years. There was no significant association between the duration of lithium treatment and corrected calcium, parathormone and 24-h urinary calcium excretion. The point prevalence of hypercalcemia was 2.7% and 47.8% for raised parathormone. There was an unexpected but significant negative association between the duration of lithium treatment and vitamin 25OH D, with 76.9% vitamin 25OH D deficiency (

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.

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.

Item does not contain fulltext OBJECTIVE: Lithium is a drug with a narrow therapeutic window. Concomitantly used medication is a potentially influencing factor of lithium serum concentrations. We conducted a multicentre retrospective case-control study with the aim of investigating lithium-related drug interactions as determinants of elevated lithium serum levels in daily clinical practice. METHODS: Cases were patients with an increase of at least 50% in lithium serum concentrations resulting in an elevated lithium serum level of at least 1.3 mmol/L, and who were not suspected of a suicide attempt. Controls were patients who showed stable lithium serum levels within the therapeutic range. Use and start of non-steroidal anti-inflammatory drugs, diuretics, renin-angiotensin inhibitors, theophyllin and antibiotics were investigated as potential determinants of the elevated lithium serum levels. Irregularity in lithium dispensing pattern, change in lithium dosing regimen, age, gender, prescribing physician and laboratory parameters were investigated as potential confounders. RESULTS: We included 51 cases and 51 controls in our study. Five (9.8%) controls and 15 (29.4%) cases used potentially interacting co-medication [OR of 3.83 (95%CI 1.28-11.48)]. Start of potentially interacting co-medication was observed in eight (15.7%) cases and in zero (0%) controls resulting in an OR of 20.13 (95% CI 1.13-359). After adjustment for co-medication, irregularity in lithium dispensing pattern, change in lithium dosing regimen, and age, the statistically significant association was lost. We report an OR of 2.70 (95% CI 0.78-9.31) for use of concomitant medication, with a large contribution of antibiotic agents, and an OR of 3.14 (95% CI 1.15-8.61) for irregularity in lithium dispensing pattern. CONCLUSION: Use of co-medication, especially antibiotics, tends to be associated with elevated lithium serum levels.

Objectives To determine the prevalence and determinants of thyroid dysfunction in older patients with affective disorders divided into lithium and nonlithium patients. Methods This study was conducted as a retrospective cross-sectional study in patients of 65 years and older with affective disorders according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. The presence of thyroid disorders was determined on the index date defined as the date of the first available thyroid-stimulating hormone in 2005. The presence of thyroid disorder was diagnosed according to defined criteria and in case of a previous diagnosis, confirmed by researching the medical files. In a subgroup of 45 lithium patients, thyroperoxidase- and thyroglobulin antibodies were determined. Results A total of 79 lithium patients and 85 nonlithium patients were included. The prevalence of hypothyroidism (subclinical and clinical) was 35.4% among the lithium patients, with women having a prevalence as high as 41.3% and men 12.6%. In the nonlithium patients, the prevalence was 7.1%; very close to that in the general population. No other determinant than female gender was identified. Seventeen of the 26 lithium patients were diagnosed with hypothyroidism in the first 3½ years after the start of lithium. The prevalence of thyroid antibodies was 27% in 45 lithium patients, which was no different than the prevalence in the same age group in the general population. Conclusion The prevalence of hypothyroidism during lithium treatment was very high in the elderly, especially in women. Autoimmunity did not seem to play a major part in lithium-associated hypothyroidism in this age group. The timeframe between start of lithium and diagnosis of hypothyroidism suggests an individual susceptibility. The prevalence of hypothyroidism in nonlithium patients with affective disorders was not very different from the general population.

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.

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.