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      Prevalence of Therapeutic Drug Monitoring for Lithium and the Impact of Regulatory Warnings: Analysis Using Japanese Claims Database

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          Therapeutic drug monitoring (TDM) for lithium is recommended in guidelines; however, the prevalence of TDM for lithium is seldom reported. We have therefore investigated the prevalence of TDM for lithium and evaluated the impact of the regulatory warnings requiring routine TDM for lithium.


          Monthly claims data covering around 1.7 million persons aged 20–74 years old during the period January 1, 2005, and March 31, 2015, were evaluated. All patients who had at least one prescription for lithium were selected and included to calculate the annual prevalence of TDM for lithium. Also we assessed whether the 2 regulatory warnings requiring routine TDM for lithium and issued in April 2012 and September 2012 had an impact on TDM for lithium, using segmented regression analysis.


          Between 2005 and 2014, 136,956 prescriptions of lithium were issued to 5823 patients, and the annual prevalence of TDM for lithium was 14.9% (95% confidence interval, 14.7%–15.1%). The analysis revealed that the mean prevalence increased abruptly by 6.9% ( P = 0.001) after the regulatory warning in April 2012, whereas that the warning in September 2012 decreased by 1.2% ( P = 0.47). There was no significant change in trends of period prevalence after the warning in April 2012 (April 2012–August 2012) compared with prevalence before the warning (April 2010–March 2012). Similarly, no significant change was observed in the trends before (April 2012–August 2012) and after (September 2012–March 2014) the subsequent warning in September 2012.


          Results showed that the prevalence of TDM for lithium was low, although TDM for lithium was strongly recommended by the guidelines. Regulatory warnings requiring compliance with the measurement of blood levels during treatment with lithium, issued twice during the five-month period, were associated with an increase in the prevalence of TDM for lithium. However, the impact of the second warning was not remarkable compared with the first warning.

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          Most cited references 24

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          Lithium side effects and toxicity: prevalence and management strategies

          Despite its virtually universal acceptance as the gold standard in treating bipolar disorder, prescription rates for lithium have been decreasing recently. Although this observation is multifactorial, one obvious potential contributor is the side effect and toxicity burden associated with lithium. Additionally, side effect concerns assuredly play some role in lithium nonadherence. This paper summarizes the knowledge base on side effects and toxicity and suggests optimal management of these problems. Thirst and excessive urination, nausea and diarrhea and tremor are rather common side effects that are typically no more than annoying even though they are rather prevalent. A simple set of management strategies that involve the timing of the lithium dose, minimizing lithium levels within the therapeutic range and, in some situations, the prescription of side effect antidotes will minimize the side effect burden for patients. In contrast, weight gain and cognitive impairment from lithium tend to be more distressing to patients, more difficult to manage and more likely to be associated with lithium nonadherence. Lithium has adverse effects on the kidneys, thyroid gland and parathyroid glands, necessitating monitoring of these organ functions through periodic blood tests. In most cases, lithium-associated renal effects are relatively mild. A small but measurable percentage of lithium-treated patients will show progressive renal impairment. Infrequently, lithium will need to be discontinued because of the progressive renal insufficiency. Lithium-induced hypothyroidism is relatively common but easily diagnosed and treated. Hyperparathyroidism from lithium is a relatively more recently recognized phenomenon.
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            Guideline for treatment of bipolar disorder by the Japanese Society of Mood Disorders, 2012.

            The Japanese Society of Mood Disorders established a committee for treatment guidelines of mood disorders, which created the first edition of a treatment guideline for bipolar disorders on 10 March 2011. The committee has now created a second edition, which we report here. In creating this treatment guideline, the first step was to have several bipolar disorder specialists review well-conducted studies and meta-analyses. Based on this evidence, and with a consensus among the specialists, treatment procedures that were considered optimal were compiled and the strength of recommendation for each treatment method was determined. The first draft, prepared in this manner, was further revised through a process of critical investigation by all committee members to produce the final edition.
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              The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 2: Review, Grading of the Evidence, and a Precise Algorithm

              Abstract Background: The current paper includes a systematic search of the literature, a detailed presentation of the results, and a grading of treatment options in terms of efficacy and tolerability/safety. Material and Methods: The PRISMA method was used in the literature search with the combination of the words ‘bipolar,’ ‘manic,’ ‘mania,’ ‘manic depression,’ and ‘manic depressive’ with ‘randomized,’ and ‘algorithms’ with ‘mania,’ ‘manic,’ ‘bipolar,’ ‘manic-depressive,’ or ‘manic depression.’ Relevant web pages and review articles were also reviewed. Results: The current report is based on the analysis of 57 guideline papers and 531 published papers related to RCTs, reviews, posthoc, or meta-analysis papers to March 25, 2016. The specific treatment options for acute mania, mixed episodes, acute bipolar depression, maintenance phase, psychotic and mixed features, anxiety, and rapid cycling were evaluated with regards to efficacy. Existing treatment guidelines were also reviewed. Finally, Tables reflecting efficacy and recommendation levels were created that led to the development of a precise algorithm that still has to prove its feasibility in everyday clinical practice. Conclusions: A systematic literature search was conducted on the pharmacological treatment of bipolar disorder to identify all relevant random controlled trials pertaining to all aspects of bipolar disorder and graded the data according to a predetermined method to develop a precise treatment algorithm for management of various phases of bipolar disorder. It is important to note that the some of the recommendations in the treatment algorithm were based on the secondary outcome data from posthoc analyses.

                Author and article information

                Ther Drug Monit
                Ther Drug Monit
                Therapeutic Drug Monitoring
                Therapeutic Drug Monitoring
                April 2018
                09 February 2018
                : 40
                : 2
                : 252-256
                [* ]Nihon University School of Pharmacy, Funabashi, Chiba, Japan;
                []Department of Pharmaceutical Sciences, Tohoku University Hospital;
                []Division of Public Health, Hygiene and Epidemiology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan; and
                [§ ]NPO Drug Safety Research Unit Japan, Bunkyo-ku, Tokyo, Japan.
                Author notes
                Correspondence: Nobuhiro Ooba, PhD, Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan (e-mail: ooba.nobuhiro@ 123456nihon-u.ac.jp ).
                TDM17-112-Oe 00012
                Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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