{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T20:16:16Z","timestamp":1790021776166,"version":"4.0.1"},"reference-count":46,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T00:00:00Z","timestamp":1642377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Therapeutic drug monitoring (TDM) is an effective tool used to improve the pharmacological treatment in clinical practice, especially to detect subtherapeutic drug plasma concentration (Cp) in order to consider a change of dosage during treatment and reach its putative therapeutic range. In this study, we report the Cp values of lithium and valproic acid (VPA), alone and in combination, mostly in bipolar patients admitted to an Italian clinical center of the University of Pisa during the years 2016\u20132020, which include 12,294 samples of VPA, 7449 of lithium and 1118 of both in combination. Lithium and VPA are the most utilized drugs in treating bipolar disorders, and their TDM is strongly recommended by recent guidelines. In relation to lithium Cp monitoring, several studies have underlined that 0.5\u20130.8 mmol\/L is the optimal range for chronic treatment, and below 0.4 mmol\/L, it is unlikely to produce a clinical response. For VPA, the therapeutic range is 50\u2013100 \u03bcg\/mL and a linear correlation between Cp and clinical efficacy has been proposed, where below 50 \u03bcg\/mL, the clinical efficacy of VPA has not been proven thus far. Toxic levels of both drugs were rarely found in our study, while a high percentage of patients, about one-third, had sub-therapeutic Cp during their treatments. In addition, in several cases of patients receiving multiple blood sampling, the initial subtherapeutic Cp changed only partially without reaching its therapeutic window. In relation to age, we found a higher percentage of lithium and VPA Cp values in range in the adolescents than in the adults and elderly groups. No differences were reported when analyzing the distribution of Cp values in males and females. In conclusion, this present study suggests that TDM is widely used by many specialists, but there is still a window of improvement for optimizing pharmacological treatments in clinical practice.<\/jats:p>","DOI":"10.3390\/ph15010105","type":"journal-article","created":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T20:46:03Z","timestamp":1642452363000},"page":"105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A 5-Year Study of Lithium and Valproic Acid Drug Monitoring in Patients with Bipolar Disorders in an Italian Clinical Center"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1447-4947","authenticated-orcid":false,"given":"Marco","family":"Carli","sequence":"first","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Risaliti","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mena","family":"Francomano","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivakumar","family":"Kolachalam","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biancamaria","family":"Longoni","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7120-9141","authenticated-orcid":false,"given":"Guido","family":"Bocci","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4436-2356","authenticated-orcid":false,"given":"Roberto","family":"Maggio","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Scarselli","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13643-020-1274-3","article-title":"Psychotropic medication non-adherence and its associated factors among patients with major psychiatric disorders: A systematic review and meta-analysis","volume":"9","author":"Semahegn","year":"2020","journal-title":"Syst. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"119342","DOI":"10.1016\/j.lfs.2021.119342","article-title":"Pharmacology of lacosamide: From its molecular mechanisms and pharmacokinetics to future therapeutic applications","volume":"275","author":"Carona","year":"2021","journal-title":"Life Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"0300060520952281","DOI":"10.1177\/0300060520952281","article-title":"Impact of gender, albumin, and CYP2C19 polymorphisms on valproic acid in Chinese patients: A population pharmacokinetic model","volume":"48","author":"Guo","year":"2020","journal-title":"J. Int. Med. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1007\/s00228-016-2087-0","article-title":"Impact of age, gender and CYP2C9\/2C19 genotypes on dose-adjusted steady-state serum concentrations of valproic acid\u2014A large-scale study based on naturalistic therapeutic drug monitoring data","volume":"72","author":"Smith","year":"2016","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1055\/s-0043-116492","article-title":"Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017","volume":"51","author":"Hiemke","year":"2018","journal-title":"Pharmacopsychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1111\/j.1528-1167.2008.01561.x","article-title":"Antiepileptic drugs\u2014Best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies","volume":"49","author":"Patsalos","year":"2008","journal-title":"Epilepsia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1097\/PRA.0000000000000493","article-title":"Lithium Prescribing and Therapeutic Drug Monitoring in Bipolar Disorder: A Survey of Current Practices and Perspectives","volume":"26","author":"Fernandes","year":"2020","journal-title":"J. Psychiatr. Pract."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1055\/s-2003-39983","article-title":"Therapeutic drug monitoring of tricyclic antidepressants: How does it work under clinical conditions?","volume":"36","author":"Dragicevic","year":"2003","journal-title":"Pharmacopsychiatry"},{"key":"ref_9","first-page":"19","article-title":"Therapeutic drug monitoring of antipsychotics","volume":"35","author":"Perry","year":"2001","journal-title":"Psychopharmacol. Bull."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Connolly, K.R., and Thase, M.E. (2011). The clinical management of bipolar disorder: A review of evidence-based guidelines. Prim. Care Companion CNS Disord., 13.","DOI":"10.4088\/PCC.10r01097"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"734689","DOI":"10.1155\/2014\/734689","article-title":"Identification and Prevention of Antiepileptic Drug Noncompliance: The Collaborative Use of State-Supplied Pharmaceutical Data","volume":"2014","author":"Hodges","year":"2014","journal-title":"ISRN Pediatr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1097\/YIC.0000000000000260","article-title":"Personalized and precision medicine as informants for treatment management of bipolar disorder","volume":"34","author":"Perugi","year":"2019","journal-title":"Int. Clin. Psychopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1097\/YIC.0000000000000373","article-title":"Treatment adherence and tolerability of immediate- and prolonged-release lithium formulations in a sample of bipolar patients: A prospective naturalistic study","volume":"36","author":"Barbuti","year":"2021","journal-title":"Int. Clin. Psychopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S0140-6736(09)61828-6","article-title":"Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): A randomised open-label trial","volume":"375","author":"Geddes","year":"2010","journal-title":"Lancet"},{"key":"ref_15","first-page":"118","article-title":"Valproate in the treatment of acute bipolar affective episodes complicated by substance abuse: A pilot study","volume":"56","author":"Brady","year":"1995","journal-title":"J. Clin. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113","DOI":"10.4088\/JCP.07m04022","article-title":"A 6-month, double-blind, maintenance trial of lithium monotherapy versus the combination of lithium and divalproex for rapid-cycling bipolar disorder and Co-occurring substance abuse or dependence","volume":"70","author":"Kemp","year":"2009","journal-title":"J. Clin. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"29","DOI":"10.2165\/00023210-200620010-00003","article-title":"Polytherapy in bipolar disorder","volume":"20","author":"Lin","year":"2006","journal-title":"CNS Drugs"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.euroneuro.2019.04.003","article-title":"Monotherapy vs. combination therapy for post mania maintenance treatment: A population based cohort study","volume":"29","author":"Brandt","year":"2019","journal-title":"Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.pharmthera.2018.06.012","article-title":"Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences","volume":"192","author":"Aringhieri","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.euroneuro.2017.02.005","article-title":"Clozapine as the most efficacious antipsychotic for activating ERK 1\/2 kinases: Role of 5-HT2A receptor agonism","volume":"27","author":"Aringhieri","year":"2017","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Carli, M., Kolachalam, S., Longoni, B., Pintaudi, A., Baldini, M., Aringhieri, S., Fasciani, I., Annibale, P., Maggio, R., and Scarselli, M. (2021). Atypical antipsychotics and metabolic syndrome: From molecular mechanisms to clinical differences. Pharmaceuticals, 14.","DOI":"10.3390\/ph14030238"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1111\/j.1399-5618.2007.00475.x","article-title":"What is the optimal serum lithium level in the long-term treatment of bipolar disorder--a review?","volume":"10","author":"Severus","year":"2008","journal-title":"Bipolar Disord."},{"key":"ref_23","first-page":"515","article-title":"Long-term treatment of bipolar disorder: How should we use lithium salts?","volume":"47","author":"Muti","year":"2012","journal-title":"Riv. Psichiatr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s40345-016-0068-y","article-title":"Lithium side effects and toxicity: Prevalence and management strategies","volume":"4","author":"Gitlin","year":"2016","journal-title":"Int. J. Bipolar Disord."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bocchetta, A., Ardau, R., Fanni, T., Sardu, C., Piras, D., Pani, A., and Del Zompo, M. (2015). Renal function during long-term lithium treatment: A cross-sectional and longitudinal study. BMC Med., 13.","DOI":"10.1186\/s12916-014-0249-4"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1097\/YIC.0b013e3283642348","article-title":"Prescribing patterns of lithium or lithium+valproate in manic or mixed episodes: A naturalistic study","volume":"28","author":"Muti","year":"2013","journal-title":"Int. Clin. Psychopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1097\/FPC.0b013e32835ea0b2","article-title":"Valproic acid pathway","volume":"23","author":"Thorn","year":"2013","journal-title":"Pharmacogenet. Genom."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104786","DOI":"10.1016\/j.phrs.2020.104786","article-title":"Epileptogenesis and oncogenesis: An antineoplastic role for antiepileptic drugs in brain tumours?","volume":"156","author":"Cucchiara","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1176\/appi.ajp.163.2.272","article-title":"Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania","volume":"163","author":"Allen","year":"2006","journal-title":"Am. J. Psychiatry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1517\/17425250902911455","article-title":"A review of valproate in psychiatric practice","volume":"5","author":"Haddad","year":"2009","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chateauvieux, S., Morceau, F., Dicato, M., and Diederich, M. (2010). Molecular and therapeutic potential and toxicity of valproic acid. J. Biomed. Biotechnol., 2010.","DOI":"10.1155\/2010\/479364"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1097\/00007691-200502000-00004","article-title":"Cost-effectiveness of therapeutic drug monitoring: A systematic review","volume":"27","author":"Touw","year":"2005","journal-title":"Ther. Drug Monit."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1176\/ajp.156.7.1014","article-title":"Therapeutic drug monitoring of mood stabilizers in medicaid patients with bipolar disorder","volume":"156","author":"Marcus","year":"1999","journal-title":"Am. J. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1124\/pr.111.005512","article-title":"Therapeutic potential of mood stabilizers lithium and valproic acid: Beyond bipolar disorder","volume":"65","author":"Chiu","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1097\/MJT.0b013e31818a88da","article-title":"Therapeutic Drug Monitoring of Lithium in Patients With Bipolar Affective Disorder: Experiences From a Tertiary Care Hospital in India","volume":"16","author":"Sharma","year":"2009","journal-title":"Am. J. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1001\/archpsyc.1992.01820050035005","article-title":"Subsyndromal symptoms in bipolar disorder. A comparison of standard and low serum levels of lithium","volume":"49","author":"Keller","year":"1992","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_37","first-page":"277","article-title":"Monitoring of lithium treatment through determination of lithium concentration","volume":"22","author":"Amdisen","year":"1975","journal-title":"Dan. Med. Bull."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1073\/pnas.95.5.2642","article-title":"Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx","volume":"95","author":"Nonaka","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1126\/science.281.5381.1322","article-title":"The Bcl-2 protein family: Arbiters of cell survival","volume":"281","author":"Adams","year":"1998","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"570","DOI":"10.2174\/138161212799316163","article-title":"Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI\/MRS study","volume":"18","author":"Berger","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_41","first-page":"229","article-title":"Low-dose valproate: A new treatment for cyclothymia, mild rapid cycling disorders, and premenstrual syndrome","volume":"54","author":"Jacobsen","year":"1993","journal-title":"J. Clin. Psychiatry"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1097\/01.pra.0000367781.26507.86","article-title":"Low-Dose Divalproex in Agitated Patients with Alzheimer\u2019s Disease","volume":"16","author":"Dolder","year":"2010","journal-title":"J. Psychiatr. Pract."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.brainresrev.2009.06.003","article-title":"Bipolar disorder and mechanisms of action of mood stabilizers","volume":"61","author":"Rapoport","year":"2009","journal-title":"Brain Res. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1177\/070674379303800213","article-title":"Treatment of rapid cycling bipolar disorder with combination therapy of valproate and lithium","volume":"38","author":"Sharma","year":"1993","journal-title":"Can. J. Psychiatry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1176\/ajp.155.1.12","article-title":"Mood stabilizer combinations: A review of safety and efficacy","volume":"155","author":"Freeman","year":"1998","journal-title":"Am. J. Psychiatry"},{"key":"ref_46","first-page":"CD003196","article-title":"Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder","volume":"2013","author":"Cipriani","year":"2013","journal-title":"Cochrane Database Syst. Rev."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/1\/105\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:02:20Z","timestamp":1760133740000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/1\/105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,17]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ph15010105"],"URL":"https:\/\/doi.org\/10.3390\/ph15010105","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,17]]}}}