Abstract
Safety and tolerability of mood stabilisers are major clinical concerns when used in bipolar patients. Side effects of lithium and some antiepileptics have been reviewed in the context of a spontaneous reporting database over the last 10 years (FDA database and published reports). During pregnancy, antiepileptics show great concerns, and adverse events are all related to childbirth, whilst congenital abnormalities are not higher than previously estimated. Cutaneous adverse reactions are the most prevalent in children and adolescent. In adult lithium-treated patients, nephrotoxicity is still a major problem; the combination with carbamazepine and valproate can increase the risk of hypothyroidism. Hyperparathormonemia and hypercalcaemia are unrecognised and underappreciated adverse effects. Acute exacerbation of psoriasis is still a major problem, and the risk of skin reactions with eosinophilia and systemic symptoms is higher when mood stabilisers are used concomitantly; when associated with antipsychotics, the risk of pneumonia is possible (highest risk for olanzapine plus carbamazepine). A decrease in total body water and the decline of glomerular filtration rate represent the main lithium adverse effects in elderly patients. Long-term treatment is associated with impairment in immediate verbal learning and memory and creativity performance. Antiepileptics display significant adverse events (hyponatraemia, cardiac toxicity) and the risk of multiple drug-drug interactions is very high. Cumulative exposure to antipsychotics and mood stabilisers can be associated with vascular stiffness (elevated systolic blood pressure), hypertriglyceridaemia, insulin resistance and low HDL cholesterol. In light of the above considerations, clinicians should continuously and further assess risks and benefits of mood stabilisers when treating bipolar patients.
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References
Acharya NV, Pickering RM, Wilton LW et al (2005) The safety and effectiveness of newer antiepileptics: a comparative postmarketing cohort study. J Clin Pharmacol 45:385–393
Adab N, Kini U, Vinten J et al (2004) The longer-term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 75:1575–1583
Arvilommi P, Suominen K, Mantere O et al (2014) Predictors of adherence to psychopharmacological and psychosocial treatment in bipolar I or II disorders – an 18-month prospective study. J Affect Disord 155:110–117
Baldessarini RJ, Tondo L (2008) Lithium and suicidal risk. Bipolar Disord 10:114–115
Baldessarini RJ, Perry R, Pike J (2008) Factors associated with treatment non-adherence among US bipolar disorder patients. Hum Psychopharmacol Clin Exp 23:95–105
Baranzini F, Poloni N, Diurni M et al (2009) Polypharmacy and psychotropic drugs as risk factors for falls in long-term care setting for elderly patients in Lombardy. Recenti Prog Med 100:9–16
Barclay ML, Brownlie BE, Turner JG et al (1994) Lithium associated thyrotoxicosis: a report of 14 cases, with statistical analysis of incidence. Clin Endocrinol 40:759–764
Bassilios N, Martel P, Godard V et al (2008) Monitoring of glomerular filtration rate in lithium-treated outpatients—an ambulatory laboratory database surveillance. Nephrol Dial Transplant 23:562–565
Bauer M, Glenn T, Pilhatsch M et al (2014) Gender differences in thyroid system function: relevance to bipolar disorder and its treatment. Bipolar Disord 16(1):58–71
Bech P (2006) The full story of lithium (1918–2005). A tribute to Mogens Schou. Psychother Psychosom 75:265–269
Bendz H, Schön S, Attman PO et al (2010) Renal failure occurs in chronic lithium treatment but is uncommon. Kidney Int 77(3):219–224, Epub 2009 Nov 25
Berens SC, Wolff J, Murphy DL (1970) Lithium concentration by the thyroid. Endocrinology 87(5):1085–1087
Bicknell LT, Sanches M, Schatte DJ (2012) Erythema multiforme vs. DRESS syndrome associated with the combined use of lamotrigine and cyclobenzaprine: a case report. Int J Psychiatry Med 44(4):305–314
Bocchetta A, Mossa P, Velluzzi F et al (2001) Ten-year follow-up of thyroid function in lithium patients. J Clin Psychopharmacol 21:594–598
Bocchetta A, Ardau R, Carta P et al (2013) Duration of lithium treatment is a risk factor for reduced glomerular function: a cross-sectional study. BMC Med 11:33
Boton R, Gaviria M, Batlle DC (1987) Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis 10(5):329–345
Bourne C, Aydemir O, Balanza-Martinez V et al (2013) Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis. Acta Psychiatr Scand 128(3):149–162
Brauchli YB, Jick SS, Curtin F et al (2009) Lithium, antipsychotics, and risk of psoriasis. J Clin Psychopharmacol 29(2):134–140. doi:10.1097/JCP.0b013e31819a4b7c
Bromley RL, Mawer GE, Briggs M et al (2013) The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry 84(6):637–643
Broome JT, Solorzano CC (2011) Lithium use and primary hyperparathyroidism. Endocrinology 17(Suppl 1):31–35
Burrow GN, Burke WR, Himmelhoch JM et al (1971) Effect of lithium on thyroid function. J Clin Endocrinol Metab 32(5):647–652
Cade JF (1949) Lithium salts in the treatment of psychotic excitement. Med J Aust 2(10):349–352
Castro-Pastrana LI, Ghannadan R, Rieder MJ et al (2011) Cutaneous adverse drug reactions in children: an analysis of reports from the Canadian pharmacogenomics network for drug safety (CPNDS). J Popul Ther Clin Pharmacol 18(1):e106–e120
Chakrabarti S (2011) Thyroid functions and bipolar affective disorder. J Thyroid Res 2011:306–367
Chan HL, Wing Y, Su R et al (2000) A control study of the cutaneous side effects of chronic lithium therapy. J Affect Disord 57:107–113
Chong KW, Chan DW, Cheung YB et al (2014) Association of carbamazepine-induced severe cutaneous drug reactions and HLA-B*1502 allele status, and dose and treatment duration in paediatric neurology patients in Singapore. Arch Dis Child 99(6):581–584
Coresh J, Astor BC, Greene T et al (2003) Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 41:1–12
De Paulo J, Correa E, Sapir D (1986) Renal function and lithium: a longitudinal study. Am J Psychiatry 143:892–895
Dols A, Sienaert P, van Gerven H et al (2013) The prevalence and management of side effects of lithium and anticonvulsants as mood stabilizers in bipolar disorder from a clinical perspective: a review. Int Clin Psychopharmacol 28(6):287–296
Dutcher SK, Rattinger GB, Langenberg P et al (2014) Effect of medications on physical function and cognition in nursing home residents with dementia. J Am Geriatr Soc 62(6):1046–1055
Famularo G, De Simone C, Minisola G (2005) Stevens-Johnson syndrome associated with single high dose of lamotrigine in a patient taking valproate. Dermatol Online J 11(1):25
Ferrier N, Ferrier LJ, Macritchie KA (2006) Lithium therapy. Adv Psychiatry Treat 12:256–264
Fiedorowicz JG, Coryell WH, Rice JP et al (2012) Vasculopathy related to manic/hypomanic symptom burden and first generation antipsychotics in a sub-sample from the Collaborative Depression Study (CDS). Psychother Psychosom 81(4):235–243
Findling RL, Frazier JA, Kafantaris V et al (2008) The Collaborative Lithium Trials (CoLT): specific aims, methods, and implementation. Child Adolesc Psychiatry Ment Health 2(1):21
Findling RL, Kafantaris V, Pavuluri M et al (2013) Post-acute effectiveness of lithium in pediatric bipolar I disorder. Child Adolesc Psychopharmacol 23(2):80–90
Fountoulakis KN, Vieta E, Sanchez-Moreno J et al (2005) Treatment guidelines for bipolar disorder: a critical review. J Affect Disord 86(1):1–10
Frangou S, Donaldson S, Hadjulis M et al (2005) The Maudsley bipolar disorder project: executive dysfunction in bipolar disorder I and its clinical correlates. Biol Psychiatry 58:859–864
Gaily E, Kantola-Sorsa E, Hiilesmaa V et al (2004) Normal intelligence in children with prenatal exposure to carbamazepine. Neurology 62:28–32
Galbally M, Roberts M, Buist A (2010) Perinatal psychotropic review group. Mood stabilizers in pregnancy: a systematic review. Aust N Z J Psychiatry 44(11):967–977. doi:10.3109/00048674.2010.506637
Gau SS, Chao PF, Lin YJ et al (2008) The association between carbamazepine and valproate and adverse cutaneous drug reactions in patients with bipolar disorder: a nested matched case-control study. J Clin Psychopharmacol 28(5):509–517
Gau CS, Chang CJ, Tsai FJ et al (2010) Association between mood stabilizers and hypothyroidism in patients with bipolar disorders: a nested, matched case-control study. Bipolar Disord 12(3):253–263. doi:10.1111/j.1399-5618.2010.00814.x
Geddes JR, Goodwin GM, Rendell J et al (2010) Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 375:385–395
Gitlin MJ (1993) Lithium-induced renal insufficiency. J Clin Psychopharmacol 13:276–279
Goodwin GM (2009) Evidence-based guidelines for treating bipolar disorder: revised second edition – recommendations from the British Association for Psychopharmacology. J Psychopharmacol 23(4):346–388
Goodwin GM, Bowden CL, Calabrese JR et al (2004) A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry 65:432–441
Grandjean EM, Aubry JM (2009) Lithium: updated human knowledge using an evidence-based approach: part III: clinical safety. CNS Drugs 23:397–418
Greil W, Häberle A, Schuhmann T et al (2013) Age and adverse drug reactions from psychopharmacological treatment: data from the AMSP drug surveillance programme in Switzerland. Swiss Med Wkly 143:w13772
Grunze H, Vieta E, Goodwin GM et al (2009) The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment of acute mania. World J Biol Psychiatry 10(2):85–116
Hansen HE (1981) Renal toxicity of lithium. Drugs 22(6):461–476
He N, Min FL, Shi YW et al (2012) Cutaneous reactions induced by oxcarbazepine in Southern Han Chinese: incidence, features, risk factors and relation to HLA-B alleles. Seizure 21(8):614–618
Hydzik P, Balicka-Slusarczyk B, Jastrzebski M (2011) Cardiologic interaction carbamazepine with atypical neuroleptics. Acute mixed carbamazepine and quetiapine intoxication-case report. Przegl Lek 68(8):499–502
Ide A, Kamijo Y (2007) Intermittent complete atrioventricular block after long term low-dose carbamazepine therapy with a serum concentration less than the therapeutic level. Intern Med 46:627–629
Iorio ML, Moretti U, Colcera S et al (2007) Use and safety profile of antiepileptic drugs in Italy. Eur J Clin Pharmacol 63:409–415. doi:10.1007/s00228-006-0236-6
Irga N, Kosiak W, Jaworski R et al (2013) Pediatrician! Do you know the symptoms of DRESS syndrome? A case report of a 4-year-old girl. Pediatr Emerg Care 29(4):504–507
Jacobson SJ, Jones K, Johnson K et al (1992) Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester. Lancet 339(8792):530–533
Jafferany M (2008) Lithium and skin: dermatologic manifestations of lithium therapy. Int J Dermatol 47(11):1101–1111
Janowsky DS, Soares J, Hatchm JP et al (2009) Lithium effect on renal glomerular function in individuals with intellectual disability. J Clin Psychopharmacol 29:296–299
Jensen S, Rickers H (1984) Glomerular filtration rate during lithium therapy. Acta Psychiatr Scand 70:235–238
Johnson FR, Ozdemir S, Manjunath R et al (2007) Factors that affect adherence to bipolar disorder treatments: a stated preference approach. Med Care 45(6):545–552
Jonsdottir H, Opjordsmoen S, Birkenaes AB et al (2012) Predictors of medication adherence in patients with schizophrenia and bipolar disorder. Acta Psychiatr Scand 127(1):23–33
Kallen B, Tandberg A (1983) Lithium and pregnancy. A cohort study on manic depressive women. Acta Psychiatr Scand 68:134–139
Källén B, Tandberg A (1983) Lithium and pregnancy. A cohort study on manic-depressive women. Acta Psychiatr Scand 68(2):134–139
Kibirige D, Luzinda K, Ssekitoleko R (2013) Spectrum of lithium induced thyroid abnormalities: a current perspective. Thyroid Res 6(1):3
Kim JY, Lee J, Ko YJ et al (2013) Multi-indication carbamazepine and the risk of severe cutaneous adverse drug reactions in Korean elderly patients: a Korean health insurance databased study. PLoS One 8(12). doi:10.1371/journal.pone.0083849
Kocak S, Girisgin SA, Gul M et al (2007) Stevens-Johnson syndrome due to concomitant use of lamotrigine and valproic acid. Am J Clin Dermatol 8(2):107–111
Koda R, Aoyagi R, Okazaki E et al (2012) Acute tubulointerstitial nephritis with multiple organ involvement including fatal adrenalitis: a case report with autopsy findings. Intern Med 51:2917–2922
Koutsampasopoulos K, Zotos A, Papaioannou K (2014) Carbamazepine induced atrial tachycardia with complete AV block. Hippokratia 18(2):185–186
Kupfer DJ (2005) The increasing medical burden in bipolar disorder. J Am Med Assoc 293:2528–2530
Landi F, Onder G, Cesari M et al (2005) Silver Network Home Care Study Group. Psychotropic medications and risk for falls among community-dwelling frail older people: an observational study. J Gerontol A Biol Sci Med Sci 60:622–626
Lepkifker E, Sverdlik A, Iancu I et al (2004) Renal insufficiency in long-term lithium treatment. J Clin Psychiatry 65:850–856
Levi N, Bastuji-Garin S, Mockenhaupt M et al (2009) Medications as risk factors of Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis. Pediatrics 123(2):e297–e304
Lin LC, Lai PC, Yang SF et al (2009) Oxcarbazepine-induced Stevens-Johnson Syndrome: a case report. Kaohsiung J Med Sci 25(2):82–85
Lindop P, Padfield GL (1975) The renal pathology in a case of lithium-induced diabetes. J Clin Pathol 28:472–475
Livingstone C, Rampes H (2006) Lithium: a review of its metabolic adverse effects. J Psychopharmacol 20:347–355
Malhi GS, Tanious M, Das P et al (2012) The science and practice of lithium therapy. Aust N Z J Psychiatry 46:192–211
Markowitz GS, Radhakrishnan J, Kambham N et al (2000) Lithium nephrotoxicity: a progressive combined glomerular and tubulo-interstitial nephropathy. J Am Soc Nephrol 11:1439–1448
Martino DJ, Igoa A, Marengo E et al (2008) Cognitive and motor features in elderly people with bipolar disorder. J Affect Disord 105:291–295
Matsuda H, Saito K, Takayanagi Y et al (2013) Pustular-type drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to carbamazepine with systemic muscle involvement. J Dermatol 40(2):118–122
McKnight RF, Adida M, Budge K et al (2012) Lithium toxicity profile: a systematic review and meta-analysis. Lancet 379:721–728
Meador K, Baker GA, Browning N et al (2009) Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 360:1597–1605
Müller-Oerlinghausen B, Berghöfer A, Bauer M (2002) Bipolar disorder. Lancet 359(9302):241–247
Murray CJ, Lopez AD (1997) Global mortality, disability, and the contribution of risk factors: global burden of disease study. Lancet 349:1436–1442
Murray N, Hopwood S, Balfour DJK et al (1983) The influence of age on lithium efficacy and side-effects in out-patients. Psychol Med 13:53–60
Nora JJ, Nora AH, Toews WH (1974) Letter: lithium, Ebstein’s anomaly, and other congenital heart defects. Lancet 2:594–595
Olin JT, Fox LS, Pawluczyk S et al (2001) Pilot randomized trial of carbamazepine for behavioral symptoms in treatment-resistant outpatients with Alzheimer disease. Am J Geriatr Psychiatry 9(4):400–405
Özerdem A, Tunca Z, Çımrın D et al (2014) Female vulnerability for thyroid function abnormality in bipolar disorder: role of lithium treatment. Bipolar Disord 16(1):72–82
Pacchiarotti I, Bond DJ, Baldessarini RJ et al (2013) The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry 170(11):1249–1262
Pachet AK, Wisniewski AM (2003) The effects of lithium on cognition: an updated review. Psychopharmacology 170(3):225–234, Epub 2003 Sep 19
Perucca E, Meador KJ (2005) Adverse effects of antiepileptic drugs. Acta Neurol Scand 112(Suppl 181):30–35
Perucca E, Beghi E, Dulac O et al (2000) Assessing risk to benefit ratio in antiepileptic drug therapy. Epilepsy Res 41:107–139
Pfennig A, Bschor T, Falkai P et al (2013) The diagnosis and treatment of bipolar disorder: recommendations from the current S3 guideline. Dtsch Arztebl Int 110(6):92–100
Pinheiro D (2008) Anticonvulsant mood stabilizers in the treatment of behavioral and psychological symptoms of dementia (BPSD). Encéphale 34(4):409–415
Presne C, Fakhouri F, Noël LH et al (2003) Lithium-induced nephropathy: rate of progression and prognostic factors. Kidney Int 64(2):585–592
Prien RF, Caffey EM Jr, Klett CJ (1972) Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Report of the Veteran Administration and National Institute of Mental Health Collaborative Study Group. Arch Gen Psychiatry 26(2):146–153
Raja M (2011) Lithium and kidney, 60 years later. Curr Drug Saf 6(5):291–303
Rockwell WJ, Ellinwood EH Jr, Trader DW (1983) Psychotropic drugs promoting weight gain: health risks and treatment implications. South Med J 76(11):1407–1412
Rolnitsky A, Merlob P, Klinger G (2013) In utero oxcarbazepine and a withdrawal syndrome, anomalies, and hyponatremia. Pediatr Neurol 48:466–468
Ross CJ, Carleton B, Warn D et al (2007) Genotypic approaches to therapy in children: a national active surveillance network (GATC) to study the pharmacogenomics of severe adverse drug reactions in children. Ann N Y Acad Sci 10:177–192
Rosser R (1976) Thyrotoxicosis and lithium. Br J Psychiatry 128(48):61–66
Sarantidis D, Waters BA (1983) A review and controlled-study of cutaneous conditions associated with lithium-carbonate. Br J Psychiatry 143:42–50
Saunders BD, Saunders EF, Gauger PG (2009) Lithium therapy and hyperparathyroidism: an evidence-based assessment. World J Surg 33(11):2314–2323
Schou M, Vestergaard P (1988) Prospective studies on a lithium cohort: II renal function. Water and electrolyte metabolism. Acta Psychiatr Scand 78:427–433
Schou M, Goldfield M, Weinstein MR et al (1973) Lithium and pregnancy, I: report from the Register of Lithium Babies. BMJ 2:135–136
Schouws SN, Stek ML, Comijs HC, Beekman AT (2010) Risk factors for cognitive impairment in elderly bipolar patients. J Affect Disord 25:330–335
Seely EW, Moore TJ, LeBoff MS et al (1989) A single dose of lithium carbonate acutely elevates intact parathyroid hormone levels in humans. Acta Endocrinol 121:174–176
Sharma B, Sannegowda RB, Gandhi P et al (2013) Combination of Steven-Johnson syndrome and neuroleptic malignant syndrome following carbamazepine therapy: a rare occurrence. BMJ Case Rep. doi:10.1136/bcr-2013-008908
Slater V, Milanes F, Talcott V et al (1984) Influence of age on lithium therapy. South Med J 77:153–154, 158
Sproule BA, Hardy BG, Shulman KI (2000) Differential pharmacokinetics of lithium in elderly patients. Drugs Aging 16:165–177
Strakowski SM, Fleck DE, Maj M (2011) Broadening the diagnosis of bipolar disorder: benefits vs. risks. World Psychiatry 10(3):181–186
Tica OS, Tica AA, Brailoiu CG et al (2013) Sirenomelia after phenobarbital and carbamazepine therapy in pregnancy. Birth Defects Res A Clin Mol Teratol 97(6):425–428
Torrent C, Amann B, Sánchez-Moreno J et al (2008) Weight gain in bipolar disorder: pharmacological treatment as a contributing factor. Acta Psychiatr Scand 118(1):4–18
van Melick EJ, Souverein PC, den Breeijen JH et al (2013) Age as a determinant of instability of serum lithium concentrations. Ther Drug Monit 35(5):643–648
Vanderpump MP, Tunbridge WM, French JM et al (1995) The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol 43(1):55–68
Velligan DI, Weiden PJ, Sajatovic M et al (2010) Strategies for addressing adherence problems in patients with serious and persistent mental illness: recommendations from the expert consensus guidelines. J Psychiatr Pract 16(5):306–324
Vestergaard P, Schou M (1981) Kidney morphology and function in lithium-treated patients. Bibl Psychiatr 161:104–114
Von Knorring L, Wahlin A, Nystr K et al (1990) Uremia induced by long-term lithium treatment. Lithium 1:251–253
Weinstein MR (1980) Lithium treatment of women during pregnancy and in the post-delivery period. In: Johnson FN (ed) Handbook of lithium therapy. MTP, Lancaster, pp 421–429
Weinstein MR, Goldfield M (1975) Cardiovascular malformations with lithium use during pregnancy. Am J Psychiatry 132:529–531
Weintraub D, Buchsbaum R, Resor SR Jr et al (2005) Effect of antiepileptic drug comedication on lamotrigine clearance. Arch Neurol 62:1432–1436
Wijeratne C, Draper B (2011) Reformulation of current recommendations for target serum lithium concentration according to clinical indication, age and physical comorbidity. Aust N Z J Psychiatry 45(12):1026–1032
Wingo AP, Wingo TS, Harvey PD, Baldessarini RJ (2009) Effects of lithium on cognitive performance: a meta-analysis. J Clin Psychiatry 70:1588–1597
Wisner KL, Leckman-Westin E, Finnerty M et al (2011) Valproate prescription prevalence among women of childbearing age. Psychiatr Serv 62(2):218–220
Wong IC, Lhatoo SD (2000) Adverse reactions to new anticonvulsant drugs. Drug Saf 23(1):35–56
Yacobi S, Ornoy A (2008) Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review. Isr J Psychiatry Relat Sci 45(2):95–106
Yang SY, Liao YT, Liu HC et al (2013) Antipsychotic drugs, mood stabilizers, and risk of pneumonia in bipolar disorder: a nationwide case-control study. J Clin Psychiatry 74(1):e79–e86
Yatham LN, Kennedy SH, Parikh SV et al (2013) Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord 15:1–44
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Fabrazzo, M., Tortorella, A. (2016). Safety and Tolerability of Mood Stabilisers. In: Spina, E., Trifirò, G. (eds) Pharmacovigilance in Psychiatry. Adis, Cham. https://doi.org/10.1007/978-3-319-24741-0_11
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