Vol 10 #4

Alan Eppel MB, FRCPC


In a recent editorial Michael Bauer wrote “when used correctly lithium unquestionably produces the most dramatic benefits of any medication in psychopharmacology I have seen in clinical practice during the past three decades” [1].

Lithium is unique among mood stabilizing medications. Recent meta-analyses, and population-based studies have reconfirmed its efficacy in the prevention of both depressive and manic episodes [2,3,4]

Lithium is recommended in all the principal bipolar treatment guidelines [5-8].

In addition lithium has been shown to reduce completed suicide in double-blind  randomized controlled clinical trials [9]

Lithium has neuroprotective effects. The latter may have application in dementia and neurodegenerative diseases [9,10]

Patients with a clinical profile that includes manic and depressive episodes with full remission between episodes, a family history of similar disorders and limited comorbidities show excellent response to lithium with stabilization lasting for decades (11). These authors note that the addition of antidepressants can destabilize the course of illness in lithium responders and may lead to rapid cycling.

Effectiveness studies have demonstrated the superiority of lithium and other mood stabilizers in the management of bipolar illness for both psychiatric and medical outcomes [12]




Several recent reviews have identified very significant decrease in the use of lithium [12,13,14]. Data from the National Ambulatory Medical Care Survey in the United States has shown that the utilization of lithium has decreased dramatically while the use of antipsychotic medications has increased over the past two decades [13].

Between 1997 and 2000 the use of primary mood stabilizers(lithium, valproate, carbamazepine, lamotrigine) decreased from 62% in the years 1997–2000 to 26% in the years 2013 – 2016. Antidepressant prescriptions occurred in 47% of visits in the first group, but had risen to 57% in the years 2013–2016. Prescription of an antidepressant without a mood stabilizer increased from 17% to 41%.

The persisting high rate of antidepressant use runs counter to most findings in the past decade. Antidepressants may lead to an acceleration of mood cycling, unrecognized mixed mood states, and long-term lack of stabilization [11]. This in turn can lead to higher rates of completed suicide [15]. A recent randomized controlled trial

demonstrated that the addition of an antidepressant to a mood stabilizer conferred no benefit in outcomes when compared to placebo in both acute and maintenance phases.

However the use of antidepressant in the maintenance phase led to worsened manic symptoms [16]..


Reasons for the drop in usage of lithium include:


  • Aggressive marketing of second generation antipsychotics
  • Misunderstanding of the relative risks of side effects
  • Lack of long term follow up and continuity of care
  • Deficiencies in training
  • Perceived difficulty of laboratory monitoring




Rates of side effects to lithium [9]:

  • Hypothyroidism occurs in 2 to 4% of patients and can be treated with thyroid hormone replacement.


  • Hyperparathyroidism is infrequent but calcium levels should be monitored yearly.


  • Chronic renal insufficiency has a rate of 1-5% after 10 to 20 years of treatment.


  • End-stage renal disease occurs in 0.53% versus 0.2% in the general population.


Lower maintenance blood levels should be used in lithium prescribed in one dose per 24 hrs, and not multiple times per day. Lithium should be titrated according to clinical response and not to a specific targeted numerical blood level.

In older persons, lower therapeutic levels of around 0.4 nmol/L may reduce side effects [9].

Second generation antipsychotics both oral and long-acting exhibit significant side effects: weight gain, metabolic syndrome, diabetes mellitus, cardiovascular disease, and akathisia [17-20]. This can lead to prolonged morbidity, reduce quality-of-life, and earlier age of death.




Lithium remains the most effective agent for long-term prevention of depressive episodes of bipolar disorder and manic episodes and the maintenance of mood stabilization and bipolar disorder.

Long-term lithium treatment is more effective than second-generation antipsychotics. For the majority of patients, the side effect profile of lithium carries less risk than the use of second generation antipsychotic medications.




  1. Bauer M, Lithium: about discrepancies between efficacy and clinical use.

Acta Psychiatr Scand. 2020;142:159–160

DOI: 10.1111/acps.13230

  1. Severus E, Bauer M, Geddes J. Efficacy and effectiveness of  lithium in the long-term treatment of bipolar disorders: An Update 2018. Pharmacopsychiatry. 2018;51:173–176.


  1. Kessing LV, Bauer M, Nolen WA, Severus E, Goodwin GM, Geddes J. Effectiveness of maintenance therapy of

lithium vs other mood stabilizers in monotherapy and in combinations: a systematic review of evidence from

observational studies. Bipolar Disord. 2018;20:419–431.


4.Malhi GS, Bell E, Boyce P et al. Make Lithium Great Again. Bipolar Disorders. 2020; 22:325-327.


  1. Hammett S, Youssef NA. Systematic review of recent guidelines for pharmacological treatments of bipolar disorders in adults. Ann Clin Psychiatry. 2017;29(4):266-282.


  1. Malhi GS, Outhred T, Morris G, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders: bipolar disorder summary. Med J Aust. 2018;208(5):219-225.


  1. Sakurai H, Kato M, Yasui-Furukori N, Suzuki T, Baba H, Watanabe K et al. Medical Education Panel of the Japanese Society of Clinical Neuropsychopharmacology. Pharmacological management of bipolar disorder: Japanese expert consensus. Bipolar Disord. 2020;22(8):822-830. doi: 10.1111/bdi.12959


  1. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.


  1. Barroilhet SA, Ghaemi SN. When and how to use lithium. Acta Psychiatr Scand. 2020;142(3):161-172.

doi: 10.1111/acps.13202.


  1. Won E, Kim YK. An Oldie but Goodie: Lithium in the Treatment of Bipolar Disorder through Neuroprotective and Neurotrophic Mechanisms. Int J Mol Sci. 2017;18(12):2679. doi: 10.3390/ijms18122679.


  1. Grof P, Duffy A. Lithium stabilization and misunderstandings: Toward understanding why lithium is underutilized. Bipolar Disorders. 2021;23:95–96.    doi: 10.1111/bdi.13000


  1. Sleem A, El-Mallakh RS. Advances in the psychopharmacotherapy of bipolar disorder type I. Expert Opin Pharmacother. 2021. doi: 10.1080/14656566.2021.1893306.


  1. Rhee TG, Olfson M, Nierenberg AA, Wilkinson ST. 20-Year Trends in the Pharmacologic Treatment of Bipolar Disorder by Psychiatrists in Outpatient Care Settings. Am J Psychiatry. 2020;177(8):706-715. doi: 10.1176/appi.ajp.2020.19091000.


  1. Post RM. The New News about Lithium: An Underutilized Treatment in the United States. Neuropsychopharmacology. 2018;43(5):1174-1179. doi:10.1038/npp.2017.238


  1. Eppel AB. Antidepressants in the treatment of bipolar disorder: decoding contradictory evidence and opinion. Harv Rev Psychiatry. 2008;16(3):205-9. doi:10.1080/10673220802160381


  1. Ghaemi SN, Whitham EA, Vohringer PA, Barroilhet SA, et al. Citalopram for Acute and Preventive Efficacy in Bipolar Depressiona (CAPE-BD): A Randomized, Double-Blind, Placebo-Controlled Trial. J Clin Psychiatry. 2021;82(1):19m13136. doi: 10.4088/JCP.19m13136. PMID:33434956.


  1. Chow CL, Kadouh NK, Bostwick JR, VandenBerg AM. Akathisia in Newer Second-Generation Antipsychotic Drugs: A Review of Current Evidence. Pharmacotherapy. 2020;40(6):565-574. doi: 10.1002/phar.2404


  1. Endomba FT, Tankeu AT, Nkeck JR, Tochie JN. Leptin and psychiatric illnesses: does leptin play a role in antipsychotic-induced weight gain? Lipids Health Dis. 20207;19(1):22. doi: 10.1186/s12944-020-01203-z.


  1. Klein CC, Topalian AG, Starr B, Welge et al. The Importance of Second-Generation Antipsychotic-Related Weight Gain and Adherence Barriers in Youth with Bipolar Disorders: Patient, Parent, and Provider Perspectives. J Child Adolesc Psychopharmacol. 2020;30(6):376-380. doi: 10.1089/cap.2019.0184.


  1. Demyttenaere K, Detraux J, Racagni G, Vansteelandt K. Medication-Induced Akathisia with Newly Approved Antipsychotics in Patients with a Severe Mental Illness: A Systematic Review and Meta-Analysis. CNS Drugs. 2019;33(6):549-566. doi: 10.1007/s40263-019-00625-3.


Print Friendly, PDF & Email