section name header

Information ⬇

Lithium

Mechanism of Action

Lithium is implicated in a wide range of biological processes, with a multiplicity of effects. Consequently it has proven very difficult to ascertain the key mechanism(s) of action of lithium in regulating mood and behaviour. For example, there is some older evidence that people with bipolar illness have higher intracellular concentrations of sodium and calcium than controls and that lithium can reduce these. Interestingly, calcium-related genes have been implicated by genetic studies in bipolar disorder.1 GSK3 (glycogen synthase kinase 3), CREB (cAMP response element-binding protein) and Na+/K+ adenosine triphosphatase (ATPase) related mechanisms may be important for lithium's effects.2 Lithium may have neuroprotective effects that preserve the function of neurons and neuronal circuits.3 Lithium also promotes neurogenesis in the hippocampus, which is important for learning, memory and stress responses.4 A meta-analysis suggests lithium may prevent transition to dementia5 and lithium appears to be more effective than aducanumab in preventing cognitive decline.6 However, the largest study to date showed no beneficial effect on risk of neurocognitive disorders.7 Both reversible and irreversible neurotoxicity related to lithium are recognised adverse effects.8, 9 Lithium is present in low levels in the environment (e.g. in drinking water sources) and environmental lithium concentration has been reported to be inversely related to suicide and dementia at a population level.10, 11

Clinical Indications

Acute Treatment of Mania

Lithium is effective for the treatment of mania, at a plasma level of 0.8-1.0mmol/L.12 If a faster onset of action is needed an adjunctive or single-agent antipsychotic with an evidence base for treating mania is recommended.12 It can be difficult to achieve therapeutic plasma lithium levels rapidly and monitoring may be problematic if the patient is uncooperative. Treatment may be most successful in those without psychotic symptoms or evidence of rapid cycling.13

Treatment of Acute Mania in Patients Already on Long-Term Lithium

The 2016 British Association for Psychopharmacology guidelines12 suggest that in the event of relapse, an urgent plasma lithium level should be obtained to indicate the level of compliance with lithium therapy and inform possible dose adjustment. If lithium level measurement indicates non-compliance, the reason should be ascertained. If the lithium level is confirmed to be optimal, but the control of mania is inadequate, then adding a dopamine antagonist, dopamine partial agonist or valproate (given the conditions with regard to reproductive potential) is recommended.12

Bipolar Depression

Lithium is widely used in bipolar depression but evidence supporting robust efficacy for acute episodes is somewhat unconvincing.14, 15 Evidence for prevention of depressive episodes is more compelling.

Maintenance Treatment of Bipolar Disorder

Aim for the highest tolerable lithium plasma level in the range of 0.6-0.8mmol/L12, 16 with the option to reduce it to 0.4-0.6mmol/L in case of good response but poor tolerance, or to increase it to 0.8-1.0mmol/L in case of insufficient response and good tolerance. The aim of treatment is complete remission and prevention of both manic and depressive episodes.17 Lithium is the best-performing mood stabiliser for bipolar disorder in practice with a prophylactic effectiveness similar to long-acting antipsychotics.18 In 2024, it remains the gold standard treatment for bipolar disorder.19

Augmentation of Antidepressants in Unipolar Depression

Approximately 30-50% of patients fail to respond to trials of first- or second-line antidepressants and outcomes from treatment-resistant depression are poor.20 Evidence-based guidelines for treating depressive disorders with antidepressants21 suggest that either lithium or quetiapine is the agent of first choice for augmenting the existing antidepressant and that lithium augmentation is most effective at a lithium plasma level of 0.6-1.0mmol/L. Recent meta-analyses suggest robust efficacy for lithium, alongside quetiapine, D2 partial agonists and ketamine.22, 23 One meta-analysis suggested lithium to be most effective.24 Clinical predictors associated with a better outcome in lithium augmentation for treatment-resistant depression included more severe depressive symptomatology, psychomotor retardation, significant weight loss, a family history of major depression or a personal experience of more than three episodes.25 Of course, compliance with lithium augmentation should also be added to this list. Lithium is widely underused in resistant depression.26

Prophylaxis of Unipolar Depression

Lithium is significantly superior to antidepressants in preventing relapses that require hospitalisation, with a relative risk of 0.34.27 Lithium prophylaxis is indicated in unipolar depression (i) if a patient has suffered two depressive episodes in 5 years; (ii) after one episode if the episode is severe and there is a strong suicide risk; (iii) with indefinite treatment if there is adherence and adverse events are not problematic, particularly if a bipolar background is suspected.28

Other Uses of Lithium

Lithium is also used to treat aggressive and self-mutilating behaviour and studies have confirmed benefits29 to both prevent and treat steroid-induced psychosis30 and to raise the white blood cell count in patients receiving clozapine.31

Lithium and Suicide

It is estimated that 15% of people with bipolar disorder eventually take their own life.32 A meta-analysis of clinical trials concluded that lithium reduced the risk of both attempted and completed suicide by 80% in patients with bipolar illness,33 and large database studies have shown that lithium-treated patients are less likely to complete suicide than patients treated with other mood-stabilising drugs.34

In patients with unipolar depression, lithium also seems to protect against suicide although the mechanism of this protective effect is unknown.33 As noted, environmental lithium has been reported to be inversely related to suicide at a population level.10, 35

Plasma Levels

The minimum effective plasma level for prophylaxis of mood disorder episodes is probably 0.4mmol/L, with the optimal concentration being in the range 0.6-0.8mmol/L.36 Levels above 0.75mmol/L offer additional protection only against manic symptoms37 so the target range for prophylaxis is effectively 0.6-0.8mmol/L.16, 38 Changes in plasma levels in either direction seem to worsen the risk of relapse.37 The optimal plasma level range in patients who have unipolar depression is less clear.39 Taking account of evidence from clinical trials, naturalistic studies and lithium in drinking water, studies seem to suggest that various benefits of lithium begin at a low concentration and increase over a narrow range up to 1.0mmol/L. Low-dose lithium regimens are under investigation but not yet clinically recommended.40

Children and adolescents may require higher plasma levels than adults to ensure that an adequate concentration of lithium is present in the central nervous system (CNS).41

Lithium is rapidly absorbed from the gastrointestinal tract but has a long distribution phase. Blood samples for plasma lithium level estimations should be taken 10-14 (ideally 12) hours post-dose in patients who are prescribed a single daily dose of a prolonged-release preparation at bedtime.12

Formulations

There is no clinically significant difference in the pharmacokinetics of the two most widely prescribed brands of lithium in the UK: Priadel and Camcolit. In other countries, standard lithium carbonate tablets are often given twice or three times daily.

The amount of elemental lithium varies by salt used.

  • Lithium carbonate 400mg tablets each contain 10.8mmol lithium.

  • Lithium citrate liquid is available in two strengths:

    • 5.4mmol/5mL (equivalent to 200mg lithium carbonate).
    • 10.8mmol/5mL (equivalent to 400mg lithium carbonate).

Lack of clarity over which liquid preparation is intended when prescribing can lead to the patient receiving a sub-therapeutic or toxic dose. Liquid preparations need to be given 12-hourly.

Adverse Effects

Most adverse effects are dose- and plasma level-related. These include mild gastrointestinal upset, fine tremor, polyuria and polydipsia. Polyuria may occur more frequently with twice daily dosing.42, 43 Propranolol can be useful in lithium-induced tremor. Some skin conditions such as psoriasis and acne can be aggravated by lithium therapy. Lithium can also cause a metallic taste in the mouth, ankle oedema and weight gain.

Lithium can cause a reduction in urinary concentrating capacity - nephrogenic diabetes insipidus - hence the occurrence of thirst and polyuria. This effect is usually reversible in the short to medium term, but renal effects may be irreversible after long-term treatment (>15 years).44 Lithium treatment can also lead to a reduction in the glomerular filtration rate (GFR) although the magnitude of the risk is uncertain.44 Lithium levels of >0.8mmol/L are associated with a higher risk of renal toxicity and prolonged lithium treatment of course requires regular monitoring of kidney function.45 Hypertension and a diagnosis of bipolar disorder worsen the risk of lithium-related chronic kidney disease.46

In the longer term, lithium increases the risk of hypothyroidism;47 in middle-aged women the risk may be up to 20%.48 A case has been made for testing thyroid autoantibodies in this group before starting lithium (to better estimate risk) and for performing thyroid function tests (TFTs) more frequently in the first year of treatment.49 Hypothyroidism is readily treated with thyroxine. TFTs usually return to normal when lithium is discontinued. Lithium also more rarely causes hyperthyroidism.50

Hyperparathyroidism causes hypercalcaemia in about 4% of patients51 and calcium levels should be monitored in patients on long-term treatment.50, 52 Clinical consequences of chronically increased serum calcium include renal stones, osteoporosis, dyspepsia, hypertension and renal impairment.

Lithium Toxicity

Toxic effects reliably occur at levels >1.5mmol/L and usually consist of gastrointestinal symptoms (increasing anorexia, nausea and diarrhoea) and CNS effects (muscle weakness, drowsiness, confusion, ataxia, coarse tremor and muscle twitching).53 Above 2mmol/L, increased disorientation and seizures usually occur, which can progress to coma and ultimately death. In the presence of more severe symptoms, osmotic or forced alkaline diuresis should be used in a medical facility. Above 3mmol/L, peritoneal or haemodialysis is often used. These plasma levels are only a guide and individuals vary in their susceptibility to symptoms of toxicity. Neurotoxicity at normal plasma levels has also been described, as brain lithium levels may not be reflected by concentration in the plasma.54, 55

Most risk factors for toxicity involve changes in sodium levels or in the way the body handles sodium, for example low salt diets, dehydration, drug interactions (see later Table 2.2) and some uncommon physical illnesses such as Addison's disease.

Information relating to the symptoms of toxicity and the common risk factors (especially drug interactions) should always be given to patients when treatment with lithium is initiated.56 This information should be repeated at appropriate intervals to make sure that it is clearly understood.

Pre-Treatment Tests

Before prescribing lithium, renal, thyroid and cardiac function should be checked. As a minimum, the estimated GFR (eGFR),57 urea and electrolytes (U&Es) and TFTs should be checked. A baseline calcium level is also helpful. An electrocardiogram (ECG) is also recommended in patients who have risk factors for, or existing, cardiovascular disease. A baseline measure of weight is also desirable.

Lithium is a putative human teratogen. Women of child-bearing age should be advised to use a reliable form of contraception. See the section on psychotropics and pregnancy (Chapter 7).

On-Treatment Monitoring12, 58

Plasma lithium, eGFR, U&Es and TFTs should be checked every 6 months. More frequent tests may be required in those who are prescribed interacting drugs, who are elderly or who have established chronic kidney disease. Weight (or body mass index [BMI]) should also be monitored. Lithium monitoring in clinical practice in the UK is known to be suboptimal59 although there has been a modest improvement over time.60 The use of automated reminder systems has been shown to improve monitoring rates.61

Discontinuation

Intermittent treatment with lithium may worsen the natural course of bipolar illness. A much greater than expected incidence of manic relapse is seen in the first few months after abruptly discontinuing lithium,62 even in patients who have been symptom-free for as long as 5 years.63 Lithium treatment should not be started unless there is a clear intention to continue it for several years and where compliance can be reasonably assured.64 This advice has obvious implications for initiating lithium treatment against a patient's will (or in a patient known to be non-compliant with medication) during a period of acute illness.

The risk of relapse is probably reduced by decreasing the dose gradually over a period of at least a month65 and avoiding decremental plasma level reductions of >0.2mmol/L.37 In contrast with these recommendations, a naturalistic study found that, in patients who had been in remission for at least 2 years and had discontinued lithium very slowly, the recurrence rate was at least three times greater than in patients who continued lithium and that significant survival differences persisted for many years. Patients maintained on high lithium levels before discontinuation were particularly prone to relapse.66

One large US study based on prescription records found that half of those prescribed lithium took almost all of their prescribed doses, a quarter took between 50% and 80% and the remaining quarter took less than 50%. A third of patients took lithium for less than 6 months in total.67 A large audit found that 1 in 10 patients prescribed long-term lithium treatment had a plasma level below the therapeutic range.68 It is clear that suboptimal adherence limits the effectiveness of lithium in clinical practice. One database study suggested the extent to which lithium was taken was directly related to the risk of suicide (more prescriptions were associated with lower suicide rate).69 Less convincing data support the emergence of depressive symptoms in bipolar patients after lithium discontinuation.62 There are few data relating to patients with unipolar depression.

Table 2.1 summarises the prescribing and monitoring of lithium.

Table 2.1 Lithium: Prescribing and Monitoring.

IndicationsMania, hypomania, prophylaxis of bipolar affective disorder and recurrent depression. Reduces aggression and suicidality.
Pre-lithium work-upEstimated glomerular filtration rate (eGFR) and thyroid function tests (TFTs). ECG recommended in patients who have risk factors for, or existing, cardiovascular disease. Baseline measure of weight desirable. U&Es (including calcium).
PrescribingStart at 400mg at night (200mg in the elderly). Plasma level after 7 days, then 7 days after every dose change until the desired level is reached (0.4mmol/L may be effective in unipolar depression, 0.6-1.0mmol/L in bipolar illness, slightly higher levels in this range in difficult to treat mania). Blood should be taken 12 hours after the last dose. Take care when prescribing liquid preparations to clearly specify the strength required.
MonitoringPlasma lithium every 6 months (more frequent monitoring is necessary in those prescribed interacting drugs, the elderly and those with established renal impairment or other relevant physical illness). eGFR, U&Es and TFTs every 6 months. Weight (or body mass index) should also be monitored.
StoppingReduce slowly over at least 1 month and preferably 3 months. Avoid reductions in plasma levels of >0.2mmol/L at a time (see section on discontinuation).

Interactions with Other Drugs70, 71, 72

Because of lithium's relatively narrow therapeutic index, pharmacokinetic interactions with other drugs can precipitate lithium toxicity. Most clinically significant interactions are largely with drugs that alter renal sodium handling. Rarely, neurotoxicity results from co-prescribing lithium and antipsychotics.73, 74

Ace Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors can (i) reduce thirst, which can lead to mild dehydration; and (ii) increase renal sodium loss leading to increased sodium reabsorption by the kidney, resulting in an increase in lithium plasma levels. The magnitude of this effect is variable, from no increase to a fourfold increase. The full effect can take several weeks to develop. The risk seems to be increased in patients with heart failure, dehydration and renal impairment (presumably because of changes in fluid balance/handling). In the elderly, ACE inhibitors increase sevenfold the risk of hospitalisation due to lithium toxicity. ACE inhibitors can also precipitate renal failure so, if co-prescribed with lithium, more frequent monitoring of eGFR and plasma lithium is required.

The following drugs are ACE inhibitors: captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.

Care is also required with the angiotensin II receptor antagonists candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan.

Diuretics

Diuretics can reduce the renal clearance of lithium, the magnitude of this effect being greater with thiazide than with loop diuretics. Lithium levels usually rise within 10 days of a thiazide diuretic being prescribed; the magnitude of the rise is unpredictable and can vary from an increase of 25% to 400%.

The following drugs are thiazide (or related) diuretics: bendroflumethiazide, chlortalidone, cyclopenthiazide, indapamide, metolazone and xipamide.

Although there are case reports of lithium toxicity induced by loop diuretics, many patients receive this combination of drugs without apparent problems. The risk of an interaction seems to be greatest in the first month after the loop diuretic has been prescribed and additional lithium plasma level monitoring during this time is recommended if these drugs are co-prescribed. Loop diuretics can increase sodium loss and subsequent reabsorption by the kidney. Patients taking loop diuretics may also have been advised to restrict their salt intake; this may contribute to the risk of lithium toxicity in these individuals.

The following drugs are loop diuretics: bumetanide, furosemide and torasemide.

Non-Steroidal Anti-Inflammatory Drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of renal prostaglandins, thereby reducing renal blood flow and possibly increasing renal reabsorption of sodium and therefore lithium. The magnitude of the rise in lithium concentration is unpredictable for any given patient; case reports vary from increases of around 10% to over 400%. The onset of effect also seems to be variable, from a few days to several months. Risk appears to be increased in those patients who have impaired renal function, renal artery stenosis or heart failure and who are dehydrated or on a low salt diet. There are a number of case reports of an interaction between lithium and COX-2 inhibitors. NSAIDs do not appear to diminish the therapeutic effects of lithium,75 as has previously been reported.

NSAIDs (or COX-2 inhibitors) can be very carefully combined with lithium, but they should be prescribed regularly, not intermittently, and more frequent plasma lithium monitoring is essential. Some NSAIDs can be purchased without a prescription, so it is particularly important that patients are aware of the potential for interaction.

The following drugs are NSAIDs or COX-2 inhibitors: aceclofenac, acemetacin, celecoxib, dexibuprofen, dexketoprofen, diclofenac, diflunisal, etodolac, etoricoxib, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, lumiracoxib, mefenamic acid, meloxicam, nabumetone, naproxen, piroxicam, sulindac, tenoxicam and tiaprofenic acid.

Carbamazepine

There are rare reports of neurotoxicity when carbamazepine is combined with lithium. Most reports are old and in the context of treatment involving high plasma lithium levels. It is of note though that carbamazepine can cause hyponatraemia, which may in turn lead to lithium retention and toxicity. Similarly, rare reports of CNS toxicity implicate selective serotonin reuptake inhibitors (SSRIs), another group of drugs that can cause hyponatraemia.

Table 2.2 summarises drugs that may clinically interact with lithium.

Table 2.2 Lithium: Clinically Relevant Drug Interactions.

Drug groupMagnitude of effectTimescale of effectAdditional information
ACE inhibitors

Unpredictable

Up to fourfold increases in [Li]

Develops over several weeks

Sevenfold increased risk of hospitalisation for lithium toxicity in the elderly

Angiotensin II receptor antagonists may be associated with similar risk

Thiazide diuretics

Unpredictable

Up to fourfold increases in [Li]

Usually apparent in first 10 days

Loop diuretics are safer

Any effect will be apparent in the first month

NSAIDs

UnpredictableFrom 10% to over fourfold increases in [Li]

Variable; few days to several months

NSAIDs are widely used on a when necessary basis

Can be bought without a prescription

ACE, angiotensin-converting enzyme; [Li], lithium concentraction; NSAIDs, non-steroidal anti-inflammatory drugs.

References ⬆

  1. BrayNJ, et al. The genetics of neuropsychiatric disorders. Brain Neurosci Adv 2019; 2:2398212818799271.
  2. BortolozziA, et al. New advances in the pharmacology and toxicology of lithium: a neurobiologically oriented overview. Pharmacol Rev 2024; 76:323-357.
  3. JopeRS, et al. Lithium to the rescue. Cerebrum 2016; 2016:cer-02-16.
  4. HansonND, et al. Lithium, but not fluoxetine or the corticotropin-releasing factor receptor 1 receptor antagonist R121919, increases cell proliferation in the adult dentate gyrus. J Pharmacol Exp Ther 2011; 337:180-186.
  5. MatsunagaS, et al. Lithium as a treatment for Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis 2015; 48:403-410.
  6. TeraoI, et al. Comparative efficacy of lithium and aducanumab for cognitive decline in patients with mild cognitive impairment or Alzheimer's disease: a systematic review and network meta-analysis. Ageing Res Rev 2022; 81:101709.
  7. HuangQ, et al. Lithium exposure and risk of major neurocognitive disorders: a systematic review and meta-analysis. J Clin Psychopharmacol 2024; 44:418-423.
  8. NettoI, et al. Reversible lithium neurotoxicity: review of the literature. Prim Care Companion CNS Disord 2012; 14:PCC.11r01197.
  9. Adityanjee, et al. The syndrome of irreversible lithium-effectuated neurotoxicity. Clin Neuropharmacol 2005; 28:38-49.
  10. MemonA, et al. Association between naturally occurring lithium in drinking water and suicide rates: systematic review and meta-analysis of ecological studies. Br J Psychiatry 2020; 217:667-678.
  11. KessingLV, et al. Association of lithium in drinking water with the incidence of dementia. JAMA Psychiatry 2017; 74:1005-1010.
  12. GoodwinGM, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016; 30:495-553.
  13. HuiTP, et al. A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder. Acta Psychiatr Scand 2019; 140:94-115.
  14. BahjiA, et al. Comparative efficacy and tolerability of pharmacological treatments for the treatment of acute bipolar depression: a systematic review and network meta-analysis. J Affect Disord 2020; 269:154-184.
  15. TaylorDM, et al. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand 2014; 130:452-469.
  16. NolenWA, et al. What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium. Bipolar Disord 2019; 21:394-409.
  17. SeverusE, et al. Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord 2014; 2:15.
  18. LähteenvuoM, et al. Real-world effectiveness of pharmacological treatments for bipolar disorder: register-based national cohort study. Br J Psychiatry 2023; 223:456-464.
  19. AirainerM, et al. Lithium, the gold standard drug for bipolar disorder: analysis of current clinical studies. Naunyn Schmiedebergs Arch Pharmacol 2024; 397:9723-9743.
  20. DunnerDL, et al. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry 2006; 67:688-695.
  21. CleareA, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015; 29:459-525.
  22. ScottF, et al. Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression. J Psychopharmacol 2023; 37:268-278.
  23. NuezNA, et al. Augmentation strategies for treatment resistant major depression: a systematic review and network meta-analysis. J Affect Disord 2022; 302:385-400.
  24. VázquezGH, et al. Efficacy and tolerability of combination treatments for major depression: antidepressants plus second-generation antipsychotics vs. esketamine vs. lithium. J Psychopharmacol 2021; 35:890-900.
  25. BauerM, et al. Role of lithium augmentation in the management of major depressive disorder. CNS Drugs 2014; 28:331-342.
  26. ErcisM, et al. When and how to use lithium augmentation for treating major depressive disorder. J Clin Psychiatry 2023; 84:23ac14813.
  27. CiprianiA, et al. Lithium versus antidepressants in the long-term treatment of unipolar affective disorder. Cochrane Database Syst Rev 2006; 4:CD003492.
  28. Abou-SalehMT, et al. Lithium in the episode and suicide prophylaxis and in augmenting strategies in patients with unipolar depression. Int J Bipolar Disord 2017; 5:11.
  29. CorrellCU, et al. Biological treatment of acute agitation or aggression with schizophrenia or bipolar disorder in the inpatient setting. Ann Clin Psychiatry 2017; 29:92-107.
  30. SiroisF.Steroid psychosis: a review. Gen Hosp Psychiatry 2003; 25:27-33.
  31. AydinM, et al. Continuing clozapine treatment with lithium in schizophrenic patients with neutropenia or leukopenia: brief review of literature with case reports. Ther Adv Psychopharmacol 2016; 6:33-38.
  32. HarrisEC, et al. Excess mortality of mental disorder. Br J Psychiatry 1998; 173:11-53.
  33. CiprianiA, et al. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ 2013; 346:f3646.
  34. HayesJF, et al. Self-harm, unintentional injury, and suicide in bipolar disorder during maintenance mood stabilizer treatment: a UK population-based electronic health records study. JAMA Psychiatry 2016; 73:630-637.
  35. FadaeiA.An investigation into the association between suicide mortality rate and lithium levels in potable water: a review study. Int Clin Psychopharmacol 2023; 38:73-80.
  36. NolenWA, et al. The association of the effect of lithium in the maintenance treatment of bipolar disorder with lithium plasma levels: a post hoc analysis of a double-blind study comparing switching to lithium or placebo in patients who responded to quetiapine (Trial 144). Bipolar Disord 2013; 15:100-109.
  37. SeverusWE, et al. What is the optimal serum lithium level in the long-term treatment of bipolar disorder-a review?Bipolar Disord 2008; 10:231-237.
  38. ManchiaM, et al. Lithium and its effects: does dose matter?Int J Bipolar Disord 2024; 12:23.
  39. YoungAH. Lithium for long-term treatment of unipolar depression. Lancet Psychiatry 2017; 4:511-512.
  40. StrawbridgeR, et al. Lithium: how low can you go?Int J Bipolar Disord 2024; 12:4.
  41. MooreCM, et al. Brain-to-serum lithium ratio and age: an in vivo magnetic resonance spectroscopy study. Am J Psychiatry 2002; 159:1240-1242.
  42. BowenRC, et al. Less frequent lithium administration and lower urine volume. Am J Psychiatry 1991; 148:189-192.
  43. LjubicicD, et al. Lithium treatments: single and multiple daily dosing. Can J Psychiatry 2008; 53:323-331.
  44. GongR, et al. What we need to know about the effect of lithium on the kidney. Am J Physiol Renal Physiol 2016; 311:F1168-F1171.
  45. AiffH, et al. Effects of 10 to 30 years of lithium treatment on kidney function. J Psychopharmacol 2015; 29:608-614.
  46. ParsaikAK, et al. Effects of long-term lithium therapy on kidney functioning in mood disorders: a population-based historical cohort study. Bipolar Disord 2024; doi: 10.1111/bdi.13501.
  47. FryeMA, et al. Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies. Acta Psychiatr Scand 2009; 120:10-13.
  48. JohnstonAM, et al. Lithium-associated clinical hypothyroidism. Prevalence and risk factors. Br J Psychiatry 1999; 175:336-339.
  49. LivingstoneC, et al. Lithium: a review of its metabolic adverse effects. J Psychopharmacol 2006; 20:347-355.
  50. McKnightRF, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet 2012; 379:721-728.
  51. VandermeulenL, et al. Lithium-associated hypercalcemia and hyperparathyroidism: a systematic review and meta-analysis. World J Biol Psychiatry 2024; 25:417-429.
  52. CzarnywojtekA, et al. Effect of lithium carbonate on the function of the thyroid gland: mechanism of action and clinical implications. J Physiol Pharmacol 2020; 71:191-199.
  53. OttM, et al. Lithium intoxication: incidence, clinical course and renal function - a population-based retrospective cohort study. J Psychopharmacol 2016; 30:1008-1019.
  54. BellAJ, et al. Lithium neurotoxicity at normal therapeutic levels. Br J Psychiatry 1993; 162:689-692.
  55. SmithFE, et al. 3D 7Li magnetic resonance imaging of brain lithium distribution in bipolar disorder. Mol Psychiatry 2018; 23:2184-2191.
  56. GerrettD, et al. Prescribing and monitoring lithium therapy: summary of a safety report from the National Patient Safety Agency. BMJ 2010; 341:c6258.
  57. MorrissR, et al. Lithium and eGFR: a new routinely available tool for the prevention of chronic kidney disease. Br J Psychiatry 2008; 193:93-95.
  58. National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical guideline [CG185]. 2014 (last updated December 2023, last accessed October 2024); https://www.nice.org.uk/guidance/cg185.
  59. CollinsN, et al. Standards of lithium monitoring in mental health trusts in the UK. BMC Psychiatry 2010; 10:80.
  60. PatonC, et al. Monitoring lithium therapy: the impact of a quality improvement programme in the UK. Bipolar Disord 2013; 15:865-875.
  61. KirkhamE, et al. Impact of active monitoring on lithium management in Norfolk. Ther Adv Psychopharmacol 2013; 3:260-265.
  62. CavanaghJ, et al. Relapse into mania or depression following lithium discontinuation: a 7-year follow-up. Acta Psychiatr Scand 2004; 109:91-95.
  63. YaziciO, et al. Controlled lithium discontinuation in bipolar patients with good response to long-term lithium prophylaxis. J Affect Disord 2004; 80:269-271.
  64. GoodwinGM. Recurrence of mania after lithium withdrawal. Implications for the use of lithium in the treatment of bipolar affective disorder. Br J Psychiatry 1994; 164:149-152.
  65. BaldessariniRJ, et al. Effects of the rate of discontinuing lithium maintenance treatment in bipolar disorders. J Clin Psychiatry 1996; 57:441-448.
  66. BielMG, et al. Continuation versus discontinuation of lithium in recurrent bipolar illness: a naturalistic study. Bipolar Disord 2007; 9:435-442.
  67. SajatovicM, et al. Treatment adherence with lithium and anticonvulsant medications among patients with bipolar disorder. Psychiatr Serv 2007; 58:855-863.
  68. PatonC, et al. Lithium in bipolar and other affective disorders: prescribing practice in the UK. J Psychopharmacol 2010; 24:1739-1746.
  69. KessingLV, et al. Suicide risk in patients treated with lithium. Arch Gen Psychiatry 2005; 62:860-866.
  70. Pharmaceutical Press. Medicines Complete 2024; https://www.pharmaceuticalpress.com/services/medicinescomplete/.
  71. JuurlinkDN, et al. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc 2004; 52:794-798.
  72. FinleyPR. Drug interactions with lithium: an update. Clin Pharmacokinet 2016; 55:925-941.
  73. NettoI, et al. Lithium neurotoxicity due to second-generation antipsychotics combined with lithium: a systematic review. Prim Care Companion CNS Disord 2019; 21:17r02225.
  74. KoniecznyK, et al. The syndrome of irreversible lithium-effectuated neurotoxicity: a scoping review. Alpha Psychiatry 2024; 25:190-205.
  75. Kohler-ForsbergO, et al. Nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol do not affect 6-month mood-stabilizing treatment outcome among 482 patients with bipolar disorder. Depress Anxiety 2017; 34:281-290.