Lithium as a Mood Stabilizer: Evidence Across Psychiatric Disorders

Abstract

Lithium has remained a cornerstone of mood stabilization for over half a century, primarily in bipolar disorder. Increasing evidence suggests its therapeutic benefits extend across multiple psychiatric conditions. Despite advances in psychopharmacology, lithium continues to occupy a unique position due to its efficacy, neuroprotective potential, and anti-suicidal properties. This review aims to synthesize the available evidence on lithium as a mood stabilizer across psychiatric disorders, highlighting its clinical efficacy, underlying mechanisms, and therapeutic relevance beyond bipolar disorder. A systematic search of PubMed, Scopus, and Web of Science databases was conducted to identify clinical trials, meta-analyses, and observational studies from 1990 to 2025. Studies evaluating lithium in bipolar disorder, major depressive disorder, schizoaffective disorder, and related psychiatric conditions were included. Findings were categorized by disorder and outcome measures. Lithium demonstrates robust efficacy in preventing relapse and stabilizing mood in bipolar disorder. Evidence also supports its augmentation role in treatment-resistant depression and its potential in schizoaffective disorder. Long-term use is associated with reduced suicide risk, independent of diagnosis. Emerging data indicate possible benefits in borderline personality disorder and neuroprotective effects in neuropsychiatric populations. However, concerns remain regarding side effects, narrow therapeutic index, and declining clinical use. Lithium remains the most evidence-based mood stabilizer across psychiatric disorders, with proven efficacy and unique anti-suicidal properties. Broader clinical application and renewed research may reinforce its role as a transdiagnostic treatment.

Keywords

Lithium, Mood Stabilizer, Bipolar Disorder, Major Depression, Schizoaffective Disorder, Suicide Prevention, Neuroprotection, Borderline Personality Disorder, Pharmacotherapy, Psychiatry

Introduction

Peak plasma concentrations of lithium are reached in 1-3 hours for immediate-release formulations and a little longer for sustained-release formulations due to the quick absorption of lithium from the gastrointestinal tract^14,15. With a volume of distribution of roughly 0.6–0.9 L/kg¹⁶, distribution mostly takes place in total body water. Lithium has predictable kinetics since it is not protein-bound and does not undergo hepatic metabolism like the majority of psychotropic drugs do¹⁷. Nearly all excretion occurs in the kidneys, with sodium transport routes reabsorbing 80% of it in the proximal tubules¹⁸. This explains why the therapeutic index is narrow (0.6–1.2 mmol/L for maintenance) and why frequent serum monitoring is necessary to prevent toxicity, especially in patients with renal impairment or abnormalities of sodium balance^19,20.

Molecular Targets

A number of intracellular processes related to mood regulation are impacted by lithium. Lithium inhibits inositol monophosphates, which lowers inositol recycling and weakens phosphatidylinositol signalling cascades, according to the inositol depletion hypothesis^21,22. At the same time, lithium suppresses GSK-3, a serine/threonine kinase involved in neural plasticity, apoptosis, and circadian regulation^23,24. Lithium alters neuroplasticity, neurotransmission, and stress response pathways by inhibiting GSK-3²⁵. Lithium also contributes to long-term neuronal survival by controlling calcium signalling, improving mitochondrial function, and reducing oxidative stress^26,27.

Neurotrophic and Neuroprotective Effects

By increasing brain-derived neurotrophic factor (BDNF), which improves synaptic resilience and neuronal survival, long-term lithium therapy produces neurotrophic effects²⁸. Gray matter volume preservation has been repeatedly shown in neuroimaging investigations, especially in the prefrontal cortex and hippocampus, areas linked to mood regulation and cognitive control^29,30. To further support its neuroprotective profile, lithium also decreases inflammatory signalling and increases the expression of anti-apoptotic genes³¹. These results imply that lithium may alter the course of sickness by maintaining brain structure and function in addition to providing immediate mood stabilization³².

Mood Stabilization and Suicidality Reduction

Lithium's strong therapeutic effectiveness is based on the combination of these pharmacological and neurobiological effects. Lithium has the unique ability to lower the risk of suicide, which is not always the case with other mood stabilizers or antidepressants, in addition to reducing manic and depressed episodes³³. According to meta-analyses, lithium lowers suicide rates by over 60% without affecting mood stability. This may be due to neuroprotection, serotonergic modulation, and a decrease in impulsive-aggressive behaviors^32,33.

Lithium's pharmacological profile thus demonstrates why it continues to be the "gold standard" mood stabilizer, providing the ability to both regulate symptoms and change disease. Its many different mechanisms set it apart from other psychotropics and keep researchers interested in it.

Evidence in Bipolar Disorder

Acute Mania

Lithium remains the prototypical mood stabilizer in bipolar disorder and has been extensively studied for more than five decades. Its efficacy in acute mania, both as monotherapy and in combination with other agents, is well documented. Furthermore, lithium has been compared with other standard treatments such as valproate, carbamazepine, and antipsychotics, highlighting its central role in the management of acute manic episodes.

Efficacy in Monotherapy and Adjunctive Use

Clinical trials consistently demonstrate that lithium is effective in reducing manic symptoms when used as monotherapy. Early placebo-controlled studies confirmed its superiority over placebo in reducing acute manic symptoms within one to two weeks of initiation³⁴. Furthermore, adjunctive use of lithium with antipsychotics such as haloperidol or atypical antipsychotics enhances clinical response, especially in severe manic episodes³⁵. The combination approach is often adopted in clinical practice, where rapid symptom control is required³⁶.

Comparative Trials

Lithium vs Valproate

Lithium has been compared extensively with valproate in acute mania. While both agents are effective, several trials suggest that lithium may be more potent in classic euphoric mania, whereas valproate may have relative advantages in mixed states and rapid cycling³⁷. The BALANCE trial confirmed lithium’s superiority over valproate in relapse prevention, though acute efficacy was generally similar³⁸.

Lithium vs Carbamazepine

Carbamazepine, another anticonvulsant with mood-stabilizing properties, has been evaluated against lithium. Comparative trials demonstrate broadly similar efficacy, though lithium appears to have a faster onset of action in acute mania³⁹. Carbamazepine may be better tolerated in some patients, but it is generally reserved for second-line use due to drug–drug interactions and tolerability issues⁴⁰.

Lithium vs Antipsychotics

Antipsychotics, both typical and atypical, are highly effective in acute mania and often provide faster symptom relief than lithium alone. However, head-to-head trials indicate that lithium is comparable in efficacy over several weeks, though antipsychotics achieve more rapid sedation and agitation control⁴¹. Lithium is frequently combined with antipsychotics to optimize both rapid symptom relief and long-term stabilization⁴².

Bipolar Disorder

The role of lithium in bipolar depression has been widely studied, though evidence presents mixed results. While lithium is a cornerstone in mania prevention, its efficacy in acute bipolar depression is less robust. Early controlled trials indicated some benefit, but effect sizes were modest compared to its strong prophylactic effects against mania⁴³.

Monotherapy studies often report limited efficacy of lithium in treating acute depressive episodes in bipolar disorder⁴⁴. Meta-analyses show that while lithium can reduce depressive symptoms in some patients, response rates are generally lower than for manic symptoms⁴⁵. This has led to the frequent use of augmentation strategies, such as combining lithium with antidepressants or anticonvulsants⁴⁶.

The STEP-BD study found that adding antidepressants to a mood stabilizer, including lithium, did not significantly improve outcomes compared with mood stabilizer monotherapy⁴⁷. However, lithium continues to play a role in combination strategies, particularly when augmentation with selective serotonin reuptake inhibitors (SSRIs) or bupropion is attempted⁴⁸.

Lamotrigine has shown superiority over lithium in preventing depressive relapses, although lithium remains more effective against manic recurrence⁴⁹. The balance between these agents highlights the need for individualized treatment approaches, where lithium may serve as a base therapy complemented by other agents to address depressive polarity.

Importantly, lithium’s role extends beyond acute symptom relief. Long-term studies suggest lithium reduces recurrence of depressive episodes and contributes to overall stability, particularly when compared to placebo or some anticonvulsants⁵⁰. Furthermore, its unique anti-suicidal effect provides additional justification for its continued use in patients with predominant depressive polarity⁵¹.

Maintenance Therapy

Lithium remains the gold standard for maintenance therapy in bipolar disorder, with decades of evidence supporting its role in preventing relapse into both mania and depression⁵². Its unique position among mood stabilizers is reinforced by long-term studies and meta-analyses showing superior prophylactic efficacy and improvement in long-term outcomes⁵³.

One of lithium’s greatest strengths is its ability to reduce recurrence of both poles of illness. Early trials demonstrated lithium’s superiority over placebo in preventing manic relapses, and subsequent studies confirmed its benefit in preventing depressive recurrences as well⁵⁴. Comparative studies highlight that while anticonvulsants such as carbamazepine and valproate are effective, lithium shows more consistent results across both mania and depression⁵⁵.

The BALANCE trial provided robust evidence that lithium monotherapy was more effective than valproate monotherapy in preventing relapse, with combination therapy offering the strongest protection⁵⁶. Similarly, long-term trials comparing lithium and lamotrigine suggest that lithium is particularly effective against manic recurrence, while lamotrigine may have a stronger effect against depressive relapse⁵⁷. This underlines the importance of individualized treatment strategies, but positions lithium as the foundation for maintenance therapy.

Long-term outcomes with lithium are favorable. Patients maintained on lithium demonstrate fewer hospitalizations, longer time to recurrence, and better functional recovery compared with those treated with other mood stabilizers⁵⁸. Additionally, lithium’s protective effect against suicide contributes significantly to improved mortality outcomes⁵⁹.

Evidence also suggests benefits beyond bipolar disorder. In recurrent unipolar depression, lithium has been effective as a prophylactic agent and in reducing suicidal behavior⁶⁰. Population-based studies further emphasize lithium’s broad utility across mood disorders, reinforcing its status as a uniquely versatile treatment⁶¹.

Suicide Prevention

Among its many therapeutic properties, lithium has the strongest evidence base for suicide prevention in bipolar disorder and related mood disorders. Unlike other mood stabilizers, lithium has demonstrated consistent reductions in suicide risk across randomized controlled trials, long-term observational cohorts, and meta-analyses^62,63.

A landmark meta-analysis by Cipriani et al. found that lithium significantly reduced suicides and deliberate self-harm compared to placebo or other pharmacological agents⁶⁴. This effect was evident not only in bipolar disorder but also in recurrent unipolar depression, suggesting a broad protective mechanism. Subsequent systematic reviews reinforced this finding, showing lithium reduced suicide risk by nearly 60% compared with alternatives such as carbamazepine or valproate⁶⁵.

Population-based registry studies further confirm lithium’s unique anti-suicidal effect. For example, Baldessarini and colleagues reported substantially decreased suicide rates during long-term lithium treatment compared to periods off treatment⁶⁶. Kessing et al. found that lithium was associated with the lowest rates of suicidal behavior among all mood-stabilizing medications in large Danish registry cohorts⁶⁷.

The mechanism underlying lithium’s protective effect is not fully understood but may involve serotonergic modulation, reduction of impulsivity, and stabilization of affective dysregulation⁶⁸. Additionally, lithium’s role in recurrence prevention indirectly lowers suicide risk, as relapses into depressive or mixed states are strongly linked with suicidal behavior⁶⁹.

Importantly, lithium’s anti-suicidal efficacy has not been consistently replicated with other agents. Anticonvulsants such as valproate and lamotrigine lack comparable evidence, and atypical antipsychotics, while useful in mood stabilization, do not demonstrate the same reduction in suicide rates⁷⁰. This positions lithium as uniquely effective among psychiatric medications for suicide prevention.

Domain	Meta-Analytic Findings
Acute Mania (Bipolar I)	Lithium significantly superior to placebo; effect sizes comparable to antipsychotics, though slower onset.
Maintenance Therapy (Bipolar Disorder)	Lithium most effective single agent for relapse prevention (mania + depression); superior to valproate and carbamazepine.
Bipolar Depression	Limited acute efficacy; stronger effect in relapse prevention; often combined with lamotrigine or antidepressants.
Unipolar Depression (TRD)	Lithium augmentation increases remission rates (40–50% vs 14% placebo); accelerates antidepressant response.
Suicide Prevention	Lithium reduces suicide attempts and completions by >60%; effect independent of mood stabilization.
Comparative Effectiveness	Network meta-analyses confirm lithium’s superior balance of efficacy and long-term outcomes compared with other mood stabilizers.

Evidence in Major Depressive Disorder

Lithium is historically recognized as the gold standard in the treatment of bipolar disorder, but its role extends into unipolar major depressive disorder (MDD). In this context, lithium is most often used as an augmentation strategy in treatment-resistant depression (TRD), where first-line antidepressants fail to produce sufficient response. Over several decades, lithium has demonstrated robust evidence not only for symptom improvement but also for reducing suicidal risk in patients with unipolar depression⁷¹.

Lithium Augmentation in Treatment-Resistant Depression

Treatment-resistant depression, typically defined as non-response to at least two adequate antidepressant trials, presents a significant clinical challenge. Lithium augmentation is one of the best-validated strategies in this population⁷². Early randomized controlled trials (RCTs) demonstrated that lithium significantly improves response rates when combined with tricyclic antidepressants⁷³. Later research extended this efficacy to selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), making lithium augmentation a standard second-line approach in clinical guidelines⁷⁴.

The proposed mechanisms include modulation of serotonergic neurotransmission, regulation of glutamatergic signaling, and neuroprotective effects via glycogen synthase kinase-3 (GSK-3) inhibition⁷⁵. These mechanisms may explain lithium’s ability to potentiate antidepressant effects and promote mood stabilization even in unipolar depression.

Meta-Analyses: Effect Size and Remission Rates

Meta-analyses consistently support the efficacy of lithium augmentation. A meta-analysis by Bauer and Döpfmer reported a pooled response rate of 41.2% with lithium augmentation compared to 14.4% with placebo⁷⁶. Crossley and Bauer further confirmed that lithium provides both faster onset and higher remission rates compared to placebo when added to antidepressant therapy⁷⁷.

Subsequent systematic reviews reinforced these findings, reporting effect sizes in the moderate-to-large range, with remission rates often exceeding 40% among patients with TRD⁷⁸. Importantly, lithium appears to maintain its efficacy across different classes of antidepressants, suggesting a broad applicability as an augmentation agent⁷⁹.

Role in Reducing Suicidal Risk in Unipolar Depression

Lithium’s most distinctive benefit lies in its anti-suicidal properties. Suicide risk is significantly elevated in MDD, and long-term lithium treatment has been associated with marked reductions in both suicide attempts and deaths⁸⁰. A comprehensive meta-analysis by Cipriani et al. showed that lithium reduced suicide risk by more than 60% compared to placebo or alternative treatments⁸¹. This effect seems to extend beyond symptom relief, indicating a unique mechanism that directly influences suicidality.

Population-based studies confirm these findings, showing lower suicide rates in patients with unipolar depression treated with lithium compared to other mood stabilizers or antidepressants⁸². This property alone makes lithium a uniquely valuable option in MDD, especially for patients at high risk of suicide.

Clinical Implications

Despite strong evidence, lithium remains underutilized in MDD due to concerns about tolerability, narrow therapeutic index, and the need for serum monitoring. However, its proven efficacy in TRD, robust meta-analytic support, and unparalleled role in suicide prevention highlight its importance. Clinical guidelines consistently recommend lithium augmentation as a key second-line or third-line treatment in resistant depression, and as a first-line consideration in patients with elevated suicide risk⁸³.

Evidence Across Psychiatric Disorders

• Schizoaffective Disorder

Lithium has mostly been utilized as a mood stabilizer for people with schizoaffective disorder who exhibit strong emotional characteristics.  When used alongside antipsychotic medicine, lithium has been shown in clinical trials to enhance the control of affective symptoms.  Lithium augmentation in schizoaffective disorder, especially the manic subtype, has been linked to improved mood stabilization and decreased relapse risk, according to controlled studies^84-85.  Instead of being used as a monotherapy, this evidence supports its use as an adjuvant treatment for neuroleptics.                           

• Schizophrenia

Lithium plays a smaller part in schizophrenia.  Systematic reviews and meta-analyses reveal no consistent impact on functional outcomes^86-87 and no improvement in core psychotic symptoms.  Lithium has, however, demonstrated modest but clinically significant reductions in mood lability, aggressiveness, and hostility in schizophrenia patients with high levels of impulsivity or behavioral dysregulation⁸⁸.  Lithium is therefore not advised for the regular treatment of schizophrenia, but it may be taken into consideration as an adjuvant in some situations.

• Borderline Personality Disorder (BPD)

Additionally, lithium has been researched in relation to borderline personality disorder (BPD), focusing on affective instability, aggression, and impulsivity.  Lithium use has been linked to decreases in hostile and self-harming behaviors, according to preliminary controlled research⁸⁹.  Subsequent evaluations, however, revealed inconsistent and conflicting results, with small study numbers and methodological problems restricting generalizability⁹⁰.  As a result, lithium is not regarded as a conventional treatment for BPD; nonetheless, it might be a viable alternative for patients who are resistant to treatment and exhibit significant impulsivity or violence.

• Other Psychiatric and Neurological Disorders

Lithium has been tested for a number of ailments besides mood and psychotic disorders, including:

Treatment-resistant OCD: Lithium augmentation with SSRIs or clomipramine was investigated in small controlled studies.  The evidence is still weak and contradictory generally, even though some patients saw slight improvements⁹¹.

Cluster Headaches: Studies have shown that lithium is effective in lowering the frequency of attacks, especially in chronic cluster headache subtypes.  Although early observational studies indicated significant clinical benefit, widespread use is limited by side effects and narrow therapeutic margins⁹².

Adverse Effects, Monitoring, and Challenges

• Acute Toxicities

Lithium is known to have a number of acute adverse effects, even when taken within prescribed limits.  These include the most often reported gastrointestinal disturbances (diarrhea, vomiting, and nausea), fine tremor, and polyuria/polydipsia⁹³.  Serum levels above 1.5 mmol/L cause clinical signs of toxicity, such as lethargy, ataxia, disorientation, dysarthria, and coarse tremor⁹⁴.  If severe intoxication is not treated right once, it can cause seizures, unconsciousness, and even death (>2.5 mmol/L)⁹⁵.  NSAIDs, ACE inhibitors, thiazide diuretics, and renal impairment increase the risk of these toxicities, as does dehydration⁹⁶.

• Chronic Toxicities

Long-term lithium use has been associated with negative consequences on multiple systems.

Effect on the endocrine system: Long-term users and women are more likely to develop hypothyroidism as a result of lithium's interference with the production and release of thyroid hormones⁹⁷. Additionally, reports of hyperparathyroidism and hypercalcemia have been made⁹⁸.

Long-term treatment raises the risk of chronic renal disease, tubulointerstitial nephropathy, and decreased concentration⁹⁹. Early onset and persistence of polyuria and nephrogenic diabetic insipidus are possible¹⁰⁰.

Weight gain has been linked to lithium use, which has a detrimental influence on long-term results and adherence¹⁰¹.

Effects on the nervous system and skin: Some patients have experienced memory problems, acne, psoriasis flare-ups, and cognitive slowing¹⁰².

These toxicities highlight the significance of ongoing observation and prompt problem identification.

• Monitoring Requirements

Lithium has a limited therapeutic window, therefore careful and ongoing monitoring is crucial.  According to current recommendations,

Serum lithium levels should be monitored every three to six months after starting or changing a dose, and then every five to seven days until they stabilize¹⁰³.

Serum creatinine, eGFR, and urinalysis are examples of renal function tests that should be performed at baseline and subsequently every 6 to 12 months, or more frequently in older or at-risk populations¹⁰⁴.

Given the high prevalence of hypothyroidism, thyroid function tests (TSH, free T4) should be performed at baseline and at least once a year¹⁰⁵.

Parathyroid hormone and calcium: sometimes, particularly during long-term treatment¹⁰⁶.

One of the most practical issues in clinical settings, particularly when resources are scarce, is this monitoring load.

• Barriers to Widespread Use

Lithium is still underutilized globally despite a solid body of research supporting it.

Physician hesitancy: A lot of psychiatrists are reluctant to prescribe lithium because they are worried about its toxicity, the possibility of legal action, and the availability of substitutes¹⁰⁷.

Patient adherence: Adherence is greatly decreased by side effects like weight gain, polyuria, and tremor, as well as the inconvenience of repeated blood tests¹⁰⁸.

Pharmaceutical dynamics: Despite lithium's unparalleled long-term advantages, the marketing of more recent mood stabilizers and atypical antipsychotics has helped to reduce its use¹⁰⁹

Limitations in resources: Lithium is less practical than alternatives in low-resource environments because frequent monitoring infrastructure may not be possible¹¹⁰.

FUTURE DIRECTIONS

Even after decades of therapeutic practice, there are still a number of unanswered questions on how to best understand and utilize lithium's function as a mood stabilizer for a variety of mental illnesses. Finding trustworthy biomarkers to forecast treatment response, recurrence risk, and unfavourable outcomes is one of the most urgent needs¹¹¹. Developments in neuroimaging and genetics could lead to the discovery of molecular signals unique to each patient that account for lithium responsiveness¹¹². Lithium's molecular mechanisms, such as its impact on neurotrophic factors, inflammation, and circadian control, also need further investigation to elucidate how these pathways support mood stabilization¹¹³.

Another issue that needs careful investigation is long-term safety monitoring. Lithium is well known, but large-scale prospective studies with standardized outcome reporting are necessary due to concerns about renal, thyroid, and cognitive effects¹¹⁴. The development of new formulations, including targeted delivery systems or sustained-release preparations, may be able to lower toxicity without sacrificing therapeutic efficacy¹¹⁵.

The use of lithium in precision psychiatry is a new area of study. By combining clinical, genetic, and digital health data, it may be possible to identify patients who will benefit from lithium the most while reducing exposure in non-responders¹¹⁶. Another promising tactic for enhancing therapeutic results is the use of digital tools and mobile health platforms to track blood levels, adherence, and early warning indicators of relapse¹¹⁷.

Future studies should compare lithium's efficacy to that of more recent mood stabilizers and adjunctive therapies, particularly in populations with conditions other than bipolar disorder, like schizoaffective disorder and treatment-resistant unipolar depression¹¹⁸. Since no other mood stabilizer has shown such strong effects, it is especially important to increase study into lithium's anti-suicidal qualities¹¹⁹. Lastly, to guarantee consistent clinical use, monitoring, and integration into individualized treatment frameworks, cooperative efforts are required to create international recommendations and standardized protocols¹²⁰.

CONCLUSION

Lithium continues to be one of the most reliable and long-lasting mood stabilizers, with strong prophylactic effects for bipolar disorder and increasing evidence for other mental illnesses such major depressive disorder, schizoaffective disorder, and suicidality¹²¹. Lithium's capacity to lower suicide risk and relapse rates is unmatched, even with the advent of more recent medications¹²². Preclinical and clinical investigations have also shown its neuroprotective qualities, emphasizing effects on oxidative stress, neurogenesis, and cellular resilience¹²³. As a result, lithium is being investigated as a possible supplemental treatment for neurodegenerative diseases like Parkinson's and Alzheimer's disease¹²⁴. However, the medication's limited therapeutic range and potential for thyroid, renal, and metabolic issues make careful observation necessary¹²⁵. Patient adherence is still a problem, which emphasizes the necessity of digital tools, education, and streamlined formulations to maximize long-term results¹²⁶.

Recent developments in pharmacogenetics raise the possibility that genetic and molecular markers could predict treatment response to some extent, opening the door to customized lithium use in precision psychiatry¹²⁷. However, despite the growing usage of atypical antipsychotics and anticonvulsants, comparative efficacy studies continue to support lithium's utility as a first-line treatment for mood disorders¹²⁸.

Lithium is distinguished from other mood stabilizers and antidepressants by its distinct anti-suicidal properties, which are consistently supported by the evidence base¹²⁹. Stronger clinical recommendations, better monitoring techniques, and fair access to lithium therapy especially in low-resource settings all depend on ongoing international cooperation¹³⁰.

To sum up, lithium remains a key component in the management of mental and emotional illnesses. Advances in precision psychiatry, digital monitoring, and biomarker identification provide promise for enhancing its usage in future clinical practice, even though safety management and patient selection still present problems.

REFERENCES

1. Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2(10):349-52. Available from: https://pubmed.ncbi.nlm.nih.gov/18142718/
2. Shorter E. The history of lithium therapy. Bipolar Disord. 2009;11 Suppl 2:4-9. Available from: https://doi.org/10.1111/j.1399-5618.2009.00706.x
3. Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. 2nd ed. New York: Oxford University Press; 2007. Available from: https://global.oup.com/academic/product/manic-depressive-illness-9780195135794
4. Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672-82. Available from: https://doi.org/10.1016/S0140-6736(13)60857-0
5. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. Available from: https://www.bmj.com/content/346/bmj.f3646
6. Nierenberg AA, Friedman ES, Bowden CL, Sylvia LG, Thase ME, Ketter TA, et al. Lithium: still a major option in bipolar disorder treatment. Int J Bipolar Disord. 2018;6:15. Available from: https://doi.org/10.1186/s40345-018-0120-x
7. Malhi GS, Tanious M, Das P, Coulston CM, Berk M. The science and practice of lithium therapy. Int J Bipolar Disord. 2017;5:15. Available from: https://doi.org/10.1186/s40345-017-0086-x
8. Rybakowski JK. Lithium in neuropsychiatry: a 2021 update. World J Psychiatry. 2021;11(5):139-50. Available from: https://doi.org/10.5498/wjp.v11.i5.139
9. Forlenza OV, De-Paula VJR, Diniz BS. Lithium as a neuroprotective agent for Alzheimer’s disease: translational evidence and clinical implications. CNS Drugs. 2014;28(1):1-9. Available from: https://doi.org/10.1007/s40263-013-0125-0
10. Bauer M, Gitlin M. Lithium in the treatment of major depressive disorder. CNS Drugs. 2016;30(4):331-42. Available from: https://doi.org/10.1007/s40263-016-0325-2
11. Hayes JF, Marston L, Walters K, Geddes JR, King M, Osborn DPJ. Lithium vs. valproate vs. olanzapine in maintenance therapy of bipolar disorder: real-world outcomes. JAMA Psychiatry. 2016;73(6):614-23. Available from: https://doi.org/10.1001/jamapsychiatry.2016.0432
12. Severus E, Taylor MJ, Sauer C, Pfennig A, Ritter P, Bauer M, et al. Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord. 2014;2:15. Available from: https://doi.org/10.1186/s40345-014-0015-8
13. Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and ISBD 2018 guidelines for management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170. Available from: https://doi.org/10.1111/bdi.12609
14. Grandjean EM, Aubry JM. Lithium: updated human knowledge using an evidence-based approach. CNS Drugs. 2009;23(3):225-40. Available from: https://doi.org/10.2165/00023210-200923030-00003
15. Malhi GS, Tanious M, Das P, Coulston CM, Berk M. The science and practice of lithium therapy. Int J Bipolar Disord. 2017;5:15. Available from: https://doi.org/10.1186/s40345-017-0086-x
16. Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar Disord. 2016;4:27. Available from: https://doi.org/10.1186/s40345-016-0068-y
17. Severus E, Taylor MJ, Sauer C, Pfennig A, Ritter P, Bauer M, et al. Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord. 2014;2:15. Available from: https://doi.org/10.1186/s40345-014-0015-8
18. McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379(9817):721-8. Available from: https://doi.org/10.1016/S0140-6736(11)61516-X
19. Shine B, McKnight RF, Leaver L, Geddes JR. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis. Lancet. 2015;386(9992):461-8. Available from: https://doi.org/10.1016/S0140-6736(14)61842-0
20. Kessing LV, Gerds TA, Feldt-Rasmussen B, Andersen PK, Licht RW. Lithium and renal dysfunction: a cohort study with up to 20 years follow-up. Psychol Med. 2015;45(4):867-74. Available from: https://doi.org/10.1017/S0033291714001951
21. Berridge MJ, Downes CP, Hanley MR. Neural and developmental actions of lithium: a unifying hypothesis. Cell. 1989;59(3):411-9. Available from: https://doi.org/10.1016/0092-8674(89)90026-3
22. Harwood AJ. Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited. Mol Psychiatry. 2005;10(1):117-26. Available from: https://doi.org/10.1038/sj.mp.4001618
23. O’Brien WT, Klein PS. Validating GSK3 as an in vivo target of lithium action. Biochem Soc Trans. 2009;37(Pt 5):1133-8. Available from: https://doi.org/10.1042/BST0371133
24. Beurel E, Grieco SF, Jope RS. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther. 2015;148:114-31. Available from: https://doi.org/10.1016/j.pharmthera.2014.11.016
25. Chiu CT, Chuang DM. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther. 2010;128(2):281-304. Available from: https://doi.org/10.1016/j.pharmthera.2010.07.006
26. Rowe MK, Chuang DM. Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med. 2004;6(21):1-18. Available from: https://doi.org/10.1017/S1462399404008042
27. Quiroz JA, Gould TD, Manji HK. Molecular effects of lithium. Mol Interv. 2004;4(5):259-72. Available from: https://doi.org/10.1124/mi.4.5.6
28. Machado-Vieira R, Manji HK, Zarate CA. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects. Bipolar Disord. 2009;11 Suppl 2:92-109. Available from: https://doi.org/10.1111/j.1399-5618.2009.00714.x
29. Hajek T, Bauer M, Simhandl C, Rybakowski J, O’Donovan C, Pfennig A, et al. Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder: a multicenter study. Biol Psychiatry. 2014;76(5):356-62. Available from: https://doi.org/10.1016/j.biopsych.2013.11.026
30. Lyoo IK, Dager SR, Kim JE, Yoon SJ, Friedman SD, Dunner DL, et al. Lithium-induced gray matter volume increase: a longitudinal study. Neuropsychopharmacology. 2010;35(8):1743-50. Available from: https://doi.org/10.1038/npp.2010.41
31. Berk M, Dodd S, Kauer-Sant’Anna M, Malhi GS, Bourin M, Kapczinski F, et al. Dopamine dysregulation syndrome: implications for lithium’s mechanisms. Aust N Z J Psychiatry. 2007;41(5):407-14. Available from: https://doi.org/10.1080/00048670701266696
32. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated meta-analysis. BMJ. 2013;346:f3646. Available from: https://www.bmj.com/content/346/bmj.f3646
33. Smith KA, Cipriani A. Lithium and suicide in mood disorders: updated meta-review. Bipolar Disord. 2017;19(7):575-86. Available from: https://doi.org/10.1111/bdi.12543
34. wann AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, et al. Depression during mania. Treatment response to lithium or divalproex. Am J Psychiatry. 1997;154(10):1468-74. https://doi.org/10.1176/ajp.154.10.1468
35. Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA. 1994;271(12):918-24. https://doi.org/10.1001/jama.1994.03510360046034
36. Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments in acute mania: a systematic review and meta-analysis. Bipolar Disord. 2015;17 Suppl 2:1-18. https://doi.org/10.1111/bdi.12380
37. Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients. Arch Gen Psychiatry. 2003;60(4):392-400. https://doi.org/10.1001/archpsyc.60.4.392
38. Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, Ostacher MJ, et al. Lithium plus valproate combination therapy vs monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375(9712):385-95. https://doi.org/10.1016/S0140-6736(09)61828-6
39. Hartong EG, Moleman P, Hoogendoorn AW, Broekman TG, Nolen WA. Prophylactic efficacy of lithium vs carbamazepine in bipolar disorder: a randomized, open trial. J Clin Psychiatry. 2003;64(4):383-90. https://doi.org/10.4088/JCP.v64n0404
40. Lerer B, Moore N, Meyendorff E, Cho SR, Gershon S. Carbamazepine vs lithium in mania: a double-blind study. Arch Gen Psychiatry. 1987;44(9):872-5. https://doi.org/10.1001/archpsyc.1987.01800210052006
41. Sachs GS, Grossman F, Ghaemi SN, Okamoto A, Bowden CL. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison. Arch Gen Psychiatry. 2000;57(6):593-600. https://doi.org/10.1001/archpsyc.57.6.593
42. Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KNR, Daniel DG, et al. Olanzapine vs placebo in the treatment of acute mania. Am J Psychiatry. 1999;156(5):702-9. https://doi.org/10.1176/ajp.156.5.702
43. Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672-82. https://doi.org/10.1016/S0140-6736(13)60857-0
44. Tondo L, Baldessarini RJ, Hennen J. Lithium treatment and risk of depressive recurrence in bipolar disorder. Am J Psychiatry. 1998;155(5):638-40. https://doi.org/10.1176/ajp.155.5.638
45. Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments in acute mania: a systematic review and meta-analysis. Bipolar Disord. 2015;17 Suppl 2:1-18. https://doi.org/10.1111/bdi.12380
46. Bauer M, Adli M, Ricken R, Severus E, Pilhatsch M. Role of lithium augmentation in the management of major depressive disorder. CNS Drugs. 2014;28(4):331-42. https://doi.org/10.1007/s40263-014-0152-2
47. Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-22. https://doi.org/10.1056/NEJMoa064135
48. Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel I, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158(6):906-12. https://doi.org/10.1176/appi.ajp.158.6.906
49. Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients. Arch Gen Psychiatry. 2003;60(4):392-400. https://doi.org/10.1001/archpsyc.60.4.392
50. Kessing LV, Vradi E, Andersen PK. Nationwide and population-based prescription patterns in bipolar disorder. Bipolar Disord. 2016;18(2):174-82. https://doi.org/10.1111/bdi.12380
51. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. https://doi.org/10.1136/bmj.f3646
52. RGoodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. 2nd ed. Oxford: Oxford University Press; 2007    https://global.oup.com/academic/product/manic-depressive-illness-9780195135794
53. Müller-Oerlinghausen B, Berghöfer A, Bauer M. Bipolar disorder. Lancet. 2002;359(9302):241-7. https://doi.org/10.1016/S0140-6736(02)07450-0
54. Coppen A, Noguera R, Bailey J, Burns BH, Swani MS, Hare EH. Prophylactic lithium in affective disorders: controlled trial. Lancet. 1971;297(7705):275-9. https://doi.org/10.1016/S0140-6736(71)92352-6
55. Hartong EG, Moleman P, Hoogendoorn AW, Broekman TG, Nolen WA. Prophylactic efficacy of lithium vs carbamazepine in bipolar disorder: a randomized, open trial. J Clin Psychiatry. 2003;64(4):383-90. https://doi.org/10.4088/JCP.v64n0404
56. Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, Ostacher MJ, et al. Lithium plus valproate combination therapy vs monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375(9712):385-95. https://doi.org/10.1016/S0140-6736(09)61828-6
57. Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients. Arch Gen Psychiatry. 2003;60(4):392-400. https://doi.org/10.1001/archpsyc.60.4.392
58. Kessing LV, Vradi E, Andersen PK. Nationwide and population-based prescription patterns in bipolar disorder. Bipolar Disord. 2016;18(2):174-82. https://doi.org/10.1111/bdi.12380
59. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. https://doi.org/10.1136/bmj.f3646
60. Bauer M, Adli M, Ricken R, Severus E, Pilhatsch M. Role of lithium augmentation in the management of major depressive disorder. CNS Drugs. 2014;28(4):331-42. https://doi.org/10.1007/s40263-014-0152-2
61. Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord. 2006;8(5 Pt 2):625-39. https://doi.org/10.1111/j.1399-5618.2006.00344.x
62. Tondo L, Hennen J, Baldessarini RJ. Lower suicide risk with long-term lithium treatment in major affective illness: a meta-analysis. Acta Psychiatr Scand. 2001;104(3):163-72. https://doi.org/10.1034/j.1600-0447.2001.00291.x
63. Müller-Oerlinghausen B, Berghöfer A, Bauer M. Bipolar disorder. Lancet. 2002;359(9302):241-7. https://doi.org/10.1016/S0140-6736(02)07450-0 
64. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. https://doi.org/10.1136/bmj.f3646
65. Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord. 2006;8(5 Pt 2):625-39. https://doi.org/10.1111/j.1399-5618.2006.00344.x
66. Baldessarini RJ, Tondo L. Suicidal risks during treatment of bipolar disorder patients with lithium vs anticonvulsants. Pharmacopsychiatry. 2009;42(2):72-5. https://doi.org/10.1055/s-0028-1103292
67. Kessing LV, Søndergård L, Kvist K, Andersen PK. Suicide risk in patients treated with lithium. Arch Gen Psychiatry. 2005;62(8):860-6. https://doi.org/10.1001/archpsyc.62.8.860
68. Oquendo MA, Currier D, Mann JJ. Prospective studies of suicidal behavior in major depressive and bipolar disorders: what is the evidence for predictive risk factors? Acta Psychiatr Scand. 2006;114(3):151-8. https://doi.org/10.1111/j.1600-0447.2006.00829.x
69. Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. 2nd ed. New York: Oxford University Press; 2007. https://global.oup.com/academic/product/manic-depressive-illness-9780195135794
70. Song J, Sjölander A, Joas E, Bergen SE, Runeson B, Larsson H, et al. Suicidal behavior during lithium and valproate treatment: a within-individual 8-year prospective study of 50,000 patients with bipolar disorder. Am J Psychiatry. 2017;174(8):795-802. https://doi.org/10.1176/appi.ajp.2017.16050542
71. Bauer M, Adli M, Ricken R, Severus E, Pilhatsch M. Role of lithium augmentation in the management of major depressive disorder. CNS Drugs. 2014;28(4):331-42. https://doi.org/10.1007/s40263-014-0152-2
72. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller HJ. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for unipolar depressive disorders. World J Biol Psychiatry. 2013;14(5):334-85. https://doi.org/10.3109/15622975.2013.804195
73. de Montigny C, Cournoyer G, Morissette R, Chaput Y. Lithium carbonate addition in tricyclic antidepressant-resistant depression. Arch Gen Psychiatry. 1983;40(12):1327-34. https://doi.org/10.1001/archpsyc.1983.01790110097012
74. Nelson JC, Baumann P, Delucchi K, Joffe R, Katona C. Lithium augmentation in antidepressant-resistant patients: a double-blind, placebo-controlled study. J Clin Psychiatry. 2014;75(8):e892-8. https://doi.org/10.4088/JCP.13m08911
75. Machado-Vieira R, Manji HK, Zarate CA Jr. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord. 2009;11(Suppl 2):92-109. https://doi.org/10.1111/j.1399-5618.2009.00714.x
76. Bauer M, Döpfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol. 1999;19(5):427-34. https://doi.org/10.1097/00004714-199910000-00006
77. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry. 2007;68(6):935-40. https://doi.org/10.4088/JCP.v68n0611
78. Bauer M, Adli M, Ricken R. Lithium augmentation in depression: clinical evidence and neurobiological mechanisms. Aust N Z J Psychiatry. 2014;48(9):808-18. https://doi.org/10.1177/0004867414533836
79. Undurraga J, Baldessarini RJ. Randomized, placebo-controlled trials of antidepressants for acute major depression: thirty-year meta-analytic review. Neuropsychopharmacology. 2012;37(4):851-64. https://doi.org/10.1038/npp.2011.306
80. Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord. 2006;8(5 Pt 2):625-39. https://doi.org/10.1111/j.1399-5618.2006.00344.x
81. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. https://doi.org/10.1136/bmj.f3646
82. Kessing LV, Søndergård L, Kvist K, Andersen PK. Suicide risk in patients treated with lithium. Arch Gen Psychiatry. 2005;62(8):860-6. https://doi.org/10.1001/archpsyc.62.8.860    
83. Malhi GS, Bell E, Boyce P, Bassett D, Berk M, Bryant R, et al. The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2021;55(1):7-117. https://doi.org/10.1177/0004867420979353
84. Maj M, Pirozzi R, Bartoli L, Bucci P. Lithium and neuroleptics in schizoaffective disorder: a controlled study. Acta Psychiatr Scand. 1992;85(2):114-8. Available from: https://doi.org/10.1111/j.1600-0447.1992.tb01451.x
85. Keck PE, McElroy SL, Strakowski SM. Antipsychotics and mood stabilizers in schizoaffective disorder. J Clin Psychiatry. 1996;57 Suppl 9:17-24. Available from: https://pubmed.ncbi.nlm.nih.gov/8909320/
86. Leucht S, Kissling W, McGrath J. Lithium for schizophrenia revisited: a systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry. 2004;65(12):1776-84. Available from: https://doi.org/10.4088/JCP.v65n1212
87. Kane JM, Rifkin A, Quitkin F, Nayak D, Ramos-Lorenzi J, Howard A. Lithium in the treatment of schizophrenia. Arch Gen Psychiatry. 1982;39(7):769-76. Available from: https://doi.org/10.1001/archpsyc.1982.04290070017002
88. Sheard MH. Lithium and the reduction of aggression and hostility in schizophrenia. Am J Psychiatry. 1975;132(4):442-6. Available from: https://doi.org/10.1176/ajp.132.4.442
89. Links PS, Steiner M, Boiago I. Lithium therapy for borderline patients: preliminary findings. J Pers Disord. 1990;4(2):173-81. Available from: https://doi.org/10.1521/pedi.1990.4.2.173
90. Stein G. Lithium in the treatment of borderline personality disorder: review and commentary. J Pers Disord. 1992;6(3):238-46. Available from: https://doi.org/10.1521/pedi.1992.6.3.238
91. McDougle CJ, Goodman WK, Leckman JF, Barr LC, Price LH. Lithium augmentation in fluvoxamine-refractory obsessive-compulsive disorder: a controlled trial. J Clin Psychopharmacol. 1991;11(3):190-5. Available from: https://doi.org/10.1097/00004714-199106000-00009
92. Ekbom K, Waldenlind E. Lithium treatment in cluster headache: a review of 50 patients. Cephalalgia. 1981;1(2):71-7. Available from: https://doi.org/10.1046/j.1468-2982.1981.0102071.x
93. Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar Disord. 2016;4(1):27. https://doi.org/10.1186/s40345-016-0068-y
94. McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379(9817):721–8. https://doi.org/10.1016/S0140-6736(11)61516-X
95. Amdisen A. Clinical features and management of lithium poisoning. Med Toxicol Adverse Drug Exp. 1988;3(1):18–32. https://doi.org/10.1007/BF03259819
96. Sproule BA. Lithium in bipolar disorder: can drug interactions compromise therapeutics? J Psychiatry Neurosci. 2002;27(5):331–6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC161702/
97. Bocchetta A, Loviselli A. Lithium treatment and thyroid abnormalities. Clin Pract Epidemiol Ment Health. 2006;2:23. https://doi.org/10.1186/1745-0179-2-23
98. Albert U, De Cori D, Aguglia A, Barbaro F, Lanfranco F, Maina G. Hyperparathyroidism and hypercalcaemia during lithium treatment. World J Biol Psychiatry. 2013;14(6):461–72. https://doi.org/10.3109/15622975.2012.667217
99. Shine B, McKnight RF, Leaver L, Geddes JR. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet. 2015;386(9992):461–8. https://doi.org/10.1016/S0140-6736(14)61842-0
100. Tondo L, Alda M, Bauer M, Bergink V, Grof P, Hajek T, et al. Clinical use of lithium salts: guide for users and prescribers. Int J Bipolar Disord. 2019;7(1):16. https://doi.org/10.1186/s40345-019-0151-2
101. Kessing LV, Thomsen AF, Mogensen UB, Andersen PK. Treatment with lithium and anticonvulsants and the risk of weight gain in patients with bipolar disorder. Acta Psychiatr Scand. 2010;121(6):451–7. https://doi.org/10.1111/j.1600-0447.2009.01493.x
102. Bauer M, Gitlin M. Lithium and its role in psychiatry: a reappraisal. World Psychiatry. 2016;15(3):224–5. https://doi.org/10.1002/wps.20352
103. 103.Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, O’Donovan C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines. Bipolar Disord. 2018;20(2):97–170. https://doi.org/10.1111/bdi.12609
104. McKnight RF, Geddes JR, Sharpley AL, Lotrich FE, Goodwin GM. Lithium toxicity and renal function: a review. Clin Pract Epidemiol Ment Health. 2012;8:113–26. https://doi.org/10.2174/1745017901208010113
105. Kirov G, Tredget J, John R, Owen MJ, Lazarus JH. A cross-sectional and a prospective study of thyroid disorders in lithium-treated patients. J Affect Disord. 2005;87(2–3):313–7. https://doi.org/10.1016/j.jad.2005.03.012
106. Bendz H, Sjödin I, Toss G, Berglund K. Hyperparathyroidism and long-term lithium therapy—a cross-sectional study and the effect of lithium withdrawal. J Intern Med. 1996;240(6):357–65. https://doi.org/10.1046/j.1365-2796.1996.193712000.x
107. Severus E, Bauer M. Why lithium should be considered the first-line treatment in bipolar disorder. Eur Psychiatry. 2013;28(2):146–9. https://doi.org/10.1016/j.eurpsy.2012.09.001
108. Hayes JF, Marston L, Walters K, Geddes JR, King M, Osborn DPJ. Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder. JAMA Psychiatry. 2016;73(6):559–67. https://doi.org/10.1001/jamapsychiatry.2016.0125
109. Shorter E. The decline of lithium treatment in bipolar disorder: a historical perspective. J Affect Disord. 2009;113(1–2):1–8. https://doi.org/10.1016/j.jad.2008.05.002
110. Malhi GS, Gessler D, Outhred T. The use of lithium for the treatment of bipolar disorder: recommendations from clinical practice guidelines. J Affect Disord. 2017;217:266–80. https://doi.org/10.1016/j.jad.2017.04.031
111. Hou L, Heilbronner U, Degenhardt F, et al. Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. Lancet. 2016;387(10023):1085–1093. https://doi.org/10.1016/S0140-6736(16)00143-4
112. Singh A, Hallahan B, Harte M, et al. Neuroimaging predictors of lithium response in bipolar disorder: systematic review and meta-analysis. World J Biol Psychiatry. 2021;22(5):365–380. https://doi.org/10.1080/15622975.2020.1781572
113. Quiroz JA, Gould TD, Manji HK. Molecular effects of lithium. Mol Interv. 2004;4(5):259–272. https://doi.org/10.1124/mi.4.5.6
114. Shine B, McKnight RF, Leaver L, Geddes JR. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet. 2015;386(9992):461–468. https://doi.org/10.1016/S0140-6736(14)61842-0
115. Severus E, Bauer M. The enduring clinical relevance of lithium in the treatment of bipolar disorder: results of recent studies on efficacy and safety. Pharmacopsychiatry. 2013;46(3):119–123. https://doi.org/10.1055/s-0033-1347931
116. Malhi GS, Bell E, Boyce P, et al. The 2021 CANMAT and ISBD guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2021;23(8):767–788. https://doi.org/10.1111/bdi.13105
117. Hidalgo-Mazzei D, Murru A, Reinares M, et al. Big data in mental health: a critical review of large-scale data sets and their potential use in clinical psychiatry. Eur Psychiatry. 2016;36:15–23. https://doi.org/10.1016/j.eurpsy.2016.03.010
118. Yatham LN, Kauer-Sant’Anna M, Bond DJ, et al. Comparative efficacy of mood stabilizers in the treatment of bipolar disorder: evidence from randomized controlled trials. J Affect Disord. 2013;144(1-2):16–22. https://doi.org/10.1016/j.jad.2012.05.040 
119. Baldessarini RJ, Tondo L, Hennen J. Lithium treatment and suicide risk in major affective disorders: update and new findings. J Clin Psychiatry. 2003;64 Suppl 5:44–52. https://pubmed.ncbi.nlm.nih.gov/12720484/
120. Severus E, Taylor MJ, Sauer C, et al. Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord. 2014;2:15. https://doi.org/10.1186/s40345-014-0015-8
121. Miura T, Noma H, Furukawa TA, et al. Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis. Lancet Psychiatry. 2014;1(5):351–359. https://doi.org/10.1016/S2215-0366(14)70314-1
122. Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161(2):217–222. https://doi.org/10.1176/appi.ajp.161.2.217
123. Chiu CT, Chuang DM. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther. 2010;128(2):281–304. https://doi.org/10.1016/j.pharmthera.2010.07.006
124. Forlenza OV, Diniz BS, Radanovic M, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011;198(5):351–356. https://doi.org/10.1192/bjp.bp.110.080044
125. McKnight RF, Adida M, Budge K, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379(9817):721–728. https://doi.org/10.1016/S0140-6736(11)61516-X
126. Hidalgo-Mazzei D, Mateu A, Reinares M, et al. Self-monitoring and psychoeducation in bipolar disorders: a randomised trial using a smartphone-based system. Eur Psychiatry. 2016;32:24–28. https://doi.org/10.1016/j.eurpsy.2015.11.005
127. Song J, Bergen SE, Kuja-Halkola R, et al. Genome-wide polygenic score for lithium response in bipolar disorder. Mol Psychiatry. 2021;26(3):979–988. https://doi.org/10.1038/s41380-019-0619-0
128. Carvalho AF, Dimellis D, Gonda X, et al. Rapid cycling in bipolar disorder: a systematic review. J Clin Psychiatry. 2014;75(6):e578–e586. https://doi.org/10.4088/JCP.13r08726
129. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. https://doi.org/10.1136/bmj.f3646 
130. Malhi GS, Tanious M, Das P, et al. The science and practice of lithium therapy. Aust N Z J Psychiatry. 2012;46(3):192–211. https://doi.org/10.1177/0004867412437346