Lithium in Mood and Bipolar Disorders: Historical Development, Mechanisms, and Clinical Implications

Lithium occupies a singular position in psychopharmacology: It is one of the oldest modern treatments for bipolar disorder and remains one of the few agents with strong evidence across acute mania, long-term prophylaxis, and suicide prevention. Nevertheless, prescribing has declined steadily in many countries, with clinicians more often initiating anticonvulsants or second-generation antipsychotics despite guideline endorsements of lithium as a first-line maintenance agent.^1–6 This paradox—strong evidence but diminishing use—raises questions about how historical experience, commercial forces, and evolving safety concerns have shaped lithium’s contemporary reputation.

A historical lens is useful for understanding this trajectory. Lithium was first introduced to medicine for a purpose entirely unrelated to mood disorders. Its subsequent disappearance, reemergence in psychiatry, and rise to “gold standard” status were punctuated by safety scares and regulatory delays that continue to color clinical attitudes.^8–10 In parallel, converging molecular and systems-level models now offer plausible explanations for lithium’s broad therapeutic profile, particularly its antisuicidal effects, yet these mechanistic insights have only slowly diffused into everyday practice.^17–22 This narrative review integrates lithium’s medical history with contemporary evidence for its efficacy in bipolar disorder and suicide prevention and then discusses leading psychopharmacologic mechanisms that may bridge clinical effects and neurobiology. The goal is not to argue that lithium is universally preferred but to clarify why it should remain a prominent, actively considered option rather than a relic of an earlier era.

For practicing clinicians, understanding the history and emerging mechanisms of lithium is more than an academic exercise. The historical context explains why many patients and clinicians hold strong prior beliefs for or against lithium, while mechanistic data help answer the practical question of why this medication can be uniquely effective for relapse prevention and suicide risk. Together, these perspectives can improve how clinicians explain lithium to patients and families, address concerns about adverse effects, and decide when lithium is an appropriate option in shared decision-making for bipolar disorder and recurrent mood disorders.

METHODS

This article is a narrative review based on a selective literature search. The author searched PubMed and Google Scholar for English-language articles up to early 2025 using combinations of the terms lithium, bipolar disorder, mood disorder, maintenance treatment, suicide, neuroprotection, neuroimaging, inositol, and glycogen synthase kinase-3 (GSK-3). Priority was given to landmark historical descriptions, randomized controlled trials, meta-analyses, and recent translational reviews that link mechanisms to clinical outcomes. Additional references were identified by screening the reference lists of key articles. No formal quality rating, meta-analytic methods, or systematic review procedures were applied, and no new data were collected.

RESULTS

Early Medical Uses of Lithium

Lithium’s medical story began in the context of gout rather than psychiatry. In the mid-19th century, Alfred Baring Garrod observed elevated uric acid levels in patients with gout and, inspired by in vitro studies showing that lithium carbonate could dissolve uric acid crystals, and proposed oral lithium as a urate-lowering therapy.⁸ Its use peaked around 1859, but clinical enthusiasm waned as it became apparent that lithium did not reliably dissolve urate deposits in vivo, and better treatments for gout emerged.

Despite this disappointment, lithium persisted as a kind of “chemical panacea” through the late 19th century. Alexander Haig, a Scottish physician, championed the idea that uric acid caused a wide range of maladies—from migraine and dyspepsia to cardiovascular disease—and promoted lithium as a remedy for “uric acid diathesis.”^8,9 Overextension of these claims, coupled with mounting recognition of lithium toxicity and the lack of clear benefit for most indications, eventually led to its near disappearance from mainstream American medicine in the early 20th century.

Even during this period of decline, isolated psychiatric uses appeared. William Hammond in the United States reported treating manic patients with lithium in the 1870s, and Danish psychiatrist Frederik Lange described its use in melancholic depression in 1894.⁸ These reports, however, did not coalesce into a coherent therapeutic program, and lithium remained largely peripheral to psychiatric practice until the mid-20th century.

The Rediscovery of Lithium in Psychiatry

The turning point came with John Cade’s work in postwar Australia. In 1949, Cade published his observations that lithium salts produced striking improvement in 10 patients with “psychotic excitement,” offering a comparatively gentle alternative to then-prevailing interventions such as prefrontal lobotomy and prolonged sedation.¹¹ His reasoning—based initially on experiments with guinea pigs and observations about uric acid—was imperfect, but the clinical signal was compelling.

Cade’s findings stimulated interest, particularly in Europe. In 1951, Noack and Trautner reported an open trial of lithium in more than 100 manic patients, noting high rates of symptomatic improvement and providing practical guidance on dosing and monitoring.¹² Shortly thereafter, Schou and colleagues in Denmark conducted the first placebo-controlled trial of lithium in acute mania, demonstrating clear superiority to placebo.¹³ Schou went on to show that lithium could prevent recurrent mood episodes in bipolar disorder, effectively inaugurating the modern concept of a “mood stabilizer.”^9,10

Yet, lithium’s broader clinical adoption was delayed by an unrelated safety crisis. In the United States, lithium chloride was marketed as a sodium-free salt substitute for patients with cardiac disease. Doses were unregulated, and several cases of severe toxicity and death were reported, prompting regulatory withdrawal of lithium-containing products.⁸ This episode, though unrelated to psychiatric dosing, created a lasting association between lithium and danger that contributed to caution among regulators and clinicians.

Only in the late 1960s and early 1970s, after accumulating controlled trials and careful clinical experience, did regulators in the United States approve lithium for acute mania (1970) and maintenance treatment (1975), aligning US practice more closely with that in parts of Europe and Australia.^8–10 For the next 2 decades, lithium was widely regarded as the cornerstone of bipolar disorder treatment.

Lithium’s Rise as the Prototypical Mood Stabilizer

From the 1970s through the 1990s, lithium became the primary pharmacologic treatment for bipolar disorder in many health systems. Long-term studies and meta-analyses showed that lithium reduced the risk of relapse into both manic and, to a lesser extent, depressive episodes compared with placebo.¹⁴ Subsequent work extended these findings, with systematic reviews and network meta-analyses confirming that lithium remains among the most effective monotherapies for preventing any mood episode over the long term.^3,4

Notably, key syntheses supporting lithium’s status as a first-line maintenance agent have been published. Severus and colleagues’ meta-analysis of prevention trials concluded that, with no other drug showing similarly consistent evidence, lithium “remains the most valuable treatment option” for long-term prophylaxis in bipolar disorder.⁴ Nolen later emphasized that, when both efficacy and long-term safety are considered, lithium should arguably be recommended as the single preferred first-line maintenance treatment in many cases.³ Volkmann and coworkers further reviewed lithium treatment “over the lifespan,” highlighting its durable effectiveness and manageable long-term safety profile when monitoring is optimized.⁵

Clinically, these data translated into structured “lithium clinics” in many countries, with dedicated systems for serum monitoring, patient education, and collaborative management with primary care. Within this infrastructure, lithium was often viewed as the default choice for maintenance therapy, particularly in patients with classical bipolar I presentations and recurrent mania.

The Contemporary Decline in Lithium Use

Despite this strong evidence base, lithium prescribing has decreased markedly in recent decades. Surveys and prescribing data from multiple countries document a shift toward valproate, lamotrigine, and second-generation antipsychotics as initial treatments for bipolar disorder.^1,2,5 Several factors likely contribute to this trend.

First, safety concerns loom large. Lithium has a narrow therapeutic index, requires regular laboratory monitoring, and carries risks of renal and thyroid dysfunction, as well as potential teratogenicity. When clinicians are pressed for time or lack support systems for monitoring, the perceived burden of lithium may outweigh its benefits. At the same time, long-term cardiometabolic and mortality risks associated with some antipsychotic alternatives are less immediately salient in day-to-day prescribing decisions.⁵

Second, market forces play a role. As a naturally occurring ion, lithium is not patent-protected, and there is little commercial incentive to promote it compared with newer branded medications.^1,2 In contrast, extensive marketing of alternative mood stabilizers and antipsychotics has increased clinician familiarity with these agents, particularly in training environments where lithium expertise may be diminishing.

Third, the proliferation of off-label and add-on uses for second-generation antipsychotics may foster a sense that they are more versatile or rapidly acting, even when long-term data favor lithium. For some patients, particularly those with mixed features, rapid cycling, or comorbid substance use, clinicians may default to antipsychotic-based regimens without fully considering lithium.

Finally, patient perceptions matter. Online discussion and historical stigma portraying lithium as “toxic,” “old-fashioned,” or inherently dangerous can discourage acceptance, especially when contrasted with heavily marketed alternatives framed as “modern” or “targeted.”^1,2 In many clinical encounters, lithium is offered only after other treatments fail, effectively relegating it to a third-or fourth-line option.

Evidence for Mood Stabilization and Relapse Prevention

Despite these trends, contemporary data strongly support lithium’s role in preventing relapse across the bipolar spectrum. Geddes and colleagues’ meta-analysis of randomized controlled trials found that long-term lithium treatment significantly reduced the risk of any mood episode compared with placebo, with particularly strong effects on manic relapse.¹⁴ Severus et al⁴ later updated and extended this work, again showing that lithium monotherapy prevents manic, depressive, and overall mood episodes and remains one of the most robustly supported maintenance options in nonenriched samples.

Nolen’s editorial synthesis emphasized that, unlike many alternatives, lithium’s evidence arises largely from trials that do not selectively enroll prior responders, strengthening confidence in its generalizability.³ Network meta-analyses that include a range of mood stabilizers and antipsychotics typically find that, among monotherapies, only lithium and quetiapine consistently prevent both mania and depression when compared with placebo, and lithium’s evidence is more firmly grounded in nonenriched designs.³

Clinically, lithium’s long-term benefits appear most pronounced in patients with classic episodic bipolar I disorder, a family history of lithium response, or prominent manic-predominant polarity.⁵ In such patients, lithium not only reduces the frequency of episodes but may also lessen their severity and duration, contributing to improved functional outcomes over time.

Lithium and Suicide Prevention

Perhaps the most distinctive element of lithium’s clinical profile is its association with reduced suicide risk. Observational cohorts and randomized trials suggest that, across unipolar and bipolar mood disorders, long-term lithium treatment reduces suicide deaths and suicide attempts compared with placebo or other mood stabilizers.^6,7,15

Lewitzka and colleagues’ narrative review synthesized over 2 decades of data and concluded that lithium exerts a specific suicide-preventive effect that cannot be fully explained by mood stabilization alone.⁶ A meta-analysis by Cipriani et al⁷ of randomized trials found that lithium reduced the risk of suicide by roughly 60% compared with placebo and also lowered all-cause mortality in mood disorders. Sarai and colleagues¹⁵ subsequently emphasized lithium’s underutilization as a suicide-preventive agent, especially given its relatively low cost and the global burden of suicide.

More recent data have nuanced this picture. Katz and colleagues¹⁶ conducted a large randomized trial in veterans with major depression or bipolar disorder and prior suicide-related events, finding no significant advantage of lithium augmentation over usual care for the composite outcome of repeat suicide-related events. However, interpretation is complicated by trial design, adherence challenges, and the heterogeneity of diagnoses and treatments. Taken together, the totality of evidence still supports a meaningful protective effect in many patients, particularly in the context of sustained, adherent treatment and careful follow-up.^6,7,15,16

From a clinical standpoint, lithium’s antisuicidal properties are especially compelling in bipolar disorder, where lifetime suicide risk is markedly elevated and many patients experience recurrent suicidal crises despite mood symptom control. In such cases, the decision to favor lithium over alternatives may rest less on marginal differences in relapse rates and more on its potential to reduce the lethality and frequency of suicidal behavior.

Psychopharmacologic Mechanisms: Linking Neurobiology to Clinical Effects

Advances in basic and translational neuroscience have begun to clarify how lithium’s molecular actions might translate into mood stabilization and suicide risk reduction. While no single mechanism fully accounts for its therapeutic profile, several convergent pathways have emerged.^17–22

Direct Molecular Targets

Two major, interrelated targets have dominated mechanistic discussions: inositol-related phosphomonoesterases (particularly inositol monophosphatase) and GSK-3. Phiel and Klein’s seminal review cataloged lithium-sensitive enzymes, proposing that inhibition of inositol monophosphatase reduces free inositol and alters phosphoinositide signaling, while direct inhibition of GSK-3 modulates Wnt/β-catenin and other key pathways.¹⁷

Yu and Greenberg¹⁸ later integrated these hypotheses, suggesting that inositol depletion and GSK-3 inhibition are mechanistically intertwined and may jointly underlie the therapeutic effects of both lithium and valproate. In this framework, lithium’s actions converge on intracellular signaling systems that regulate synaptic plasticity, gene expression, and cellular resilience—processes that are often dysregulated in mood disorders.

Neurotrophic and Neuroprotective Effects

At the cellular level, lithium promotes neurotrophic and neuroprotective cascades in both preclinical and clinical models. Diniz and colleagues¹⁹ reviewed translational evidence that lithium upregulates neurotrophic factors such as brain-derived neurotrophic factor, enhances antiapoptotic proteins, modulates mitochondrial function, and reduces oxidative stress, collectively supporting neuronal survival under adverse conditions.

Forlenza and colleagues focused on neurodegenerative disorders, showing that lithium at low to moderate doses can attenuate amyloid and τ pathology, preserve synaptic markers, and potentially slow cognitive decline in at-risk populations.²⁰ While these findings arise outside bipolar disorder per se, they highlight lithium’s broader neuroprotective potential and suggest that its benefits in mood disorders may extend beyond episode suppression to preservation of neural integrity over time.

Puglisi-Allegra and coauthors²¹ synthesized animal and human data on lithium-induced brain plasticity, emphasizing its capacity to enhance synaptic remodeling, stabilize stress-responsive circuits, and normalize behavioral responses to environmental challenges. Such effects may be particularly relevant to the chronic stress, affective instability, and cognitive dysregulation observed in bipolar disorder.

Circuit-Level and Imaging Findings

At the systems level, functional magnetic resonance imaging (fMRI) studies indicate that lithium normalizes activity and connectivity in frontolimbic networks implicated in emotion regulation, impulsivity, and reward processing. Bergamelli and colleagues’ review of fMRI studies in bipolar disorder found that lithium treatment is consistently associated with more typical activation patterns in prefrontal regions and interconnected limbic areas compared with either untreated states or treatment with some alternative agents.²²

These imaging findings dovetail with clinical observations: patients on sustained lithium therapy often exhibit reduced affective reactivity, diminished impulsive aggression, and greater capacity for delay and reflective decision-making. In light of emerging models that link suicidal behavior to impaired top-down control over limbic and midbrain systems, lithium’s reinforcement of prefrontal regulatory circuits offers a plausible neurobiological substrate for its antisuicidal properties.^6,7,15,22

CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS

Synthesizing historical, clinical, and mechanistic data suggest several practical implications. First, lithium remains underutilized relative to its evidence base, particularly for maintenance treatment of classic bipolar I disorder and in patients with elevated suicide risk.^3–7 In many cases, reframing lithium not as a “last resort” but as a default long-term option—discussed early and revisited as circumstances evolve—would align practice more closely with available data.

Second, optimal use of lithium requires supportive infrastructure: reliable laboratory access, clear protocols for initiation and dose adjustment, proactive management of emergent renal or thyroid abnormalities, and systematic patient education about hydration, drug interactions, and what to do in the setting of intercurrent illness. Where such infrastructure is lacking, system-level innovations (eg, centralized monitoring clinics, telehealth-supported follow-up, or shared-care agreements with primary care physicians) may be as important as individual prescribing decisions in reestablishing lithium as a viable option.

Third, mechanistic insights suggest that lithium’s benefits may extend beyond symptom suppression to resilience of neural circuits implicated in stress response, reward, and cognitive control.^17–22 This raises the possibility that earlier, sustained lithium treatment in carefully selected patients could have long-term neuroprotective benefits—a hypothesis that remains to be tested rigorously but is supported by converging preclinical and clinical signals.^19–21

Future research directions include the following:

• Identification of biomarkers (eg, genetic, inflammatory, neuroimaging) that predict lithium response and tolerability, enabling more personalized treatment selection.
• Exploration of low-dose or microdose lithium regimens for neuroprotection and mood stabilization, particularly in older adults and those with comorbid neurodegenerative risk.²⁰
• Development of digital tools and point-of-care assays that simplify monitoring and improve adherence, potentially lowering practical barriers to lithium use.

CONCLUSIONS

Lithium’s story in psychiatry is neither a simple narrative of triumph nor one of obsolescence. Rather, it is a cycle of discovery, enthusiasm, caution, and reappraisal. Historically, lithium was the first true mood stabilizer, transforming the management of bipolar disorder and reducing relapse and suicide risk in ways that remain unmatched by many newer agents. Over time, concerns about toxicity, monitoring demands, and the availability of heavily marketed alternatives contributed to its declining use, even as high-quality evidence and mechanistic understanding continued to accumulate.

Viewed through a contemporary lens, lithium appears less like an outdated treatment and more like an underused resource, particularly for patients with classic bipolar presentations and elevated suicide risk. Clinicians who are familiar with its history, evidence base, and neurobiologic mechanisms are better positioned to discuss lithium transparently with patients, balancing its burdens against its unique and potentially life-saving benefits.

Reintegrating lithium into the everyday therapeutic conversation will not be achieved by nostalgia for an earlier era, but by clear, data-driven communication and thoughtful systems of care that make safe, collaborative lithium treatment feasible. In this sense, lithium’s “rise and fall” may ultimately give way to a more nuanced, sustainable role in the long-term management of bipolar disorder.

Article Information

Published Online: April 16, 2026. https://doi.org/10.4088/PCC.25nr04160
© 2026 Physicians Postgraduate Press, Inc.
Submitted: December 5, 2025; accepted January 27, 2026.
To Cite: Reinfeld S, Gill P. Lithium in mood and bipolar disorders: historical development, mechanisms, and clinical implications. Prim Care Companion CNS Disord 2026;28(2):25nr04160.
Author Affiliations: Department of Psychiatry, Stony Brook University Hospital, Stony Brook, New York (Reinfeld, Gill).
Corresponding Author: Samuel Reinfeld, DO, Department of Psychiatry, Stony Brook University Hospital, Stony Brook, NY ([email protected]).
Financial Disclosure: None.
Funding/Support: None.

Clinical Points

• Lithium remains one of the most effective maintenance treatments for classic bipolar disorder and should be considered as an early option rather than only after multiple prior treatment failures.
• Long-term lithium treatment is associated with a meaningful reduction in suicide attempts and deaths, an advantage that is important to discuss with patients and families at elevated suicide risk.
• Safe use of lithium in routine practice depends on simple but explicit systems for serum monitoring, management of renal and thyroid function, and clear communication between psychiatry and primary care about ongoing responsibilities.