Lithium Salts

Lithium salts are among the oldest and most scientifically validated treatments in the history of modern psychiatry. Introduced in the 1950s, they remain the gold standard for the prophylaxis of bipolar disorder and have also proven effective in treatment-resistant major depression and suicide prevention.

Unlike antidepressants, which target specific symptoms, and antipsychotics, which primarily modulate dopaminergic activity, lithium functions as a true mood stabilizer, capable of long-term stabilization of affective fluctuations and of acting on deep neurobiological mechanisms.

Mechanism of Action

Lithium exerts its effects through a series of complex mechanisms involving both neurotransmission and intracellular processes. One of the most significant effects is the inhibition of the enzyme glycogen synthase kinase-3β (GSK-3β), which plays a role in gene expression regulation, neuroplasticity, and neurogenesis. GSK-3β inhibition increases the expression of neurotrophic factors such as BDNF, enhances neuronal survival, and improves adaptation to chronic stress.

At the synaptic level, lithium modulates glutamatergic transmission, reducing the excess excitatory activity characteristic of acute phases of bipolar disorder. This neuroprotective effect helps prevent neuronal damage and restore the balance between inhibition and excitation in brain circuits that regulate mood. In addition, lithium enhances serotonergic transmission and modulates dopaminergic activity, acting on limbic and fronto-striatal circuits involved in the regulation of impulsivity, motivation, and affective tone.

This integrated action allows lithium to prevent both manic and depressive episodes, reduce relapse risk, and act on the underlying affective vulnerability, contributing also to the containment of self-directed aggression and suicidal behavior.

Therapeutic Indications and Dosage

Lithium is primarily indicated for the prophylaxis of bipolar disorder, both type I and II. Its ability to reduce the risk of relapse is well documented and applies to both manic and depressive episodes. The recommended therapeutic range for maintenance is 0.6–0.8 mmol/L, maintained with careful titration. Initial doses usually range from 300 to 600 mg per day, divided into two or three doses and adjusted based on serum lithium levels.

In acute manic episodes, lithium can be used as monotherapy or combined with antipsychotics, targeting plasma levels of 0.8–1.2 mmol/L. Therapeutic effects typically appear within 7–10 days. In particularly agitated presentations, short-term co-administration with sedatives may be helpful.

In treatment-resistant major depression, lithium is widely used as an augmentation strategy. It is indicated for patients who have not responded to at least two adequate antidepressant trials. Its efficacy often emerges within 1–3 weeks, even at doses lower than those used in bipolar disorder. In this context, the optimal therapeutic range is 0.4–0.8 mmol/L. Lithium is especially beneficial in patients with anergia, apathy, psychomotor slowing, and suicidal ideation.

Another officially recognized indication is suicide prevention. Lithium is the only psychotropic agent with demonstrated efficacy in specifically reducing suicide mortality, with stable effects over time—even in unipolar patients. The plasma level associated with this benefit is typically ≥ 0.6 mmol/L. This effect appears to be independent of the antidepressant response and is associated with reduced impulsivity and dysphoric aggression.

Lithium may also be useful in schizoaffective disorders, impulsive affective dysregulation, and certain forms of borderline personality disorder with high suicide risk. In such contexts, its effectiveness is often linked to its ability to stabilize affective fluctuations and curb impulsive behaviors.

Side Effects, Toxicity, and Monitoring

Lithium is generally well tolerated, but requires careful clinical management and regular monitoring due to its narrow therapeutic window and the risk of dose-dependent or cumulative adverse effects. The most common side effects result from lithium’s interaction with organs particularly sensitive to its osmotic, endocrine, and neurotransmitter-modulating actions.

A frequent effect is polyuria with polydipsia, caused by lithium’s inhibition of the kidney’s ability to respond to antidiuretic hormone (ADH). This leads to an acquired form of nephrogenic diabetes insipidus, with free water loss and increased urine output. In chronic cases, there is a progressive reduction in the kidney’s concentrating capacity, posing a dehydration risk, especially in the elderly or those on diuretics.

Lithium also affects thyroid function by inhibiting the release of thyroid hormones and altering the response to thyroid-stimulating hormone (TSH). This often results in subclinical or overt hypothyroidism, more frequent in women and in long-term treatment. Symptoms such as fatigue, weight gain, or psychomotor slowing should prompt thyroid function testing.

Another common, early, and dose-related side effect is fine postural tremor, due to altered dopaminergic transmission and intracellular ion balance in motor neurons. This is usually benign and controllable with β-blockers such as propranolol.

Lithium may also cause weight gain, due to water retention, metabolic changes, and reduced thyroid activity. Some patients report mild cognitive symptoms such as concentration difficulties or slowed thinking, usually reversible with dose reduction.

Acute toxicity typically occurs due to overdose, dehydration, or drug interactions (especially with NSAIDs, ACE inhibitors, and thiazide diuretics). Initial symptoms include nausea, vomiting, and diarrhea, followed by coarse tremor, dysarthria, ataxia, and confusion. In severe cases, seizures, arrhythmias, and coma may occur. Plasma concentrations > 1.5 mmol/L require clinical assessment; levels > 2 mmol/L are potentially dangerous and may warrant hemodialysis.

Chronic toxicity develops gradually over time, particularly with long-term treatment, and is associated with tubulointerstitial kidney damage. This may progress to chronic nephropathy, often subclinical at first but irreversible. The risk increases with treatment duration, advanced age, and concurrent use of other nephrotoxic drugs.

To prevent complications and detect side effects early, regular clinical and laboratory monitoring is essential. Key parameters include:

• Serum lithium level: check after 5–7 days from initiation or dose change, with blood drawn 12 hours after the last dose. In maintenance, monitor every 3–6 months.
• Renal function (creatinine, eGFR): every 6 months or more frequently in at-risk individuals, to detect early signs of chronic tubular damage.
• Thyroid function (TSH, fT4): at least annually, more frequently if symptoms or risk factors are present.
• Plasma electrolytes (sodium, potassium, calcium): imbalances may increase toxicity or reduce treatment efficacy.
• ECG: recommended in patients with known cardiovascular disease, elderly individuals, or in case of neurological symptoms, to detect bradycardia or conduction abnormalities.

Following these monitoring protocols allows lithium to be used safely and effectively, maximizing its benefits while minimizing both short- and long-term risks. A strong therapeutic alliance with the patient is crucial for adherence and for preventing serious complications related to inappropriate use.

Final Considerations

Despite the arrival of second- and third-generation psychotropic agents, lithium remains an irreplaceable therapeutic tool in psychiatric practice. Its effectiveness in bipolar disorder surpasses that of any other mood stabilizer, with a unique ability to prevent both manic and depressive relapses.

Even more remarkable is its proven role in suicide prevention, a benefit unmatched by any other psychotropic drug. Moreover, in treatment-resistant depression, lithium is a highly effective augmentation strategy, especially in patients with unstable affective traits or partial response to antidepressants.

While its use requires clinical expertise, ongoing monitoring, and open patient communication, the benefits it offers—particularly in severe and refractory cases—amply justify the therapeutic rigor. In experienced hands, lithium is not just a drug, but a valuable ally in treating chronic psychiatric suffering.

Summary Table

References
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