Lithium is a reference treatment for maintenance therapy in bipolar disorder and an augmentation strategy in major depression with insufficient response. Selection depends on phase, risk profile, renal and thyroid function, interactions and the feasibility of monitoring.
Lithium is a mood stabilizer with complex mechanisms that are not fully defined; its efficacy and safety profile depend on the indication, clinical phase and monitoring.
Mechanisms such as modulation of second messengers, GSK-3 and plasticity are supported mainly by preclinical data and do not definitively explain the clinical efficacy of lithium.
Effects on GSK-3, neurotrophic factors and plasticity have been observed mainly in experimental models and biomarker studies. It has not been demonstrated that lithium directly prevents clinically measurable neuronal damage in depression.
Lithium is effective in preventing manic and depressive relapses in many patients with bipolar disorder. Observational studies and meta-analyses also suggest a possible reduction in suicide or self-harm, but the magnitude of the effect and causality are not uniformly defined.
Lithium is primarily indicated for prophylaxis of bipolar disorder, both type I and type II. Its ability to reduce recurrence risk is well documented for both manic and depressive episodes. The recommended therapeutic range for prevention is 0.6 to 0.8 mmol/L, maintained consistently through careful titration. The initial dose generally ranges from 300 to 600 mg per day, divided into two or three administrations, with gradual adjustment according to serum lithium levels.
In acute manic episodes, lithium may be used as monotherapy or combined with antipsychotics, achieving plasma concentrations between 0.8 and 1.2 mmol/L. The therapeutic effect generally appears within 7–10 days. In particularly agitated presentations, combination with sedatives is useful during the initial phase.
Lithium augmentation is a possible strategy after insufficient response to adequate antidepressant treatment; the timing of this choice depends on the quality of previous treatments, severity, risk and preferences, not on a universal threshold of two medications. No symptom profile, including anergia or apathy, reliably identifies patients who will respond.
Observational studies and some meta-analyses suggest that lithium may reduce suicide and self-harm in mood disorders. The magnitude of the effect, causality and optimal concentration are not defined by a universal threshold, however, and lithium is not the only relevant intervention for suicide prevention.
Lithium is not a standard treatment for borderline personality disorder or isolated impulsivity; any off-label use requires specialist justification and cannot be presented as an established indication.
Lithium is generally well tolerated, but requires careful clinical management and regular monitoring because of its narrow therapeutic window and the possible occurrence of dose-dependent or cumulative adverse effects. The most common adverse effects result from lithium’s interaction with organs that are particularly sensitive to its osmotic, endocrine, and neurotransmitter effects.
One of the most frequent effects is polyuria associated with polydipsia, resulting from inhibition of the renal tubules’ ability to respond to antidiuretic hormone (ADH). This mechanism induces an acquired form of nephrogenic diabetes insipidus, with free-water loss and increased urine output. In chronic cases, there is a risk of progressively reduced urine-concentrating ability, with dehydration especially in older adults or patients treated with diuretics.
Lithium may also interfere with thyroid activity, inhibiting thyroid hormone release and altering the response to thyroid-stimulating hormone (TSH). This effect often results in subclinical or overt hypothyroidism, which is more frequent in women and during long-term treatment. The appearance of fatigue, weight gain or psychomotor slowing should always prompt assessment of thyroid function.
Another common effect, often early and dose-related, is a fine postural tremor. The mechanism is not defined by a single dopaminergic alteration; after toxicity and aggravating factors have been excluded, interventions such as dose adjustment or propranolol may be considered case by case.
Lithium may be associated with weight gain and subjective or measurable cognitive symptoms. Mechanisms, intensity and reversibility vary; thyroid function, dose, comorbidities and therapeutic alternatives must be assessed.
The decision to use hemodialysis in lithium poisoning does not depend on a single concentration. It must integrate neurological and cardiac symptoms, renal function, acute or chronic exposure, the trend in levels, and toxicological and nephrological recommendations.
Chronic use may cause tubulointerstitial nephropathy and reduced renal function; reversibility varies, and risk increases with duration, episodes of toxicity and other factors.
To prevent complications and manage adverse effects early, regular clinical and laboratory monitoring is essential. The main parameters to assess are:
Following these monitoring protocols allows lithium to be used effectively and safely, maximizing its benefits while minimizing short- and long-term risks. A strong therapeutic alliance with the patient is essential to ensure adherence and prevent potentially serious complications associated with inappropriate use.
Lithium is a reference treatment for maintenance in bipolar disorder, but selection relative to other mood stabilizers depends on the episode profile, previous response, safety and preferences; it is not superior to every alternative for all outcomes and all patients.
Observational studies and some meta-analyses suggest a reduction in suicide or self-harm during lithium treatment, particularly in mood disorders. The magnitude of the effect and comparative superiority are not certain in every population; suicide risk alone is not an automatic indication.
Its use requires monitoring, clinical expertise and active communication. The decision must balance expected benefits, renal, thyroid and toxicological risks, interactions, preferences and the feasibility of regular checks.
| Indication | Therapeutic range (mmol/L) | Key clinical notes |
| Bipolar disorder—prophylaxis | 0.6 – 0.8 | Reference treatment for maintenance in selected patients |
| Acute manic episode | 0.8 – 1.2 | Gradual effect; also useful in combination therapy |
| Treatment-resistant depression (augmentation) | 0.4 – 0.8 | Benefit cannot be predicted from a single symptom profile |
| Possible effect on suicide and self-harm | Not defined by a universal threshold | Possible reduction in suicide and self-harm; magnitude of effect not defined by a universal threshold |