Bipolar Disorder (BD) is a chronic condition characterized by significant mood shifts between episodes of mania or hypomania and depression. Lithium, a naturally occurring element administered as a salt, is a foundational mood stabilizer in the treatment of BD. It is one of the most effective medications for reducing the recurrence of both manic and depressive episodes. Lithium is also associated with a significant reduction in the risk of suicide in individuals with BD. This agent is often a first-line treatment option, especially for the long-term management of the disorder.
How Lithium Stabilizes Mood
The action of lithium is complex, involving multiple systems within the brain, but it centers on stabilizing communication pathways between nerve cells. One primary biological effect is the inhibition of the enzyme glycogen synthase kinase-3 beta (GSK-3β), which is often overly active in BD. By inhibiting GSK-3β, lithium affects cellular processes that regulate mood, inflammation, and neuronal survival, dampening the extreme swings in neuronal activity.
Lithium also modulates neurotransmitter systems. It enhances the function of the serotonin system while reducing excessive signaling in the dopamine system, helping to balance mood extremes. Furthermore, lithium interferes with the inositol signaling pathway, a key mechanism for cell communication that can become dysregulated in BD. Disrupting this cycle effectively calms hyperactive neuronal networks.
A long-term benefit of lithium is its neuroprotective capacity, preserving the health and structure of brain cells. Lithium promotes the expression of Brain-Derived Neurotrophic Factor (BDNF), a protein that supports the growth and survival of neurons. This effect may help counteract the loss of gray matter volume sometimes observed in individuals with BD.
Initiating and Monitoring Lithium Treatment
Beginning lithium therapy requires a careful, step-wise approach due to the drug’s narrow therapeutic window—the small difference between a helpful dose and a potentially toxic one. Treatment typically starts with a low dose, gradually increased over several weeks. The goal is to reach a concentration in the blood, known as the serum lithium level, that is high enough to be effective but low enough to be safe.
The target therapeutic range for serum lithium is generally between 0.6 and 1.2 millimoles per liter (mmol/L). Maintenance therapy often aims for the lower end (0.6–0.8 mmol/L) to maximize tolerability, while higher levels may be sought during acute manic episodes. Full stabilization of mood is not immediate, often taking four to six weeks of consistent use before optimal benefits are observed.
Before treatment begins, baseline blood tests are necessary to ensure safety. These tests include kidney function (creatinine, eGFR), thyroid function (TSH), and electrolytes, including serum calcium. For patients over 40 or those with cardiac risk factors, an electrocardiogram (ECG) is also recommended.
Once a stable dose is achieved, monitoring becomes a regular routine. Serum lithium levels must be checked frequently—typically 12 hours after the last dose (trough level)—until stable, and then every three to six months for maintenance. Periodic checks of kidney and thyroid function, usually every six to twelve months, are also conducted to detect any potential long-term changes early.
Recognizing Side Effects and Toxicity
Common side effects may occur early in treatment, though they often lessen as the body adjusts. These acute effects include mild nausea, diarrhea, and a fine hand tremor. Lithium can also cause increased thirst (polydipsia) and subsequent frequent urination (polyuria). These side effects are usually manageable by optimizing the dose or adjusting the timing of the medication.
The primary concern is the risk of toxicity, which can arise when the serum level rises too high, often above 1.5 mmol/L. Early toxicity symptoms are a worsening of common side effects, including severe vomiting, persistent diarrhea, and a coarse, noticeable tremor. As toxicity progresses, more serious neurological symptoms emerge, requiring immediate medical attention.
Signs of moderate to severe toxicity include confusion, slurred speech, muscle twitches, and problems with balance and coordination (ataxia). High levels of lithium are medical emergencies that can lead to seizures, coma, or permanent neurological damage. Factors that rapidly increase lithium levels include any condition causing dehydration, such as fever, excessive sweating, or severe gastrointestinal illness.
Drug interactions also pose a significant risk by affecting how the kidneys clear lithium. Medications like Nonsteroidal Anti-inflammatory Drugs (NSAIDs) such as ibuprofen can reduce lithium excretion and raise its concentration. Similarly, certain diuretics, especially thiazide diuretics, can cause the kidneys to retain more lithium. Consistent salt and fluid intake is necessary to maintain a steady level and reduce toxicity risk.
Long-Term Organ System Considerations
Chronic use of lithium necessitates careful consideration of its effects on the kidneys and the thyroid gland. A common long-term renal effect is Nephrogenic Diabetes Insipidus (NDI). This condition results from lithium interfering with the kidney’s ability to respond to vasopressin, the anti-diuretic hormone. Lithium disrupts the function of aquaporin-2 water channels in the renal collecting tubules, preventing the reabsorption of water back into the body. The consequence is excessive water loss, leading to severe polyuria and polydipsia.
The thyroid gland is also susceptible to long-term lithium exposure. Lithium can accumulate in thyroid tissue and interfere with the synthesis and release of thyroid hormones. This disruption often leads to hypothyroidism, detected by an elevation in TSH levels during routine monitoring. Hypothyroidism is typically managed with thyroid hormone replacement therapy without discontinuing the lithium.
Chronic lithium use is also linked to changes in calcium regulation, specifically an increased risk of hyperparathyroidism and elevated serum calcium levels. Lithium alters the function of the calcium-sensing receptors on the parathyroid glands, leading to an overproduction of parathyroid hormone. Monitoring of calcium and parathyroid hormone levels is a routine part of long-term care.