Lithium

Mechanism of Action
​Lithium's exact mechanism of action remains not fully understood, but it is believed to work through several pathways:
  1. Neurotransmitter Modulation:
    • Enhances serotonergic activity and may reduce dopamine transmission.
    • Stabilizes mood by balancing excitatory and inhibitory neurotransmitters in the brain.
  2. Intracellular Signaling Pathways:
    • Inhibits inositol monophosphatase, leading to altered phosphatidylinositol signaling, which regulates mood and neuroplasticity.
    • Modulates glycogen synthase kinase-3 beta (GSK-3β), influencing cellular resilience and neuroprotection.
  3. Neuroprotective Effects:
    • Promotes the survival of neurons and enhances synaptic plasticity.
    • Reduces oxidative stress and may protect against neurodegeneration.
Sources:
  • Malhi et al., "Lithium: A Neuroprotective Agent" (PubMed)
  • NIH: Mechanisms of Action for Lithium
Clinical Benefits
  1. Mood Stabilization:
    • Effective in preventing manic and depressive episodes in bipolar disorder.
    • Considered the "gold standard" for long-term maintenance therapy.
  2. Acute Mania:
    • Reduces the intensity of manic symptoms, such as euphoria, hyperactivity, and irritability.
  3. Suicide Prevention:
    • Unique among mood stabilizers, lithium significantly reduces the risk of suicide in patients with mood disorders.
  4. Off-Label Uses:
    • May be used for treatment-resistant depression (as adjunct therapy).
    • Investigated for neurodegenerative diseases like Alzheimer's disease due to its neuroprotective properties.
Sources:
  • Goodwin & Jamison, "Bipolar Disorder: Lithium in Practice"
  • NICE Guidelines for Bipolar Disorder Treatment

Dosage
  1. Initial Dosing:
    • Typically starts at 300 mg to 600 mg daily, divided into two or three doses.
  2. Maintenance Dosing:
    • Adjusted based on serum lithium levels (therapeutic range: 0.6–1.2 mEq/L).
    • Typical maintenance doses range from 900 mg to 1,200 mg daily.
  3. Serum Monitoring:
    • Regular blood tests (every 1–3 months) are critical to ensure levels remain within the therapeutic range and avoid toxicity.
    • Target serum level for acute mania: 0.8–1.2 mEq/L.
Sources:
  • FDA Prescribing Information for Lithium
  • Clinical Psychiatry Guidelines

Prevalence of Side Effects - Common Side Effects (10–30% of patients):
  • Gastrointestinal: Nausea, diarrhea, abdominal discomfort.
  • Neurological: Tremor, fatigue, cognitive slowing.
  • Weight Gain: Frequently reported with prolonged use.
  • Increased Thirst and Urination: Due to nephrogenic diabetes insipidus.
Serious Side Effects (less common):
  1. Thyroid Dysfunction:
    • Hypothyroidism occurs in ~10–20% of patients.
  2. Kidney Impairment:
    • Long-term use can affect renal function; regular monitoring of kidney function is essential.
  3. Lithium Toxicity:
    • Symptoms include confusion, severe tremor, ataxia, and seizures. Toxicity occurs at serum levels >1.5 mEq/L.
  4. Cardiac Effects:
    • Risk of arrhythmias, particularly in individuals with pre-existing cardiac conditions.
Sources:
  • BMJ: Lithium Monitoring and Side Effects
  • PubMed: Long-Term Safety of Lithium

Prevalence of Elevated TSH with Lithium

  • General prevalence: Around 10–20% of patients on chronic lithium therapy develop clinically significant hypothyroidism (requiring treatment).
  • Subclinical hypothyroidism (elevated TSH, normal T4): Rates are higher, ranging from 20–30% in some studies.
  • Gender differences: Women are affected more frequently than men — in some cohorts, up to 25–30% of women on long-term lithium show increased TSH compared to 10–15% of men.
  • Duration: Risk rises with the length of treatment. The majority of cases develop within the first 2–5 years, but the risk remains elevated with ongoing therapy.​
Mechanism
  • Lithium inhibits thyroid hormone release from the thyroid gland.
  • It may also interfere with iodine uptake and thyroid hormone synthesis.
  • This creates a tendency toward goiter and hypothyroidism, reflected as increased TSH.
Monitoring Recommendations
  • Baseline thyroid function tests (TSH, Free T4 ± antibodies) before starting lithium.
  • Regular monitoring: Guidelines typically suggest checking TSH every 6–12 months, more often if symptoms develop or if the patient is female/older/has thyroid antibodies.
 Clinical Implications
  • Many patients remain asymptomatic with mildly elevated TSH.
  • Others require levothyroxine supplementation, which usually allows continuation of lithium without issues.
  • Importantly, lithium-induced hypothyroidism is reversible in some cases if lithium is discontinued, though not always.
​Summary: Long-term lithium therapy is associated with increased TSH in roughly 20–30% of patients (subclinical + clinical hypothyroidism combined), with women and longer treatment durations at higher risk. Regular thyroid monitoring is essential, and hypothyroidism is generally manageable with thyroid hormone replacement.