Mechanism of Action of Lithium (Mood Stabilizer)

Introduction

Lithium is the gold-standard mood stabilizer, used for managing bipolar disorder, especially to control acute manic episodes and prevent future mood swings. Though its exact mechanism isn’t completely understood, it’s known to influence intracellular signaling, neurotransmitter modulation, and second messenger systems. Lithium is also one of the few psychiatric medications that significantly reduces suicide risk.

It’s a high-yield drug in exams like USMLE, NCLEX, GPAT, and NEET-PG.

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Stepwise Mechanism of Action of Lithium

1. Inhibition of inositol monophosphatase
   Lithium inhibits inositol monophosphatase, preventing the regeneration of free inositol, a key component in the phosphatidylinositol (PI) second messenger system.
2. Reduced IP3 and DAG production
   This leads to reduced levels of IP3 and DAG, important for signal transduction of various neurotransmitters like norepinephrine and serotonin.
3. Inhibition of glycogen synthase kinase-3 (GSK-3)
   Lithium inhibits GSK-3, an enzyme that plays a role in cell apoptosis, circadian rhythm, and neuroplasticity. This may help stabilize mood.
4. Modulation of neurotransmitters
   Lithium is believed to enhance serotonergic activity, reduce dopaminergic overactivity, and stabilize glutamate levels in the brain.
5. Neuroprotective effects
   Lithium may promote neuronal survival and neurogenesis, contributing to its long-term mood-stabilizing action.

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Pharmacokinetic Parameters of Lithium

Parameter	Value
Bioavailability	95–100%
Onset of action	5–7 days for antimanic effect
Half-life	18–36 hours (longer in elderly)
Metabolism	Not metabolized (excreted unchanged)
Excretion	Renal – >95% via glomerular filtration
Therapeutic range	0.6–1.2 mEq/L (narrow therapeutic index)

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Clinical Uses of Lithium

• Bipolar disorder (acute mania and maintenance)
• Schizoaffective disorder
• Augmentation in refractory depression
• Cluster headaches (off-label)
• Suicide prevention in mood disorders

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Adverse Effects of Lithium

• Tremor
• Hypothyroidism (inhibits thyroid hormone synthesis)
• Nephrogenic diabetes insipidus (polyuria, polydipsia)
• Weight gain
• GI upset (nausea, diarrhea)
• Leukocytosis
• Teratogenicity – causes Ebstein’s anomaly (if taken during 1st trimester)
• Toxicity – confusion, ataxia, seizures, coma (esp. with NSAIDs, diuretics)

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Comparative Analysis: Lithium vs Valproate (Another Mood Stabilizer)

Feature	Lithium	Valproate
Onset of action	Slow (5–7 days)	Faster (2–4 days)
Metabolism	Not metabolized (renal excretion)	Hepatic metabolism
Teratogenicity	Ebstein anomaly	Neural tube defects
Use in rapid cycling	Less effective	More effective
Therapeutic range	Narrow	Moderate

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Practice MCQs

Q1. Lithium primarily inhibits which enzyme?
a. Tyrosine hydroxylase
b. Monoamine oxidase
c. Inositol monophosphatase ✅
d. COMT

Q2. Lithium is most effective in:
a. Acute psychosis
b. Bipolar mania ✅
c. OCD
d. PTSD

Q3. Which organ excretes lithium?
a. Liver
b. Kidney ✅
c. Lungs
d. Pancreas

Q4. Lithium toxicity risk increases with:
a. ACE inhibitors
b. Diuretics
c. NSAIDs
d. All of the above ✅

Q5. Which cardiac defect is linked to lithium use in pregnancy?
a. Tetralogy of Fallot
b. ASD
c. Ebstein anomaly ✅
d. PDA

Q6. Lithium can cause:
a. Hyperthyroidism
b. Hypothyroidism ✅
c. Hyperparathyroidism
d. Pheochromocytoma

Q7. Which is NOT a known side effect of lithium?
a. Tremor
b. Leukopenia ✅
c. Weight gain
d. Polyuria

Q8. Lithium is most dangerous when combined with:
a. Paracetamol
b. Metoprolol
c. NSAIDs ✅
d. SSRIs

Q9. What is the therapeutic plasma range for lithium?
a. 0.2–0.6 mEq/L
b. 0.6–1.2 mEq/L ✅
c. 1.5–2.5 mEq/L
d. 2.5–3.5 mEq/L

Q10. Neuroprotective action of lithium is partly due to:
a. GABA enhancement
b. Inhibition of GSK-3 ✅
c. MAO inhibition
d. NMDA blockade

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FAQs

Q1: How long does lithium take to work?
It usually takes 5–7 days for antimanic effects to begin.

Q2: Is lithium safe during pregnancy?
No. It’s teratogenic, especially in the first trimester.

Q3: What tests are needed during lithium therapy?
Monitor serum lithium levels, renal function, thyroid function, and electrolytes regularly.

Q4: What happens in lithium toxicity?
Symptoms include tremor, confusion, ataxia, seizures, and coma.

Q5: Can lithium be used long-term?
Yes, but requires strict monitoring due to narrow therapeutic index and renal risks.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Sparsh Gupta – Review of Pharmacology
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK526101/