• Lithium is a drug of its own kind à suppress mania and to exert a prophylactic effect in bipolar (manic) disorder at doses which have no overt CNS effects.
  • standard antimanic and mood stabilizing drug.
  • Several anticonvulsants and atypical antipsychotics à alternatives to lithium.

Actions and mechanism

1 . CNS

  • no acute effects in normal individuals as well as in bipolar patients.
  • neither sedative nor euphorient; but on prolonged administration, it acts as a mood stabiliser in bipolar disorder.
  • Given to patients in acute mania à gradually suppresses the episode taking 1- 2 weeks; continued treatment prevents cyclic mood changes.
  • markedly reduced sleep time of manic patients is normalized.

mechanism ànot known – proposed mechanism

  • Li+ partly replaces body Na+ and is nearly equally distributed inside and outside the cells (contrast Na+ and K+ which are unequally distributed); this may affect ionic fluxes across brain cells or modify the property of cellular membranes.
  • Lithium decreases the presynaptic release of NA and DA in the brain of treated animals without affecting 5-HT release. This may correct any imbalance in the turnover of brain monoamines.

The above hypothesis cannot explain why Li+ has no effect on people not suffering from mania.

Alternative hypothesis:

Reduces intraneuronal concentration of inositol in human brain by inhibiting de nova inositol synthesis.

in therapeutic concentration range à inhibits hydrolysis of inositol- I -phosphate à free inositol for regeneration

of IP3 and DAG, is reduced

The hyperactive neurones involved in the manic state may be preferentially. Thus, lithium may ignore normally operating receptors, but ‘search out’ and selectively, though indirectly, dampen signal transduction in the overactive receptors functioning through phosphatidy l inositol hydrolysis.

Other actions

  • inhibits the action of ADH on distal tubules in the kidney and causes a diabetes insipidus like state.
  • An insulin-like action on glucose metabolism is exerted.
  • Leukocyte count is increased by lithium therapy

Prior to beginning lithium, clinicians should obtain a

  • urinalysis,
  • blood urea nitrogen, creatinine,
  • thyroid function studies, calcium,
  • pregnancy test for women of childbearing potential, and
  • an electrocardiogram for patients over age 40.
  • Blood urea nitrogen and creatinine should be checked every two to three months during the first six months of therapy, and every 6 to 12 months thereafter.
  • Thyroid function should be checked once or twice during the first six months, and every 6 to 12 months thereafter.

Pharmacokinetics and control of therapy

  • well absorbed orally (peak level in 2-3 hours)
  • Lithium is handled by the kidney in much the same way as Na+. Nearly 80% of the filtered Li+ is reabsorbed in the proximal convoluted tubule.
  • When Na+ is restricted, a larger fraction of filtered Na+ is reabsorbed, so is Li+, tending to raise serum Li+.
  • The t½ à 16-30 hours.
  • Since the margin of safety à narrow, monitoring of serum lithium concentration is essential for optimising therapy;
  • 0.5-0.8 mEq/ L à maintenance therapy in bipolar disorder,
  • 0.8- 1.2 mEq/ L  à for episodes of acute mania
  • Toxicity à serum levels exceed 1.5 mEq/L.
  • excreted in sweat and saliva as well, and secreted in breast milk.
  • Mothers on lithium should not breastfeed.

Adverse effects

Side effects are common, but are mostly tolerable.

• Nausea, vomiting and mild diarrhoea occur initially à  minimized by starting at lower doses.

Thirst and polyuria à experienced by most patients

Fine tremors à may occur even at therapeutic concentrations.

CNS toxicity à as plasma concentration rises producing

  • coarse tremors, giddiness, ataxia, motor incoordination, nystagmus, mental confusion, slurred speech, hyper-reflexia.

Overdose symptoms à muscle twitchings, drowsiness, delirium, coma and convulsions. Vomiting, severe diarrhoea,

albuminuria, hypotension and cardiac arrhythmias à features of Li+ toxicity.

Treatment à symptomatic.

  • No specific antidote.
  • Osmotic diuretics and sod. bicarbonate infusion promote Li+ excretion.
  • Haemodialysis is indicated if serum levels are > 4 mEq/L.

• long-term use à renal diabetes insipidus. Most patients gain some body weight.

Goiter à 4%.

  • due to interference with release of thyroid hormone àfall in circulating T3,T4 levels à
  • TSH secretion from pituitary enlargement (goiter) and stimulation of thyroid .

Lithium induced goiter and hypothyroidism à does not warrant discontinuation of therapy;

Easily managed by thyroid hormone supplementation.

• contraindicated during pregnancy à foetal goiter and other congenital abnormality

  • At higher levels, SA node and A-V conduction may be depressed àcontraindicated in sick sinus syndrome.

• Lithium can cause dermatitis and worsen acne.

Contraindications — Lithium is contraindicated in patients with:

●Significant renal impairment

●Sodium depletion


●Significant cardiovascular disease


  • Diuretics (thiazide, furosemide) à Na+ loss — promote proximal tubular reabsorption of Na+ as well as Li+  plasma levels of lithium rise.
  • Tetracyclines, NSAIDs and ACE inhibitors à also cause lithium retention.
  • Lithium tends to enhance insulin/sulfonylurea induced hypoglycaemia.

Uses: 1. Acute mania

  • (inappropriate cheerfulness or irritability, motor restlessness, high energy level, nonstop talking, racing thoughts, flight of ideas. little need for sleep and progressive loss of contact with reality; sometimes violent behaviour).
    • Though lithium is effective in controlling acute mania, response is slow
    • control of plasma levels is difficult during the acute phase.
    • Most psychiatrists prefer to use an atypical antipsychotic orally or by i.m. injection, with or without a potent BZD like clonazepam/lorazepam, and start lithium after the episode is under control.
    • Maintenance lithium therapy à for 6-12 months to prevent recurrences.
  • Bipolar disorder
  • gradually introduced and maintained at plasma concentration between 0.5- 0.8 mEq/L.
  • lengthens the interval between cycles of mood swings: episodes of mania as well as depression are attenuated, if not totally prevented in upto 70% patients.
  • However, because of frequent side effects and problems in maintaining narrow range of serum Li+ levels, valproate and other alternative drugs are more frequently used now.

3. sporadically used in many other recurrent neuropsychiatric illness, cluster headache and as adjuvant to antidepressants in resistant nonbipolar major depression.


  • Approximately 30% patients of mania and bipolar disorder (especially rapidly cycling cases) show incomplete or poor response to lithium.
  • Many do not tolerate it. or are at special risk of toxicity.
  • Sodium valproate
    • Relatively high dose used à first line treatment for mania.
    •  acts faster than lithium but slower than antipsychotics ± a BZD.
    • Better safety profile than lithium.
    • Divalproex, a complex of valproic acid, is more commonly used due to better gastric tolerance.
    • A combination of valproate with an atypical antipsychotic has high efficacy in acute mania.
    • also an effective prophylactic in bipolar disorder

2 . Carbamazepine

  •  control mania and to prolong remission in bipolar disorder.
  • less effective than lithium or valproate in acute mania.

3 . Lamotrigine

  • strong evidence of efficacy of this newer anticonvulsant for prophylaxis of depression in bipolar disorder.
  • not effective for treatment as well as prevention of mania.

4 . Atypical antipsychotics

  • Olanzapine, risperidone, aripiprazole, quetiapine, with or without a BZD, are now the first line drugs for control of acute mania, except cases requiring urgent parenteral therapy, for which i.m. olanzapine or haloperidol arc the most effective.
  • Aripiprazole has recently emerged as the favoured drug for treatment of mania in bipolar I disorder, both as monotherapy as well as adjuvant to lithium or valproate.
  • Maintenance therapy with aripiprazole prevents mania. Olanzapine à not considered suitable for long-term therapy due to higher risk of weight gain, hyperglycaemia

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