Lithium

Indications

• FDA-approved for the treatment of acute manic and mixed episodes of bipolar I disorder in adults and in children aged 7 years and older.
• FDA-approved for maintenance therapy of bipolar I disorder to reduce the frequency and intensity of subsequent manic episodes.
• Off-label but strongly supported for reducing suicide and all-cause mortality in recurrent mood disorders, an effect not shown for other stabilizers.
• Off-label augmentation of antidepressants in treatment-resistant unipolar depression, typically targeting a level of 0.6 to 0.8 mEq/L.
• Off-label adjunct for schizoaffective disorder, for aggression and impulsivity, and for cluster headache prophylaxis in specialist practice.
• Preferred over valproate for classic euphoric mania with fewer episodes and a family history of lithium response.

Mechanism of action

• Inhibits inositol monophosphatase, depleting myo-inositol and dampening phosphatidylinositol second-messenger signaling in overactive neurons.
• Inhibits glycogen synthase kinase-3 beta, shifting downstream transcription toward neuroprotection, circadian regulation, and synaptic plasticity.
• Modulates dopamine and glutamate transmission and enhances GABAergic tone, which underlies the antimanic and antiaggressive effects.
• Increases expression of neurotrophic proteins such as BDNF and Bcl-2, consistent with the gray matter preservation seen on imaging.
• Effects are gradual because they depend on gene expression changes rather than acute receptor blockade, giving a 5 to 7 day antimanic onset.

Pharmacokinetics

• Absorption is complete with peak levels at 1 to 2 hours for immediate-release salts and 4 to 5 hours for extended-release tablets.
• Lithium is not metabolized and not protein bound; it is eliminated unchanged by the kidney, so renal function drives all dosing decisions.
• The elimination half-life is 18 to 36 hours, lengthening to 36 hours or more in older adults and in chronic kidney disease.
• Steady state is reached in about 5 days, so serum levels are drawn 5 days after any dose change and 12 hours after the last dose.
• Roughly 80 percent of filtered lithium is reabsorbed in the proximal tubule in competition with sodium, so sodium depletion raises levels sharply.

Dosing

• Start immediate-release lithium carbonate at 300 mg two or three times daily, or extended-release 450 mg twice daily in healthy adults.
• Titrate by 300 mg every 5 to 7 days guided by 12-hour trough levels, with most adults stabilizing on 900-1800 mg/day in divided doses.
• Target 0.8-1.2 mEq/L for acute mania and 0.6-1.0 mEq/L for maintenance; levels above 1.5 mEq/L carry substantial toxicity risk.
• Once-nightly extended-release dosing reduces peak-related tremor and may lower the risk of long-term renal concentrating defects.
• Reduce the dose by roughly one-third to one-half when creatinine clearance falls below 50 mL/min, and avoid lithium below 30 mL/min.
• Discontinue by tapering over at least 2 to 4 weeks; abrupt cessation markedly increases the risk of rebound mania within weeks.

Adverse effects

• Fine hand tremor affects roughly a quarter of patients, along with polyuria and polydipsia in up to 30 to 40 percent from nephrogenic diabetes insipidus.
• Gastrointestinal upset, nausea, and diarrhea are common early and often improve with extended-release tablets taken with food.
• Weight gain, acne, psoriasis exacerbation, cognitive dulling, and benign leukocytosis are frequent reasons patients ask to stop.
• Hypothyroidism develops in up to 20 percent, especially women, and hyperparathyroidism with hypercalcemia occurs in about 10 percent.
• Long-term use causes chronic tubulointerstitial nephropathy in a minority, with slow decline in eGFR over decades of exposure.
• Toxicity above 1.5 mEq/L brings coarse tremor, ataxia, vomiting, confusion, and at higher levels seizures, renal failure, and death.

Monitoring

• Draw serum lithium as a 12-hour trough 5 days after any dose change, then every 3 months for the first year and every 6 months once stable.
• Check creatinine with eGFR and TSH at baseline, at 3 months, and then every 6 to 12 months, with calcium at baseline and annually.
• Obtain baseline electrolytes, CBC, urinalysis, pregnancy test, and an ECG in patients over 40 or with known cardiac disease.
• Recheck levels urgently during any illness with vomiting, diarrhea, fever, dehydration, or when a diuretic, NSAID, or ACE inhibitor is started.
• Track weight and waist circumference at each visit, and reassess renal function more often once eGFR falls below 60 mL/min.

Interactions

• NSAIDs other than aspirin reduce renal lithium clearance and can raise levels by 25 to 60 percent within days of regular use.
• Thiazide diuretics increase proximal reabsorption and commonly raise lithium levels by 25 to 40 percent; loop diuretics are less problematic.
• ACE inhibitors and angiotensin receptor blockers reduce clearance, with the greatest risk in older adults and in volume depletion.
• Dehydration, sodium restriction, vomiting, diarrhea, and heavy sweating all concentrate lithium and are frequent precipitants of toxicity.
• Combining lithium with haloperidol or other antipsychotics rarely causes an encephalopathic syndrome; carbamazepine adds neurotoxicity risk.

Special populations

• First-trimester exposure raises the risk of Ebstein anomaly; absolute risk remains under 1 percent and cardiac malformation risk is dose-related.
• If lithium is continued in pregnancy, check levels every 4 weeks, weekly near term, and hold at labor onset because clearance falls abruptly.
• Lithium enters breast milk at 10 to 50 percent of maternal levels; breastfeeding is possible with infant level, thyroid, and renal monitoring.
• Approved from age 7; children clear lithium faster and may need weight-based dosing with more frequent level checks during titration.
• In older adults reduce doses substantially, target the lower end of the range, and expect neurotoxicity even at therapeutic levels.

Clinical pearls

• Always draw the level 12 hours post-dose; a random level is uninterpretable and drives wrong dose changes.
• Any new NSAID, thiazide, or ACE inhibitor should trigger a lithium level within one week.
• Stopping lithium abruptly causes rebound mania; taper over at least 2-4 weeks whenever possible.