Pharmacology of lithium

Lithium carbonate salt structure

The best psychiatric medication

PL will engage in a bit of hyperbole when introducing lithium.  We are of the belief that this drug is the best psychiatric medication available.  By this we mean that when used for persons with depressive and/or manic episodes (not just bipolar illness, as described elsewhere), it is extremely effective, in many ways, more so than other medication classes for other psychiatric conditions. 

The extent of lithium's many benefits will be explained in other posts. In this posting, extensive attention is provided mainly to its side effects.  However, those side effects should always be weighed against its extensive benefits, not only for mood episode prevention (where its efficacy is proven with a replication unmatched by any other psychotropic drug), but for improved mortality (reduced suicide and death by heart disease) and prevention of dementia (which is markedly increased in persons with mood episodes).  


Lithium is a naturally occurring cation.  The standard lithium formulation is lithium carbonate.  Other lithium formulations are lithium citrate, which can be better tolerated than the carbonate compound in the setting of severe nausea, and lithium carbonate ER, a generic controlled release type of lithium.  ER lithium leads to lower serum peaks  and may be associated with fewer cognitive side effects, such as poor concentration or sedation.

The usual dosage of lithium is around 900 mg/d (range 600-1500 mg/d).  It often is given two or three times daily, but it should be given in a one time dose since its mean half-life is about 24 hours.  Once daily dosing is associated with less long-term kidney impairment, and, of course, enhanced medication compliance.   It is dosed to a serum therapeutic range of 0.6-1.2, somewhat lower in the elderly (0.4-0.8).   A standard level for acute and maintenance treatment is 0.8 (0.4 in the elderly).  Lithium is not metabolized in the liver and is excreted unchanged by the kidney.  Thus, its only drug interactions involve other medications that can affects its renal excretion .

Mechanisms of Action

For many years, the mechanism of action of lithium was unknown.  Lithium has mildly pro-serotonergic effects, but it does not significantly affect other major neurotransmitters (like dopamine or norepinephrine).  Recent data strongly indicate that lithium’s main effects do not occur at the synapse with neurotransmitters, but post-synaptically, at the level of G-proteins and other second messengers (such as phosphatidylinositol phosphate, PIP).  It is these cellular effects that probably mediates lithium’s clinical utility. 

Specifically, lithium inhibits the alpha unit of G-proteins, especially those connected to Beta-adrenergic receptors via cyclic adenosine monophosphate (cAMP).  By blocking the G-protein transmission of messages from these noradrenergic receptors, lithium may interfere with the neuronal activity that occurs with mania.  Similar effects on G-proteins linked to other neurotransmitters may produce lithium’s antidepressant effects.  Furthermore, lithium may inhibit PIP function when PIP is excessively active, but lithium has no effect when PIP is normally active. Thus, by its complex second messenger functions, lithium may essentially be re-establishing intracellular homeostases that underlie larger neural circuits subserving mood, accounting for its mood-stabilizing effects.

Dosing and Laboratory Tests

Lithium should only be dosed once daily since it has a half life of about 24 hours.  The common practice of dosing lithium multiple times daily is based on habit without any general rationale. In some cases, if lithium is dosed all at once, a patient may experience some sedation or cognitive impairment. In such cases, more than once daily dosing may be necessary.  Dosing lithium at night minimizes such side effects. Another option is to use slow release lithium (like the ER generic formulation), which minimizes the peak blood level side effects.  Slow release formulations may also lead to somewhat less impairment of urinary concentration capacity. It is  the PL practice to use generic lithium carbonate ER, all given at night.  If gastrointestinal effects predominate, the liquid lithium citrate formulation may be best tolerated.

Remember, long-term dosing multiple times daily worsens kidney impairment.  Once daily dosing is MUCH safer for the long-term in relation to kidney function.  (Essentially, by dosing the drug once a day, the kidney sees low levels for much of the day and is thus less affected). 

It is advisable to check thyroid and kidney function tests about  one month after treatment begins, three months later, and then every 6-12 months in maintenance treatment.

Side Effects 

Lithium has four groups of side effects: nuisance, medically serious, toxic, and teratogenic.

Nuisance side effects

Nuisance side effects occur at therapeutic levels and lower, are often related to noncompliance, and are experienced as troublesome.  These include sedation, cognitive difficulties like poor concentration and memory, a sense of decreased creativity, dry mouth, hand tremor, increased appetite, weight gain, increased fluid intake (polydipsia), increased urination (polyuria), nausea, diarrhea, psoriasis, and acne.  Polydipsia and polyuria persist in about 25% of patients during maintenance treatment with lithium.  When severe, this increased urination may represent nephrogenic diabetes insipidus, a condition due to lithium’s inhibition of the kidney’s sensitivity to the pituitary’s antidiuretic hormone (ADH, or vasopressin). 

Some of these side effects are treatable: sedation and cognitive effects may improve with the controlled release formulation; dry mouth can be minimized by use of sugar-free candy; increased appetite and weight gain can be responsive to carbohydrate restriction (since lithium has a mild insulin-like effect) and exercise; nausea and diarrhea may respond to the citrate formulation, hand tremor may improve with the use of propanolol, and polydipsia/polyuria can improve with the use of thiazide diuretics, like the hydrochlorothiazide/triamterene combination.  Since thiazide diuretics increase lithium levels, lithium doses should be decreased by about 50% in coadminstration and levels followed.  It should be noted that because of lithium’s mild insulin-like effect, the insulin regimen of diabetic patients receiving lithium may also need to be altered.  Frequently, despite these measures, individuals are unable to tolerate lithium solely due to these nuisance side effects, which are the main source of lithium noncompliance (Table 14.1).

Medically serious side effects

Medically serious side effects (excluding toxicity) fall into three sub-categories:  thyroid abnormalities, chronic renal insufficiency, and cardiac effects. 

Lithium’s thyroid effects can occur early in treatment, but often appear after years of use as well.  Lithium has a direct reversible antithyroid effect, and thus it can lead to hypothyroidism (usually in about 5% of patients).  It inhibits the thyroid gland’s sensitivity thyroid stimulating hormone (TSH). High TSH levels on laboratory tests indicates a need to either discontinue lithium or supplement it with thyroid hormone replacement.  Either T4 or T3 formulations can be use, alone or in combination; the most common practice is to use T4 (l-thyroxine), since it is metabolized in the body to T3 naturally. 

Lithium’s kidney effect is more long-term, usually seen after 10-20 years of chronic therapy.  Unlike the acute direct inhibition of renal concentrating ability (including diabetes insipidus), this long-term effect of lithium is often irreversible and may involve renal glomerular function, resulting in a mild azotemia in most cases (mildly elevated creatinine levels).  Lithium appears to reduce glomerular filtration rate, usually slightly.  In rare instances, it can lead to severe chronic renal insufficiency and nephrotic syndrome, with glomerular pathologies of varying types.  In the setting of new azotemia, the clinician needs to consider switching from lithium to another agent, although sometimes lithium can safely be continued, as long as future kidney function tests do not worsen beyond mild abnormalities.  

Lithium’s cardiac effects mainly consist of some decrease in cardiac conduction efficiency, which can result in sick sinus syndrome.  Lithium can produce blockade of the sinoatrial node, premature ventricular beats, and atrioventricular blockade.    If lithium use is essential in a patient with these effects, a cardiac pacemaker may be necessary.  Otherwise, the use of a different mood stabilizer may be indicated. 

It is noteworthy that lithium mildly increases free calcium levels, possibly by stimulating direct release of parathyroid hormone from the pituitary gland, but this effect has little clinical significance, and hypercalcemia is not a serious problem. Lithium can also produce a mild leukocytosis, although this as well is without clinical sequelae.


Lithium toxicity occurs in non-elderly adults usually beginning at a level of 1.2, with minimal side effects of tremor, nausea, diarrhea, and ataxia.  Levels from 1.5-2.0 are associated with a higher risk of seizures.  Above 2.0, acute renal failure can occur and dialysis may be warranted.  Above 2.5, coma and death can occur and dialysis is indicated.  In the elderly, these signs of toxicity can occur at half the levels.  A special warning is appropriate for the elderly depressed patient who experiences diminished appetite: decreased fluid intake will raise lithium levels to toxic ranges quickly.  If renal failure is produced, lithium levels rise exponentially, greatly increasing the risk of death.  Thus, dialysis is essential in such cases.


Early reports based on retrospective data found that lithium was associated with increased levels of congenital cardiac malformations in children of mothers treated during pregnancy.  Specifically, Ebstein’s anomaly, a malformation of the tricuspid valve, was associated with lithium use in the first trimester of pregnancy.  Recent prospective studies report lower risks than in the past.  However, cardiac malformations, specifically Ebstein’s anomaly, are still generally thought to be a risk with lithium use during pregnancy.  These risks are probably lower than the risks of neural tube defects associated with the use of anticonvulsant mood stabilizers, like divalproex and carbamazepine, in pregnancy.  Thus, in the severely ill manic patient who requires treatment, lithium use, with or without high-potency conventional antipsychotics, may at times be necessary, ideally after the first trimester of pregnancy.  However, if possible, lithium use is still generally avoided during pregnancy. 

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