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Lithium pharmacology

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This article discusses the pharmacological uses of lithium salts; for information on the
chemistry of individual lithium salts, see Category:Lithium compounds.

Lithium in pharmacology refers to use of the lithium ion, Li+, as a drug. A number of
chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the
treatment of bipolar disorder, where they have a role in the treatment of depression and
particularly of mania, both acutely and in the long term. As a mood stabilizer, lithium is
probably more effective in preventing mania than depression, and may reduce the risk of
suicide.[1] In depression alone (unipolar disorder) lithium can be used to augment other
antidepressants. Lithium carbonate (Li2CO3), sold under several trade names, is the most
commonly prescribed, while the citrate salt lithium citrate (Li3C6H5O7), the sulfate salt
lithium sulfate (Li2SO4), lithium aspartate and the orotate salt lithium orotate are

Upon ingestion, lithium becomes widely distributed in the central nervous system and
interacts with a number of neurotransmitters and receptors, decreasing norepinephrine
release and increasing serotonin synthesis.


• 1 History
• 2 Treatment
• 3 Mechanism of action
• 4 Harmful effects of lithium
• 5 Lithium and culture
• 6 References
• 7 Selected bibliography

• 8 External links

[edit] History
Solutions of lithium will dissolve uric acid crystals.[citation needed] Against the background of
nineteenth century theories linking excess uric acid to a range of disorders, including
depressive and manic disorders, Carl Lange in Denmark[2] and William Alexander
Hammond in New York[3] used lithium to treat mania from the 1870s onwards.
However, by the turn of the century, the use of lithium in this way died out and was
seemingly forgotten. This was also due to the reluctance of the pharmaceutical industry to
invest in a drug that could not be patented.[4]

The use of lithium salts to treat mania was rediscovered by the Australian psychiatrist
John Cade in 1949. Cade was injecting rodents with urine extracts taken from
schizophrenic patients, in an attempt to isolate a metabolic compound which might be
causing mental symptoms. Since uric acid in gout was known to be psychoactive
(purinergic neurons are stimulated by it), Cade needed soluble urate for a control. He
used lithium urate, already known to be the most soluble urate compound, and observed
that this caused the rodents to be tranquilized. Cade traced the effect to the lithium ion
itself. Soon, Cade proposed lithium salts as tranquilizers, and soon succeeded in
controlling mania in chronically hospitalized patients with them. This was one of the first
successful applications of a drug to treat mental illness, and it opened the door for the
development of medicines for other mental problems in the next decades.[5]

The rest of the world was slow to adopt this revolutionary treatment, largely because of
deaths which resulted from even relatively minor overdosing, and from deaths reported
from use of lithium chloride as a substitute for table salt. Largely through the research
and other efforts of Denmark's Mogens Schou in Europe, and Samuel Gershon in the
U.S., this resistance was slowly overcome. The application of lithium for manic illness
was approved by the United States Food and Drug Administration in 1970.[6]

[edit] Treatment
Lithium treatment is used to treat mania in bipolar disorder. Initially, lithium is often used
in conjunction with antipsychotic drugs as it can take up to a month for lithium to have an
effect. Lithium is also used as prophylaxis for depression and mania in bipolar disorder. It
is sometimes used for other psychiatric disorders such as cycloid psychosis and unipolar
depression. Non-psychiatric uses are limited however, its use in the prophylaxis of some
headaches related to cluster headaches (trigeminal autonomic cephalgias:- particularly
hypnic headache is well established). More recently, Lithium has shown promising
results in a human trial in the neurodegenerative disease amyotrophic lateral sclerosis. It
is sometimes used as an "augmenting" agent, to increase the benefits of standard drugs
used for unipolar depression. Lithium treatment was previously considered to be
unsuitable for children, however more recent studies show its effectiveness for treatment
of early-onset bipolar disorder in children as young as eight. The required dosage (15-
20mg per kg of body weight) is slightly less than the toxic level, requiring blood levels of
lithium to be monitored closely during treatment. In order to prescribe the correct dosage,
the patient's entire medical history, both physical and psychological, is sometimes taken
into consideration.

Those who use lithium should receive regular serum level tests and should monitor
thyroid and kidney function for abnormalities. As it interferes with the regulation of
sodium and water levels in the body, lithium can cause dehydration. Dehydration, which
is compounded by heat, can result in increasing lithium levels.
High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used
with lithium; irreversible toxic encephalopathy has been reported.

Lithium salts have a narrow therapeutic/toxic ratio and should therefore not be prescribed
unless facilities for monitoring plasma concentrations are available. Patients should be
carefully selected. Doses are adjusted to achieve plasma concentrations of 0.6 to 1.2
mmol Li+/litre (lower end of the range for maintenance therapy and elderly patients,
higher end for pediatric patients) on samples taken 12 hours after the preceding dose.
Overdosage, usually with plasma concentrations over 1.5 mmol Li+/litre, may be fatal and
toxic effects include tremor, ataxia, dysarthria, nystagmus, renal impairment, and
convulsions. If these potentially hazardous signs occur, treatment should be stopped,
plasma lithium concentrations redetermined, and steps taken to reverse lithium toxicity.
The most common side effects end up being an overall dazed feeling and a fine hand
tremor. These side effects are generally present during the length of the treatment but can
sometimes disappear in certain patients. Other common side effects such as nausea and
headache, can be generally remedied by a higher intake of water. Lithium unbalances
electrolytes; to counteract this, increased water intake is suggested.

Lithium toxicity is compounded by sodium depletion. Concurrent use of diuretics that

inhibit the uptake of sodium by the distal tubule (e.g. thiazides) is hazardous and should
be avoided. In mild cases withdrawal of lithium and administration of generous amounts
of sodium and fluid will reverse the toxicity. Plasma concentrations in excess of 2.5
mmol Li+/litre are usually associated with serious toxicity requiring emergency treatment.
When toxic concentrations are reached there may be a delay of 1 or 2 days before
maximum toxicity occurs.

In long-term use, therapeutic concentrations of lithium have been thought to cause

histological and functional changes in the kidney. The significance of such changes is not
clear but is of sufficient concern to discourage long-term use of lithium unless it is
definitely indicated. Doctors may change a bipolar patient's medication from lithium to
another mood stabilizing drug, such as Depakote (divalproex sodium), if problems with
the kidneys arise. An important potential consequence of long-term lithium usage is the
development of renal diabetes insipidus (inability to concentrate urine). Patients should
therefore be maintained on lithium treatment after 3-5 years only if, on assessment,
benefit persists. Conventional and sustained-release tablets are available. Preparations
vary widely in bioavailability, and a change in the formulation used requires the same
precautions as initiation of treatment. There are few reasons to prefer any one simple salt
of lithium; the carbonate has been the more widely used, but the citrate is also available.

[edit] Mechanism of action

Unlike other psychoactive drugs, Li+ produces no obvious psychotropic effects (such as
euphoria) in normal individuals at therapeutic concentrations.

The precise mechanism of action of Li+ as a mood-stabilizing agent is currently unknown.

It is possible that Li+ produces its effects by interacting with the transport of monovalent
or divalent cations in neurons. However, because it is a poor substrate at the sodium
pump, it cannot maintain a membrane potential and only sustains a small gradient across
biological membranes. Yet Li+ is similar enough to Na+ in that under experimental
conditions, Li+ can replace Na+ for production of a single action potential in neurons.

Recent research suggests three different mechanisms which may act together to deliver
the mood-stabilizing effect of this ion [7]. The excitatory neurotransmitter glutamate could
be involved in the effect of Lithium as other mood stabilizers such as valproate and
lamotrigine exert influence over glutamate, suggesting a possible biological explanation
for mania.[citation needed] The other mechanisms by which lithium might help to regulate
mood include the alteration of gene expression[8] and the non-competitive inhibition of an
enzyme called inositol monophosphatase.

An unrelated proposed mechanism of action put forth at the University of Pennsylvania

in 1996 posits that lithium ion deactivates the GSK-3B enzyme.[9] The regulation of
GSK-3B by lithium may affect the circadian clock -- and recent research (Feb 2006)
seems to support this conclusion. When GSK-3B is activated, the protein Bmal1 is unable
to reset the "master clock" inside the brain; as a result, the body's natural cycle is
disrupted. When the cycle is disrupted, the routine schedules of many functions
(metabolism, sleep, body temperature) are disturbed.[10] Lithium may thus restore normal
brain function after it is disrupted in some people. The complete mechanism related to
mood in this mechanism is not hypothesized.

Another mechanism proposed in 2007 is that lithium may interact with nitric oxide (NO)
signalling pathway in the central nervous system which plays a crucial role in the neural
plasticity. Ghasemi et al. (2008) have shown that the NO system could be involved in the
antidepressant effect of lithium in the Porsolt forced swimming test in mice [11].

[edit] Harmful effects of lithium

Lithium is much less teratogenic than previously thought, though it does double the
likelihood of Ebstein's anomaly (a cardiac defect), occurring at 0.1% when used during
the first trimester of pregnancy.

The average developmental score for the lithium-exposed group of children was 7-8
points lower than the control group (siblings), but well within the normal range of

There have also been long term effects on the kidney, including diabetes insipidus with
secondary distortion of bladder and urinary tract. Animal studies show long-term physical
and behavioural effects extending beyond the first generation.[citation needed]

Lithium is known to be responsible for (sometimes significant) weight gain, acne with
scarring, thinning of hair, and pronounced tremor, usually in the hands but extending to
lips and tongue when the person is stressed, or after prolonged use.[13][14][15] [16][17]
[edit] Lithium and culture
As with many other psychoactive drugs (but relatively few therapeutic psychoactive
drugs), songs have been written about its effects; "Lithium Sunset" by Sting, "Lithium"
by Nirvana, "Tea and Thorazine" by Andrew Bird, and "Lithium" by Evanescence are
some examples.

Hundreds of soft drinks included lithium salts or lithia water (naturally occurring mineral
waters with higher lithium amounts). An early version of Coca Cola available in
pharmacies' soda fountains called Lithia Coke was a mixture of Coca Cola syrup and
lithia water. The soft drink 7 Up, originally named "Bib-Label Lithiated Lemon-Lime
Soda", contained lithium citrate[18] until it was reformulated in 1950. Additionally, Lithia
light beer was brewed at the West Bend Lithia Company in Wisconsin. All of these were
forced to remove lithium in 1948.

In popular HBO series The Sopranos Tony Soprano received Prozac and lithium as the
medications from Dr. Melfi for anxiety attacks. Dr. Melfi later stopped the lithium,
because she thinks that lithium caused Tony's hallucinations about Isabella, an exchange
student from Italy who temporarily lived next door.

In the Darren Aronofsky film Pi, the protagonist Maximillian Cohen takes Lithium to
relieve his mental illness.

In the Zach Braff film Garden State, the protagonist Andrew Largeman stops taking
Lithium and begins to experience life very differently.

What Is Lithium?
Lithium (Eskalith®, Eskalith CR®, Lithobid®) is a prescription medication
approved to treat bipolar disorder (also known as manic depression).

(Click Lithium Uses for more information, including possible off-label


Who Makes Lithium?

Lithium is made by a number of different manufacturers (see Generic

How Does It Work?

Lithium is a naturally occurring element, like potassium or calcium. In
the 1800s, scientists thought that lithium might be an effective
treatment for gout, although it was found to be ineffective for this use.
Later, in the 1940s, it was used as a salt substitute, until it was
withdrawn from the market due to several deaths that were caused by
lithium toxicity. Later, it was discovered that lithium works for mania.
In 1970, the U.S. Food and Drug Administration (FDA) approved the
medication for the treatment of bipolar disorder.

The exact way in which the drug works to treat bipolar disorder is not
known. Lithium may affect various chemicals in the brain called
neurotransmitters, which could explain the its effectiveness in treating
bipolar disorder. The medication is not a cure for the condition,
however -- it only helps to control symptoms (see Bipolar Disorder

When and How to Take Lithium

The following are some general considerations for when and how to
take lithium:

• The medication comes in several different forms, including

regular tablets, extended-release tablets, capsules, and a syrup.
It is taken by mouth, usually two to four times a day, depending
on the lithium dosage and the particular product.

• You can take lithium with or without food. If the medication

bothers your stomach, try taking it with food.

• Extended-release tablets (Lithobid) should not be chewed,

crushed, or broken. They should be swallowed whole.

• Lithium should be taken at the same times each day to maintain

an even level in your blood.
• For the medication to work properly, it must be taken as
prescribed. Lithium will not work if you stop taking it.

Dosing Information
The dose of lithium your healthcare provider recommends will vary,
depending on a number of factors, including:

• How you respond to the medication

• The particular product being used
• Other medical conditions you may have
• Other medications you may be taking.

As always, do not adjust your dose unless your healthcare provider

specifically instructs you to do so.

Side Effects of Lithium

As with any medicine, side effects are possible with lithium. However,
not everyone who takes the drug will experience side effects. In fact,
most people tolerate it quite well. If side effects do occur, in most
cases, they are minor and either require no treatment or can be easily
treated by you or your healthcare provider. Serious side effects are
less common.

Common side effects include but are not limited to:

• Diarrhea
• Drowsiness
• Loss of appetite
• Nausea or vomiting.
(Click Lithium Side Effects to learn more, including potentially serious
side effects you should report immediately to your healthcare

You can also read more about specific side effects in the following
eMedTV articles:

• Lithium and Dry Mouth

• Lithium and Hair Loss.

Drug Interactions
Lithium can potentially interact with a number of other medicines (see
Lithium Drug Interactions).

What Should I Tell My Healthcare Provider Before

Taking It?
Talk with your healthcare provider prior to taking lithium if you have:

• Kidney disease, including kidney failure (renal failure)

• Heart disease
• Dehydration
• Low sodium levels in your blood (hyponatremia)
• Any allergies, including allergies to food, dyes, or preservatives.

Also, let your healthcare provider know if you are:

• Pregnant or thinking of becoming pregnant (see Lithium and

• Breastfeeding (see Lithium and Breastfeeding).
You should also make sure to tell your healthcare provider about all of
the medicines you take, including prescription and non-prescription
medicines, vitamins, and herbal supplements.

What If I Take an Overdose?

People who take too much lithium may have overdose symptoms that
could include:

• Diarrhea and vomiting

• Drowsiness
• Muscle weakness
• Coordination problems
• Blurred vision
• Ringing in the ears (tinnitus)
• Increased urination
• Shakiness (especially in the hands)
• Thirst.

If you happen to overdose on the drug, seek immediate medical


(Click Lithium Overdose for more information.)

How Should Lithium Be Stored?

Lithium should be stored at room temperature, away from moisture
and heat. It should also be stored in an airtight container.

Keep lithium and all other medications out of the reach of children.

What Should I Do If I Miss a Dose?

If you do not take your lithium as scheduled, take your missed dose as
soon as you remember. If it is almost time for your next dose, skip the
missed dose and continue with your regular schedule. Do not take a
double dose. Make sure to tell your healthcare provider if you miss any
lithium doses, especially if the level in your blood is being monitored.

Available Strengths
Lithium is available in the following strengths and forms:

• Lithium carbonate 150 mg capsules

• Lithium carbonate 300 mg capsules (Eskalith)
• Lithium carbonate 600 mg capsules
• Lithium carbonate 300 mg tablets
• Lithium carbonate 300 mg extended-release tablets (Lithobid)
• Lithium carbonate 450 mg extended-release tablets (Eskalith
• Lithium citrate syrup, containing 8 mEq lithium per 5 mL, which
is equivalent to 300 mg lithium carbonate per 5 mL or per

Lithium Toxicity
People who are taking lithium for bipolar disorder may develop lithium
toxicity because the effective dose is close to the toxic dose. To
prevent and detect this, healthcare providers usually require regular
blood tests that measure the lithium level in the blood. Based on
these tests, your dosage may be adjusted. Symptoms of toxicity
include shakiness, increased urination, and coordination problems.

An Introduction to Lithium Toxicity

Lithium (Eskalith®, Eskalith CR®, Lithobid®) is a prescription medication
approved to treat bipolar disorder. While it is one of the more effective
and affordable bipolar medications available, it can cause significant
toxicity. All medications can produce toxicity if taken in high enough
doses. For most medications, however, the effective dose is much
lower than the toxic dose (and toxicity is rare, except in cases of an
overdose). With other medications, such as lithium, the effective dose
is close to the toxic dose, and toxicity is more common.
Toxic Lithium Levels
In order to prevent and detect lithium toxicity, healthcare providers
usually require regular blood tests that measure the level of lithium in
your blood. Based on your lithium level (as well as any lithium side
effects or symptoms of bipolar disorder you are experiencing), your
healthcare provider may adjust your lithium dosage. Unfortunately,
some people will experience lithium toxicity even if their levels are
within the recommended range. In general, levels greater than 1.5
milliequivalents per liter (mEq/L) increase the risk of lithium toxicity
and require medical attention.

In order for your lithium blood level to be meaningful, it should be

taken at a certain time, preferably just before a dose of lithium (about
8 to 12 hours after the previous dose). Levels taken at other times are
typically less useful, as your dose is less stable during these times.

Symptoms of Toxicity
Many side effects of lithium are related to lithium levels and are,
therefore, symptoms of lithium toxicity. In general, the following side
effects may be signs of mild to moderate toxicity:

• Mild shakiness, especially in the hands

• Thirst
• Increased or frequent urination
• Diarrhea
• Vomiting
• Drowsiness
• Muscle weakness
• Coordination problems.

Signs of more severe toxicity include:

• Giddiness
• Blurred vision
• Ringing in the ears (tinnitus)
• Severe shakiness
• Seizures.

Because the effective lithium blood level is so close to the toxic blood
level, many people must endure mild symptoms of lithium toxicity in
order to take an effective dosage. It is not unusual for people to have
mild hand shakiness (tremors), thirst, and increased urination the
entire time they are taking lithium. However, if your symptoms
become worse (or if you have new symptoms), this may signal a
problem with lithium toxicity.

Treatment for Toxic Levels of Lithium

The treatment for lithium toxicity depends on a few factors, including
the level of lithium in the blood. If an overdose was taken, pumping
the stomach (or administering certain medications to prevent the body
from absorbing the drug from the digestive tract) can help. If the level
in the blood is very high, dialysis can be helpful. Stopping lithium for a
while may be necessary, although a dose reduction may be adequate
in mild cases. Administering fluids intravenously (by IV) can also be

Preventing Lithium Toxicity

In most cases, toxic levels of lithium are preventable. In order to
decrease your risk, consider the following suggestions:

• Follow your lithium dosing instructions carefully, and do not take

more than prescribed.
• Drink plenty of fluids, as being dehydrated increases the risk of
lithium toxicity.
• Do not start a low-salt (low-sodium) diet without discussing the
risks of toxicity with your healthcare provider, as decreasing
your salt intake may increase your risk.
• Make sure to have your lithium levels checked regularly.
• Contact your healthcare provider and have your lithium level
checked if you notice any symptoms of toxicity.