The Discovery and History of Lithium as a Mood Stabilizer

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When was lithium first discovered as a drug for mental health, and what is the history of this medication? How does it actually work? And what is the current thought and controversy considering the role of lithium in the treatment of bipolar disease?


Lithium is a naturally occurring element (number three on the periodic table) that was first discovered in 1817 and was found in mines in Australia and Chili. It's mood stabilizing effects, however, were not recognized until late in that century.

Of interest, Lithium was first used to treat the arthritic inflammatory condition, gout. (At least one doctor, in fact, concluded from this that gout was the cause of mood disorders.) It was first used for mania in 1871, with Denmark leading the way, but little was published about the medication for more than half a century. Later on, in the 1940s, lithium was used as a blood pressure medication but soon proved to have too many side effects to be effective in this use.

It was Australian psychiatrist John Cade who, in 1949, published the first paper on the use of lithium in the treatment of acute mania. From that time on, lithium was prescribed widely, and mineral springs containing lithium were touted for their healing properties.

The U.S. Food and Drug Administration did not approve lithium for use until 1970, and the use of lithium in the U.S. began later, and shifted to other drugs earlier, than for many other countries around the world.

How It Works

Knowing that lithium is a naturally occurring element, one might think that prescribing the drug may support a deficiency in the body. Yet research has never indicated that that bipolar disorder might be caused by a lithium deficiency. Rather, it happens that this naturally occurring substance has the fortunate effect of acting as a mood stabilizer.

For almost 50 years, manic-depressive people were treated with lithium even though medical science did not have any idea why or how it worked. (The name manic-depressive disorder was officially changed to bipolar disorder in 1980.)

Then in 1998, University of Wisconsin researchers unlocked the mystery. The secret of lithium has to do with nerve cells in the brain, and the receptors for the neurotransmitter glutamate. To understand this, let's back up and talk about the function of neurotransmitters in the brain and their relationship to mental health disorders.

Neurotransmitters and Mental Health

How do messages in one part of the brain travel, and in doing so, result in actions? It's only been in the last few decades—when scientists have isolated neurotransmitters, the chemical messengers of the brain that act to convey information from one region to another—that we are beginning to understand this process.

Neurotransmitters are contained at the end of one neuron (or nerve.) An electrical impulse traveling along with the nerve results in neurotransmitters being released into space (the synapse) between one nerve and the next. Some of the neurotransmitters bind to receptors on the next nerve cell, which response by transforming that message to another electrical impulse. Neurotransmitters that are left in the synapse (those which do not bind to receptors on the next neuron) are taken back up into the original neuron to be used again.

There are several types of neurotransmitters in the brain. Some of these include:

  • Serotonin
  • Norepinephrine
  • Dopamine
  • Acetylcholine
  • GABA (gamma-aminobutyric acid)
  • Glutamate

Glutamate appears to be the neurotransmitter most involved in the manic phase of bipolar disorder (although this is very simplistic and most mental health disorders involve a confusing combination of neurotransmitters as well as other processes.) Glutamate is the most abundant neurotransmitter in the brain and is thought to be an excitatory neurotransmitter involved in learning and memory. GABA, in contrast, is an inhibitory neurotransmitter.

Lithium and Glutamate Stabilization

The University of Wisconsin researchers found that lithium exerts a dual effect on receptors for the neurotransmitter glutamate—acting to keep the amount of glutamate active between cells at a stable, healthy level, neither too much nor too little.

University of Wisconsin Medical School professor of pharmacology Dr. Lowell Hokin, who directed the research, said that from their research it could be postulated that too much glutamate in the space between neurons causes mania, and too little, depression.

There has to be more to it than that, since antidepressant medications, for example, work on the receptors of other neurotransmitters such as serotonin and dopamine. However, this was certainly a giant step forward in understanding the biological basis of bipolar disorder.

Note: a large amount of extra glutamate can lead to epileptic seizures or even kill the second cell from overstimulation (this is thought to play at least some role in Alzheimer's disease and in strokes).

While lithium does seem to play a role in moderating glutamate levels in the brain, and hence, the balance of excitation and depression, there are many questions left to answer. Even now, the effects of lithium on the brain are far from understood.

Other Potential Uses

In addition to bipolar disorder, lithium is sometimes used for unipolar depression (major depression) and schizoaffective disorder.

Because of lithium's stabilizing effect on glutamate receptors, scientists are also studying whether this medication can protect from the cell death that occurs in conditions such as Parkinson's, Huntington's, and Alzheimer's disease.

Toxicity and Side Effects

As with many medications on the market, lithium comes with a list of side effects and precautions. Lithium toxicity can be very serious, with both acute and chronic effects. The side effects of lithium are common as well, and as with many mental health medications, these side effects often interfere with its use.

In addition, lithium is known to interact with a wide variety of medications, such as other mental health drugs, blood pressure medications, drugs for Parkinson disease, and some painkillers.

All of that said, there are few medications available for the treatment of bipolar disorder that do not have significant side effects.

Role in Treatment of BPD

The answer to the question, "What role should lithium play in the treatment of bipolar disease today?" will vary depending on who you ask and where you live.

In addition to a roller-coaster history, there are widely varying opinions regarding the use of lithium today. Some physicians have gone so far as to call lithium "dangerous nonsense" whereas others view lithium as the best established long-term treatment available for bipolar disorder. Some physicians even claim that lithium is the single most important treatment for mental health which has been discovered.

As with many other issues related to mental health, the real answer probably lies somewhere between these extremes and is reflected in different practices around the world.

The United States has the reputation of being the "last in and first out" with regard to the use of the drug, being late among countries to adopt its use, and early to recommend alternatives (other mood stabilizers such as Depakote (valproic acid) and antipsychotic medications).

In the U.S., lithium is seldom used first-line for people with bipolar disorder, though it is still frequently used for severe bipolar disorder in combination with other medications. A 2017 study did, however, suggest that there is a strong role for lithium first line in the treatment of mania in the elderly.

The Bottom Line

The history of lithium is important to understand when looking at the discovery of methods to stabilize moods, and more recently in prompting scientists to investigate the chemical nature of mood disorders in the brain.

This newer understanding of the chemical messengers in the brain responsible for mental health disorders is important in further reducing the stigma of mental health disorders. While there is still a long way to go, and mental health still suffers more of a stigma than say heart disease, the research going on today—such as the mechanism by which lithium works—is an excellent step in the right direction.

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