Although bipolar disorder affects between 1% and 3% of the population , the great variability of its possible causes means that its nature remains relatively unknown. Something similar happened until recently with lithium, the drug of choice in the treatment of this disorder, which has been used for decades without its mechanism of action being known.

A study by Evan Snyder, Brian Tobe and other authors recently published in the journal Proceedings of the National Academy of Sciences has provided fundamental clues about the mechanism of action of lithium and the cause of the cases of bipolar disorder that improve with this drug. Specifically, they have detected alterations in the CRMP2 protein.

Characteristics of Bipolar Disorder

Bipolar disorder is characterized by periods of weeks to months when mood is pathologically low (depression), along with periods when energy levels increase significantly and a sense of emotional euphoria (mania) predominates .

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Both manic and depressive episodes significantly interfere with a person’s normal functioning; in fact, this disorder is the sixth most common cause of disability in the world’s population.

Specifically, the diagnosis of bipolar disorder is associated with a marked increased risk of suicide and self-harm . This is one of the reasons why it is customary to treat with strong medications; if these don’t work, electroconvulsive therapy may even be applied.

The causes of this disorder

The onset of bipolar disorder has been linked to a number of different causes. It is believed that genetic inheritance accounts for approximately 70% of the risk of developing this disorder .

However, the specific causal genes are not clear, as they appear to vary from case to case; the dominant hypothesis is that multiple genes are involved.

Furthermore, the finding of structural and functional alterations in regions such as the lateral ventricles, basal ganglia and amygdala suggests that anatomical and physiological factors also play a relevant causal role.

On the other hand, not all people with a biological predisposition to bipolar disorder develop it. For this to happen it is often necessary for psychosocial stress to occur , especially during the early stages of life; it is striking that 30-50% of affected persons report having suffered abuse or trauma in childhood.

What is lithium?

Lithium is a chemical element of the metal family. It is the solid element, and therefore also the lightest metal of all. On a pharmacological level, lithium salts are used to regulate mood in the treatment of bipolar disorder and other similar psychological problems, such as schizoaffective disorder or cyclical depression.

Among other effects, lithium decreases the risk of suicide for people with these disorders. Although it is the drug of choice for treating bipolar disorder, lithium is only effective in about one-third of affected people.

In addition, since the therapeutic dose is very close to the toxic dose, lithium carries risks and causes relevant secondary symptoms and adverse reactions, such as emotional numbness, weight gain, muscle tremors, nausea or the onset of diabetes insipidus and hypothyroidism.

Lithium started being used as a psychopharmaceutical about 60 years ago. Although its effectiveness in treating the symptoms of bipolar disorder (as we have seen, in one third of the cases) has been widely demonstrated during this time, until very recently the cause of these effects, i.e., its mechanism of action, was not known.

The mechanism of action of lithium

The research team led by Evan Snyder analysed the brain cells of people with bipolar disorder distinguishing between those that responded well to lithium and those that did not. Specifically, they used artificial stem cells to study the pathway of lithium once it has been introduced into the body.

Snyder and his collaborators found that in cases of bipolar disorder that benefit from lithium treatment, the CRMP2 protein, which regulates the central nervous system , is involved. It appears that the activity of CRMP2 is altered, as it is much lower in these patients than in those who do not respond adequately to lithium.

This finding indicates that there are different variants of bipolar disorder, which reinforces the prevailing theory that it is a polygenic (i.e., not determined by a single gene) disorder.

The discovery of the mechanism of action of lithium may favour the development of more effective drugs with fewer side effects, as it allows research efforts to be focused on the most relevant biological processes.

Likewise, the study by Snyder’s team suggests that identifying the causes of bipolar disorder in each specific case should be considered a determining factor in choosing the most appropriate pharmacological treatment for the individual.