For many years, psychiatry has relied on the pharmacological usage of lithium (Li+), alone or in combination with other anti-depressants, as a treatment for bipolar disorder, depression, mania, etc. This, despite the fact that very little is known WHY Lithium works, let alone HOW.
The actual prescribed “dose” of lithium is not a pure metal, but rather as lithium “salts”: lithium carbonate, lithium oxybutyrate, lithium sulfate, among others. In 1949, Australian physician John Cade discovered that the administration of lithium salts (lithium urate) in animals resulted in a tranquilizing effect. He proposed the use of lithium in human patients, which did indeed successfully control or treat a host of mood disorders, and was one of the (if not THE) first successful drugs to treat any mental illness. The FDA approved the application of lithium for manic illnesses in 1970. (Interestingly, the soft drink 7 Up, originally named “Bib-Label Lithiated Lemon-Lime Soda”, contained lithium citrate until it was reformulated in 1950. There also existed “Lithia-Beers” and a lithium-containing version of Coca-Cola.)
Still, modern science is having a tough time explaining why lithium works at all. However, an interesting theory has been offered. (More under the fold……………..)
Specifically, there is a growing body of evidence that suggests that lithium increases the effect of antidepressants by acting at the presynaptic serotoninergic receptor to up-regulate 5-HT (serotonin) release. The effect may also be linked to a decrease in the sensitivity of presynaptic 5-HT receptors, which results in an increase in the amount of serotonin absorbed at the post-synaptic level.
Serotonin is a hormone and a neurotransmitter, acting as a chemical messenger which regulates many diverse aspects of the nervous system (roles in sleep, memory, appetite, mood, sex, endocrine function, among others) . Altered serotonin levels have been found in many different kinds of nervous disorders, from depression to anorexia to Parkinson’s to schizophrenia. A depletion of serotonin through either drugs or mis-aligned neurochemistry can be a powerful trigger for depression, and has been suggested to play a role in many other disorders. Correcting this serotonin depletion is the target of drugs such as Paxil.
It takes time for lithium to exert a meaningful ans therapeutic change in the brain. Interestingly, when lithium is administered chronically (3 weeks +) , this increase in serotonin is focused in the hippocampus, rather than globally. Conversely, when lithium is administered for only a short time (1 week), an increase in serotonin is seen more globally, throughout the cortex. The therapeutic effects of lithium are only evidenced after a few weeks, suggesting that it is the increase of serotonin in the hippocampus which is the target for anti-depressive treatment. This may also explain one of the side effects of lithium use: memory loss. The hippocampus is crucial in the formation of new memories and the maintenance of old ones, so memory loss can occur when the activity in this region changes.
Lithium also enhances the effect of selective serotonin reuptake inhibitors (SSRIs), a type of drug commonly prescribed to treat depression:
Muraki et al. (2001), investigated the effect of citalopram (SSRI) on median prefrontal cortex (mPFC) 5-HT levels
following a subchronic (1 week) lithium diet treatment. The subchronic lithium treatment group showed a significantly higher basal levels of extracellular 5-HT compared to control group; thus this indicates that lithium potentiates the neurobiochemical effect of an acute dose of SSRI on the mPFC.
Furthermore, it has been hypothesized that lithium blocks presynaptic 5-HT (1B) receptors only (partial agonist)—-which prevents the presynaptic terminal from taking released serotonin back. The serotonin must instead stay in the synaptic cleft, and therefore more likely to act on the un-blocked post-synaptic end. This in effect reverses the pre-existing “depletion” of serotonin at the nerve terminal, which could have been responsible for depression etc.
Source: Franck Chenu and Michel Bourin. 2006. Potentiation of Antidepressant-Like Activity with Lithium: Mechanism
Involved. Current Drug Targets, 7, 159-163 159.
For more on the role of serotonin in depression, check out this concise paper written for lay people.