Retrospectacle: A Neuroscience Blog

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.

Comments

  1. #1 coturnix
    September 6, 2006

    And then, there is the alternative possible mechanism…

  2. #2 Vaughan
    September 6, 2006

    …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.

    There is virtually no consistent evidence for this. Really, try and find some on PubMed. It doesn’t exist.

    It still amazes me that the low serotonin theory of depression still gets bandied about by neuroscientists.

    Anyway, I shall get off my hobby horse, but I think it’s important we offer theories of mental illness to the public based on the weight of scientific evidence.

  3. #3 Blas
    September 6, 2006

    > This may also explain one of the side effects of lithium use: memory loss.

    I wonder how this memory loss relates to the antidepressive effect. Many old shock therapies produced memory loss too. Maybe forgetting about traumas and the possibility to rewire in different patterns is what lifts mood.

    I also wonder if the action of psychiatric drugs work in part because they produce “any” change in the brain that moves things in a different direction. SSRIs work but also tianeptine. I would like to know if this could be understood as a complex syetem adaptation.

    Is the memory loss from lithium reversable?

    Give me the original 7-up and Coke back!. It is unjust that I could never tried them, I desperately need them!. Psychopharmachology at the vending machine sounds good for me.

    Many online vitamin stores sell lithium orotate, I donīt know if it is effective. I know doses of lithium carbonate for bipolar have to be monitored in blood because of toxicity level close to the therapeutic one right?.

    The French say one of their mineral waters is rich in lithium and also champagne. Maybe lithium and not fluoride is what must go into tap water :-)

  4. #4 Blas
    September 6, 2006

    Vaughan, it is what low serotonin causes, not the low serotonin per se. The catecholamine hypothesis has evolved.

    Anyway, thereīs isnīt any proof for most of things, like that you and me are individuals, have a mind, can think,etc.

    SSRI treatment is not obsolete, but the process by which it works is perhaps not a previously thought. Raising serotonin in the body, it was found, increases the levels of a protein known as CREB (cAMP response element-binding protein), which increases BDNF levels which gives rise to neurogenesis. These new discoveries about brain physiology in depressed patients create promising new treatment options for depressed patients. New treatments, it is thought, will deal directly with chemical cascades inside the cell, rather than with neurotransmitter manipulations (Farley, 2004).
    http://www.bio.davidson.edu/people/vecase/SeniorColloquium/04/Mental%20Webpage/Mental%20-%20Phys/BrainPhysHome.htm

  5. #5 Navneet
    September 6, 2006

    I had come across this hypothesis that lithium ions also interfered with the Phospholipase-IP3 signal transduction cascade. Is this in anyway linked to the hypothesis that you discuss?

  6. #6 Shelley Batts
    September 6, 2006

    I have also heard that hypothesis Navneet, although it wasn’t touched on in the review paper I read. Looking over the literature (and pointed out by coturnix) there are several different theories, all of which are likely true to a degree. For the sake of brevity I just discussed the serotonin theory—-please feel free to post a comment on this theory?

  7. #7 Vaughan
    September 7, 2006

    Vaughan, it is what low serotonin causes, not the low serotonin per se. The catecholamine hypothesis has evolved.

    The catecholamine hypothesis has evolved but not to suggest that low 5HT causes depression. In fact, there is barely any consistent evidence for a correlation, let alone a causation. [NN review 1, NN review 2]

    The tryptamine washout studies have induced a mild dysphoria at best and reserpine, a drug that lowers monamines, can be used as a treatment for depression (for a more complex effect, see tianeptine, which is a selective serotonine reuptake enhancer).

    SSRI treatment is not obsolete… [plus explanation of neurogenesis / CREB / BDNF theories]

    I agree with this wholeheartedly. SSRIs are useful in treating depression and I look forward to their continued improvement. I also look forward to seeing more of this type of research that is attempting to uncover the neurochemistry of depression on the basis of consistent reliable evidence.

  8. #8 Blas
    September 7, 2006

    > >Vaughan, it is what low serotonin causes, not the low serotonin per se. The catecholamine hypothesis has evolved.
    >
    > The catecholamine hypothesis has evolved but not to suggest that low 5HT causes depression. In fact, there is barely any consistent evidence for a correlation, let alone a causation. [PubMed search, NN review 1, NN review 2]

    It depends on what you call evidence: animal models of depression, in vitro, in vivo, clinical experience of psychiatrists?

    I think there is “evidence” for a correlation at least and definitive causes are only for theologists.

    I am not a reductionist and I donīt think there is compelling evidence for anything regarding treatments for the human mind. There is not much evidence e.g. for psychoanalysis or CBT depending on who evaluates the data.

    >
    > The tryptamine washout studies have induced a mild dysphoria at best

    AFAIK in “normal” people. In people witj alterred sero transports I think the rsult would be different.

    >and reserpine, a drug that lowers monamines, can be used as a treatment for depression

    I higly doubt it because reserpine is well known for causing depression in the times unfortunate people suffering hypertension did not have even propranolol to use.

    > (for a more complex effect, see tianeptine, which is a selective serotonine reuptake enhancer).

    Which is a different thing than supressing serotonin.

    >
    >> SSRI treatment is not obsolete… [plus explanation of neurogenesis / CREB / BDNF theories]
    >

    BTW recently I read some news discrediting the neurogenesis theory.

    > I agree with this wholeheartedly.
    > SSRIs are useful in treating depression and I look forward to their continued improvement.

    Yes, especially because they do not work that well.

    >I also look forward to seeing more of this type of research that is attempting to uncover the neurochemistry of depression on the basis of consistent reliable evidence.

    From what I see the honest psychiatrists do, they use drugs because of their experience and data but not because of the ammount of experimental evidence, they try and see what works for a particular patient. And if they donīt work they do not insist.

    The rest is marketing from companies.

    p.s. this blog script has many problems

  9. My name is Jason Gorman and I am 45 years old. My wife was taking 1200mg of Lithium Carbonate daily prescribed by the doctor for over two years. During this time no lab work was ever ordered. It built up in her system over a period of time. She was taken to the ER where she almost died. Her pulse was down to 31 and her blood pressure as low as 43 over 17. She under went kidney dialysis continuously for over 30 hours in ICU. She spent a total of 5 days in the hospital. I strongly recommend against taking Lithium. At least have periodic Lab Work done. Also if you do take this medication look up the side effects on the internet.

    My wife has experienced some of these side effects-
    Dizziness, Vomiting, Diarrhea, Confusion, Tremors, Muscle Weakness, Loss of Bladder Control, Inability to talk

    I hope this information will be useful to others,
    Jason Gorman

  10. #10 Dentist Vaughan
    July 26, 2009

    It is surprising that after all this time, we do not fully understand how lithium works in treating depression.

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