Lithium: what it is, when we use it, and what to know if you take it.

Lithium (also known as lithium carbonate, lithium citrate, and Lithobid in the US), is the oldest medication for bipolar disorder, discovered in 1949. Even though it has been around for a long time and has been well studied, there is still a lot of stigma and misinformation surrounding the medication. In this post we will talk about when we use lithium, how it works, possible side effects, lithium levels, and more.

As always, this is for educational purposes only and not medical advice. If you have questions or concerns, it's important to talk to your doctor or pharmacist as everyone is different! This is not a comprehensive list of everything you need to know about lithium treatment, but hopefully, it gives you a jumping-off point to discuss more with your doctor.

When We Use Lithium

Lithium is most commonly used for treating bipolar disorder and is actually the most effective medication for bipolar disorder. Lithium has shown benefits when used during manic, hypomanic, and depressive episodes. It can also be used as "maintenance therapy" (used in between episodes in order to prevent repeat episodes).

Lithium is also used (along with other medications) for schizoaffective disorder and treatment-resistant depression. Lithium is a unique medication in that it also reduces the risk of suicide, so it is sometimes used for that reason.

How it Works

Despite lithium being one of the best-studied psychiatric drugs, we still don't fully understand how it works! But to summarize, people with bipolar disorder may have brains that are more easily stimulated. Lithium may work by calming overstimulation and preventing it from damaging the brain. Here are some specific ways we think lithium might do this (for the clinicians and neuroscience nerds):

1. Lithium decreases levels of glutamate and dopamine (excitatory neurotransmitters) and increases levels of GABA (inhibitory neurotransmitter), which may have the effect of calming down the brain (Vecera, 2021; Malhi, 2013).

2. Lithium action on the phospho-inositide pathway, adenyl cyclase pathway, and protein kinase C may also have a calming effect on the brain (again by decreasing excitatory neurotransmission) (Malhi, 2013).

3. Lithium corrects abnormal calcium activity at the N-methyl-D-aspartate (NMDA) ionotropic receptor, a receptor that has been implicated in mood disorders (Malhi, 2016).

4. Lithium keeps neurons (brain cells) and their connections healthy by decreasing oxidative stress, blocking the action of glycogen synthase kinase 3, and increasing neuroprotective hormones like brain-derived neurotrophic factor (Malhi, 2013).

5. And more!

Lithium Levels

Part of the reason that there is so much stigma around lithium is that in the past doctors used the medication more casually and at much higher doses without the stringent monitoring we use today. As a result, side effects and chronic toxicity were common and people understandably became anxious about the medication.

Nowadays, we have a much better understanding of how to safely use lithium. Part of safe lithium use involves regular monitoring of blood lithium levels, kidney function, thyroid function, and other routine blood tests. We typically check blood lithium levels five days after a change in dose (because that is how long it takes for the drug to reach a "steady-state" in the blood), or any time we suspect that the lithium level has changed (for example, due to new side effects or worsening of the person's mental health). Once someone is stable on their lithium dose and there are no issues, monitoring can usually be spaced out to once every 6 to 12 months.

For most patients, we aim to keep lithium levels between 0.6 and 1.2 mEq/L (or 0.6 to 1.2 mmol/L). Some patients may get better with lower levels. Levels above 1.5 mEq/L significantly increase the risk for side effects and lithium toxicity (see below).

There are several things that can alter the blood level of lithium including:

• A change in lithium dose

• Missing or taking extra lithium

• A significant change in sodium intake

• Dehydration

• Taking certain diuretics (medications usually used for high blood pressure)

• Taking NSAIDs (such as naproxen or ibuprofen)

The dose required to reach a therapeutic blood level of lithium varies depending on the person and it takes time to increase the dose to an effective level. Most people need between 900 mg and 1800 mg of lithium (usually given in divided doses throughout the day).

Common Side Effects of Lithium:

Some of the most common side effects of lithium treatment include:

• Nausea

• Diarrhea

• Increased thirst

• Increased urination

• Mild tremor

• Sexual problems

• Feeling tired

• Skin problems like acne or psoriasis

• Weight gain

Depending on the severity of these symptoms and the person's underlying mental illness, we can address this by decreasing the lithium dose and/or using other medications to treat the side effects. If these side effects become bothersome and are not improved by other strategies, we sometimes have to switch to an alternative treatment.

Other Possible Side Effects of Lithium:

• Thyroid problems

• Overactive parathyroid glands/high calcium levels

• Problems with the heart rhythm

• Memory problems

• Seizures

These side effects are less common and the risk is generally highest with high blood levels of lithium and long-term treatment.

Lithium and Kidney Disease

Lithium is associated with a risk of kidney disease, with most studies estimating the risk to be between 10-15% of patients on long-term lithium therapy. The risk of kidney problems is higher in patients who have been treated with lithium for longer and in patients who develop lithium toxicity (see below). Most kidney problems that develop from lithium use are mild and reversible if they are caught early, which is a big part of the reason why we monitor labs so frequently. If there are signs of kidney problems, we talk about the risks and benefits of continuing treatment or stopping the lithium in favor of an alternative medication (Van Alphen, 2021).

Lithium Toxicity and Overdose

As above, lithium levels over 1.5 mEq/L increase the risk for side effects and lithium toxicity. Signs of lithium toxicity include:

• Tremor/shaking

• Nausea/vomiting/diarrhea

• Difficulty walking/problems with coordination

• Confusion

• Sedation

• Coma

If not treated, lithium toxicity can be fatal so it is important to let your doctor know if you develop these symptoms or any others!

Lithium and Alzheimer's Disease

There have been approximately 18 studies, summarized and individually cited by Thunell and colleagues (2021) suggesting that lithium use (in some studies, even in microdoses) may decrease the risk of Alzheimer's disease and similar forms of dementia. We think this may have something to do with the neuroprotective effects of lithium discussed above. It is a fascinating subject so look out for more research to come!

Lithium Orotate

It is important to note that lithium orotate is NOT the same as the other forms of lithium described above. It is not something that we use for patients with psychiatric illnesses because there is not enough scientific evidence that it is helpful, possibly because of differences in bioavailability and much lower levels of lithium in lithium orotate formulations. Even though it is available over the counter it should not be taken without physician supervision as it can cause serious side effects when used incorrectly.

Final Thoughts

Although there is a risk for some potentially scary side effects, these are generally quite rare and can be avoided or mitigated with careful patient selection and close monitoring. In patients with bipolar disorder, schizoaffective disorder, and treatment-resistant depression, lithium can be life-saving.

References and Further Reading

Malhi GS, Outhred T. Therapeutic mechanisms of lithium in bipolar disorder: Recent advances and current understanding. CNS Drugs. 2016; 30(10):931.

Malhi GS, Tanious M, Das P. Potential mechanisms of action of lithium in bipolar disorder. CNS Drugs. 2013; 27: 135–153.

Thunell J, Yi Chen GJ, Barthold D, Shekelle PG, Brinton RD, Zissimopoulos J. Drug therapies for chronic conditions and risk of Alzheimer's disease and related dementias: A scoping review. Alzheimers Dement. 2021 Jan; 17(1): 41–48.

Van Alphen AM, Bosch, TM, Kupka RW. Chronic kidney disease in lithium-treated patients, incidence and rate of decline. Int J Bipolar Disord. 2021; 9(1).

Vecera CM, Fries GR, Shahani LR, Soares JC, Machado-Vieira R. Pharmacogenomics of lithium response in bipolar disorder. Pharmaceuticals. 2021; 14(4):287.