The medical field has life saving drugs.  A few notable examples, aside from the obvious antibiotics, include cancer treatments such as immunotherapy, responsible for both President Carter’s miraculous recovery, and the equally miraculous 100% remission of colorectal cancer of four patients with another form of immunotherapy in 2022. Additionally, HIV was once a death sentence, but today we have drugs which allow infected people to live full, productive lives for many years as shown by Magic Johnson. These drugs address medical ailments that were once virtually untreatable.  

But what about Psychiatry as a medical specialty?  Suicide is the primary concern for us. We do not have a newly developed medication that can prevent suicide. However, there is a substance as old as the universe itself which can – lithium.  

Why has lithium not been thought of as a miracle drug? A short list includes: 

Ignorance:

1) lithium is old, and doctors and the public think newer developments are better; 

2) the antisuicidal, antidepressant effects, and neuroprotective benefits of lithium are not widely known amongst most psychiatrists or the medical profession generally. 

Dosage Mismanagement: 

3) it can cause some organ impairment if used over a  long period at too high of a dosage (there may be effects on the kidney occurring in 1-5% of persons after 10-20 years of continuous usage); 

4) it could be fatal in an overdose. However, this is also true for valproate acid (Depakote), lamotrigine (Lamictal), and carbamazepine (Tegretol), and all of these are FDA approved for manic and mixed symptoms.

A brief description of lithium’s history will clarify. 

Lithium (Li) follows hydrogen and helium on the periodic table, and it is the third simplest element and the first solid one. 

Minutes after the Big Bang, the universe was made almost entirely of hydrogen and helium, with trace amounts of lithium.. A new NASA-funded study suggests that most of the lithium in our solar system — and even in the galaxy — came from bright stellar explosions called classical novae. 

Back here on earth, lithium has been found in groundwater and soil. Lithia Springs Georgia is named for “lithia” (lithium), its natural mineral water springs. Lithia Spring Water (also called Lithia) is an American brand of high mineral content lithia water that naturally contains lithium carbonate 500 mcg. (1 mg elemental lithium found in ground water is equal to 25 mg lithium carbonate medication.)  Lithia Springs was frequented for its soothing waters by Mark Twain and Presidents Cleveland, Taft, McKinley, and Theodore Roosevelt, respectively. 

In 1929, Bib-Label Lithiated Lemon-Lime Soda, containing lithium, was introduced, though the name was later changed to 7UP. It was a popular drink until 1948 when it was banned by the FDA due to a variety of adverse effects  of the salt substitute lithium chloride form being overused. (Lithium: A Doctor, a Drug, and a Breakthrough- 2019 By Walter A. Brown)

With this ban, all lithium forms, such as carbonate and citrate, were prohibited from any product sold in the U.S., including 7UP. This ban is one of the reasons why the United States became the 50^th (and the last developed country) to approve lithium’s use in 1970, when the FDA finally approved lithium as a medicine for the treatment of mania. 

 

Lithium is naturally occurring

As mentioned above, lithium is found naturally in groundwater and soil, however, amounts do vary by location.  

Recommended human daily intake: 2 mg/d. (an essential trace mineral for humans).   M Anke et al, Biological importance of lithium. In Schrauzer GN, Klippel KF (eds): “Lithium in Biology and Medicine.” Weinheim: VCH Verlag, pp 149–167, 1991

Human diet (ground water and food) contains 1-2.5 mg/d of lithium. GN Schrauzer, KP Shrestha, Biological Trace Element Research, 1990, 25: 105-113

Yes, lithium is old…

… but so is penicillin and prednisone and people raise no objections to those venerable treatments. Since not much history is taught in residency programs, most psychiatrists are unaware that: 

• The two most effective medications in the history of psychiatry are lithium and penicillin (because penicillin successfully treated early stages of neurosyphilis in the late 1940’s and for the next few decades). Penicillin was a true cure for the mania, depression, and psychosis that caused neurosyphilis allowing patients to leave the hospitals. 
• The two most effective treatments in psychiatry are lithium and electroconvulsive therapy (ECT). See 2019 Clinical Psychopharmacology by S.N. Ghaemi and many of his publications and Ed Shorter, The history of lithium therapy Bipolar Disord. 2009 June; 11(Suppl 2): 4–9 for a comprehensive review of these treatments.

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Lithium is the only substance/drug in the entire medical field that is proven in multiple studies to prevent completed suicides as illustrated below. 

Worldwide Studies on Lithium Reducing Suicides

Cipriani et al, Lithium vs Placebo: Suicide prevention – BMJ, 2013;346:f3646 (based on worldwide databases over 50 years). 

• Four double-blinded, placebo-controlled trials which show that lithium can reduce completed suicides (from 1973-2008). No antidepressant can do this. 

Japan:

H, Ohgami  et. al. Lithium levels in drinking water and risk of suicide. British Journal of Psychiatry, 2009, 194: 464-465 

• “We found that lithium levels were significantly and negatively associated with suicide standardized mortality ratio (SMR) averages for 2002-2006. These findings suggest that even very low levels of lithium in drinking water may play a role in reducing suicide risk within the general population.”

Chile:

Lithium in Drinking Water as a Public Policy for Suicide Prevention: Relevance and Considerations. Pablo Araya, et. al. Front Public Health 2022 Feb 17.

”Although suicide is considered a major preventable cause of mortality worldwide, we do not have effective strategies to prevent it. Lithium has been consistently associated with lowering risk of suicide. This effect could occur at very low concentrations, such as trace doses of lithium in tap water. Several ecological studies and recent meta-analysis have suggested an inverse association between lithium in water and suicide in the general population, with a lack of knowledge of clinically significant side effects.”

Impact of natural lithium resources on suicide mortality in Chile 2000-2009: a geographical analysis. Daniel König et. al. Neuropsychiatr. 2017 Jun;31(2):70-76.

Conclusions: “Chilean regions rich in naturally occurring lithium salts show lower suicide mortality rates in comparison to other regions. Although causality cannot be proven by this design, these findings add to previous findings and warrant further research on the effects of naturally occurring low-dose lithium on health.” 

United States:

KP Shrestha et. al. Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biol Trace Elem Res. 1990 May;25(2):105-13 

• “Highest dose in Texas ground water (El Paso) was water was 123mcg/l which equals .000123 mg. The lowest dose of lithium capsules is 150 mg. Indicating that trace amounts of lithium in ground water can lower suicide rates.”

• “It is shown that the incidence rates of suicide, homicide, and rape are significantly higher in counties whose drinking water supplies contain little or no lithium than in counties with water lithium levels ranging from 70-170 micrograms.”

• “Lithium in Texas water reduces homicide and suicide by about one-half.”

• “These results suggest that lithium at low dosage levels has a generally beneficial effect on human behavior, which may be associated with the functions of lithium as a nutritionally-essential trace element.”

Lithium may have lower risk for self-harm than other bipolar disorder treatments. Hayes JF, et al. JAMA Psychiatry. 2016; May 11, 2016 

“Individuals with bipolar disorder prescribed lithium had lower rates of self-harm and unintentional injury, compared with their peers prescribed valproate, olanzapine and quetiapine.” 

 How does lithium prevent suicide?

The explanation below covers the most frequently cited brain mechanisms as to lithium’s antisuicidal effects:

“Neurobiological research has focused on lithium’s influence on neurotransmitters such as serotonin, noradrenalin, and dopamine, on the cortisol stress hormone system, the γ-aminobutyric acid, second messenger systems such as the inositol metabolism, glycogen synthase kinase 3, and more. The most common hypothesis is that lithium leads to a decrease in impulsivity and aggression via several influences within the nerve cell (Müller-Oerlinghausen and Lewitzka 2010; Mühlbauer and Müller-Oerlinghausen 1985). Over-activity of the corticotrophin-releasing hormone as well as dysfunction of the noradrenergic and serotonergic systems may be implicated in suicide (Steiner et al. 2008; Erhardt et al. 2013). Further, these dysfunctions may be linked to microglial hyperactivity, and chinolidinic acid deriving from tryptophan could lead to a lowered cerebral level of tryptophan and serotonin (Steiner et al. 2012). It could be that lithium, through its serotonin agonistic properties, counteracts this deficiency at the neurotransmitter level.” 

 Lewitzka U. The suicide prevention effect of lithium: more than 20 years of evidence—a narrative review. International Journal of Bipolar Disorders volume 3, Article #15 (2015)

Lithium does not prevent the uptake of neurotransmitters like serotonin in the synapse as do the SRI antidepressants, although it is purported to have mild pro-serotonin effects and does not affect dopamine or norepinephrine in this manner.  It is thought to work post-synaptically in a complex interaction of G-proteins, cAMP (cyclic adenosine monophosphate), PIP (phosphoinositid), and PKC (protein kinase C) in second-messenger neurons. It also raises the levels of neuroprotective brain-derived neurotrophic factor (BDNF). Since it does not work in the synapse, its effects are delayed compared to antidepressants but are longer lasting. Due to this neurochemical complexity, it has both antimanic and antidepressant benefits. It is properly called a second-messenger modifier.

(The term “mood stabilizer” has no scientific basis. It was coined by Abbott Labs in 1994, when it received FDA approval for valproic acid. Abbott Labs used the term as a marketing tool to compare it (falsely) to lithium. Valproic acid is proven to be as effective as lithium in treating acute manic episodes only, but not for preventing future episodes, and it is not FDA approved for maintenance. Valproic acid does not prevent suicide attempts or completed suicides.  Since the nebulous term “mood stabilizer” has no scientific definition, chamomile tea could also be called a “mood stabilizer”). 

Is lithium too dangerous for Kids?

Some doctors think so, but here are some facts:

Lithium was FDA approved in 2018 for ages 7-17, (previously 12-17) based on these studies:

1. Robert L. Findling, MD et. al. Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study.  (ages 7-17) Pediatrics  2015 Nov;136(5):885-94 

• The change in Young Mania Rating Scale (YMRS) score was significantly larger in lithium-treated participants (5.51 [95% confidence interval: 0.51 to 10.50]) after adjustment for baseline YMRS score, age group, weight group, gender, and study site (P = .03)).
•  Overall Clinical Global Impression–Improvement scores favored lithium (n = 25; 47% very much/much improved) compared with placebo (n = 6; 21% very much/much improved) at week 8/ET (P = .03)

CONCLUSIONS: “Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial. Lithium was generally well tolerated in this patient population and was not associated with weight gain, distinguishing it from other agents commonly used to treat youth with bipolar disorder.” 

2. Max S. Rosen, M.D. Lithium in Child and Adolescent Bipolar Disorder. AJP 10 Feb 2017, (ages 7-17):

• “It is generally tolerated, but several treatment-emergent effects exist, such as gastrointestinal, thyroid, renal, and weight abnormalities. Though pediatric bipolar disorder includes symptoms such as irritability and other symptoms shared by other pediatric psychiatric conditions, lithium has increasingly proven efficacious in the treatment paradigm of pediatric bipolar disorder.”

• “In recent systematic studies, lithium salts are demonstrating efficacy for improving acute manic symptoms, as well as weaker evidence for maintenance and antidepressive treatment in pediatric bipolar disorder and anti-aggressive properties in pediatric conduct disorder.” 

CONCLUSIONS: “Lithium is a useful and safe medication in the treatment of acute mania in children and adolescents with bipolar disorder. It is a medication that has been studied in modern psychiatry since 1949 and functions likely by depleting inositol in neurons. While it does not affect other drug levels, its own drug level, which correlates with efficacy, is affected by several medications and physical conditions.” 

And for suicide prevention in youth:

3. Hafemann et.al. Lithium Versus Other Mood Stabilizing Medications in a Longitudinal Study of Bipolar Youth RH = Lithium in Youth With Bipolar Disorder. J Am Acad Child Adolesc Psychiatry. 2020 October ; 59(10): 1146–1155:

• “Youth taking lithium were about half as likely to attempt suicide as those taking other medications.”

•  “Youth taking lithium also reported lower scores on assessments for depressive symptoms and aggression as well as less social impairment relative to youth taking other medications.”

Conclusion: “Findings are consistent with adult studies, showing that lithium is associated with decreased suicidality, less depression, and better psychosocial functioning.”

A case study from the Neuroscience Educational Institute in June of 2022:  example of a teen hospitalized for mania and depression with lithium.

4. Author: Jeffrey R. Strawn, MD Professor, Department of Psychiatry and Behavioral Neuroscience, Departments of Pediatrics and of Clinical Pharmacology, University of Cincinnati College of Medicine, Cincinnati, OH Clinical Psychiatrist, University of Cincinnati Medical Center, UC Health; and Cincinnati Children’s Hospital Medical Center, Division of Child & Adolescent Psychiatry; Cincinnati, OH

• Reported a 13 yr. old girl with history of an initial full depressive episode treated with fluoxetine, followed by a full manic episode. Fluoxetine was stopped. Asenapine was added. Patient’s mania was successfully treated with lithium 600 mg three times a day with a level of 0.9 with no toxicity or lab abnormalities. 

This would be a high dose for a full-grown adult, but illustrates the effectiveness of lithium for young people. Therefore its use should not be avoided. 

More training for lithium use in psychiatric residency programs is needed. I see this as a public health issue. It has been on the World Health Organization’s list of essential medicines since the 1970’s. The multitude of lithium’s benefits need not be withheld from the public just as the benefits of penicillin and prednisone should not be withheld even though they also have serious side effects. 

The Unfortunate Decline of Lithium in the U.S.

Since the mid 1990’s when valproic acid (Depakote) was FDA approved for acute mania, and subsequently when lamotrigine was approved in the early 2000’s (for prevention of future mood episodes but not for acute mania or depression), lithium had been unfortunately deemphasized in psychiatric training programs. An entire generation of psychiatrists and providers is relatively uninformed about the multiple benefits of lithium. This trend appears in the following studies:

As you can see on the graph, lithium (green line) usage has dropped from 30% in 1997 to 15% in 2016.  30% was already too low. Ideally, it should have been greater than 60%. 

Another example of the woeful under usage of lithium: 

“The most commonly prescribed first drug class was antidepressants (50% of patients), followed by mood stabilizers (25%: anticonvulsants, 17%, and lithium, 8%), sedatives (15%), and antipsychotics (11%).

Ross J. Baldessarini, M.D. Patterns of Psychotropic Drug Prescription for U.S. Patients With Diagnoses of Bipolar Disorders. ps.psychiatryonline.org – January 2007 Vol. 58 No. 1

The other unique benefit of Lithium

 (it’s not just for mania)

One of the most unique benefits of lithium, in addition to its anti-suicidal effects, is its ability to modify the course* of Manic-Depressive Illness or MDI (i.e. recurrent episodes of severe depression with or without mania); or what is called “bipolar” since 1980, which is a smaller subset of MDI, the true disease entity (see prior posts). (*Course refers to: timing of the first mood episode in life; whether the moods were depressed, mixed, or manic; the duration; and the frequency of subsequent mood epIsodes). 

Other anti-manic substances like valproic acid (Depakote), carbamazepine (Tegretol) or lamotrigine (Lamictal) do not affect the course, nor can antidepressants. Lithium’s antidepressant properties have been published for over 50 years but for unclear reasons has not received FDA approval specifically for suicide prevention or depression. (This likely would not be welcome by the anti-depressant makers.) 

Additional benefits of Lithium

Jari Tiihonen et. al. Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. Lancet Psychiatry 2017 Jul;4(7):547-553

• The nationwide cohort for this study consisted of all 123,712 patients in Finland hospitalized once or more between January 1, 1987, and December 31, 2012, for unipolar depression without schizophrenia or bipolar disorder.

• Risk for hospital readmission was lower during periods of lithium monotherapy.

• Compared with no lithium use, lithium use was associated with a lower risk for repeat hospitalization for mental illness.

• Antidepressants and antipsychotics were associated with a slightly increased risk for hospital readmission.

• After lithium, specific agents associated with the next lowest risk for readmission were clozapine and amitriptyline.

Conclusions and Clinical Implications:

• Lithium, especially when used as monotherapy, is the medication associated with the lowest risk for hospital readmission for mental illness in patients with severe unipolar depression, based on a Finnish nationwide cohort study.
• The investigators suggest consideration of lithium therapy for a wider population of severely depressed patients, weighing the potential risks and adverse effects against the benefits.

 

From Medscape Psychiatry in 2017 regarding this article:

In an accompanying editorial,[2] Allan H. Young, MD, PhD, director, Center for Affective Disorders, Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom, notes that although the findings need to be replicated, “they suggest that lithium monotherapy might be the best long-term prophylactic drug.”

“Lithium is not simply a medicine, but an element present in the natural environment and in both food and drinking water to varying degrees,” he writes.

Noting its association with reductions in suicide prevalence at a population level, Dr. Young adds that “all aspects of lithium and its effects on the brain and behaviour should be the focus of continuing rigorous scientific enquiry.”

Discussing the study with Medscape Medical News, Dr. Young agreed with Dr. Tiihonen that there are “a number of problems” with the study’s suggestion that the use of lithium be expanded, not least that its use has declined in recent years.

He noted that, although the drug is recommended by various guidelines, “there’s a lack of education and training of clinicians in using it (lithium)…and people with unipolar depression tend not to see a specialist in specialist clinics.”

In a review of some recent textbooks in the field:

In the 2014, 6th edition of the Textbook of Psychiatry from the American Psychiatric Association Publishing comprising 1473 pages, there is not one mention of lithium in preventing suicide. 

Nor is there any mention of lithium’s known properties in prevention of suicide in the 2016, 2nd edition, Dulcan’s Textbook of Child and Adolescent Psychiatry comprising 1179 pages.  (Also from American Psychiatric Association Publishing.) 

The 2013 3rd Essentials of Clinical Pharmacology (from American Psychiatric Association Publishing) stated on pages 424-425:

 “Tondo et. al. (1997) reviewed the studies of the use of lithium in the treatment of major mood disorders, these included 28 studies that involved more than 17,000 patients. Risk of completed and attempted suicides were 8.6 fold higher in patients who were not given lithium compared with those who were.” 

Also, in a meta-analysis of studies of treatment with lithium in major mood disorders, Tondo et. al (2001), Baldessarini et. al. (2006) and Guzzetta et. al. (2007) found significantly lower suicide risk for subjects who were receiving treatment lithium. 

The 2012 2nd edition New Oxford Textbook of Psychiatry, Volume 1 states on page 971:  (not associated with the American Psychiatric Association Publishing).  

 “A systematic review of trials of lithium therapy, versus a range of other drugs and placebo in patients with affective disorders, has shown convincing evidence that lithium may prevent suicide.”

The 2013, 4th edition of Sthal’s Essential Psychopharmacology – Cambridge University Press, states on page 372, (not associated with the American Psychiatric Association Publishing). “Lithium is well established to help prevent suicide in patients with mood disorders.”  

The text books and articles with the most comprehensive documentation of lithium benefits including reducing completed suicides and suicidality and its underutilization will be found in:

• Robert Post. The New News about Lithium: An Underutilized Treatment in the United States. Neuropsychopharmacology (2018) 43, 1174–1179 Official journal of the American College of Neuropsychopharmacology
• Nassir Ghaemi’s Clinical Psychopharmacology – Principles and Practice. 2019 (Oxford University Press)
• Manic-Depressive illness – Bipolar Disorders and Recurrent Depressions. 2007, 2nd edition, Goodwin and Jamison Oxford University press.

Lithium is neuroprotective

Another underappreciated benefit unique to lithium is its neuroprotective properties which I will discuss in more detail in a future blog given the growing public awareness of Chronic traumatic encephalopathy (CTE).

A new avenue for lithium: intervention in traumatic brain injury. ACS Chem Neurosci. 2014 Jun 18;5(6):422-33.2014 Apr 11.