Lithium is THE BEST AND MOST IMPORTANT DRUG IN ALL OF PSYCHIATRY.  It isn't even close.  You would think there were many medications that reduced the risk of suicide in our field, but there aren't.  Lithium is the only drug in psychiatry that definitively REDUCES PEOPLE's RISK OF SUICIDE!  (I'm not as convinced with the Clozapine data, but I'm not NOT convinced either; I'm ABSOLUTELY not convinced that Ketamine actually reduces suicide rate, but we'll discuss that one another time).  In treating a condition in bipolar disorder that is implicated as the underlying diagnosis for the majority of annual suicides, why do we only prescribe it to ~10% of bipolar patients in the United States?  While some may argue its the side effect profile, this has been drastically over-exaggerated, and with severe symptoms of manic-depression, now known as bipolar disorder, the benefits often outweigh the risks.  If someone kills themselves, then potential early thyroid dysfunction (easily treated and reversible with lithium discontinuation) AND kidney disease (takes around 30 years to take effect) seem a bit more trivial.  Bipolar doses (and even lower doses used for major depressive disorder - which formerly would have been included in manic-depression) of lithium have been shown to reduce the risk of suicide by almost 10x.  That is a HUGE fucking effect.  Why are we not using more lithium?

It's almost as if there has been a culture of fear instilled around the use of a drug that might make ALL of us a little healthier (to be covered soon). It's almost as if there are covert influences pushing people in my position away from prescribing a disease-modifying drug (not to be confused with a symptom-modifying drug, which represents the vast majority of pharmaceuticals in use today).  Why do we get alerts in the Electronic Medical Records (EMR) when we're trying to prescribe lithium warning of the risk of serotonin syndrome?  I've certainly never seen it.  I've talked to one of, if not THE, world expert on serotonin syndrome, who also cannot imagine why we receive that warning.  It MIGHT have something to do with the fact that a 90-day prescription of lithium, even without insurance, is about 10$When your health interrupts the industry's profit margins, that's a problem!  This is NOT A PARTISAN ISSUE; whether it be Republican- or Democratic-run government, ~90% of big pharmaceutical company lobbyists' money goes to WINNING CANDIDATES.  And politicians know... you can't bite the hands that feed you.  Lithium use decreases the dosages and number of other medications needed to control bipolar disorder (and common sense would lead a reasonable person to believe several other conditions as well)... and if too many people are getting well, that might be a problem for the bottom line.  If someone's job is to make their company as much money as possible, then the ones that rise to the top of the executive ranks are going to do whatever it takes to make their company as much money as possible.  Our government should not allow this to happen.  We, the American people, should not allow elect officials who allow this to happenWe conscientious and outcome-focused doctors are LOSING OUR GRIP on deciding what is safe and effective in this country; that role increasingly falls more and more to political figureheads and the marketing departments of major pharmaceutical and healthcare companies.  Lithium is a classic example of a low-cost natural substance that works considerably better than any of its competing drugs, but is used at embarrassingly low rates in the United States.

There's a couple more really crazy and mind-boggling aspects of the low Lithium use rates in the US.  One is that Lithium retains its anti-suicide effect even at low doses, around 150mg Lithium Carbonate (equivalent to 28mg of elemental lithium; lowest available prescription dose), and even micro-dose concentrations (120mg of Lithium Orotate ~ 5mg of elemental lithium (supplement; no prescription required).  Studies have been reproduced over and over again all around the world (including Japan, Europe, United States) showing lower rates of suicide, homicide, and violent crime, all very impulsive behaviors, in counties with higher levels of lithium in their water supply compared to neighboring counties with lower levels of lithium.  The side effect risk of low-dose lithium is nearly non-existent aside from a lesser, but still considerable risk of thyroid problem.  I've yet to see any serious side effects to microdoses of lithium.  Psychiatrists and other mental health providers who just do as they're told by their teachers, institutions, and establishments are doing their patients a massive disservice.  You don't need to listen to me, a young, green psychiatrist with an H-index below 1, just do your own research and come at it like any clinical question, with an uncertain mindset and a curiosity for the truth.  OR... listen to the rock stars and experts of the field that understand the medication and bipolar disorder the best (not to be confused with industry-sponsored or promoted "experts," more like 'talking heads').  We've got to prescribe more lithium to reduce the number of people killing themselves every year.

In fact, many of the medications that we prescribe to people who are depressed (and by "we," I mean the field, not myself personally), including SSRIs, actually increase people's risk of suicide in the first 2 weeks.  Unless, of course, you buy into the idea that 'this only occurs in children and adolescents,' which have a black box warning for the increased risk of suicide... because kids were killing themselves too often after starting them early in their pharmaceutical career.  So unless the drug itself knows when someone turns 18, or 21, or 16, or whatever arbitrary cutoff age someone 'becomes an adult,' then it exists in adults too.  The thousands of lawsuits against their makers over the last 3 decades for suicides and homicides, including one in my city involving Joseph Wesbecker and the largest mass shooting in Louisville history, offer another piece of convincing evidence this EXTREMELY UNREASONABLY SERIOUS SIDE EFFECT is real.  Just think about the motivations of these companies.  Read about the litany of court cases.  Listen to conscientious folks who worked on the development of these drugs.  It's insane that we prescribe medications for depression that have a legitimate risk of causing our patients to kill themselves AND don't prescribe a medication that reduces their risk of killing themselves nearly 10-fold.

Dissidents of lithium have lopped it in with other psychiatric drugs as being toxic... which, admittedly, it is, at high doses.  Just like Soooooo many other drugs and/or substances.  What happens if you take 10x your dose of your high blood pressure pill?  You may drop your blood pressure so low that you experience a hypovolemic infarct because oxygenated blood cannot get to some or all of your vital organs due to your now excessively LOW blood pressure.  What happens if you drink 1 glass of red wine, which may offer some cardioprotective effect, versus 15 glasses of red wine?  One may help you, one may poison and kill you.  The examples here are endless.  Those that argue lithium is strictly and always "neurotoxic" does not appreciate the nuance of variable dosing including the near absence of side effects on microdoses, and clearly do not understand some of the underlying mechanisms of action.  To say that it doesn't correct an underlying chemical abnormality is likely false as well, as the most reproduced abnormality in bipolar disorder, whether a patient is manic or depressed, is an accumulation of excess sodium in the neurons of SOME brain cells.  Lithium preferentially enters those cells with higher sodium and some of that sodium effluxes out of the cell, leading to a restoration of a more-normal amount of sodium in that cell, and therefore that neuron becomes less electrically active.  Even better, lithium exerts its effect on diseased brain cells preferentially over brain cells with normal amounts of sodium; therefore, it is not sedating to the degree other 'mood stabilizers' are; sedation is reported by roughly ~1 out of every 30 patients (compared to 1 out of 4 on depakote).  This is another common misconception about its effects at therapeutic levels, AND definitely at microdose or low-dose levels.  Yes, like so many other drugs and substances, (including Vitamin D, which can lead to an excess calcium level and symptoms of hypercalcemia), lithium is toxic in excess, but has such therapeutic potential at lower concentrations.

Lithium should certainly be the first-line medication in bipolar disorder.  All bipolar patients should have a failed trial of lithium prior to initiating other mood stabilizers (which offer more of a blanket effect, affecting all neurons).  The accepted symptom reduction is as follows: 1/3 bipolar patients on lithium will have remission of their symptoms, 1/3 will have a significant reduction in their symptoms, and 1/3 will NOT respond.  And... Lithium actually impacts at least one of the likely underlying abnormalities in bipolar disorder.  There is SO much data on it, from the original 10-patient case series published by Australian psychiatrist John Cade using it on institutionalized bipolar patients in the 1940s, to Alec Coppin's 20-year lithium clinic follow up studies revealing its anti-suicide (and therefore, antidepressant) effect.  Hopefully our series on it is illuminating and changes the way some people prescribe.  We've got to stop relying so heavily on psychiatric medications that just mask symptoms and cause withdrawal phenomena when abruptly stopped, leading users to think they NEED the medication and instead promote treatments that may actually correct an underlying abnormality and are backed up by the most important objective outcome measures including morbidity and mortality data, the number of inpatient psychiatric hospitalizations, and the overall use of other psychiatric medications like antipsychotics.  

I certainly hope in the next 10 years that the field recognizes the errors of its ways, and we have more of a standardized approach to utilize lithium before other medications as a first-line treatment.  Though I worry we will continue to fall victim to the concerted and financially-backed efforts of pharmaceutical companies to prescribe the latest, greatest, state-of-the-art, patented medications that don't have an adequate amount of or methodologically-sound long term safety and efficacy data.

Lithium Literature:

When and How to use Lithium.  Nassir Ghaemi.

The suicide prevention effect of lithium: more than 20 years of evidence- a narrative review; Int J Bipolar Disord, 3 (2015), p. 15;

Low dosage lithium augmentation in venlafaxine resistant depression: an open-label study; Psychiatriki, 23 (2012)

Phelps, 2016 “Low-Dose Lithium: A Different, Important Tool,” Psychiatric Times 9/13/16

Schrauzer, (1990) “Lithium in drinking water and the incidence of crimes, suicides, and arrests related to drug addiction,” Biologic Trace Elements May; 25:105-13

Association of lithium in drinking water with the incidence of dementia; JAMA Psychiatry, 74 (2017), pp. 1005-1010;

The new news about lithium: An underutilized Treatment in the United States' Neuropsychopharmacology, 43 (2018), pp. 1174-1179;

Lithium salts in the treatment of psychotic excitement; Med J Austr (1949), p. 349;

Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis; BMJ, 346 (2013), 10.1136/bmj.f3646

Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis; Int J Bipolar Disord, 2 (15) (2014), 10.1186/s40345-014-0015-8

Low-dose lithium treatment for agitation and psychosis in Alzheimer disease and frontotemporal dementia: a case series; Alzheimer Dis Assoc Disord, 31 (1) (2017), pp. 73-75

Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations; Bipolar Disord, 18 (8) (2016), pp. 692-695

Mini-review: Anomalous association between lithium data and lithium use. – Janusz Rybakowski The history of lithium therapy – Edward Shorter, PhD -Jaime Lowe – bipolar patient who was Rx’d lithium  -Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid; Beyond Bipolar Disorder (Chi-Tso Chiu, et al. David Sibley associate editor). 2013.

-Long ass article on Lithium/VPA in neurodegenerative conditions Low-dose lithium uptake promotes longevity in humans and metazoans

*Shows reduced all-cause mortality in 1+ mil Japanese persons in 18 neighboring municipalities organized by drinking water lithium concentrations (p = 0.003)

*Also, found that exposure to comparably low concentration of lithium chloride in Caenorhabditis elgans (small roundworm used for anti-aging studies) (p=0.047)


The Ghaemi Psychiatry Podcast - Lithium-An Ignored Solution to suicide

            Statistics: -½ of ppl with severe dep have SI         -10% of sev. Dep make SAs

            -80-90% ppl with SI never make an attempt

            -Of those who attempt, only ~10% eventually complete

            -4-5% vs general population at fractions of a percent

            -30-40k/yr in U.S.; #1 severe depression/manic-depressive, #2ptsd, #3         teens/young adults – correlating with Social Media in last 2 decades

            -completed rate among girls almost doubled in last decade

            -Lithium most effective in preventing suicide in mood illnesses > PTSD,          though geological studies show suicide rate in gen pop ½ in areas with more        lithium in the water Info about Paul Blachly’s fight against FDA regarding lithium Rx

A History of the Pharmacological Treatment of Bipolar Disorder: Why Lithium is a Good Option for Treating Bipolar, with Dr. Walter A. Brown. Psychiatry and Psychotherapy Podcast with Dr. David Puder.

            *50% of people with bipolar in European and Scandinavian countries vs 10% in US. A/t Brown, major reason is ‘after the 1980s, other drugs, particularly Depakote, came onto the market that could also prevent mania/dep, and drug companies marketed those heavily (Depakote took over lithium’s gold standard role). Lithium toxicity definitely plays a role as one can die from it.  ‘I think the primary reason that it is underused is the aggressive marketing of other drugs.’ ‘there’s a tremendous concern on the part of the psychiatric and research establishment over the lack of real innovation, particularly in treatment.’ 

-DAVID PUDER Podcast: Lithium Indications, Mechanisms, Monitoring, and Side Effects: Michael Cummings

            -Lithium contraindicated in breastfeeding despite very low penetrance (1%             of plasma concentration) and no side effects found in offspring of mother’s            taking lithium and breastfeeding

            -NNT 4-5 for taking potassium supplement with lithium

PODCAST - Lithium: Everything Everywhere Daily - Aug 12, 2022 episode (Gary Arndt)

Lithium Chloride as a substitute for sodium chloride in the diet; observations on its toxicity (Lawrence W. Hamlon – JAMA 1949) Lithium Salts in the Treatment of Psychotic Excitement, 1949, Medical Journal of Australia AstraZeneca paying for Seroquel mishaps similar to Valproate for nursing home agitation/aggression Depakote ghostwriters

-ALEC COPPEN = British psychiatrist who came to prominence in 50s/60s/70s Interview from February 2022, though references all from 60s-80s

-Suicide rate general population 7/1000, pts on long-term lithium maintenance 1/1000

-No justification of giving lithium twice a day

-Ran study keeping patient on lithium vs placebo for 2 years with their psychiatrist being blinded and could give other needed treatments. Results staggering:

            *Morbidity much lower, amount of other meds needed much decreased

            *Effective in unipolar and bipolar

            *After this study, set up a lithium clinic x 20 years, see above suicide rate

Rhee et al, 2020, AJOP, 20-Year Trends in the Pharmacologic Treatment of Bipolar Disorder by Psychiatrists in Outpatient Care Settings - compares 1997-2000 to 2013-2016: antipsychotics from 12.4% of biplar outpt visits to 51.4%, mood stabilizers decreased from 62.3# to 26.4%

*Driven primarily by decrease in non-lithium MS from 35.4 to 4.9%, lithium from 30.4% to 17.6%

 *antiDEPs in 47% to 57.5% and antiDEP c/o MS up from 17.9% to 40.9% Overview of lithium’s use: a nationwide survey Reduced rate of recurrent genital herpes with lithium carbonate (JD Amsterdam, 1990); 10 healthy women with chronic recurrent genital herpes infections with significant reductions in total monthly duration, average duration of each infection, and gradual prophylaxis that increased with duration of tx. Lasted 1 year

Lithium as a Treatment for Alzheimer's Disease: A Systematic Review and Meta-Analysis, Matsunaga 2015; first meta-analysis of randomized placebo-controlled trials of lithium in AD and MCI, primary outcome was MMSE/cognitive testing -3 clinical trials of 232 participants with lithium significantly decreasing cognitive decline compared to placebo by standardized mean difference of -.41, p = 0.04 -unknown length of treatment or parameters,We%20assessed%20the%20association%20between%20lithium%20use%20and%20the%20incidence,with%20either%20AD%20or%20VD  Chen. Retrospective cohort 2005-2019 with 30k patients, ~550 on lithium, at least 50 yrs old and no MCI/AD, -Lithium pts: 53 (9.7%) with dementia (36 AD, 13 VD), others: 11.2%, despite lithium cohort more likely to have MCI RFs: current/former smoker, antipsychtc   use, DEP, DM2, bipolar, HTN, central vasc dz, HLD, HR 0.56 for dementia Clinical relevance of treatments for acute bipolar disorder: balancing therapeutic and adverse effects –Srivastaka 2020 Lithium poisoning from the use of salt substitutes, 1949, Corcoran,adults%20with%20BD4%2C5. Lithium versus other mood stabilizing medications in a longitudinal study of bipolar youth RH = lithium in youth with bipolar disorder, Hafeman 2020 -413 youth, 7-17yo at intake, with BD (questionable…) Li vs OMS -340 participants contributed >2600 six-month f/u periods, mean f/u of 10 years; 886 Lithium, 1752 Other Mood Stabillizers

*Li half as many SAs, fewer DEP symptoms, less psychosocial impairment, less aggression Effectiveness of maintenance therapy of lithium vs other mood stabilizers in monotherapy and in combinations: a systematic review of evidence from observational studies, Kessing 2018; Li superior in ~14k patients Small article by Samuel Gershon Trends in prescriptions of lithium and other medications for patients with bipolar disorder in office-based practices in the United States, 1996-2015, Lin; Lithium in 38.1% in 1996 to 14.3% in 2006 Lithium in cluster headaches, 1981 Ekborn Lithium treatment in cluster headache: the literature, Abdel-Maksoud 2009 Lithium toxicity profile: a systemic review and metaanalysis, Mcknight 2012 Arjan M. Van Alphen, 2021 -On lithium effect on kidney function, 1000 patients followed 2000-2015  -118 developed CKD with avg eGFR decline of 1.8 mL/min/yr -894 pts did not develop CKD with avg eGFR decline of 0.5mL/m/y -Median time to reach CKD 3 was 41 years -Pts who developed CKD had mean GFR 70 at start, patients who did not mean baseline GFR 80; p .004  -Compared to controls (not controlled for being psych patients), 1.3x risk Lithium therapy and its interactions, Malhi 2020           -No 5-HT talk, only AKI drugs -Reduction in mortality in 26k bipolar pts for all MSs, best w/ lithium

  ,the%20lowest%20risk%20of%20mortality. -Lowest rates of non-adherence = Lithium/Clozapine *Journal of Affective Disorders, Non-Adherence to MS/antipsyc in 33k BD pts

-REM discuss telomere shortening and possible MOA for these effects *Extends lifespan of Drosophila

Lithium in COVID References:

1     Taquet M, Luciano S, Geddes JR, Harrison PJ. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. Lancet Psychiatry 2021; 8: 130–40.

2     Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry 2021; 8: 416–27.

3     Casey JA, Schwartz BS, Stewart WF, Adler NE. Using Electronic Health Records for Population Health Research: A Review of Methods and Applications. Annu Rev Public Health 2016; 37: 61–81.

4     Cowie MR, Blomster JI, Curtis LH, et al. Electronic health records to facilitate clinical research. Clin Res Cardiol 2017; 106: 1–9.

5     Jetley G, Zhang H. Electronic health records in IS research: Quality issues, essential thresholds and remedial actions. Decis Support Syst 2019; 126: 113137.

6     de Lusignan S, Dorward J, Correa A, et al. Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study. Lancet Infect Dis 2020; published online May 15. DOI:10.1016/S1473-3099(20)30371-6.

7     Zhang J-J, Dong X, Cao Y-Y, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy 2020.

8     Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395: 507–13.

9     Wang QQ, Kaelber DC, Xu R, Volkow ND. COVID-19 risk and outcomes in patients with substance use disorders: analyses from electronic health records in the United States. Mol Psychiatry 2021; 26: 30–9.

10   Williamson EJ, Walker AJ, Bhaskaran K, et al. OpenSAFELY: factors associated with COVID-19 death in 17 million patients. Nature 2020; published online July 8. DOI:10.1038/s41586-020-2521-4.

11   Taquet M, Dercon Q, Luciano S, Geddes JR, Husain M, Harrison PJ. Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLoS Med 2021; 18: e1003773.

12   Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 1994; 81: 515.

13   VanderWeele TJ, Ding P. Sensitivity Analysis in Observational Research: Introducing the E-Value. Ann Intern Med 2017; 167: 268–74.