[16] In 1970, lithium was approved by the United States Food and Drug Administration (FDA) for the treatment of bipolar disorder, which remains its primary use in the US.

[5] The results of different clinical studies of the efficacy of combining lithium with antipsychotic therapy for treating schizophrenic disorders have varied.

[32] Lithium is one of the few augmentation agents for antidepressants to demonstrate efficacy in treating MDD in multiple randomized controlled trials and it has been prescribed (off-label) for this purpose since the 1980s.

However, meta-analyses, faced with evidence base limitations, have yielded differing results, and it therefore remains unclear whether or not lithium is efficacious in the prevention of suicide.

[37][38][39][40][41][42] However, some evidence suggets it is effective in significantly reducing the risk of self-harm and unintentional injury for bipolar disorder in comparison to no treatment and to anti-psychotics or valporate.

[49] It also promotes the redirection of the influx of calcium ions into the lumen of the endoplasmic reticulum of the cells to reduce the oxidative stress within the mitochondria.

The dehydration is due to lithium inhibition of the action of antidiuretic hormone, which normally enables the kidney to reabsorb water from urine.

[52] Lithium concentrations in whole blood, plasma, serum, or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdosage.

[56] Given the risks of kidney malfunction, serum creatinine, and eGFR should be checked before lithium is instituted and monitored after 3–6 months at regular intervals.

[71] Because lithium competes with the antidiuretic hormone in the kidney, it increases water output into the urine, a condition called nephrogenic diabetes insipidus.

Case reports and several retrospective studies have demonstrated possible increases in the rate of a congenital heart defects including Ebstein's anomaly if taken during pregnancy.

[83] For patients who are exposed to lithium, or plan to stay on the medication throughout their pregnancy, fetal echocardiography is routinely performed to monitor for cardiac anomalies.

[88][89] It is estimated that impaired urinary concentrating ability is present in at least half of individuals on chronic lithium therapy, a condition called lithium-induced nephrogenic diabetes insipidus.

[68] Nielsen et al. (2018), citing 6 large observational studies since 2010, argue that findings of decreased kidney function are partially inflated by surveillance bias.

[69] Davis et al. (2018), using literature from a wider timespan (1977–2018), also found that lithium's association with chronic kidney disease is unproven with various contradicting results.

Lithium plasma concentrations are known to be increased with concurrent use of diuretics—especially loop diuretics (such as furosemide) and thiazides—and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen.

[97] Lithium is known to be a potential precipitant of serotonin syndrome in people concurrently on serotonergic medications such as antidepressants, buspirone and certain opioids such as pethidine (meperidine), tramadol, oxycodone, fentanyl and others.

During acute toxicity, lithium distributes later into the central nervous system resulting in mild neurological symptoms, such as dizziness.

[56] In chronic toxicity, people have primarily neurological symptoms which include nystagmus, tremor, hyperreflexia, ataxia, and change in mental status.

[5] Upon ingestion, lithium becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing norepinephrine release and increasing serotonin synthesis.

[105] Unlike many other psychoactive drugs, Li+ typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations.

[115] Another mechanism proposed in 2007 is that lithium may interact with nitric oxide (NO) signaling pathway in the central nervous system, which plays a crucial role in neural plasticity.

[119] It was found that patients with bipolar disorder had lower GABA levels, which results in excitotoxicity and can cause apoptosis (cell loss).

[119] Over a long period of lithium treatment, cyclic AMP and adenylate cyclase levels are further changed by gene transcription factors.

This practice and the sale of lithium itself were both banned in the United States in February 1949, following the publication of reports detailing side effects and deaths.

[131] They were injecting rodents with urine extracts taken from manic patients in an attempt to isolate a metabolic compound which might be causing mental symptoms.

Since uric acid in gout was known to be psychoactive, (adenosine receptors on neurons are stimulated by it; caffeine blocks them), they needed soluble urate for a control.

[132] The rest of the world was slow to adopt this treatment, largely because of deaths that resulted from even relatively minor overdosing, including those reported from the use of lithium chloride as a substitute for table salt.

Largely through the research and other efforts of Denmark's Mogens Schou and Paul Baastrup in Europe,[129] and Samuel Gershon and Baron Shopsin in the U.S., this resistance was slowly overcome.

Characters in Pi, Premonition, Stardust Memories, American Psycho, Garden State, and An Unmarried Woman all take lithium.