Saturday, January 22, 2022

When Was Lithium Discovered For Bipolar

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Lithium Imaging Method Could Shine New Light On Bipolar Disorder Treatment

Why Does Lithium Help Bipolar Disorder?

DNAzyme-Based Lithium-Selective Imaging Reveals Higher Lithium Accumulation in Bipolar Disorder Patient-Derived NeuronsACS Central Science

Since 1949, lithium has been a mainstay for treating bipolar disorder , a mental health condition marked by extreme mood swings. But scientists still dont have a clear understanding of how the drug works, or why some patients respond better than others. Now, researchers reporting in ACS Central Science developed a method for imaging lithium in living cells, allowing them to discover that neurons from BD patients accumulate higher levels of lithium than healthy controls.

The authors acknowledge funding from the National Institutes of Health.

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Early Applications Of Lithium Salts In Psychiatry

The use of lithium in psychiatry has roots in the mid-1800s. Some credit this early interest in lithium to Alfred Baring Garrod, who used lithium in the treatment of gout , as uric acid was often considered to be at the root of a host of diseases. In 1871, William Hammond became the first physician to prescribe lithium for mania, specifically lithium bromide . By the late 1890s, Li2CO3 had been used in the treatment of 35 patients with melancholic depression in Denmark . Surprisingly, this early Danish work with Li2CO3 was seemingly forgotten, as the use of lithium in psychiatry would not experience a revival until 1949 courtesy of Australian psychiatrist John Cade .

Lithium Use In Pregnant And Postpartum Women With Bd

Women with BD are at an elevated risk of recurrence during the peripartum and postpartum period with relapse rates as high as 4070% . Recent research suggests that lithium discontinuation may be responsible for the elevated relapse risk during pregnancy, as pregnancy itself only has a small or even no effect on relapse rates in BD . A majority of pregnant women with BD decide to self-discontinue lithium or even have problems getting a prescription for lithium . There is a high variability in the available information and recommendations regarding lithium treatment during pregnancy . While lithium is the most recommended agent in BD during pregnancy, there is a lack of high-quality data. Observational studies support the use of lithium in the postpartum period in relapse prevention . However, the benefits of relapse prevention have to be weighed against potential adverse effects on mother and child .

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Dosing Strategies In Paediatric Bd

The elimination half-time of lithium is significantly shorter and the clearance of lithium significantly higher in paediatric patients. Therefore, Landersdorfer et al. recommend a twice-daily dosing of lithium to achieve acceptable blood concentrations. Data are missing for once-daily dosing of lithium in paediatric BD and is thus not recommended.

To summarize, lithium is an effective treatment strategy in the treatment of paediatric BD in different phases of the disease, in mixed and manic episodes and in the maintenance phase.

The Modern Understanding Of Lithium For Bipolar


While earlier clinical trials demonstrated that lithium could prevent manic episodes in approximately two-thirds of patients, naturalistic studies throughout the 1990s showed less benefits, with only one-third of patients responding well to lithium therapy. However, upon analysis, it was concluded that real world situations often suffered from non-compliance and attrition. Long-term side effects on thyroid and kidney function were also recognized .

More recently, the latest meta-analyses are reaffirming the benefits of lithium treatment, especially in comparison with other medications. A network meta-analysis in 2014 showed that lithium was effective in preventing both manic and depression episodes in patients suffering from bipolar disorder. The quality of the evidence was considered robust with minimal bias. While other medications may be comparable, bias was of concern due to study protocols and funding from the pharmaceutical industry. As such, the authors stood by the standard recommendation of lithium as first-line treatment for the prevention of bipolar mood episodes of either polarity . To this day, there are concerns that lithium remains underutilized in the United States for bipolar treatment.

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Closing Remarks: The Future Of Lithium Orotate

There is one certainty regarding the future of LiOr in psychiatric applications: more research is needed. Orotic acid has shown promise as a mineral carrier for calcium , magnesium , and lithium however, concerns regarding its toxicity have also been noted . In short, while the potential of lithium orotate in the management of BD symptomatology is fascinating, clinical application is not recommended at this time due to the scarcity of literature concerning its benefits and risks .


Before LiOr can be seriously considered as an alternative to Li2CO3, studies exploring its efficacy in both basic science and clinical settings need to be conducted. This need is especially pressing given the nutraceutical status of LiOr, and the consequent wide-spread use of the compound within the self-medicating population. Furthermore, some physicians and alternative health practitioners recommend small doses of LiOr to their patients, plausibly for its mood stabilizing properties at such concentrations . While these small doses are likely to be safe, the potential toxic effects of micro-dosing LiOr still warrants further examination. However, it is reassuring that daily intake of 150 mg of LiOr over 6-months during an alcohol-abuse cessation study resulted in only minor adverse effects in 8 out of 42 patients , and even excessive use of LiOr tablets failed to elicit a severe acute adverse reaction in a case report presented by Pauze and Brooks .

The History Of Orotic Acid And Its Relevance To Human Biology

Orotic acid is a carboxylic acid and a pyrimidinedione, that was first discovered in whey, a proteinaceous liquid component of milk, by researchers Biscaro and Belloni in 1905 . Historically, this compound was believed to be part of the vitamin B complex after it was determined in the 1950s that the previously unidentified growth enhancement factor vitamin B13, first isolated from distiller’s dried grains with solubles in the late 1940s , was in fact orotic acid . During this period, orotic acid was identified as a precursor of pyrimidine biosynthesis , highlighting its essential role in mammalian metabolism. While it is now known that orotic acid is not a vitamin, its previous status as B13 provides insight into its historical importance as a dietary component.

In sum, orotic acid appears to serve many roles in in the human body, both directly, through its contributions to DNA/RNA synthesis, and indirectly, through its downstream metabolites uridine, β-alanine, and carnosine. While speculative in nature, the putative benefits conferred by orotic acid and its metabolites may offer an additional boon to LiOr that is absent in Li2CO3.

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Summary Of Association Studies

From the review so far we can see that the potential number of candidate genes to study in relation to lithium response and/or lithium responsive BD is enormous. And conversely, many positive findings can appear plausible by a post hoc neurobiological explanation as relevant to lithiums effect. A number of association studies examining lithium responsive BD and/or difference between responders and nonresponders have been reported in the literature. Recent reviews by Severino et al. and by Geoffroy et al. list analyses of 97 and 88 genes respectively. Notably, most of these studies are based on small samples . In addition to low statistical power, these studies suffer from other limitations such as retrospective evaluation of treatment response, a number of separately published papers based on the same clinical samples, and analyses of only few or even a single marker per gene, especially in older studies. No positive findings have been replicated in at least two samples of 200 or more subjects. The best results in more than one study point to possible associations with nuclear receptor subfamily 1, group D, member 1 , GSK3,, serotonin transporter ,, BDNF, , CREB,, and the transcription factor XBP1., Notably, the reported effect sizes are such that they would be detectable by the existing GWAS which has not been the case.

Lithium: The Story Behind The Raging Nirvana Classic

The Mystery of Lithium & Bipolar Disorder

On this raging masterpiece, Kurt Cobain pit drugs and religion against the often brutal nature of reality.

Nirvanas Lithium may have shared the emphatically shifting dynamics of Come As You Are, and the latent singalong infectiousness of Neverminds Smells Like Teen Spirit, but it stands distinct from the others in that it feels less of a perceptibly personal and agonized admission from its author.

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Lithium Orotate: A Superior Option For Lithium Therapy

Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada


Lane K. Bekar, Department of Anatomy, Physiology and Pharmacology, Department of Pharmacology, College of Medicine, GD 30.1 HLTH, 107 Wiggins Road, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada.

Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada


Lane K. Bekar, Department of Anatomy, Physiology and Pharmacology, Department of Pharmacology, College of Medicine, GD 30.1 HLTH, 107 Wiggins Road, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada.

Lithium: The Gripping History Of A Psychiatric Success Story

John Cade, pictured in 1974, was the first person to test lithium as a treatment for biopolar disorder.Credit: News Ltd/Newspix

Lithium: A Doctor, a Drug, and a BreakthroughWalter A. Brown Liveright

Some 70 years ago, John Cade, an Australian psychiatrist, discovered a medication for bipolar disorder that helped many patients to regain stability swiftly. Lithium is now the standard treatment for the condition, and one of the most consistently effective medicines in psychiatry. But its rise was riddled with obstacles. The intertwined story of Cade and his momentous finding is told in Lithium, a compelling book by US psychiatrist Walter Brown.

Bipolar disorder, labelled manic-depressive illness until 1980, affects around 1 in 100 people globally. Without treatment, it can become a relentless cycle of emotional highs and lows. Suicide rates for untreated people are 1020 times those in the general population. Fortunately, lithium carbonate derived from the light, silvery metal lithium can reduce that figure tenfold.

Browns telling of Cades eventful life covers much of the same ground as Finding Sanity , a rather hagiographic biography by Greg de Moore and Ann Westmore. What Brown does superbly well is to show that Cade made his discovery without access to advances in technology or to modern facilities and almost despite them. His finding was the happy result of being forced to work with the simplest of means.

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The 20th Century: Kraepelins And Leonhards Classifications

The history of bipolar disorder changed with Emil Kraepelin, a German psychiatrist who broke away from Sigmund Freuds theory that society and the suppression of desires played a large role in mental illness.

Kraepelin recognized biological causes of mental illnesses. Hes believed to be the first person to seriously study mental illness.

Kraepelins Manic Depressive Insanity and Paranoia in 1921 detailed the difference between manic-depressive and praecox, which is now known as schizophrenia. His classification of mental disorders remains the basis used by professional associations today.

A professional classification system for mental disorders has its earliest roots in the 1950s from German psychiatrist Karl Leonhard and others. This system was important to better understand and treat these conditions.

Toxicity And Side Effects

Lithium by Lauryn Smith

As with many medications on the market, lithium comes with a list of side effects and precautions. Lithium toxicity can be very serious, with both acute and chronic effects. The side effects of lithium are common as well, and as with many mental health medications, these side effects often interfere with its use.

In addition, lithium is known to interact with a wide variety of medications, such as other mental health drugs, blood pressure medications, and some painkillers.

There are few medications available for the treatment of bipolar disorder that do not have significant side effects.

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Lithium In Treatment Of Mania

While manic episodes are often the most impressive part of BD, their duration is usually shorter compared to that of other disease phases in both BD-I and BD-II. A number of pharmacological agents have been investigated and have proven their efficacy in the treatment of mania, including lithium . The network meta-analysis by Cipriani et al. found an effect size of 0.40 SMD, indicating a moderately sized effect, which is comparable to other anti-manic agents . For example, lithium showed a comparable efficacy to quetiapine in a 12-week RCT . Despite its proven anti-manic properties, lithium has lost some of its relevance in the treatment of mania in the recent years, partly due to the large number of SGAs that have been licensed for this indication. Reasons for favoring SGAs over lithium include the shorter time of dosage increase and sedation, a common side effect of SGAs that is often welcomed during manic agitation. Further potential disadvantages of lithium include the small therapeutic window and hence the necessity for repeated serum level controls . In addition, no parenteral application is available for lithium. Notwithstanding these limitations, lithium should be considered as a first-line therapy for manic episodes, as long-term phase-prophylactic treatment is almost always required afterward, for which lithium is considered the first choice. In the treatment of manic episodes, higher levels of 0.8 to 1.2 mmol/L are required in order to achieve optimal response.

The History Of Lithium

The following is a simplification of an excellent history by Dr. Robert Howland.

Lithium was first discovered as a chemical element in 1817.By the mid-1800s, there was great interest in urate imbalances, which were thought to explain a variety of diseases, including mania and depression. Around this time, it was discovered that a solution of lithium carbonate could dissolve stones made of urate.

The first recorded use of lithium for the treatment of mania, based in part on the urate/lithium connection, was 1871. Use of lithium carbonate to prevent depression came in 1886.

As the public learned about lithium, great interest in this mineral led to the use of mineral-rich spring waters in spas, baths, and beverages. Because most of these mineral waters actually contained only traces of lithium, the dangers of lithium and higher concentrations were not recognized. When a tablet form was used as a salt substitute in low-sodium diets, there were many reports of severe lithium side effects, and some deaths.

Just as the dangers of lithium were becoming apparent, an Australian psychiatrist named John Cade began treating patients with mania using lithium . He too was led to this approach from a focus on lithium and urate. He had injected guinea pigs with lithium urate and found that they became placid, and somewhat tranquilized. Only later did he determined that the calming effect was from lithium, not urate.

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The Meaning Of Nirvanas Lithium

Put to tape successfully the following day, Lithium was finally complete. Its lyrics paint a picture of a protagonist whose despondency is alleviated by an enlightening conversion in which God becomes his protector. There is cause to suggest that he himself may have been responsible for his girlfriends death , but whether the song becomes a plea for his repentance, or whether he feels responsible through his own failings and is simply grieving and clutching at Christianity for salvation, is quite unclear.

Meanwhile, the title itself alludes to the lead characters mental state. Lithium is a medication prescribed to treat bipolar disorders and major depression, and its mood-stabilizing effects are known to reduce the risk of suicide in patients. Kurts cousin, Beverly Cobain, a registered psychiatric nurse, once claimed that he had been diagnosed as bipolar. Bipolar illness has the same characteristics as major clinical depression, but with mood swings, which present as rage, euphoria, high energy, irritability, distractability, overconfidence, and other symptoms, she said, As Kurt undoubtedly knew, bipolar illness can be very difficult to manage, and the correct diagnosis is crucial. Unfortunately for Kurt, compliance with the appropriate treatment is also a critical factor.

I Dont Believe In God But I Believe In Lithium

Lithium: How it Might Protect the Brain (8 of 11)

My 20-year struggle with bipolar disorder.

The salt flats of the vast Salar de Uyuni, in Bolivia, beneath which lies roughly 50 percent of the worlds supply of lithium.Credit…Olaf Otto Becker

Supported by

    The manila folder is full of faded faxes. The top sheet contains a brief description of my first medically confirmed manic episode, more than 20 years ago, when I was admitted as a teenager to U.C.L.A.s Neuropsychiatric Institute: Increased psychomotor rate, decreased need for sleep , racing thoughts and paranoid ideation regarding her parents following her and watching her, as well as taping the phone calls that she was making.

    I believed I had special powers, the report noted I knew when the end of the world was coming due to toxic substances and felt that I was the only one who could stop it. There was also an account of my elaborate academic sponsorship plan so I could afford to attend Yale some corporation would pay for a year of education in exchange for labor or repayment down the line.

    After I was admitted to the institute’s adolescent ward, I thought the nurses and doctors and therapists were trying to poison me. So was the TV in the rec room. I warned my one friend in the ward that its rays were trying to kill him. The generator outside my window was pumping in gas. The place, I was sure, was a death camp.

    What I saw was someone who resembled me, looked related to me, whom I remembered being. It was me without lithium.

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    Lithium In Maintenance Treatment

    Preventing new episodes in BD is essential with regard to quality of life, participation in society and preventing long-term disability. Lithium remains the gold standard in achieving this goal. It is effective in both type I and type II BD ). Only for lithium, randomized controlled trials without an enriched design, favoring the substance to be investigated, have been performed . Several meta-analyses of randomized placebo-controlled, long-term trials could verify that lithium significantly reduces the risk of new episodes compared to placebo ). A Cochrane review found the risk of any relapse to be 36% for lithium and 61% for Placebo over the course of 1 year, corresponding to an absolute risk reduction of 25% . Kessing et al. as well as Hayes et al. found lithium monotherapy to be superior to monotherapy with other maintenance mood stabilizers in real life conditions . This is reflected by its status as the first-line drug in many international guidelines . For optimal efficacy in long-term treatment of BD, target serum levels should generally be around 0.60.8 mmol/L, while specific treatment situations and patients may require slightly higher or lower lithium levels .

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