History of Lithium Therapy- Gold Standard Treatment for Bipolar Disorder and My Tryst with Lithium

Author’s Note” This blog is the the largest piece of a single article in any format written by the Author. It has a reason and a  purpose. Its proximate reason is a recent debate triggered on social media platform Twitter in India (including in the psychiatric community) that due its serious side effects Lithium has lost its earlier sheen of “Gold Standard Treatment” of Bipolar Disorder and that more effective new generation medicines have replaced it with better efficacy none of the side effects of lithium. This blog  postulates that except for a minority of patients to be carefully decided through trial and error by psychiatric community Lithium was, is and will remain the “Gold Standard Treatment” of Bipolar Disorder at present level of scientific knowledge.

Caveat: It is the caveat of the author that he is neither a researcher or a scientist nor pretends to be one. The compendium of History Of Lithium Therapy” as presented here are solely on account of the fact, that the author had a two years tryst with Lithium Therapy and has more than sufficient reasons to lament and say decisively-

“!Alas the History of his”Mad and Sad Life” could have been different had the author patientlygiven Lithium a Chance.

PART A- MY TRYST WITH LITHIUM THERAPY

MY TRYST WITH LITHIUM

I was first put on lithium therapy in October 1998 when the psychiatrist changed my diagnosis from Major Depressive Disorder to Bipolar Disorder-1. My life with lithium to start with was not easy, in many ways life with lithium was hell or this is what I thought.

My biggest problem with being on lithium was total  cognitive dissonance and dulling which severely interfered with my type of work- then working in a very demanding, stressful, very long hours and often humiliating work schedule as a corporate honcho- I was youngest Vice President in a large Indian family run corporate business group .

Nonetheless I  stayed put on lithium without missing a single dosage as prescribed by my psychiatrist for a year and half. With all the problems I faced with leading a life with Bipolar disorder, being on lithium and the side effects related to lithium  therapy after few months of being in vegetative state I did return to the work albeit at very low level of functionality. Side effects of lithium therapy that made life unbearable during the period included but were not limited to severe cognitive dissonance and dulling, impaired memory, loss of concentration and trembling of hands. 

It my new sub-normal  new normal existence with lithium. Suffices to say at this stage that this is an acquired knowledge in hindsight and at that point of time my mind malady was so severe and mind was disrupted to such an extent that I had no way of differentiating the systems of my Bipolar Depression and the problems I faced due to side effects of my principal medication “Lithium Carbonate”

THE GAME OF RUSSIAN ROULETTE- MY PARTIAL  LITHIUM NONCONFORMITY 

Time changed and by mid 1999 and despite dangling dangerously in depression and under heavy medication of  2400 mg of lithium carbonate per day, fate took me across oceans to Philippines to pursue Masters in Management course at Asian Institute of Management (Manila), a premier business school of Asia Pacific.

Once at Manila without my shrink and caregivers, I suddenly found me a free bird. And there was a severe problem, in the sense that cognitive dissonance and dulling, impaired memory and loss of concentration almost made the academic pursuit impossible at a very high pressured business school.

The impairment level was so high that I almost dropped from the Business School.

My non-conformity with lithium (partial) began at Manila due to a play of serendipity  ( in hindsight it was a dangerous game of Russian Roulette). Non-believers will find it difficult to comprehend that for first three months at the business school (AIM) professors did not allow a student to sleep for more that couple of hours on weekdays. Worse over weekend three was a stupid WAAC test, which demanded almost forty eight hours work over less than two days. Thus began my partial non-conformity with lithium dosage, and miraculously my cognitive dissonance, dulling, memory impairment and loss of concentration reduced substantially initially. 

Partial non-conformity with lithium that started accidentally sooner became the self fulfilling prophecy. 

MY  FLIRTING WITH GOOGLE-THE DANGEROUS MISTRESS OF WORLD WIDE WEB

It was around this time that I also got fascinated with a new toy or should I say the new tempestuous mistress of “world wide web (www)-the newly arrived Google . Founded in 1998 Google was in its first year but still the search engine to me was more powerful in returning me search results of queries as compared with all other search engines I had used for years altogether

At once I started flirting with  Google to find answers to to enhance my academic knowledge,  to solve queries of my inquisitive mind other queries and more importantly for finding answers to my persistent worries. One such nagging worry was ”  Side effects of Lithium Therapy”.  Till then I was not even aware that lithium worked in a very narrow therapeutic range and unless the lithium serum level was monitored closely the danger always dangled that I could enter the dragon of lithium toxicity.

Mouse of my desktop, lighted my desktop screen with following side effects of Life on Lithium- 

  • Hand tremor 
  • Increased thirst
  • Increased urination
  • Diarrhea
  • Vomiting
  • Weight gain
  • Impaired memory
  • Poor concentration
  • Drowsiness

This revelation was  tantalizing invitation to let go of  my”quarterly Quota of my lithium carbonate” sent by my wife using costly air courier route from India. 

THE CARDINAL MISTAKE I MADE-THROWING LITHIUM IN SOUTH CHINA SEA

But the results further fueled my desire to know about all side effects of lithium and at once I asked “Google”– Serious Side Effects of Long Term Lithium Therapy .

And the answer I got was bone-chilling- “Kidney Damage, Renal Failure and in severe cases death due to Kidney Failure”

This was final nail in the coffin for the uneasy marriage between me and lithium carbonate. On the 14th day of October 1999, the day Pervez Musharraf deposed Nawaz Sharif in a Bloodless coup in Pakistan at Boracay ( breathtakingly beautiful beach in Philippines) I ceremonially gave a watery funeral to all my lithium carbonate tablets.

The immediate after math of this crazy act was- I became well- my depression fled and all side effects of lithium (with sole exception of hand tremor) vanished. But soon there after I became dangerously well. A couple of months before graduation from AIM, I became dangerously ill, when the choke hold of psychotic mania took over. And I almost failed to complete my Masters in Manage. The tsunami of madness that destroyed my life over next two years, in hind sight was solely attributable to my throwing Lithium, my life saver at South China Sea at Boracay.

That story is subject matter of many separate blogs. It also consumes four chapters in the boon on my accursed life- “Of Madness and Sadness”- Life and Times of a Manic Depressive Indian.

ALAS! I HAD ALSO ASKED GOOGLE- BENEFITS OF LITHIUM THERAPY

When I was dangerously flirting with Google, it never occurred to me first search for benefits of Lithium Therapy. I had a blinder then. Life on Lithium was living hell of me . Finding coping with lithium impossible I was looking for easy exit route from life on lithium. And Google liberated me. Had I looked for the benefits with my dexterity on research on www I would have learnt within no time that-

  • Lithium is “Gold Standard” treatment for Mania in Bipolar and also as parplaxic agent.
  • Armamentarium of psychopharmacology has few agents to combat bipolar depression. But lithium in high dosage also has efficacy in Bipolar Depression
  • Lithium is that rare psychotropic agent which has anti-suicidal properties.

Alas! I did not give lithium a chance. I did so with life shattering half-lie half-truth of my Google Gyan that Bipolar Disorder would kill me in long term (all of us are dead in long term in any case) but renal failure due to lithium will bring accelerated painful death.

Following excerpts from -Kay Redfield Jamison and Frederick K. Goodwin (2007) in their book “Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression”  ( which is a classic treatise on all aspects of my illness, even today numb me-

“It is beyond regrettable many young psychiatrists in the USA have never really learnt the science and art of lithium treatment, and  they excuse their ignorance by convincing themselves that lithium has been surpassed by more effective medications or it is too difficult to use-a self fulfilling prophesy. It is our belief that clinicians who are unable or unwilling to include the skillful use of lithium in their armamentarium should not be competent to treat bipolar disorder”

 

PART B: LITIHIUM A BRIEF HISTORY AND ITS USES

WHAT IS LITHIUM Lithium gets its name from lithos, the Greek word for stone, and is dug from the ground. It is found in stones including granite, in seawater, mineral springs, meteorites, the sun and every other star and all humans. It is the third element of the periodic table and is lightest of all metals.

DISCOVERY OF LITHIUM : Lithium was discovered in the form of mineral petalite (LiAl(Si2O5)2) in 1817 in the Swedish island Utö by Johann August Arfvedson.  A year later in 1918 C.G. Gmelin observed that lithium salts colour flames bright red. Neither Gmelin nor Arfvedson could isolate the element itself from lithium salts, which was first isolated by William Thomas Brande and Sir Humphrey Davy through the electrolysis of lithium oxide (Li2O). Today, larger amounts of the metal are obtained through the electrolysis of lithium chloride (LiCl).

 In 1923 the first commercial production of lithium metal was achieved by Metallgesellschaft AG in Germany using the electrolysis of a molten mixture of lithium chloride and potassium chloride, exploiting a suggestion made by Guntz in 1893.

 USES OF LITHIUM: Lithium and its compounds have many uses. Lithium has highest specific heat of any solid element and is used in heat transfer applications. It is used to make special glasses and ceramics, including the Mount Palomar telescope’s 200 inch mirror. Lithium is also the lightest known metal and can be alloyed with aluminumcoppermanganese, and cadmium to make strong, lightweight metals for aircraft. Lithium hydroxide (LiOH) is used to remove carbon dioxide from the atmosphere of spacecraft. Lithium stearate (LiC18H35O2) is used as a general purpose and high temperature lubricant. Lithium is also used in space-craft, other industrial applications like heat resistant glass, batteries and cars-lithium ion batteries are embedded in Teslas fastest accelerating car as well as Boeing-787, Dream-liner

 Lithium carbonate (Li2CO3) is used as a drug to treat manic depression disorder.

Non-medical uses consume ninety percent of lithium production.

PART C: HISTORY OF LITHIUM THERAPY FOR MENTAL ILLNESS:

Use of lithium therapy for mental illness has had a long history-in the Greek and Roman era, people soaked themselves in alkali-rich mineral springs to improve both ‘‘melancholia’’ and ‘‘mania. Vedic scriptures too describe such medicinal uses.

In the modern era the History of lithium therapy is one of discovered, forgotten and rediscovered

In the modern era it was London internist, Alfred Baring Garrod who first made lithium treatment of gout—including “brain-gout” —widely known in his 1859 work, The Nature and Treatment of Gout and Rheumatic Gout and later editions. Also in 1870, Philadelphia neurologist Silas Weir Mitchell recommended the use of lithium bromide as anticonvulsant and hypnotic[1].

Both treatments did not pickup.

 

EFFICACY OF LITHIUM  IN PSYCHIATRY : THE HUMBLE BEGINNING

The claims for efficacy of lithium in psychiatry were first made by Hammond in USA and the Lange brothers in Denmark. 

In 1871, William Hammond professor of Diseases of Mind and Nervous System at New York Bellevue Hospital Medical College was possibly the first to use lithium bromide to treat mania. In his Treatise- “Diseases of the Nervous System” (1871), he describes the condition as acute mania with exaltation or acute mania with depression-akin to later classical descriptions of manic-depressive insanity[2].

 He said “I have used lithium bromide in cases of acute mania, and have more reason to be satisfied with it than any other medicine“. Hammond treated mania with high dosages-as high as 45 mmol or even more, repeated every 2 to 3 hours and later reduced.

Psychiatric Researcher and Historian, Samuel Gershon reports “as Hammond did not mention use of lithium in later works 1882, 1883 and 1890 one could speculate as to whether stopped using it due to toxicities from the high doses he administered”. Gershon concludes-“whatever be reasons lithium departed the scene and was forgotten”.

The use of lithium resurfaced 1880s in Denmark where it was used for treatment and prophylaxis of depression by Lange brothers – Carl[3] (neurologist) and Frederick (psychiatrist). Their assumption was that the periodic depressions occurred due to “uric acid diathesis”.  In 1894, Frederik Lange made said he had treated 35 depression patients with lithium-carbonate.

Lange brothers also gave clinical description of recurrent, remitting and long lasting periodic depression, its organic nature and heritable or familial relationship and postulated that treatment had to continue for long term much beyond the current episode. They were first to propose therapeutic value of maintenance treatment with which began prophylactic protocol in psychiatry.

 

Like all good works Lange’s also was forgotten for three reasons-

 

One, their Danish language work had limited audience.

 

Two, vociferous objections to the concept of periodic depression by Danish and European psychiatrists including Kraeplin (most influential of the era) shredded “Lange Theory of Depression”.

 

Three, very concept of relationship of “uric acid diathesis” to depression was decimated at medical society meeting in Copenhagen in 1911.

 

ENTER 20TH CENTURY: VANISHING ACT OF LITHIUM FROM PSYCHIATRY

At the dawn of 20th century, the reference to lithium in psychiatric literature was largely gone though in sporadic cases lithium treatment continued in Europe. French physician Roger Reyss-Brion talked of “Dr. Gustin’s Lithium” used in South France as primary reason why Marseilles did not have many manic-depressives.

For next 50 years, Lithium therapy got lost to the world.

!940s- AN ACCIDENT THAT KILLED LITHIUM IN USA

Lithium resurfaced in 1940s in USA when lithium (chloride) was given as replacement for sodium-chloride to cardiac patients. But with death of cardiac patients blamed on lithium poisoning, FDA banned all lithium formulations in February, 1949-a ban lifted only in 1970s.

BUT DIVINITY HAS OTHER IDEAS- SERENDIPITY SMILES IN OCEANA——

But, serendipity smiled again.

Around the time when the lithium formulations were banned in 1949 in the USA, a young psychiatrist in the farthest corner of the world in Oceana, was silently testing the-“Efficacy of Lithium Salts to treat Mania”.

THE JOHN CADE STORY…….

37 Year, John Cade, was son of a psychiatrist and had spent his own formative years in various asylums. Cade became interested in the life of insane  when he himself was prisoner of war at Changi Singapore for three during second world war, where as lone psychiatrist he started treating mentally ill prisoners. On return to Australia after three year incarceration, working in war veteran Bundoora hospital outside Melbourne he found serendipitously“lithium ions had sedative effect on guinea-pigs”.

 

Cade soon applied his déjà-vu moment to treat mentally ill.

 

Deeply religious and compassionate that he was, Cade first used lithium for weeks on self and once found it safe, he administered it on his first patient- Bill Brand who had been psychotic suffering from extreme mania. Brand improved dramatically on lithium treatment and after two months, walked out of the Bundoora asylum to freedom perfectly sane and back to his old job.

 

Nothing like this had happened in an asylum before.

 

After Brand, Cade used lithium on nine more mania patients, six schizophrenia patients and on three melancholics. His results with mania patients were startling, most of them improved dramatically. However, those with schizophrenia and melancholia showed no improvement.

 

Cade started with multiple high dosages and once the acute symptoms ebbed he reduced lithium dosage and frequency in manic patients – often a single dose in night- in contrast to the treatment I received decades later. He summed his findings in 1949 classic paper: “Lithium Salt in the Treatment of Psychotic Excitement” in an obscure journal- “The Medical Journal of Australia” –

 

“In manic patients improvement closely paralleled treatment and this criterion was fulfilled in chronic and sub-acute cases just as closely as in case of more recent onset.…”

 

He also observed- “It is natural to suppose because lithium causes mania to subside; continued dosage might precipitate depressive episode. So far there are no evidences. Three patients suffering from chronic depression were given lithium nitrate for several weeks in same dosage as those with mania -but there was neither improvement nor aggravation”.

 

When lithium arrived, the armamentarium of psychopharmacology was empty “way to treat depression and mania was ECT of dubious integrity.   Samuel Gershon[4] reports, in 1952 in Australia, he, one more resident and superintendent in two state facilities, managed 500 patients with “sedatives, ECT and insulin”

 

Cade’s report initially did not have much impact outside Australia. Also he never undertook any more studies with lithium but the article fired first salvo bringing modern era of psychopharmacology –“on the trail of lithium followed anti-depressants with 10 years lag and neuro-leptics after 25 years

 

Psychiatrists Samuel Gershon, and Goodwin and Ghaemi[5] say-

 

It heralded “The Third Revolution in Psychiatry” – Psychopharmacology

 

SUCHOU AND OTHERS SAVED LITHIUM

The discovery of Cade almost had the same fate as that of William Hammond and Lange brothers. US imposed ban on lithium. Also there were lithium induced fatalities in Australia were bad publicity. But worst was the death of Bill the first patient whom Cade had treated with lithium. He died due to lithium overdose. Cade worried about serious lithium poisoning discontinued lithium therapy.

But lithium was saved this time by spirited action of many across the world-

 Australia: E.M. Trautner and Charles Noack, in Australia and their 1951 paper-“Lithium Treatment of Maniacal Psychosis” (published in Medical Journal of Australia), with finding emphasized “The very beneficial effect of drug in cases of mania did not justify abandonment of lithium treatments”. Their seminal contribution included providing safe ways for lithium use, blood lithium level assessment of patients and the discovery that there was narrow therapeutic safety range of lithium.

 

They provided the value of a ‘therapeutic window’ for Lithium.

 

France: In France around same time in 1951 ‘Despinoy M and De Romeuf J’ at the Saint-Albain mental hospital administered lithium citrate to ten patients with “chronic mania,” and found, “use of lithium in mania was particularly effective”.

 

IT IS LIFE TIME WORK OF SCHOU THAT SAVED LITHIUM:

However it was in Denmark that the real crusade to save lithium as treatment option for mania and as prophylaxis of manic depressive illness began. In 1952 Erik Stromgren,(head Aarhus University psychiatric clinic at Risskov) and Mogen Schou his staff psychiatrist undertook randomly controlled trial of lithium in mania as a follow up to Cade (1949) and Trautner and Noack’s (1951) work . The time random control experiments in psychiatric drug trials had just begun. Schou randomized mania patients with a flip of a coin to lithium or placebo, and published his results in 1954 published in a British journal. Beginning with his classic 1954[9] paper, till he died in 2005 Schou made research on lithium therapy life mission producing 500 plus papers covering all aspects and making lithium gold standard  treatment for bipolar disorder.

 

The contribution of Schou is considered “humungous contribution by one man to cause of one treatment regime”. It is rightly said [10] -“Cade gave birth to efficacy of Lithium Therapy in mania but Schou was the obstetrician who ensured its safe delivery.”

 

Schou famously wrote in his classic 1954 paper-

“Authors all agree, lithium is ineffective or only slightly sedative in depression and schizophrenia, but considerable improvement…is seen in mania. All ten cases treated by Cade (1949) responded favorably. Ashburner (1950) reports, of his 50 patients, a dozen were able to leave hospital. Noack and Trautner (1951) treated more than 30 manic patients and only one or two failed to respond … Our results too are in line… Lithium therapy appears to offer a useful alternative to ECT since many patients can be kept in normal state by administration of maintenance dose”

 

He further added- “Beneficial effects of lithium in mania offers new possibilities for study of patho-physiology of manic-depressive psychoses.” It is study of this pathophisiology and effectiveness, safety and efficacy of lithium that Schou made his life’s mission.

 

NOTE: To begin with Cade and Schou did not find efficacy of lithium in depression. As clock moved forward, its poor efficacy also became evident in mixed-states, rapid-cycling and mania with psychotic syndromes. But many later studies established efficacy of lithium at higher dosage in depression and European psychiatrists use it as a choice medication for both recurring uni-polar and bipolar depression.

 

Schou in his 1954 paper had one more finding-

 “Lithium dosages necessary for clinical effect are close to those giving rise to toxic symptoms….in practical usefulness of lithium therapy, unquestionable toxicity has to be taken into account. A careful clinical and biochemical control of patients under lithium treatment appears advisable.”

 

And he provided long-list of side-effects of toxicity-

 

“Nausea, vomiting, diarrhea, hand tremors, muscular weakness, general fatigue, drowsiness, vertigo, fasciculation in facial muscles, mental confusion, slight depression, sweating, dryness of mouth, tinnitus, blood pressure lowering, reflex hyperirritability, coma, paralysis of limbs, epileptic seizures,  E.C.G. and E.E.G changes, lowering of body temperature, and diastolic heart stop

 

It was Schou who put lithium on the pedestal of “gold standard treatment for bipolar disorder” even though John Cade, person who introduced lithium to armamentarium of psychopharmacology largely remains unknown outside core psychiatric community.

 

THE BLOODY WAR THAT LITHIUM FOUGHT IN USA

But it was long and bloody war for approval of lithium therapy in USA.  

A subtle change began when Samuel Gershon was back to “Schizophrenia and psycho-pharmacology joint research project of the University of Michigan at the mental hospital in Ypsilanti, Michigan”, after spending eight years in Australia in the company of Trautner et.al. On Gershon with Arthur Yuwiler published first North American publication on lithium.

Meanwhile in 1962, George Winokur at Washington successfully treated a patient with lithium. He had not shown any improvement earlier with chlorpromazine and 18 rounds of ECT.

Now studies on lithium began under the leadership of Gershon. Also mid 1960s Ronald Fieve converted New York State psychiatric Institute into epicenter of research on lithium, and in 1966 published an influential open-label study.

Many more followed. And results were always dramatic

 

It all led to a large American “lithium underground” army of psychiatrists prescribing lithium. Paul Blachy even made public declaration he would l. prescribe lithium with or without FDA approval. In 1968 at New York University Gershon and his colleagues conducted many studies on lithium. Dr Shopsi also published the first textbook entitled, “Lithium: Its Role in Psychiatric Research and Treatment” in 1973.

 

Under assault from all sides, FDA approved lithium for treatment of mania in 1970 and approved lithium prophylaxis in 1975. But even today it does not accept lithium prophylaxis in depression despite evidence of its efficacy. For bipolar treatment even today in USA-valproate, antipsychotics and antidepressants are preferred to lithium.

 

TO SUM UP:

As I end historiography of lithium, one can safely assume it has wonderful efficacy in mania, at higher doses also works well in manic depression and is an effective antidote against recurrence of mania and depression.Also, lithium has proved to be a potent anti-suicidal ideation agent. 

 

One cannot ask for more properties in one drug.

 

AND THE ICING  ON THE CAKE:

The cheap lithium available in abundance in nature (cannot be patented by pharma companies) is indubitably the biggest gift of scientists and god in fight against bipolar disorder. It has also saved hundred thousands from causing them self-inflicted-death, and made life of millions bipolar sufferers livable.

AND THE MYSTERY_ How Lithium Works……

Irrespective of lithium proving wonder drug for bipolar disorder, the medical science is largely clueless- “Why and how does lithium work to keep the insane, sane”. Following is what the author has understood from secondary sources-makes no claim of their accuracy

 The biochemical and physiological effects of lithium is complex, wide-ranging, and probably affect hundreds, if not thou­sands, of genes and gene products. Despite extensive research, the exact mechanism of how lithium works as mood stabilizer is mystery. Evidence suggests lithium might be modulating intra-cellular signaling through inhibition of two intracellular enzymes, ‘inositol monophosphate’ and ‘glycogen synthase kinase’, both in turn regulating protein Kinase C. However, exactly how inhibition of these two enzymes results in ‘mood stabilization’ is unknown. Lithium is also understood to be interacting with serotonin, noradrenaline, glutamate and GABA neurotransmission. Glutamate is an excitatory neurotransmitter and hypothesis is Lithium ‘stabilizes’ glutamate levels, which may explain why lithium is useful in Mania. Also lithium has shown to enhance norepinephrine and serotonin levels in the brain, which could explain its anti-depressant effects.

 

In  July 7 , 2016 issue of Current Biology, MIT scientists working on worms reported lithium treatment silences activity in neurons that rely on BPNT1, (BPNT1 is a protein already known to be inhibited by lithium and BPNT1 removes phosphate groups from a compound known as PAP, a process critical to maintaining normal cell function. Many human brain cells also depend on this protein). In humans, PAP, which BPNT1 degrades, is usually found in neurons that secrete dopamine, epinephrine, or norepinephrine, which are all neurotransmitters that stimulate brain activity.  It is the first study to show in a multicellular system that the BPNT-1 protein might be the target for lithium’s action and the findings suggest that lithium treatment silences activity in neurons that rely on BPNT1. Researchers believe that though this does not prove how lithium works in humans, it nonetheless provides a very solid experimental foundation for exploring a hypothesis that lithium might have therapeutic effects in specific neurons through inhibition of BPNT1,” Kim says.

 

In another study in also July 2016, using a series of nuclear magnetic resonance (NMR) experiments, scientists from Institute for Bioscience and Biotechnology Research (IBBR) and the Center for Biomedical Engineering and Technology (BioMET) at the University of Maryland, Baltimore, have proposed a new molecular model of lithium’s biologically active form. Writing  of Biophysical Journal, they also reported evidence that this bioactive form can significantly prolong the activity of a signaling pathway in the brain’s nerve cells (neurons), while also connecting seemingly disparate results of previous studies of the drug.

 

The new model provides a fresh perspective that can sharpen research aimed at pinning down lithium’s biochemical targets, and pathways through which it exerts its beneficial psychological effects. The model also could guide design of new treatments of mood disorders that are as effective as lithium but with fewer side effects. “No one has yet found the binding site on a protein through which lithium exerts its pharmacological effects, which means we still don’t have a target that might be used to steer drug development,” said John Marino, the National Institute of Standards and Technology (NIST) researcher who leads the Bimolecular Structure and Function Group at IBBR, a joint institute of NIST and the University of Maryland. “In our model,” he explained, “lithium acts as a kind of force multiplier,” exerting the equivalent of a gentle, yet very helpful nudge to abundant molecular complexes essentially composed of phosphate and magnesium. In a sense, lithium may be a performance modulator for these functionally diverse complexes.

 

On October 18 in another significant report in Molecular Psychiatry a team led by Ben Cheyette, a neuroscientist at the University of California in San Francisco (UCSF), linked success of lithium therapy in bipolar disorder to influence over dendritic spines, tiny projections where excitatory neurons form connections, or synapses, with other nerve cells. In their study lithium treatment restored healthy numbers of dendritic spines in mice engineered to carry a genetic mutation that is more common in people with autism, schizophrenia, and bipolar disorder than in unaffected people. The lithium also reversed symptoms in these mutant mice—lack of interest in social interactions, decreased motivation, and increased anxiety—that mimic those in the human diseases.

 

“They showed there’s a correlation between the ability of lithium to reverse not only the behavioral abnormalities in the mice, but also the [dendritic] spine abnormalities,” says Scott Soderling, a neuroscientist at Duke University in Durham, North Carolina, who studies how dysfunctions in signaling at brain synapses lead to psychiatric disorders. Soderling further adds that the work also sheds light on the roots of these diseases. “It gives further credence to this idea that these spine abnormalities are functionally linked to the behavioral disorders.”

 

[1] http://news.mit.edu/2016/new-clue-how-lithium-works-brain-bipolar-0707

[2] http://www.sciencemag.org/news/2016/10/new-clues-how-lithium-soothes-bipolar-brain-may-shed-light-other-mental-illnesses

[1] Mitchell SW. On the use of bromide of lithium. Am J Med Sci. 1870;60:443–445.

[2] Samuel Gershon, August, 2010

[3] Famous for James-Lange theory of emotion published in 1885

[4] Samuel Gershon, M.D. Emeritus Professor, Department of Psychiatry University of Pittsburgh Medical Center in his address delivered in August 2010 in  John Curtin Medical Research Building of the National University of Australia, in Canberra, Australia

[5] Goodwin FK,  Ghaemi NS.  The impact of the discovery of lithium on psychiatric thought and practice in the USA and Europe. Australian and New Zealand Journal of Psychiatry, 1999,

 

[6] Elsevier Advances in Psychology, Volume 66,  1990

[7] http://psychology.jrank.org/pages/494/Philippe-Pinel.html

[8] The History and Influence of American Psychiatric Association, Walter E. Barton; 2007 page 144

[9] M. Schou, N. Juel-Nielsen, E. Stromgren and H. Voldby “The Treatment of Manic Psychoses by the Administration of Lithium Salts, J, Neurol. Neurosurg. Psychiat., 1954, 17 250-260

[10] Lithium Treatment of Bipolar Disorder Phillip B. Mitchell and Dusan Hadji Pavlovic, Bulletin of the World Health Organization 78 (4) Page 516-17

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