Lithium- its unlikely journey toward an effective treatment for bipolar disease

Lithium is a naturally occurring silvery-white alkali metal that is so soft that it can be cut with a knife and floats in water. It is also a chemical element and is in position number three (atomic number) in the periodic table of elements. Lithium compounds have a wide variety of uses most commonly in the production of lithium batteries but are also important in the manufacture of glass and ceramics, in metallurgy, air purification and in optics. 

Lithium salts were first used as a medicine to treat gout in the early 19th century based on the observation that they were effective in dissolving uric acid crystals that in gout accumulate in the kidney and bladder as well as in swollen painful joints that are characteristic of the disease. Their use was popularized by a prominent English physician, Alfred Baring Garrod, who in 1848 demonstrated that gout was associated with increased levels of uric acid in the blood. He also advocated that they be used for the treatment of 'irregular gout', a rather poorly defined condition that included mood disturbances and "gouty mania" and went so far as to suggest the lithium be used prophylactically for the treatment of recurrent mood disorders.  Another physician, Alexander Haig, believed that high levels of uric acid in the blood contributed to the symptoms in migraine, depression and mania and wrote widely on the concept of "uric acid diathesis".  A leading Philadelphia neurologist, Silas Weir Mitchell, recorded using the medication for the treatment of seizures and as a sedative in some patients.  However, it was William Hammond a professor of neurology in New York and former Surgeon General, who in 1871 was the first to document the effectiveness of 'bromide of lithium" for the treatment of acute mania. The most extensive documentation of the effectiveness of lithium salts for the prophylactic treatment of periodic depression in the 19th century was in a 1886 monograph by Danish neurologist Carl Lange who described the successful treatment of 700-800 patients. 

Despite the apparent success of Lange using lithium in the treatment of mental disorders its use for these conditions declined in the early 20th century as the promotion of lithium as a general nostrum for a wide spectrum of medical conditions beginning with gout but extending to back pain, rheumatism, headache and even as an anti-malarial agent, began to grow. The popularity of lithium as a general medical panacea led to the production and sale of lithiated spring water and even beer. However, the use of lithium had declined by the 1940s when the significant side effects of its medicinal use were becoming obvious.  One of its few remaining roles for its use in the the medical armamentarium was as a salt substitute (as lithium chloride) in patients with heart disease.  A report of the death of several of these patients because of the toxic effects of lithium led to the FDA banning the use of the substance in the United States in 1949, coincidentally the same year that a paper on the beneficial effects of lithium in the treatment "psychotic excitement" (mania) that presaged its current role in treatment of mental disorders was published by Dr. John Cade, a psychiatrist in Australia.

Cade who believed that toxins excreted in the urine of patients with mania might be related to the disorder performed experiments in which he injected urea into guinea pigs many of whom died because of seizures. When he added another toxin to the urea injection, uric acid in the form of its lithium salt, all of the guinea pigs survived. The injection of the lithium urate alone into the animals was associated with a short period of lethargy but no other ill effects.  Cade concluded that lithium may have both anti-convulsant and anti-manic properties. In the 1949 paper he went on to describe ten patients with manic-depressive disorder treated with lithium all of whom showed significant improvement that could be sustained with long term administration of the drug. Several years later in 1954, a Danish psychiatrist Morgens Schou and his colleagues reported the beneficial effect of lithium in 34 patients in which lithium was administered with placebo control in at least some of the patients. Over the next few decades studies in many different countries confirmed the efficacy of lithium in the treatment of acute mania and bipolar disease. The development of a method to measure lithium levels in the blood in 1958 made it possible to monitor lithium dosing and toxicity. In 1970, the FDA lifted the ban on the medicinal use of lithium and approved its use for treating bipolar disease. Currently, lithium is the 197th most commonly prescribed drug in the USA with more then 2 million prescriptions annually.

The history of lithium illustrates the roles of serendipity, persistence and chance in medicine. Lithium was first used as a medication because it dissolved uric acid crystals in the joints and kidney/bladder of patients with gout, however, it does not lower the elevated uric acid levels in the blood which cause gout and is not an effective treatment for the disease. Uric acid and other toxic substances were thought to be the cause of depression, mania and other disturbances of mood - the uric acid diathesis - hence the rationale for using lithium to treat these disorders. After nearly a century of the inconsistent use of lithium in small numbers of subjects, it was finally established that it is effective in treating bipolar disease.  Following decades of controversy, recent data suggest that subjects with bipolar disease do in fact have blood uric acid levels that are higher than those without the disease. However, although lithium is an effective treatment of bipolar disease, it does not lower blood uric acid levels and its exact mechanism of action in the disease is not known.

COVID-19 Statistics

COVID-19 is a dangerous pandemic that has thus far been responsible for approximately 70,000 deaths worldwide.  The USA, most European countries, China, South Korea, India and Japan have all instituted restrictions on social interactions and economic activity that will likely precipitate a global recession but these measures appear to be having a significant impact on the spread of the virus. Much of the reporting on on the pandemic focuses on irrelevant or difficult to interpret statistics. The number of diagnosed cases is a frequently reported statistic that conveys little information without being given more context.  The number of diagnosed cases is very dependent on the number of tests that are performed in a specific population (county, city, state, country). For example, on April 10 the total number of diagnosed cases was similar in France in Germany (approximately 125,000) which might lead one to conclude that disease severity is similar in both countries. However, the rate of testing (tests/million of population) was three time higher in Germany than in France. If one really wants to know the severity of the disease in a particular country then the number of deaths is a much more informative statistic; by April 10 the total number of deaths in France stood at 13,832 compared to a total of 2871 in Germany. Clearly the disease is much more severe in France than in Germany but the total number of diagosed cases in each country gives no indication of this fact.  Another frequently reported statistic is the number of recovered cases which is again virtually impossible to interpret for a disease that in most infected persons causes mild or no noticeable symptoms.  The recovered cases are those who were admitted to hospital because of the disease and eventually discharged. It is depenent on the number of hospital beds, on the overall occupancy of the hospital beds, on the criteria for hospital admission, and on the quality of medical care. For this particular disease, the only statistic that unequivocally describes the severity is the number of deaths and this is the number we should focus on.

Should we be wearing face masks when out in public?

The answer to this question is almost certainly, yes (but see caveat at the end of the piece). The rationale for doing do is quite strong. Three countries that have successfully dealt with the pandemic (China, Japan and South Korea) used the wearing of face masks in public as a major component of their disease fiting strategy. Although the U. S. Centers for Disease Control (CDC) do not currently recommend the routine wearing of facemaks in public their guidance on the issue is contradictory. The CDC advises that only those diagnosed with COVID-19 infection and those with symptoms consistent with infection should wear masks in public. However, we know that patients may be infected with and secreting the COVID-19 virus for up to three days before any signs or symptoms of the disease appear. Therefore, given the relatively low level of testing, the only rationale approach to reducing the spead of the virus among the public is to assume that all people may have symptomatic infection and should wear masks. The apparent reluctance of the CDC to recommend that all those in public spaces should wear masks is because, in view of the global shortage of face masks, this practice might deprive some in the medical community of desparately needed protection.   The CDC should immediately take two simple steps to reduce the spread of COVID-19 infection while safeguarding the medical community: (i) advise that everyone in public should wear protective face masks, and (ii) provide instructions on how to make effective face masks from ordinary household materials (cotton clothing, scarves etc.).

Case Fatality Rate of COVID-19 by Country

At this point in the COVID-19 pandemic it is difficult to get a reliable estimate of how deadly the disease might be. A useful metric that can be calculated from publicly available data is the case fatality rate (CFR) which is the proportion of persons diagnosed with a condition who die of that condition within a specific time period. For example, if there are 30 deaths among 600 patients diagnosed with disease X then the CFR for the disease is 5% [= 30 (deaths)/600 (cases) * 100)].  The reliability of the CFR as a measure of the severity of disease depends on whether one has a good estimate of the total number of patients with the disease; if one underestimates the cases the CFR will artificially high, if one overestimates the cases the CFR will be artificially low.  The issue of accurate estimation of cases is a particular problem with COVID-19 because of the relatively low rate of testing in the population and the likelihood that large numbers of cases with no or minimal symptoms do not seek medical attention.  Although estimates of the CFR of COVID-19 using currently available data are likely to significantly overestimate its severity, I thought it might be interesting to tabulate the CFR by country for those countries reporting at least 9500 cases on March 29, 2020. Further notes of the sources of the data used in the table and any assumptions made will be found in the Notes on Data paragraph below.

COVID-19 Case Fatality Rates (CFR)

The table shows that there appears to be a wide variation in the severity of the disease in different countries. The adjusted CFR is likely the best estimate of disease severity because the baseline CFR has been adjusted for the rate of testing in the population of eacj country.  Comparatively, COVID-19 infection seems least severe in Germany with an adjusted CFR of 0.79% compared to the worldwide average CFR of 4.68%.  Belgium and the United States also achieve adjusted CFRs of approximately 1% or less. Similarly, the UK, France, and South Korea show less severe infection with an adjusted CFR of approximately 2% or less. The clear outliers at the other end of the severity spectrum are Italy and Spain with adjusted CFRs of 13.38% and 11.03% respectively.  There is no easy explanation for the comparative differences in severity across countries. Total health care expenditure does not seems to be related: the USA and Germany rank number 1st and 5th, respectively, in terms of health care dollars per person in 2016, however Switzerland (2nd) and the Netherlands (8th) do not perform nearly as well as France (14th), the U.K. (17th), or South Korea (24th).  The organization of the individual national health care systems is also an unlikely explanation as those in the table represent the full spectrum from primarily market driven organization in the United States, to a a mixture of public and private insurance in Germany to a universal national health service in the U.K. Population density if also unlikely to be a significant variable as it is much higher in countries with less severe infection such as Belgium (22nd most densely populated), the U.K. (32nd) and Germany (41st) than in Italy (51st) and Spain (89th).  It is possible that the apparent high mortality in Spain and Italy is because the virus in these countries has been disseminated across a great percentage of the population and the prevalence of the virus has not be adequately reflected in the limited testing that has been performed.

Notes on the Data: The principal data in the table (Cases, Cases/Million, and Deaths) were taken from the Coronavirus (COVID-19) Map published on Google (google.com/covid-19-map) on March 29th. These data were filtered to include only those countries that had recorded more than 9500 cases by March 29th.  The Tests/Million data were taken from Wikipedia (en.wikipedia.org/wiki/COVID-19_testing) also on May 29th.  The CFR was = number of Deaths/number of Cases * 100.  I adjusted  the CFR for the density of testing in the population (Tests/Million) normalizing to the testing density in Germany as follows: Adjusted CFR = CFR /[(Tests-Million Germany/Tests-Million Country X)]. No adjustments were made for Worldwide, Iran or China because of unavailable or unreliable data. 

Games of Chance, Games of Skill, Probability and the Kerry-Dublin replay

Games of chance are those in which the outcomes is governed by a probability over which the participants have no control. The probability of a specific outcome depends on the game. For example, the probability of “heads” in a coin toss is 1/2 whereas the probability of a "6" from the roll of a dice is 1/6. People have made wagers on games of chance for centuries and the payout for a particular wager is proportional to the probability of the outcome. Because the outcome in these games is entirely governed by chance or luck, and are independent of the skill of the player, in the long run it is impossible to make money by gambling in this fashion.

The most common form of betting is on games of skill in which the skill or the participant(s) is a major determinant of the outcome with chance playing a greater or lessor role depending on the game. In poker, for example, the cards that the player receives are determined by chance but the outcome is significantly influenced by the skill of the player. Horse racing is a game of skill in which each animal has its specific set of racing skills that are impossible to quantify exactly but can be estimated based on ‘form’ which is a qualitative variable related to racing history, pedigree etc. The form of a horse relative to other horses in the race determines its probability of winning and the odds of winning offered by bookies and betting houses are directly related to this probability. For example, a horse thought to have a 1/2 (or 50:50) chance of winning is likely to have 1/1 odds or ‘even money’, one with a less than 50% chance will be given long odds (2/1, 3/1 etc.) and one with a greater than 50% chance will have short odds (1/2, 1/3, etc.). Though the relative skill of the horses is a major determinant of the winner of a horse race, chance can also have a significant influence; the most skillful horse may not win the race on a particular day.

Team sports are also games of skill but the outcome of any specific match has a certain element of chance just as with horse races. This brings us rather circuitously to predicting the winner of the Kerry-Dublin All-Ireland final replay. The current betting odds for the replay on September 15th are 1/4 for a Dublin win and 7/2 for Kerry which translates into a 0.8 probability of Dublin winning the game. The probability of Dublin winning the original match based on the betting odds was approximately 0.82. Therefore, the fact that Dublin could only draw a closely contested game that they were generally expected to win has had virtually no effect on the expectations and predictions of the betting community on the outcome of the replay. Given the information about the respective strengths of the Dublin and Kerry teams that can be gleaned from the drawn game, are the current expectations about the outcome of the replay rational? I think not.

The unchanged predictions (and betting odds) for the replay are presumably driven by the fact that in repeated matches between two teams that differ significantly in skill, the more skillful team will tend to win more of the matches. This reasoning assumes that Dublin is clearly the more skillful team and that this conclusion is not changed in any way by the new information provided by the last match between the teams. The information provided by the last match is that Dublin are not invincible, that the Dublin forwards can be shut down by the Kerry backs, that Dublin were prevented from turning the dynamic of the game mid-way through the second half, and most importantly that Kerry managed a draw in a game in which their star forwards (Clifford, Ganey) significantly underperformed. I believe that the prediction and the betting odds are not consistent with the information we have about the teams and that Kerry will win the replay by three or more points.

When was Freddie Grey Injured: a Neurological Perspective

Mr. Freddie Grey who was arrested in Baltimore on April 14th, 2015, was seriously injured while in police custody, immediately hospitalized and subsequently died at the University of Maryland Shock Trauma Center on April 19th. Six Baltimore City Police officers have just been charged with a variety of offenses from manslaughter to second degree homicide in connection with Mr. Grey's death. Although several witnesses independently recorded video footage of Mr. Grey's arrest, there is no consensus on the details of how and where he sustained his injuries.  Were the injuries sustained during a 'rough ride' in the back of a police van or were they inflicted before Mr. Grey was first placed in the paddy wagon?  I believe that viewing the issue objectively from a neurological perspective can help to peel away some of the uncertainty about when he was injured.

The videos that are publicly available show Mr. Grey lying face down on the pavement, screaming in pain with two police officers kneeling beside him. The officers then lift Mr. Grey, one under each arm pit, to transport him to a police van that was parked nearby.  Once Mr. Grey had been lifted into a standing position, it is clear that he was unable to use his legs; this is not a merely an astute observation on my part but was also noted on the audiotape by several of the witnesses at the scene. He was then dragged to the back of the police van with his legs trailing limply behind him. According to the police, Mr. Grey was placed in the back of the van but not restrained by a seat belt. After moving less than two blocks from the site of the arrest, the van stopped and Mr. Grey had his legs placed in shackles and he was positioned face down on the floor.  Approximately 45 minutes later and several stops later, Mr. Grey was unresponsive and not breathing.  After his death, an autopsy found that his spinal cord was completely severed in the upper neck and three adjacent vertebrae were fractured.

It seems highly improbable that Mr. Grey sustained his spinal injury because he was not restrained by a seat belt during a two block ride in the back of a police van; it is almost inconceivable that he caused the injury to himself by violently banging his head against the side of the van.  The video evidence suggests that he already had a spinal injury when he was first loaded into the van; therefore, he was injured sometime between his arrest and the time of the first video images of him lying face down on the ground flanked by two police officers.  If one accepts that his spinal injury was sustained before he was placed in the van, how did his overall condition deteriorate from one in which he was able to respond and interact (though not able to use his legs) to where he was unresponsive and not breathing?  I believe that his catastrophic decline was because of respiratory failure or neurogenic shock as a direct result of his spinal injury.  Injury to the upper cervical spinal can paralyze the diaphragm and also affect the function of the respiratory muscles of the chest; respiratory failure is a common cause of death in acute cervical spinal cord injuries.  Mr. Grey's complaints about finding it difficult to breath may have been the first indication that his breathing was compromised as a result of the spinal injury.  Severe respiratory failure, if untreated, will lead to low blood oxygen levels, loss of consciousness and eventual death.  Neurogenic shock, also associated with acute spinal injuries, leads to profoundly low blood pressure, inability to deliver blood (and oxygen) to vital organs, and eventual death.  It is not clear which of these two conditions (respiratory failure and neurogenic shock) was responsible for Mr. Grey's decline into a state of unconsciousness; it is possible that both contributed.  All the information we have related to Mr. Grey's arrest and tragic death suggest that his spinal injury was inflicted before he was placed in the police van and his decline into unconsciousness over the course of less than an hour was as a direct result of that injury.

Mental Illness and Violence

The deliberate crash of a Germanwings commercial airline flight by a co-pilot, known to be suffering from depression, killing himself and all 149 others on board has yet again raised concerns about the relationship between mental illness and homicidal behavior. The perpetrators in several high profile mass murders in the United States in the past four years all suffered from severe mental illnesses. The news organizations that report on these events tend to regard mental illness as a single disease category and rarely dwell on the characteristics of the large number of distinctly different mental syndromes (diseases) that this descriptor can cover. Therefore, it is not surprising that the general public has a similarly vague conception of mental illness and is often unaware that each particular mental disorder (depression, schizophrenia, obsessive-compulsive disorder, anxiety etc.) is defined by a unique set of behaviors and thoughts that enable us to predict how those afflicted with the condition will act. 

When we consider the potential contribution of mental illness to acts of violence, it is essential that this be done in the context of the specific mental disorder thought to be involved. In the case of the Germanwings tragedy, we know that the co-pilot had a history of depression and was under the care of a psychiatrist at the time of the crash. If the depression suffered by the pilot motivated his decision to crash the plane, this association will have major implications for how we insure the safety and welfare of individuals not just in the airline industry but throughout society.  However, it is not at all clear how governments and regulatory agencies could devise a set of rules, based on the premise that an individual with depression may be a danger to others, that would reduce the probability of similar events occurring in the future. At any point in time, approximately 5% of the US population suffers from depression (Centers for Disease Control). Therefore, it would be impossible (and unjust) to implement legislation that would prevent those being treated for depression being in a position in which they have responsibility for the lives of others. 

When one examines the evidence of a link between mental illness and homicide, the facts are more complex than suggested by a cursory analysis of the Germanwings crash.  Among the many distinct mental disorders, only schizophrenia and substance abuse/addiction are consistently related to a higher risk of homicide of individuals unrelated to the perpetrator.  In depression, there is a higher risk of homicide-suicide in which the victims of the homicide are usually either family members (spouse or children) or friends but not of an increased risk of homicide per se.  Whichever mental illness contributed to the crash in the French Alps, it is certain that it affected the co-pilots perception of reality and ability to think rationally.  The key to preventing similar tragedies in the future may be to identify mental states (e.g. irrational, delusional, or paranoid), common to many mental diseases, that predispose to acts of violence, and to insure that persons with such symptoms receive effective and timely treatment; doing so, while respecting patient privacy and avoiding further stigmatization of those with mental disease, will not be a trivial task.