Manic depressive psychosis in India and the possible role of lithium as a natural prophylactic. I--Hypothesis.
A tentative hypothesis is presented in this paper, that the relatively low reported incidence of manic depressive psychosis (AMP) in India may be related to certain alterations in the metabolism of lithium as a trace element.
One of Hippocrates' aphorisms states that mania and depression are diseases of the spring and summer, indicating an association with the warm seasons. A relatively low incidence of mania and depression in tropical countries is being increasingly recognized., ,  At any rate, it is not equal to its prevalence in the West.
The possible role of lithium as a naturally occurring prophylactic for this disorder deserves further consideration. It is necessary here to point out that the bulk of the studies on lithium have been under experimental or therapeutic conditions in which a high dosage of lithium has been administered for therapeutic purposes. Little is known about the effect of lithium as a trace element in the diet. It is possible that lithium in minute quantities can exert a significant effect via several probable mechanisms. There might be a cumulative action of low doses of lithium given for prolonged periods, and conversely, there might be cumulative deficiency by lifelong exposure to marginal deficiencies. Another possibility is that there is a "herd effect" of lithium which occurs when it is ad ministered to all individuals in the same environment, who together act as the "stressor."
Evidence indicates that lithium is an element essential to life. It is found in a large number of foods, in the soil, and in water. It is found in trace quantities in nearly all organs of most animals investigated. Lithium has also been shown to affect physiological processes in lower aniriials.
Lithium, in trace quantities, has been used for years in the form of alkaline waters for the treatment of AMP. In a book written in the 5th century, Caelus Aurelianus had recommended the use of alkaline springs for the treatment of mania. Henderson and Gillespie4 write" In medieval Europe, certain wells were considered to have special virtue. Of these, the most famous were those of St. Fillans ...." Some wells in England, particularly in Cornwall, Wales, Scotland and Ireland were considered to have more than a local reputation. Based on this observation, the use of lithium salts was extended beyond medical prescription and almost all the bottled curative waters now on the market are advertised for their high lithium contents. This lithium content has been estimated to be 1.m. equiv. or 7 mg./1.
The importance of lithium as a trace element can also be deduced from recent studies which implicate it in the etiology of atherosclerotic heart disease. According to Mayer-Gross et al the pyknic habitus is more frequent in patients with affective disorders than in the general population. There is also a predisposition to arteriosclerosis (amongst several other ailments) for this particular type of physical constitution. High doses of lithium have an established beneficial influence on at least 4/5 prominent atherosclerotic heart disease risk factors including hypomaniac behaviour.,  It is well known that there is a negative correlation between atherossclerotic heart disease and the hardness of drinking water. Voors[2l] further states that this observation strongly suggests that there is a common biochemical mechanism through which these risk factors operate. The recently discovered tentative association between lack of lithium in municipal drinking water and atherosclerotic heart disease implies that lithium may be protective against arterosclerosis in a dose equal to that received by our phylogenetic ancestors in sea water. Statistically speaking, water hardness accounts for about 20% of the total variation of atherosclerotic heart disease mortality. It is possible that this association is secondary and can be explained by a third and yet unknown variable. Nevertheless, it needs to be studied seriously. Of all the known major determinants of atherosclerotic heart disease, none except hypertension has a distinct correlation with geography. Yet geographic correlation is clearly associated with atherosclerotic heart disease in a pattern consistent with causal action exerted by geographical characteristics and suggesting geological involvement. The known geographic differences in atherosclerotic heart disease incidence are more evident between cities than within cities, and would suggest a factor such as water mineralisation., 
Though minerals may also be supplied by food or polluted air, it has been noted that deficiencies are more likely to be determined by-the supply rate from water rather than that from food. In considering such a supply of lithium, it is interesting to note that the daily lithium intake through drinking water exceeds that from food. It has also been shown that the capacity of the human body for storing lithium as well as the reabsorption from the renal tubules are both limited. Hence deficiency of lithium in the drinking water would lead to lithium depletion of the serum, and in turn of all organs, including the central nervous system eventually. Unlike human beings, certain plants such as those belonging to the Ranunculaceae and Solanacea families are known to be able to accumulate lithium. Ingestion of these plants as articles of diet would be important as supply sources of lithium. These vegetables are common articles of diet in India. Crude sea salt and rock salt are also consumed to a greater extent in India than in western countries, where refined table salt is used. Crude sea salt and rock salt have been found to have a higher lithium content than refined table salt.
The genetic basis of MDP has been well documented and firmly established. Amongst the few psychiatric findings that have proved consistent and reliable has been the observation that primary affective disorders are of a familial nature and can be traced through several generations in the same family.
It has been shown9 that the therapeutic effect of lithium is related to the high ratio of RBC/plasma lithium in patients treated with therapeutic doses of the drugs. There is evidence that this RBC lithium concentration is at least partly under genetic control. MDP may be related to a genetically determined abnormality in sodium and lithium ion flux. It has also been shown that factors which regulate lithium ion flux across the cell membrane- are the same as those which regulate sodium ion permeability.
Evidence has been presented elsewhere that:
(a) The lithium intake in Indians appears to be higher than in the western population.
(b) Despite this higher intake of lithium, the serum levels of lithium are not high, but the 24-hour urinary excretion of sodium and lithium are both high.
(c) Total exchangeable sodium levels have been found to be higher in Indians as compared to subjects from temperate countries.
It is possible that lithium can substitute for sodium in carrying the current of action potentials. Hence a greater amount of exchangeable sodium would provide a greater scope for the action of lithium.
Several attempts have been made to estimate variations in the relative frequency of mental disorders in different cultures. These are either based on hospital statistics or on census reports. Although Wittkower expresses serious doubts about the use of hospital records for these purposes, Stoller has stated that these can provide useful comparisons. The method of census examination has also been widely used for this purpose, but cross cultural comparisons are extremely difficult with this method because of differences in the population, resistance to survey procedures, differences in sampling methods and in the diagnostic criteria of mental disorder, and the intensity of the investigator. This would explain the widely divergent findings obtained in important studies of psychiatric epidemiology -reported from India during the last few years.
In this connection, it is worth noting Shepherd's criticism in a recent review of a study by Carstairs on psychiatric morbidity in an Indian village. To quote the author's own words: "Because of differences in data collection procedures... the results in this study cannot be strictly compared with those obtained in other studies carried out in India or abroad."
An alternative explanation to the theme of this paper, viz. that the low incidence of MDP in India is caused chemically rather than culturally, is in terms of the prevailing practice of prolonged mourning rituals. This is an integral part of the Indian cultural system. This explanation is neither acceptable nor logical. The Indian Parsi community has a very high incidence of depression6 in spite of an elaborate and prolonged mourning ritual. There have been no controlled studies which show that the incidence of depression is a function of the duration of mourning after bereavement. The majority of the cases of depression are not directly related to bereavement, either covert or overt. Prolonged mourning also does not explain the usually late onset of the illness.
It is true that the amount of lithium required for treating MDP and the range of therapeutic serum levels are far in excess of the amount of lithium which is physiologically present; and there is no evidence to suggest that the level of endogeneous lithium is low in AMP. However, the physiological action of a trace element may be different from its action in therapeutic doses. It is well established that certain trace elements affect enzymatic reactions by various means including activation and inhibition, and by influencing other biological parameters such as alteration in cell permeability.
In conclusion, the postulate is submitted that lithium intake and total tissue lithium content may be important contributing factors in the genesis of MDP.
The authors thank Dr. C. K. Deshpande, Dean, K.E.M. Hospital and Seth G.S. Medical College, Bombay, for permission to publish this paper.