Clinical and epidemiological data point to specific properties of Li in prevention of suicidal behavior, which are at least partially independent of its mood-normalizing effect [65]. Li is a well-known element of normothymic action and has been used as a part of preventive treatment of patients with suicidal tendencies, as confirmed at the level of meta-analyses [56, 68, 76,77,78] and randomized placebo-controlled clinical trials [79, 80].

Number of studies indicate a negative correlation between concentration of Li naturally occurring in water and mortality rate due to suicide [7,8,9, 11, 12, 57, 63, 64, 81]. This relationship is somewhat surprising, as the doses of Li used in therapy are several times higher than naturally occurring in the environment [68]; however, this association has been confirmed in different latitudes on various population groups (Table 3).

Table 3 Association between lithium concentration in water and suicide rate as observed in epidemiological studies (+ positive correlation; − negative correlation; x no correlation) Full size table

For the first time, an inverse correlation between the concentration of Li in drinking water and suicide rates was recorded in the USA. Differences in the incidence of suicides, murders, and rapes were reported in the population of 27 counties in Texas which were divided according to Li concentration into three groups: high, 70–160 μg/L; medium, 13–60 μg/L; and low, 0–12 μg/L [7]. Research carried out in 226 counties of Texas and 34 Greek prefectures indicated the inverse correlation of lithium concentration in water and suicide rates; however, in this study, these effects were also not considered separately depending on the sex [12, 63]. Such differences could be potentially expected as some data from therapeutic use of Li indicates that men may be more responsive to Li [83, 84]. It is also postulated that Li may exert its antisuicidal effects by lowering testosterone levels [85].

The first study to potential differences between male and female in response to trace Li in drinking water was conducted in the Oita prefecture of Japan. As reported, the concentration of Li (at a level of 0.7–59 μg/L) was inversely correlated with the frequency of standardized mortality rates (SMR) only among men [9]. These results were later confirmed by a study covering 274 municipalities of Kyushu Island in Japan [81] and confirmed by another, larger survey [82]. In Europe, this type of study was carried out for nine Lithuanian cities. A significant correlation was found between the concentrations of lithium (ranging from 0.5–35 μg/L) in water and SMR in the whole population and in the group of men. The observed concentrations of Li ranged from 0.5 to 35.5 μg/L [13].

Contrary to this, a study carried out in Austria [10] and Japan [11] indicated a relationship between the concentration of lithium in drinking water (0–82.3 and 0–13 μg/L, respectively) and the SMR in the general population and among women, and did not detect any similar association in men. Similarly, a study conducted in the Aomori prefecture of Japan also linked Li higher concentrations with lower SMR in women, with no such correlation observed for men [11]. In Italy, the concentration range in drinking water from 145 areas was in turn from 0.1 to 61 μg/L. The results were analyzed using SMR based on data from 1980 to 1989, 1990 to 1999, and 2000 to 2011. An SMR correlation with the tested lithium concentrations was found in the first time interval for the general population and for women, while in the remaining time intervals, a statistically significant relationship was found only for the suicide rate among women [64].

The study conducted in the eastern part of England, where Li concentrations ranged up to 21 μg/L, did not find them to be significantly associated with SMR, regardless of the sex of the studied population [58]. Surprisingly, in Denmark, despite a similar geographical location and similar ranges of Li concentrations (0.6 to 31 μg/L), the frequency of suicides has been shown to increase with increasing Li concentration in drinking water [55].

The above studies indicate differences in responses to environmental concentrations of lithium depending on gender although contradictory results have been reported with some studies suggesting antisuicidal action in women, others finding it only in men, and some not reporting such associations or reporting potentially pro-suicidal correlation. These differences may be due to geographically diversified response to Li but may also result from limitations of conducted studies. Particularly, the pioneering research in this field lacked the results of weighted variables used in the analyses, as well as reference to potentially disturbing socioeconomic factors. The risk of error in the majority of conducted studies may increase by the use of data on overall lithium concentration in a given region instead of basing such analysis on the individual Li intake levels [9, 11, 12, 58, 63, 64, 68, 82]. Knudsen et al. (2017) were the first to study the link at the individual level, using prospective data collected in Danish registers, and found no antisuicidal effect of Li [55]. It should be remembered that Li concentrations occurring in surface, ground, or underground waters in a particular area, and therefore also in tap water, do not necessarily reflect the intake of this element in the population because the examined individuals may consume bottled mineral water originating from regions distant from the place where they live.

On the other hand, extremely different results may derive from large variations in Li concentrations. In two studies in which no correlation was found, the lowest levels of Li in drinking water were demonstrated at the same time [55, 58]. A small range of concentrations may itself limit a detection of any statistically significant relationship. It can be hypothesized, therefore, that relatively higher concentrations of Li in drinking water (although still much lower from therapeutic doses) may potentially be associated with a reduced frequency of suicides [10, 86]. Further in-depth large-scaled investigations that will consider realistic, individual Li intakes and adjustment for possible confounding factors influencing suicide risk are however required to clarify this hypothesis.