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Lithium Levels in Tap Water and theMental Health Problems of Adolescents:

Shuntaro Ando, MDa,‡; Shinsuke Koike, MDb,‡; Shinji Shimodera, MDc; Ryosuke Fujito, MDc;
Ken Sawada, MDc; Takeshi Terao, MDd; Toshi A. Furukawa, MDe; Tsukasa Sasaki, MDf;
Shimpei Inoue, MDg; Nozomu Asukai, MDa; Yuji Okazaki, MDh; and Atsushi Nishida, PhDa,*

ABSTRACT
Objective: We investigated the association between lithium level in tap
water and mental health problems, including depressive symptoms,
anxiety, and aggressive and suicidal behaviors, in a general populationof adolescents using a large individual-level dataset.
Methods: A school-based, cross-sectional survey was conducted in
Kochi Prefecture in Japan between 2008 and 2009. Students in 24
public junior high schools were asked to anonymously complete a selfreport questionnaire. The main outcome measures were mental healthproblems, including those on the 12-item General Health Questionnaire,interpersonal violence, bullying, destructive behavior, self-harm, andsuicidal ideation. Samples were collected from sources that supplied
drinking water to schools, and lithium levels were measured using
atomic absorption spectrophotometry. The associations of lithium levels
with mental health problems were examined using a generalized linear
mixed model with schools as the fixed effect. Potential confounding
factors were also added into the model.
Results: A total of 3,040 students among 3,311 students responded tothe self-report questionnaire (response rate, 91.8%). The mean lithium
concentration in tap water was 0.48 μg/L (SD = 0.52; range, 0.01 to 2.10;
skewness = 2.01; kurtosis = 4.04), and it was relatively low compared withprevious studies. In multivariable regression analysis, lithium level in tap
water had an inverse association with depressive symptoms (P = .02) andinterpersonal violence (P = .02) but not with suicidal behaviors (suicidal
ideation, P = .82; self-harm, P = .46).
Conclusions: Lithium level in tap water was inversely associatedwith depressive symptoms and interpersonal violence among a
general population of adolescents and may have antidepressive andantiaggressive effects.
J Clin Psychiatry 2017;78(00):e000–e000

https://doi.org/10.4088/JCP.15m10220© Copyright 2017 Physicians Postgraduate Press, Inc.
aDepartment of Psychiatry and Behavioral Science, Tokyo Metropolitan Instituteof Medical Science, Tokyo, Japanb Office for Mental Health Support, Division for Counseling and Support,

University of Tokyo, Tokyo, Japan
cDepartment of Neuropsychiatry, Kochi Medical School, Kochi, JapandDepartment of Neuropsychiatry, Oita University Faculty of Medicine, Oita, JapaneDepartment of Cognitive-Behavioral Medicine, Kyoto University School of
Public Health, Kyoto, Japanf Department of Health Education, Graduate School of Education and Office for
Mental Health Support, University of Tokyo, Tokyo, Japan
gDepartment of Neuropsychiatry, Aizu Medical Center, Fukushima Medical
University, Fukushima, Japan
hTokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan‡To be considered as joint first authors.
*Corresponding author: Atsushi Nishida, PhD, Department of Psychiatry and
Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, 2-1-6
Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan (nishida-at@igakuken.or.jp).

M

any mental health problems that have theironset in adolescence1 are the leading causesof disability-adjusted life-years in this age group.2
Further, with the high potential of life-years lost bysuicide,3 suicide prevention in this group is a serious
public health issue. In this context, a public healthstrategy is required to prevent mental health problems
in adolescence.
Lithium could potentially be used to help minimize
mental health problems in a large segment of the
population. Lithium is a natural trace element that is
dissolved in groundwater and drinking water4 and has
been widely used for the treatment of mood disorders
because of its antisuicidal effects.5,6 Previous ecologicalstudies have reported an inverse association between
lithium level in water and regional suicide and violent
crime rates,7–10 whereas other studies have reported
no significant association between them.11,12 Because
these were ecological studies, the inconsistent results
may be caused by an ecological fallacy (overestimationof the population association).13 Only 1 individuallevel study14 on the association between lithium levelin tap water and mental health has been reported, andno association between lithium levels in tap water anddepressive symptoms was found. However, the study
used a small sample of adults and classified lithium
water levels into 3 categorical levels.14
To date, no individual-level study has been
conducted on the relationship between lithium level intap water and mental health problems in adolescents.
Here we explored the association of lithium level in tap
water with depressive symptoms, aggressive behaviors,and suicidal behaviors in a general population ofadolescents in Japan using a large individual-level data
set. We hypothesized that lithium level in tap water had
an inverse association with mental health problems inadolescents.
METHODS

Study Design and Settings
The present study was a part of a school-based
cross-sectional survey15 that was conducted in Japan.
The principal investigators approached all public juniorhigh schools (students aged 12–15 years; seventh to

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An Individual-Level Cross-Sectional Survey

Ando et al

Clinical Points■■ No large-scale individual-level study has examined theassociation between lithium level in tap water and mental
health problems in adolescents.

■■ This large individual-level study showed an inverse

association between lithium level in tap water anddepressive symptoms and interpersonal violence in a
general adolescent population.

■■ The results support the potential of low-dose lithium

therapy on depressive symptoms, anxiety, and aggressionin adolescents.

ninth grade) in Kochi Prefecture, which had a populationof approximately 790,000 between 2008 and 2009. The
students were asked to answer the questionnaires and seal
them in envelopes after completion. Before the survey, we
informed parents of the survey via letter and asked them tonotify the school if they did not want their child to respond.
In addition, on the day of the survey, students could opt outof the survey. The students were told that their participation
was anonymous and voluntary and no disadvantage
would occur due to nonparticipation. We included all datafrom the students who answered the survey except fromthose who were from schools with less than 5 students.
We excluded those schools from the analysis because theopportunities for bullying and interpersonal violence weremuch fewer than those in other schools. This study wasapproved by the ethics committee of Kochi Medical School
and the Tokyo Metropolitan Institute of Medical Science.
Measures
The self-report questionnaires included items
concerning the following: (1) depressive symptoms(the Japanese version of the 12-item General Health
Questionnaire [GHQ-12]16); (2) aggressive behaviors,such as interpersonal violence, bullying, and destructive
behavior; (3) suicidal behaviors, including suicidal ideationand self-harming behavior; and (4) other variables,
including demographic characteristics.
Depressive symptoms. The GHQ-12,16 which is one of
the most widely used self-report screening tools for anxiety
and depressive symptoms occurring in the previous month,
was originally applied to adult populations and later usedand validated for younger groups.15 The response options
are “less than usual,” “no more than usual,” “rather morethan usual,” or “much more than usual.” As in previous
studies,15 we assigned 1 point for “rather more thanusual” or “much more than usual” and 0 points for other
responses. The sums of each of the questions ranged from0 (good mental health) to 12 (poor mental health).
Aggressive behaviors. Interpersonal violence, bullying,and destructive behavior in the previous year were
determined from the questions, “Have you physicallyabused someone in your family or your friends during theprevious year?” “Have you bullied someone during theprevious year?” and “Have you been extremely frustrated

response options were “no” or “yes,” and the latter response
indicated aggressive behaviors. We referred to the items in
the Rutter Behavior Scales17 and applied similarly simple
wordings to avoid misunderstanding of questions.
Suicidal behaviors. Current suicidal ideation wasdetermined by the question, “Have you thought that yourlife was no longer worth living during the previous month?”
The response options were “no,” “probably no,” “possibly
yes,” or “yes.” We defined the individuals who answered yes
as those who had suicidal ideation. Self-harming behavior
was determined by the question, “Have you intentionallyhurt yourself within the past year?” The response options
were “no” or “yes.” Respondents who answered yes wereasked to provide a description of the actual method of selfharm. On the basis of a previous study,18 self-harm wasdefined as a nonfatal act in which an individual deliberately
did 1 or more of the following: (1) initiated behavior(eg, self-cutting, jumping from a height) intending tocause self-harm, (2) ingested a substance in excess of theprescribed or generally recognized therapeutic dose, or (3)ingested a noningestible substance or object. Identificationof deliberate self-harm episodes was based on independent
ratings by 2 raters. The κ value for interrater agreement was
0.83 (95% confidence interval [CI] = 0.79–0.86).
Other variables. The potential confounders included
age, sex, number of students in school, and living withparents. Because lithium levels in tap water can differ
between regions, factors that could be associated withboth region and mental health problems were considered
as potential confounders.
Tap-water sampling and measurement of lithium
concentrations. Water samples were collected from thewater sources that supplied tap water to each student’s
residential area in Kochi Prefecture. If there was morethan 1 water source for a school, the average concentrationof the water sources was determined. Lithium levels
in tap water were measured using atomic absorption
spectrophotometry (Hitachi z-9000) at Kochi University.
The detection limit for lithium was 0.01 μg/L.

Statistical Analysis
Similar to previous studies, 11,12 because the
distribution of lithium levels was skewed (skewness = 2.01;
kurtosis = 4.04), the relationship between lithium
concentrations in tap water and mental health–related
variables was analyzed by logarithmic transformation(LogLithium). We analyzed the associations of lithium
concentrations with depressive symptoms, interpersonal
violence, bullying, destructive behavior, and suicidal
behaviors independently by using a generalized linear
mixed model (GLMM) with schools as the fixed effect. In
the adjusted model, potential confounders were also added
to the GLMM. P values < .05 were taken as indicating
statistical significance. Descriptive and regression analyses
were performed by using SPSS, version 20.0 (IBM,Armonk, New York).

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somethingduringthe previous
year?” TheLithium in Tap Water and Adolescent Mental Health

Variable
Age, mean (SD), y
Living with parents, n (%)
Depressive symptoms,c mean (SD)Interpersonal violence, n (%)
Bullying, n (%)
Destructive behavior, n (%)
Suicidal ideation, n (%)
Self-harming behavior, n (%)

Total(n = 3,040)
13.7 (0.9)
2,377 (78.2)
2.98 (3.04)
839 (27.6)
428 (14.1)
1,077 (35.4)
115 (3.8)
111 (3.7)

Male
Participants(n = 1,551)
13.6 (0.9)
1,208 (77.9)
2.35 (2.78)
493 (31.8)
255 (16.4)
532 (34.2)
45 (2.9)
14 (0.9)

FemaleParticipants(n = 1,489)
13.7 (0.9)
1,169 (78.5)
3.62 (3.17)
346 (23.2)
173 (11.6)
545 (36.6)
70 (4.7)
97 (6.5)

aBoldface is used for variables that showed P values < .05.
bTwo-tailed t tests.

cTotal score of the 12-item General Health Questionnaire.
**P < .01.

Table 2. Associations Between Lithium Levels in Tap Water
and Depressive Symptoms, Aggressive Behaviors,
and Suicidal Behaviorsa
Variable
Depressive symptomsc
Interpersonal violence
Bullying
Destructive behavior
Suicidal ideation
Self-harming behavior

β
–0.22
–0.36
0.11
–0.15
–0.06
–0.17

Unadjusted
SE
P Value
0.10
.02*
0.15
.01*
0.22
.62
0.14
.28
0.30
.85
0.28
.54

Adjustedb
β
–0.23
–0.34
0.15
–0.14
–0.06
–0.20

SE
0.09
0.15
0.23
0.14
0.28
0.27

P Value
.02*
.02*
.51
.32
.82
.46

aBoldface is used for variables that showed P values < .05. Missing data were

excluded in each statistical analysis. Statistical significance was set at .05.
Lithium concentration was transformed to its logarithm in the statisticalanalysis.
bAdjusted for age, sex, number of students in school, and living withparents.
cTotal score of the 12-item General Health Questionnaire.
*P < .05.

RESULTS
Descriptive Statistics
All cities except Kochi City in Kochi Prefecture allowed
water sample collection, and all 25 public junior high schools
in those cities agreed to participate in the survey. Because
1 school had only 1 student, we excluded this school fromfurther analysis and finally used the data from 3,311 students
in 24 schools (mean [SD] n = 127 [116]). Of the 3,311
students, 3,040 students (91.8%) gave analyzable responses(absent, n = 200; response refusal, n = 71; males, n = 1,551[51.0%]). Their mean (SD) age was 13.7 (0.9) years (range,
12–15).
The demographic characteristics, mean GHQ-12 score,and presence of interpersonal violence, bullying, destructive
behavior, self-harming behavior, and suicidal ideation aresummarized in Table 1. Because 2 water samples had lithium
concentrations below the detection limit of 0.01 μg/L, thisvalue was assigned as the lithium concentration for further
analysis. The mean (SD) lithium concentration in tap water
was 0.48 (0.52) μg/L (range, 0.01 to 2.10; skewness = 2.01;
kurtosis = 4.04) and LogLithium was −0.57 (0.57) (range,−2.00 to 0.32; skewness = −1.11; kurtosis = 1.86).

P
Valueb.06.68< .01**< .01**< .01**.16< .01**< .01**and Mental HealthA higher LogLithium was associated with lower
depressive symptoms (unadjusted: β = −0.22, 95%
CI = −0.42 to −0.02, P = .02; adjusted: β = −0.23,
95% CI = −0.41 to −0.05, P = .02; Table 2). Similarly,
a higher LogLithium was significantly associatedwith reduced prevalence of interpersonal violence(unadjusted: β = −0.36, 95% CI = −0.65 to −0.07,
P = .01; adjusted: β = −0.34, 95% CI = −0.63 to−0.05, P = .02). On the other hand, bullying,
destructive behavior, suicidal ideation, and selfharming behaviors were not associated withlithium concentration or LogLithium in both
unadjusted and adjusted models.

DISCUSSION
Principal Findings
To the best of our knowledge, this study is the first toshow that lithium levels in tap water had small but significant
inverse associations with depressive symptoms andinterpersonal violence in a general population of adolescentsby using a large individual-level data set.
Possible Explanations
The present study showed an inverse association between
lithium water levels and self-reported depressive symptoms
in adolescents. A previous study14 suggested that there
was no association between lithium level in tap water anddepressive symptoms; however, that study compared themean depression levels in 3 groups of adults defined bylithium levels and did not conduct individual-level analysisof the association between depression and lithium levels.
The results of the present study are consistent with thoseof previous clinical studies that supported the effectivenessof lithium augmentation therapy for mood disorders.6
Although there has been little evidence for the effectivenessof lithium monotherapy on depressive episodes,19 theresults of this study suggest that lithium in tap water has
antidepressive effects.
An inverse association between lithium water levels andinterpersonal violence in adolescents was observed in thisstudy. This observation was consistent with those in previous
ecological studies that showed an inverse association between
lithium water levels and regional homicide20 or crime rates.12
Our study, which used a large individual-level data set,
adds further evidence for an inverse association between
lithium water levels and violent behaviors in adolescents.
The inverse association between lithium level in tap waterand interpersonal violence shown in this study also accords
with a previous review that suggested lithium’s effects on
decreasing aggression and impulsivity.21
Although no association between lithium water levels andsuicidal ideation or self-harming behavior was observed,
there are 2 possible explanations for this observation.
First, the lithium water levels in this study were relatively

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Association Between Lithium Concentration

Table 1. Demographic Characteristics and the Prevalence of Mental
Health Problems of the Participants in This Studya

Ando et al

Implications
There are 2 implications of the results obtained in thisstudy. First, promoting intake of lithium-rich foods andwater could be a potential public health strategy to minimize
mental health problems in adolescents if no adverse effects
are observed in further studies. Second, although the study
results were obtained from a nonclinical survey using selfreported measurement of mental health problems, theresults suggest the potential of low-dose lithium therapy
for treatment of depressive symptoms and aggression inadolescents.
Strengths and Weaknesses
This study was the first to examine the association
between lithium levels in tap water and mental healthproblems in adolescents by using a large individual-level
data set. In addition, because the response rate was very
high in this study, generalizability of the results should behigh. Nonetheless, this study had several limitations. First,
data were not obtained on lithium intake from food, which
generally exceeds that from drinking water.4 Second, we did

contains more lithium than tap water. However, Japanesepeople drink tap water more than bottled water26; thus, use ofbottled water may not be a significant factor. Third, we could
not obtain the economic status of each student. However,
because the land price and socioeconomic status of families
were similar within regions and students were assigned to thenearest public junior high schools in Japan, the use of schools
as the fixed effect might compensate for this limitation tosome extent. Fourth, we did not collect information on theuse of psychotropic medications that could have affected
mental health problems. Fifth, the reliability and validityof the measurements of aggressive behaviors have notbeen established. The query about “physical abuse against
family or friends” may have underestimated interpersonal
violence because the participants may not have reported
violence against peers who were not their friends. However,
we applied simple wordings, such as those used in the
Rutter Behavior Scales, to avoid misunderstandings of thequestions,17 and the prevalence of bullying in this study waswithin the range reported in a large international survey.27
Sixth, the large size of the sample may have led to finding
associations between lithium and the outcome variables thatwere statistically significant but not clinically significant.
Future studies should examine lithium intake both fromfood and water. In addition, an individual-level study should
be considered in an area where the lithium concentration in
tap water is higher than the concentrations in the water ofthe sites in this study.
CONCLUSION
Lithium levels in tap water were inversely associatedwith depressive symptoms and interpersonal violence in a
general adolescent population. Thus, lithium in tap water
may have antidepressive and antiaggressive effects. A
future individual-level study is warranted to examine theassociation between mental health problems and lithium
intake from both food and water in regions where thelithium concentration of tap water is higher than those of
the sites in this study.

Submitted: July 7, 2015; accepted April 20, 2016.
Online first: Month 00, 2017.
Author contributions: Dr Nishida had full access to all of the data in the study
and takes responsibility for the integrity of the data and accuracy of the data
analysis.
Potential conflicts of interest: Dr Furukawa has been a consultant toSekisui and Takeda Science Foundation; has received grants from Mochida
and Mitsubishi Tanabe; and has received honoraria from Eli Lilly, MSD,
Pfizer, Mitsubishi Tanabe, and Otsuka. Drs Ando, Koike, Shimodera, Fujito,
Sawada, Terao, Sasaki, Inoue, Asukai, Okazaki, and Nishida have no financial
relationships to disclose relevant to this article.
Funding/support: This work was supported by a Japan Society for the
Promotion of Science Grant-in-Aid for Young Scientists (grant number
22791158) and Grant-in-Aid for Scientific Research on Innovative Areas(23118002; Adolescent Mind & Self-Regulation) from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
Role of the sponsor: The funding sources had no role in any part of themanuscript.
Acknowledgments: The authors thank all of the participants in this study.

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which possibly

low. Similar nonassociations between water levels andthe regional suicide rate have been reported in a previous
study,11 whereas several studies have suggested a significant
inverse association between lithium water levels and suicide
rate.7–10 Because the lithium water levels in the present study
were similar to those in the study11 that found no association
and relatively lower than those in the 4 studies7–10 that did
find associations, the preventive effects on suicide may becaused by specific lithium levels. Although several clinicalstudies5,22 have shown the effectiveness of lithium on suicide
prevention in patients with mood disorders, a previous
study23 suggested that the lithium effectiveness on suicide
prevention depended on the dose. Second, the definitionof suicidality used in this study possibly attenuated theassociation with lithium exposure. The suicidal ideationquestion asked about ideation in the past month, whereas
the 4 aggressive-behaviors questions asked about behaviors
in the past year. This difference could have underestimatedsuicidal ideation and reduced the power for detecting an
association between suicidal ideation and lithium levels.
In addition, because we used a conservative definition ofsuicidal ideation by considering “possibly yes” to be thesame as “no,” this interpretation might have attenuated theassociation.
The biological mechanisms underlying the effect oflithium on aggression and depression are unclear, but aneuroprotective property of lithium has been proposed.
Antiapoptotic genes have been shown to be up-regulated
and proapoptotic genes to be down-regulated in lithium
responders relative to the expressions in nonresponders.24
Further, a study25 involving inpatients with bipolar disorder
showed that long-term lithium treatment was associatedwith increased gray matter volumes in the same areas,
whereas suicide attempts were associated with decreased
gray matter volumes.

Lithium in Tap Water and Adolescent Mental Health

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REFERENCES