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Lithium and suicide prevention in mood disorders and in the general

population: A systematic review

L. Del Matto, M. Muscas, A. Murru, N. Verdolini, G. Anmella, G.

Fico, F. Corponi, A.F. Carvalho, L. Samalin, B. Carpiniello, A.
Fagiolini, E. Vieta, I. Pacchiarotti

PII: S0149-7634(20)30444-9
DOI: https://doi.org/10.1016/j.neubiorev.2020.06.017
Reference: NBR 3814

To appear in: Neuroscience and Biobehavioral Reviews

Received Date: 19 December 2019

Revised Date: 6 April 2020
Accepted Date: 10 June 2020

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Lithium and suicide prevention in mood disorders and in the general population: A
systematic review

Del Matto L*1 & Muscas M*2, Murru A3, Verdolini N3, Anmella G3, Fico G5, Corponi F4,
Carvalho AF6, Samalin L7, Carpiniello B2, Fagiolini A1, Vieta E3, Pacchiarotti I3

1Department of Molecular Medicine, University of Siena School of Medicine and

Department of Mental Health, University of Siena Medical Center (AOUS), viale Mario
Bracci 16, 53100, Siena, Italy.
2Section of Psychiatry, Department of Medical Sciences and Public Health, University of
Cagliari, Italy

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3Bipolar Disorders and Depressive Unit, Institute of Neuroscience, Hospital Clínic,
University of Barcelona, iDiBAPS, CiBeRSAM, Barcelona, Catalonia, Spain

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4Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna,
Italy
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5Department of Psychiatry, University of Campania Luigi Vanvitelli, Largo Madonna delle

Grazie 80139, Naples, Italy

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6 Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre of
Addiction and Mental Health (CAMH), Toronto, ON, Canada
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7 CHU Clermont-Ferrand, Department of Psychiatry, EA 7280, Clermont-Ferrand

University, Clermont-Ferrand, France
*The first two authors contributed equally to this work
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Corresponding Author: Eduard Vieta, Hospital Clinic, Institute of Neuroscience,

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University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st., Barcelona, Catalonia,

Spain. Tel +34932275400, email: evieta@clinic.cat
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Short running head: Lithium and suicide prevention

Word count: Abstract 170; Manuscript 5207; 1 Figure; 3 Tables; 72 References.

Highlights

 Most ecological studies about lithium found in drinking water reported a reduction
in suicide in the general population, mostly in males
  Most uncontrolled trials and controlled trials open label have shown a reduction
in the risk of consumed attempts suicide during long-term lithium treatment in
mood disorder

 The evidence seems to attribute an intrinsic anti-suicidal property of lithium,

independent of its proven efficacy as mood stabilizer

Abstract
Suicide contributes to 1-4% of deaths worldwide every year. We conducted a systematic review
aimed at summarizing evidence on the use of lithium for the prevention of suicide risk both in

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mood disorders and in the general population.

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We followed the PRISMA methodology (keywords: “lithium”, “suicide” AND “suicidal” on
Pubmed, Cochrane CENTRAL, Clinicaltrial.gov, other databases). Inclusion criteria: lithium

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therapy in mood disorder or found in drinking water or scalp in the general population. Exclusion
criteria: no lithium administration.
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From 918 screened references, 18 prospective (number of participants: 153786), 10 retrospective
(number of participants: 61088) and 16 ecological studies (total sample: 2062) were included. Most of
the observational studies reported a reduction in suicide in patients with mood disorders. All
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studies about lithium treatment’s duration reported that long-term lithium give more benefits than
short-term lithium in suicide risk
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The evidence seems to attribute an intrinsic anti-suicidal property of lithium, independent of its
proven efficacy as a mood stabilizer.
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Keywords:
Bipolar Disorder; Lithium; Major Depressive Disorder; Recurrent Depressive Disorder;
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Suicide; Schizoaffective Disorder; Drinking Water.

Introduction:
Suicidal behavior (SB) is a very complex, multicausal event, involving several psychiatric,
psychosocial, demographic, genetic and cultural components (Alda & Manchia, 2018)
(Zalsman et al., 2016) (Hawton & van Heeringen, 2009) (Kellner et al., 2005) (O’Connor
& Nock, 2014) (Hawton et al., 2015) (van Heeringen & Mann, 2014)(Mann et al., 2005).
Noteworthy, it has been found that between 1 and 4% of deaths worldwide are caused
by suicide, which has been recognized also as the second leading cause of death among
15-24 years old population and the 18th leading cause of death in 2016 (WHO 2016);
world age-standardized crude suicide rates were higher in male (13,5 per 100000
population) than female (7,7 per 100000 population) (WHO 2016). Nevertheless, the
complexity of this phenomenon and the unlikelihood of the event occurring make the

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research on suicide prevention very demanding (Zalsman et al., 2016). Up to 90% of all
suicide-related deaths occur in patients with current major psychiatric disorders,

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particularly bipolar disorder (BD) and major depressive disorder (MDD). Regarding BD,
a close association between suicide and bipolar depression emphasizes the need for
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improving a correct diagnosis and treatment of such condition (L. & R.J., 2018)(Rihmer
& Gonda, 2012) (Popovic et al., 2015)(Cavazzoni et al., 2007). It has been previously
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reported that long-term treatment with Lithium (Li) reduced suicide risk (RS) in mood
disorders compared with placebo (PBO) or other drugs (Cipriani, Hawton, Stockton, &
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Geddes, 2013). Especially among patients with BD, long-term Li treatment was
associated with reduced RS and suicide attempts (SA). (Ahrens et al., 1995) (Cavazzoni
et al., 2007) (Ross J Baldessarini et al., 2006). Furthermore, the prevalence of suicide or
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SA was 0.435% per year during Li treatment, compared with 2.63% per year without
lithium (R J Baldessarini, Tondo, & Hennen, 1999) (Ross J Baldessarini et al., 2006).
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Despite the known effect of Li in preventing suicide, it has received a relatively minor
role in most suicide prevention strategies (WHO, 2014) (NICE, 2011) (Smith et al., 2017).
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To summarize the available evidence, we conducted a systematic review of studies

assessing the efficacy of lithium on suicide at therapeutic doses in mood disorders but
also in the general population through epidemiological studies on lithium in drinking
water.

2. Method
This review has been conducted according to the PRISMA (Preferred Reporting Items for
Systematic Reviews and Meta-Analyses) statement (Moher et al., 2009). Search
Methods and Results are highlighted in Figure 1.

2.1. Literature search

We systematically searched the MEDLINE/Pubmed/Index medicus, Cochrane CENTRAL,
and clinicaltrials.gov databases to any time to 30 July 2019, cross-checking the obtained
references. The systematic search was performed by two blind independent research
teams (led by LDM and MM), searching as follows:
 MEDLINE/Pubmed/Index medicus: the authors used the following search

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strategy: (suicide OR suicidal*) AND (lithium) that produced 890 records.
 For the Cochrane library, we used the same search strategy; the search produced

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5 records. It added 3 records to the PubMed search.
 For the https://clinicaltrials.gov/database, keywords were the same and


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produced 10 records. It added 1 record to the PubMed search.
Of all the additional 13 records that were identified through other
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sources/reference list, 2 were added to the pool of records identified by and
selected from PubMed.
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2.2. Study selection

We included longitudinal studies on the anti-suicidal effect of lithium. Studies could be
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prospective, retrospective, randomized clinical trials (RCT), or ecological studies. We

excluded animal studies, publications in which only the abstract was available and
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studies resulting from our initial research, through keywords we considered, but not
concerning the anti-suicidal effect of Lithium (Li). Meta-analyses and reviews were not
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used as evidence to support information that could not be drawn from individual
studies. Open studies, case reports or series, letters to the editor, opinion papers,
editorials, studies focusing only on biomarkers, like genetic and neurobiological
investigations were excluded. Furthermore, we only considered clinical studies with
more than 70 patients, since for most issues we were comparing two groups (lithium
exposure/no lithium exposure). For this review, we filled-in the PICO worksheet (Miller
2001) and the PRISMA checklist (Moher, Liberati, Tetzlaff, & Altman, 2009) which we
provide as an on-line Supplementary file. Study quality for RCTs has been assessed
independently by pairs of raters from the authorship group using the Cochrane Risk of
Bias version 2 (RoB2). RoB2 domains included: selection bias, performance bias,
detection bias, attrition bias, and other bias. Any disagreement was resolved through
consensus between authors.

3. Results
3.1. Systematic search results
The pooled records amounted to 918 records (Fig. 1). Excluded were: 14 duplicated
results, 749 based on title or abstract, 4 studies still recruiting, 5 studies that do not

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grant access data, 2 studies withdrawn, 1 status unknown, 6 studies not specifying the
number of patients with Li, 23 articles not found, 46 genetic and neurobiological studies,

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24 not of interest studies. This left 44 records to include. We included 28 studies
(prospective, retrospective and RCTs) and 16 ecological studies. The details of each
study are reported in Table 1, Table 2 and Table 3.
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In all these studies, parameters related to suicidal behavior will be sought (i.e., SR
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[Suicide Rate], SA [Suicide Attempt] Rate, SC [Suicide Completion] Rate, SMR [Standard
Mortality Ratio], RS [Suicide Risk], number of SA, number of SC).
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3.2. Content results

3.2.1. Prospective studies
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A total of 18 prospective studies were included in the present review; 12 prospective

cohort studies, and 6 Randomized Control trials (Table 1).
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3.2.1.1 Prospective cohort studies

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A 5-year prospective cohort study (Vestergaard & Aagaard, 1991) assessed the impact
of prophylactic Li on mortality in a population of 133 patient (MDD, BD, BD not
otherwise specified), detecting that mortality for patients without Li was 4.35 times
greater than the expected: 5.27 times in men and 3.59 times in women. 5 suicide
completions (SC) (1 man and 4 women) were observed; 22 patients died, 15 on Li and 7
discontinued Li 3-37 months before death.
An 11-year prospective cohort study (Coppen et al., 1991) assessed the impact of
prophylactic Li on mortality and suicidality in a population of 103 patients
(BD, MDD, SAD) on Li and treatment as usual (TAU), detecting that relative risk (RR) of
suicide was higher for patients without Li [0.60 (95% CI 0.29-1.12)], compared with
patients treated with Li and with the general population. This finding suggested that Li
might reverse the excess of mortality (including suicidal death) associated with recurrent
mood disorders. A 7-year prospective cohort study (Nilsson, 1995) studied the impact of
prophylactic Li on mortality in a population of 362 patients (MDD, BD or SAD),
hospitalized at least once between 1970 and 1977 and treated for a minimum of one
year, finding that the relative risk (RR) of suicide for patients without Li was 4.8 times

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higher than patients treated with Li (p < 0.02; 95 % CI 1.1-12.6). The SMR was 2.1
compared to the general population (1.0, p < 0.00, 1.95 % CI 1.8-2.5). The RR of death

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was 1.7 times higher (p < 0.01, 95 % CI 1.2-2.6) in periods without Li versus periods with
Li.
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A 44-years prospective cohort study (Angst, Angst, Gerber-Werder, & Gamma, 2005b),
assessed the impact of prophylactic Li in preventing suicidality in a population of 406
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inpatients (MDD, BD I, BD II and manic). SMR for suicide was significantly lower among
patients treated with Li (5.7) than inpatients untreated (16.5). No differences between
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males and females were noticed. The survival curve of bipolar patients under treatment
showed a trend to fewer suicides in patients with long-term medication (p = 0.08).
In a 13+-3/12+-1 average years period cohort study (Born, Dittmann, Post, & Grunze,
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2005), Inventory of Depressive Symptomatology Clinician Rating (IDS-C) scale,

particularly ‘‘item 18-suicidality’’, the Young Mania Rating Scale (YMRS) scale and the
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Clinical Global Impressions Bipolar Patients (CGI-BP) scale scores were evaluated in a
sample of 128 bipolar patients treated with various mood stabilizers (MSs)(61 with Li),
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noticing that the RR of suicidal ideation was higher for patients treated with others MSs
compared to those treated with Li, but this finding was no statistically significant. Thirty-
eight (29.7%) patients had IDS-C Item-18+. The RR of suicidality was 1 for Li, 1.54 for
carbamazepine (CBZ) (p = 0.14), 0.85 for lamotrigine (LAM) (p = 0.17), 1.16 for divalproex
(VPA) (p = 0.14).
A 10-years prospective cohort study (Gonzalez-Pinto, Mosquera, Alonso, López, et al.,
2006), studied the association between occurrences of one or more SA and compliance
to long-term Li maintenance treatment in 72 BD I patients. It was noticed a greater SA
risk among poor adherent compared to highly adherent patients treated with Li (p <
0.005).
A 20-years prospective cohort study (Bocchetta et al., 2007) studied the impact of
prophylactic Li on mortality in a population of 1411 patient taking Li and TAU (BD, MDD,
BD NOS, and SAD), evaluating the Hazard Ratio (HR) (probability of survival between
patients who had attended for less than 2 years and 2 years or more), detecting that
patients under long-term treatment (more than 5 years) had a reduced mortality rate
(MR), similar to the general population, and that suicidal death and length of controlled
exposure to Li seemed to be inversely related.

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In a 35 years cohort study of 4441 inpatients (Sani et al., 2011), evaluated the duration
and the efficacy of Li treatment compared to antidepressants (ADs), antipsychotics (APs)

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and other MSs. 96 patients of the sample committed suicide. Short-term Li treatment (p
< 0.0001) and MSs (p = 0.037) were associated with higher SR; conversely, this finding
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was not found for ADs (Chi 2 = 8.22; p = 0.004). No significant differences were found
for longer or shorter-term treatments with APs. Shorter-term treatment with Li and
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anticonvulsants (AC), longer-term treatment with ADs, history of SA, suicidal thoughts
(ST), and single status positively predicted SC.
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A 9-years prospective cohort study with a follow up of 1 year (E. G. Smith et al., 2014),
conducted in a sample of 93335 Veterans patients (21468 with Li), with more than 6
months without Li or VPA, studied the impact of prophylactic Li on mortality in a
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population compared to VPA, noticing that risk of SC increased after

discontinuation/modification of Li, over the first 180 days of treatment (p = 0.015).
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A prospective cohort study (Pompili et al., 2014) assessed a sample of 71 discharged BD

patients (30 with Li) with a follow up of 5-75 months noticing that Li, in comparison with
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other treatments (MSs, anxiolytics, ADs and atypical APs), was associated with higher
rates of previous SA (p = 0.01) and secondly less often Li at discharge from hospital (p =
0.01), underlining the impact of prophylactic Li on suicidality.
A prospective cohort study (Toffol et al., 2015), with a recruited period of 7 years and a
mean of follow up of 3,5 years, studied the impact of prophylactic Li in a population of
826 BD patients, evaluating the RR of SA leading to hospitalization, SC, and overall
mortality, comparing Li users (307) with Li no users and with TAU (VPA, benzodiazepines
(BDZ) and ADs). Li was associated with a lower RR of SA and with decreased SC (RR =
0.39, 95% CI: 0.17–0.93, p = 0.03), Cox (HR = 0.37, 95% CI: 0.16–0.88, p = 0.02).
Moreover, treatment with LI decreased all-cause mortality by 49%.
An 8-year comparative cohort study (Song et al., 2017) studied the impact of
prophylactic Li in comparison to VPA, evaluating the risk of suicide-related events
(defined as SA or SC or undetermined intent), finding that SR was reduced by 14% during
periods under Li treatment (HR = 0.86, 95% CI 0.78–0.95) versus periods under VPA
treatment (HR = 1.02, 95% CI 0.89–1.15; Chi 2 test of 4.29 p = 0.038) for suicide-related
events.

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3.2.1.2 Randomized controlled trials studies
A 4-week double-blind, PBO-controlled trial (Khan et al., 2011), investigated the effect

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of Li on both suicidal behavior and thoughts, by investigating Li as adjunctive treatment
to ADs. A subgroup of the patients assigned to lithium and citalopram achieved
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therapeutic lithium levels and had significantly higher remission based on the reduction
in the Sheehan Suicidality Tracking Scale (S-STS) scores compared to patients assigned
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to placebo and citalopram.
A 12 months double-blind, PBO control trial, (Lauterbach et al., 2008) investigated the
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effectiveness of Li in preventing suicide compared to PBO in 167 individuals who had

committed SA in the context of a depressive spectrum disorder. No significant treatment
effects on the repetition of self-harm for Li (OR 0.99, 95% CI 0.33 to 2.95) or the
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secondary outcomes of depression scores, hopelessness, suicidal ideation or suicide

were found. The authors concluded that there was no difference between the groups in
suicide rates whilst accepting that this may be secondary to the small number of event
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rates.
A randomized, parallel-group, assessor-blinded superiority clinical trial (Girlanda et al.,
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2014), evaluated the efficacy of Li in reducing the risk of Deliberate Self Harm (DSH) in
adult patients with MDD diagnosis, that were allocated to adjunctive Li (0.4-1.0 mmol/l)
to TAU (intervention arm) versus TAU alone (control arm). It was detected that survival
probability did not differ between the two treatment arms (p = 0.676); indeed, 6 patients
in the Li plus TAU group and 7 in the TAU group committed acts of DSH during the follow-
up phase.
A double-blind 2.5-years RCT (Oquendo et al., 2011) investigated Li adjunctive therapy
(mean duration 495 days) or VPA adjunctive therapy (mean duration 550 days) among
98 patients with MDD or BD with a history of SA. No suicide deaths occurred during the
study and there were no significant differences between rates of SA between the two
groups, but numbers were small and the study is unlikely to have had sufficient power
to show a difference.
A 2.5-years RCT observational prospective study (Kleindienst & Greil, 2000), investigated
the efficacy of Li in protecting against AS and SC, compared to carbamazepine (CBZ), in
a sample of 94 patients (BD or SAD). A trend in favor of Li (0.5-0.73 mmol/l) was found:
5 AS and only 1 SC observed during the study period occurred in the CBZ group.

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An 8-weeks multicentre, prospective, masked parallel RCT (Salpekar et al., 2015)
investigated the effectiveness of Li on depression and suicidality during acute manic or

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mixed episodes compared to VPA and RSP, in a population of 6-15 years BD children.
Suicidality status was analyzed by using the suicidal ideation survey from the Children’s
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Depression Rating Scale (CDRS). Suicidality was infrequent among the sample and it was
not found an overall effect of treatment on suicidality ratings.
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3.2.2. Retrospective studies
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A total of 18 retrospective studies were included in the present review (Table 2).
An 8-years cohort study (Goodwin et al., 2003a), compared the risk of SA and SC during
Li treatment with VPA and CBZ in a sample of 20623 BD patients (7121 taking lithium),
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founding that the risk of SA or SC was 1.5 to 3 times higher during periods of treatment
with VPA than during periods of treatment with Li (p = 0.03), with a greater risk of SA
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resulting in hospitalization during periods of treatment with CBZ (HR = 2.9, p < 0.001).
A 5-years observational study (Collins & McFarland, 2008) detected that risk of SC was
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significantly greater (2.6 times) among patients treated with gabapentin (GBP) than in
patients treated with Li (p < 0.001) and that risk of SA increased among VPA users (2.7)
compared to Li users (HR 2.7, p < 0.001). Furthermore, it was found the lowest rate of
SC (0.78 per thousand person-years) in the Li users group.
A 3469-months observational study (Yerevanian, Koek, & Mintz, 2003a) compared the
rates of ST, suicidal behavior, hospitalizations for suicidal ideation and SC in a population
of 140 patients with BD (131) and SAD bipolar type (9), noticing that rates of all suicide
events were significantly lower (Chi-square = 4.05, p = 0.04) for patients on Li and other
anticonvulsants (AC) combined, with no differences between of Li, and either CBZ or
VPA, regarding the incidence of non-lethal SB (SA: p = 0.77; hospitalizations: p = 0.77).
In a 20-years retrospective case-control study (Gaertner, Gilot, Heidrich, & Gaertner,
2002) the pharmacotherapy of 61 suicide victims (0.24% of 27.078 admissions from
January 1, 1980, to December 31, 1999) was compared to that of a control group
matched for age, gender and diagnosis at the time of discharge, finding the effect of MS
in preventing suicide among patients with Schizophrenia (Sch+) and SAD (p < 0.05) and
patients with affective psychosis (p = 0.04), without detecting the superiority of Li when
compared to VPA and CBZ.

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Two studies (Kallner, Lindelius, Petterson, Stockman, & Tham, 2000) (Ahrens & Muller-
Oerlinghausen, 2001) assessed the role of Li prophylaxis in preventing suicide death in

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patients with affective disorders. Kallner et al. (Kallner et al., 2000) evaluated the impact
of Li prophylaxis on mortality in 497 patients (405 bipolar and 92 unipolar) who attended
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the same out-patient lithium clinic for up to 30 years. It was noticed that the group of
patients who attended the clinic and took Li until death or the end of the study
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presented lower mortality (SMR = 14.0, p < 0.001 for BD patients; 0 suicides for MDD
patients), in comparison to the group of patients who left the clinic but continued to
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take Li (SMR = 21.4, p < 0.01 among BD patients), and to the group of patients that both
left the clinic and stopped taking Li (SMR = 33.3, p < 0.001 among BD patients; SMR =
50.0, p < 0.001 among MDD patients).
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A 6.7-years cohort study (Ahrens & Muller-Oerlinghausen, 2001) investigated the

efficacy of Li prophylaxis in prolonging survival in a population of 827 patients (BD and
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affected by a recurrent affective disorder or SAD). It was observed a considerable

reduction of SA not only among the group of excellent Li responders but also among
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moderate Li responders or even among poor Li responders (21 SA observed).

Furthermore, it was shown a significant reduction of SA per year, as compared to a
corresponding pre-Li period, in all three groups (0.10 vs. 0.33 for excellent responders,
p < 0.007; 0.06 vs. 0.27 for moderate responders, p < 0.0001; 0.02 vs. 0.26 for poor
responders, p < 0.0001).
A 6-years retrospective cohort study (Sondergard, Lopez, Andersen, & Kessing, 2008)
investigated whether maintenance treatment with MS was associated with a reduced
SR in a population of 5926 patients discharged from psychiatric hospital as in- or
outpatient from 1995 and 2000 in Denmark with a diagnosis of BD. It was noticed that a
switch to or an augmentation with Li among patients first treated with AC reduced the
SR significantly (rate ratio = 0.28, 95% CI = 0.20–0.40, p < 0.0001), whereas a switch to
or augmentation with AC to patients first treated with Li did not affect the rate of
subsequent suicide.
A recent observational study (Popiolek et al., 2018) aimed at determining the impact of
pharmacological approaches on the risk of rehospitalization or suicide (RoS) in a sample
of 1255 patients treated with ECT for bipolar depression during hospitalization, finding
that Li, after discharge, only showed numerical, non-significant superiority towards a

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lower risk of RoS, compared with other medications (HR 0.87, 95% CI 0.73–1.03, p =
0.11).

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Another cohort study (Isometsa, Sund, & Pirkola, 2014) investigated factors modifying
the Hazard Ratio of post-discharge suicides of patients after hospitalizations for BD,
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detecting that HR was 8.05 (95% CI: 2.49–26.04; p < 0.001) after hospitalization with an
intra-episodic SA and 3.63 (95% CI: 2.12–6.23; p < 0.001) for male patients, but 0.186
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(95% CI: 0.07–0.52; p = 0.001) for patients taking Li.
The last retrospective study we included in our review (Ko et al., 2014), examined the
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correlates of lifetime exposure to Li in a cohort of 13-19 years adolescents BD patients

(20 under Li therapy vs 80 no under Li therapy) noticing that subjects with Li exposure
reported significantly less self-injurious behaviors (p = 0.028), and were less likely to
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have suicidal ideation (p = 0.101) and a family history of SA (p = 0.102).

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3.2.3. Ecological studies in the general population

Although natural Li intake doses are significantly lower than those used for the
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treatment of patients with psychiatric disorders, there is growing evidence that even
very low Li levels induced by routine consumption of Li contained in tap water may have
anti-suicidal effects both in patients with mood disorders and in the general population.
A total of 16 ecological studies were included in the present review (Table 3). 11/16
studies found a significant, inverse association between local Li levels and Suicide Rate
(SR). Most of the studies were conducted by using ecological analysis with the Standard
Mortality Ratio (SMR) of various geographical areas, and one investigating Li levels in
human scalp.
In a 5-years ecological study (Ohgami, Terao, Shiotsuki, Ishii, & Iwata, 2009), it was found
that levels of Li (0.7 - 59 µg/L) in drinking water reduced SR in the general population (β
= -0.65, p < 0.004). This significant association was detected in males (β = -0.61, p <
0.008), while a marginal significance was found in females (β = 0.46, 0.055, p = < 0.06).
An ecological study (Kapusta et al., 2011) found a connection between Li levels in
drinking water and suicide in Austria and underlined that the overall SR (R2 = 0.15, b = -
0.39, t = -4.14, p = 0.000073) and SMR (R2 = 0.17, b = 70.41, t = 74.38, p = 0.000030)
were inversely associated with levels of Li.

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An ecological study in United Kingdom (Kabacs, Memon, Obinwa, Stochl, & Perez, 2011),
found that there was no association between Li levels and suicide for both males and

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females (r = -0.054, p = 0.715 for males; r = 0.042, p = 0.777 for females; r = -0.03, p =
0.838 for the general population) in drinking tap water.
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An observational cohort ecological study conducted in Tokyo (Schopfer & Schrauzer,
2011), investigated Li levels in the scalp of the sample considered, finding that Li
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deficiency, as well as suboptimal vitamin B12 status, might be considered as a potential
SR factor.
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Another ecological study in Japan (Sugawara, Yasui-Furukori, Ishii, Iwata, & Terao, 2013),
detected that Li level might have a protective effect on the SR among female (β = −0.37,
p < 0.10) but not among males (β = 0.12, p = 0.597).
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In a 3-months ecological study (Giotakos, Nisianakis, Tsouvelas, & Giakalou, 2013), it was
observed a positive correlation between Li levels and SR among the general population
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(β = −0.17, t = −2.10, p < 0.05).

An ecological study conducted in the USA (Bluml et al., 2013), detected that the Li level
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might have a protective effect on the SR (RR: 0.88 for 100 mg/l; 95%CI: 0.84, 0.93).
In a 5-years ecological study conducted in Austria, (Helbich, Bluml, Leitner, & Kapusta,
2013), it was found that Li in public water might have a protective effect in SR (rs = 0.970,
p = 0.000), and in suicide SMR (rs = -0.26, p = 0.009).
Another study conducted by the same authors (Helbich, Leitner, & Kapusta, 2015)
confirmed this result among males (r= 0.970, p = 0.001), but not among females.
In a cohort study in Italy (Pompili et al., 2015), it has been reported that in public water
Li concentrations and local SR were significantly inversely related, during the period
between 1980 and 1989 particularly among females (β = – 0.231, p = 0.005).
In a 4-years ecological study in Japan (Ishii et al., 2015) it was found that Li
concentrations in drinking water might be associated with a low SR only among the male
population (p = 0.019) but not in females.
In a 6-years ecological study in Japan (Shiotsuki et al., 2016), after adjustment of
meteorological factors, it was noticed that there was a significant inverse association
between Li levels and suicidal behavior in the male population (p = 0.070).
A 5-years ecological study in Lithuania (Liaugaudaite, Mickuviene, Raskauskiene,

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Naginiene, & Sher, 2017), noticed a protective effect of higher Li concentration against
SR among men (β = –0.70, p = 0.013), but not among women (β = 0.15, p = 0.70).

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A 22-years ecological study with a follow up in Denmark (Knudsen et al., 2017), found
that SR decreased from 29.7 per 100000 person-years in 1991 to 18.4 per 100000
-p
person-years in 2012, but there was no significant association between increasing five-
year time-weighted average Li exposure level in drinking water and decreasing SR.
re
In a 6-years cohort study in Texas (Fajardo, LeBlanc, & Fajardo, 2018) Li concentration in
drinking water was negatively associated with all the causes of mortality (r = -0.18, p =
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0.006) and with years of potential life lost (r = -0.22, p = 0.001).

In a 6-years ecological study in Portugal (Oliveira, Zagalo, Madeira, & Neves, 2019) it was
not found a statistically significant correlation between Li concentration in drinking
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water and a decreased SR, concluding that Li levels in public water are not protecting
against SR in the general population (r = 0.001, p = 0.996).
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4. Discussion
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The present systematic review aimed at assessing lithium anti-suicidal activity and its
capacity for preventing suicide in patients with mood disorders and the general
population. The heterogeneity of samples, diagnoses, comparators, study durations,
phases of illness and methods make difficult the interpretation of our findings.
Nonetheless, the studies we collected show good evidence that lithium reduces the risk
of relapse in patients with mood disorders. It is also reasonable that, even if most suicide
attempts occur in periods of mood instability, and SB occurs more in association with
depressed mood, if mood can be improved and euthymia prolonged, a reduction in
suicide attempts will be seen (Smith 2015) (van Heeringen K 2014) (Popovic et al., 2015).
The effect of Li on suicidal behavior has been observed even when mood stabilization
has not occurred, supporting the hypothesis of a specific effect of lithium in preventing
suicide regardless of the effect on affective recurrences. (Muller-Oerlinghausen, Muser-
Causemann, & Volk, 1992). Moreover, it has been noticed the effect of lithium on non-
suicide mortality, and on non-suicide related deaths (E. G. Smith et al., 2015). The
observational studies (prospective and retrospective studies) of this present review
considered a large sample of suicidal patients, detecting the good proprieties of Li in
preventing SB. Prospective studies about treatment’s duration conducted in BD

of
patients, underlined the efficacy of long-term lithium treatment compared to short-
term treatment in preventing suicide (Bocchetta et al., 2007) (Gonzalez-Pinto,

ro
Mosquera, Alonso, Lopez, et al., 2006)(Sani et al., 2011)(Kallner, Lindelius, Petterson,
Stockman, & Tham, 2000)(Angst, Angst, Gerber-Werder, & Gamma, 2005), also
-p
highlighting an increased risk of suicide in case of lithium discontinuation. Some of the
selected studies compared Li with other MSs, underling an overall superiority of Li in
re
preventing SB compared with other anticonvulsants (Angst, Angst, Gerber-Werder, &
Gamma, 2005a) (E. G. Smith et al., 2014) (Collins & McFarland, 2008) (Goodwin et al.,
lP

2003b) (Yerevanian, Koek, & Mintz, 2003b). On the contrary, other studies did not
confirm the superiority of Li as an anti-suicidal drug compared to other mood stabilizers
(Grant & Salpekar, 2018) (Oquendo et al., 2011). The ethical issue in conducting studies
na

that consider suicide as a potential outcome is daunting and makes use of PBO-
controlled conditions in RCTs highly problematic. Such trials are rare, probably reflecting
ur

the ethical, clinical, and liability challenges of efforts to test for reduction of SR, as well
as the lack of clear commercial advantages of such an achievement (Leonardo Tondo &
Jo

Baldessarini, 2018). In the RCTs included in this review, lithium was mainly used as a
comparator for other medicaments, to investigate which MS may be more effective in
prevention against SB. (Tondo et al., 2018) (L Tondo, Pompili, Forte, & Baldessarini,
2016). The infrequent observation of SB in RCTs, even in high-risk samples, makes it
difficult to show the anti-suicidal proprieties of lithium from samples of modest size
followed for limited times, even with well-matched exposures in parallel groups
randomly assigned to alternative treatments. At least, an observational study
considered a cohort of adolescents with BD (Ko et al., 2014), showing that subjects with,
versus subject without lifetime Li exposure, reported significantly less self-injurious
behavior and were less likely to have suicidal ideation and a family history of SAs. In this
present review, we also considered a total of 16 ecological studies and results confirm
strong evidence for suicide, where higher drinking water lithium has been associated
with lower suicide rates in the general population across different continents and time
in the majority of studies (Brown et al 2018). Only 2 studies did not identify any
relationship between lithium and suicide. Interestingly, the two negative studies were
from England (Kabacs, Memon, Obinwa, Stochl, & Perez, 2011) and Denmark (Knudsen
et al., 2017) where the range of drinking water lithium was found to be low. Sex

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differences in the association of drinking water lithium and suicide were described.
Several papers reported a negative association in men and a weaker association or no

ro
association in women (Liaugaudaite, Mickuviene, Raskauskiene, Naginiene, & Sher,
2017) (Helbich, Leitner, & Kapusta, 2015) (Ishii & Terao, 2018)(Ohgami, Terao, Shiotsuki,
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Ishii, & Iwata, 2009) (Shiotsuki et al., 2016), whereas only one study see a possible
association in women and no association in men (Sugawara, Yasui-Furukori, Ishii, Iwata,
re
& Terao, 2013). More frequent use violent means of suicide among men has been
proposed as an explanation for the observed sex differences (Liaugaudaite et al.,
lP

2017)(Ishii & Terao, 2018)(Shiotsuki et al., 2016), with lithium suspected to reduce
suicide via reduction of violence and aggression (Smith & Cipriani, 2017). We underline
that the mechanism by which minuscule concentrations of lithium confers its protective
na

effect remains unclear even if researchers found central importance of glycogen

synthase kinase-3β (GSK3β) because it modulates multiple systems that have been
ur

repeatedly implicated in suicide, and which Li also exerts effects on; for example, lithium
has been reported to increase the volume of the prefrontal cortex and anterior cingulate
Jo

gyrus. Further research is needed into the underlying neurobiological mechanisms by

which even minuscule concentrations of Lithium can prevent suicide, but data seem to
support that even tiny doses of lithium can have some effect at the population level.

4.1. Limitations
As we have already mentioned, the findings herewith reviewed face many difficulties in
the interpretation of studies aimed at testing for anti-suicidal effects of specific
treatments and the heterogeneity of samples and methods. (Leonardo Tondo &
Baldessarini, 2018). The paucity of RCTs is also a major limitation in the evaluation of
preventive interventions. Another limitation regards the fact that suicide is a complex
phenomenon resulting from several interacting factors, which can also occur outside of
mood disorders (Malhi et al., 2018)(van Heeringen & Mann, 2014). Moreover, because
of the heterogeneity of the studies (observational, prospectives and retrospectives,
ecological) we considered in our systematic review and the heterogeneity in the
approaches on the anti-suicidal effect of Lithium, it was not possible to carry out a meta-

of
analysis. At least, in many studies considered (7 prospective, and 1 retrospective) in our
review Li level was not specified. Therefore, we believe this could be an interesting

ro
aspect on which to focus future research, to observe which therapeutic level of lithium
could be more effective in preventing suicide.

5. Conclusions
-p
re
The anti-suicidal actions of lithium have been consistently reported over the past 40
years, in both observational studies and RCTs. Whilst each design has possible
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weaknesses, as already discussed, the combined evidence is overwhelmingly in favor of

the anti-suicidal action of lithium, with a specific anti-suicidal effect over and above
its action on mood episodes. Unfortunately, this unique effect of lithium had not
na

translated into guidelines or clinical practice regarding the management of suicide

behaviors. The mechanism by which lithium confers its protective effect remains
ur

unclear. In this sense, further research is needed into the underlying neurobiological
mechanisms by which lithium prevents suicide.
Jo

Based on this review, environmental exposure to low lithium levels in drinking water is
negatively associated with suicide in the general population. Should these results be
confirmed in further large-scale epidemiological studies lithium supplementation of tap
water may open a new avenue in suicide prevention, leading to important prevention
implications in terms of public health.

Acknowledgments
EV thanks the support of the Spanish Ministry of Science, Innovation (PI15/00283,
PI18/00805) integrated into the Plan Nacional de I+D+I y cofinanciado por el
ISCIIISubdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional
(FEDER); CIBERSAM; and the Comissionat per a Universitats i Recerca del DIUE de la
Generalitat de Catalunya to the Bipolar Disorders Group (2017 SGR 1365) and the
project SLT006/17/00357, from PERIS 2016-2020 (Departament de Salut).

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-p
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Fig. 1 PRISMA flow diagram and results of our literature search, including reasons for
exclusion and typology of included studies.
lP

From Moher et al. (2009) www.prisma-statement.org.

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 f
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Table 1. Prospective studies
Ref Design Duration Sample Arms Primary aim / Inclusion Criteria Results
(N) Primary outcome

pr
- Age: 18+ ys -5-yr mortality in patients without Li: 4.35 times higher:
N = 133
cohort AD -SMR - Dx: BD, BD NOS (DSM-III semi- 5.27 m and 3.59 f
Vestergaad 5 ys Li = 133
study APD -SR structured) -5 SC: 1 m, 4 f
(1991)
Li - Manic or depressive episode - 22 patients died: 15 on Li, 7 discontinued Li 3-37 ms

e-
- APD, AD, Li before death
- Dx: BD, MDD, SA (DSM-III semi-
cohort AD -Mortality patients
Coppen 11 ys N = 103 structured) -RR suicide=0.60 (95% CI 0.29-1.12)
study APD with vs. patients
(1991) Li =103 - AD, APD + Li -No SA
Li without Li / RR suicide

Pr
-Li =0.5-0.6 mmol/l
- Dx: MDD, BD, SAD (DSM-III semi-
-SMR=2.1 (p < 0.00 1,95 % CI 1.8-2.5)
-Mortality patients structured)
N = 362 -RR death 1.7 times higher (p < 0.01, 95 % CI 1.2-2.6)
Nilsson cohort 7 ys with Li vs. patients - 1+ year prophylactic Li
Li = 152 Li + TAU without Li
(1995) study without Li / SMR and -Li/3 ms
-RR suicide 4.8 times higher (p < 0.02, 95 % CI 1.1-12.6)
RR suicide -Li < 0.5 mmol/l if clinical
without Li
acceptable
observation l CBZ LAM Li - IDS-C (score 2 of the
- Dx: BD (semi-structured) -No SA or SC
na
Born M= 13+-3 / N = 128 VPA ‘‘item 18- Suicidality’’)
al study -Monotherapy and combination -NS RR of having item18 + (Li: RR=1, CBZ: RR=1.54 p=.14,
(2005) 12+-1 ys Li = 61 LEV OXC -YMRS
dosed and prescribed >3 months LAM: RR=.85 p=.17, VPA: RR 1.16 p=.14)
TOP -CGI-BP
Angst cohort Recruited 5 ys N = 406 Li -SMR -Dx: DM, BD (I, II and manic), MDD -SMR < in patients with Li (5.7) vs. without Li (16.5)
(2005) study Follow up 44 Li = 84 AD -effect of long-term (ICD 9-DSMIII semi-structured) - SMR < treated /no treated (1.2 vs 1.7, p < 0.05)
ys APD treatment with Li -Li monitored - <suicides Li vs no long-term treatment (p = 0.08)
ur

BDZ MS
-Age range 28 +/- 12.2 ys -SA rate=2.01%/year, SC rate= 0.143%/year, a 5.2 fold
Gonzalez-Pinto cohort 10 ys N = 72 Li + TAU - 1+ SA and -Dx: BDI (DSM-III/DSM-IV semi- (95% CI: 1.5-18.6)
(2006) study Li = 72 compliance to long- structured) - > RS among patients rated poorly vs highly adherent to
term Li maintenance -Average 14.5 +- 11.1 ys of illness, Li
Jo

treatment 0.5 +-hospitalization/ys -SA in 7/56 adherent vs 7/16 non-adherent (p < 0.005)
- Li ≤ 0.5 mmol/l
Notes: AD antidepressant, ADHD attention-deficit/hyperactivity disorder, APD antipsychotic drug, BD Bipolar Disorder, BPD Borderline personality disorder, BDZ Benzodiazepine, CBZ Carbamazepine, CD
conduct disorder, CGI-BP clinical global impression-Bipolar, Cit Citalopram, DSH deliberate self-harm, f female, LAM Lamotrigine, LEV Levetiracetam, Li Lithium, m male, MDD Major depressive disorder,
MDE major depressive episode, Ms Months, MS mood stabilizers, NS Non significant, NOS not otherwise specified, ODD oppositional defiant disorder, OXC Oxcarbazepine, p variable of pearson, PBO
Placebo, RCT Randomized-controlled trial, Ref reference, RR relative risk, RSP Risperidone, SA attempted suicide, SAD Schizoaffective disorder, SB Suicidal behaviour, SC suicide completion, Sch+
 f
Schizophrenia, SE suicide event, SGA Second generation antipsychotic, SM suicide mortality, SUD Substance Use Disorder, TAU treatment as usual, TOP Topiramate, TOT Total, VPA Valproic acid, Yr year,

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Ys years, Ws Weeks, X2 Chi-square test, YMRS Young mania rating scale

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Table 1. Prospective studies
Ref Design Duration Sample Arms Primary aim / Inclusion Criteria Results
(n) Primary outcome

e-
-SMR and HR -Dx: DB I-II, DDM, Sch+, SAD -> 5 ys with Li had reduced SMR
Bocchetta cohort study -Probability of survival inpatients (DSM-IV semi- - HR death for external causes at 3 ys: 15.8 (95% CI, 2.1–119.0),
20 ys N = 1411 Li+ TAU
(2007) 2 group: attend <2/>2 structured) 5 ys: 4.1 (95% CI, 1.5–10.9), 10 ys: 2.9 (95%CI, 1.5–5.6)
N = 1411

Pr
years - Li = 0.5–1.0 mmol/l -Mortality and exposure to Li inversely related SMR
-Dx: BD I BD II MDE MDD
-Mortality and HR
Sani N = 4441 Li, APs, ADs, inpatients -Short-term Li treatment (p < 0.0001) and MSs (p = 0.037)
cohort study 35 ys duration of treatment
(2011) Li = 203 MSs - SAD Sch+ SUD (DSM-IV associated with higher SR
semi-structured)
-NS in SC
Smith cohort study l
Recruited 9 ys N = 93335 (Li + TAU) Li vs VPA in reduction -Dx: BD or MMD or SAD -Li/Val (OR= 1.22, 95% CI 0.82, 1.81, p=0.32)
na
(2014) Follow Li = 21468 (VPA+TAU) risk of SC -Incident users -Initial Li or VPA (OR=0.86, 95% CI 0.46, 1.61, p=0.63)
up 1 ys -Past 30 days at least 1 -After discontinued (OR 1.51, 95% CI 0.91,2.50 p=0.11)
outpatient prescription - Risks of SC discontinuation/modification Li over the first 180
days (p=0.015)
-Age > o = 18 years >psychosocial problems functioning with:
Follow up Li,SGA
Pompili N = 71 HoNOS scale - BD (DSM-IV semi- -history of SA (p=0.01)
ur

5-75 ms AD, BDZ

(2014) cohort study Li = 30 structured) inpatient, -prescribed anxiolytics during hospitalization (p=0.05)
MS
follow up after discharge -less Li at discharge (p=0.01)
-RR of SA -Age > 16 years -VPA (RR=1.53, 95% CI: 1.26–1.85 p<0.001), AD (RR=1.49, 95%
-SC -SA inpatients BD before CI: 1.23–1.8, p<0.001), BDZ (RR=1.49, 95% CI: 1.23–
Jo

Recruited 7 ys AD -Overall mortality the index attempt (ICD 10 1.80, p<0.001) increased risk of SA
Toffol N = 826
cohort study mean follow APD during Li vs no-Li, APD semi-structured) - Li<risk of SA, and suicide mortality (RR=0.39, 95% CI: 0.17–
(2015) Li= 307
up 3,5 ys VPA vs no-APD, VPA vs no- - Index period: the first 0.93, p=0.03), Cox (HR=0.37, 95% CI: 0.16–0.88, p=0.02) and
VPA, AD vs no-AD and hospital treatment period marginal structural models (HR=0.31, 95% CI 0.12-0.79, p=0.02)
BDZ vs no-BDZ due to SA - Li decreased all-cause mortality by 49%
 f
Song Cohort Li vs VPA in risk of -14% reduced rate of suicide-related events for periods on/off Li
(2017) comparative 8 ys N = 51535 Li suicide-related events -BD (I, II, NOS), SAD treatment (HR 0.86, 95% CI 0.78–0.95)

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study Li = 21129 VPA defined as SA or SC -Li and VPA treatment -NS VPA (HR 1.02, 95% CI 0.89–1.15)
-HRs for suicide-related events Li vs VPA (X2=4.29, p=0.038)

Notes: AD antidepressant, ADHD attention-deficit/hyperactivity disorder, APD antipsychotic drug, BD Bipolar Disorder, BPD Borderline personality disorder, BDZ Benzodiazepine, CBZ Carbamazepine, CD conduct
disorder, Chi-2 Chi-square test, Cit Citalopram, DSH deliberate self-harm, f female, HoNOS healt of the nation outcome, LAM Lamotrigine, LEV Levetiracetam, Li Lithium, m male, MDD Major depressive disorder,
MDE major depressive episode, Ms Months, MS mood stabilizers, NS Non significant, NOS not otherwise specified, ODD oppositional defiant disorder, OXC Oxcarbazepine, p variable of pearson, PBO Placebo,

pr
RCT Randomized-controlled trial, Ref reference, RR relative risk, RSP Risperidone, SA attempted suicide, SAD Schizoaffective disorder, SB Suicidal behaviour, SC suicide completion, Sch+ Schizophrenia, SE suicide
event, SGA Second generation antipsychotic, SMR suicide mortality rate, SR Suicide rate, SUD Substance Use Disorder, TAU treatment SA usual, TOP Topiramate, TOT Total, VPA Valproic acid, Ys years, Ws Weeks

e-
l Pr
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Table 1. Prospective studies
Ref Design Duration Sample Arms Primary aim / Inclusion Criteria Results

f
(n) Primary outcome

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- Age: 6-15 ys
Multicenter, Anti-manic medications - Dx: BD-I, ADHD, ODD, CD
TOT = 279 Li
Salpekar prospective, effectiveness on depression and (DSM-IV semi-structured)
8 ws Li = 15 VPA NS
2015 masked parallel suicidality/ Improvement CGI-BP-I-D - BD-I manic or mixed episode, CGAS<60,
RSP
RCT and CDRS - Doses: Li = 1.1-1.3 mmol/l, VPA=111-125 mcgr/mL,

pr
RSP= (4-6 mg)
- Age: 18+ years
TOT = 58
Girlanda Li + TAU Li efficacy in reducing risk of SB / nº - DSH /last 12 months
Parallel RCT 12 ms Li = 29 NS
2014 SC and acts of DSH - Resistant depression

e-
- Li = 0.4-1.0 mmol/l
- 2 ws
RCT -Age: 18-75 ys
stabilization Compare Li vs VPA protection
double-blinded TOT = 94 -BD-I, BD-II, BD-NOS (DSM-IV semi-structured)
Oquendo - 6 ms Li + TAU against SB / Time to SC, SA, SE
+ open-label Li = 46 - Depressive or mixed episode NS
2011 continuation VPA + - Changes in C-SSRS, BSS

Pr
adjunctive - 1+ past SA
- 2 ys TAU - Changes in SADS-C, CGAS
treatment - Li = 0.6–1.0 mmoli/l, VPA = 45–125 mcgr/ml
maintenance
- Complete remission with
RCT, double- - Age: 18-75 years
therapeutic Li levels: (5/11, 45%) (p =
blind, parallel TOT = 80 Cit + Li - MDD, NOS, dysthymia, NOS, BPD (DSM-IV semi-
Khan 2011 6 ws Changes in S-STS>8 0.049)
+ Post hoc Li + Cit = 40 Cit + PBO structured)
- >50% reduction in S-STS scores
analysis - Li = 0.4-1.0 mmol/l
with Li + Cit: (7/11, 64%)
Kleindienst l
- 2 ws TOT = 285 Li Evaluation efficacy Li vs CBZ, vs Li + - Age: 18-65 years 5 SA and 1 SC in CBZ group
na
2000 observational stabilization Li = 86 CBZ CBZ / nº SA and SC - BD (DSM-IV semi-structured), BD or SAD (ICD-9) 0 SA and SC in Li Group
RCT, - 6 ms Li + CBZ - Current episode of affective or SAD
multicenter continuation - 1+ MDE /last 4 ys, 1+ BD episode/last 5 ys, 1+ SA /3 ys
study - 2.5 ys - Li = 0.5-0.73 mmol/l CBZ = 4.85-7.39 mcrg/mL
maintenance
ur

Lauterbach Randomized, 12 ms TOT =167 Li + TAU Suicide preventive effects of Li / - - Age > 18 years All SC occurred with PBO (p=0.049)
2008 PBO-controlled, Li = 84 PBO + Occurrences of SA or SC, - Changes - MDD (DSM-IV semi-structured)
+ Post hoc TAU in MDS, SIS, R-R - SA 3 ms prior to first drug administration
analysis - SA, depressive spectrum disorder
- Li = 0.6-0.8 mmol/l
Jo

Notes: AD antidepressant, ADHD attention-deficit/hyperactivity disorder, APD antipsychotic drug, BD Bipolar Disorder, BPD Borderline personality disorder, BDZ Benzodiazepine, CBZ Carbamazepine, CD conduct disorder, Chi-2 Chi
square test, Cit Citalopram, DSH deliberate self-harm, f female, LAM Lamotrigine, LEV Levetiracetam, Li Lithium, m male, MDD Major depressive disorder, MDE major depressive episode, Ms Months, MS mood stabilizers, NS Non
significant, NOS not otherwise specified, ODD oppositional defiant disorder, OXC Oxcarbazepine, p variable of pearson, PBO Placebo, RCT Randomized-controlled trial, Ref reference, RR relative risk, RSP Risperidone, SA attempted
suicide, SAD Schizoaffective disorder, SB Suicidal behaviour, SC suicide completion, Sch+ Schizophrenia, SE suicide event, SGA Second generation antipsychotic, SMR suicide mortality rate, SR Suicide rate, SUD Substance Use Disorder,
TAU treatment SA usual, TOP Topiramate, TOT Total, VPA Valproic acid, Yr year, Ys years, Ws Weeks
 f
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pr
e-
Table 2. Retrospective studies
Ref Design Duration Sample (n) Arms Primary aim / Inclusion Criteria Results
Primary outcome
Kallner 2000 Retrospective 30 ys TOT = 497 - Comparing MR of patients with Li - Age: 16-83 ys - 3 groups:

Pr
observational Li = 363 with those who left the clinic / SC - Dx: BD, MDD (DSM III) A. Attending the clinic and taking Li: SMR 14.0 (p < 0.001) in BD; no SC in
Li + TAU
study and SMR - Li = 0.5-0.7 mmol/L MDD
- Intergroup comparison / SR per B. Left the clinic but continued taking Li: 3 SC among BD, SMR of 21.4 (p
patients-ys < 0.01)
C. Left the clinic and not taking Li any longer: excess of SC among BD
(SMR = 33.3, p < 0.001) and MDD (SMR = 50.0, p < 0.001).
- SR of 3.5 per 1000 patient-ys for BD in group A; SR increased to 6.3 or

l by 80% if in Group C; SR in Group C increased by 45% compared to

Group B
na
Ahrens 2001 Retrospective 6.7 ys TOT = 827 Efficacy of Li prophylaxis in - Dx : BD, Recurrent affective, - Less SA in excellent Li responders (3 SA) compared to moderate (14
cohort study Li = 167 prolonging survival / n° SA and SAD (DSM III) SA), and poor Li responders (21 SA).
(subanalysis) changes in SA/year - 1 + past SA - Less SA/year in the 3 groups as compared to a corresponding pre-Li
-
- Minimum 2 ys on Li period: 0.10 vs 0.33 in poor responders (p < 0.007); 0.06 vs 0.27 in
moderate response (p < 0.0001); 0.02 vs 0.26 in excellent response, (p <
0.0001)
ur

Gaertner 2002 Retrospective 20 ys TOT = 122 Li + TAU Evaluation of - Age: average of 40 ys - Sch+ and SAD group: no patients in suicide group with MS; 3 controls
case control Li = 10 psychopharmacological - Dx: Sch+, SAD, Affective on Li and 2 on CBZ (p < 0.05)
study interventions in suicide group and psychoses, Other no organic - Affective psychosis group: 1 patient in suicide group, but 6 controls
control group / n° patients taking psychoses, mixed diagnostic received Li (p = 0.04)
MS in both groups categories (ICD-9, ICD-10)
Jo

- Median 8 yr history of
psychiatric disease
Goodwin 2003 Retrospective 8 ys TOT = 20623 Li Li vs CBZ and VPA / RS and HR for - Age: > 14 ys - Li vs VPA: 1.5- to 3-fold reduced risk of SA and SC with Li (p = 0.03);
cohort study Li = 7121 CBZ SA and SC - Dx: BD I- II (DSM IV) greater HR for SA and SC with VPA (2.7 SC, p < 0.03; 1.7 SA resulting in
VPA - At least 1 prescription for Li, hospitalization, p < 0.002; 1.8 SA ascertained in ED);
VPA or CBZ - CBZ vs Li: greater HR for SA resulting in hospitalization (2.9, p < 0.001).
Yerevanian 2003 Retrospective 3469 ms TOT = 140 CBZ Li vs CBZ and VPA / Rate of ST, SB, - Dx: BD I e II, Cyclotimic, SAD Lower rate of SE (Chi-2 = 4.05, p = 0.04) during period on, compared
cohort study Li = 140 for 2043 Li hospitalization or SC Bipolar type (DSM III e DSM IV) with off MS, for patients with Li + AC
months VPA - 6 + months under care
 f
Collins 2008 Retrospective 5 ys TOT = 7017 Li + TAU SC (or fatal poisoning) and ED visits - Age: average of 39 ys Overall 12 SC, 81 SA: 2 SC, 15 SA (Li); 2 SC, 41 SA (VPA); 7 SC, 19 SA
cohort study Li = 2558 VPA + TAU related to SA / SR per 1000 - Dx: BD (I o II) (Gaba); 4 SA (CBZ)

oo
Gaba + TAU personas ys, HR for SA and for SC. - At least one receipt of Li, VPA, -Li: lowest SR per 1000 persons ys (0.78)
CBZ +TAU CBZ or Gaba - Gaba vs Li: HR for SC 2.6 times greater (p < 0.001)
- VPA vs Li: HR for SA 2.7 times greater (p < 0.001)
Søndergård 2008 Retrospective 6 ys TOT = 5926 Li Evaluation of efficacy of Li vs other - Age > 18 ys
cohort study Li = 3815 (891 Li; Li + MS MS / Reduction of SR. - Dx: BD (ICD-10) in- and SR decreased (rate ratio = 0.28, 95% CI = 0.20-0.40) (p<0.0001), when
2924 Li + MS) MS outpatients switching to or augmentation with Li to patients initiated on AC

pr
Notes: AC Anticonvulsants, AD Antidepressant, APD Antipsychotic drug, BD Bipolar disorder, BPD Borderline personality disorder, CBZ Carbamazepine, Chi-2 Chi quadro test, CI Confidence Interval, ED Emergency
department, Gaba Gabapentin, HR hazard ratio, Li Lithium, MDD Major depressive disorder, MDE Major depressive episode, MR mortality rate, Ms Months, MS mood stabilizers, NOS not otherwise specified, p
Pearson variable, Ref Reference, RoS rehospitalisation or suicide, RR relative risk, RS suicide risk, SA suicide attempts, SAD Schizoaffective disorder, SB suicidal behaviour, SC suicide completion, Sch+ Schizophrenia,
SE Suicide events, SH self-harm, SMR Standardized mortality ratios, SR suicide rate, ST suicidal thoughts, TAU Treatment as usual, TOT total, VPA Valproic acid, Years Ys, Ws Weeks

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Table 2. Retrospective studies
Ref Design Duration Sample (n) Arms Primary aim / Inclusion Criteria Results
Primary outcome

Pr
Ko 2014 Retrospective - TOT = 100 Li + TAU Examine the correlates of lifetime - Age: 13-19 ys Less self-injurious behaviour (p = 0.028) in Li group; less (but n.s.) ST
study Li = 20 exposure to Li (Li group vs no Li - Dx: BD-I, BD-II, BD-NOS (KSADS- (p = 0.101), SA (p = 0.248) and family psychiatric history of SA (p =
group) PL) 0.102)

Isometsa 2014 Retrospective 16 ys TOT = 13581 Li RS post-discharge according to Dx: BD (ICD-10) inpatients - HR 8.05 (p < 0,001) after hospitalizations for bipolar depression with
cohort study Li = 3919 VPA type of illness phase and risk a SA
AD factors / Changes in HR - HR 3.63 (p < 0,001) m
- HR 0,186 (p = 0,001) for Li
Popiolek 2018 Retrospective 4 ys
l TOT = 1255 Li + TAU Evaluation of efficacy of - Age: 17-92 years Li associated with a lower risk of RoS (HR 0.87, 95% CI 0.73-1.03,
na
observational Li = 628 pharmacological approaches on - BD, MDE (ICD-10) p=0.11)
study risk of RoS in patients after ECT / - ECT for bipolar depression
HR during hospitalization
Notes: AC Anticonvulsants, AD Antidepressant, APD Antipsychotic drug, BD Bipolar disorder, BPD Borderline personality disorder, CBZ Carbamazepine, Chi-2 Chi quadro test, CI Confidence Interval, ECT
electroconvulsive therapy, ED Emergency department, Gaba Gabapentin, HR hazard ratio, Li Lithium, MDD Major depressive disorder, MDE Major depressive episode, MR mortality rate, Ms Months, MS mood
stabilizers, NOS not otherwise specified, p Pearson variable, Ref Reference, RoS rehospitalisation or suicide, RR relative risk, RS suicide risk, SA suicide attempts, SAD Schizoaffective disorder, SB suicidal behaviour,
ur

SC suicide completion, Sch+ Schizophrenia, SE Suicide events, SH self-harm, SMR Standardized mortality ratios, SR suicide rate, ST suicidal thoughts, TAU Treatment as usual, TOT total, VPA Valproic acid, Years Ys,
Ws Weeks
Jo

Table 3. Ecological studies about general population

Ref Geographical [Li + ] (µg/L) Sample Duration Outcomes Results
area
Ohgami Japan 0.7–59 18 5 ys SMR Less suicide with higher [Li]> in general population (β = -0.65, p < 0.004), in m
2009 (β = -0.61, p < 0.008), but not in f (β =-0.46, 0.055 <p<0.06)
 f
Kabacs 2011 United Kingdom 1-21 47 - SMR NA; r = -0.054, p = 0.715 in m; r = 0.042, p = 0.777 in f; r = -0.03, p = 0.838 in
the general population.

oo
Kapusta 2011 Austria 11-27 99 - -SR per 100 000 Less suicide with higher [Li], < SR (R2 = 0.15, b = -0.39, t = -4.14, p = 0.000073)
-SMR and SMR (R2 = 0.17, b = -0.41, t = -4.38, p = 0.000030)
Schopfer 2011 Tokyo - 100 m - -[Li] in scalp Less suicide with higher [Li] in scalp
100 f -Suicide incidence
Helbich 2012 Austria 11-27 99 5 ys SMR Less suicide with higher [Li], only at lower altitudes, rs -0.26, p = 0.009

pr
Sugawara 2013 Japan 0-13 40 - SMR NA between [Li] and SR (β = −0.37, p < 0.10) in f; (β = 0.12, p = 0.597) in m
SR
Giotakos 2013 Greece 11-21 34 3 ms SR/100 000 Less suicide with higher [Li] (β = −0.17, t = −2.10, p < 0.05)
Bluml 2013 USA 2.8-219 226 SR adj Less suicide with higher [Li], (Rate ratio: 0.88 for 100 mg/l; 95%CI: 0.84, 0.93)

e-
Helbich 2015 Austria 11-27 99 5 ys -SMR Less suicide with higher [Li], particularly in m (r = 0.970; p = 0.001)

Pompili 2015 Italy 4.08 – 6.48 145 - -SR annual average/ Less suicide with higher [Li], particularly in f (β = – 0.231, p = 0.005)
100 000

Pr
Ishii 2015 Japan - 434 4 ys -SMR Less suicide with higher [Li], particularly in SMRm (p = 0.019)

Shiotsuki 2016 Japan 0.1-43 153 6 ys SMR Less suicide with higher [Li] > in m, after adjustment of meteorological factors
(p = 0.070), annual total sunshine and annual mean temperature (p = 0,002 and
p = 0,025)
Liaugaudaite Lithuania 0.5-36 22 5 ys -SMR Less suicide with higher [Li] > in m (β = –0.70, p = 0.013) than in f (β = 0.15, p =
2017
l -Suicide incidence 0.70)
na
Fajardo 2017 Texas 3-539 234 6 ys -SMR [Li] negatively associated with all causes mortality, (r = -0.18, p = 0.006) and
-Premature death years of potential life lost (r = -0.22, p = 0.001)

Knudsen 2017 Denmark 0.6-31 158 22 ys SR NA, but SR decreased from 29.7 per 100000 person-years in 1991 to 18.4 per
100000 person-years in 2012
Oliveira 2019 Portugal 10.88-27.18 54 6 ys SMR NA: (r = 0.001, p = 0.996) in general population; (r = 0.024, p = 0.862) in m; (r =
ur

0.000, p = 0.999) in f
Notes: CI Confidence Intervals, DS Standard deviation, f female, Li Lithium, m male, NA No association, p variable of pearson, SR Suicide risk, r Pearson correlation, Ref reference, rs Spearman
correlation, SMR Standard mortality ratio, SR Suicide rate, ys years.
Jo