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DOI: 10.1111/bdi.13300

ORIGINAL ARTICLE

Lithium and risk of cardiovascular disease, dementia and

venous thromboembolism

Katja Ponzer1,2,3 | Vincent Millischer1,2,4 | Martin Schalling1,2 | Mika Gissler1,2,5 |

Catharina Lavebratt1,2 | Lena Backlund1,2,3

1
Department of Molecular Medicine and
Surgery, Karolinska Institutet, Stockholm, Abstract
Sweden
Objective: To determine if long-­term lithium treatment is associated with protective
2
Center for Molecular Medicine,
Karolinska University Hospital, Stockholm,
effects or increased risk of vascular, neurological, and renal disorders.
Sweden Methods: Using nationwide registers, we included all citizens of Finland with dis-
3
Centre for Psychiatry Research, pensations of lithium for three or more consecutive years between 1995 and 2016.
Karolinska Institutet & Stockholm
Health Care Services, Region Stockholm, We identified 9698 cases and matched 96,507 controls without lithium treatment.
Stockholm, Sweden Studied outcomes were vascular, neurological, renal disorders, and suicide. Analyses
4
Department of Psychiatry and
were performed applying Cox proportional hazards modeling in full cohort and in fur-
Psychotherapy, Medical University of
Vienna, Vienna, Austria ther subcohort analysis of individuals with a comparable diagnosis of mood or psy-
5
Department of Knowledge Brokers, chotic disorder.
Finnish Institute for Health and Welfare,
Helsinki, Finland Results: Lithium users had a significantly higher overall disease burden compared to
matched population controls, including a higher risk of cardiovascular and cerebrovas-
Correspondence
Catharina Lavebratt, Center for Molecular cular disorders and dementia. However, compared to individuals with a diagnosis of
Medicine, L8:00, Visionsgatan 18, mood or psychotic disorders without lithium treatment, we observed a lower risk of
Karolinska University Hospital, S-­171 76
Stockholm, Sweden. cardiovascular and cerebrovascular disorders (HR = 0.80, 99% CI = 0.73–­0.89), and
Email: [email protected] no significant difference for dementia (HR = 1.15, 99% CI = 0.99-­1.33), in lithium
Funding information users. Pulmonary embolism was more common in the lithium-­treated cases both in
Foundation for Psychiatric Health; comparison to the general population (HR = 2.86, 99% CI = 2.42–­3.37) and in com-
Hjärnfonden; Stiftelsen Professor
Bror Gadelius Minnesfond; Stiftelsen parison to the psychiatric subcohort (HR = 1.68, 99% CI = 1.31–­2.17). Similarly, the
Söderström Königska Sjukhemmet; risks of Parkinson's disease and kidney disease were higher in both comparisons.
Stockholm läns landsting; Vetenskapsrådet
Conclusions: We conclude that individuals prescribed lithium have a lower risk of car-
diovascular and cerebrovascular disease, but no marked effect on dementia, com-
pared to individuals with a mood or psychotic disorder not prescribed lithium. Venous
thromboembolism, Parkinson's disease, and kidney disease were significantly more
prevalent in individuals prescribed lithium.

KEYWORDS
bipolar, cardiovascular, lithium, neuroprotective, somatic, thrombosis

Katja Ponzer and Vincent Millischer contributed equally.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.

Bipolar Disorders. 2023;00:1–11.  wileyonlinelibrary.com/journal/bdi | 1

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2 PONZER et al.

1 | I NTRO D U C TI O N 2 | M E TH O D S

Lithium is a common and widely used mood-­stabilizing agent for 2.1 | Study population and registers
bipolar disorder.1 In addition, lithium is frequently used in severe
recurrent depression and schizoaffective disorder. These conditions This is a register-­
based cohort study. Cases were defined as all
are all associated with greatly increased morbidity and mortality, citizens and permanent residents in Finland that had at least one
both with regard to somatic disease as well as suicide. 2-­4 The most dispensation of prescribed lithium (ATC-­
code N05AN) for three
common cause of death in bipolar disorder is cardiovascular dis- or more consecutive years from January 1, 1995 to December 31,
ease. 2,5 Furthermore, bipolar disorder appears to be associated with 2016 as defined by data in the Register for Reimbursements for
poorer long-­term cognitive outcome and a higher risk of developing Prescription Medicines (RRD, Kela), kept by the National Social
dementia.6 A similar relationship seems to exist between depression Insurance Institution. 21 This register contains data on all medica-
7 8
and dementia, as well as psychosis and dementia. tion dispensations since 1995. It uses the Anatomical Therapeutic
It is well known that lithium treatment is associated with mul- Chemical (ATC) classification system for drugs. Ten age-­, sex-­, and,
tiple adverse side effects and somatic complications. However, municipality-­
matched controls per case were selected from the
over the last 20 years, there is growing evidence, from both an- general population using the Central Population Register (Digital
imal and human studies, that lithium can have neuroprotective and Population Data Services Agency DVV). Based on unique per-
effects. For example, lithium treatment has been shown to have sonal identification numbers given to all Finnish citizens and perma-
protective and antiapoptotic effects on hippocampal neurons nent residents, information from the aforementioned registers was
after irradiation, and improves cognitive performance in mice.9,10 linked and merged with the national Care Register for Health Care
In humans, lithium has been shown to be associated with higher (HILMO), managed by the Finnish Institute of Health and Welfare
brain gray matter volume,11,12 and appears to have a positive ef- (THL), and with Statistics Finland. HILMO contains data on all hos-
fect on cognitive performance in Alzheimer's disease and mild pital in-­patient treatments (since 1969) as well as out-­patient treat-
cognitive impairment in individuals without psychiatric disor- ments by physicians in specialized care (since 1998)22 and Statistics
13
ders. Lithium has also been studied in both humans and rodents Finland provided information on cause of death. The study and data
with regard to ischemic stroke with indications of neuroprotec- analyses were conducted from October 2018 to September 2020.
14,15
tive effects.
A retrospective chart review investigating the effects of lithium
treatment on several neurological and cardiovascular disorders, 2.2 | Outcomes and covariates
including 1028 adult psychiatric outpatients attending lithium clin-
ics in New York City (USA) found a lower prevalence of dementia, The cases and controls were followed up in HILMO until December
seizures, and amyotrophic lateral sclerosis (ALS) in patients treated 31, 2016 for somatic diagnosis outcomes. Outcomes were largely
with lithium compared to patients of the same clinics who did not cardiovascular, cerebrovascular, and neurodegenerative disorders,
receive lithium.16 A systematic review and meta-­analysis by Velosa as well as well-­known lithium-­associated disorders (kidney disease)
et al. published in 2020, included six studies on lithium and risk of and suicide. The International Statistical Classification of Diseases
dementia, of which four indicated that lithium has a protective effect and Related Health Problems, Tenth Revision (ICD-­
10) diagnosis
on dementia development in some instances, e.g., continued use in codes were used throughout the study as they were in routine use
elderly bipolar patients.17 since 1996. ‘Diagnosis at death’ was taken from the Cause-­of-­Death
Lithium has also been proposed to reduce excess mortality from Register and was included to address survival bias.
cardiovascular disease in affective disorders (n = 827 patients),18 and The following outcome diagnoses were included: cardiovascular
was associated with a lower risk of myocardial infarction among the and cerebrovascular disorders (myocardial infarction [ICD-­10 code
1028 patients attending lithium clinics.16 There is some indication I21], angina pectoris [I20], chronic ischemic heart disease [I25], cere-
that lithium may have beneficial effects on cardiac remodeling fol- bral infarction [I63], transient cerebral ischemic attacks and related
lowing ischemia.19 A small study by Kallner et al. (n = 497 patients) syndromes [G45]), venous thromboembolic disorders (phlebitis and
published in 2000 suggested excess mortality from pulmonary em- thrombophlebitis [I80], pulmonary embolism [I26]), neurodegener-
bolism in lithium-­treated individuals. 20 These findings have, to our ative disorders (dementia [F00, F01, F02, F03, F05.1, G30, G31],
knowledge, not been investigated further since. Parkinson disease [G20], ALS [G12.2], Huntington disease [G10]),
All things considered, the relationship between long-­term lith- neuroinflammatory disorders (optic neuritis [H46], multiple sclerosis
ium treatment and health outcomes remains unclear; hence, large [G35]), as well as other neurological disorders previously studied in
population-­based studies are needed. In this nationwide register-­ the context of lithium (brain tumors [C70, C71, C72, C79.3, D32,
based study, we set out to examine if long-­term lithium treatment D33, D42, D43], migraine [G43], seizures [G40, R56.8] and collapse
is associated with a higher or lower risk of common disorders with [R55]). Finally, we included kidney diseases (drug-­and heavy-­metal-­
a focus on vascular and neurological disorders, within the Finnish induced tubulointerstitial and tubular conditions [N14], acute renal
population. failure [N17], chronic kidney disease [N18], unspecified kidney
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PONZER et al. 3

failure [N19]), and suicide [X60-­X84, Y87.0] (as a cause-­of-­death (THL/2218/5.05.00/2018, Kela 67/522/2018, VRK/5862/2018–­1,
only). TK-­52-­1109-­19) after consulting the data protection authority.
Information on smoking (ICD-­10 code F17) and alcohol abuse
(F10), as well as well-­known risk factors for cardio-­and cerebro-
vascular disorders, were also obtained from HILMO and RRD: 3 | R E S U LT S
Hypertension (ICD-­
10 codes I10, I15 and/or ATC C10 dispensa-
tion), hypercholesterolemia (ICD-­10 codes E78.0, E78.5 and/or ATC A total of 9698 lithium-­treated cases and 96,507 general popula-
C07 dispensation), diabetes mellitus type 2 (ICD-­10 codes E11, E14 tion controls without lithium prescription were identified for the
and/or having special rights for medication reimbursement for the full cohort analyses. For the subcohort analyses of individuals with
treatment of non-­insulin-­treated diabetes) and use of antipsychotic a mood or psychotic disorder diagnosis (ICD-­10 F20-­F29, F31-­F33),
medication (ATC N05A excluding lithium). These risk factors were, a total of 8762 lithium-­treated cases and 8786 controls were identi-
together with sex, age, and municipality, used as covariates in dif- fied. The 936 lithium-­treated cases not included in the subcohort
ferent models. were treated in primary care only and therefore had no diagnosis
except diabetes in HILMO. The demographic characteristics are
presented in Table 1, and the geographic origin of the subjects is
2.3 | Statistical analysis represented in eFigure 1A–­D. While the subjects were matched for
age, sex, and municipality in the full cohort comparison, several dif-
Using Cox proportional hazards modeling, the effect of lithium on ferences were observed regarding diagnoses and cardiovascular risk
later somatic diagnosis outcomes was estimated for all cases and factors, such as higher prevalence of psychiatric disorders overall,
all controls. To consider the effects of psychiatric illness on over- antipsychotic medication usage, kidney disorders, diabetes mellitus
all health, we performed analyses using a subgroup of the controls type 2, smoking and alcohol usage among the lithium-­treated cases.
consisting of individuals having received a diagnosis of a mood or In the subcohort analyses, comparing lithium-­treated cases to the
a psychotic disorder. Specifically, this subcohort was defined as in- group of controls with a diagnosis of mood or psychotic disorder,
dividuals having received at least one of the following psychiatric prevalence of antipsychotic usage (p = 0.001), diabetes mellitus
diagnoses (where lithium is a treatment option) during their lifetime: type 2 (p < 0.0001), hypercholesteremia (p = 0.0004), and kidney
schizophrenia and psychotic disorders [F20-­F29] bipolar disorder disorders (p < 0.001) were higher amongst cases, whilst hyperten-
[F31], and depressive episodes and disorders [F32-­F33]. sion (p = 0.0889) and alcohol-­related disorders (p = 0.246) were not
For all outcomes, crude rates were matched for age, sex, and mu- statistically different in frequency compared to in controls. Amongst
nicipality (model 1). For cardiovascular disorders, three more models the lithium-­treated cases, diagnoses of bipolar disorder and psy-
were used: model 2 included the covariates of model 1, as well as the chotic disorders were more common, whereas depressive disorders
presence of common cardiovascular risk factors (hypercholesterol- were in majority in the subcohort control group. In these subgroup
emia [no/yes], hypertension [no/yes], diabetes mellitus type 2 [no/ analyses, the cases and controls were not individually matched, but
yes]). Model 3 included the model 2 covariates as well as the pres- no major differences were observed for age, sex, or municipality
ence of any kidney disorder [no/yes], as this is a major cardiovascular (Table 1, eFigure 1C,D).
risk factor and common in lithium users. Model 4 was only run for
analyses concerning the psychiatric control group and included the
model 3 covariates, plus dispensation of prescribed antipsychotic 3.1 | Effects of lithium treatment on disease
medication (N05A, except lithium) at any time during the observa- compared to the general population
tion period.
All statistical analyses were performed using SAS, version 9.4 In the comparison between lithium users and individuals repre-
(SAS Institute Inc). Statistical significance was set at α = 0.01 in two-­ senting the general population, the lithium-­treated cases had a
sided tests. higher somatic disease burden overall (Table 2, Figure 1, left panel).
Lithium treatment was associated with a higher risk for cardiovas-
cular and cerebrovascular disorders as a group (HR = 1.15, 99%
2.4 | Ethical permission CI = 1.07–­1.23), driven by the higher risk for myocardial infarction,
cerebral infarction, and transient cerebral ischemic attacks. There
The data protection authority and the authorities providing the data was a lower risk for angina pectoris in the lithium users in com-
approved the study. Informed consent was not obtained, as this parison to controls (HR = 0.83, 99% CI = 0.72–­0.94) (Figure 1, left
is not required for anonymous register data according to Finnish panel). These effect sizes were similar when correcting for common
regulations. A personal identification number, issued to all Finnish cardiovascular risk factors (hypercholesterolemia, hypertension,
citizens and permanent residents, was used to link and combine diabetes mellitus type 2 in model 2), and kidney disease (model 3)
data from different registries and datasets. This was conducted ­(eFigure 2, left panel). In the lithium users, we found a markedly
as set out in the permission from the data-­keeping organizations higher risk for venous thromboembolic events as a group (HR = 2.29,
 |

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4 PONZER et al.

TA B L E 1 Demographic description of lithium-­treated cases and population-­based controls in full cohort matched for age, sex, and
municipality, and in subcohort of individuals with a diagnosis of a mood or psychotic disorder (ICD-­10 F20-­F29, F31-­F33)

Controls (Mood/
Cases (Mood/psychotic psychotic disorder
Cases (Full cohort) Controls (Full cohort) disorder subcohort) subcohort)

N 9698 96,507 8762 8786

a
Age (years, mean, SD) 45.0 (13.1) 45.0 (13.1) 44.7 (13.1) 44.0 (12.8)
Sex (M/F)a 4434/5264 44,117/52,390 3914/4848 3349/5437

N (%) N (%) N (%) N (%)

Smoking (F17) 76 (0.8) 246 (0.3) 75 (0.9) 52 (0.6)

Alcohol abuse (F10) 1685 (17.4) 4563 (4.7) 1645 (18.8) 1710 (19.5)
Hypercholesterolemia (E78.0, E78.5) 5977 (61.6) 47,330 (49.0) 5473 (62.5) 5261 (59.9)
Hypertension (I10, I15) 5063 (52.2) 38,043 (39.4) 4643 (53.0) 4543 (51.7)
Diabetes type 2 (E11, E14) 1593 (16.4) 9526 (9.9) 1482 (16.9) 1246 (14.2)
Antipsychotic usage (N05A excluding 9104 (93.9) 10,558 (10.9) 8385 (95.7) 4914 (55.9)
lithium)
Kidney disorders (N14, N17, N18, N19) 630 (6.5) 1561 (1.6) 590 (6.7) 200 (2.3)
Psychiatric diagnoses in specialized 8762 (90.3) 8786 (9.1) 8762 (100.0) 8786 (100.0)
health care
Psychotic disordersb (F20-­29) 4347 (44.8) 2279 (2.4) 4347 (49.6) 2279 (25.9)
Bipolar affective disorder (F31) 5991 (61.8) 805 (0.8) 5991 (68.4) 805 (9.2)
Depressive episode, recurrent 3494 (36.0) 6973 (7.2) 3494 (39.9) 6973 (79.4)
depressive disorder (F32-­F33)

Note: Differences in the between cases and controls subcohort of individuals with a diagnosis of a mood or psychotic disorder were tested using two-­
sided chi-­squared tests.
a
Matching criteria: age, sex, and municipality, for geographical origin, see eFigure 1A–­D.
b
Schizophrenia (ICD-­10 code F20), schizotypal disorder (F21), Persistent delusional disorders (F22), Acute and transient psychotic disorders (F23),
Induced psychotic disorder (F24), Schizoaffective disorders (F25), Other nonorganic psychotic disorders (F28), Unspecified nonorganic psychosis (F29).

99% CI = 2.04–­2 .58), and for thrombophlebitis (HR = 1.93, 99% users had a lower risk for cardiovascular and cerebrovascular disor-
CI = 1.66–­2 .25) and pulmonary embolism separately (HR = 2.86, ders as a group (HR = 0.80, 99% CI = 0.73–­0.89), driven by a lower
99% CI = 2.42–­3.37) (Figure 1, left panel). Regarding neurological risk for angina pectoris (HR = 0.61, 99% CI = 0.51–­0.73) and chronic
disorders, lithium treatment was associated with higher risk for ischemic heart diseases (HR = 0.71, 99% CI = 0.61–­0.82), and cer-
dementia (HR = 2.64, 99% CI = 2.38–­2 .94) and Parkinson's dis- ebral infarction (HR = 0.84, 99% CI = 0.70–­0.99) (Figure 1, right
ease (HR = 3.82, 99% CI = 3.13–­4.66), seizures (HR = 2.32, 99% panel). These effect sizes remained similar when correcting for the
CI = 2.04–­2 .63) and collapse (HR = 1.54, 99% CI = 1.32–­1.79) aforementioned common cardiovascular risk factors (model 2), renal
(Figure 1, left panel). However, we could not detect any differ- disease (model 3) and the use of antipsychotic medication (model
ences between individuals prescribed lithium and controls for risk 4) (eFigure 2). A higher risk for venous thromboembolic disorders
of ALS, Huntington's disease, neuroinflammatory disorders, brain as a group was apparent in the lithium-­treated cases (HR = 1.42,
tumors, or migraine (Figure 1, left panel). Furthermore, the risk of 99% CI = 1.20-­1.69), although not of the same magnitude as noted
kidney disorders as a group, and for all specific kidney diagnoses in the beforementioned general population (full cohort) comparison
separately, were higher in the cases (HR = 4.86, 95% CI = 4.30–­ (Figure 1, right panel). Indeed, higher risks were detected for both
5.50); Figure 1, left panel. Finally, the risk of suicide was markedly thrombophlebitis (HR = 1.26, 99% CI = 1.01–­1.57) and pulmonary
higher in the lithium-­treated cases (HR = 4.18, 99% CI = 3.29–­5.30; embolism (HR = 1.68, 99% CI = 1.31–­2.17) separately. Similarly,
Figure 1, left panel) compared to the general population. the higher hazard ratios for lithium users for diagnoses of dementia
and Parkinson's disease in these analyses, although present, were
considerably smaller than in comparison with the general popula-
3.2 | Effects of lithium treatment on disease tion (Figure 1, right panel). Interestingly, migraine and collapse were
compared to the psychiatric control group less common in the lithium-­treated cases compared to the controls
(Figure 1, right panel). The hazard ratio for suicide showed no signifi-
Comparing lithium users to individuals with a diagnosis of mood or cant difference between lithium users and controls in this compari-
psychotic disorder without lithium treatment, we found that lithium son (Figure 1, right panel).
 TA B L E 2 The prevalence of somatic disorders (ICD-­10 codes) in lithium-­treated patients and population-­based controls, in the full cohort and in subcohort of individuals with a diagnosis of a
mood or psychotic disorder (ICD-­10 F20-­F29, F31-­F33)

Cases, Mood/psychotic disorder Controls, Mood/psychotic disorder

PONZER et al.

Cases, full cohort Controls, full cohort subcohort subcohort

Death, Death, Death,

Hospitalization, new Hospitalization, Death, new Hospitalization, new Hospitalization, new
N cases, N All, N (%) N cases, N All, N (%) N cases, N All, N (%) N cases, N All, N (%)

Cardiovascular and 1508 170 1678 14,535 1081 15,616 1351 151 1502 1614 101 1715 (19.5)
cerebrovascular (17.3) (16.2) (17.1)
disorders
Myocardial infarction 368 81 449 (4.6) 3849 582 4431 (4.6) 333 69 402 (4.6) 382 51 433 (4.9)
(I21)
Angina pectoris (I20) 462 1 463 (4.8) 5754 2 5756 (6.0) 417 1 418 (4.8) 626 —­ 626 (7.1)
Chronic ischemic heart 559 129 688 (7.1) 6932 836 7768 (8.0) 496 114 610 (7.0) 694 88 782 (8.9)
disease (I25)
Cerebral infarction (I63) 495 20 515 (5.3) 4040 66 4106 (4.3) 442 18 460 (5.2) 515 7 522 (5.9)
Transient cerebral 416 4 420 (4.3) 3726 14 3740 (3.9) 316 0 316 (3.6) 361 0 361 (4.1)
ischemic attacks and
related syndromes
(G45)
Thromboembolic 647 31 678 (7.0) 3142 50 3192 (3.3) 600 28 628 (7.2) 428 11 439 (5.0)
Phlebitis and 381 23 404 (4.2) 2151 35 2186 (2.3) 361 19 380 (4,3) 281 8 289 (3.3)
thrombophlebitis (I80)
Pulmonary embolism (I26) 318 14 332 (3.4) 1240 21 1261 (1.3) 289 14 303 (3.5) 177 3 180 (2.0)
Neurodegenerative 932 41 973 (10.0) 3983 146 4129 (4.3) 864 38 902 688 19 707 (8.0)
(10.3)
Dementia (F00, F01, F02, 757 37 794 (8.2) 3382 145 3527 (3.7) 703 36 739 (8.4) 594 21 615 (7.0)
F03, F05.1, G30, G31)
Parkinson (G20) 233 4 237 (2.4) 713 5 718 (0.7) 214 2 216 (2.5) 136 1 137 (1.6)
ALS (G12.2) 16 —­ 16 (0.2) 106 4 110 (0.1) 12 —­ 12 (0.1) 10 1 11 (0.1)
Huntington (G10) 2 —­ 2 (0) 6 —­ 6 (0.0) 2 —­ 2 (0) 1 —­ 1 (0.0)
Neuroinflammatory 43 —­ 43 (0.4) 399 1 400 (0.4) 41 —­ 41 (0.5) 65 —­ 65 (0.7)
disorders
Optic neuritis (H46) 5 —­ 5 (0.1) 105 —­ 105 (0.1) 5 —­ 5 (0.1) 19 —­ 19 (0.2)
Multiple sclerosis (G35) 41 —­ 41 (0.4) 336 1 337 (0.3) 39 —­ 39 (0.4) 54 —­ 54 (0.6)
Others 1265 —­ 1265 7539 12 7551 (7.8) 1164 —­ 1164 1312 1 1313 (14.9)
(13.0) (13.3)
| 5

(Continues)

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 | 6

TA B L E 2 (Continued)

Cases, Mood/psychotic disorder Controls, Mood/psychotic disorder

Cases, full cohort Controls, full cohort subcohort subcohort

Death, Death, Death,

Hospitalization, new Hospitalization, Death, new Hospitalization, new Hospitalization, new
N cases, N All, N (%) N cases, N All, N (%) N cases, N All, N (%) N cases, N All, N (%)

Brain tumors (C70, C71, 105 —­ 105 (1.1) 862 10 872 (0.9) 90 —­ 90 (1.0) 91 1 92 (1.0)
C72, C79.3, D32, D33,
D42, D43)
Migraine (G43) 196 —­ 196 (2.0) 1888 —­ 1888 (2.0) 185 —­ 185 (2.1) 321 —­ 321(3.7)
Seizures (G40, R56.8) 688 —­ 688 (7.1) 2946 2 2948 (3.1) 626 —­ 626 (7.1) 636 —­ 636 (7.2)
Collapse (R55) 413 —­ 413 (4.3) 2669 —­ 2669 (2.8) 387 —­ 387 (4.4) 442 —­ 442 (5.0)
Suicide (X60-­X84, Y87.0) 165 (1.7) 408 (0,4) 148 (1.7) 1678 (1.9)
Kidney disorders 630 1 631 (6.5) 1561 3 1564 (1.6) 590 1 591 (6.7) 200 —­ 200 (2.3)
Drug-­ and heavy-­metal-­ 37 —­ 37 (0.4) 7 —­ 7 (0.0) 36 —­ 36 (0.4) 3 —­ 3 (0.0)
induced tubulo-­
interstitial and tubular
conditions (N14)
Acute renal failure (N17) 218 —­ 218 (2.2) 708 —­ 708 (0.7) 200 —­ 200 (2.3) 114 —­ 114 (1.3)
Chronic kidney disease 384 1 385 (4.0) 863 2 865 (0.9) 359 1 360 (4.1) 91 —­ 91 (1.0)
(N18)
Unspecified kidney failure 137 —­ 137 (1.4) 291 1 292 (0.3) 131 —­ 131 (1.5) 32 —­ 32 (0.4)
(N19)
PONZER et al.

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PONZER et al. 7

F I G U R E 1 Adjusted Cox Hazard Ratios (HRs) and 99% CI:s for somatic diseases in full cohort (left panel) and subcohort of individuals
with a diagnosis of a mood or psychotic disorder (ICD-­10 F20-­F29, F31-­F33) (right panel). Model 1 is shown with adjustments for age, sex,
and municipality. Additional models are shown in eFigure 1.

4 | DISCUSSION significantly higher somatic disease burden compared to the general

population. However, when compared to other individuals with a
This is by far the largest study investigating the associations of long-­ mood or a psychotic disorder diagnosis, lithium-­treated patients had
term lithium treatment with a broad spectrum of health outcomes a lower risk of cardiovascular and cerebrovascular disorders. The risk
both in comparison with the general population, as well as in com- of venous thromboembolic events was higher in lithium users both
parison with individuals with a diagnosis of mood or psychotic dis- compared to the general population and compared to individuals with
order without lithium treatment. In this study, lithium users had a a mood or a psychotic disorder diagnosis without lithium treatment.
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8 PONZER et al.

It is well known that patients with severe mental illnesses such as lithium-­treated patients has been previously described. 20 This pos-
bipolar disorder, major depression, and schizophrenia have a higher sible association of lithium with VTE is not well understood, nor is
disease burden from cardiovascular disorders than the general pop- it routinely considered in clinical practice. Overlapping risk factors
ulation.23 The results from our study support that this is true also for for thrombosis with disease manifestations of bipolar disorder (e.g.,
lithium-­treated individuals in comparison with the general population. immobility due to depression), consequences of acute management
However, when comparing lithium users to individuals having received (e.g., use of physical restraints in mania37 and/or use of antipsychot-
a diagnosis of a mood or a psychotic disorder with no lithium use, lith- ics27 ), or properties of lithium specifically such as hematological
ium treatment was associated with lower cardio-­and cerebrovascular effects of lithium, including effects of bone marrow hemopoietic
disease risk, particularly with regards to chronic ischemic heart dis- stems cells, neutrophil, and platelet count, might all contribute.38-­41
ease and cerebral infarction, pointing to a possible cerebrovascular-­ Although this question remains complex, the findings in this study
and cardioprotective effect of lithium. These results remained largely do further strengthen the evidence of an association of venous
unchanged in our different analysis models, for example, after correct- thromboembolic disease with lithium. Further investigation on this
ing for cardiovascular risk factors and the use of antipsychotic medi- clinically relevant question is however needed.
cation. However, we cannot conclude whether this is a direct effect A four-­fold higher risk of suicide was seen in our cases compared
of lithium, or if long-­term lithium use is a proxy-­marker for a stable to the general population. This is expected as this represents the
treatment regimen with high compliance, regular medical follow-­up, over-­risk associated with psychiatric illness. In comparison with indi-
or in other ways a proxy for an altogether different health behavior viduals diagnosed with mood or psychotic disorders without lithium
compared to other mood or psychotic disorder patients. treatment, there was no over-­risk for suicide. This is particularly re-
Contrary to the cardioprotective effects, we could not replicate markable as more severe diagnoses like bipolar disorder and schizo-
the neuroprotective effect of lithium on dementia and ALS reported phrenia, which both carry a substantially higher risk of suicide,42-­4 4
16
in earlier studies. In contrast to the conclusion of the systemic re- were over-­represented among the cases in the subcohort (Table 1).
17
view and meta-­analysis by Velosa et al., we found no indication that This result may therefore be attributed to the probable antisuicidal
lithium treatment significantly reduces the risk of dementia. In our effect of lithium45,46 compensating for the difference in diagnoses.
study, comparing lithium users to individuals with a diagnosis of mood As expected, the HR for kidney disease was significantly higher
or psychotic disorder without lithium treatment, the risk for dementia in the lithium-­treated group both in comparison to the general pop-
among lithium users showed no significant difference. However, the ulation and to individuals having received a diagnosis of a mood or
discrepancy of the diagnostics groups within the psychiatric subco- psychotic without lithium treatment. It is a well-­known fact is that
hort may influence the results, as the risk of dementia in mood disor- lithium can cause nephrogenic diabetes insipidus, reduced glomerular
ders seems to be associated with severe affective episodes24 which filtration, and chronic kidney disease, but the issue of lithium's ability
are likely more frequent in the lithium group, that consists mainly of to cause end-­stage kidney disease is a more complex question.47 This
individuals with bipolar disorder. A recently published study by Chen study supports the notion that lithium is associated with and likely
et al.25 including 548 cases exposed to lithium, concludes that lithium causal of different types of kidney disease to a high degree. However,
is associated with lower risk of dementia and its subtypes in older due to the limited sample size of chronic kidney disease diagnoses
adults. Our results do not contradict this as we have not investigated in this study, a sub-­analysis of different stages of chronic kidney dis-
different age groups, nor subtypes of dementia. ease, including end-­stage kidney disease, was not possible. Important
We also assessed the risk for thromboembolic events as psy- to note, however, is that due to close monitoring in lithium patients,
chiatric illness, psychotic, and mood disorders in particular, appear there is an obvious risk of surveillance bias in terms of kidney disease.
to be associated with a higher risk of venous thromboembolism Bipolar disorder has been shown to be associated with an in-
(VTE). 26 Although psychotropic medication may play a role in this creased risk of developing Parkinson's disease.48,49 Our results sup-
correlation, 27,28 to our knowledge, lithium has not been comprehen- port this notion, as a greater risk of Parkinson's disease is seen in both
sively studied in this context. In our study, the risk for VTE was sig- comparisons (where the lithium-­treated cases are predominately bi-
nificantly higher in lithium-­treated individuals, in comparison with polar). Lithium's role in this relationship is not easily uncovered, as
the general population, as well as in comparison with individuals bipolar disorder and long-­term lithium treatment are tightly linked.
having received a diagnosis of a mood or psychotic disorder without The main strength of this study is the very large, population-­based
lithium medication. Previous research has linked major depression, sample of lithium-­treated individuals and the 10-­fold-­sized control
bipolar disorder and schizophrenia with VTE. 29-­31 The use of antide- group that approximates the general population very well. This has
pressants has been suggested to be causal for venous thrombosis in been made possible by the use of personal identification numbers
this context, 32 and antipsychotics have also been linked to higher risk and the comprehensive registers of the whole Finnish population for
of VTE. 27,31 There are a few case reports on VTE in lithium-­treated inpatients and outpatients, regarding diagnoses, medication dispen-
33,34
patients associated with lithium toxicity, and case reports of sations, age, sex, and municipality. In line with clinical experience and
lithium-­induced nephrogenic diabetes insipidus contributing to the previous studies,50 lithium maintenance treatment was defined as at
35
development of dural sinus and superior sagittal sinus thrombo- least one lithium prescription/year continuously for three or more
sis, 36 respectively. Excess mortality from pulmonary embolism in years, which represents a significant treatment time.
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PONZER et al. 9

There are, however, limitations to this study. There is a lack of de- of lithium treatment on cardiovascular and cerebrovascular health
tailed information regarding the time of receiving lithium treatment in individuals with a mood or psychotic disorder diagnosis, we also
before the follow-­up period; therefore, it was not possible in this study provide evidence that this effect does not compensate for the higher
to analyze the impact of time (on lithium treatment). Further, in the somatic disease burden that is associated with psychiatric illness.
comparison to the general population, there is an obvious and nearly
complete overlap between psychiatric diagnosis and lithium treat- AU T H O R C O N T R I B U T I O N S
ment, making it difficult to distinguish between the effects of psy- Concept and design: Millischer, Ponzer, Schalling, Lavebratt,
chiatric illness and that of lithium treatment. However, these results Backlund. Acquisition, analysis, or interpretation of data: All authors.
are important as they illustrate that the potential protective effects of Drafting of the manuscript: Ponzer, Millischer, Backlund. Critical re-
lithium cannot compensate for the heavy disease burden associated vision of the manuscript for important intellectual content: All au-
with psychiatric illness in general, and bipolar disorder in particular. thors. Statistical analysis: Millischer, Gissler, Lavebratt. Obtained
The subcohort analyses allowed us to more specifically look at lithium funding: Ponzer, Schalling, Lavebratt, Backlund. Administrative,
effects within populations with a hypothesized similar baseline health technical, or material support: Gissler. Supervision: Lavebratt,
and somatic disease risk. It is important to note though, the discrep- Backlund. Responsible for submission: Lavebratt.
ancy in psychiatric diagnoses between cases and controls; within the
lithium-­treated group, patients with bipolar disorder were in major- AC K N O​W L E​D G E​M E N T S
ity, followed by individuals with a diagnosis of a psychotic disorder, Access to Data: Dr Gissler had full access to all of the data in the
whereas in the subcohort control group, diagnoses of depressive study and takes responsibility for the integrity of the data and the
episode or depressive disorder were by far the most common. It was accuracy of the data analysis.
not possible to match the psychiatric diagnoses entirely because the
absolute majority of bipolar patients were prescribed lithium. While F U N D I N G I N FO R M AT I O N
this dissimilarity might influence the results, it would be expected that This project was supported by grants from The Söderström-­Königska
patients with bipolar or psychotic disorder have more severe comor- Foundation (Dr Backlund), The Bror Gadelius Foundation (Ponzer),
bidities. Therefore, our results, support the idea that lithium treatment The Foundation for Psychiatric Health (Drs Backlund and Lavebratt),
is associated with reduced somatic morbidity. However, no conclusion The Swedish Brain Foundation (Drs Schalling and Lavebratt),
on causality can be drawn, nor can we say whether these effects are the Swedish Research Council (Drs Schalling and Lavebratt), and
exerted by direct biological effects of lithium or if long-­term lithium Psychiatry Southwest, Huddinge Hospital, Stockholm. Financial sup-
treatment is associated with, or a proxy-­marker for, a stable treatment port was also provided through the regional agreement on medical
regimen with high compliance and regular medical follow-­ups. training and clinical research (ALF and PPG) between the Stockholm
There is a risk of multiple testing in this study due to investigat- County Council and Karolinska Institutet (Drs Backlund, Schalling
ing association with several disorders. Therefore, we chose a more and Lavebratt).
stringent significance threshold and report 99% CIs to reduce the
risk of false positives.16 C O N FL I C T O F I N T E R E S T
Alcohol use and smoking are common and well-­known risk fac- The authors of this paper do not have any commercial or other as-
tors associated with somatic disorders as well as mood and psychotic sociation that constitutes a conflict of interest.
disorders. However, these conditions are likely to be underreported
in clinical settings and probably even less often coded with their DATA AVA I L A B I L I T Y S TAT E M E N T
ICD-­codes, especially in the large control group from the general The data that support the findings of this study are available from
population and therefore these variables were not used in this the Finnish Institute for Health and Welfare. Restrictions apply to
study. Furthermore, there are more unmeasured variables known to the availability of these data, which were used under license for this
be associated with psychiatric illnesses influencing the incidence of study. Data are available with the permission of the Finnish Social
somatic disorders, such as food behavior patterns, obesity, physical and Health Data Permit Authority Findata.
activity as well as socioeconomic factors which may therefore act as
confounders. ORCID
In conclusion, lithium use was associated with a lower risk of Catharina Lavebratt https://orcid.org/0000-0003-4987-2718
cardiovascular and cerebrovascular disease, but shows no marked
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