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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: catharina.lavebratt@ki.se 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

 |
2 PONZER et al.
1 | I NTRO D U C TI O N
Lithium is a common and widely used mood-­stabilizing agent for
bipolar disorder.1 In addition, lithium is frequently used in severe
recurrent depression and schizoaffective disorder. These conditions
are all associated with greatly increased morbidity and mortality,
both with regard to somatic disease as well as suicide. 2-­4 The most
common cause of death in bipolar disorder is cardiovascular dis-
ease. 2,5 Furthermore, bipolar disorder appears to be associated with
poorer long-­term cognitive outcome and a higher risk of developing
dementia.6 A similar relationship seems to exist between depression
7 8
and dementia, as well as psychosis and dementia.
It is well known that lithium treatment is associated with mul-
tiple adverse side effects and somatic complications. However,
over the last 20 years, there is growing evidence, from both an-
imal and human studies, that lithium can have neuroprotective
effects. For example, lithium treatment has been shown to have
protective and antiapoptotic effects on hippocampal neurons
after irradiation, and improves cognitive performance in mice.9,10
In humans, lithium has been shown to be associated with higher
brain gray matter volume,11,12 and appears to have a positive ef-
fect on cognitive performance in Alzheimer's disease and mild
cognitive impairment in individuals without psychiatric disor-
13
ders. Lithium has also been studied in both humans and rodents
with regard to ischemic stroke with indications of neuroprotec-
14,15
tive effects.
A retrospective chart review investigating the effects of lithium
treatment on several neurological and cardiovascular disorders,
including 1028 adult psychiatric outpatients attending lithium clin-
ics in New York City (USA) found a lower prevalence of dementia,
seizures, and amyotrophic lateral sclerosis (ALS) in patients treated
with lithium compared to patients of the same clinics who did not
receive lithium.16 A systematic review and meta-­analysis by Velosa
et al. published in 2020, included six studies on lithium and risk of
dementia, of which four indicated that lithium has a protective effect
on dementia development in some instances, e.g., continued use in
elderly bipolar patients.17
Lithium has also been proposed to reduce excess mortality from
cardiovascular disease in affective disorders (n = 827 patients),18 and
was associated with a lower risk of myocardial infarction among the
1028 patients attending lithium clinics.16 There is some indication
that lithium may have beneficial effects on cardiac remodeling fol-
lowing ischemia.19 A small study by Kallner et al. (n = 497 patients)
published in 2000 suggested excess mortality from pulmonary em-
bolism in lithium-­treated individuals. 20 These findings have, to our
knowledge, not been investigated further since.
All things considered, the relationship between long-­term lith-
ium treatment and health outcomes remains unclear; hence, large
population-­based studies are needed. In this nationwide register-­
based study, we set out to examine if long-­term lithium treatment
is associated with a higher or lower risk of common disorders with
a focus on vascular and neurological disorders, within the Finnish
population.
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2 | M E TH O D S
2.1 | Study population and registers
This is a register-­
based cohort study. Cases were defined as all
citizens and permanent residents in Finland that had at least one
dispensation of prescribed lithium (ATC-­
code N05AN) for three
or more consecutive years from January 1, 1995 to December 31,
2016 as defined by data in the Register for Reimbursements for
Prescription Medicines (RRD, Kela), kept by the National Social
Insurance Institution. 21 This register contains data on all medica-
tion dispensations since 1995. It uses the Anatomical Therapeutic
Chemical (ATC) classification system for drugs. Ten age-­, sex-­, and,
municipality-­
matched controls per case were selected from the
general population using the Central Population Register (Digital
and Population Data Services Agency DVV). Based on unique per-
sonal identification numbers given to all Finnish citizens and perma-
nent residents, information from the aforementioned registers was
linked and merged with the national Care Register for Health Care
(HILMO), managed by the Finnish Institute of Health and Welfare
(THL), and with Statistics Finland. HILMO contains data on all hos-
pital in-­patient treatments (since 1969) as well as out-­patient treat-
ments by physicians in specialized care (since 1998)22 and Statistics
Finland provided information on cause of death. The study and data
analyses were conducted from October 2018 to September 2020.
2.2 | Outcomes and covariates
The cases and controls were followed up in HILMO until December
31, 2016 for somatic diagnosis outcomes. Outcomes were largely
cardiovascular, cerebrovascular, and neurodegenerative disorders,
as well as well-­known lithium-­associated disorders (kidney disease)
and suicide. The International Statistical Classification of Diseases
and Related Health Problems, Tenth Revision (ICD-­
10) diagnosis
codes were used throughout the study as they were in routine use
since 1996. ‘Diagnosis at death’ was taken from the Cause-­of-­Death
Register and was included to address survival bias.
The following outcome diagnoses were included: cardiovascular
and cerebrovascular disorders (myocardial infarction [ICD-­10 code
I21], angina pectoris [I20], chronic ischemic heart disease [I25], cere-
bral infarction [I63], transient cerebral ischemic attacks and related
syndromes [G45]), venous thromboembolic disorders (phlebitis and
thrombophlebitis [I80], pulmonary embolism [I26]), neurodegener-
ative disorders (dementia [F00, F01, F02, F03, F05.1, G30, G31],
Parkinson disease [G20], ALS [G12.2], Huntington disease [G10]),
neuroinflammatory disorders (optic neuritis [H46], multiple sclerosis
[G35]), as well as other neurological disorders previously studied in
the context of lithium (brain tumors [C70, C71, C72, C79.3, D32,
D33, D42, D43], migraine [G43], seizures [G40, R56.8] and collapse
[R55]). Finally, we included kidney diseases (drug-­and heavy-­metal-­
induced tubulointerstitial and tubular conditions [N14], acute renal
failure [N17], chronic kidney disease [N18], unspecified kidney

PONZER et al.
failure [N19]), and suicide [X60-­X84, Y87.0] (as a cause-­of-­death
only).
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:
Hypertension (ICD-­
10 codes I10, I15 and/or ATC C10 dispensa-
tion), hypercholesterolemia (ICD-­10 codes E78.0, E78.5 and/or ATC
C07 dispensation), diabetes mellitus type 2 (ICD-­10 codes E11, E14
and/or having special rights for medication reimbursement for the
treatment of non-­insulin-­treated diabetes) and use of antipsychotic
medication (ATC N05A excluding lithium). These risk factors were,
together with sex, age, and municipality, used as covariates in dif-
ferent models.
2.3 | Statistical analysis
Using Cox proportional hazards modeling, the effect of lithium on
later somatic diagnosis outcomes was estimated for all cases and
all controls. To consider the effects of psychiatric illness on over-
all health, we performed analyses using a subgroup of the controls
consisting of individuals having received a diagnosis of a mood or
a psychotic disorder. Specifically, this subcohort was defined as in-
dividuals having received at least one of the following psychiatric
diagnoses (where lithium is a treatment option) during their lifetime:
schizophrenia and psychotic disorders [F20-­F29] bipolar disorder
[F31], and depressive episodes and disorders [F32-­F33].
For all outcomes, crude rates were matched for age, sex, and mu-
nicipality (model 1). For cardiovascular disorders, three more models
were used: model 2 included the covariates of model 1, as well as the
presence of common cardiovascular risk factors (hypercholesterol-
emia [no/yes], hypertension [no/yes], diabetes mellitus type 2 [no/
yes]). Model 3 included the model 2 covariates as well as the pres-
ence of any kidney disorder [no/yes], as this is a major cardiovascular
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
medication (N05A, except lithium) at any time during the observa-
tion period.
All statistical analyses were performed using SAS, version 9.4
(SAS Institute Inc). Statistical significance was set at α = 0.01 in two-­
sided tests.
2.4 | Ethical permission
The data protection authority and the authorities providing the data
approved the study. Informed consent was not obtained, as this
is not required for anonymous register data according to Finnish
regulations. A personal identification number, issued to all Finnish
citizens and permanent residents, was used to link and combine
data from different registries and datasets. This was conducted
as set out in the permission from the data-­keeping organizations
|
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3
(THL/2218/5.05.00/2018, Kela 67/522/2018, VRK/5862/2018–­1,
TK-­52-­1109-­19) after consulting the data protection authority.
3 | R E S U LT S
A total of 9698 lithium-­treated cases and 96,507 general popula-
tion controls without lithium prescription were identified for the
full cohort analyses. For the subcohort analyses of individuals with
a mood or psychotic disorder diagnosis (ICD-­10 F20-­F29, F31-­F33),
a total of 8762 lithium-­treated cases and 8786 controls were identi-
fied. The 936 lithium-­treated cases not included in the subcohort
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
represented in eFigure 1A–­D. While the subjects were matched for
age, sex, and municipality in the full cohort comparison, several dif-
ferences were observed regarding diagnoses and cardiovascular risk
factors, such as higher prevalence of psychiatric disorders overall,
antipsychotic medication usage, kidney disorders, diabetes mellitus
type 2, smoking and alcohol usage among the lithium-­treated cases.
In the subcohort analyses, comparing lithium-­treated cases to the
group of controls with a diagnosis of mood or psychotic disorder,
prevalence of antipsychotic usage (p = 0.001), diabetes mellitus
type 2 (p < 0.0001), hypercholesteremia (p = 0.0004), and kidney
disorders (p < 0.001) were higher amongst cases, whilst hyperten-
sion (p = 0.0889) and alcohol-­related disorders (p = 0.246) were not
statistically different in frequency compared to in controls. Amongst
the lithium-­treated cases, diagnoses of bipolar disorder and psy-
chotic disorders were more common, whereas depressive disorders
were in majority in the subcohort control group. In these subgroup
analyses, the cases and controls were not individually matched, but
no major differences were observed for age, sex, or municipality
(Table 1, eFigure 1C,D).
3.1 | Effects of lithium treatment on disease
compared to the general population
In the comparison between lithium users and individuals repre-
senting the general population, the lithium-­treated cases had a
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%
CI = 1.07–­1.23), driven by the higher risk for myocardial infarction,
cerebral infarction, and transient cerebral ischemic attacks. There
was a lower risk for angina pectoris in the lithium users in com-
parison to controls (HR = 0.83, 99% CI = 0.72–­0.94) (Figure 1, left
panel). These effect sizes were similar when correcting for common
cardiovascular risk factors (hypercholesterolemia, hypertension,
diabetes mellitus type 2 in model 2), and kidney disease (model 3)
­(eFigure 2, left panel). In the lithium users, we found a markedly
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%
CI = 1.66–­2 .25) and pulmonary embolism separately (HR = 2.86,
99% CI = 2.42–­3.37) (Figure 1, left panel). Regarding neurological
disorders, lithium treatment was associated with higher risk for
dementia (HR = 2.64, 99% CI = 2.38–­2 .94) and Parkinson's dis-
ease (HR = 3.82, 99% CI = 3.13–­4.66), seizures (HR = 2.32, 99%
CI = 2.04–­2 .63) and collapse (HR = 1.54, 99% CI = 1.32–­1.79)
(Figure 1, left panel). However, we could not detect any differ-
ences between individuals prescribed lithium and controls for risk
of ALS, Huntington's disease, neuroinflammatory disorders, brain
tumors, or migraine (Figure 1, left panel). Furthermore, the risk of
kidney disorders as a group, and for all specific kidney diagnoses
separately, were higher in the cases (HR = 4.86, 95% CI = 4.30–­
5.50); Figure 1, left panel. Finally, the risk of suicide was markedly
higher in the lithium-­treated cases (HR = 4.18, 99% CI = 3.29–­5.30;
Figure 1, left panel) compared to the general population.
3.2 | Effects of lithium treatment on disease
compared to the psychiatric control group
Comparing lithium users to individuals with a diagnosis of mood or
psychotic disorder without lithium treatment, we found that lithium
users had a lower risk for cardiovascular and cerebrovascular disor-
ders as a group (HR = 0.80, 99% CI = 0.73–­0.89), driven by a lower
risk for angina pectoris (HR = 0.61, 99% CI = 0.51–­0.73) and chronic
ischemic heart diseases (HR = 0.71, 99% CI = 0.61–­0.82), and cer-
ebral infarction (HR = 0.84, 99% CI = 0.70–­0.99) (Figure 1, right
panel). These effect sizes remained similar when correcting for the
aforementioned common cardiovascular risk factors (model 2), renal
disease (model 3) and the use of antipsychotic medication (model
4) (eFigure 2). A higher risk for venous thromboembolic disorders
as a group was apparent in the lithium-­treated cases (HR = 1.42,
99% CI = 1.20-­1.69), although not of the same magnitude as noted
in the beforementioned general population (full cohort) comparison
(Figure 1, right panel). Indeed, higher risks were detected for both
thrombophlebitis (HR = 1.26, 99% CI = 1.01–­1.57) and pulmonary
embolism (HR = 1.68, 99% CI = 1.31–­2.17) separately. Similarly,
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-
tion (Figure 1, right panel). Interestingly, migraine and collapse were
less common in the lithium-­treated cases compared to the controls
(Figure 1, right panel). The hazard ratio for suicide showed no signifi-
cant difference between lithium users and controls in this compari-
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

This is by far the largest study investigating the associations of long-­
term lithium treatment with a broad spectrum of health outcomes
both in comparison with the general population, as well as in com-
parison with individuals with a diagnosis of mood or psychotic dis-
order without lithium treatment. In this study, lithium users had a
population. However, when compared to other individuals with a
mood or a psychotic disorder diagnosis, lithium-­treated patients had
a lower risk of cardiovascular and cerebrovascular disorders. The risk
of venous thromboembolic events was higher in lithium users both
compared to the general population and compared to individuals with
a mood or a psychotic disorder diagnosis without lithium treatment.
 |
8 PONZER et al.
It is well known that patients with severe mental illnesses such as
bipolar disorder, major depression, and schizophrenia have a higher
disease burden from cardiovascular disorders than the general pop-
ulation.23 The results from our study support that this is true also for
lithium-­treated individuals in comparison with the general population.
However, when comparing lithium users to individuals having received
a diagnosis of a mood or a psychotic disorder with no lithium use, lith-
ium treatment was associated with lower cardio-­and cerebrovascular
disease risk, particularly with regards to chronic ischemic heart dis-
ease and cerebral infarction, pointing to a possible cerebrovascular-­
and cardioprotective effect of lithium. These results remained largely
unchanged in our different analysis models, for example, after correct-
ing for cardiovascular risk factors and the use of antipsychotic medi-
cation. However, we cannot conclude whether this is a direct effect
of lithium, or if long-­term lithium use is a proxy-­marker for a stable
treatment regimen with high compliance, regular medical follow-­up,
or in other ways a proxy for an altogether different health behavior
compared to other mood or psychotic disorder patients.
Contrary to the cardioprotective effects, we could not replicate
the neuroprotective effect of lithium on dementia and ALS reported
16
in earlier studies. In contrast to the conclusion of the systemic re-
17
view and meta-­analysis by Velosa et al., we found no indication that
lithium treatment significantly reduces the risk of dementia. In our
study, comparing lithium users to individuals with a diagnosis of mood
or psychotic disorder without lithium treatment, the risk for dementia
among lithium users showed no significant difference. However, the
discrepancy of the diagnostics groups within the psychiatric subco-
hort may influence the results, as the risk of dementia in mood disor-
ders seems to be associated with severe affective episodes24 which
are likely more frequent in the lithium group, that consists mainly of
individuals with bipolar disorder. A recently published study by Chen
et al.25 including 548 cases exposed to lithium, concludes that lithium
is associated with lower risk of dementia and its subtypes in older
adults. Our results do not contradict this as we have not investigated
different age groups, nor subtypes of dementia.
We also assessed the risk for thromboembolic events as psy-
chiatric illness, psychotic, and mood disorders in particular, appear
to be associated with a higher risk of venous thromboembolism
(VTE). 26 Although psychotropic medication may play a role in this
correlation, 27,28 to our knowledge, lithium has not been comprehen-
sively studied in this context. In our study, the risk for VTE was sig-
nificantly higher in lithium-­treated individuals, in comparison with
the general population, as well as in comparison with individuals
having received a diagnosis of a mood or psychotic disorder without
lithium medication. Previous research has linked major depression,
bipolar disorder and schizophrenia with VTE. 29-­31 The use of antide-
pressants has been suggested to be causal for venous thrombosis in
this context, 32 and antipsychotics have also been linked to higher risk
of VTE. 27,31 There are a few case reports on VTE in lithium-­treated
33,34
patients associated with lithium toxicity, and case reports of
lithium-­induced nephrogenic diabetes insipidus contributing to the
35
development of dural sinus and superior sagittal sinus thrombo-
sis, 36 respectively. Excess mortality from pulmonary embolism in
13995618, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bdi.13300 by Cochrane Greece, Wiley Online Library on [10/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
lithium-­treated patients has been previously described. 20 This pos-
sible association of lithium with VTE is not well understood, nor is
it routinely considered in clinical practice. Overlapping risk factors
for thrombosis with disease manifestations of bipolar disorder (e.g.,
immobility due to depression), consequences of acute management
(e.g., use of physical restraints in mania37 and/or use of antipsychot-
ics27 ), or properties of lithium specifically such as hematological
effects of lithium, including effects of bone marrow hemopoietic
stems cells, neutrophil, and platelet count, might all contribute.38-­41
Although this question remains complex, the findings in this study
do further strengthen the evidence of an association of venous
thromboembolic disease with lithium. Further investigation on this
clinically relevant question is however needed.
A four-­fold higher risk of suicide was seen in our cases compared
to the general population. This is expected as this represents the
over-­risk associated with psychiatric illness. In comparison with indi-
viduals diagnosed with mood or psychotic disorders without lithium
treatment, there was no over-­risk for suicide. This is particularly re-
markable as more severe diagnoses like bipolar disorder and schizo-
phrenia, which both carry a substantially higher risk of suicide,42-­4 4
were over-­represented among the cases in the subcohort (Table 1).
This result may therefore be attributed to the probable antisuicidal
effect of lithium45,46 compensating for the difference in diagnoses.
As expected, the HR for kidney disease was significantly higher
in the lithium-­treated group both in comparison to the general pop-
ulation and to individuals having received a diagnosis of a mood or
psychotic without lithium treatment. It is a well-­known fact is that
lithium can cause nephrogenic diabetes insipidus, reduced glomerular
filtration, and chronic kidney disease, but the issue of lithium's ability
to cause end-­stage kidney disease is a more complex question.47 This
study supports the notion that lithium is associated with and likely
causal of different types of kidney disease to a high degree. However,
due to the limited sample size of chronic kidney disease diagnoses
in this study, a sub-­analysis of different stages of chronic kidney dis-
ease, including end-­stage kidney disease, was not possible. Important
to note, however, is that due to close monitoring in lithium patients,
there is an obvious risk of surveillance bias in terms of kidney disease.
Bipolar disorder has been shown to be associated with an in-
creased risk of developing Parkinson's disease.48,49 Our results sup-
port this notion, as a greater risk of Parkinson's disease is seen in both
comparisons (where the lithium-­treated cases are predominately bi-
polar). Lithium's role in this relationship is not easily uncovered, as
bipolar disorder and long-­term lithium treatment are tightly linked.
The main strength of this study is the very large, population-­based
sample of lithium-­treated individuals and the 10-­fold-­sized control
group that approximates the general population very well. This has
been made possible by the use of personal identification numbers
and the comprehensive registers of the whole Finnish population for
inpatients and outpatients, regarding diagnoses, medication dispen-
sations, age, sex, and municipality. In line with clinical experience and
previous studies,50 lithium maintenance treatment was defined as at
least one lithium prescription/year continuously for three or more
years, which represents a significant treatment time.

PONZER et al.
There are, however, limitations to this study. There is a lack of de-
tailed information regarding the time of receiving lithium treatment
before the follow-­up period; therefore, it was not possible in this study
to analyze the impact of time (on lithium treatment). Further, in the
comparison to the general population, there is an obvious and nearly
complete overlap between psychiatric diagnosis and lithium treat-
ment, making it difficult to distinguish between the effects of psy-
chiatric illness and that of lithium treatment. However, these results
are important as they illustrate that the potential protective effects of
lithium cannot compensate for the heavy disease burden associated
with psychiatric illness in general, and bipolar disorder in particular.
The subcohort analyses allowed us to more specifically look at lithium
effects within populations with a hypothesized similar baseline health
and somatic disease risk. It is important to note though, the discrep-
ancy in psychiatric diagnoses between cases and controls; within the
lithium-­treated group, patients with bipolar disorder were in major-
ity, followed by individuals with a diagnosis of a psychotic disorder,
whereas in the subcohort control group, diagnoses of depressive
episode or depressive disorder were by far the most common. It was
not possible to match the psychiatric diagnoses entirely because the
absolute majority of bipolar patients were prescribed lithium. While
this dissimilarity might influence the results, it would be expected that
patients with bipolar or psychotic disorder have more severe comor-
bidities. Therefore, our results, support the idea that lithium treatment
is associated with reduced somatic morbidity. However, no conclusion
on causality can be drawn, nor can we say whether these effects are
exerted by direct biological effects of lithium or if long-­term lithium
treatment is associated with, or a proxy-­marker for, a stable treatment
regimen with high compliance and regular medical follow-­ups.
There is a risk of multiple testing in this study due to investigat-
ing association with several disorders. Therefore, we chose a more
stringent significance threshold and report 99% CIs to reduce the
risk of false positives.16
Alcohol use and smoking are common and well-­known risk fac-
tors associated with somatic disorders as well as mood and psychotic
disorders. However, these conditions are likely to be underreported
in clinical settings and probably even less often coded with their
ICD-­codes, especially in the large control group from the general
population and therefore these variables were not used in this
study. Furthermore, there are more unmeasured variables known to
be associated with psychiatric illnesses influencing the incidence of
somatic disorders, such as food behavior patterns, obesity, physical
activity as well as socioeconomic factors which may therefore act as
confounders.
In conclusion, lithium use was associated with a lower risk of
cardiovascular and cerebrovascular disease, but shows no marked
effect on dementia in individuals with a mood or psychotic disor-
der diagnosis. Venous thromboembolism, Parkinson's disease, and
kidney disease were significantly more prevalent in individuals pre-
scribed lithium, in comparison with both the general population and
individuals with a similar psychiatric background. The association of
VTE and lithium treatment constitutes an important area of further
research. Overall, while supporting the potential beneficial effects
|
13995618, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bdi.13300 by Cochrane Greece, Wiley Online Library on [10/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
9
of lithium treatment on cardiovascular and cerebrovascular health
in individuals with a mood or psychotic disorder diagnosis, we also
provide evidence that this effect does not compensate for the higher
somatic disease burden that is associated with psychiatric illness.
AU T H O R C O N T R I B U T I O N S
Concept and design: Millischer, Ponzer, Schalling, Lavebratt,
Backlund. Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Ponzer, Millischer, Backlund. Critical re-
vision of the manuscript for important intellectual content: All au-
thors. Statistical analysis: Millischer, Gissler, Lavebratt. Obtained
funding: Ponzer, Schalling, Lavebratt, Backlund. Administrative,
technical, or material support: Gissler. Supervision: Lavebratt,
Backlund. Responsible for submission: Lavebratt.
AC K N O​W L E​D G E​M E N T S
Access to Data: Dr Gissler had full access to all of the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
F U N D I N G I N FO R M AT I O N
This project was supported by grants from The Söderström-­Königska
Foundation (Dr Backlund), The Bror Gadelius Foundation (Ponzer),
The Foundation for Psychiatric Health (Drs Backlund and Lavebratt),
The Swedish Brain Foundation (Drs Schalling and Lavebratt),
the Swedish Research Council (Drs Schalling and Lavebratt), and
Psychiatry Southwest, Huddinge Hospital, Stockholm. Financial sup-
port was also provided through the regional agreement on medical
training and clinical research (ALF and PPG) between the Stockholm
County Council and Karolinska Institutet (Drs Backlund, Schalling
and Lavebratt).
C O N FL I C T O F I N T E R E S T
The authors of this paper do not have any commercial or other as-
sociation that constitutes a conflict of interest.
DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from
the Finnish Institute for Health and Welfare. Restrictions apply to
the availability of these data, which were used under license for this
study. Data are available with the permission of the Finnish Social
and Health Data Permit Authority Findata.
ORCID
Catharina Lavebratt https://orcid.org/0000-0003-4987-2718
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