Research

JAMA Neurology | Original Investigation

Risk of Developing Parkinson Disease in Bipolar Disorder

A Systematic Review and Meta-analysis
Patrícia R. Faustino, MD; Gonçalo S. Duarte, MD; Inês Chendo, MD; Ana Castro Caldas, MD;
Sofia Reimão, MD, PhD; Ricardo M. Fernandes, MD, PhD; José Vale, MD; Michele Tinazzi, MD, PhD;
Kailash Bhatia, MD, PhD; Joaquim J. Ferreira, MD, PhD

Supplemental content
IMPORTANCE Parkinson disease (PD) manifests by motor and nonmotor symptoms, which
may be preceded by mood disorders by more than a decade. Bipolar disorder (BD) is
characterized by cyclic episodes of depression and mania. It is also suggested that dopamine
might be relevant in the pathophysiology of BD.

OBJECTIVE To assess the association of BD with a later diagnosis of idiopathic PD.

DATA SOURCES An electronic literature search was performed of Cochrane Controlled

Register of Trials, MEDLINE, Embase, and PsycINFO from database inception to May 2019
using the terms Parkinson disease, bipolar disorder, and mania, with no constraints applied.

STUDY SELECTION Studies that reported data on the likelihood of developing PD in BD vs

non-BD populations were included. Two review authors independently conducted the study
selection.

DATA EXTRACTION AND SYNTHESIS Two review authors independently extracted study data.
Data were pooled using a random-effects model, results were abstracted as odds ratios and
95% CIs, and heterogeneity was reported as I2.

MAIN OUTCOME AND MEASURES Odds ratios of PD.

RESULTS Seven studies were eligible for inclusion and included 4 374 211 participants overall.
A previous diagnosis of BD increased the likelihood of a subsequent diagnosis of idiopathic
PD (odds ratio, 3.35; 95% CI, 2.00-5.60; I2 = 92%). A sensitivity analysis was performed by
removing the studies that had a high risk of bias and also showed an increased risk of PD in
people with BD (odds ratio, 3.21; 95% CI, 1.89-5.45; I2 = 94%). Preplanned subgroup analyses
according to study design and diagnostic certainty failed to show a significant effect.

CONCLUSIONS AND RELEVANCE This review suggests that patients with BD have a significantly
increased risk of developing PD compared with the general population. Subgroup analyses
suggested a possible overestimation in the magnitude of the associations. These findings
highlight the probability that BD may be associated with a later development of PD and the
importance of the differential diagnosis of parkinsonism features in people with BD.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Joaquim J.
Ferreira, MD, PhD, Laboratory of
Clinical Pharmacology and
Therapeutics, Faculdade de Medicina
da Universidade de Lisboa, Avenida
Professor Egas Moniz, Lisbon
JAMA Neurol. doi:10.1001/jamaneurol.2019.3446 1649-028, Portugal
Published online October 14, 2019. (joaquimjferreira@gmail.com).

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 Research Original Investigation
B
ipolar disorder (BD) is a mood disorder that has an early
onset at a median age of 20 years. It is a long-term and
recurrent disorder characterized by cyclic episodes of
depression and either mania (BD type 1) or hypomania (BD type
2). Although the etiology of BD has not been established, it is
a multifactorial disorder with genetic and environmental fac-
tors playing an important role.1 Despite the pathophysiology
of BD being uncertain, there is a putative role of the dopamin-
ergic system, as levodopa has been shown to induce hypoma-
nia or mania in patients with BD,2 and antipsychotic medica-
tions that block dopamine receptors can improve manic
symptoms.3 There is also evidence that the switch from a de-
pressive to a manic state occurs concurrently with an upregu-
lation of dopamine receptors.4
The standard treatment for BD that includes lithium, an-
tipsychotic medications, and antiepileptic medications may be
associated with drug-induced parkinsonism, which is not clini-
cally distinguishable from Parkinson disease (PD), both being
characterized by bradykinesia, resting tremor, rigidity, and pos-
tural instability.5-7 Since drug-induced parkinsonism is more
common among patients with BD, physicians may be more in-
clined to misdiagnose PD as drug-induced parkinsonism. On
the other hand, PD is typically seen in older patients. Small
studies have previously shown that BD may be more com-
mon in patients with PD compared with the general
population.6 Therefore, we conducted a systematic review to
assess the possible association of BD with a later diagnosis of
idiopathic PD.
Methods
This study was registered on PROSPERO (CRD42018090100).
This study followed the Preferred Reporting Items for
Systematic Reviews and Meta-analyses (PRISMA) reporting
guideline and the Meta-analysis of Observational Studies in
Epidemiology (MOOSE) reporting guideline. We searched
Cochrane Controlled Register of Trials, MEDLINE, Embase, and
PsycINFO from database inception to May 2019 for
observational studies of any design, namely cohort, case-
control, or cross-sectional studies, that reported data on the
association of idiopathic PD in BD vs non-BD populations
(eMethods in the Supplement). Two review authors (P.R.F. and
G.S.D.) independently screened all titles and abstracts
identified from the search. We retrieved any articles identified
as potentially relevant by at least 1 review author. Two review
authors (P.R.F. and G.S.D.) independently screened full-text
articles, with discrepancies resolved through discussion. The
references of relevant studies were cross-checked for additional
studies not identified by the electronic search.
Two review authors (P.R.F. and G.S.D.) independently
extracted data from the included studies using a piloted data
extraction form, resolving any discrepancies through discus-
sion. The information extracted included the study charac-
teristics (publication year, country of origin, study period, study
design, and length of follow-up), participant characteristics
(number, age, and sex), selection of cases and controls in case-
control studies, assessment of BD diagnosis and outcome, ad-
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Risk of Developing Parkinson Disease in Bipolar Disorder
Key Points
Question Is there a greater risk of developing Parkinson disease
(PD) in people with bipolar disorder (BD)?
Findings In this meta-analysis and systematic review including 7
studies and more than 4 million participants, a previous diagnosis
of BD increased the likelihood of a subsequent diagnosis of
idiopathic PD.
Meaning If patients with BD present parkinsonism features, a
diagnosis of PD should be considered, independently of
concomitant medication.
justment for potential confounders, and estimates of the as-
sociation of BD with PD.
We assessed the risk of bias using the Newcastle-Ottawa
Scale8 and arbitrarily judged studies with scores greater than
6 as having a low overall risk of bias. We conducted data analy-
ses using Review Manager version 5.3 (Cochrane). We pooled
data, where adequate, using a random-effects model and re-
ported results using odds ratio (OR) estimates with correspond-
ing 95% CIs. We quantified heterogeneity using I2. We further
explored our results using preplanned subgroup analyses ac-
cording to study design, duration of follow-up, and if the BD
diagnosis was clearly established before PD diagnosis, with an
arbitrary cutoff of 9 years. We also conducted a preplanned sen-
sitivity analysis by pooling only studies at a low overall risk of
bias. We intended to assess the possibility of publication bias,9
although we were unable to do so owing to an insufficient num-
ber of included trials. Variables were compared using χ2 tests.
All tests were 2-tailed, and we considered a P value less than
.05 to be statistically significant.
Results
The electronic database search identified 471 articles. After title
and abstract screening, 32 articles were retained for full-text
assessment, with 7 fulfilling our review criteria, including 4
cohort studies10-13 and 3 cross-sectional studies14-16 (Figure 1).
Most of the included studies did not state the criteria used
to establish the diagnosis of PD, as these were generally based
on data from registers and medical records, and one study used
a self-report questionnaire.14 Another study mentioned using
computed tomography or magnetic resonance imaging to ex-
clude other neurological diseases.10 However, none used spe-
cific imaging methods for the differential diagnosis of PD and
parkinsonism. Only 1 of the included trials reported the aver-
age age at onset of PD.13 The population characteristics and out-
comes of the included studies are summarized in Table 1.
Systematic Review
The cohort study by Lin et al10 included 73 597 patients with
an established psychiatric disorder who were recruited be-
tween 2001 and 2003, among whom 1203 had BD, and these
individuals were matched with 220 971 controls. The selec-
tion was made using medical records of hospitalizations and
jamaneurology.com
 Risk of Developing Parkinson Disease in Bipolar Disorder
Figure 1. PRISMA Flow Diagram
471 Records identified through database
searching
14 Additional records identified through
other sources
484 Records after duplicates removed
484 Records screened
452 Records excluded
32 Full-text articles assessed for eligibility
25 Full-text articles excluded
4 Included ineligible base population
4 Included iatrogenic parkinsonism
6 Had ineligible order of diagnosis
11 Had wrong study design
7 Studies included in qualitative synthesis
6 Studies included in quantitative synthesis
(meta-analysis)
ambulatory care. Patients were observed for 6 years to iden-
tify PD. In this 6-year follow-up, patients with BD were at an
increased risk of developing PD compared with the control
group (adjusted hazard ratio, 5.02; 95% CI, 3.85-6.55). This re-
sult was adjusted for age and sex.
The use of lithium and PD diagnosis was assessed in a study
by Marras et al11 that used data from the Ontario administra-
tive health care database between 2002 and 2011. The results
showed that compared with antidepressant therapy (285 154
patients), lithium monotherapy (1749 patients) was associ-
ated with an increased risk of antiparkinsonian drug use or PD
diagnosis (adjusted hazard ratio, 1.68; 95% CI, 1.13-2.48). This
result was adjusted for age, long-term care residence, demen-
tia, Charlson Commodity Index score, and antipsychotic use
after the index date. However, the diagnostic code may not dif-
ferentiate PD from other causes of parkinsonism, and cases of
atypical parkinsonism may have been included. Neverthe-
less, patients using an antiparkinsonian medication who had
a history of PD or parkinsonism in the previous 5 years were
excluded. The control group in this study consisted of pa-
tients with unipolar depression, which also increases the risk
of developing PD over time.
Nilsson et al12 assessed psychiatric admissions between
1977 and 1993 among 164 722 patients with multiple psychi-
atric and nonpsychiatric disorders. Patients with the diagno-
sis of mania at discharge were compared with a control group
who had osteoarthritis or diabetes. The difference in the risk
of PD diagnosis in the mania vs control groups was not statis-
tically significant, but among 2007 patients with mania, 7 pa-
tients (0.3%) developed PD. It is important to consider that par-
kinsonism was not excluded in this study, implying that
incorrect diagnoses may have occurred.
A cohort study by Huang et al,13 conducted with data from
2001 to 2009 and with follow-up until 2011, was designed to
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Original Investigation Research
assess the risk of developing PD among people with BD. A total
of 56 340 patients with BD and 225 360 healthy controls were
included. Excluding the diagnosis of PD within the first year
of the observation period, the study found an increased risk
of PD among patients with BD during the follow-up period
(hazard ratio, 5.82; 95% CI, 4.89-6.93).
Forty et al14 conducted a cross-sectional study that en-
rolled 1720 patients with BD who were interviewed regarding
their history of multiple medical conditions, among which PD
was included. The data were compared with data from a simi-
lar population who had unipolar mood disorders (1737 pa-
tients) and a control group (1340 patients). In the BD group, a
0.6% lifetime rate of self-reported PD was found, while in both
the unipolar mood disorder and control groups, the rate of self-
reported PD was 0.1%. This study also found a significant dif-
ference between BD types 1 and 2, with those with BD type 2
having a greater self-reported proportion of PD. This study has
the notable issue of being based on self-reported diagnoses,
an unreliable data collection method. Additionally, the con-
trol group was selected from a different source than patients
with BD and unipolar depression.
An additional cross-sectional study by Kilborune et al15 en-
rolled 4310 patients with BD receiving care in veteran centers
and retrospectively analyzed these patients for PD. This study
found a significantly lower number of patients with PD in the
BD group compared with controls. However, this study was
conducted using a specific subgroup of veterans, and the data
present challenges regarding both their internal and external
validity.
Another cross-sectional study by Smith et al,16 with pa-
tients from primary care practices in Scotland, identified 2582
patients with BD and 1 421 796 patients without PD. The preva-
lence of PD or parkinsonism was higher for patients with BD
compared with the control group (OR, 3.05; 95% CI, 1.83-
5.09). In this cross-sectional study, it is not clear which
diagnosis came first, BD or PD, and the possibility of drug-
induced parkinsonism is not excluded, which may lead to an
overestimation of the risk of PD in the BD cohort.
The risk of bias of the included studies was moderate over-
all. A total of 5 studies were considered to have a low overall
risk of bias (Table 2).
Meta-analysis
We decided to exclude the results from the cross-sectional
study that enrolled a population of veterans15 because of doubts
over internal and external validity. We pooled data reporting
the risk of PD in BD vs non-BD populations, as defined in the
studies, and found that a previous diagnosis of BD signifi-
cantly increased the risk of subsequent PD diagnosis (OR, 3.35;
95% CI, 2.00-5.60; I2 = 92%) (Figure 2). We conducted a sen-
sitivity analysis by removing the studies that had a high risk
of bias, which also showed an increased risk of PD in people
with BD (OR, 3.21; 95% CI, 1.89-5.45; I2 = 94%) (eTable in the
Supplement).
In the subgroup analysis based on the duration of fol-
low-up (Figure 3), we found that both subgroups, ie, those with
more and less than 9 years of follow-up, reported an in-
creased risk of PD (more than 9 years: OR, 1.75; 95% CI, 1.36-
(Reprinted) JAMA Neurology Published online October 14, 2019 E3
 Research Original Investigation Risk of Developing Parkinson Disease in Bipolar Disorder

Table 1. Characteristics of Included Studies

Method of Diagnosis; Age at Onset

Control
Source Study Design Location Population; Age Population BD PD Results
Forty et al,14 Cross-sectional United 1720 Patients with BD and General Medical records using Self-reported Lifetime rate of
2014 Kingdom 1340 controls (70% population DSM-IV and ICD-10; diagnosis of PD; NR self-reported PD,
female); median age in BD median (IQR) age, 20 0.6% in BD group
group, 47 y (7-55) y vs 0.1% in
control group
Huang et al,13 Prospective Taiwan 56 340 Patients with BD General Medical records using Medical records using Adjusted HR,
2019 cohort and 225 360 age-and population ICD-9; median (SD) ICD-9; median (SD) 5.82; 95% CI,
(2001-2011) sex-matched controls; NR age, 39.98 (13.63) y age, 64.25 (11.63) y 4.89-6.93
Kilbourne Cross-sectional United 4310 Patients with BD and US army Medical records using Record linkage Lifetime rate of
et al,15 2004 States 3 408 760 controls (10% veterans ICD-9; NR diagnosis; NR self-reported PD,
female); median age in BD 0.1% in BD group
group, 53 y vs 0.9% in
control group
Lin et al,10 Retrospective Taiwan 1203 Hospitalized patients General Record linkage Record linkage Adjusted OR,
2014 cohort with BD and 220 971 population diagnosis using diagnosis; NR 5.02; 95% CI,
(2001-2009) controls (38% female); NR ICD-9; NR 3.85-6.55
Marras et al,11 Retrospective Ontario, 1749 Patients medicated General Medical records via Record linkage Adjusted HR,
2016 cohort Canada with lithium, 285 154 population lithium medication; diagnosis via 1.68; 95% CI,
(2002-2013) patients medicated with NR antiparkinsonian 1.13-2.48
antidepressants (54% to medication; NR
58% female); NR
Nilsson et al,12 Prospective Denmark 2007 Patients with mania Hospital Medical records; NR Record linkage 7 of 2007
2001 cohort and 162 715 healthy setting diagnosis; NR Patients with
(1977-1993) controls (53% female); mania (0.4%)
median age in mania group, developed PD
50.6 y
Smith et al,16 Cross-sectional Scotland 2582 Patients with BD General Medical records using Record linkage OR, 3.05; 95%
2013 (61% female); median age, population Read Codes; NR diagnosis; NR CI, 1.83-5.09
54.5 y
Abbreviations: BD, bipolar disorder; DSM, Diagnostic and Statistical Manual of Diseases and Related Health Problems; IQR, interquartile range; NR, not
Mental Disorders; HR, hazard ratio; ICD, International Statistical Classification of reported; OR, odds ratio; PD, Parkinson disease.

Table 2. Study Assessment According to Newcastle-Ottawa Rating Scalea

Total
Source Study Design Selection Comparability Exposure/Outcome Score
Forty et al, 14
Cross-sectional NA NA 夹夹 2
2014
Huang et al,13 Prospective cohort 夹夹夹夹 夹 夹夹夹 8
2019
Kilbourne Cross-sectional 夹夹 夹 夹夹夹 6
et al,15 2004
Lin et al,10 Retrospective 夹夹夹夹 夹夹 夹夹 8
2014 cohort
Marras et al,11 Retrospective 夹夹夹夹 夹 夹夹夹 8
2016 cohort
Nilsson Prospective cohort 夹夹夹夹 夹夹 夹夹夹 9
et al,12 2001
Smith et al,16 Cross-sectional 夹夹夹夹 夹夹 夹夹夹 9 Abbreviation: NA, not applicable.
2013 a
Rated on a scale of 1 star to 9 stars.

2.26; I2 = 0%; less than 9 years: OR, 5.20; 95% CI, 4.26-6.35;
I2 = 34%). However, we found a statistically significant differ-
ence between the subgroups, indicating that the subgroup with
the shorter follow-up was associated with a greater increase
in the risk of PD diagnosis. In the subgroup analysis based on
study design and diagnosis certainty, we found both sub-
groups reported an increased risk of PD, although subgroup
analyses did not show a statistically significant difference
between the subgroups.
Given a possible overlap between the participants in 2 of
the included studies,10,13 we conducted a post hoc sensitivity
analysis by removing the study by Lin et al.10 The results were
consistent with the overall results, and there was still a sig-
nificant association of BD with subsequent PD diagnosis (OR,
2.99; 95% CI, 1.50-5.98; I2 = 93%).
A post hoc sensitivity analysis was conducted to include
the single study with a negative association between BD and
PD.15 The results were consistent with the overall results, there
still being an association of BD with subsequent PD diagnosis
(OR, 2.42; 95% CI, 1.35-4.33; I2 = 93%).
Discussion
The findings of this systematic review and meta-analysis sug-
gest that people with BD have a significantly increased likeli-
hood of later developing PD. When placed in the context of
other systematic reviews looking at risk factors for PD, our
statistical evidence is highly suggestive. Only 7 of 38 reviews
included in an overview of systematic reviews presented

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 Risk of Developing Parkinson Disease in Bipolar Disorder Original Investigation Research

Figure 2. Odds Ratios (ORs) for Association of Bipolar Disorder With Parkinson Disease

Favors No Favors Weight,

Study or Subgroup OR (95% CI) Association Association %
Forty et al,14 2014 7.79 (1.00-60.78) 4.8
Huang et al,13 2019 5.82 (4.89-6.93) 21.0
Lin et al,10 2014 5.28 (4.13-6.75) 20.5
Marras et al,11 2016 1.81 (1.38-2.38) 20.3
Nilsson et al,12 2001 1.37 (0.65-2.89) 14.8
Smith et al,16 2013 3.48 (2.22-5.46) 18.5
Total 3.35 (2.00-5.60) 100
Heterogeneity: τ2 = 0.32; χ25 = 63.26;
P < .001; I2 = 92%
Test for overall effect: z = 4.61; P < .001

0.1 1 10
OR (95% CI)

Figure 3. Odds Ratios (ORs) for Association of Bipolar Disorder With Parkinson Disease by Duration of
Follow-up

Favors No Favors Weight,

Study or Subgroup OR (95% CI) Association Association %
>9 y follow-up
Marras et al,11 2016 1.81 (1.38-2.38) 20.3
Nilsson et al,12 2001 1.37 (0.65-2.89) 14.8
Subtotal 1.75 (1.36-2.26) 35.1
Heterogeneity: τ2 = 0.00; χ21 = 0.47; P = .49; I2 = 0%
Test for overall effect: Z = 4.30; P < .001
<9 y follow-up
Forty et al,14 2014 7.79 (1.00-60.78) 4.8
Huang et al,13 2019 5.82 (4.89-6.93) 21.0
Lin et al,10 2014 5.28 (4.13-6.75) 20.5
Smith et al,16 2013 3.48 (2.22-5.46) 18.5
Subtotal 5.20 (4.26-6.35) 64.9
Heterogeneity: τ2 = 0.01; χ23 = 4.53; P = .21; I2 = 34%
Test for overall effect: Z = 16.22; P < .001
Total 3.35 (2.00-5.60) 100
Heterogeneity: τ2 = 0.32; χ25 = 63.26; P < .001; I2 = 92%
Test for overall effect: Z = 4.61; P < .001
Test for subgroup differences: χ21 = 43.34; P < .001

0.1 1 10
OR (95% CI)

results at least as robust as the evidence we present.17 This is
a result of the large number of events in our review, the very
small P values for the association, and the fact that the 95%
CIs of the largest study does not cross the null value.
The pathophysiological rationale between BD and PD might
be explained by the dopamine dysregulation hypothesis,4
which states that the cyclical process of BD in manic states
leads to a downregulation of dopamine receptor sensitivity
(depression phase), which is later compensated by upregula-
tion (manic state). Over time, this phenomenon may lead to
an overall reduction of dopaminergic activity, the prototypi-
cal PD state. This hypothesis justifies the highly suggestive
association we found of BD with PD. Reinforcing the link
between BD and PD is the well-known fact that mood
changes are related to the on-time/off-time phenomena in
PD. In the on-time phase, mania-like symptoms are more
common, unlike the off-time phase, which is more com-
monly associated with depressive symptoms.18 However, it
should be mentioned that BD is not associated with overt evi-
dence of neurodegeneration, and while mood phenomena
fluctuations may be similar, the processes underlying the
on-time/off-time mood states in PD are distinct from sus-
tained abnormal mood fluctuations in BD, including involve-
ment of other neurochemical systems besides dopamine.
It would be of interest to establish the causal relationship
of this association, although this remains elusive. The patho-
physiological rationale would seem to corroborate our find-
ings as well as the reported improvement of motor symptoms
seen with the manic episodes and the worsening of mania with
the dopaminergic medication reported in some studies. There
is also a possibility that the increased risk of PD in patients with
BD derives from long-term lithium use, since most patients
with BD are prescribed the drug for long-term use and, along
with other drugs used in the management of BD, such as an-

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 Research Original Investigation Risk of Developing Parkinson Disease in Bipolar Disorder

tipsychotics, may lead to parkinsonism. However, treatment
with lithium is foundational in BD, and so to separate the causal
effect from a potential confounder would be particularly dif-
ficult. Beyond this, it may be a purely academic effort, as the
very fact that this association is present would already be of
clinical value for patients with BD.
The evidence from subgroup analysis suggests that these
are not spurious findings based on data dredging of health
care databases. The door is open for future research to inves-
tigate the reasons for the association. Is there overlap in
genetic risk factors for BD or PD? Is the risk of developing PD
greater in patients with BD with PD genetic factors, head
trauma, other evidence of synucleinopathies, or other envi-
ronmental exposures? Is BD just one more example of a brain
disorder that is evident earlier in life that confers a risk for a
later neurodegenerative disorder? The study of those with BD
as a high-risk population for developing PD may further be
explored as a form of enrichment for PD populations. Future
studies should be designed to provide a more definitive
answer regarding this association. Ideally, the criteria used
for both the diagnosis of BD and PD should be clearly stated,
as should the age of diagnosis for each disorder. Bearing in
mind the difference in the expected age at onset, the
follow-up period ought to be longer. Also, when necessary,
specific imaging methods should be used to differentiate PD
from drug-induced parkinsonism so there is lower uncer-
tainty regarding PD diagnosis.
Limitations
The main limitation comes from a subgroup analysis showing
a greater likelihood of PD diagnosis in shorter studies, leading
to concern over the misdiagnosis of parkinsonism (probably
drug-induced in origin) as PD and residual confounding. In
fact, one study explicitly did not differentiate between the 2
conditions.16 As the subgroup analysis based on follow-up
time suggests, this contamination may overestimate the
association. However, in the subgroup with longer follow-up,
where the likelihood of misclassification is expected to be
lower, the association was strong and without statistical
heterogeneity. As our results were overwhelmingly based on
real-world medical records, this estimate may be considered
generalizable to the general population. This should reinforce
the importance of the differential diagnosis between parkin-
sonism and PD in the BD population.
It is relevant to explore the statistical heterogeneity in
the included studies. Since the association between these 2
conditions is not commonly looked for, most of the data
came from studies where this was not the primary objective.
This may partially account for the high degree of statistical
heterogeneity found on meta-analysis. It is nonetheless rel-
evant that the overall tendency of the results, as seen on
visual inspection of the forest plot, is apparently homoge-
neous, with all but 2 studies suggesting the association. Addi-
tionally, statistical heterogeneity decreased in the subgroup
analysis, suggesting that the overall heterogeneity is also par-
tially due to the difference between shorter-term and longer-
term studies. As the results of the included studies are based
on large databases with few PD-specific reported characteris-
tics, we were unable to assess other factors that may have
contributed to the observed heterogeneity.
Conclusions
The main clinical implication of this review should be to un-
derline that if patients with BD present with parkinsonism fea-
tures, this may not be drug induced and may recommend the
investigation of PD. To clinically distinguish parkinsonism from
PD in clinical practice, the use of functional neuroimaging
methods may be of particular interest, as PD classically pre-
sents with nigrostriatal degeneration while drug-induced par-
kinsonism does not. Additionally, there are implications for the
care of patients with BD, namely with longitudinal motor as-
sessments, monitoring for prodromal motor or nonmotor signs
of PD, and eventually by parkinsonism risk mitigation via medi-
cation selections and nonpharmacological treatments.
These results may invite many questions from people with
BD and their physicians. Are all subtypes of BD at an equal risk?
Is the risk present even when the diagnosis is made at a young
age? What are the roles of lithium and antipsychotics? We
would be interested in seeing these questions examined in large
prospective cohorts of patients with BD, including detailed
movement disorder evaluations and dopamine transporter
imaging outcomes.

ARTICLE INFORMATION
Accepted for Publication: August 23, 2019.
Published Online: October 14, 2019.
doi:10.1001/jamaneurol.2019.3446
Author Affiliations: Laboratory of Clinical
Pharmacology and Therapeutics, Faculdade de
Medicina da Universidade de Lisboa, Lisbon,
Portugal (Faustino, Duarte, Reimão, Fernandes,
Ferreira); Instituto de Medicina Molecular, Lisbon,
Portugal (Faustino, Duarte, Castro Caldas, Reimão,
Fernandes, Ferreira); Psychiatry Department,
Department of Neurosciences, Hospital de Santa
Maria, Lisbon, Portugal (Chendo); Clínica
Universitária de Psiquiatria, Faculty of Medicine,
University of Lisbon, Lisbon, Portugal (Chendo);
CNS—Campus Neurológico Senior, Torres Vedras,
Portugal (Chendo, Castro Caldas, Ferreira);
Neurology Service, Department of Neurosciences,
Hospital de Santa Maria, Lisbon, Portugal (Castro
Caldas); Neurological Imaging Department,
Hospital de Santa Maria, Lisbon, Portugal (Reimão,
Vale); Neurology Department, Hospital de Beatriz
Angelo, Loures, Portugal (Vale); Department of
Neuroscience, Biomedicine and Movement
Sciences, Università di Verona, Verona, Italy
(Tinazzi); Institute of Neurology, University College
London, London, United Kingdom (Bhatia).
Author Contributions: Drs Duarte and Ferreira had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis. Drs Faustino and
Duarte contributed equally to this study.
Study concept and design: Faustino, Duarte,
Chendo, Castro Caldas, Tinazzi, Bhatia, Ferreira.
Acquisition, analysis, or interpretation of data:
Faustino, Duarte, Chendo, Reimão, Fernandes, Vale.
Drafting of the manuscript: Faustino, Duarte.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Faustino, Duarte.
Administrative, technical, or material support:
Faustino, Duarte.
Study supervision: Ferreira, Duarte, Chendo, Castro
Caldas, Vale, Tinazzi, Bhatia.
Conflict of Interest Disclosures: Dr Tinazzi has
received grants from the Cattolica Foundation,
University of Verona, Verona Brain Research
Foundation, and Zambon as well as personal fees
from AbbVie, International Parkinson and
Movement Disorder Society, Lundbeck, UCB, and
Zambon. Dr Ferreira has received grants and
personal fees from Allergan, GlaxoSmithKline,
Novartis, and Teva Pharmaceutical Industries;

E6 JAMA Neurology Published online October 14, 2019 (Reprinted) jamaneurology.com

© 2019 American Medical Association. All rights reserved.

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 Risk of Developing Parkinson Disease in Bipolar Disorder
grants from Merck Sharp & Dohme, Grünenthal,
and Medtronic; consulting fees from AbbVie,
Acadia Pharmaceuticals, BIAL, Biogen, Ipsen,
Lundbeck, Merck Serono, Merz Pharma, Solvay, and
Sunovion Pharmaceuticals; and personal fees for
serving on the advisory board from BIAL. No other
disclosures were reported.
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