Vol.1, No.1, 5-10 (2012) Advances in Parkinson’s Disease
Association of adverse effects with monoamine
oxidase type B inhibitor and catechol-o-methyl
transferase inhibitor combination therapy in
Parkinson’s disease patients
Rui Zhang, Danielle C. Spengler, Marie-Helene Saint-Hilaire*, Anna D. Hohler
Department of Neurology, Boston University School of Medicine, Boston, USA;
*Corresponding Author: Marie.Saint-Hilaire@bmc.org
Received 1 July 2012; revised 24 July 2012; accepted 22 August 2012
Currently, levodopa is the most effective and
commonly used medication to control motor
symptoms in Parkinson’s disease (PD). However,
its long-term use is associated with adverse effects
(AEs). Combination therapy of a monoamine
oxidase type B inhibitor (MAOBI) with levodopa
or a catechol-O-methyl transfer ase inhibitor (COMTI)
with levodopa provides benefits to PD patients.
Direct comparison of efficacy and side effect
profiles is complex. The aim of this study is to
investigate the different AE profiles of MAOBI
and COMTI combination therapies. Data used to
analyze the AEs of different PD medications
were retrieved from “The Boston University Me-
dical Center’s Parkinson’s Disease and Move-
ment Disorder Database”. Ten categories of AEs
were compared between patients receiving
MAOBI and COMTI combination treatment. In
total, 87 subjects were included in the analysis.
Out of ten AEs, the presence of dementia was
signifi- cantly different between the MAOBI and
COMTI groups with an OR of 6.9 (COMTI vs
MAOBI, 95% CI 1.3 - 37.0). Motor fluctuations
were also found to be differently distributed in
the two medication groups with an OR of 3.1
(COMTI vs MAOBI, 95% CI 1.0 - 9.8). In this ret-
rospective database analysis of patients treated
with combination treatment for PD, combination
therapy of a COMTI with levodopa was more
likely to be associated with dementia and motor
fluctuations than a MAOBI with levodop a.
Keywords: Catechol-O-Methyl Transferase
Inhibitors; Dementia; Monoamine Oxidase Type B
Inhibitors; Motor Fluctuations; Parkinson ’s Disease
Parkinson’s disease (PD) is a neurodegenerative disorder
[1], characterized by resting tremor, rigidity or stiffness,
bradykinesia and postural instability [2]. While the eti-
ology of PD remains uncertain [3,4], the progressive loss
of dopaminergic neurons in the substantia nigra (SN) is
considered a marker of the motor disorder of PD [5].
Currently, medication therapy is the most widely used
treatment for PD. Several types of medications have been
approved by the US Food and Drug Administration (FDA)
for the treatment of PD, including levodopa (L-Dopa)/
carbidopa (dopa-decarboxylase inhibitor), rasagiline and
selegiline (monoamine oxidase type B inhibitors, MAOBIs),
entacapone and tolcapone (catechol-o-methyl transferase
inhibitors, COMTIs), ropinirole and pramipexole (non-
ergolin dopamine agonists), and amantadine (which has
both anticholinergic and antiglutaminergic properties)
Levodopa is the most effective and commonly used
medication to control motor symptoms in PD [12]. The
long-term treatment of PD using levodopa, however, has
been shown to induce several adverse effects (AEs). The
most common AEs include motor fluctuations (“on-off”
phenomenon), dyskinesia, and psychosis [8,13]. As a
result, other classes of medication, including COMTIs,
MAOBIs, and dopamine agonists, have been widely used
as alternatives or adjuncts in treating PD [14].
Combination therapy of a MAOBI with levodopa has
been proven to decrease the required dosage of levodopa,
improve symptom relief, and reduce “off” time [8,14-17].
However, the combination of a MAOBI with levodopa
has been observed to cause more frequent AEs than levodopa
monotherapy, including dyskinesia, hypotension, nausea,
dizziness, dry mouth, psychiatric abnormalities, and bal-
ance difficulties [7,8,16,18-20].
The combination therapy of levodopa with a COMTI can
increase levodopa duration of action [21], regulate the
Copyright © 2012 SciRes. Openly accessible at http://www.scirp.org/journal/apd/
R. Zhang et al. / Advances in Parkinson’s Disease 1 (2012) 5-10
motor fluctuations, and reduce levodopa dose [8,14,22-26].
Adjunct therapy with a COMTI is also associated with
increased frequency of dopaminergic AEs, including
dyskinesia, nausea, postural hypotension, and hallucina-
tions [8,20,24].
There have been some comparative studies involving
MAOBIs and COMTIs. One randomized, double-blinded
trial involving 687 subjects on levodopa compared the
efficacy and safety between the additions of rasagiline
(MAOBI), entacapone (COMTI), or placebo (levodopa
monotherapy), and found that the overall relative fre-
quency of dopaminergic AEs was similar among the
three groups. Rasagiline was, however, better tolerated
with less early-discontinuation than entacapone and pla-
cebo [27]. A meta-analysis study evaluated the efficacy
and safety of MAOBIs or COMTIs as adjunct therapies
with levodopa. It concluded that the efficacy of combina-
tion therapy was superior to monotherapy with levodopa,
but the incidence of dyskinesia was observed to be
higher in both combination therapy groups than with
monotherapy. However, no direct comparison between
the two adjunct therapy groups was reported [20]. A
meta-analysis review study of 44 clinical trials demon-
strated, through indirect comparison of the drugs, more
dyskinesia and higher overall incidence of AEs with
COMTIs than with MAOBIs [14].
Although these studies have been helpful in elucidat-
ing the differences in the safety profiles of these combi-
nation therapies (MAOBI vs COMTI), available data are
too limited to directly compare them. The aim of this
study is to investigate and compare the difference be-
tween the AE profiles of MAOBIs and COMTIs when
used in combination with levodopa for the treatment of
Data were taken from “The Boston University Medical
Center’s Parkinson’s Disease and Movement Disorder
Database”, a collection of information acquired from
movement disorder patients seen at the Boston Univer-
sity Neurological Associates Clinic. The data collection
form contains three major sections: demographic infor-
mation, relevant disease information and medications.
The relevant disease information section includes the
neurological diagnosis with onset and diagnosis dates,
family history of related disease, and common complica-
tions of disease/therapy. These include compulsive be-
havior, dyskinesia, dementia, depression, freezing, hallu-
cinations, motor fluctuations, orthostatic hypotension,
psychosis, and other autonomic dysfunction. Subjects
were asked about their current and previous medication
use. In addition, subjects were asked about surgical in-
terventions such as Deep Brain Stimulation (DBS) and
pallidotomy to treat their movement disorders.
To be included in the analysis for this study, subjects
had to meet the following inclusion and exclusion crite-
ria. The subject must have a diagnosis of PD in “The
Boston University Medical Center’s Parkinson’s Disease
and Movement Disorder Database”, and have been be-
tween the ages of 18 and 89. (Subjects who were over 89
years old were excluded in order to meet the privacy
regulation for de-identified data research.) Furthermore,
the subject must have been able to provide medication
information, and have had history of current or prior use
of levodopa combined with a MAOBI but never used a
COMTI, or vice versa. Potential subjects were excluded
if they were diagnosed with any movement disorder
other than PD. Subjects who fit the criteria and who were
entered in the database between January 2007 and Janu-
ary 2011 were included in the final analysis. In addition
to complications and medication use, other variables
were included in the analysis as covariates, including
gender, family history, occupation, ethnicity, education
level, other PD medication use, age, and disease dura-
Fisher’s exact test was applied to test whether different
AEs were associated with the different PD medications
(MAOBI vs COMTI). Multivariate logistic regression
models were applied to test whether discovered associa-
tions would still exist after controlling for other possible
confounding factors, such as age, disease duration, edu-
cation level, and other PD medication use. Two models
of multivariate logistic regression were applied: general
model (including all the potential covariates) and step-
wise model (only including those covariates with statis-
tical significance with entry criterion p 0.1 and removal
criterion p > 0.1). Odds ratio (OR) and 95% confidence
interval of OR were calculated to show the strength of
association. To account for occasional missing data in the
database, relative frequency, mean and interquartile
range (IQR) were used to compare distributions of vari-
ous variables in non-missing cohort and sample cohort.
SAS (Statistical Analysis System) 9.1.3, provided by
SAS Institute Inc., was employed to conduct all the data
analysis. Results were considered significant if the two-
tailed p value was < 0.05. This study (H-31069) was de-
termined to be exempt from review by the IRB of Bos-
ton University Medical Campus and Boston Medical
Of the 577 subjects in the database, 87 met all inclu-
sion and exclusion criteria and were included in the data
analysis (Table 1). The reasons for excluding subjects
included: never used a MAOBI or a COMTI (140, 51%),
used both a MAOBI and a COMTI (78, 28%), and were
prescribed a MAOBI or a COMTI without levodopa (58,
21%). In those 87 subjects, 39 took a MAOBI with
Copyright © 2012 SciRes. Openly accessible at http://www.scirp.org/journal/apd/
R. Zhang et al. / Advances in Parkinson’s Disease 1 (2012) 5-10 7
levodopa currently or previously, and the remaining 48
subjects took a COMTI with levodopa currently or pre-
viously (Ta b l e 2 ). In the MAOBI group, an equal num-
ber of subjects took rasagiline and selegiline, in com-
parison with the COMTI group, where the majority took
entacapone (37 out of 47) and only 10 subjects took tol-
capone. In the study cohort, 57% of the subjects were male,
and the majority of subjects were Caucasian (91%), which
is consistent with the incidence disparity of PD in the gen-
eral population [28,29].
Of the 10 recorded AEs, the most frequent was dyski-
nesia (59%), and the least frequent was psychosis (4.6%)
(Figure 1). In this sample cohort, 16 (18%) subjects did
not experience any of the recorded AEs. However, 43%
of subjects were reported to have 3 or more AEs and as
many as 8 AEs were reported in one subject (Table 3).
Table 1. Demographic characteristics of categorical variables
in sample cohort (N = 87).
Items Category Frequency N (%)
Female 37 (43)
(N = 86) Male 49 (57)
Yes 28 (32)
Family History
(N = 87) No 59 (68)
Yes 66 (76)
Other PD medications1
(N = 87) No 21 (24)
Caucasian 78 (91)
(N = 86) others 8 (9)
Not in the Labor Force 59 (71)
(N = 83) Others 24 (29)
Public insurance 45 (58)
(N = 77) Private insurance 32 (42)
Below college 26 (32)
College or associate degree 32 (40)
(N = 81)
Graduate or Professional 23 (28)
No AE 16 (18)
1 AE 12 (14)
2 AEs 22 (25)
(N = 87)
3 AEs 37 (43)
1Other PD medications included anticholinergics, apomorphine, amantadine,
botulinum toxin, dopamine agonists. 2AEs included compulsive behavior,
hallucinations, dyskinesia, motor fluctuations, dementia, orthostatic hy-
potension, depression, other autonomic dysfunction, freezing and psychosis.
Table 2. MAOBI and COMTI medication distributions in sam-
ple cohort.
Combined medication
(N = 87)
N (%)
(N = 85)*
N (%)
Rasagiline 19 (22)
MAOBI 39 (45)
Selegiline 19 (22)
Entacapone 37(43)
COMTI 48 (55)
Tolcapone 10 (11)
*Excluded 1 subject, who had taken both entacapone and tolcapone and 1
subject, who had both taken rasagiline and selegiline.
Figure 1. Relative frequency of ten recorded adverse effects.
Table 3. Distributions of adverse effects in MAOBI and
COMTI groups.
AEs CategoryMAOBI N (%) COMTI N (%)p
Yes 3 (8) 2 (4)
behavior No 36 (92) 46 (96) 0.65
Yes 8 (21) 18 (38)
Hallucinations No 31 (80) 30 (63) 0.10
Yes 23 (59) 28 (58)
Dyskinesia No 16 (41) 20 (42) 1.00
Yes 17 (44) 30 (63)
fluctuations No 22 (56) 18 (38) 0.09*
Yes 2 (5) 16 (33)
Dementia No 37 (95) 32 (67) 0.0012**
Yes 5 (13) 9 (19)
hypotension No 34 (87) 39 (81) 0.56
Yes 7 (18) 9 (19)
Depression No 32 (82) 39 (81) 1.00
Yes 2 (5) 7 (15)
dysfunction No 37 (95) 41 (85) 0.18
Yes 5 (13) 12 (25)
Freezing No 34 (87) 36 (75) 0.18
Yes 2 (5) 2 (4)
Psychosis No 37 (95) 46 (96) 1.00
No AE9 (23) 7 (15)
1 AE 7 (18) 5 (10)
2 AEs10 (26) 12 (25)
Combined AEs
3 AEs13 (33) 24 (50)
*Fisher’s exact test p < 0.1; **Fisher’s exact test p < 0.05.
Copyright © 2012 SciRes. Openly accessible at http://www.scirp.org/journal/apd/
R. Zhang et al. / Advances in Parkinson’s Disease 1 (2012) 5-10
Using Fisher’s exact test to compare the AE profiles of
the different combination treatments, only the frequency
of dementia was found to be statistically significantly
different between the MAOBI and COMTI groups (p =
0.0012, Table 3): subjects who took a COMTI with
levodopa had a higher relative frequency of dementia
compared to subjects who took a MAOBI (33% versus
5%). Motor fluctuations also showed a different distribu-
tion between the two medication groups (p = 0.09): the
COMTI subjects had a higher relative frequency of mo-
tor fluctuations than the MAOBI subjects (63% versus
44%). The differences of relative frequency of other AEs
between the two groups were not statistically significant
in the sample cohort (Table 3).
As subjects could not be randomized as part of this
study design, the distributions of other potential con-
founding factors were compared with available informa-
tion in the database and were included in multivariable
logistic regressions.
Two multivariable logistic models were applied to test
the association between dementia and PD medication
use. Only those subjects with complete data were re-
tained in the analysis (n = 61). The stepwise model only
contained those variables with at least p = 0.1 signifi-
cance level.
Variables of treatment (MAOBI or COMTI) and age
were retained in the stepwise logistic regression model.
The OR of developing dementia was 6.9 (COMTI vs
MAOBI, 95% CI: 1.3 - 37.0).
Based on the general logistic regression model, which
included all of the potential confounding factors with
recorded information, the OR of developing dementia
was 8.0 (COMTI vs MAOBI, 95% CI: 1.2 - 52.6), marking
an increase from 6.9 in the stepwise model. This indi-
cated that after controlling for the potential confounding
factors, the association between dementia and COMTI
was still statistically significant.
Multivariable logistic models were also employed to
test the association between PD medication use and mo-
tor fluctuations. In the stepwise model, with at least p =
0.1 significance level, 2 variables, treatment of MAOBI
or COMTI, and disease duration, were retained in step-
wise logistic regression model. The OR of developing
motor fluctuations was 3.1 (COMTI vs MAOBI, 95% CI:
1.0 - 9.8, p = 0.05). The stepwise statistical model also
suggested that, for a PD subject treated with MAOBI
combination therapy with an average disease duration of
10 years, the probability of experiencing motor fluctua-
tions was 44.8% compared to 71.1% in a similar subject
treated with COMTI combination therapy.
After taking into account all of the potential con-
founding factors with available information in general
regression analysis, the OR of developing motor fluctua-
tions was 3.7 (COMTI vs MAOBI, 95% CI: 1.01 - 13.8),
indicating that the association between motor fluctua-
tions and COMTI became stronger and statistically sig-
nificant after controlling for the potential confounding
factors. Twenty-six subjects were removed from the lo-
gistic regression models because data were incomplete.
Upon examination of the distribution of all testing vari-
ables, no major differences were observed in the two
groups, and all the variables were similarly distributed
between non-missing data cohort and sample cohort.
Results from other studies have indicated that com-
pared to levodopa monotherapy, MAOBI and COMTI
adjunct therapies increase therapeutic effects, reduce
levodopa dose, and are more effective in controlling mo-
tor fluctuations [8,14,16,21-23]. However, the combined
therapies have also been associated with more frequent
AEs, especially dyskinesia [8,14,20]. Despite the wide
use of these medication regimens, few studies have di-
rectly and systematically compared their AE profiles, as
this one has. The results are interesting and incite further
questions and ideas for future prospective comparative
Based on the results of Fisher’s exact test, out of the
10 recorded complications analyzed, only dementia
showed a statistically significant difference among pa-
tients on MAOBI and COMTI combination therapies
with levodopa. Patients on COMTI had a higher relative
frequency of dementia than patients on MAOBI (33% vs
5%) (Table 3).
There are various estimates of the prevalence of de-
mentia (8% - 93%) in PD patients. Cognitive difficulties
can greatly impact the PD treatment plan and influence
the quality of life of PD subjects [30]. In the current
sample cohort, the subjects on COMTI were slightly
older than the MAOBI group; the middle 50% percent of
subjects were 60 - 77 years old in the COMTI group,
versus 59 - 74 years old in the MAOBI group. Since age
is known to be an important risk factor for dementia
[31,32], this difference could slightly impact the associa-
tion of the medications with dementia found in the cur-
rent study. The logistic regression model took the sub-
ject’s age into account. The OR age was 1.1 in the step-
wise logistic regression model, which indicated that, with
an increase of 1 year in age, the risk of dementia would
increase 10%, regardless of the treatment group.
Severity of motor symptoms is also considered to be a
risk factor for dementia [30,31]. This, however, cannot
be estimated using the current database. The Hoehn and
Yahr stage information was only collected for some sub-
jects to record the severiy of PD, and only 25 out of 87
(29%) subjects had an “off” Hoehn and Yahr score, and
therefore provides limited information.
Motor fluctuations, also known as deterioration at the
Copyright © 2012 SciRes. Openly accessible at http://www.scirp.org/journal/apd/
R. Zhang et al. / Advances in Parkinson’s Disease 1 (2012) 5-10 9
end of a dose or wearing-off, consist of fluctuations be-
tween “on” and “off” states. They are prevalent in long-
term PD patients and appear to be an inevitable outcome
of levodopa treatment [33]. In our sample cohort, 54% of
subjects had motor fluctuations. This proportion was
higher in the group on combination treatment with a
COMTI compared to the group treated with an MAOBI
(63% vs 44%, p = 0.09) (Table 3).
Because motor fluctuations increase with the progres-
sion of PD and long-term usage of levodopa, disease
duration should be considered a risk factor for these
fluctuations. In this study, disease duration was signifi-
cantly associated with motor fluctuations with an OR of
1.2 (p < 0.05). This suggests a 20% increase in the risk of
motor fluctuations for every 1 year after the diagnosis of
the disease.
Both COMTI and MAOBI combination regimens with
levodopa have been found to reduce “off” time and mo-
tor fluctuations [8,14-17,22-24]. Our study showed that
COMTI subjects had a higher relative frequency of mo-
tor fluctuations with an OR of 2.2 in the single variable
model (95% CI: 0.9 to 5.1). This association became
significant and stronger (OR = 3.7) after controlling for
confounding factors. These results suggest that compared
to COMTI combination therapy, MAOBI combination
therapy may be better able to control motor fluctuations.
This study relied on available data in the movement
disorders database, which occasionally lacked specific
data points. The current and previous medication use had
to be taken into account as a factor over time. In this
study all AEs included both side effects from medication
and symptoms/signs of the underlying illness; we were
therefore unable to specifically link the causality be-
tween a specific AE and PD medication.
The study design did not allow subjects to be random-
ized into medication groups, which would have ensured
that they were comparable at baseline with respect to
confounding factors. To control for this, we applied mul-
tivariable logistic regression models, which incorporated
potential confounding factors.
Based on the available data, combination therapy with
a COMTI combined with levodopa was more likely to be
associated with dementia and motor fluctuations than a
MAOBI combined with levodopa in PD patients. Physi-
cians pay close attention to side effect profiles when
prescribing medications. These study results may impact
decision making related to PD medication choice in pa-
tients with concomitant dementia or motor fluctuations.
Prospective head to head trials would be useful to further
assess the significance of these adverse effects in vul-
nerable populations.
This work did not receive outside financial support. A. D. Hohler
wishes to disclose that she is currently on the speaker’s bureau for
TEVA pharmaceuticals. The remainder of the authors has no conflicts
of interest to disclose.
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