Parkinsonism and Related Disorders 10 (2003) 5965

www.elsevier.com/locate/parkreldis

Review

Systematic review of antidepressant therapies in Parkinsons diseaseq

T.H. Chunga, K.H.O. Deaneb, S. Ghazi-Noorib, H. Rickardsc, C.E. Clarkeb,*
a
Department of Medicine, Kwong Wah Hospital, Kowloon, Hong Kong, China
b
Department of Neurology, City Hospital NHS Trust, University of Birmingham, Dudley Road, Birmingham B18 7QH, UK
c
Department of Psychiatry, Queen Elizabeth Psychiatric Hospital, Birmingham, UK
Received 23 December 2002; revised 19 June 2003; accepted 23 June 2003

Abstract
Depression is the most common psychiatric disturbance in Parkinsons disease. We conducted a Cochrane systematic review to assess the
efficacy and safety of antidepressant therapies in idiopathic Parkinsons disease. Relevant trials were identified from electronic databases,
reference lists and queries to antidepressant manufacturers.
Three randomised controlled trials examined oral antidepressants in 106 patients with Parkinsons disease. No eligible trials of
electroconvulsive or behavioural therapy were found. In the first arm of the crossover trial by Andersen et al. n 22; nortriptyline treated
patients showed a larger improvement than placebo in a unique depression rating scale after 16 weeks although significance levels were not
provided. A parallel group trial by Wermuth et al. n 37 did not show any significant difference between citalopram and placebo in
Hamilton score after 52 weeks. Rabey et al. n 47 performed an open-label trial comparing fluvoxamine with amitriptyline. Similar
numbers in each group had a 50% reduction in Hamilton score after 16 months. Major side effects including visual hallucinations and
confusion were reported with fluvoxamine and amitriptyline.
Insufficient data on the effectiveness and safety of antidepressant therapies in Parkinsons disease are available on which to make
recommendations for their use. Large scale randomised controlled trials are urgently required.
q 2003 Elsevier Ltd. All rights reserved.
Keywords: Parkinsons disease; Depression; Treatment; Randomised controlled trials; Systematic review

Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
3.1. Trial design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
3.2. Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3.3. Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3.4. Concomitant medications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3.5. Outcomes measure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3.6. Antidepressant efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3.7. Effects on Parkinsons disability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3.8. Adverse events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3.9. Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

q
This review is an abbreviated version of one of the authors published in 1. Introduction
the Cochrane Library in electronic form [11]. It is reproduced here with the
permission of John Wiley and Sons.
* Corresponding author. Tel.: 44-121-507-4073; fax: 44-121-507- Physical disability has a clear effect on health-related
5442. quality of life in patients with Parkinsons disease and has
E-mail address: c.e.clarke@bham.ac.uk (C.E. Clarke). consistently been the focus of therapeutic research.
1353-8020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S1353-8020(03)00108-1
60 T.H. Chung et al. / Parkinsonism and Related Disorders 10 (2003) 5965
However, it is becoming increasingly apparent that
psychiatric disorders have a considerable impact on quality
of life. Depression is one of the most common psychiatric
disturbances in Parkinsons disease. Previous studies have
shown that 40% of the observed reduction in quality of life
in Parkinsons disease can be explained by depression [1,2].
Similarly, in the Global Parkinsons Disease Survey 58% of
the observed variation in quality of life could be attributed
to depression compared with only 17% for the management
of physical symptoms [3]. Depression also has a significant
impact on the burden of caregivers [4].
The clinical features of depression include low mood,
anhedonia, pessimistic thoughts, lethargy, sleep disturb-
ance, loss of appetite and weight and depressed facial
appearance. Many of these symptoms are common in
Parkinsons disease patients who are not depressed, often
making the diagnosis of depression in Parkinsons disease
difficult. This is particularly true for the psychomotor
retardation seen in patients with severe depression.
Interestingly though, reviews of studies on depression in
Parkinsons disease has revealed that the profile of
depressive symptoms observed in Parkinsons disease is
not identical to that reported in patients with idiopathic
depression. Depression in Parkinsons disease shows some
distinct features including relatively preserved short term
memory, no association with severity of Parkinsons
symptoms, greater anxiety and lower level of self punitive
ideation [5,6].
At the moment, the pathophysiology of depression in
Parkinsons disease is not clear. It may have an
endogenous origin, perhaps related to the neurotransmitter
changes in the condition or be an exogenous reaction to
disability or a combination of the two. The deficiency of
dopamine in Parkinsons disease cannot fully explain the
mechanism, as its replacement does not resolve
depression except where it occurs as a non-motor
fluctuation. Other neurotransmitters changes have been
recognised. A loss of norepinephrine transmission result-
ing from degeneration of the locus coeruleus and its
projections to frontal cortex and limbic system correlates
with depressive symptoms [7]. In addition, a significantly
lower cerebrospinal fluid level of 5-hydroxyindoleacetic
acid (5-HIAA) in depressed Parkinsonian patients indi-
cates that an impaired serotonin transmission may play a
role in the aetiology [8].
Currently four groups of antidepressants are recognised:
selective serotonin reuptake inhibitors (e.g. citalopram,
sertraline, fluvoxamine), tricyclic and related antidepress-
ants (e.g. amitriptyline, nortriptyline, trazodone), mono-
amine oxidase inhibitors (e.g. phenelzine, moclobemide)
and a miscellaneous category (nefazodone, venlafaxine) [9].
Tricyclic antidepressants and monoamine oxidase inhibitors
indiscriminately inhibit the reuptake of noradrenaline and
serotonin increasing their functional availability. Selective
serotonin reuptake inhibitors have greater potency and
selectivity for inhibiting the reuptake of serotonin. It has
been suggested that some antidepressants (notably selective
serotonin reuptake inhibitors) may exacerbate the physical
symptoms of Parkinsons disease [10]. The common side
effects of tricyclic antidepressants are mostly secondary to
the antimuscarinic activity and result in drowsiness, dry
mouth, constipation and urinary retention. Cardiac arrhyth-
mia is occasionally seen in those vulnerable patients with
underlying heart disease, particularly after taking amitripty-
line. Compared with tricyclic antidepressants, serotonin
selective reuptake inhibitors can cause similar side effects
but with fewer antimuscarinic side effects, less sedation and
less cardiotoxicity in overdosage. However, gastrointestinal
upsets, anorexia with weight loss and hypersensitivity
reactions are common with selective serotonin reuptake
inhibitors usage [9].
Should antidepressant medication fail to control
depressive symptoms or if psychotic symptoms are severe
then electroconvulsive therapy (ECT) may be used.
Cognitive behavioural therapy is used in conjunction
with oral antidepressants or as sole therapy in mild
depression to encourage patients back into a more normal
daily routine and to reduce anxiety and pessimistic
symptoms.
Although many of the above therapies have been used to
treat depression in Parkinsons disease, the general percep-
tion is that little hard evidence of their efficacy and safety
exists [1,5]. The aim of this Cochrane systematic review
was to assess the efficacy and safety of these therapies in
managing depression in Parkinsons disease. This paper is
based on the longer version already published in the
Cochrane Library [11].
2. Methods
We performed electronic searches of the Cochrane
Controlled Trials register (Cochrane Library Issue 3,
2001), MEDLINE (1966 2001), EMBASE (1974 2001),
Psyclit (1974 2001) and CINAHL (1982 2001) databases
for relevant trials. We also wrote to the manufacturers of
antidepressants requesting information on any relevant
clinical trials they may have on their database whether
published or not. The reference lists of all trial reports and
relevant reviews were examined.
Trials were included if they had a randomised controlled
design, were of any duration and examined oral anti-
depressants, ECT or cognitive behavioural therapy (CBT).
Both genders and all ages were included. Patients had to
have a clinical diagnosis of idiopathic Parkinsons disease
(as defined by authors of the trials) and clinical depression
(as defined by the authors of the trials). The information on
outcome measures abstracted from trial reports included:
quality of life (QoL) and health economics assessments;
diagnostic semi-structured interview assessments for
depression; depression rating scales; Parkinsons disease
activities of daily living rating scales; Parkinsons disease
 T.H. Chung et al. / Parkinsonism and Related Disorders 10 (2003) 5965 61

Table 1
Characteristics of included trials

Trials Trial design Active drug(s) Number Mean age Mean Parkinsons Trial
(duration) (dose per day) (male: female) (range) disease duration duration

Anderson Randomised placebo controlled Nortriptyline (25150 mg) 22 (12:7)a 59 yrsa,b (4875)a 6.5 yrsa,b 16 weeks
et al. [12] cross over (8 weeks in each arm
without washout phase)
Rabey Randomised open-label (not stated) Fluvoxamine and amitriptyline 47 (not stated) 75 years (not stated) 7 years Not stated
et al. [13] (78 and 69 mg)
Wermuth Randomised placebo controlled Citalopram (2040 mg for 37 (16:21) 64 years 4479 Not stated 52 weeks
et al. [14] (Acute phase 6 weeks plus ,65 yrs and 1020 mg for
continuous phase 46 weeks) .65 yrs or older)
a
Of those completed the study only.
b
Median.

motor impairment rating scales; adverse event frequency; 3. Results

number of withdrawals due to non-compliance, lack of
efficacy, and side effects.
The methodological quality of the full papers was
assessed independently by two authors and design issues
that could introduce bias were recorded. Disagreements
about inclusion were resolved by discussion. Eligible data
was abstracted on to standardised forms independently by
two authors, checked for accuracy and amalgamated.
Quantitative synthesis of the results was planned but was
not appropriate given the lack of evidence available.
Forty-three trials were identified by the search strategy.
No eligible studies of ECT and behavioural therapy were
found. The three trials matching the inclusion criteria are
summarised in Tables 1 and 2 [12 14].
3.1. Trial design
The trial by Andersen et al. [12] (nortriptyline versus
placebo) was a double-blind crossover study performed in

Table 2
Results of included trials

Trials Active Baseline Co-intervention Measurement Results Dropout Adverse effects

treatment (L -Dopa) (except L -Dopa) tools (%) (number of patients)
of active treatment
groups

Anderson Nortriptyline 2.53.6 g Anticholinergics (1) Anderson (1) Significant improvement 3 (14) (1) Orthostatic hypotension (3)
et al. [12] n 22 scalea at the end p , 0:001
N 22
(2) Neurological (2) A small improvement in (2) Significantly lower mean
signs nortriptyline group in the systolic blood pressure
first arm (p value unknown)
(3) No significant difference
in clinical signsb
Rabey Fluvoxamine vs. 0.5 g Not stated HAM-Dc 60% vs. 55% patients had 20 (43) Confusion and visual
et al. [13] Amitriptyline 50% HAM-D reduction hallucination (7 vs. 10)
N 47 n : 20 vs: 27 (p value unknown)
Tremor (1 vs. 0)
Dry mouth and somnolence
(0 vs. 1)
Wermuth Citalopram Not Dopamine agonists HAM-D, MESc (1) No significant difference 27 (73) Dry mouth (1), palpitation (1),
et al. [14] n 18 stated Benzodiazepines UPDRSd in depression scores increased sweating (4), nausea
N 37 and vomiting (3), diminished
sexual desire (2), diarrhoea (1)e
(2) UPDRS: no significant
difference

N; total number of patients recruited to the trial. n; number of patients for whom data was provided by the authors.
a
Anderson Scale: a unique 0 3 points 31-item rating scale measuring depressive signs and symptoms, median scores was used.
b
Items included posture, gait, general motility, finer movements, rigidity, akninesia and tremor.
c
HAM-D Hamilton Depression Rating score; MES Melancholia Scale.
d
Unified Parkinsons disease Rating scale.
e
UKU Scale side effect scale used in acute phase, the listed side effects were more common than placebo.
62 T.H. Chung et al. / Parkinsonism and Related Disorders 10 (2003) 5965
two neurological outpatient departments in Denmark. The
study was completed in 16 weeks with an 8-week crossover
point and no washout period. Rabey et al. [13] performed an
open-label study in Israel to compare fluvoxamine against
amitriptyline but the exact study duration was not stated.
Wermuth et al. [14] conducted a double-blind controlled
study with a parallel group design to test citalopram against
placebo in six neurological centres in Denmark. The trial
took place over a total period of 52 weeks, which was
divided into an acute phase (first six weeks) and a
continuation phase (the last 46 weeks).
3.2. Participants
A total of 106 patients were studied in the three trials. In
Andersen et al. [12] a total of 22 patients were recruited but
demographic data of only 19 patients who completed the
study was provided (seven women and 12 men, median age
59 years). They had been diagnosed with Parkinsons
disease for a median of 6.5 years. Rabey et al. [13] recruited
47 patients (mean age 75 years, mean Parkinsons disease
duration 7 years). The trial by Wermuth et al. [14]
comprised 37 patients (16 men and 21 women; mean age
64 years).
3.3. Interventions
Nortriptyline was given in the range 25 150 mg daily.
The mean dose of fluvoxamine and amitriptyline were 78
and 69 mg per day, respectively, but the range of each drug
dose within the trial population was unclear. The dose of
citalopram depended on the age and clinical response of
participants. Citalopram 20 40 mg daily was prescribed for
those younger than 65 years old. A half dose was given for
those 65 years or older.
3.4. Concomitant medications
Andersen et al. [12] kept the dose of levodopa constant
(range 2500 3600 mg) for each individual throughout the
study. Seven patients who were on anticholinergics prior to
the study had these continued for the duration of the study.
In Rabey et al. [13] trial levodopa was given at a mean dose
of 500 mg per day. In Wermuth et al. [14] trial the dose of
levodopa was not stated and dopamine agonists were
allowed.
3.5. Outcomes measure
Andersen et al. [12] adopted a self-made 0 3 points 31
item rating scale to measure depression. Another scale
measured neurological signs (e.g. posture, gait, akinesia,
rigidity and tremor). Rabey et al. [13] took a 50%
reduction of the Hamilton Depression Score compared
with baseline as an end point for analysis. Wermuth et al.
[14] employed the Hamilton Depression Score and
the Melancholia Scale for psychiatric assessment and
also the Unified Parkinsons disease Rating Scale (UPDRS)
for neurological assessment. A standardised side effect
recording scale was used in the acute phase of the trial
which was based on the selective serotonin reuptake
inhibitor-related items of the Udvalg for Kliniske Under-
sogelser (UKU) side effect scale [15].
3.6. Antidepressant efficacy
Andersen et al. [12] suggested that nortriptyline
significantly reduced depression p , 0:001 when analysed
on a per protocol basis across the two arms of the study.
Nortriptyline also showed a larger improvement of median
depression score over placebo in the first arm of the
crossover trial (baseline median 26 for both groups,
nortriptyline group 13 and placebo group nine after
treatment) but statistical significance was not calculated.
In the trial by Rabey et al. [13], 55% of the amitriptyline
group (15/27) and 60% of the fluvoxamine group (12/20)
showed a 50% decrease in Hamilton score after mean
treatment period of 16 and 17 months, respectively.
Wermuth et al. [14] reported only a small but significant
reduction p , 0:05 in the Hamilton Depression Scale and
the Melancholia Scale scores in both the citalopram and the
placebo groups between baseline and the end of the acute
phase. There was no significant difference between the two
groups in scores between baseline to end of continuation
phase or end of acute phase to end of continuation phase.
This was true for both per protocol and intention-to-treat
analysis.
3.7. Effects on Parkinsons disability
The patients in the nortriptyline group [12] did not show
any significant difference in posture, gait, general motility,
finer movements, rigidity, akinesia or tremor before and
after treatment. In the citalopram trial [14] no significant
difference was observed in Parkinsons disease symptoms as
assessed by the UPDRS from baseline to acute phase or to
the end of the trial on either per protocol or intention-to-treat
analysis.
3.8. Adverse events
In Andersen et al. [12] trial, mean systolic blood pressure
when standing was found to be significantly lowered by
nortriptyline treatment. However, mean systolic and
diastolic blood pressure was not significantly different in
the recumbent position. Cardiac arrhythmia was not present
in any of the patients and ECG results did not change during
the treatment. Three patients dropped out of the trial: two
complained of dizziness and drop attacks at the beginning of
nortriptyline treatment probably due to orthostatic hypoten-
sion and one after the crossover from the active to the
placebo period because of lack of effect.
 T.H. Chung et al. / Parkinsonism and Related Disorders 10 (2003) 5965
In Rabey et al. [13] eight patients (40%) treated with
fluvoxamine and 12 (45%) treated with amitriptyline
dropped out. This was due to confusion and visual
hallucinations in seven fluvoxamine and 10 amitriptyline
patients, somnolence in one amitriptyline patient, tremor in
one fluvoxamine and dry mouth in one amitriptyline patient.
Wermuth et al. [14] used the UKU scale to monitor side
effects only in the acute phase of the trial. This showed that
inner unrest (7/17), reduced duration of sleep (3/17) and
headache (4/17) were more frequently observed in patients
in the placebo group than in the citalopram group. In
comparison diarrhoea (1/13), increased sweating (4/13),
diminished sexual desire (2/13) and nausea and vomiting (3/
13) were more prominent in the citalopram group. Two
patients who withdrew from the trial in the acute phase
experienced palpitation or mouth dryness.
3.9. Characteristics of excluded studies
The 40 excluded studies [16 58] were excluded because
of lack of control group (22/40), use of a drug not
specifically approved for the treatment of depression (15/
40), inclusion of non-depressed patients (15/40) and
inclusion of patients with secondary Parkinsonism (4/40).
4. Discussion
Only three randomised controlled trials were identified
which examined oral antidepressant therapy in the
treatment of depression in idiopathic Parkinsons disease.
No eligible trials of electroconvulsive or behavioural
therapy were found. Given the small numbers of patients
in the identified studies and flaws in trial design and
reporting, it has to be concluded that insufficient data on
the efficacy and safety of antidepressant therapies in
Parkinsons disease is available on which to make
recommendations for their use. Further trials are required
to examine these issues.
The three included studies suffered from a large number of
flaws in trial design, presentation of results and data analysis.
Only a total of 106 patients were involved in the three studies
and the dropout rate in these relatively short trials ranged
from 14 to 73%. Thus, the results cannot be generalised to the
entire population of patients with depression and Parkinsons
disease. There was also no indication that sample size
calculations were used to determine the number of patients
needed for an expected effect size and so false positive or
negative results could be reached.
The cross-over study examining nortriptyline by Ander-
son et al. [12] did not indicate a washout period so carry
over effects might have occurred. Because of its open-label
design, the study by Rabey et al. [13] was liable to
performance bias. Also, the results of this trial were
published in abstract form so it is difficult to assess their
validity. The procedure for blinding assessors was not clear
63
in Rabey et al. [13] and Wermuth et al. [14] possibly leading
to performance bias. The details of randomisation and
concealment of allocation were not stated in Rabey et al.
[13] and Wermuth et al. [14] Complete baseline character-
istics of the patients were not provided in all three trials so a
comparison between treatment groups was not possible.
This may have led to selection bias.
Anderson et al. [12] used a 31-item scoring system for
depression measurement throughout the study. To our
knowledge, this unique scoring scale had not been tested
for its validity in depression measurement. Besides, the
subgroups median depression scores and their differences in
each arm were listed in a table but statistical significance
was not calculated. Finally, none of the trials assessed
health-related quality of life or health economics outcomes
in spite of the impact of Parkinsons disease on these.
All three trials reported positive effects for nortriptyline,
amitriptyline, fluvoxamine and citalopram in the treatment
of depression in Parkinsons disease, albeit with some
potentially serious side effects. However, fundamental
flaws in the design of these small studies, the presentation
of the results and analysis of the data were found.
Therefore, it must be concluded that insufficient data on
the efficacy and safety of antidepressant therapies in
Parkinsons disease is available on which to make
recommendations for their use. Further trials are required
to examine the efficacy and safety of antidepressant
therapies in Parkinsons disease. Such trials should include
valid number of patients with depression, of sufficiently
long duration and follow the CONSORT [59] reporting
guidelines.
Acknowledgements
The authors thank the following pharmaceutical compa-
nies: Antigen Pharmaceuticals, Ashbourne Pharmaceuticals
ltd, BASF Pharma, Bristol-Mayer Squibb, Cambridge
Laboratories, CP pharmaceuticals Ltd, Generics UK Ltd,
Genus Pharmaceuticals, GlaxoSmithKline, Goldshield,
Hansam Healthcare Ltd, Kent pharmaceuticals Ltd,
Lagap, Lundbeck, Merck, Norton Healthcare, Novartis,
Pfizer, Pharmacia Ltd, Roche, Rosemont Pharmaceuticals
Ltd, Sanofi-Synthelabo, Solvay Healthcare and Sovereign
Medical, Sterwin Medicines for providing additional help in
searching for relevant studies.
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