Medicines Q&As
Q&A 71.3
How should depression be treated in a patient with Parkinson’s
disease?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: November 2011
Background
Depression is the most common psychiatric complication in Parkinson’s disease (PD) and is thought to
affect 40-50% of PD patients. However, there is little exact epidemiological data and rates of
depression between 4% and 70% have been reported (1). Non-motor symptoms can predate the first
occurrence of motor signs by several years and dominate the clinical picture of advanced PD.
However, these symptoms are often poorly recognised and inadequately treated (2). The diagnosis of
depression may not be easy because the symptoms of depression can overlap with, or be mistaken
for, those of PD (3).
There is debate regarding the cause of depression in PD patients. Depression could be exogenous, a
reaction to being diagnosed with a disabling, chronic illness. However, the high rates of depression in
PD patients are not completely explained as a reaction to the stress of the illness. There is no clear
correlation between the level of disability in PD patients and the severity of depressive symptoms (4).
One suggestion is that depression in PD might be associated with a specific loss of dopamine and
noradrenaline innervation in the limbic system (2). The information available suggests that
psychological, behavioral, and physiological factors all contribute to depression in PD (4).
Answer
The treatment of depression in PD should first entail a careful screen for underlying treatable causes
such as hypothyroidism. The incidence of hypothyroidism in PD is increased (5). Some clinicians
recommend checking thyroid-stimulating hormone and free T4 in any PD patient with cognitive,
memory or mood changes, as hypothyroidism may be a cause of treatable dementia (6).
There are many and varied methods for the treatment of depression, however there is a lack of
randomized clinical trials of the treatment of depressed PD patients.
The National Institute for Health and Clinical Excellence (NICE) recommends that the management of
depression in people with Parkinson’s disease should be tailored to the individual, in particular, to their
co-existing therapy (7).
Selective serotonin reuptake inhibitors
The selective serotonin reuptake inhibitors (SSRIs) are considered to be the first choice
antidepressants in PD patients and are the most frequently prescribed first-line class of
antidepressants in PD despite a lack of data on their efficacy in this population (4,5,6). The SSRIs are
preferred because of their tolerability and decreased absence of anticholinergic side effects as
compared with tricyclic antidepressants (TCAs) (1,6).
There is a concern that SSRIs could cause extra-pyramidal effects, although the evidence appears to
be mixed with some studies showing an increase in Parkinsonian type adverse effects with SSRIs and
others showing no change (1,8).
An open study investigated the effect of paroxetine, in doses up to 20mg daily, on motor function and
depressive symptoms in 33 PD patients (9). Paroxetine did not worsen motor function but did reduce
depressive symptoms. One patient showed a marked worsening of tremor after paroxetine treatment.
It was thought that this might have been the result of an additive tremor-inducing effect of paroxetine
as tremor is a frequent side effect of this drug. The authors of this study suggested several reasons for
the sporadic reports of SSRI-induced worsening of motor function in PD. It may be a result of
discontinuing previous tricyclic antidepressants that can have antiparkinsonian effects based on
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anticholinergic properties. Alternatively there may be the existence of an individual susceptibility,
presumably on genetic grounds (9).
An open study of 310 patients investigated the long term effects on motor status of adding sertraline to
the treatment of PD patients with depressive symptoms. The addition of sertraline resulted in a
significant improvement in mood scores that was not accompanied by a significant aggravation of the
motor symptoms of the disease. The most frequent adverse reactions reported were within those
expected for sertraline and other SSRIs in general populations including tremor. The authors
concluded that whilst worsening of tremor could be expected in some patients, sertraline appears as a
relatively safe and effective treatment for depressive symptoms associated with PD. Evidence from
double-blind studies is still needed (10).
Tricyclic antidepressants
Tricyclic antidepressants (TCAs) are effective in treating depression in PD but orthostatic hypotension,
sedation, cognitive and anticholinergic side effects may limit their use. However, their anticholinergic
effects may improve motor symptoms and the sedation can be useful in an agitated patient (1,2).
Recent studies have been undertaken to investigate whether tricyclics and SSRI antidepressants differ
in their efficacy and acceptability in the treatment of depression in PD patients.
SSRIs vs TCAs
The short-term efficacy of desipramine and citalopram was assessed in a double-blind, randomised,
placebo-controlled study of 48 PD patients suffering from major depression (11). Major depression in
PD was greatly improved by 1 month of antidepressant therapy, compared with placebo. In the very
short term there was a better response with desipramine than with citalopram. However, citalopram’s
acceptability was twice as high as that of desipramine. Minor and transient adverse events were
reported twice as frequently by patients on desipramine. The authors concluded that desipramine
could be useful for rapidly alleviating symptoms in PD depression and that both SSRI and tricyclic
antidepressants appear to have an equivalent efficacy profile after 1 month of treatment. However,
given the better acceptability of SSRIs and the slight difference in efficacy compared with TCAs, SSRIs
are also highly valuable for treating PD depression (11).
A single-blind randomised study assessed the effect of 3 months treatment of sertraline or amitriptyline
on depression and quality of life in 31 patients with PD (12). Both sertraline and amitriptyline improved
depressive symptoms but a significant benefit on quality of life was observed only with sertraline. No
difference in the frequency of adverse effects between the two drugs was observed, although
significant side effects (confusion and visual hallucinations in 2 patients) occurred in patients treated
with amitriptyline confirming concerns about the use of TCAs in PD (12).
A randomised, double-blind, placebo controlled trial assessed the effect of paroxetine CR, nortriptyline
or placebo on depression in 52 depressed PD patients over an 8 week period (13). 53% of the
nortriptyline group were classified as responders compared to 11% of the paroxetine CR group and
24% of the placebo group. The treatment effect of nortriptyline was significant for both the overall
change in the depression rating scale and in the percent responders, while paroxetine CR was not.
Nortriptyline was also superior to placebo on many of the secondary outcomes, such as anxiety, while
paroxetine CR was not. The authors concluded that while nortriptyline, given its potential for cardiac
adverse effects, needs to be used cautiously, emerging evidence suggests that its benefits are
substantial. Further studies, with larger number of patients, broader entrance criteria, and
antidepressants that effect neurotransmitters other than serotonin are needed (13).
Dopamine Agonists
Recent studies have emphasized the importance of dopaminergic mechanisms for depression in
patients with PD, giving rise to the rationale for treating depressive symptoms with dopamine agonists
in patients with PD (14).
The authors of an 8 month study investigating the efficacy of pramipexole and pergolide in the
treatment of depression in 41 PD patients demonstrated an antidepressant effect for pramipexole in
the treatment of mild and moderate depression but they were unable to make any conclusions
regarding pergolide. There were a number of limitations to this study, the patient numbers were small
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and the trial was not fully blinded or placebo controlled. The authors concluded that the results should
be verified through a double-blind, placebo controlled study with a larger group of patients (15).
A 14 week multi-centre, randomised, parallel group study evaluated pramipexole compared with
sertraline for the management of depressive symptoms in PD patients without motor complications and
under stable levodopa treatment (16). Both pramipexole and sertraline improved depressive
symptoms, as indicated by a significant reduction in the depression rating scale total score. In a
secondary analysis of the percentage of recovered patients pramipexole was significantly more
effective than sertraline. Whilst there was some improvement in motor symptoms in those patients on
pramipexole, no statistical correlation was found between motor improvement and relief of depressive
symptoms, suggesting that pramipexole might exert an antidepressant activity independent of its effect
on motor symptoms. Although the antidepressant efficacy of sertraline was found to be similar to that
of pramipexole, the patients receiving sertraline experienced more adverse effects, resulting in
treatment discontinuation in 5 patients. The authors concluded that dopamine agonists may be an
alternative to antidepressant drugs for treating depression in PD (16).
A 12 week multi-centre, randomised, double-blind, placebo-controlled trial investigated the effects of
pramipexole on clinically relevant depressive symptoms in 296 patients with PD without motor
fluctuations who were on stable antiparkinsonian treatment (17). The primary outcome was the
change in total score on the Beck depression inventory (BDI; range 1-63, with higher scores
suggesting more severe depression) between baseline and 12 weeks. BDI scores decreased by an
adjusted mean 5.9 points in the pramipexole group and 4.0 points in the placebo group. Whilst
outcome measures showed greater improvement with pramipexole than with placebo, the between
group difference of 2 points on the BDI scale at the end of the study suggests a small treatment effect.
The authors comment that this relatively small difference is not surprising given that patients on
average experienced depression of mild-to-moderate severity, according to baseline BDI scores, which
might have limited the potential size of treatment effect. The authors suggest that this strategy might
offer a combined, although independent, benefit on motor disability, depressive symptoms, and quality
of life. It remains to be established whether optimising the dose of pramipexole in patients with
depressive symptoms already taking this drug can reduce depressive symptoms, and whether the drug
is effective in severe depression. Direct comparisons between antidepressants and dopamine
agonists are needed to compare the effects of these two drug classes on depressive symptoms of
patients with PD (17).
A recent systematic review concluded that although dopamine agonists have recently attracted
attention as a potential treatment for depressive disorder or depressive symptoms in PD patients, there
is as yet insufficient evidence to recommend such a strategy (18). Treatment of depressive symptoms
should be based on interventions with known efficacy in this population. However, emerging evidence
supports further study of the effects of these agents on mood and depressive disorder, as well as other
psychiatric and cognitive symptoms and syndromes in PD (18).
Drug Interactions
Interactions between antiparkinsonian and antidepressant drugs may be a concern. A few cases of
serotonin syndrome and other serious CNS disturbances have been seen when selegiline was given
with tricyclic antidepressants, fluoxetine or venlafaxine (19). The manufacturers of selegiline contraindicate the use of selegiline in patients taking antidepressant drugs (20,21).
The manufacturers of rasagiline recommend that the concomitant use of rasagiline and fluoxetine or
fluvoxamine should be avoided. Serious adverse reactions have been reported with the concomitant
use of SSRIs, SNRIs, tricyclic, tetracylic antidepressants and MAO inhibitors. Therefore, in view of the
MAO inhibitory activity of rasagiline, antidepressants should be administered with caution (22).
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Medicines Q&As
Summary


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Depression is the most common psychiatric complication in Parkinson’s disease
There is limited evidence from randomized controlled trials on the efficacy or safety of
antidepressant therapy in Parkinson’s disease patients.
When choosing treatment consider the possibility of increasing or inducing parkinsonian
symptoms, the adverse effect profile and the potential for interactions with concurrent
medication.
Selective serotonin reuptake inhibitors are considered to be first choice antidepressants in
Parkinson’s disease patients.
Tricyclic antidepressants are effective in treating depression in Parkinson’s disease but their
adverse effect profile may limit their use.
Selegiline is contra-indicated in patients on antidepressants.
Dopamine agonists may have a role in the treatment of depression in Parkinson’s disease
patients.
Limitations
There is limited evidence from randomized controlled trials on the efficacy or safety of antidepressant
therapy in Parkinson’s disease patients. Many of the available studies only include small numbers of
patients and/or short term follow-up.
References
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20)
21)
22)
Lemke MR. Depressive symptoms in Parkinson’s disease. Eur J Neurol 2008;15(Suppl. 1):21-25.
Barone P. Treatment of depressive symptoms in Parkinson’s disease. Eur J Neurol 2011;18(Suppl. 1):11-15
Allain H, Schucks S, Mauduit N. Depression in Parkinson’s disease. BMJ 2000;320:1287-1288
Simuui T, Sethi K. Nonmotor manifestations of Parkinson’s disease. Ann Neurol 2008;64(suppl):S65-S80.
Taylor D, Paton C, Kapur S. editors. The Maudsley Prescribing Guidelines 10th Edition. Informa Healthcare
London; 2009, 407.
Okun MS, Watts RL. Depression associated with Parkinson’s disease. Neurology 2002;58(Suppl 1):S63-S70.
National Institute for and Health Clinical Excellence. Parkinson’s disease. Diagnosis and management in
primary and secondary care. NICE clinical guideline 35 June 2006. Accessed via
http://www.nice.org.uk/nicemedia/live/10984/30087/30087.pdf on 01/08/11
Ferreri F, Agbokou C, Gauthier S. Recognition and management of neuropsychiatric complications in
Parkinson’s disease. CMAJ 2006;175:1542-1552
Ceravolo R, Nuti A, Piccinni A et al. Paroxetine in Parkinson’s disease: Effects on motor and depressive
symptoms. Neurology 2000;55:1216-1218.
Kulisevsky J, Pagonabarraga J, Pascual-Sedono A et al. Motor changes during sertraline treatment in
depressed patients with Parkinson’s disease. Eur J Neurol 2008;15:953-959.
Devos D, Dujardin K, Poirot I et al. Comparison of desipramine and citalopram treatments for depression in
Parkinson’s disease: A double-blind randomized, placebo-controlled study. Mov Disord 2008;26:850-857.
Antonini A, Tesei S, Zecchinelli A et al. Randomized study of sertraline and low dose amitriptyline in patients
with Parkinson’s disease and depression: Effect on quality of life. Mov Disord 2006;21:1119-1122.
Menza M, Dobkin RD, Marin H et al. A controlled trial of antidepressants in patients with Parkinson disease
and depression. Neurology 2009;72:886-892.
Lemke MR. Dopamine agonists in the treatment of non-motor symptoms of Parkinson’s disease: depression.
Eur J Neurol 2008;15(Suppl. 2):9-14.
Rektorova I Rektor I, Bares M et al. Pramipexole and pergolide in the treatment of depression in Parkinson’s
disease: a national multicentre prospective randomized study. Eur J Neurol 2003; 10: 399-406.
Barone P, Scarzella L, Marconi R et al. Pramipexole versus sertraline in the treatment of depression in
Parkinson’s disease. J Neurol 2006;253:601-607.
Barone P et al. Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a
randomised, double-blind, placebo-controlled trial+. Lancet Neurol 2010;9:573-80.
Leentjens AFG. The role of dopamine agonists in the treatment of depression in patients with Parkinson’s
disease. A systematic review. Drugs 2011;71:273-286.
Baxter K (ed), Stockley’s Drug Interactions. [online] London: Pharmaceutical Press
<http://www.medicinescomplete.com/> (accessed on 9/11/11).
Summary of Product Characteristics – Eldepryl. Orion Pharma (UK) Limited. Accessed via
http://www.medicines.org.uk/emc/ on 14/11/11. [Date of revision of text June 2011]
Summary of Product Characteristics – Zelapar. Cephalon Limited. Accessed via
http://www.medicines.org.uk/emc/ on 14/11/11. [Date of revision of text 07 May 2011]
Summary of Product Characteristics – Azilect. Teva Pharmaceuticals Ltd. Accessed via
http://www.medicines.org.uk/emc/ on 14/11/11. [Date of revision of text 25/10/10].
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Quality Assurance
Prepared by
Sarah Fenner
West Midlands Medicines Information Service
Good Hope Hospital.
Date Prepared
16 November 2011
Checked by
Peter Golightly
Trent Medicines Information Service
Leicester Royal Infirmary
Date of check
1 December 2011
Search strategy
 Embase (exp parkinson disease + exp depression)
 Medline (exp parkinson disease + exp depression)
 IDIS ((disorder, depressive nec or depression, neurotic, or reaction, adjustment, depress) and
parkinson’s disease
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