Journal of Geriatric Psychiatry and Neurology
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2004 17: 120J Geriatr Psychiatry Neurol
Albert F. G. Leentjens
Depression in Parkinson's Disease: Conceptual Issues and Clinical Challenges
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120 © 2004 Sage Publications
Parkinson’s disease (PD) is a true neuropsychiatric dis-
ease. Apart from the required motor symptoms, psy-
chopathological symptoms are common and include mood
disorders, anxiety disorders, hallucinations, psychosis,
cognitive deterioration,and dementia.1The obvious expla-
nation for this diverse symptomatology is the fact that the
underlying pathophysiological process in PD is not confined
to the nigrostriatal dopaminergic system but is wide-
spread.2Other parts of the dopaminergic system are
involved as well, as are other neurotransmitter systems,
such as the serotonergic,noradrenergic,and cholinergic sys-
tems.3This review discusses the current views on depres-
sion in PD.
The co-occurrence of depression and PD often leads to the
conceptual discussion whether depressive symptoms should
be seen as an intrinsic part of this disease or as a sepa-
rate disease identity. This discussion is in part due to
semantic confusion, but it also touches some basic con-
ceptual issues of psychiatry as a whole. In its classifica-
tion of psychopathology, the Diagnostic and Statistical
Manual of Mental Disorders(DSM IV) of the American Psy-
chiatric Association (APA) uses the term disorder without
further specification.4Disorders may be diseases, with a
specified etiology, course, and prognosis, or syndromes,
with a specific constellation of symptoms,but no reference
to etiology. As a syndrome, depression can be recognized
as a separate entity in PD, but at the same time it is
intrinsic to this disease, because the 2 conditions share
aspects of their pathophysiology.5
Another point of discussion is the question whether
depression in PD is “organic”or “reactive.”Although intu-
itively plausible, there is no evidence for this distinction,
which may create the false impression that depressions of
presumed reactive origin are not accompanied by physio-
logical changes in the brain,or,vice versa,that psychological
factors are not important in depressions with a presumed
organic origin.Similarly,it creates the false suggestion that
psychotherapy is the preferred treatment in “reactive”
depressions as opposed to pharmacotherapy in “organic”
depressions.Again there is no evidence to support this posi-
tion.A distinction between presumed “organic” and “psy-
chological” etiologies does not contribute to our
understanding of the syndrome, nor does it help us with
diagnostic or therapeutic decisions, and should therefore
be abandoned.5In the past decade, a more integrated,
neuropsychiatric approach to body and mind has been
Depression in Parkinson’s Disease:
Conceptual Issues and Clinical Challenges
Albert F. G. Leentjens, MD, PhD
Background: Depression frequently accompanies Parkinson’s disease (PD) and may have a negative impact on activi-
ties of daily living, cognitive performance, and quality of life. Because of the symptom overlap between the 2 disorders,
it may be difficult to recognize depression in PD. Moreover, the partially shared pathophysiology may make it difficult
to treat depressive symptoms without influencing motor or cognitive function. Objective: To review the current knowl-
edge of the epidemiology, etiology, pathophysiology, and treatment of depression in patients with Parkinson’s disease.
Method: Discussion of recent studies and relevant literature. Conclusion: Not only conceptually but also in terms of
etiology, pathophysiology, and treatment, the relationship between PD and depression remains a challenge.There are
still many questions to be answered. In the therapeutic domain, large, placebo-controlled trials are necessary to eval-
uate the efficacy of antidepressant treatment and allow the development of evidence-based guidelines. (J Geriatr
Psychiatry Neurol 2004; 17:120-126)
Keywords: Parkinson’s disease; depression
From the Department of Psychiatry,Maastricht University Hospital,the
Address correspondence to:Albert F. G. Leentjens, MD, PhD, Consultant
Psychiatrist,Department of Psychiatry,Maastricht University Hospital,
P.O.Box 5800,6202 AZ Maastricht,the Netherlands;e-mail:a.leentjens@
Depression in Parkinson’s Disease / Leentjens
promoted,in which biological and psychological processes
are considered to be thoroughly intertwined.6-8In PD,
such an integrated neuropsychiatric approach should be
DIAGNOSIS AND ASSESSMENT
Major depression, as defined by the criteria of the DSM
IV, and PD have a number of symptoms in common.4
Tiredness and reduced energy,psychomotor retardation and
lack of facial expression, mental slowing, difficulties con-
centrating, reduced appetite, and insomnia may occur in
both depression and PD. This overlap of symptoms may
make it difficult to recognize depression in PD patients.
Many studies have addressed the question whether
depression in PD is characterized by a specific symptoma-
tology that distinguishes it from depression in physically
healthy people or people with other neurological diseases.
So far, no consistent profile of depressive symptoms has
been identified for depression in PD, although anxiety
symptoms may be more prominently present, as well as
dysphoria and irritability,whereas self-blame tendencies,
feelings of guilt, and suicidality are less prevalent.9-14
From a clinical point of view,studies into the sensitivity,
rather than the specificity,of depressive symptoms are more
relevant, because in the clinical situation, the question is
how to recognize depression in a patient with known PD.
The only study that specifically addressed this issue found
that core symptoms of depression, lowered mood, anhe-
donia, and lack of interest also constitute the most sensi-
tive symptoms for depression in PD.Somatic symptoms of
depression had less power to discriminate between
depressed and nondepressed patients, with the exception
of some symptoms, such as reduced appetite and early
morning wakening, which did have high discriminative
There is no general agreement on how to deal with
these somatic symptoms in the assessment of depression
in PD.The DSM IV advises to count all somatic symptoms
toward a major depressive episode except “when they are
clearly and fully accounted for by a general medical con-
make such an attribution.From a pragmatic point of view,
it is advisable to make the syndromal diagnosis of “major
depressive disorder” purely on the basis of reported com-
plaints and observed symptomatology. Ignoring vital or
physical symptoms is no solution to the diagnostic prob-
lem,because as shown above,these symptoms differ among
themselves in terms of diagnostic sensitivity,and some are
indeed sensitive symptoms for depression.15
4In clinical practice, it is hardly ever possible to
The prevalence of depression in PD is high, but there are
large differences in reported prevalences. This may be
due to a number of factors.The first of these is the nature
of the population under study.In community studies,point
prevalences of 2.7% to 7.7% have been reported, which is
2 to 3 times higher than the average prevalence of 1.8% of
major depressive disorder in the elderly population.16-18In
outpatient populations, higher prevalences have been
reported, ranging from 4% to 90%, with an average of
25% to 40%.1,19In some cross-sectional studies, point-
prevalences are used, whereas in others monthly preva-
lences are employed,which may lead to different prevalence
rates. Next, it matters whether an inclusive or an exclu-
sive approach with regard to physical symptoms is followed.
In an inclusive approach,all vital and psychomotor symp-
toms count toward the diagnosis of depressive disorder,irre-
spective of their presumed etiology,whereas in an exclusive
approach,only symptoms that cannot be attributed to PD
count toward this diagnosis.The prevalence of depressive
disorder in PD decreases substantially if an exclusive,
instead of an inclusive,approach is followed.20In older stud-
ies, a cutoff score on a depression rating scale was often
used to establish the diagnosis. Research into the con-
current validity of depression rating scales with the DSM
IV diagnostic criteria shows that cutoff points for screen-
ing and diagnosis are different for patients with various
physical diseases and that higher cutoff scores should be
used than those applied to physically healthy persons.21
Lastly, it matters how strict one is in applying diagnostic
criteria to syndromes that do not fully meet the criteria
of major depressive disorder,such as in dysthymia,coping
problems,lability of affect,mood changes in relation to med-
ication intake or on/off periods,anxiety syndromes,and per-
sonality changes. It may be difficult to classify these
symptoms in terms of DSM criteria.
The different approaches to the assessment of depres-
sion and the interpretation of, and adherence to, diag-
nostic criteria for depression may theoretically result in
both overdiagnosis and underdiagnosis. If pharmacologi-
cal treatment of depression is considered an indicator for
diagnosis,then undertreatment constitutes a serious prob-
lem in clinical practice.A study by Weintraub et al showed
that only 35% of PD patients with depression were receiv-
ing treatment with antidepressants.22
Often, depression has been considered an understand-
able reaction to having to cope with a chronic and debili-
tating disease. However, future PD patients have a 2.4
times higher risk of depression even before the diagnosis
of PD is made. Especially in the last 3 years before diag-
nosis,the incidence of depression rises.23This supports the
hypothesis that PD constitutes a biological risk factor for
depression. Apart from (preclinical) PD being a risk fac-
tor for depression, 2 studies have shown that depression
also predisposes for PD.24,25This is not a finding that is
specific for PD,because depression may also predispose to
a number of other diseases, such as Alzheimer’s disease,
cancer,and cardiovascular diseases.26-29A possible expla-
nation for these findings may be found in the hypothesis
of “allostatic load.”This hypothesis states that depression
is accompanied by an allostatic state, which may lead to
atrophy of nerve cells in the brain,which in turn could lead
to neurodegenerative diseases.30
In patients with PD,the same risk factors for depres-
sion apply as in the general population. These general
risk factors for depression include female sex,higher age,
personal or family history of depression, and comorbid
somatic diseases.31Research has been directed toward
potential disease-specific risk factors for depression in
PD.In the search for disease-specific risk factors for depres-
sion, there is evidence that an earlier age of onset, more
severe disability, the presence of on/off fluctuations, a
higher dose of levodopa, and a family history of PD may
increase the risk of depression in PD.32-36The value of these
findings is uncertain, however, because none of the stud-
ies has corrected for the potential confounding influence
of general risk factors for depression.Variables that appear
to be risk factors in a bivariate approach may not be pre-
dictive in a multivariate approach.In a study that followed
such a multivariate approach and corrected for general risk
factors, the only marker of depression in PD was a right-
sided onset of motor symptoms (left-sided cerebral involve-
ment). This marker had only a marginal additional
predictive effect over a model that included only the gen-
eral risk factors.31Although a small effect, it is interest-
ing from an etiological point of view,because an association
with left-sided brain pathology has also been described in
somatically healthy patients with depression, as well as
in stroke patients.37-39
There still is much controversy about the influence of
anti-Parkinson medication on mood.Anticholinergics gen-
erally improve mood and can even have euphoric effects.
Although there are case histories of depressions induced
by dopa-agonists, the general consensus is that they
improve mood. Recent publications of the antidepressant
effect of pramipexole in patients with PD have led to clin-
ical investigations of the usefulness of pramipexole in the
treatment of depression in non-PD patients.40-42Levodopa
can have both mood-improving and mood-lowering effects.43
Several hypotheses try to provide a pathophysiological
explanation for the higher prevalence of depression in PD
patients,none of which have been empirically tested.The
most well-known are the “serotonergic”and the “dopamin-
ergic” hypotheses. The serotonergic hypothesis was for-
mulated by Mayeux et al in 1984 and is based on the
finding that serotonergic activity in the cerebrospinal
fluid and the brains of PD patients is lowered.44As sero-
tonin has the ability to inhibit striatal dopamine release,
reduction of serotonergic activity is seen as a functional
mechanism compensating for the reduced availability in
the striatum.45At the same time,it is known that a reduced
serotonergic tone is a risk factor for depression.46This may
explain the higher prevalence of depression in PD and the
fact that depression may occur even before the diagnosis.
It also explains the exacerbation of extrapyramidal symp-
toms that may occur during treatment with a selective sero-
tonin reuptake inhibitor (SSRI).47,48
The dopaminergic hypothesis,also described in 1984,
considers degeneration of the mesolimbic and mesocorti-
cal structures of the dopaminergic system as the cause of
depression.These pathways play an important role in the
so-called self-reward systems.Compromising these struc-
tures would increase the risk of depression.49This hypoth-
esis also explains the higher prevalence of depression in
PD and the mood-elevating effects of some of the dopamine
The cholinergic-adrenergic hypothesis is of older date
and is less in line with current views on the pathophysi-
ology of depression. In this theory, depression is seen as a
state of relative cholinergic overactivity in relation to
adrenergic activity.50This theory could also be applied to
depression in PD.Recently it attracted some new interest
after a mood-stabilizing effect of donepezil,a cholinesterase
inhibitor, was demonstrated.51
Other researchers have followed an approach along the
lines of “functional psychopathology” and hypothesized a
more direct link between depressive symptoms and altered
neurotransmitter activities,rather than propose a higher
vulnerability.In both depression and PD,lowered dopamin-
ergic activity in the frontal lobe is associated with psy-
chomotor retardation,reduced noradrenergic activity with
anhedonia,and reduced serotonergic activity with depres-
sive symptoms, anxiety, and insomnia.52For several rea-
sons, this approach is probably too simplistic. It may be
assumed that not the regional absolute activity of one
neurotransmitter but the balance of different neuro-
transmitter activities is responsible for the production of
symptoms.53,54The hypothesis also fails to explain why
some patients do have and others do not have depressive
complaints in spite of similar pathophysiological abnor-
coping strategies also play a role in the complex interac-
tion of biological and psychological factors.55The “vulner-
ability model” is thus a more appealing hypothesis to
explain interindividual differences.
In the past few years, the influence of deep brain
stimulation (DBS) of the subthalamic nucleus (STN) on
mood has shed a new light on depressive symptoms in PD,
but also on mood regulation in general.It has been demon-
strated that STN DBS may lead to improved mood,some-
times progressing to pathological laughter or mania.56-60
Unintentional stimulation of the substantia nigra, or
deeper subthalamic structures,may produce acute depres-
sion, with delusions and even suicidality.61,62These find-
Journal of Geriatric Psychiatry and Neurology / Vol. 17, No. 3, September 2004
Depression in Parkinson’s Disease / Leentjens
ings imply a role for the basal ganglia in mood regulation
that yet has to be explored.It will be a challenge to extend
existing neuroanatomic hypotheses of the pathophysiology
of depression, such as the model of dysfunctional limbic-
cortical pathways proposed by Mayberg, with this newly
discovered role of the basal ganglia.63
Treatment of depression in PD is important because
depression has a negative influence on cognitive per-
formance, activities of daily living, and perceived quality
of life in PD patients.64,65In principle,the same guidelines
for the treatment of depression apply for PD patients as
for somatically healthy patients.In case of mild depression,
the treatment of choice is supportive psychotherapy,which
addresses problems with accepting the diagnosis, coping
strategies,and the emotional consequences for the patient
and the partner of having to deal with the diagnosis.Fur-
thermore,it may stimulate the patient to do physical exer-
cise and engage in social activities.In case of more severe
depression, pharmacological treatment is warranted.66
However, the efficacy of antidepressant treatment of
depression in PD has never been convincingly estab-
lished.67The only 2 published double-blind, randomized
placebo-controlled studies of the efficacy of SSRIs, one
with citalopram and one with sertraline, were character-
ized by very high placebo-responses of up to 80%, with no
significant difference in response between the active and
placebo conditions.68,69A double-blind,placebo-controlled
study of nortriptyline that followed a crossover design
also reported a high placebo-response.Unfortunately,the
statistical analysis was performed in such a way that no
valid conclusions about the efficacy of nortriptyline can be
drawn.70The place of other antidepressants, such as the
reversible monoamine-oxidase-A (MAO-A) inhibitors,also
remains uncertain due to lack of evidence.Apart from the
SSRIs,the APA treatment guideline advises bupropion,a
dopamine reuptake inhibitor, as a first-choice treatment
of depression in PD.66Although this seems a plausible
choice from a theoretical point of view,there is no evidence
for its efficacy in PD,apart from one open study and a case
report.71,72Moreover,bupropion may precipitate a dopamin-
ergic psychosis in PD.73Electroconvulsive therapy (ECT)
remains an option for the treatment of depression in PD.
A number of case reports and case series describe benefi-
cial effects on depression in PD, without negative side
effects, and often even temporary improvement of motor
symptoms.74,75Indeed,ECT has been tried as a treatment
for motor symptoms in PD patients without depression,
with apparent positive results,lasting from several weeks
Looking at the limited number of studies, and their
largely negative results, it is not surprising that 2 sys-
tematic reviews have concluded that there is insufficient
evidence for the efficacy and safety of SSRIs and tricyclic
antidepressants (TCAs) in the treatment of depression in
PD, with the exception of a possible efficacy of nortripty-
The most important consequence of the high placebo-
response in the aforementioned double-blind studies is that
studies that have not followed a placebo-controlled design
will never provide evidence of a superior efficacy of anti-
depressant treatment. It also has implications for our
pathophysiological views on depression in PD, and the
possible mechanism of action of antidepressants. In the
dopaminergic theory, depression is thought to be caused
by deficient self-reward mechanisms,which are located in
the mesocortical and mesolimbic dopaminergic struc-
tures.49Stimulation of the self-reward system can be done
by specific interventions,such as treatment with placebo.
The expectation of reward may result in actual clinical
improvement. The recent finding that PD patients are
also susceptible for placebo response in the treatment of
motor symptomatology provides additional support for
There are case reports and case series describing
potential side effects and interactions of SSRIs. SSRIs
may have a negative influence on motor symptoms.47,48The
incidence of this side effect is unknown,but clinically it is
not presumed very important. Practice guidelines favor
treatment with an SSRI over treatment with TCA because
the risk of impairment of motor function is considered
less a problem than the potential negative influence on cog-
nition and perception because of the anticholinergic prop-
erties of TCAs.66,83Parkinsonism may occasionally occur
during the treatment of depression in a patient not known
to suffer from PD. In these cases, one should be alert for
the possibility that preclinical PD may have become appar-
ent due to the treatment.84Both SSRIs and TCAs may give
rise to a “serotonergic syndrome” when used in conjunc-
tion with selegiline,an irreversible MAO-B inhibitor used
in the treatment of motor symptoms of PD.85Such a sero-
tonergic syndrome is characterized by tremor,hypertonia,
myoclonia, autonomic symptoms, hyperthermia, and hal-
lucinosis.In extreme cases,this my lead to death.The inci-
dence of this complication is estimated at 0.24%.85Three
fatalities have been reported,which were all due to a com-
bination of a TCA with selegiline.85In this respect, SSRIs
appear to be safer than TCAs.
Having addressed these issues,the question remains
how to deal with depressed PD patients in clinical prac-
tice.Even in the absence of scientific evidence for the spe-
cific therapeutic activity of antidepressant treatment,
clinical evidence shows that the patient may still benefit
from antidepressant treatment.Thus,in the absence of bet-
ter options,a trial-treatment with an antidepressant is use-
ful.Both the APA and the American Academy of Neurology
(AAN) favor treatment with an SSRI over treatment with
a TCA.66,83Once the decision to treat is made, it is impor-
tant that the patient is treated adequately. This implies
increasing the dose in case of poor response, and, if this
still doesn’t have the desired effect,a second trial with an
antidepressant of another class. In case the patient does
not improve on an SSRI or experiences unacceptable side-
effects, treatment with a TCA may be a good second
step.66,83Weintraub et al showed that 47% of the PD
patients taking antidepressants still showed signs of
depression and were not treated adequately.22
Depression in PD remains a conceptual, diagnostic, and
therapeutic challenge. Due to the overlapping sympto-
matology of PD and depression, it is often difficult to rec-
ognize depression as a separate entity, while the partly
shared pathophysiology may make it difficult to specifically
treat mood symptoms, without influencing motor or cog-
nitive symptoms. Large placebo-controlled studies are
necessary to further evaluate the potential efficacy of
antidepressant treatment and to allow the development
of evidence-based treatment guidelines. A better under-
standing of the pathophysiology of depression in PD may
also provide valuable information in the pathophysiology
of depressive disorder in general.
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