A controlled trial of antidepressants
in patients with Parkinson disease
M. Menza, MD
R.D. Dobkin, PhD
H. Marin, MD
M.H. Mark, MD
M. Gara, PhD
S. Buyske, PhD
K. Bienfait, PhD
Background: Parkinson disease (PD) is a common neurodegenerative disease affecting up to 1
million individuals in the United States. Depression affects up to 50% of these patients and is
associated with a variety of poor outcomes for patients and their families. Despite this, there are
few evidence-based data to guide clinical care.
Methods: An NIH-funded, randomized, controlled trial of paroxetine CR, nortriptyline, and placebo
in 52 patients with PD and depression. The primary outcomes were the change in the Hamilton
Depression Rating Scale (HAM-D) and the percentage of depression responders at 8 weeks.
Results: Nortriptyline was superior to placebo for the change in HAM-D (p ? 0.002); paroxetine CR
Response rates favored nortriptyline (p ? 0.024): nortriptyline 53%, paroxetine CR 11%, placebo
Nortriptyline was also superior to placebo in many of the secondary outcomes, including sleep, anxiety,
Conclusions: Though relatively modest in size, this is the largest placebo-controlled trial done to
ment of depression and paroxetine CR was not. When compared directly, nortriptyline produced sig-
tors and selective serotonin reuptake inhibitors. Neurology®2009;72:886–892
ARR ? absolute risk reduction; DSM-IV ? Diagnostic and Statistical Manual of Mental Disorders, 4th edition; HAM-A ?
Hamilton Anxiety Scale; HAM-D ? Hamilton Depression Rating Scale; MMSE ? Mini-Mental State Examination; NNT ?
Index; SCID ? Structured Clinical Interview; SSRI ? selective serotonin reuptake inhibitor; TCA ? tricyclic antidepressant;
UPDRS ? Unified Parkinson’s Disease Rating Scale.
Parkinson disease (PD) is the second most prevalent neurodegenerative illness in the United States,
affecting approximately 1 million individuals. While the illness is defined by the motor triad of
tremor, rigidity, and bradykinesia, non-motor features are both common and functionally impor-
tant. Depression, dementia, drug-induced psychosis, impulsivity, and sleep disturbances may all
complicate the course and management of PD and are associated with a variety of poor short and
Address correspondence and
reprint requests to Dr. Matthew
Menza, Robert Wood Johnson
Medical School, D207A, 671
Hoes Lane, Piscataway, NJ 08854
Editorial, page 868
e-Pub ahead of print on December 17, 2008, at www.neurology.org.
From the Departments of Psychiatry (M.M., R.D.D., H.M., M.H.M., M.G., K.B., A.D.) and Neurology (M.M., M.H.M.) at the Robert Wood
Johnson Medical School, UMDNJ-University Behavioral HealthCare (M.M., H.M., M.G.), and the Department of Statistics at Rutgers University
(S.B.), Piscataway, NJ.
Supported by a grant from the National Institute of Neurological Disorders and Stroke (NINDS) RO1NS043144. GlaxoSmithKline provided free
paroxetine CR and matching placebo.
Disclosure: Matthew Menza, MD—research support: National Institutes of Health (NINDS), Astra-Zeneca, Bristol-Myers Squibb, Boehringer
Ingelheim, Forest Laboratories, GlaxoSmithKline, Lilly, Pfizer, Sanofi-Aventis, Sepracor, Takeda Wyeth. Consultant: National Institutes of Health
(NIMH, NINDS), GlaxoSmithKline, Kyowa, Lilly Research Laboratories, Pfizer, Sepracor, Takeda. Speaker: Sanofi-Aventis. Stocks: none. Other
financial: none; Roseanne DeFronzo Dobkin, PhD—research support: National Institutes of Health (NINDS); Humberto Marin, MD—research
support: National Institutes of Health (NINDS), GlaxoSmithKline, Lilly, Sanofi-Aventis, Sepracor, Takeda. Consultant: Lilly Research Laboratories;
Margery Mark, MD: research support: Kyowa, Cephalon. Speaker: Allergan, Boehringer Ingelheim, GlaxoSmithKline, Valeant; Michael Gara, PhD—
none; Steven Buyske, PhD—research support: National Institutes of Health (NIAAA); Karina Bienfait, PhD—none; Allison Dicke—none.
Copyright © 2009 by AAN Enterprises, Inc.
Depression is one of the most common
nonmotor aspects of PD, with a reported
prevalence of approximately 40% to 50%.2It
is of particular importance to these patients
because, in addition to personal suffering, de-
pression is associated with a faster progression
of physical symptoms, a greater decline in
cognitive skills and ability to care for oneself,
poorer treatment compliance and quality of
life, as well as greater caregiver distress.3-5In
fact, depression appears to be more predictive
of distress than motor disability.6
Despite the prevalence and importance of
depression in PD, there are few well-designed
studies that inform treatment.7There are a
variety of open label trials and some older,
methodologically flawed controlled trials, but
a recent Cochrane Review concluded that
there are insufficient data on the effectiveness
and safety of any antidepressant therapies in
PD to allow recommendations for their use.8
Nevertheless, antidepressants are appar-
ently widely used for these patients, with se-
lective serotonin reuptake inhibitors (SSRIs)
being the most commonly used medications.
A survey of physicians in the Parkinson Study
Group found that 26% of the patients with
PD were on antidepressants for depression
and 51% of the physicians used SSRIs as their
first line therapy.9A more recent Veterans Af-
fairs database study found that 63% of pa-
tients with PD and depression were taking
SSRIs, while only 7% were taking tricyclic an-
In order to begin to provide clinical guid-
ance for these patients, we conducted an
NIH-funded, controlled trial of nortriptyline,
paroxetine CR, and placebo in patients with
PD and depression. The primary outcomes
were the change in the Hamilton Depression
Rating Scale (HAM-D), from baseline to end-
point, and the percent responders to each
METHODS Study design. Clintrials.gov identifier: NCT
00062738. Dr. Buyske, Department of Statistics at Rutgers Uni-
versity, carried out the statistical analysis.
Fifty-two patients were enrolled in this 8-week, randomized,
double-blind trial of nortriptyline, paroxetine CR, or placebo.
The primary hypothesis was that patients on active drug would
have a significantly greater decrease in the baseline to endpoint
HAM-D scores and that there would be significantly more re-
sponders in the active drug groups.
Consent procedures and data collection. All procedures
used were approved by the University of Medicine and Dentistry
of New Jersey’s Institutional Review Board. All patients were
evaluated between October 2003 and July 2007.
Patients. Patients were included if they were between the ages
of 35 and 80, had a confirmed diagnosis of PD by research
criteria,11and had a diagnosis on the Structured Clinical Inter-
view12(SCID) for the Diagnostic and Statistical Manual of Men-
tal Disorders 4th ed. (DSM-IV)13of major depression or
Patients were excluded if they had cognitive impairment
(Mini-Mental State Examination [MMSE]14less than 26), were
“off” for greater than 50% of the day, or had any current
DSM-IV Axis I diagnosis other than a depressive or anxiety dis-
order. Patients were not allowed to take any psychotropic medi-
cations other than the study medication during the trial. Patients
who had been nonresponsive to more than one trial of an ade-
quate dose and length of an approved antidepressant were ex-
cluded. Patients were required to maintain a stable dose of the
PD medication that they were on at the start of the trial and all
evaluations were done in the “on” state.
Dosing. Patients were randomized, in variable length blocks, to
equivalent-appearing nortriptyline, paroxetine CR, or placebo.
Dosing was flexible with decisions on dose being made at each
visit (or between visits if the patient was having troublesome side
effects) based on efficacy and tolerability. Paroxetine CR was
started at 12.5 mg and could be increased up to 37.5 mg. Nor-
triptyline was started at 25 mg and could be increased up to 75
mg. Placebo was started at one pill and could be increased up to
Assessments. The primary outcomes were the HAM-D 17-
item15change from baseline and the percent responders. Re-
sponders were defined as patients who had a 50% or greater
decrease in their baseline HAM-D at last observation. All pa-
tients and study personnel were blind to drug assignment. Pa-
tients were assessed on primary outcomes at 2, 4, and 8 weeks.
Secondary outcomes included quality of life, which was as-
sessed using the Parkinson’s Disease Questionnaire (PDQ-8)16
and the Medical Outcome Study Short Form (SF 36),17the
Clinical Global Impression Scale,18the Hamilton Anxiety Scale
(HAM-A),19The Pittsburgh Sleep Quality Index (PSQI),20and
the Unified Parkinson’s Disease Rating Scale (UPDRS).21
We also administered a battery of cognitive tests including
the MMSE,14forward and backward digit span of the Wechsler
Adult Intelligent Test–Third Edition,22the Boston Naming
Test,23the word list recall and recognition subtests of the Wech-
sler Memory Scale–Third Edition24verbal category fluency, and
the Stroop color-word test.25All secondary outcomes were as-
sessed at baseline and at week 8 or at the last visit for those who
Data analyses. An intent-to-treat approach was used in all
analyses and included all 52 patients. The primary outcome of
HAM-D change was evaluated at baseline, 2, 4, and 8 weeks
using a mixed-model repeated measures analysis of variance as
implemented in the MIXED procedure of SAS Version 9.1 with
restricted maximum likelihood estimation.26This analysis as-
sumes that the data that are missing, most of which are attrib-
uted to patient dropout, are missing at random. Fixed effects
were treatment (placebo, nortriptyline, paroxetine CR), time of
Neurology 72 March 10, 2009
assessment (baseline, 2, 4, and 8 weeks), and the treatment by
time interaction. Random subject intercepts were included in
the model. In modeling covariance structure for all analyses,
we chose a continuous AR1structure as a function of the
square root of days from baseline that a given assessment oc-
curred for a given patient. This model yielded the lowest AIC
among all covariate structures examined. The interaction be-
tween treatment and time in the mixed model was of most
interest, since a time effect alone would only indicate im-
provement over time across all three groups, whereas a treat-
ment by time interaction indicates differential improvement
over time, depending on treatment.
For the responder analysis, an LOCF approach was used in
which a clinical response was operationally defined as at least a
50% reduction in the HAM-D score from baseline to 8 weeks.
Clinical response was cross-tabulated with treatment and Fisher
exact test was used to distinguish differences among these
Mixed models analyses were used to analyze secondary vari-
ables. Nominal p values are given for secondary outcomes.
RESULTS Sixty-seven patients signed informed
consent and 15 were screened out for a variety of
reasons (figure 1). Thus, 52 patients, 27 men and 25
women, entered the trial. Fifty of the patients had
major depression, two had dysthymia in addition to
major depression, and two had only dysthymia. The
mean age was 62.8 and the mean duration of PD was
6.6 years. The average dose of medication was 28.4
mg for paroxetine CR, 48.5 mg for nortriptyline, and
2.7 pills for placebo. Other clinical information on
the sample is found in table 1.
Primary outcomes. HAM-D. The mixed effects analysis
of the primary outcome measure, the HAM-D, re-
sulted in a significant effect for treatment by time
interaction [F(6,119) ? 2.99, p ? 0.009], using re-
peated measures collected at baseline and all available
follow-up assessments for all 52 subjects. We then
examined this treatment by time interaction for three
distinct slices of the data set: 2 weeks vs baseline, 4
weeks vs baseline, and 8 weeks vs baseline (table 2).
Table 2 shows the nominal significance level of treat-
ment at each of these three slices (p values are 0.028,
0.022, and 0.005). Table 2 also shows, for each study
group, least-squares means adjusting for other pa-
Table 1Clinical information on patients
Overall (SD)Nortriptyline (SD)Paroxetine CR (SD)Placebo (SD)
62.2 (8.7)62.9 (9.3) 62.8 (8.1)61.4 (9.2)
Age at onset, y
56.1 (9.5) 56.8 (10.0)54.2 (7.8)57.2 (10.8)
Daily dose, mg
2.7 pills (0.14)
Figure 1 Patient flow diagram
Neurology 72 March 10, 2009
rameters in the model, standard deviations, and sig-
placebo, paroxetine CR vs placebo, and nortriptyline
vs paroxetine CR).
In planned contrasts, nortriptyline was superior
to placebo at 2 weeks (p ? 0.029) and at 8 weeks
(p ? 0.002). The 8-week comparison of nortripty-
line and placebo remained significant (p ? 0.05) af-
ter a Bonferroni correction for multiple comparisons.
Paroxetine CR was not superior to placebo at any
point. Nortriptyline was (nominally) superior to par-
oxetine CR at 2 weeks (p ? 0.018) and 4 weeks (p ?
0.016) but not 8 weeks (p ? 0.079).
Table 2 also lists the Cohen’s effect sizes, which
are 1.2 for nortriptyline vs placebo, 1.02 for nortrip-
tyline vs paroxetine CR, and 0.51 for paroxetine CR
vs placebo. The change in the HAM-D scores is
shown graphically in figure 2.
Covariates. We examined the effect of patient age,
gender, and length of illness by adding these data to
the mixed model. There were no significant effects
(all p values ?0.30) for any of these variables.
Responders. The response rates at endpoint, based on
a 50% change in the HAM-D total score, also signifi-
cantly favored nortriptyline: nortriptyline 53%, parox-
etine CR 11%, placebo 24% (Fisher exact p ? 0.024).
In planned contrasts, adjusted for multiple compari-
sons, nortriptyline was superior to paroxetine CR (p ?
0.034). While not an a priori outcome, we did examine
remitter rates, using a HAM-D of 7 or less as a defini-
tion of remitter. The remitter rates were different (nor-
triptyline 41%, paroxetine CR 17%, placebo 12%) but
they did not differ statistically (p ? 0.154).
Number needed to treat. The number needed to treat
(NNT), based on responders, for nortriptyline com-
pared to placebo is 3.5, with an absolute risk reduction
(ARR) of 29%. NNT for nortriptyline compared to
paroxetine CR is 2.4 with an ARR of 42%.
Secondary outcomes. Quality of life. The total SF36
score was not different between groups; however, pa-
tients on nortriptyline reported better social func-
tioning at endpoint (drug by time interaction
p ? 0.0142; planned contrast nortriptyline vs pla-
cebo p ? 0.016). No differences between groups
were found on the PDQ 8.
Disease measures. There were no significant differ-
ences between groups found on the UPDRS.
Sleep. Patients taking nortriptyline reported signifi-
cant improvements in sleep (PSQI) compared to pla-
cebo (drug by time interaction, p ? 0.0021; planned
contrast nortriptyline vs placebo, p ? 0.008).
Anxiety. A significant time by drug interaction was
noted on the HAM-A (p ? 0.0001). In the planned
oxetine CR (p ? 0.007) and placebo (p ? 0.0001) in
alleviating anxiety. Paroxetine CR showed a trend ad-
vantage over placebo (p ? 0.0740).
Overall improvement. There was a significant effect
between treatment arms in the Clinical Global Im-
provement scale (Fisher exact, p ? 0.0297).
Cognition. There was no significant time by drug
interaction on the neuropsychological measures.
Integrity of the blind. To test the integrity of the blind-
ing we asked both the patient and the rater to guess what
Tolerability. There were no differences in the drop-
out rates among the three arms of the trial: nortripty-
line 29%, paroxetine CR 39%, and placebo 35%.
Side effects of the treatments were generally mild or
Figure 2 Change in Hamilton Depression Rating Scale
Table 2Hamilton Depression Rating Scale (HAM-D) changes
Nortriptyline ParoxetinePlaceboNominal p values
HAM-DMeanSDMeanSD Mean SD
10.84 6.2012.456.3615.81 5.780.0020.1650.0790.005
Neurology 72March 10, 2009
moderate. There was a significantly higher average
number of side effects in the paroxetine CR group
compared to placebo (Tukey contrasts, p ? 0.0281)
but no significant differences between nortriptyline
and placebo. The most common side effects are listed
in table 3.
Safety. Safety measures in the trial included measure-
ment of the QTc interval in patients on nortripty-
line, nortriptyline levels, vital signs, and serious
adverse events. The QTc of patients on nortriptyline
decreased nonsignificantly from baseline (423 msec)
to endpoint (422 msec). There was one patient with
a QTc of greater than 450 msec at baseline and two
at endpoint. No patient had a QTc above 500 msec.
Nortriptyline levels ranged between 32 and 138 with
an average of 74.88. There were no significant base-
line to endpoint changes in vital signs in any of the
groups. Six patients developed orthostatic hypoten-
sion at at least one visit in the trial: two on placebo,
two on paroxetine CR, and two on nortriptyline.
None of these patients had falls and none stopped
the trial because of this side effect. There were three
serious adverse events: one patient on paroxetine CR
was hospitalized for fainting—no cause was discov-
ered—and one patient on placebo had a severe wors-
ening of rigidity due to a Parkinson medication
change and another patient on placebo had delirium.
DISCUSSION This is the largest placebo-controlled
medication trial to date in depressed patients with
PD, and the first to compare a dual reuptake inhibi-
tor (nortriptyline) and an SSRI (paroxetine CR). It is
also the largest controlled trial to show that depres-
sion in patients with PD responds to antidepressant
treatment. Nonetheless, it is not large by clinical trial
standards and must be seen as preliminary.
While preliminary, this trial yielded results that
are perhaps surprising and may have significant clin-
ical implications. The treatment effect of nortripty-
line was significant for both the overall change in the
HAM-D and in the percent responders, while parox-
etine CR was not. Furthermore, nortriptyline, when
compared directly to paroxetine CR, produced sig-
nificantly more responders. Nortriptyline was also
superior to placebo on many of the secondary out-
comes while paroxetine CR was not. The effect size
of nortriptyline was large (1.20, based on HAM-D)
and the number needed to treat for nortriptyline was
3.5 based on response status. Both active treatments
were well tolerated, although paroxetine CR did have
significantly more side effects than placebo and nor-
triptyline did not.
Nortriptyline has been widely used in treatment
of depression in the elderly27and was found in one
study to be superior to an SSRI in patients with post-
stroke depression.28The one previous study done
with nortriptyline in depressed patients with PD, a
small crossover study which used an outcome instru-
ment that is not widely validated, did suggest that the
drug is efficacious.29
The etiology of depression in patients with PD is
unclear and any explanation of the apparent superi-
ority of nortriptyline would be speculative. While
there are significant psychosocial stressors intrinsic to
the illness, there are also numerous studies that point
to a neurobiological etiology. There is evidence im-
plicating dopaminergic, serotonergic, noradrenergic,
and cholinergic dysfunction.30In addition, changes
in trophic and inflammatory factors, such as nerve
growth factor and cytokines, which seem to play a
role in clinical depression, have also been associated
A 2005 PET study30provided evidence of a loss of
noradrenergic neurons in the limbic system in pa-
tients with PD and depression, perhaps providing a
possible way of understanding these results. Nortrip-
tyline is a dual reuptake inhibitor, that is, it inhibits
reuptake of both serotonin and norepinephrine,
whereas paroxetine CR, an SSRI, inhibits the re-
uptake of only serotonin. Thus, it is possible that the
mechanism of the apparent superiority of nortripty-
line is its effect on norepinephrine.
Another, admittedly speculative, explanation for
these results may lie in the role of norepinephrine
transporters in the prefrontal cortex. The norepi-
nephrine reuptake transporter is responsible for re-
moving dopamine from the synapse in this area of
the brain.32Blockade of these transporters by agents
such nortriptyline can acutely increase dopamine lev-
els in the frontal cortex,33facilitating dopaminergic
At present, it appears that the SSRIs are the first-
line choice for depression in PD in clinical practice
and that the TCAs are not commonly used.9,10This
study, however, suggests that the SSRI paroxetine
CR is not superior to placebo in patients with PD
and depression and may be inferior to nortriptyline.
Table 3 Side effects
12 0 17
Neurology 72March 10, 2009
The effect size for paroxetine CR on the HAM-D
was medium (0.51); a study with a larger sample size
or of longer duration might have found a significant
effect on this outcome, although paroxetine pro-
duced fewer responders than did placebo. These re-
sults are consistent with the two previous controlled
trials with SSRIs34,35(sertraline and paroxetine) in
PD which, while admittedly methodologically flawed,
did not support the efficacy of these compounds.
However, there are also numerous open-label studies
of paroxetine (non CR)36and other SSRIs7in this
population that have shown good efficacy and low
While only an 8-week trial, the improvement in
the secondary outcomes in this trial is noteworthy.
Patients on nortriptyline had significant improve-
ments in physician-rated overall improvement, social
functioning, sleep, and anxiety. These improvements
are consistent with the descriptive literature in de-
pression that suggests that depression negatively af-
fects these aspects of the patient’s condition.
Furthermore, sleep and anxiety are strongly corre-
lated with overall quality of life5and improvements
in these symptoms may be, by themselves, valuable
The tolerability and safety assessment included in
the trial indicated that both drugs were well toler-
ated. Both drug treatment arms had similar dropout
rates and, although dropout rates of this size are not
unusual in psychopharmacologic trials, their size may
limit the generalizability of the trial. The side effects
were consistent with side effects seen in non-PD
populations. Nortriptyline can increase the P–R in-
terval, QRS duration, and Q–Tcinterval and has
been associated with cardiac arrhythmias.37There
were, however, no significant effects of nortriptyline
on cardiac conduction in this trial. There were also
no significant changes in vital signs in any of the
groups and neither active drug had negative effects
While nortriptyline, given its potential for cardiac
conduction delay, needs to be used cautiously, the
emerging evidence suggests that its benefits are sub-
stantial. The two non-TCA dual reuptake inhibitors
that do not have significant cardiac effects, venlafax-
ine and duloxetine, have not been extensively evalu-
ated in depression in PD. There are ongoing trials
evaluating some of these compounds in PD, so we
await, with interest, the results of these trials. Further
studies, with larger numbers of patients, broader en-
trance criteria, and antidepressants that effect neuro-
transmitters other than serotonin, are needed.
Received March 31, 2008. Accepted in final form August 22, 2008.
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Learn. Earn. Network.
2009 AAN Annual Meeting: An Excellent Value
• Learn about the latest scientific advances in neurology
• Earn valuable CME credit and fulfill Maintenance of Certification requirements
• Network with your peers at exciting social events all week long
• Enjoy the convenience and value of all this and more—in just one meeting
Early registration and hotel deadline is March 20, 2009.
Register today at www.am.com/AM2009.
Neurology 72 March 10, 2009