Presented in the Impulse Control Disorders in Parkinson's Disease meeting of the Movement Disorder Society (Boston, 2012)

1. Citalopram Improves Response Inhibition
in more severe Parkinson’s Disease
Zheng Ye, Trevor Robbins, Ellemarije Altena, Charlotte Housden, Timothy Rittman,
Cristina Nombela-Otero, James Rowe
University of Cambridge, United Kingdom.
More info: James.Rowe@mrc-cbu.cam.ac.uk (Dr. J. Rowe) or zy250@medschl.cam.ac.uk (Dr. Z. Ye)
Methods
Participants
• PD patients (N = 21; three sessions): 10 females; right handed.
• Healthy controls (N = 20; one session): 8 females; right handed; no
history of neurological or psychiatric disorders.
Table 1: Demographics of patients and controls (means , SDs and p
values)
Background
Parkinson’s disease (PD) is characterized by cell loss of neuromodulatory
projections from the brainstem to cortex and striatum, including
serotonin (5HT) and noradrenaline (NA) in addition to dopamine.
Dopaminergic treatment, although relieving motor syndromes, has
been observed to impair behaviour control and increase impulsivity in
early PD (Cools et al. 2003). In health, both serotonin and
noradrenaline also modulate the neural systems for motor inhibition
impulsivity (Chamberlain et al 2006, 2009; Macoveanu et al., in press).
However, the roles of serotonergic and noradrenergic systems in PD
impulsivity are less well understood.
This study investigated whether serotonergic and noradrenergic
treatments enhance motor response inhibition, using a hybrid Stop-
Signal and NoGo (SNG) task. By combining the classical NoGo and
Stop-Signal Reaction Time (SSRT) paradigms, the new task enables us
to compare action restraint (the inhibition of action before it is made;
NoGo) and action cancellation (the inhibition of action after it is
initiated; Stop-signal) in a single session at the same drug level. We
have previously shown that individuals’ performances and regional
brain activations in the new hybrid task are highly correlated with
their performance when the NoGo and Stop-signal tasks are performed
separately (unpublished data). Here we tested two specific hypothesis.
Hypothesis1: Action restraint (NoGo) and cancellation (SSRT) are both
impaired in PD, more so with advanced disease.
Hypothesis2: Action restraint impairments are influenced by serotonergic
therapy (citalopram) while action cancellation deficits are modulated
by noradrenergic therapy (atomoxetine).
References and Funding
Chamberlain et al. 2007. Biol Psychiatry 62(9): 977-84. Cools et al. 2001.
Cereb Cortex 11(12): 1136-43. Cools et al. 2003. Neuropsychologia
41(11): 1431-41. Logan & Cowan. 1984. Psychol Rev 91 (3): 295-327.
This work was supported by the Wellcome Trust {088324}, Medical
Research Council and the NIHR Biomedical Research Centre.
Conclusion
This study examined two hypotheses regarding the roles of serotonergic
and noradrenergic systems in response inhibition. The results indicate:
For Hypothesis1: Action cancellation (SSRT) is impaired in PD.
For Hypothesis2: Both action cancellation (SSRT) and restraint (NG)
impairments were modulated by serotonergic treatment (citalopram)
although not by the noradrenergic therapy (atomoxetine) in these
subjects. The potential benefit of citalopram emerged with increased
severity of Parkinson's disease
Drugs and Design
• Patients were tested under placebo (PLA), atomoxetine (ATO) and
citalopram (CIT) conditions in three different sessions (at least 6 days
apart) with a randomized double-blinded crossover design.
• Atomoxetine (40 mg): a selective noradrenergic reuptake inhibitor that
increases frontal cortical noradrenaline ~3 fold
• Citalopram (30 mg): a highly specific serotonin reuptake inhibitor that
increases extracellular cortical serotonin 2-4 fold
Task and Stimuli
• In each session there were 360 Go trials (75%), 40 NoGo trials (NG,
8%) and 80 Stop-Signal trials (SS, 17%; approx 50% successful stop).
• Go: Subjects responded to a left/right black arrow on screen by
pressing left/right button (with right hand).
• NG: To a red left/right cue and beep, subjects withheld an action.
• SS: Manual button press response was cued by the left/right arrow but
signaled to stop by an auditory tone and colour change (to red) after a
variable delay. An online tracking algorithm was maintained
convergence on 50% successful cancellation (Chamberlain et al. 2007).
Items Patients Controls P (2-tailed)
Age (years) 64.00 (7.94) 65.30 (5.51) ns
Education (years) 14.57 (3.75) 15.05 (2.42) ns
MMSE 28.86 (1.21) 29.30 (0.90) ns
BDI 10.42 (4.92) 3.80 (3.80) <.001
UPDRS (motor) 20.63 (7.67) -- --
Results
Group effect (Hypothesis 1: controls vs. patients under PLA) and Drug
effect (Hypothesis 2: patients under PLA vs. ATO vs. CIT) were
examined with two-sample t-tests (1-tailed) and repeat-measures
ANOVAs respectively (Table 2). SSRT was calculated with the
integration method (Logan & Cowan 1984) and corrected for
individuals’ Go omission rates. NG error rate (NGRe) was also
corrected according to omission rate.
Group effects
• Patients under PLA tended to be slower than controls in SSRT although
they were equally fast as controls in Go trials (GoRT).
• More errors were observed for patients than controls in Go trials
(GoRe) but not in NG trials (NGRe).
Drug effects
• There were no main effects of Drug (table 2)
• However, new ANOVAs included disease severity (UPDRS) as a
covariate. The new models confirmed interactions between the Drug
and UPDRS (as covariate) for SSRT (F = 3.73, p < 0.05) and for NGRe (F
= 2.86, p = 0.08). Specifically, there were correlations between the
UPDRS and changes in SSRT, as well as between the UPDRS and
changes in NGRe (p<0.05: figure 2).
• For CIT vs. PLA, both SSRT and NGRe differences were negatively
correlated with UPDRS (Figure 1).
• However this pattern was not obtained for ATO vs. PLA.
Table 2: Group and drug effect (means, SDs and p values)
Para-
meters
Controls
Patients
PLA
Patients
ATO
Patients
CIT
Group
(p value)
Drug
(p value)
SSRT
(ms)
143
(45)
166
(52)
184
(87)
177
(76)
.060 ns
NGRe
(%)
1.63
(5.02)
3.59
(3.84)
3.77
(6.70)
5.21
(8.74)
.10 ns
GoRT
(ms)
532
(129)
557
(110)
557
(105)
559
(103)
ns ns
GoRe
(%)
0.78
(0.76)
2.15
(1.56)
2.49
(1.91)
2.12
(2.33)
<.001 ns
NGReCIT–PLA
SSRTCIT–PLA(ms)
UPDRS (motor) UPDRS (motor)
Figure 2: Negative correlations between UPDRS and SSRT/NGRe
differences under CIT vs. PLA