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Citalopram enhances action inhibition systems in Parkinson’s disease


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Presented at OHBM2013 (Seattle)

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Citalopram enhances action inhibition systems in Parkinson’s disease

  1. 1. Citalopram Enhances Action Inhibition Systems in Parkinson’s DiseaseZ Ye1, E Altena1, C Nombela-Otero1, C Housden1, H Maxwell1, T Rittman1, C Huddleston1, CL Rae2,R Regenthal3, BJ Sahakian4, RA Barker1, TW Robbins1,4, JB Rowe1,2,41University of Cambridge, UK 2Medical Research Council Cognition and Brain Science Unit, UK3University of Leipzig, Germany 4Behavioural and Clinical Neuroscience Institute, UKContact Dr poster (No.1189) Dr the Rowe in Parkinson’s disease (PD) is highlighted by the severity ofimpulse control disorders (ICDs). However, subtler impulsivity iscommon even in the absence of ICDs and is likely to be multifactorial.In addition to dopaminergic ‘overdose’1,2 and structural changes3 inthe frontostriatal circuits for motor control, we propose that changesin serotonergic projections to the forebrain also exacerbate theimpairment of response inhibition. Enhancing central serotonintransmission with selective serotonin reuptake inhibitors (SSRIs)might therefore provide adjunctive treatment for behaviouralimpulsivity in Parkinson’s disease.We investigated whether the SSRI citalopram reduces impulsivity andenhances the neural systems mediating response inhibition inParkinson’s disease. We studied two forms of inhibition: (1) restraint,using NoGo events; and (2) cancellation, in terms of the Stop-SignalReaction Time (SSRT). There is strong preclinical evidence fromanimal and human studies that serotonin plays an important role inregulating action restraint4. In contrast, the link between serotoninand action cancellation is less well established. We tested threespecific hypotheses.Hypothesis1: PD impairs both action restraint and cancellation.Hypothesis2: The effect of citalopram on behavioural performancedepends on patients’ disease severity.Hypothesis3: The behavioural effect relates to the enhancement ofinferior frontal cortical activation following citalopram.MethodsParticipants• PD patients (N=21): right-handed.• Controls (N=20): right-handed; no history of neurological orpsychiatric disorders.Table 1: Demographic data, clinical features and neuropsychologicalmeasures (means, SDs and p values of two-sample t tests)Items PD Control P (2-tailed)Sex (M:F) 11:10 12:8 n.s.Age 64 (8) 65 (6) n.s.MMSE 29 (1) 29 (1) n.s.Years of disease 11 (5) -- --UPDRS-III motor 21 (8) -- --Hoehn & Yahr 1.9 (0.4) -- --Levodopa equivalent dose(LED, mg/day)632.6 (310.6) -- --Beck DepressionInventory9.9 (5.5) 3.8 (3.9) < 0.001Simple reaction time (ms) 294 (53) 314 (72) n.s.Choice reaction time (ms) 353 (47) 392 (70) < 0.05Drug and Design• Double-blind randomised placebo-controlled crossover design• Patients (sessions ≥6 days apart): 30mg citalopram (CIT) and placebo(PLA)• Controls (one session): on drug• Citalopram: SSRI that increases extracellular cortical serotonin 4 foldTask and Stimuli• An integrated Stop-Signal and NoGo paradigm with 360 Go trials(75%), 40 NoGo trials (8%) and 80 Stop-Signal trials (SS, 17%, with~50% accuracy).• Go: Subject responded to a left/right black arrow (1000ms) with theirright hand.• NoGo: Subjects withheld a response to a red arrow (1000ms) andauditory tone.• SS: A button press was cued by the left/right black arrow butsignalled to stop by a colour change (to red) and auditory tone after avariable delay. An online tracking algorithm maintained approx. 50%successful inhibition5.Results• Behaviour (Table 2 & Fig.1A): Disease effect (Hypothesis1: controlvs. PD-PLA) and drug effect (Hypothesis2: PD under CIT vs. PLA)were examined respectively with two-sample t-tests and repeated-measures ANOVAs with disease severity, age, LED, and plasmaconcentration of CIT as covariates.• fMRI (Fig.1B): General linear models estimated brain responses tocorrect SS, Go and NoGo trials, commission errors (SS, NoGo andGo trials), and Go omission errors. Contrast maps of SS>Go andNoGo>Go were computed for each group and compared betweengroups (Hypothesis1). We focused on the RIFG which showedinhibition-related activations in controls.• Behaviour-fMRI (Fig.1C): Parameter estimates (betas) were pooledfrom the RIFG for correlation tests between changes in behaviourand changes in frontal activation following citalopram(Hypothesis3).Table 2: Disease effect on behavioural performance (means, SDs and pvalues of two-sample t tests)Parameter Control PD-PLA PD-CIT P (1-tailed)Go RT (ms) 532 (129) 554 (108) 555 (100) n.s.SSRT (ms) 142 (44) 167 (50) 180 (75) 0.05NoGo error 0.06 (0.13) 0.14 (0.13) 0.16 (0.18) < 0.05Go error 0.08 (0.05) 0.14 (0.06) 0.13 (0.08) < 0.001Fig.1A. Behaviouraleffect of CIT(changes of SSRTand NoGo errors)depended ondisease severity(p<0.05).B. The stop-relatedRIFG activationwas significantlyweaker in PD-PLAthan in controls(p<0.05 FWE-corrected).C. CIT-inducedchanges of SSRTand NoGo errorcorrelated with thechanges of inferiorfrontal corticalactivation (p<0.05).Conclusion• PD impairs both action restraint and cancellation.• Effect of citalopram on behavioural impulsivity depends on theseverity of PD and individual difference in inferior frontal corticalactivation.• This study indicates the need for patient stratification in clinicaltrials and serotonergic treatments of impulsivity in PD.References and Funding1. Voon et al. 2011. Curr Opin Neurol 24(4): 324-30.2. Rowe et al. 2008. Brain 131(Pt 8): 2094-105.3. Rae et al. 2012. Neuroimage 62(3): 1675-84.4. Eagle et al. 2008. Psychopharmacology (Berl) 199(3): 439-56.5. Chamberlain et al. 2007. Biol Psychiatry 62(9): 977-84.This work was primarily funded by