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Affect in Parkinson's disease: validation of the two-factor approach
  Affect in Parkinson's disease: validation of the two-factor approach Emmanuelle Pourcher a,b,c, ⁎ , Sophie Rémillard a , Henri Cohen a,b a Quebec Memory and Motor Skills Disorders Research Center, Clinique Sainte-Anne, Québec, Canada b Psychology and Cognitive Neuroscience Laboratory, Université Paris Descartes  —  CNRS (UMR-8189), Boulogne-Billancourt, France c Centre de Recherche Université Laval Robert-Giffard, Beauport, Canada a b s t r a c ta r t i c l e i n f o Available online xxxx Keywords: Idiopathic Parkinson's diseaseDepressionHypokinetic factorHyperkinetic factorSerotonergic drugsDopaminergic drugsPlaceboBeck Depression Inventory Depression in Idiopathic Parkinson's disease (IPD) is frequent, dif  fi cult to recognize, under managed and hasa profound impact on quality of life. Current categorization of diagnosis in psychiatry poorly applies to theprotean manifestations of mood disorders presented by parkinsonian patients. In this study we have chosento dissect the state of depressive mood as assessed with the Beck Depression Inventory (BDI) at differentpoints in time of pharmacological interventions using a dimensional approach. The 21 items of the BDI wereclassi fi ed in two new categories or factors:  hyperkinetic   and  hypokinetic  . The hyperkinetic factor included allitems related to unbalanced intrusions of negative feelings and ideas, as well as to behavioral hyperactivity.The hypokinetic factor included all items related to loss of drive for appetitive behaviors and loss of mentaland physical energy. The objectives were to (1) compare different pharmacological treatments on the two-factor approach in PD depression, (2) determine the in fl uence of levodopa therapy on the two-factorapproach, and (3) explore the two-factor approach in placebo conditions. Three sets of analyses using thehypo/hyperkinetic dichotomy favour a neurobiological dissociation of these factors in response topharmacological intervention: symptoms of the hyperkinetic factor are responsive to serotonergic drugswhile those of the hypokinetic one are not and may even show deterioration under SSRIs. In contrast, thehypokinetic factor is responsive to dopaminergic drugs and may show deterioration under serotonergicdrugs. Furthermore, the two factors seem to transiently dissociate on placebo intervention aiming atcorrecting either mood or motor status. The dimensional approach to depression symptomatology may thusbe of heuristic value in probing aminergic modulation of mood in IPD and establishing new correlationsbetween affective and motor symptoms.© 2009 Elsevier B.V. All rights reserved. 1. Introduction There is an increasing tendency to consider Parkinson's disease(PD) as a neuropsychiatric disorder and include depression in theclinical domain of PD (see [1]). The interest in the topic stems fromtwo aspects. The fi rst is that it is nowwell established that depressionhas a major impact on the quality of life of the patients and theirfamilies [2]. The second is an unsatisfactory discrepancy between thescienti fi c rationale of the motor symptoms approach and thenonspeci fi c approach of mood disorders in PD. Although depressionis frequently diagnosed in PD (prevalence of 40%; distinct from asimple maladaptive reaction to diagnosis and motor de fi cit; not welldetected and consequently under-treated), there is a paucity of controlled pharmacological studies assessing antidepressant treat-menteffectsinPD(e.g.,[3]).Anumberofauthorshaveconcludedthatthere are little data on the effectiveness of antidepressant therapy inPD, especially with regards to selective serotonin reuptake inhibitors(SSRI)[4,5].ArecentreportfromtheQualityStandardsSubcommittee of the American Academy of Neurology on depression in PDrecommends the speci fi c use of Amitryptilline to treat depression innondemented PD, as well as three useful tools to screen depression inPD  —  the Beck Depression Inventory, the Hamilton Depression Scale,and the Montgomery Asberg Depression Scale [6].ThelackofSSRIef  fi cacyintreatingdepressioninPDisatoddswiththe serotonin hypothesis of depression in PD patients, whichsrcinates from CSF data with lower 5HIAA levels in depressed vs.non depressed patients [7]. Furthermore, SSRI safety is still the objectof ongoing debates, with many clinical observations of deteriorationof motor status contrasting with objective nonsigni fi cant changes inUPDRS motor scores [8].We acknowledge, implicitly, that some mood disturbances aredirectly linked to the psycho-stimulant effect of dopamine replace-ment therapy (DRT), and that the depressive features in PD cannot allbe attributed to the same temporal and regional pattern of neurochemical disturbances. It is thus the case that the pleiomorph-ism of mood disorders in PD challenges the currently used categoricalclassi fi cation, either in anxious or in affective disorders, as well as inthe so-called premorbid personality classi fi cation.  Journal of the Neurological Sciences xxx (2009) xxx – xxx ⁎  Corresponding author. Clinique Sainte-Anne, 65, rue Sainte-Anne, Québec(Québec), Canada G1R 3X5. Tel.: +1 418 692 2227; fax: +1 418 692 3338. E-mail address: (E. Pourcher).  JNS-11128; No of Pages 5 0022-510X/$  –  see front matter © 2009 Elsevier B.V. All rights reserved.doi:10.1016/j.jns.2009.08.048 Contents lists available at ScienceDirect  Journal of the Neurological Sciences  journal homepage: ARTICLE IN PRESS Please cite this article as: Pourcher E, et al, Affect in Parkinson's disease: validation of the two-factor approach, J Neurol Sci (2009),doi:10.1016/j.jns.2009.08.048  This type of complexity does not  fi nd an easy answer in nonPDpsychopathology and requires new constructs in the evaluation of mood disturbances in PD and in basal ganglia diseases. A two-dimensional approach of mood in PD is thus proposed. It is based onclinical data derived from the systematic use of this approach withnewly diagnosed parkinsonian patients of the Quebec Memory andMotor Skills Disorders Clinic over the last seven years. The studieswere undertaken with the approval of the appropriate local ethicscommittee and in compliance with the Code of Ethical Principles forMedical Research Involving Human Subjects of the World MedicalAssociation (Declaration of Helsinki). All participants gave theirwritten informed consent prior to their inclusion in the studies. 2. Validating the two-factor approach to depression Using a component analysis of the mood scale designed byWidlöcher,  Échelle de ralentissement dépressif   ( Depressive slowing scale )[9],wederivedtwobehavioraldimensionsfordepressivemoodin IPD patients. Factor 1, labeled as the  hyperkinetic   factor, drawstogether high level indices of expressed and perceived emotions(anxiety to novelty, irritability, emotional lability, tearfulness withpleasant events, tearfulness with unpleasant events, painful sensoryacuity). Factor 2, labeled as the  hypokinetic   factor, groups low levelindices of expressed and perceived emotions (apathy, low drive,mental fatigue, affective dullness, low capacity to evoke pleasant orunpleasant memories). The six items in each factor were self-ratedfrom mild to severe (on a three point scale) in a questionnaireadministered to 40 IPD patients (DSM-IIIR criteria for majordepression, and Hamilton Depression score >18). This assessmentwas conducted at baseline and after eight weeks of treatment withSertraline (100 mg/day titrated over 2 weeks).Results showed that 17 patients with IPD were Sertralineresponders after two months, with a 50% abatement (lowering of score) of their Hamilton score, while 13 patients did not respond toSertraline. The major distinction between the nonresponders andresponders was a higher baseline score on the hypokinetic factor onthe part of the nonresponders. In the nonresponders, 5/13 scoredhigher than the other 8 nonresponders on low drive and mentalfatigue items at week 8. Accordingly, the hypokinetic factor seems tobe a predictor of poor or no response to SSRI. These results are inaccordance with a two-factor approach using the  Depressive slowing scale  in the analysis of pharmacological modulation of mood in PD. 3. The two-factor approach using the Beck Depression Inventory  As the  Depressive slowing scale  is not well known, we applied thesame two-factor approach to the 21 items in the Beck DepressionInventory [10], a better known and widely used scale to detectdepression. The BDI-21 is a self-rated questionnaire, with a score from0to3foreachitem,andwithamaximalscoreof63andacutoffscorefordepressionusuallyaround15(seeVisseretal.[11]forapresentationof the psychometric properties).We have adopted a conceptualization of depression similar toWidlöcher's,i.e.,asacomplexbehavioralsummationofinhibitionanddisinhibition.Theseprocessesarepossiblyunderdifferentbiochemicalcontrols. Again, the hyperkinetic factor in the BDI included all itemsaroundunbalancedintrusionsofnegativefeelingsandideas,aswellasbehavioral hyperactivity. The following 13 items are included in thisfactor: sadness, pessimism, failure, guilt, punishment, loss of self con fi dence, self criticism, suicidal ideas, tearfulness, agitation, height-ened alertness in sleep, irritability, and heightened appetite. Thehypokineticfactorincludedallitemsaroundlossofdriveforappetitivebehaviors, loss of mental and physical energy. The following 9 itemsare included in this factor: loss of pleasure, loss of interest,indecisiveness,lossofdrive,moresomnolence,lessappetite,sustainedattention dif  fi culty, fatigue and loss of sexual interest.Theobjectiveofthefollowingstudieswasto(1)comparedifferentpharmacological treatments on the two-factor approach in PDdepression, (2) determine the in fl uence of levodopa therapy on thetwo-factor approach, and (3) explore the two-factor approach inplacebo conditions. 4. Method TheBDIhasbeensystematicallyappliedatentryandasafollowuptool for pharmacological interventions for the last seven years in ourclinic. Three sets of data are presented as instances of differentiationof the two factors described here. Results are presented in terms of mean percentage (%) abatement (reduction of score from baseline)per groups for global BDI score, factor 1 (hyperkinetic) and factor 2(hypokinetic) sub-scores. As commonly used to assess drugs' ef  fi cacyin clinical trials, a signi fi cant improvement in BDI global score andsub-scores was observed when at least 50% abatement from baselineis achieved [12]. 4.1. Study 1: comparison between dopaminergic and serotonergic interventions on the two-factor approach using the BDI in IPD The aim of this study was to compare the clinical ef  fi cacy of threetypes of pharmacological interventions using the two-factor approachwiththe BDI inIPD depression;patients included in thestudyfollowedthe criteria of the UK Brain Bank Criteria for idiopathic Parkinson'sdisease, were within 3 years of the appearance of   fi rst symptoms andhad applied for an inaugural depression diagnosis and/or an earlydisease associated depressive syndrome, with the DSM IV diagnosiscriteria for major depression and a BDI score at Baseline ≥ 15.There were three treatment groups: Citalopram, a selectiveserotonin reuptake inhibitor (SSRI), Venlafaxine, a mixed serotoninandnorepinephrinereuptakeinhibitor(SNRI),andPramipexole,aD 2 /D 3  dopaminergic agonist. The analysis included 10 patients in eachgroup.OnegroupwastreatedwithCitalopramtitratedto20 mgonceadayoverfourweeks(5 mg,10 mg,15 mg).Asecondgroupwastreatedwith Venlafaxine titrated to 150 mg once a day over four weeks(37.5 mg, 75 mg, 112.5 mg); and a third group with Pramipexoletitrated to 1.0 mg twice a day over four weeks (0.25 mg BID, 0.50 mgBID, 0.75 mg BID). This last dosage was selected in reference to anef  fi cacy study of Pramipexole in nondepressed PD patients with anobserved ef  fi cacy at 1 mg BID. Each trial was open label. The drugwasgiven as correction for mood without supportive psychotherapy  — exceptforaweeklycallforevaluationofclinicalglobalimpression.Thethree trials were led at different points in time.Pharmacological correction of depression intervened before anyintroduction of levodopa and anticholinergics were not excludedduring the trials. Patients on Selegiline were excluded from the study.BDI global scores and sub-scores (hyperkinetic and hypokineticfactors) were obtained at 0 and 8 weeks. Demographic and treat-ment-related characteristics of the three groups were compared with t  -tests and are presented in Table 1. 4.1.1. Results The three groups were homogeneous for age, age at onset, sexratio, disease duration and BDI baseline scores as shown in Table 1.  Table 1 Demographic and clinical characteristics of participants.Citalopram n =10Venlafaxine n =10Pramipexole n =10StatisticalresultsMean dosage, mg/day 20 mg 150 mg 2 mgSex ratio women/men 6/4 5/5 4/6Age 62±7.3 64±5.2 61±8.1  p >0.05BDI baseline 18±3.5 19±7.1 18±4.7  p >0.05HY stage 2.1±0.3 1.9±0.3 2±0.4  p >0.052  E. Pourcher et al. / Journal of the Neurological Sciences xxx (2009) xxx –  xxx ARTICLE IN PRESS Please cite this article as: Pourcher E, et al, Affect in Parkinson's disease: validation of the two-factor approach, J Neurol Sci (2009),doi:10.1016/j.jns.2009.08.048  The presence of anticholinergics was not signi fi cantly different acrossthe three groups. Results showed that BDI global abatement was notsigni fi cantly different across the three trials. However, there is atendency for Venlafaxine to be superior over Citalopram andPramipexole on BDI global score. The hyperkinetic and hypokineticfactors responded in different fashion to Citalopram and Pramipexoletreatments: on one hand, an improvement of hyperkinetic symptoms(65% abatement) was observed under Citalopram while hypokineticsymptoms did not change over time (5% abatement). On the otherhand, hypokinetic symptomswere signi fi cantly abated (62% loweringof score from baseline) under Pramipexole while the hyperkinetic didnot (30% abatement). Finally, a signi fi cant abatement of both factorswasobservedunderVenlafaxinetreatment:therewas57%abatementof hypokinetic score and 63% abatement of hyperkinetic scorerespectively. Fig. 1 shows the results of this study. 4.1.2. Discussion Although the three pharmacological treatments can be all consid-ered as antidepressant, the results showed that Citalopram (SSRI) haslittle effect on the hypokinetic factor in contrast to the hyperkineticfactor. Pramipexole (D 2  D 3  agonist) is poorly effective on thehyperkinetic factor in contrast to hypokinetic, while Venlafaxine(SNRI) appears to have a balanced effect on these two factors. Theseresults support a chemical dissociation of the neurobiological mechan-isms underlying the respective expression of the two factors inParkinson's disease. The hypokinetic factor (anergia/anhedonia)seems to respond to dopaminergic drugs and may, in some cases,deteriorate under serotonergic drugs, while the hyperkinetic factorappears to respond to serotonergic drugs. 4.2. Study 2: the two-factor approach using the BDI in levodopa therapyin IPD The aim of this study was to determine the in fl uence of levodopatherapyusingthetwo-factorapproachwiththeBDIinIPD.Analysisof mood change was carried out prospectively in 40 IPD patients,nondepressed, not demented, with levodopa therapy initiation andtitration over three weeks, in an open label manner  —  levodopa beingpresentedasacorrectorforparkinsonianmotorsymptoms.BDIscoreswere obtained at baseline and after 12 weeks of treatment. Demo-graphicandclinicalcharacteristicsoftheparticipantsarepresentedinTable 2. 4.2.1. Results Fig. 2 shows the percentage of abatement(reduction of score frombaseline) on BDI global score, factors I (hypokinetic) and factor II(hyperkinetic) sub-scores of the IPD group. The  fi ndings revealed asuperior ef  fi cacy of levodopa on the hypokinetic (82% abatement)relative to the hyperkinetic factor (7% abatement), while global BDIscores improved in a mild to moderate manner (35% abatement). 4.2.2. Discussion These observations showed that the symptoms of the hypokineticfactor were signi fi cantly responsive to levodopa correction, incontrast to symptoms of the hyperkinetic factor. Considering theseresults, levodopa is not an effective antidepressant when BDI globalscores are taken into account, but it may have a signi fi cant impact onsome aspects of depression when the two-factor approach isconsidered. This adds weight to our previous observation, showingthat drugs, which act on dopaminergic pathways, are more effectiveon symptoms of the hypokinetic factor (anergia/anhedonia). 4.3. Study 3: the two-factor approach using the BDI in placebo trials The aim of this study was to use the two-factor approach inplacebo conditions and examine the effect of the patients' expecta-tions about treatment effects on depression scores. The analyses wereconductedusingretrospectivedataobtainedintwodifferentplacebo-controlled double blind studies, led at different times within awindow of three years and on various PD groups at the QuebecMemory and Motor Skills Disorders Research Center.The BDI scores of 20 patients were selected from two studies( n =10, each): one study controlling ef  fi cacy and safety of anantiparkinsonian drug with indirect D 2  stimulating properties, theother controlling ef  fi cacy and safety of a non selective Norepineph-rine/Serotonin reuptake inhibitor antidepressant drug on majordepression in IPD patients, over a 12-week trial. PD patients withsuicidal ideation were excluded from the last study. Fig. 1.  Abatement on BDI scores after 8 weeks under three pharmacological treatments.  Table 2 Demographic and clinical characteristics of IPD participants.IPD patients n =40Age 72±7Sex ratio women/men 27/13Dopa daily dose at week 8 (mg) 378±52BDI global score at baseline 9±3.7 Fig. 2.  Abatement on BDI global score and on Hypokinetic (Factor I) and Hyperkinetic(Factor II) subscores under levodopa therapy.3 E. Pourcher et al. / Journal of the Neurological Sciences xxx (2009) xxx –  xxx ARTICLE IN PRESS Please cite this article as: Pourcher E, et al, Affect in Parkinson's disease: validation of the two-factor approach, J Neurol Sci (2009),doi:10.1016/j.jns.2009.08.048  BDI Scores were retrospectively analyzed at baseline, 6 and12 weeks for the 10 patients in each trial who had been randomizedtoPlacebo.Theantiparkinsoniandrugwaspresentedasacorrectorformotorsymptomsandwasgivenforaforeseendurationof3 monthsinnondepressed PD patients. The antidepressant drug was presented asa corrector for depression, in depressed PD patients and was given fora foreseen duration of 3 months in a double blind placebo-controlledmanner. The demographic and treatment-related characteristics of the patients in each study are presented in Table 3. 4.3.1. Results Patients in the two groups were selected to obtain homogeneouscomparators; they differed in BDI baseline scores only. In the twoplacebo conditions, the two factors behaved differently over time,with an observed dissociation at six weeks, which was not seen at12 weeks. Percentageof abatementon BDI factors I (hypokinetic) andII (hyperkinetic) are presented in Fig. 3. 4.3.2. Discussion These data sustain the idea that neurobiological mechanism of placebo effect in PD could be distinct with different expectations of pharmacological intervention. Accordingly, this showed that theprinciple of a double dissociation on the two factors may be a validone. 5. General discussion The aim of the studies was toexplore the state of depressivemoodin IPD patients applying a two-factor approach to the BDI at differentpoints in time of pharmacological interventions. The observationsshowed a clear dissociation between the hypokinetic and hyperki-netic factors in response to pharmacological interventions fortreatment of depressive mood in PD. Study 1 exempli fi es how theabatement on the hypokinetic factor differs between dopaminergicand serotonergic interventions. Study 2 exempli fi es the moodelevating effect of levodopa on a subset of symptoms belonging tothe semiology of depressive mood  —  although this correctivetreatment is not a classical antidepressant, either in PD nor in nonPDpatients.Thethirdstudyexempli fi esadistinctevolutionofthetwofactors in a non pharmacological intervention based on the placeboeffect(depressedPDvs.nondepressedPD).Thisdissociationopensupa possible hypothesis about the activation of distinct chemo-anatomical mechanisms by mental states and suggests that distinctbiological mechanisms may be put to contribution depending on thelevel and type of expectation in the same disease.The design of these two factors comes from a basic interpretationof the polarity of behavior, normally integrated in basal ganglia in acombination of adaptative behavior, but eventually uncoupled insituations of dopaminergic deafferention: akinesia and reduction of self-generated behavior, with anergia, fatigue, loss of interest, socialwithdrawal, on one hand, hyperkinesia and hyperreactivity of there fl exive repertoire to exo/endogeneous stimuli on the other hand.This uncoupling between drive and disinhibition is further enhancedin cases of defective frontal control over basal ganglia integrationmechanisms, a situation common to anxious disorders, depressionand psychosis  —  although with different time scale.The interest of the dissociation between the two factors comesfrom a possibly distinct pharmacological control with currentlyavailable aminergic modulators used in the treatment of depressionandPD.Thehypokineticfactor(anergia/anhedonia)seemstorespondto dopaminergic drugs and may, in some cases, deteriorate underserotonergic drugs, while the hyperkinetic factor appears to respondto serotonergic drugs.This is to be put in parallel with what we learned from biologicalpsychiatry in non PD populations: low CSF HVA correlates withpsychomotor slowing and is found only in retarded depression withaxial slowness [13,14]; dopaminergic drug addition strategy is necessary in  “ atypical depression ”  characterized by somnolence,weight gain, anergia and fatigue [15]. Low CSF 5HIAA correlates only with dishinibition of aggressiveness and suicidality either inborderline arsonists or in depressed individuals [16].SSRI ef  fi cacy and larger effect on depressive symptoms in non PDpopulations may depend on ef  fi cient secondary regulatory control of dopaminergic function, as a result of normalized cortical function witheffectiveNE/DAand5HT/DAinteractionsatmesencephalic,striatal,andcorticoprefrontallevels.TheseinteractionsmaybevariablydefectiveinPDpatients.Thismayexplainthesmallersizeeffectofresponsefoundintreating PD depression compared to nonPD depressed individualswithinthesamegeriatricpopulationandtheapparentlowef  fi ciencyof SSRI in PD depression, when results are expressed in percentage of responses on the Hamilton scale global score.It is to be noted that the hypokinetic factor of mood overlaps withfatigue,motivation,hedoniccapacity,symptomsforwhichindependentscaleshavebeenrecentlydevised.Thismaysuggestwhythehypokineticfactor is consistently more pronounced in PD patients than in controlsubjects, and better correlated to depression than to motor status.Recent studies also con fi rm the bene fi cial effect of dopaminergic drugson apathy [17] and motivation [18] in parkinsonian patients. Finally, the recently published factorial analysis of the BDI [11]con fi rms, a posteriori, a categorization of symptoms based on basicpathogenetic mechanisms: the component analysis based on a highlevel of correlative variation, assembled in close fashion the items of the BDI into two main factors. Although the validity of this dichotomyneedsreplicationwithlargergroupsofpatientsinprospectivetrials,itis of heuristic value in probing aminergic modulation in clinic andimagery of distinct aspects of behaviors neglected up to now in thecore symptomatology of PD. It can also help in establishing new  Table 3 Demographic and clinical characteristics of Parkinson participants.Placebo depressedPD trial n =10Placebo non depressedPD trial n =10Sex ratio women/men 8/4 6/6Age 67.7±7.3 68.3±5.6Age at onset 60.2±7.4 62.5±5.2Disease duration 7.2±3 6.9±3Levodopa daily dose (mg) 758.25±157 832.31±210Agonists in pramipexoleequivalent (mg)3.4±0.7 3.5±0.5BDI baseline 23±5.6 11±2.9 Fig. 3.  Abatement on Hyperkinetic and Hypokinetic scores under antiparkinsonian andantidepressant placebo conditions.4  E. Pourcher et al. / Journal of the Neurological Sciences xxx (2009) xxx –  xxx ARTICLE IN PRESS Please cite this article as: Pourcher E, et al, Affect in Parkinson's disease: validation of the two-factor approach, J Neurol Sci (2009),doi:10.1016/j.jns.2009.08.048  correlations between affective, cognitive, and motor subtype of behaviors presently concealed by the use of traditional categoricalapproaches.  Acknowledgments These research were carried out with the support and fundingfromtheQuebec MemoryandMotorSkillsDisordersResearchCenter,Clinique Sainte-Anne. References [1] AgidY,ArnulfI,BejjaniP,BlochF,BonnetAM,DamierP,etal.Parkinson'sdiseaseisa neuropsychiatric disorder. Adv Neurol 2003;91:365 – 70.[2] Schrag A, Morley D, Quinn N, Jahanshahi M. Impact of Parkinson's disease onpatients'adolescentandadultchildren.ParkinsonismRelatDisord2004;10:391 – 7.[3] Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. Recognition and treatment of depression in Parkinson's disease. 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Pourcher et al. / Journal of the Neurological Sciences xxx (2009) xxx –  xxx ARTICLE IN PRESS Please cite this article as: Pourcher E, et al, Affect in Parkinson's disease: validation of the two-factor approach, J Neurol Sci (2009),doi:10.1016/j.jns.2009.08.048
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