practice parameter: evaluation and ... -...

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Special Article

Practice Parameter Evaluation andtreatment of depression psychosis and

dementia in Parkinson disease(an evidence-based review)

Report of the Quality Standards Subcommittee of theAmerican Academy of Neurology

JM Miyasaki MD K Shannon MD V Voon MD B Ravina MD MSCE G Kleiner-Fisman MDK Anderson MD LM Shulman MD G Gronseth MD and WJ Weiner MD

AbstractmdashObjective To make evidence-based treatment recommendations for patients with Parkinson disease (PD) withdementia depression and psychosis based on these questions 1) What tools are effective to screen for depressionpsychosis and dementia in PD 2) What are effective treatments for depression and psychosis in PD 3) What are effectivetreatments for PD dementia or dementia with Lewy bodies (DLB) Methods A nine-member multispecialty committeeevaluated available evidence from a structured literature review using MEDLINE and the Cochrane Database of Healthand Psychosocial Instruments from 1966 to 2004 Additional articles were identified by panel members Results The BeckDepression Inventory-I Hamilton Depression Rating Scale and Montgomery Asberg Depression Rating Scale should beconsidered to screen for depression in PD (Level B) The Mini-Mental State Examination and the Cambridge CognitiveExamination should be considered to screen for dementia in PD (Level B) Amitriptyline may be considered to treatdepression in PD without dementia (Level C) For psychosis in PD clozapine should be considered (Level B)quetiapine may be considered (Level C) but olanzapine should not be considered (Level B) Donepezil or rivastigmineshould be considered for dementia in PD (Level B) and rivastigmine should be considered for DLB (Level B)Conclusions Screening tools are available for depression and dementia in patients with PD but more specificvalidated tools are needed There are no widely used validated tools for psychosis screening in Parkinson disease(PD) Clozapine successfully treats psychosis in PD Cholinesterase inhibitors are effective treatments for dementiain PD but improvement is modest and motor side effects may occur

NEUROLOGY 200666996ndash1002

Statement of purpose The Quality StandardsSubcommittee (QSS) develops scientifically soundclinically relevant practice parameters to guide the

practice of neurology This article discusses treat-ments for the management of patients with depres-sion psychosis and dementia in Parkinson disease(PD) These recommendations address the needs ofneurologists and other clinicians caring for peoplewith PD patients and caregivers research fundingagencies and researchers in movement disorders

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the April 11 issue to find the title link for this article

Editorial see page 966See also pages 968 976 and 983

This article was previously published in electronic format as an Expedited E-Pub at wwwneurologyorgFrom the University of Toronto (JMM) Canada Rush University Medical Center (KS) Chicago IL NIH (VV) Bethesda MD University of Rochester (BR)NY University of Pennsylvania (GK-F) Philadelphia University of Maryland (KA LMS WJW) Baltimore and University of Kansas (GG) Kansas CityQuality Standards Subcommittee Members are listed in appendix E-4 on the Neurology Web site at wwwneurologyorgApproved by QSS July 30 2005 Practice Committee December 15 2005 Board of Directors February 23 2006Endorsed by the National Parkinson Foundation and the Parkinsonrsquos Disease FoundationDisclosures are provided after the textReceived September 9 2005 Accepted in final form February 16 2006Address correspondence and reprint requests to the American Academy of Neurology 1080 Montreal Avenue St Paul MN 55116

996 Copyright copy 2006 by AAN Enterprises Inc

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This guideline provides answers to the followingquestions

1 In patients with PD what are the most accu-rate tools to screen for depression psychosisand dementia

2 In patients with PD what are the best treat-ments for depression and psychosis

3 What is the most effective treatment of demen-tia in PD or dementia with Lewy bodies (DLB)

Background and justification PD is the secondmost common neurodegenerative disease1 Charac-terized by the cardinal signs of bradykinesia rigid-ity tremor at rest and abnormalities of balanceposture and gait the etiology of PD remains un-known in most patients2 Nonmotor symptoms in PDan increasingly recognized intrinsic feature of PDmay affect three domains autonomic neuropsychiat-ric and sensory including pain2 The prevalence ofnonmotor symptoms is high For instance a surveyof 99 patients with PD using validated question-naires for nonmotor symptoms including anxiety de-pression sensory disturbance fatigue or sleepproblems revealed that 88 of patients had at leastone nonmotor symptom and 11 had five nonmotorsymptoms3 With improved treatment of motor symp-toms it is also now evident that the nonmotor fea-tures of PD such as dementia depression andpsychosis may result in significant disability24 Yetdespite the high prevalence and associated disabilityof nonmotor symptoms in PD physician recognitionof these important clinical features is low5 Further-more many PD symptoms overlap with features ofdepression and dementia including symptoms ofwithdrawal lack of motivation flattened affect de-creased physical activity or bradyphrenia thus con-founding the identification of these behavioral andcognitive disorders It should be noted that validatedcriteria for depression psychosis and dementia inPD do not exist Hence the identification of clinicallyrelevant screening and diagnostic tools for depres-sion psychosis and cognitive decline validated spe-cifically in the PD population is necessary

In this parameter the focus in the section on val-idation studies will be on the diagnostic accuracy ofspecific measures for behavioral disorders and de-mentia in PD The mechanisms underlying nonmotorsymptoms are poorly understood and may be relatedto abnormalities of dopaminergic serotonergic adren-ergic cholinergic and other peptidergic pathways6-9

This complex pathophysiology reflects the resistance ofnonmotor symptoms to dopamine replacement strat-egies Therefore specific treatments for autonomicbehavioral and cognitive complications need to beemployed

Converging evidence suggests that the behavioralsymptoms in PD may be pathophysiologically differ-ent from the behavioral symptoms observed in thegeneral population For instance several lines of ev-idence suggest that PD depression may be related to

the underlying pathology of PD itself rather thangeneral psychiatric vulnerabilities and psychosocialassociations This suggests that reliance on the psy-chiatric treatment literature in the general popula-tion may not be sufficient and that specific treatmentstudies are required in PD

The etiology of dementia in PD is unclearWhether PD dementia represents a discrete categor-ical entity from DLB or exists on a spectrum is notknown For the purposes of this parameter we willconsider the treatments of both entities presuming asimilar underlying pathophysiology10

Throughout this parameter the term depressionwill be used to refer to major depression unless oth-erwise specified there are no validation or treatmentstudies investigating forms of depression such asdysthymia or minor depression

This parameter reviews the available evidence as-sessing diagnostic screening tools and the most effec-tive treatments for dementia depression andpsychosis in PD

Description of the analytical process The QSSof the American Academy of Neurology (AAN) identi-fied a panel of six experienced movement disorderspecialists two psychiatrists and a general neurolo-gist with methodologic expertise For the literaturereview the following databases were searchedMEDLINE EMBASE CINAHL the Cochrane Data-base of Systematic Reviews and Health and Psycho-social Instruments from 1966 to 2004 This wasfollowed by a secondary search using the bibliogra-phy of retrieved articles and knowledge of the expertpanel Two authors reviewed each abstract for topicrelevance Two authors reviewed each full article torate the level of evidence (Class IndashIV) (appendicesE-1 and E-2 on the Neurology Web site at wwwneurologyorg) If there was disagreement the entirepanel reviewed the article and the level of evidencewas decided by consensus The panel reviewed allarticles cited in the evidence below If a panelist wasan author of one of the articles at least two otherpanelists reviewed that article Conflicts of interestwere disclosed according to AAN guidelines TheAAN provided support and the Michael J Fox Foun-dation funded the writing meetings Panelists werenot compensated

Description of literature review Search termsPsychosis scale OR depression scale OR psychosisdiagnosis OR depression diagnosis OR psychosistreatment OR depression treatment OR cognitivetreatment OR dementia diagnosis OR psychoses ORhallucinations OR psychotic OR delusion OR depres-sion OR depressive disorder OR adjustment disorderOR experimental drug therapy OR dementia treat-ment AND Parkinson disease OR diffuse Lewy bodydisease OR dementia with Lewy bodies

Inclusion and exclusion criteria For depressionscales and treatment Diagnostic and StatisticalManual (DSM) criteria for depression were the gold

April (1 of 2) 2006 NEUROLOGY 66 997

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standard DSM-IV criteria for major depression wereused unless otherwise stated in the study reviewedVarious criteria for the diagnosis of PD were al-lowed Class IV studies were not considered if ClassIII studies were available Similarly Class III stud-ies were not considered if Class II studies were avail-able All Class I and II studies were included

Depression screening tools The search identified37 articles Thirty-four were rejected 31 did not ex-amine diagnostic accuracy and in 3 the patients didnot have PD Three articles were accepted (Class IClass II)

Depression treatment (pharmacologic) Thesearch identified 31 articles Twenty were excludedbecause the populations studied were not PD pa-tients with depression Two were excluded becausethey were not randomized controlled trials Nine ar-ticles were reviewed An additional 27 articles wereidentified 19 of which had been identified throughthe Cochrane bibliography Of the 36 articles re-viewed 30 were rejected as they were Class IV arti-cles Six articles were accepted that were Class I IIor III

Depression treatment (nonpharmacologic) Thesearch identified six studies one Class II and fiveClass IV because of a high risk of bias Class IVstudies were not considered One Class II study wasaccepted

Psychosis screening tools The search identified31 articles Eighteen did not examine diagnostic ac-curacy Twelve articles did not include patients withPD One Class IV article was accepted

Psychosis treatment The search identified 63 ar-ticles Twenty-five were rejected because the pa-tients did not have PD Fifteen were rejected becausethe articles did not address psychosis treatmentTwenty-three articles received a full review Elevenwere rejected because they were Class III or IVThree did not include patients with PD Three wereexcluded because they were review articles and onewas excluded because it was an epidemiologic studyFour Class I and II articles were accepted

Cognitive screening tools in PD Twenty-fourstudies were identified Ten were rejected becausethey did not examine diagnostic accuracy One didnot include patients with dementia Thirteen articlesreceived a full review five did not examine diagnos-tic accuracy five were Class IV and one did notinclude PD patients with dementia Two articleswere accepted (Class I III)

Cognitive treatment in PD or dementia with Lewybodies The search identified 331 articles A total of146 were excluded because they did not include pa-tients with PD A total of 115 were not randomizedcontrolled trials Forty-eight did not examine treat-ment for dementia Twenty-two articles received afull review An additional article was identified bythe panelists and reviewed Ten were Class III or IVFive were excluded because they were review arti-cles and two articles were excluded because theyincluded PD patients without dementia or criteria

for dementia were not adequately defined Three didnot include cognitive treatment in PD Three Class IIarticles were accepted

Analysis of evidence Question 1a In patientswith PD which are the most accurate tools to screenfor depression Evidence One Class I and twoClass II articles compared the accuracy of depressionscreening tools to an independent reference standardbased upon DSM criteria11-13 These studies reportedresults of the Beck Depression Inventory (BDI)11

which is a self completion questionnaire (21 itemsrange 0ndash63) the Hamilton Depression Rating Scale(HDRS-17) (17 items range 0ndash52)1213 and the Mont-gomery Asberg Depression Rating Scale (MADRS)(10 items range 0ndash60)12 Both the HDRS-17 andMADRS require a trained administrator and take 15to 25 minutes each to administer No studies exam-ining the diagnostic accuracy of the Geriatric De-pression Scale Hospital Anxiety and DepressionScale or Zung Self-Rating Depression Scale wereidentified

All three studies were of prospective cohort de-sign One employed a double masked methodology(Class I)11 The other two studies were not doublemasked (Class II)1213 The authors reported variouscut points and corresponding sensitivities and speci-ficities for each screening tool For the purposes ofthis article we chose the cutpoint providing thegreatest diagnostic accuracy for major depression(best specificity and sensitivity) For the BDI-I ascore of greater than 13 indicated depression with asensitivity of 67 (95 CI 39 to 86) and a specificityof 88 (95 CI 75 to 95) For the HDRS-17 (pooledresults from two studies) a score of greater than 13indicated depression with a sensitivity of 83 (95CI 67 to 92) and specificity of 95 (95 CI 89 to 98)For the MADRS the cut point was greater than 14for patients indicating depression with a sensitivityof 88 (95 CI 64 to 97) and specificity of 89 (95CI 77 to 95) Although these data suggest that theHDRS-17 and MADRS are superior to the BDI thestudies were underpowered to determine superiorityIn addition the BDI is more easily administeredrequiring at most 10 minutes

Conclusions For patients with PD the BDI (oneClass I) and HDRS (two Class II) are probably usefulto screen for depression associated with PD Basedon one Class II study MADRS is possibly useful toscreen for depression associated with PD Based onthe available evidence we cannot recommend onescreening test over another

There is insufficient evidence to support or refutethe usefulness of other rating scales for depression inPD (Level U) (appendix E-3)

Recommendation The BDI- I and HDRS shouldbe considered for depression screening in PD (LevelB) MADRS may be considered for screening for de-pression associated with PD (Level C)

998 NEUROLOGY 66 April (1 of 2) 2006

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Question 1b In patients with PD which are the mostaccurate tools to screen for psychosis Evidence Thereis no gold standard for the diagnosis of psychosis inPD There was one Class IV study14 in which anexpert-derived Parkinson Psychosis Rating Scale(PPRS) was administered to 29 patients with PD andpsychosis and compared with two scales that havebeen validated in the general population the BriefPsychosis Rating Scale (BPRS) and the Nurses Ob-servation Scale for Inpatient Evaluation (NOSIE-Psychotic) The PPRS demonstrated good interraterreliability and internal consistency There was gooddiagnostic accuracy between the PPRS and BPRS(p 001) and the PPRS and the NOSIE-Psychotic(p 001) PD patients without psychosis were notincluded in the study and therefore the specificityof this screening tool in PD cannot be determined

Conclusion Based on one Class IV study thereis insufficient evidence to support or refute PPRS asa screening tool for psychosis in PD (Level U)

Recommendation No recommendation is madeQuestion 1c In patients with PD which are the most

accurate tools to screen for dementia Evidence Therewas one Class I15and one Class III study16 In theClass I study the Cambridge Cognitive Examination(CAMCog) and Mini-Mental State Examination(MMSE) were administered to 126 patients olderthan 60 years treated for PD in the community andinstitutions Forty-four percent of this populationhad dementia by DSM-IV criteria Both the CAMCogand MMSE had similar sensitivities (95 and 98)However the CAMCog was more specific (94) thanthe MMSE (77) The CAMCog includes all items ofthe MMSE and covers additional domains (orienta-tion concentration expression memory abstractthinking drawing understanding and writing) re-quiring approximately 20 minutes to administer by atrained rater

In addition to scales procedures are proposed toscreen for PD dementia In a case control EEG study(Class III) of 10 patients with PD dementia and 10patients with PD without dementia no significantdifferences in the amplitude of delta and theta activ-ities were observed between the groups16

Conclusion The MMSE and CAMCog are proba-bly useful for screening patients with PD and DSM-defined dementia (one Class I) The MMSE is assensitive as the CAMCog and quicker to administerbut less specific

Based on one Class III study there is insufficientevidence to support the use of EEG as a screeningtool for dementia in PD (Level U)

Recommendation The MMSE and the CAMCogshould be considered as screening tools for dementiain patients with PD (Level B)

Question 2 In patients with PD what is the bestpharmacologic treatment for depression EvidenceSix studies were identified one Class I17 two ClassII1819 and three Class III20-22 All were randomizedcontrolled trials Interventions included amitripty-line nortriptyline citalopram fluoxetine sertraline

pergolide pramipexole and nefazodone Three of thestudies used placebo comparators17-19 One studycompared nefazodone to fluoxetine22 one amitripty-line to fluoxetine20 and one pramipexole to pergol-ide21 In four studies depression was defined byDSM criteria One study21 employed ICD-10 criteriafor depression In another study the authorrsquos ad hocscale was used18 In all but one study the severity ofthe depression was mild to moderate depression wassevere in the study of amitriptyline20 Outcome mea-sures varied and included BDI HAM-D MADRSZung Self Rating Depression Scale and a uniquerating scale20

Five of the six studies used masked outcome as-sessment The nefazodone vs fluoxetine study uti-lized independent but not masked outcomeassessment (Class III)22 Three studies lacked alloca-tion concealment of treatment groups (the attempt toprevent selection bias by concealing the assignmentsequence until allocation to avoid maneuvering a pa-tient to a particular assignment either intentionallyor unintentionally)20-22 one had nonstandard inclu-sion criteria19 and one had less than 80 completerswithout an intent to treat analysis20 Despite ran-domization there were confounding differences inthe severity of depression between groups in thepramipexole vs pergolide study (Class III)21

Follow-up ranged from 6 weeks to 12 months Thesingle Class I study citalopram vs placebo had theshortest duration of follow-up and used the HAMDfor assessment17

No significant benefit of treatment was observedin the studies of citalopram and sertraline1719 How-ever neither study was sufficiently powered to ex-clude a clinically important benefit Fluoxetine andnefazodone revealed equal efficacy for depressionbut this study lacked a placebo control and conse-quently we could not conclude whether either drugwas effective22

Patients treated with pramipexole improved sig-nificantly more than patients treated with pergolideon measures assessing depression21 However therewere important confounding differences in the sever-ity of depression at baseline which compromisedthese results

In the study comparing the treatment of severelydepressed patients with amitriptyline or fluoxetinepatients randomized to amitriptyline significantlyimproved (change in HAM-D of 14) while thosetreated with fluoxetine did not20 Dropout rates weregreater in the amitriptyline group due to adverseevents

In the nortriptyline study the authors report asignificant improvement in depression compared toplacebo18 However it is impossible from the publica-tion to determine if this difference was significant

Conclusions Based on one Class II study ami-triptyline is possibly effective in treating depressionassociated with PD There is insufficient evidence tosupport or refute the efficacy of other specific antide-pressants in the treatment of PD depression Anti-


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cholinergic side effects especially problematic withtricyclics are an important consideration in the PDpopulation due to concerns regarding potential wors-ening of cognition as is the concern about orthostatichypotension increasing the risk of falls

Although the age at onset of PD is generally inadulthood it should be noted that the Food and DrugAdministration issued a drug labeling change in2004 for a black box warning of the increased risk ofsuicidal ideation and suicide in adolescents and chil-dren with all antidepressants

Recommendations Amitriptyline may be consid-ered in the treatment of depression associated withPD (Level C) Although the highest level of evidenceis for amitriptyline it is not necessarily the firstchoice for treatment of depression associated withPD There is insufficient evidence to make recom-mendations regarding other treatments for depres-sion in PD Absence of literature demonstrating clearefficacy of non-tricyclic antidepressants is not thesame as absence of efficacy

Question 2b In patients with PD and depressionwhat are the best nonpharmacologic treatments

Evidence No published trials of psychotherapyfor depression associated with PD were availableThe single Class II study randomized patients totranscranial magnetic stimulation (TMS) or fluox-etine23 Outcomes were assessed in a blinded fashionusing HAM-D Completion rate was 100 A primaryoutcome measure was not specified Both groups im-proved but there was no difference in the magnitudeof improvement in the treatment groups The studywas insufficiently powered to exclude a moderate dif-ference in efficacy between the two therapies Addi-tionally because of the absence of a placebocomparator we cannot determine whether either in-tervention was effective Due to these study designweaknesses this study was downgraded to Class IIIevidence

Only Class IV studies were available regardingECT which were not further evaluated

Conclusion There is insufficient evidence to sup-port or refute the efficacy of TMS (single Class III) orECT (Class IV) in the treatment of depression asso-ciated with PD (Level U)

Recommendation No recommendations weremade

Question 2c In patients with PD and psychosiswhat is the best treatment Evidence There werefour randomized double blind controlled trials (oneClass I24 and three Class II25-27) One study comparedclozapine to quetiapine (Class II)25 Psychosis wasdefined using various criteria Three studies wereplacebo controlled

One Class I study demonstrated superiority of clo-zapine compared to placebo using the Clinical GlobalImpression Scale (CGI) (p 0001)24 This study alsodemonstrated improvement on the Brief PsychiatricRating Scale (BPRS) (p 0002) and the Scale forthe Assessment of Positive Symptoms (SAPS) (p

001) Parkinsonism did not worsen and tremor im-proved One patient discontinued due to leukopenia

Two Class II studies compared olanzapine to pla-cebo2627 In both studies psychosis failed to improveand motor symptoms worsened

One 12-week Class II study was randomized openlabel and used a blinded rater Eleven patients re-ceived quetiapine and 12 received clozapine25 End-points were change in BPRS CGI UnifiedParkinsonrsquos Disease Rating Scale (UPDRS) motorsubscore and the Abnormal Involuntary MovementScale (AIMS) BPRS improved by 91 (p 0001) forquetiapine and 107 for clozapine (p 0001) ForCGI quetiapine improved by 15 (p 0001) andclozapine by 19 (p 0001) UPDRS motor worsenedby 16 (p NS) for quetiapine and improved by 21for clozapine (p 0005) AIMS improved by 16 forquetiapine (p 005) and 18 for clozapine (p 005)

Conclusions For patients with PD and psycho-sis one Class I study and one Class II study demon-strated that clozapine is probably an effectivetreatment Clozapine improved psychosis and re-sulted in improved motor function in some cases

One Class II study demonstrated that quetiapinepossibly improves psychosis in PD

Two Class II studies demonstrated that olanzap-ine probably does not improve psychosis and worsensmotor function

There is a concern that all atypical neurolepticshave a small increased risk of mortality particularlyin elderly patients with dementia who are treated forbehavioral disorders The mechanism for increasedmortality is not clear This must be balanced by thehigh morbidity and mortality associated withpsychosis2

Recommendations For patients with PD andpsychosis clozapine should be considered (Level B)Clozapine use is associated with agranulocytosis thatmay be fatal The absolute neutrophil count must bemonitored Monitoring requirements may vary ac-cording to country

For patients with PD and psychosis quetiapinemay be considered (Level C)

For patients with PD and psychosis olanzapineshould not be routinely considered (Level B)

Question 3 what is the most effective treatment fordementia in PD or DLB Evidence One Class Istudy was identified28 The Class I study was a ran-domized double-masked placebo-controlled cross-over study in 22 subjects with PD and dementiaEach treatment period was 10 weeks separated by a6-week washout period Donepezil was administeredat 5 to 10 mgday The primary outcome measurewas the AD Assessment ScalendashCognitive Subscale(ADAScog) Donepezil was not significantly betterthan placebo based on ADAScog Secondary end-points (MMSE and CGI) were significantly betterwith donepezil UPDRS scores did not deterioratewith donepezil

Four Class II studies were identified29-32 All stud-1000 NEUROLOGY 66 April (1 of 2) 2006

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ies were randomized controlled trials with blindedoutcome assessments lasting 10 to 24 weeks Threestudies examined cholinesterase inhibitors (donepe-zil30 rivastigmine2931) One study examined pirac-etam a compound of unknown mechanism ofaction32 These studies employed DSM criteria fordementia Primary outcome measures were changein the MMSE ADAScog AD Cooperative StudyndashClinicians Global Impression of Change (ADCS-CGIC) the Clinicians Interview Based Impression ofChange Plus Caregiver Input (CIBIC) and a com-puterized cognitive assessment system speed scoreOnly one study focused on patients with DLB31

When compared with placebo piracetam did notshow a significant benefit on any measure32 How-ever the study was insufficiently powered to excludea moderate benefit of piracetam

When rivastigmine (n 362) was compared withplacebo (n 179) the ADAScog score improved 21 82 in the treatment group but decreased by 07 75 in the placebo group (p 0001)29 The numberneeded to treat for any improvement as defined bythe ADCS-CGIC was nine The number needed totreat to obtain clinically meaningful (moderate ormarked) improvement on the ADCS-CGIC was 19Tremor increased in 102 vs 39 (p 001) in thetreatment group Sixty-two (171) patients on riv-astigmine dropped out due to adverse events such asnausea vomiting and tremor For every eight pa-tients receiving rivastigmine one patient droppedout due to adverse events The number needed toharm was eight This means that eight patientsmust experience worsening of parkinsonism as as-sessed by the UPDRS for each patient experiencingclinically meaningful improvement as measured bythe ADCS-CGIC

Rivastigmine was evaluated in a randomized dou-ble blind placebo controlled trial of 120 patientswith DLB31 as defined by the DLB consensus guide-lines33 The intention to treat analysis of the primaryoutcome (computerized cognitive assessment systemspeed score) at week 20 revealed a benefit in thetreatment group (p 0048) At week 20 there wasno significant improvement in the MMSE or theClinical Global ChangendashPlus In the donepezil cross-over design study (n 14) the MMSE improved by21 (SD 27) compared to only 03 (SD 32) for placebo(p 0013)28 No change occurred in the UPDRSmotor subscale scores Two patients dropped out dueto adverse events On the CIBIC the numberneeded to treat to obtain any improvement was fourNumber needed to harm was seven

Conclusion For patients with PD dementia orDLB rivastigmine is probably effective in improvingcognitive function However the magnitude of thebenefit is modest and tremor may be exacerbated(two Class II studies)

For patients with PD dementia donepezil is prob-ably effective in improving cognitive function How-ever the magnitude of the benefits is modest (oneClass I and one Class II study)

There is insufficient evidence to support or refutethe efficacy of piracetam (Level U)Recommenda-tions Donepezil should be considered for the treat-ment of dementia in PD (Level B)

Rivastigmine should be considered for the treat-ment of dementia in PD or DLB (Level B)

Recommendations for future research Despiteadvances in treatment that improve motor symptomsfor many patients PD remains a progressive diseasewith complex long-term nonmotor symptoms thatare often unrecognized In order to identify the im-pact of depression psychosis and dementia vali-dated diagnostic questionnaires and rating scales areneeded

Depression rating scales Current studies usingthe Beck Depression Inventory Hamilton Scale forDepression and the Montgomery Asberg DepressionRating Scale are underpowered to establish their di-agnostic accuracy in this patient population Otherscales such as the Geriatric Depression Scale andZung Self-Rating Depression Scale are not formallyevaluated in PD Future research is required to de-termine the best (sensitive specific but also practi-cal for clinicians to rapidly administer) depressionscreening tool for patients with PD DSM-IV criteriahave not been validated for depression in PD

Psychosis screening tools Psychosis in PD ischaracterized by visual hallucinations and delusions(often paranoid)34 Screening tools for psychosisshould be sensitive to hallucinations as well as otherpsychosis features such as delusions Only one studyevaluated the PPRS15 which may be appropriate forpatients with PD15 However in order to determineits specificity the PPRS needs to be evaluated innonpsychotic and psychotic PD patients DSM-IV cri-teria for psychosis have not been validated in PD

Cognition screening tools Screening tools mustbe easy and quick to administer Cognitive decline inPD is characterized by impaired executive functionvisuospatial abnormalities impaired memory andlanguage deficits35 An appropriate scale that reli-ably incorporates executive function (eg frontal as-sessment battery and other practical tests ofexecutive function) should be incorporated into ascreening test for PD dementia When evaluatingnew screening tools the DSM-IV criteria for demen-tia may not be the most appropriate gold standardfor patients with PD DSM-IV criteria for dementiahave not been validated in PD In PD patients itmay be difficult to assess impairments in domainsother than memory

Depression treatment There is a need for ran-domized double-blinded placebo-controlled studiesof adequate size and duration of follow-up to assessantidepressants psychotherapies and other somatictherapies such as ECT and TMS

Psychosis treatment Due to rare but possibleagranulocytosis and concerns about increased mor-tality associated with clozapine other treatmentsshould be identified for patients with PD and psycho-


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sis Class I studies are required to evaluate the effi-cacy of quetiapine Evidence for efficacy of novelantipsychotics without dopaminergic blocking effectsis needed for effective treatment of psychosis in PD

Dementia treatment The cognitive benefits ofdonepezil and rivastigmine were small in PD demen-tia or DLB and tremor increased with rivastigmineTherefore future research should include more ClassI studies to assess the role of cholinesterase inhibi-tors and other medications in the treatment of de-mentia associated with PD Additional treatmentsneed to be developed that alleviate cognitive symp-toms without worsening parkinsonism

Disclaimer This statement is provided as an edu-cational service of the American Academy of Neurol-ogy It is based on an assessment of current scientificand clinical information It is not intended to includeall possible proper methods of care for a particularneurologic problem or all legitimate criteria forchoosing to use a specific procedure Neither is itintended to exclude any reasonable alternativemethodologies The AAN recognizes that specific pa-tient care decisions are the prerogative of the patientand the physician caring for the patient based on allof the circumstances involved

Disclosure Dr Miyasaki received research fundsfrom Boehringer Ingelheim Teva and Janssen Or-tho and consulting fees from Boehringer IngelheimDr Shannon received research funds from Teva DrShulman received research grants or unrestrictededucational grants from Pfizer Novartis and TevaDr Weiner received research grants from TevaBoehringer Ingelheim consultancy fees from Teva andis a member of Boehringer Ingelheimrsquos speakersbureau Drs Anderson Ravina and Gronseth havenothing to disclose

AcknowledgmentThe authors thank Nancy King and Wendy Edlund for adminis-trative support and Andrew Wilner MD for help with manuscriptpreparation

References1 Van Den Eeden SK Tanner CM Bernstein AL et al Incidence of

Parkinsonrsquos disease variation by age gender and raceethnicity Am JEpidemiol 20031571015ndash1022

2 Factor S Weiner W Parkinsonrsquos disease Diagnosis and clinical man-agement New York Demos 2002

3 Shulman LM Taback RL Bean J Weiner WJ Comorbidity of thenonmotor symptoms of Parkinsonrsquos disease Mov Disord 200116507ndash510

4 Weintraub D Moberg PJ Duda JE Katz IR Stern MB Effect of psy-chiatric and other nonmotor symptoms on disability in Parkinsonrsquos dis-ease J Am Geriatr Soc 200452784ndash788

5 Shulman LM Taback RL Rabinstein AA Weiner WJ Non-recognitionof depression and other non-motor symptoms in Parkinsonrsquos diseaseParkinsonism Relat Disord 20028193ndash197

6 Agid Y Taquet H Cesselin F Epelbaum J Javoy-Agid F Neuropep-tides and Parkinsonrsquos disease Prog Brain Res 198666107ndash116

7 Dubois B Hauw JJ Ruberg M Serdaru M Javoy-Agid F Agid Y[Dementia and Parkinsonrsquos disease biochemical and anatomo-clinicalcorrelation] Rev Neurol (Paris) 1985141184ndash193

8 Pillon B Dubois B Cusimano G Bonnet AM Lhermitte F Agid Y Doescognitive impairment in Parkinsonrsquos disease result from non-dopaminergic lesions J Neurol Neurosurg Psychiatry 198952201ndash206

9 Wakabayashi K Takahashi H Neuropathology of autonomic nervoussystem in Parkinsonrsquos disease Eur Neurol 1997382ndash7

10 Noe E Marder K Bell KL Jacobs DM Manly JJ Stern Y Comparisonof dementia with Lewy bodies to Alzheimerrsquos disease and Parkinsonrsquosdisease with dementia Mov Disord 20041960ndash67

11 Leentjens AF Verhey FR Luijckx GJ Troost J The validity of the BeckDepression Inventory as a screening and diagnostic instrument fordepression in patients with Parkinsonrsquos disease Mov Disord 2000151221ndash1224

12 Leentjens AF Verhey FR Lousberg R Spitsbergen H Wilmink FWThe validity of the Hamilton and Montgomery-Asberg depression ratingscales as screening and diagnostic tools for depression in Parkinsonrsquosdisease Int J Geriatric Psychiatry 200015644ndash649

13 Naarding P Leentjens AF van Kooten F Verhey FR Disease-specificproperties of the Rating Scale for Depression in patients with strokeAlzheimerrsquos dementia and Parkinsonrsquos disease J Neuropsychiatry ClinNeurosci 200214329ndash334

14 Friedberg G Zoldan J Weizman A Melamed E Parkinson PsychosisRating Scale a practical instrument for grading psychosis in Parkin-sonrsquos disease Clin Neuropharmacol 199821280ndash284

15 Hobson P Meara J The detection of dementia and cognitive impair-ment in a community population of elderly people with Parkinsonrsquosdisease by use of the CAMCOG neuropsychological test Age Ageing19992839ndash43

16 Neufeld MY Blumen S Aitkin I Parmet Y Korczyn AD EEG fre-quency analysis in demented and nondemented parkinsonian patientsDementia 1994523ndash28

17 Wermuth L Sorensen P Timm S et al Depression in idiopathic Par-kinsonrsquos disease treated with citalopram Nord J Psychiatry 199852163ndash169

18 Andersen J Aabro E Gulman N Helmsted A Pedersen H Anti-depressive treatment in Parkinsonrsquos disease A controlled trial of theeffect of nortriptyline in patients with Parkinsonrsquos disease treated withL-Dopa Acta Neurol Scand 198062210ndash219

19 Leentjens AF Vreeling FW Luijckx GJ Verhey FR SSRIs in the treat-ment of depression in Parkinsonrsquos disease Int J Geriatric Psychiatry200318552ndash554

20 Serrano-Duenas M Dosis bajas de amitriptilina frente a dosis bajas defluoxetine en el tratamiento de la depression de enfermos con Parkin-son Rev Neurol 2002351010ndash1014)

21 Rektorova I Rektor I Bares M et al Pramipexole and pergolide in thetreatment of depression in Parkinsonrsquos disease a national multicentreprospective randomized study Eur J Neurol 200310399ndash406

22 Avilla A Cardona X Martin Baranera M Maho P Satre F Bello JDoes nefazodone improve both depression and Parkinson disease Apilot randomized trial J Clin Psychopharmacol 200323509ndash513

23 Fregni F Santos CM Myczkowski ML et al Repetitive transcranialmagnetic stimulation is as effective as fluoxetine in the treatment ofdepression in patients with Parkinsonrsquos disease J Neurol NeurosurgPsychiatry 2004751171ndash1174

24 Parkinson Study Group Low-dose clozapine for the treatment of drug-induced psychosis in Parkinsonrsquos disease N Engl J Med 1999340757ndash763

25 Morgante L Epifanio A Spina E et al Quetiapine versus clozapine apreliminary report of comparative effects on dopaminergic psychosis inpatients with Parkinsonrsquos disease Neurol Sci 200223S89ndash90

26 Breier A Sutton VK Feldman PD et al Olanzapine in the treatment ofdopamimetic-induced psychosis in patients with Parkinsonrsquos diseaseBiol Psychiatry 200252438ndash445

27 Ondo W Levy JK Vuong KD Hunter C Jankovic J Olanzapine treat-ment for dopaminergic-induced hallucinations Mov Disord 2002171031ndash1035

28 Ravina B Putt M Siderowf A et al Donepezil for dementia in Parkin-sonrsquos disease a randomized double-blind placebo controlled crossoverstudy JNNP 2006 (in press)

29 Emre M Aarsland D Albanese A et al Rivastigmine for dementiaassociated with Parkinsonrsquos disease N Engl J Med 20043512509ndash2518

30 Aarsland D Laake K Larsen JP Janvin C Donepezil for cognitiveimpairment in Parkinsonrsquos disease a randomised controlled study JNeurol Neurosurg Psychiatry 200272708ndash712

31 McKeith I Del Ser T Spano P et al Efficacy of rivastigmine in demen-tia with Lewy bodies a randomised double-blind placebo-controlledinternational study Lancet 20003562031ndash2036

32 Sano M Stern Y Marder K Mayeux R A controlled trial of piracetamin intellectually impaired patients with Parkinsonrsquos disease Mov Dis-ord 19905230ndash234

33 McKeith IG Galasko D Kosaka K et al Consensus guidelines for theclinical and pathologic diagnosis of dementia with Lewy bodies (DLB)report of the consortium on DLB international workshop Neurology1996471113ndash1124

34 Weintraub D Stern MB Psychiatric complications in Parkinson dis-ease Am J Geriatr Psychiatry 200513844ndash851

35 Aarsland D Andersen K Larsen JP Lolk A Kragh-Sorensen P Preva-lence and characteristics of dementia in Parkinson disease an 8-yearprospective study Arch Neurol 200360387ndash392


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DOI 10121201wnl0000215428460573d200666996-1002 Published Online before print April 2 2006Neurology

J M Miyasaki K Shannon V Voon et al Standards Subcommittee of the American Academy of Neurology

in Parkinson disease (an evidence-based review) [RETIRED] Report of the Quality Practice Parameter Evaluation and treatment of depression psychosis and dementia

This information is current as of April 2 2006

ServicesUpdated Information amp

httpnneurologyorgcontent667996fullhtmlincluding high resolution figures can be found at

Supplementary Material

60573dDC1httpnneurologyorgcontentsuppl2006040301wnl00002154284


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Citations httpnneurologyorgcontent667996fullhtmlotherarticles

This article has been cited by 19 HighWire-hosted articles

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httpnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

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Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

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This guideline provides answers to the followingquestions

1 In patients with PD what are the most accu-rate tools to screen for depression psychosisand dementia

2 In patients with PD what are the best treat-ments for depression and psychosis

3 What is the most effective treatment of demen-tia in PD or dementia with Lewy bodies (DLB)

Background and justification PD is the secondmost common neurodegenerative disease1 Charac-terized by the cardinal signs of bradykinesia rigid-ity tremor at rest and abnormalities of balanceposture and gait the etiology of PD remains un-known in most patients2 Nonmotor symptoms in PDan increasingly recognized intrinsic feature of PDmay affect three domains autonomic neuropsychiat-ric and sensory including pain2 The prevalence ofnonmotor symptoms is high For instance a surveyof 99 patients with PD using validated question-naires for nonmotor symptoms including anxiety de-pression sensory disturbance fatigue or sleepproblems revealed that 88 of patients had at leastone nonmotor symptom and 11 had five nonmotorsymptoms3 With improved treatment of motor symp-toms it is also now evident that the nonmotor fea-tures of PD such as dementia depression andpsychosis may result in significant disability24 Yetdespite the high prevalence and associated disabilityof nonmotor symptoms in PD physician recognitionof these important clinical features is low5 Further-more many PD symptoms overlap with features ofdepression and dementia including symptoms ofwithdrawal lack of motivation flattened affect de-creased physical activity or bradyphrenia thus con-founding the identification of these behavioral andcognitive disorders It should be noted that validatedcriteria for depression psychosis and dementia inPD do not exist Hence the identification of clinicallyrelevant screening and diagnostic tools for depres-sion psychosis and cognitive decline validated spe-cifically in the PD population is necessary

In this parameter the focus in the section on val-idation studies will be on the diagnostic accuracy ofspecific measures for behavioral disorders and de-mentia in PD The mechanisms underlying nonmotorsymptoms are poorly understood and may be relatedto abnormalities of dopaminergic serotonergic adren-ergic cholinergic and other peptidergic pathways6-9

This complex pathophysiology reflects the resistance ofnonmotor symptoms to dopamine replacement strat-egies Therefore specific treatments for autonomicbehavioral and cognitive complications need to beemployed

Converging evidence suggests that the behavioralsymptoms in PD may be pathophysiologically differ-ent from the behavioral symptoms observed in thegeneral population For instance several lines of ev-idence suggest that PD depression may be related to

the underlying pathology of PD itself rather thangeneral psychiatric vulnerabilities and psychosocialassociations This suggests that reliance on the psy-chiatric treatment literature in the general popula-tion may not be sufficient and that specific treatmentstudies are required in PD

The etiology of dementia in PD is unclearWhether PD dementia represents a discrete categor-ical entity from DLB or exists on a spectrum is notknown For the purposes of this parameter we willconsider the treatments of both entities presuming asimilar underlying pathophysiology10

Throughout this parameter the term depressionwill be used to refer to major depression unless oth-erwise specified there are no validation or treatmentstudies investigating forms of depression such asdysthymia or minor depression

This parameter reviews the available evidence as-sessing diagnostic screening tools and the most effec-tive treatments for dementia depression andpsychosis in PD

Description of the analytical process The QSSof the American Academy of Neurology (AAN) identi-fied a panel of six experienced movement disorderspecialists two psychiatrists and a general neurolo-gist with methodologic expertise For the literaturereview the following databases were searchedMEDLINE EMBASE CINAHL the Cochrane Data-base of Systematic Reviews and Health and Psycho-social Instruments from 1966 to 2004 This wasfollowed by a secondary search using the bibliogra-phy of retrieved articles and knowledge of the expertpanel Two authors reviewed each abstract for topicrelevance Two authors reviewed each full article torate the level of evidence (Class IndashIV) (appendicesE-1 and E-2 on the Neurology Web site at wwwneurologyorg) If there was disagreement the entirepanel reviewed the article and the level of evidencewas decided by consensus The panel reviewed allarticles cited in the evidence below If a panelist wasan author of one of the articles at least two otherpanelists reviewed that article Conflicts of interestwere disclosed according to AAN guidelines TheAAN provided support and the Michael J Fox Foun-dation funded the writing meetings Panelists werenot compensated

Description of literature review Search termsPsychosis scale OR depression scale OR psychosisdiagnosis OR depression diagnosis OR psychosistreatment OR depression treatment OR cognitivetreatment OR dementia diagnosis OR psychoses ORhallucinations OR psychotic OR delusion OR depres-sion OR depressive disorder OR adjustment disorderOR experimental drug therapy OR dementia treat-ment AND Parkinson disease OR diffuse Lewy bodydisease OR dementia with Lewy bodies

Inclusion and exclusion criteria For depressionscales and treatment Diagnostic and StatisticalManual (DSM) criteria for depression were the gold


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practice parameter: evaluation and ... -...

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