Neuropsychiatric Aspects of Parkinsons Disease: Across the stages - PowerPoint PPT Presentation

Neuropsychiatric Aspects of Parkinson’s Disease: Across the stages Iracema Leroi MD FRCPC MRCPsych University of Manchester Manchester Mental Health and Social Care Trust

Parkinson’s Disease in the 21 st century: Non-motor symptoms (‘NMS’) • Pain syndromes • Parathesias • RLS • Fatigue • Skin symptoms – Seborrhoea – facial oiliness • Dysautonomia Prof Ray Chaudhuri – bladder instability, – altered thermal regulation – orthostatic hypotension

Other non-motor PD features ž Psychiatric Symptoms › depression › anxiety › sleep disturbance › psychosis ž Cognitive Symptoms › executive dysfunction Prof Dag Aarsland › mild cognitive impairment in PD (MCI-PD) › dementia in PD (PDD)

The Stages of Symptoms in PD • Pre-motor stage • (Prodromal stage) • Early motor stage • Moderate motor stage • Advanced stage

Non-motor symptoms correspond to the orderly progression of LB pathology (Braak stages) • olfactory bulb • Dorsal motor nucleus of the vagus nerve (DMNX) • Rostral along brain stem – Locus coeruleus – Dorsal raphe nucleus • Midbrain substantia nigra

The motor and cognitive stages of PD PRE-MOTOR EARLY-MOD ADVANCED PD normal cognition PD-mild cognitive impairment Dementia in PD

Most commonly reported neuropsychiatric symptoms (in over 20% of each group, excluding sleep & appetite) Worsening cognition PDD PD NC PD MCI In order of frequency Anxiety Anxiety Anxiety Depression Depression Depression Apathy Apathy Aggress/agitat Hallucinations Delusions Aberrant motor

Impact of NPS associated with cognitive impairment in PD

Manchester Study on QoL and disability in PD with cognitive impairment Leroi et al. (2012) • Impact of cognitive stage in PD on QoL & disability • PD-NC (n=54) • PD-MCI (n=48) • PDD (n=25) QOL Disability

PD-MCI PDD A p a t h y P s y c h o s i s A p a t h y A g i t a t i o n

How can we measure NPS in PD?

Neuropsychiatric Inventory (NPI) • Cummings et al., 1997 • 10 or 12-item scale to measure psychiatric complications • Informant-reported • Gold standard in dementia • Each domain rated as: YES/NO (presence/absence) • If YES, severity assessed: by Frequency (F) x Severity (S) • FxS = total score per item (min 0; max 12; clinically significant ≥4) • Can rate all 10 (or 12) domains OR use a single domain alone e.g apathy

Neuropsychiatric Inventory: Domains Delusions • Hallucinations • Depression/dysphoria • Irritability • Agitation/aggression • Euphoria/elation • Apathy • Anxiety • Disinhibition • Aberrant motor behaviour • Sleep • Appetite •

Early motor stage of PD

Early PD stage: Psychiatric symptoms • Depression • Anxiety more prevalent and severe – Psychological reaction to the diagnosis • Sleep – insomnia (immobility-related) • Medication side effects (GI, sleep)

Mood disturbances in PD

Early motor stage depression – Very common…up to 35% pp – Also may be prodrome (1 to 2 years) – May be relieved by initiation of PD medications – Depression is not related to motor symptoms OR disease stage – Not related to medication status (unless undertreated) – Sustained

Differential diagnosis of depressive symptoms in PD Non-depression: • Drug-induced mood changes – Drug withdrawal *DAWS... • Pathological tearfulness • Dementia • Apathy/anhedonia • Delirium • “Pseudoanhedonia” (lack of emotional expression)

Depression and motor symptoms in PD: later stages • Motor-related dysphoria: – Off-period depression and anxiety – Associated with pattern of on/off syndrome – Other non-motor symptoms present (urinary problems, confusion, pain, panic) – Improves with better motor control

Tips to diagnosis of depression in PD • 1. Consider collateral sources • 2. Work-up for reversible causes – FBC, TSH, testosterone levels, B12, folate – Dementia, delirium, medical illness • 3. Diagnostic criteria • 4. Screening Tools

Diagnostic Criteria for Major Depression: DSM-IV or V • Depressed mood or • Insomnia/hypersomnia anhedonia ≥ 2 weeks • Psychomotor • 5/9 symptoms: retardation or agitation • Depressed • Fatigue or loss of energy mood/loss of • ↓ or ↑ appetite pleasure or interest • Worthlessness or guilt, poor concentration • Suicidal ideation

NINDS/NIMH recommendations for dx of PD-related depression • Use inclusive diagnostic criteria – suggest modified DSM-IV criteria – More sensitive than “etiologic/exclusive/substitutional” approach

Depression Rating Scales in PD: MDS Task Force Recommendations (Schrag et al, 2007) • Literature review of depression scales • Expert consensus • Screening : – Hamilton depression Scale – Beck Depression Inventory – Hospital Anxiety & Depression Rating Scale – Montgomery-Asberger Depression Rating Scale – Geriatric Depression Scale • Severity : – HAM-D, Beck, Zung – Cornell scale (CSDD) needs validating in PD

Pharmacologic Treatment of Depression in PD • Inadequate evidence: – inadequately controlled & under-powered trials…but about 1/5 of PwPD take antidepressants • Elderly population • Dosing as per “start low, go slow” rule • Drug-drug interactions with selegiline, (rasagiline) • Pramipexole (D2,D3) may be useful

Pharmacological Treatment of Depression in PD: Reviews (Starkstein 2017). Author # Studies Years Type Conclusion Klaassen et 4/12 1966-1993 Meta-analysis Insufficient al, 1995 evidence Movement 5/19 ? Review Insufficient D/O (supp 4), evidence 2002 Cochrance 3 RCT (SSRI) 1800s-2001 Review Insufficient evidence 2003 Weintraub et 27 1965-2003 Meta-analysis Large effect size in active & al, 2005 & effect size N=772(668 plc groups; completers) larger in non- >80% on SSRI PD depressed

Classes of Antidepressants for use in PD SNRI – Venlafaxine, Duloxetine NDRI – Bupropion SSRI – fluoxetine, paroxetine, fluvoxamine, citalopram, escitalopram SARI – trazodone, nefazodone NASA - mirtazepine

Dopamine Agonists as antidepressants in PD? (Ferreira J 2013) • RCT of pramipexole for depression in PD (Barone 2010) • n= 296 patients • Significant improvement : – Beck Depression Inventory – Geriatric Depression Scale – UPDRS motor scale – UPDRS ADL

Summary of Opinion of Drug Treatment of depression in PD (McDonald 2010) • None of the antidepressants have a clear advantage in terms of efficacy, but the SSRIs are more easily tolerated ( Starkstein 2017) • Older patients may take longer to respond and need at least a 12 week trial at adequate dose to assess response • Older patients often need optimal doses to respond fully • Treat until remission is reached or relapse risk is high

All-Party Parliamentary Group (APPG) on Parkinson’s inquiry into anxiety and depression in Parkinson’s (2018)

Psychotherapy? (APPG) •before considering psychotropic medication, consideration should be given to psychological interventions • e.g. cognitive behavioural therapy (CBT) (Dobkin 2006, Troeung 2014). • brief psychotherapy (CBT and psychodynamic therapy) has been shown ( Xie 2015) to be effective in helping a proportion of depressed patients with PD….but there is a paucity of evidence .

Severe depression in PD • can be effective (Borisovskaya 2016) and has the benefit of transiently improving motor control •repetitive transcranial magnetic stimulation to be beneficial and but the evidence is insufficient to recommend this for clinical practice

Anxiety in PD • estimated point prevalence of all DSM anxiety disorders in Parkinson’s is around 34% • may co-occur with depression, worsening the symptoms (Menza 1993) • general anxiety disorder (GAD), panic disorder and social phobia frequently present as separate disorders in Parkinson’s disease

Anxiety in PD • clinical experience suggests that anxiety is more prominent than depression when levodopa is wearing off • anxiety can be particularly intense at night

Principles of treatment of anxiety in PD • less is known about the specific treatment of anxiety in PD than depression • the same principles of treatment for depression also apply to anxiety.

Principles of treatment of anxiety in PD • Address social factors first • Then, optimise DRT • Only use antidepressant/anti-anxiety medication if the response is unsatisfactory • • depression, urinary symptoms and sleep disturbances are most likely to influence anxiety …. need for a holistic approach to treatment (Jiang 2015).

Moderate stage: Apathy

Apathy Ratings: PD normal cognition vs PD MCI (Leroi 2012 ) Neuropsychiatric Inventory: Apathy Scale (Starkstein) Apathy subscale * 400 * 20 350 * 300 15 250 PD NC PD NC 200 10 PD MCI 150 PD MCI PDD 100 5 50 0 0 Self- rat ed Inf orm ant apat hy r ated ap ath y ANCOVA with age and motor severity as covariates: differences remained significant

Apathy has 3 key dimensions

Apathy is the only NPS that distinguishes PD from MCI-PD n=91 PwPD EB+ vs EB-

Apathy: emotional blunting ( ↑ indicates worse function) EB- EB+