7/14
Perspectives on the Neuropsychiatry of Parkinson’s
Disease
Daniel Weintraub, M.D.
Associate Professor of Psychiatry and Neurology, University of Pennsylvania;
Parkinson’s Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC),
Philadelphia VA
Disclosures • Research funding: Michael J. Fox Foundation for Parkinson’s Research,
National Institutes of Health, Novartis Pharmaceuticals, Department of Veterans Affairs, and Alzheimer’s Disease Cooperative Study
• Honoraria: Teva Pharmaceuticals, Lundbeck Inc., Pfizer, Avanir Pharmaceuticals, Merck & Co., UCB, Bristol-Myers Squibb Company, Novartis Pharmaceuticals, Eli Lilly and Company, Clintrex LLC, Theravance, Medivation, CHDI Foundation, and Alzheimer’s Disease Cooperative Study
• License fee payments: University of Pennsylvania for the QUIP and QUIP-RS
• Fees for testifying in court cases: Related to impulse controls disorders in Parkinson’s disease (March, 2013-April, 2014).
• The talk includes discussion of medications that has not been approved by the U.S. Food and Drug Administration (pimavanserin for PD psychosis, rasagiline for neuropsychiatric symptoms in PD, and naltrexone for PD ICDs)
Introduction
PD as Neuropsychiatric Model - I
• DSM-5 encapsulated for neuropsychiatric symptoms (NPS) (1) Depression (2) Psychosis (3) Cognitive impairment (4) Impulse control disorders (5) Anxiety (6) Apathy (7) Disorders of sleep and wakefulness
• Relatively common disease – 500,000-1,000,000 (and growing) in US
PD as Neuropsychiatric Model - II
• Neural substrate relevant to psychiatry (1) Brain regions (basal ganglia, prefrontal cortex) (2) Neurotransmitter deficits (dopamine, norepinephrine, serotonin, acetylcholine and glutamate) (3) Neural pathways (cortico-striatal-thalamic circuitry)
• Known neuropathology (α-synuclein) – Imaging and CSF biomarkers under development
• Inter- and intra-individual variability allows study – Affective and cognitive changes between “on” and “off”
motor states (non-motor fluctuations common)
PD as Neuropsychiatric Model - III
• NPS can predate motor symptoms – Provides biological plausibility for NPS in PD
• PD treatments used for psychiatric disorders – PD medications (selegiline transdermal patch for
depression) and deep brain stimulation (DBS) • Reversibility of some psychiatric symptoms
– Certain NPS induced by PD treatments and therefore reversible (ICDs and psychosis)
Depression
Depression as Pre-Clinical (Bio)marker of Parkinson’s Disease
Depressive disorder Osteoarthritis
APD, main effects 2.57 (1.46–4.52) 1.00 APD after 0–6 months 3.30 (1.01–10.78) 1.00 APD after 6–12 months 3.65 (1.12–11.94) 1.00 APD after +12 months 2.66 (1.31–5.41) 1.00
Rate ratios (RR) of anti-parkinson drug (APD) treatment: main effects, according to sex and according to duration of index disease.
Brandt-Christensen et al. Acta Psychiatr Scand 2007;115:466-472.
Depressive Symptoms in De Novo PD: PPMI Baseline Results
Weintraub et al. (under review).
Treatment and Neurotransmitters I: Norepinephrine
Menza et al. Neurology 2009;72:886-892.
Treatment and Neurotransmitters II: Dopamine
Barone et al. Lancet Neurology 2010;9:573-580.
Treatment and Neurotransmitters III: Serotonin
Richard et al. Neurology 2012;79:1229-1236.
Mean 12 Week ∆ in HAM-D Score Comparison Effect 95% CI P-value
Paroxetine vs. Placebo -6.2 (-9.7, -2.7) <0.001
Venlafaxine vs. Placebo -4.2 (-7.8, -0.6) 0.02
SAD-PD: Study of Antidepressants in Parkinson's Disease
MAO-B Augmentation of Antidepressant Treatment: ADAGIO Study
Difference in MDS-UPDRS depression item at end of 6-month, placebo-controlled phase (N=191)
Smith et al. (JAMA Neurology - in press).
Effect size=.29 (small-medium)
What is Risk for Serotonin Syndrome?
• In ADAGIO study, of close to 100 patients who were on combination of MAO-B inhibitor + antidepressant for 6 months, 0 cases of serotonin syndrome based on adverse event reporting
Differential Effects for DBS?
Follett et al. NEJM 2010;362:2077-2091.
“The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation.”
Suicide and DBS: What’s the Evidence?
Weintraub et al. JNNP 2013;84:1113-1118.
CSP 468 Study
Psychotherapy
Oehlberg et al. JGPN 2008;21:123-132. Dobkin et al. AJP 2011;168:1066-1074.
“Assessed 38 PD patients with depression…Many had concerns about antidepressant therapy, listing side-effects and medication dependency most frequently…many PD patients attribute their depression to psychosocial factors and endorse nonpharmacologic treatment.”
Qualitative Research
Psychosis
Update on Psychosis • Recent developments….
– Cumulative prevalence of psychosis is HIGH – Hallucinations other than visual common – Cause of psychosis complex – Multiple brain chemicals/regions affected – Antipsychotic (AP) use in PD is common but
poorly supported – Potential risks associated with AP use – New treatment for PD psychosis on horizon
Year Psychosis + Prevalence
Baseline 41/230 18%
Year 4 51/142 36%
Year 8 45/88 51%
Year 12 12/25 48%
Cumulative 137/230 60%
Non-Visual and Minor Hallucinations More Common Than Previously Thought
Fenelon et al. Movement Disorders 2010; 25: 755–759
Early Disease Course - PPMI
Psychosis (% present)
BL
12 months
24 months
Change in PD
over time
Change between groups
over time
PD 3.1% (13/423)
5.4 % (14/261)
10.4% (10/96)
11.64 (2), p=0.003
1.49 (2), 0.59 HC 0.5%
(1/195) 0%
(0/145) 2.4% (2/83)
Fischer test, p 0.076 0.003 0.038
de al Riva et al. (Neurology – in press).
Variable UPDRS Part I Hallucinations and Psychosis item
PD
Subjects (N = 423)
Healthy Controls (N = 196)
Statistic
(Chi-square)
df
p-value
Negative 410 (97%) 194 (99%) 3.95
1
0.047
Any positive score 13 (3%) 1 (1%)
Complex Etiology • PD medications
– Recent controversy regarding this • Cognitive impairment • Increasing age, duration and severity of PD
– All highly correlated • Alterations in visual pathways • Alterations in serotonergic system • Co-morbid sleep-wakefulness disorders
– RBD and EDS
Pacchetti et al. Movement Disorders 2005;20:1439-1448.
Antipsychotic (AP) Use in PD: What’s the Evidence?
• Specific antipsychotics – Quetiapine medication of choice
• However, all placebo-controlled quetiapine studies negative
– Clozapine • Efficacious in 2 placebo-controlled studies at low doses
“Based on randomized trial-derived evidence which is currently available, only clozapine can be fully recommended for the
treatment of DIP in PD.”
Frieling et al. European Neuropharmacology 2007;17:165-171.
Current AP Prescribing in PD
Weintraub et al. Archives of Neurology 2011;68:899-904.
• 50% of PD patients with psychosis prescribed an AP • Quetiapine most frequently prescribed AP (66% of treated patients) • 30% receive high potency APs (typicals + atypicals) • Clozapine rarely prescribed (<2%)
What’s the Problem? Risks With AP Use in General Dementia Patients
• Increased morbidity and mortality – Increased risk of CVAEs and mortality (1.6-1.7
times) secondary to CVEs and infections
• Issued for atypical APs in 2005 – Extended to typical APs in 2008
• Also Type 2 diabetes, orthostatic hypotension, dry mouth, sedation, dizziness, constipation
BLACK BOX WARNING
Mortality Outcomes in PD Patients Treated with an AP
Merit Review Award (Kales and Weintraub-PI’s). (unpublished data).
Pimavanserin* for PD Psychosis *5HT-2A inverse agonist
Cummings et al. The Lancet 2013;383:533-540.
Porsteinsson et al. JAMA 2014;311:682-691.
Cognitive Impairment
Patient’s Perspective
Dementia Very Common Long-Term
Mild Cognitive Impairment Also Common
Consistent Negative DBS Effect
BMT DBS Difference
Weaver et al. JAMA 2009;301:63-73.
Better Response to Cholinesterase Inhibitors in PDD Than AD?
Weintraub et al. Am J Alzheimer’s Disease & Other Dementias 2011;26:443-449.
Norepinephrine and Cognition in PD
Weintraub et al. Neurology 2010;75:448-455.
What’s in a Name? PDD vs. DLB vs. LBD – An Untenable Situation
• Strong similarities in clinical syndrome – Dementia + parkinsonism + psychosis +
fluctuating cognition / attention • Strong similarities neuropathologically • Problem
– Confusing terminology (DSM-5 example) – Under-diagnosis of DLB in specialty care – Complicates advocacy and research – Limits treatment advances
McKeith IG et al. Neurology 2005;65:1863-1872.
Impulse Control Disorders (ICDs)
DOMINION Study
• An ICD identified in 14% of patients – 29% of ICD patients had ≥2 ICDs
• Frequencies of individual ICDs were: – Problem/pathological gambling = 5.0% – Compulsive sexual behavior = 3.5% – Compulsive buying = 5.7% – Binge-eating disorder = 4.3%
Weintraub et al. Archives of Neurology 2010;67:589-595.
Multivariable Analysis of ICD Correlates Variable* Entire Study Population (N=3090)
Odds ratio [95% CI] P value PAR%&
Age (≤65 years vs. >65 years) 2.50 [1.98; 3.15] <0.001 41.2%
Marital status (not married vs. married) 1.48 [1.16; 1.89] 0.002 7.4%
Country (living in United States) 1.62 [1.25; 2.10] <0.001 27.9%
Current smoking (yes vs. no) 1.70 [1.07; 2.70] 0.02 2.9%
Family history gambling problems (yes vs. no)
2.08 [1.33; 3.25] 0.001 1.5%
DA treatment (yes vs. no) 2.72 [2.07; 3.57] <0.001 49.3%
Levodopa treatment (yes vs. no) 1.51 [1.09; 2.09] 0.01 9.6%
* Clinical and demographic variables included were those with P value <0.10 on univariate analysis; data presented for significant results only; & PAR% (population attributable risk percentage) for exposure variable = ([prevalence in the entire population – prevalence in unexposed population] / prevalence in entire population) x 100. The PAR% is a univariate calculation, so the sum of the PAR% for multiple variables can exceed 100%.
Weintraub et al. Neurology 2013;80:176-180.
Current Management Options • Do nothing
– Assess significance • Alterations to PD pharmacotherapy
– Discontinue, lower or switch DA therapy – But dopamine agonist withdrawal syndrome (DAWS)
described • Psychosocial treatment • Psychopharmacology
– Antidepressants (SSRIs), antipsychotics, and mood stabilizers (anticonvulsants) used clinically
• Consider deep brain stimulation (DBS)
Psychological Treatment (CBT) for Biological Problem
Okai et al. Neurology 2013;80:792-799.
Opioid Antagonist Study
• Michael J. Fox Foundation grant • Randomized, double-blind, placebo-controlled
clinical trial of naltrexone for all ICDs – Naltrexone is a competitive opioid receptor
anatagonist FDA-approved for Etoh dependence – Modulatory role for opioid peptides in the
nigrostriatal dopaminergic pathway • 50 subjects with ≥1 of 4 common ICDs
randomized to naltrexone or placebo
Papay et al. (Neurology – in press).
Mixed-effects model
Conclusions 1. PD is neuropsychiatric/cognitive disease 2. Multi-morbidity of psychiatric disorders is norm 3. Need for PD-specific screening instruments, rating
scales, and diagnostic criteria 4. Under-recognition and under-treatment persists 5. Limited or lack of efficacy evidence for many
existing treatments 6. PD treatments may have mixed effects on
psychiatric and cognitive status
Acknowledgements • Grant support from NIMH, NINDS, Department of
Veterans Affairs, State of Pennsylvania, Fox Foundation, and Novartis
• Patients, family members, and colleagues at PD centers at Penn and Philadelphia VA
• Current and past research staff – Jacqui Rick, Eugenia Mamikonyan, Kimberly Papay, Sarra
Nazem, Staci Stewart
