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Disclosures

Neuropsychiatric complications of Parkinson ’ s disease Greg Pontone, MD, MHS Director Parkinson’s Disease Neuropsychiatry Clinic Johns Hopkins University School of Medicine. Disclosures. No relevant financial relationships with commercial interests.

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  1. Neuropsychiatric complications of Parkinson’s disease Greg Pontone, MD, MHSDirector Parkinson’s Disease Neuropsychiatry Clinic Johns Hopkins University School of Medicine

  2. Disclosures • No relevant financial relationships with commercial interests. • The following talk includes unlabeled/unapproved use of medications.

  3. Parkinson’s disease and mental health Objectives: • To become familiar with psychiatric disturbances in Parkinson’s disease (PD) including: anxiety, depression, and apathy • Discuss how the physical/biological aspects of PD may be associated with neuropsychiatric symptoms • Learn evidence based interventions for managing neuropsychiatric disturbances in PD

  4. I. Overview of Parkinson’s as a ‘disease’ model for neuropsychiatric symptomsII. Anxiety in PDIII. Depression and apathy in PD

  5. Clinical Diagnosis of PDRequires only motor symptoms First essential criterion: Slowing of physical movement (bradykinesia) Plus at least one of the following: • Tremor (4-7hz) • Muscle rigidity Postuma RB et al Mov Disord 2015

  6. Gross Pathology of Parkinson’s Disease

  7. Essay on the Shaking Palsy“…the senses and intellects being uninjured.” James Parkinson, 1817

  8. Non-motor symptoms of Parkinson’s disease • Olfactory loss, up to 90% of PD • Dysautonomia, up to 70% of PD (constipation, gastroparesis, ED, OH) • Neuropsychiatric symptoms: mood, and anxiety disorders 40-50%, psychosis, impulse control • Sleep disturbances >30%(e.g. RBD) • Cognitive impairment; up to 40% have selective deficits at diagnosis and 80% demented within 20 years of motor symptom onset Gonera et al 1997, Tolosa et al 2009, Yarnell et al 2014

  9. Extranigral Aspects of Parkinson’s disease (Arch. Neurol 2009, Lim et al)

  10. Cognitive disorders: mild cognitive impairment and dementia stages 5 & 6 frontal cortex parietal cortex basal nucleus hippocampus Psychosis: hallucinations, delusions stage 4 Motor symptoms: bradykinesia, rigidity, tremor substantia nigra amygdala stage 3 Mood disorders: Anxiety Depression locus coeruleus medullary raphe nuclei nucleus subcoeruleus Sleep disturbances: REM behavior disorder; excessive daytime sleepiness, insomnia, restless legs syndrome stage 2 Dysautonomia: gastrointestinal disturbances, constipation, genito-urinary dysfunction, sexual dysfunction, orthostatic hypotension, cardiac sympathetic denervation Olfactory loss; Hyposmia: impairments in odor detection, identification and discrimination autonomic nervous system dorsal motor X nucleus olfactory nerve stage 1 Figure 1. Clinical correlates of pathological staging in PD. Parkinson’s as a disease model for neuropsychiatric symptoms

  11. Anxiety and depression associated with the pathological process of PD? • The rate of anxiety and depression in PD is higher than in healthy or comparably disabled controls (e.g. MS, DM1, RA) • PET studies -severity of anxiety and depression inversely correlated with binding of both DA and NE transporters in the locus coeruleus, amygdala, and ventral striatum Stein et al 1990, Remy et al 2005

  12. Meta-analysis of anxiety and depression as risk factors for PD • 11 Case-control studies OR 1.90 (95% CI 1.62-2.22) • 2 Cohort studies OR 1.79 (95% CI 1.72-1.86) • Combined OR 1.86 (95% CI 1.64-2.11) • Noyce AJ et al. Ann Neurol 2012;72:893-901

  13. 16 14 12 10 8 Frequency 6 4 2 0 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 Duration between Earliest Major Depression Episode Onset and PD Diagnosis (years) TIME ZERO = PD ONSET Depressive disorders can occur at any stage of PD Ishihara and Brayne 2006

  14. 16 14 12 10 8 Frequency 6 4 2 0 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 Duration between Anxiety Disorder Onset and PD Diagnosis (years) Anxiety disorders can occur at any stage of PD

  15. 16 14 12 10 8 Frequency 6 4 2 0 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 Duration between Psychopathology Onset and PD Diagnosis (years) TIME ZERO = PD ONSET Intersection of mental and physical health in PD • Disease diagnosed at time zero • Reaction to observable symptoms/diagnosis • Medications introduced Ishihara and Brayne 2006

  16. Anxiety in Parkinson’s disease

  17. Prevalence of anxiety and anxiety disorders in PD • Up to 55% have clinically significant anxiety symptoms • 31% have an anxiety disorder (e.g. DSM) *Non-episodic (e.g. generalized disorders) more common than episodic Yamanishi et al 2013, Broen M et al 2016

  18. Anxiety as a ‘premotor’ symptom of Parkinson’s disease • Anxiety disorders are associated with later development of PD: OR 2.2 (95% CI 1.4-3.4; p=0.0003) up to 20 years before PD onset • Symptoms of phobic anxiety are associated with increased risk of PD: RR 1.5 (95% CI 1.0-2.1; p=0.01) • Anxious personality (from MMPI) was associated with increased risk of PD: HR 1.63 (95% CI 1.16-2.27; p=0.004) Shiba et al 2000, Weisskopf et al 2003, Bower et al 2010

  19. 8 6 4 2 0 -60 -40 -20 0 20 DURATION BETWEEN FIRST ANXIETY ONSET AND PD ONSET IN YEARS n=63 First Anxiety Disorder Onset Relative to PD Onset FREQUENCY Bimodal distribution of anxiety disorder onset compared to PD onset

  20. Dopaminergic on-off motor fluctuations • Improvement in motor symptoms after L-dopa administration = “on” • Return of parkinsonian movement symptoms at the end of the dosing effect = “off”

  21. Dopaminergic medication on-off fluctuations in PD Stacey M. and Hauser R. 2007

  22. Mood and motor fluctuation with levodopa infusion Maricle RA et al 1995

  23. Anxiety fluctuation with levodopa infusion Maricle RA et al 1995

  24. Treatment of anxiety in PD • Limited evidence from RCTs • In the general population, CBT, antidepressants, and benzodiazepines • Benzodiazepines may have additional risks in PD • Optimizing motor function and addressing motor fluctuations is likely important

  25. Evidence based treatments for anxiety in PD • Cognitive Behavioral Therapy (CBT) for depression and anxiety in PD • MDS Task Force on Evidenced Based Medicine and the American Academy of Neurology conclude that “the evidence to support or refute specific treatments for anxiety is insufficient” Zesiewicz et al 2010, Seppi et al 2011

  26. Depression in Parkinson’s disease

  27. National Parkinson Foundation • Parkinson’s Outcomes Project, a longitudinal look at which treatments produce the best health outcomes in PD n=12,000+ • The impact of depression on quality of life is almost twice that of the motor impairments

  28. Prevalence of Depression in Parkinson’s disease • 25% up to 50% (major to minor depression/dysthymia) • Rates of recurrence or treatment resistance unclear • Anxiety disorders often co-occur Reijnders 2008; Mayeux, 1981; Starkstein, 1992; Meara, 1999; Global PD Survey, 2002; Weintraub 2004; Even 2012; Shakeri2015; Ghaddar 2016; Reidel 2016

  29. NET-PD Study/Neuroprotective Treatment Trials • Mild depressive symptoms predicted development of more severe depressive symptoms (RR=6.16 [95%CI 2.14.17.73]) • Depressive symptom severity, older age, longer PD duration predicted failure to remit (HR 0.83-0.92) Ravina et al 2009

  30. NET-PD Study/Neuroprotective Treatment Trials Depressive symptoms predicted • Increased need for symptomatic PD therapy (HR 1.86; 95% CI 1.29-2.68) • Increased impairment in ADLs (p<0.0001) Ravina et al 2007

  31. Objective: This study examined the association between physical disability and DSM-IV-TR depression status across six years Methods: 137 adults with idiopathic PD. A generalized linear mixed model with Northwestern Disability Scale score as dependent variable to determine the effect of baseline depression status on disability Results: 43 depressed at baseline vs 94 without depression. Symptomatic depression predicted greater disability compared to both never depressed (p=0.0133) and remitted depression (p=0.0009) after controlling for sex, education, dopamine agonist use, and motor fluctuations.

  32. Longitudinal impact of depression on disability in PD (Pontone et al 2016)

  33. AntidepressiveTx for PD Systematic Review & Meta-analysis N=893, 20 RCTs (13 meds, 4 CBT, Alexander Tech, 2 rTMS) SMD=.56 SMD=.30 SMD—Non-antidepressants=-0.29 Bomasang-Layno et al 2015

  34. APATHY IN PARKINSON’S DISEASE

  35. Apathy in Parkinson’s disease • May affect more than 1/3 of persons with PD • Associated with more severe motor symptoms and cognitive impairment; more likely to be men and older age Pagonabarraga et al 2015

  36. Apathy in Parkinson’s disease 3+ symptoms lasting more than one month and impacting function • Reduced initiative and decreased self-driven ideas • Decreased curiosity and spontaneity • Difficulty continuing activities to completion • Indifference or blunted emotional reactions • Lack of concern about personal problems • Lack of affectionate behavior

  37. Apathy vs depression in PD Pagonabarraga et al 2015

  38. Management of apathy in PD • Non-pharmacological interventions -scheduled activities (social and physical) -establish clear and achievable goals -rewards conditional on completion of goals -recruit social support for activities • Dopamine agonists, stimulants, and antidepressants can be tried

  39. Questions?

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