Medication Management of Lewy Body and Parkinson's Dementias

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1 Medication Management of Lewy Body and Parkinson's Dementias Jill Kauer, PharmD, MSPhr, BCPP September 2014 Disclosure Statement I, Jill Kauer, PharmD, MSPhr, BCPP do not have any financial interests or relationships with any manufacturers of products or providers of services I might be discussing in my presentation. I have no financial relationships with any of the companies supporting this educational event. I will not discuss any pharmaceuticals, medical procedures, or devices that are investigational or unapproved for use by the FDA. Epidemiology Dementia with Lewy Bodies (DLB) Prevalence estimates vary; approximately 15-30% of all dementia cases Parkinson s Disease with Dementia (PDD) Dementia in 24-31% of patients with Parkinson s disease Prevalence increases w/duration of Parkinson s disease Incidence ~10% of Parkinson s patients/year Similarities in DLB & PDD Common pathophysiology: disorder of α-synuclein metabolism Parkinsonian symptoms More preserved memory compared to Alzheimer s dementia but greater disturbance in attention, alertness, executive function, and visuoperceptual function Complex, well-formed visual hallucinations Sensitivity to extrapyramidal side effects of antipsychotics May be less pronounced in PDD REM sleep behavior disorder Vivid dreams associated with motor behavior during sleep Autonomic abnormalities Dodel et al. J Neurol, 2008; Troster Neuropsychol Rev, 2008 Dodel et al. J Neurol, 2008; Troster Neuropsychol Rev, 2008 Distinguishing DLB & PDD Dementia w/lewy Bodies Cognitive impairment develops prior to or concurrently w/motor symptoms Possibly more disturbance in attention Less tremor Less responsive to levodopa Parkinson s Disease w/dementia Cognitive impairment occurs after longstanding Parkinson s disease ( 1 yr) Greater asymmetry of parkinsonian symptoms Psychotic Symptoms in DLB & PDD Hallucinations Typically visual, though auditory not uncommon Most commonly animal or human figures Common delusional themes Paranoid (persecution and theft) Phantom boarder syndrome Television characters in the room Spousal infidelity Capgras syndrome may be seen in DLB Dodel et al. J Neurol, 2008; Troster Neuropsychol Rev, 2008 Weintraub & Hurtig Am J Psychiatry, 2007; Aarsland et al. Int J Geriatr Psychiatry,

2 DLB Patient Case 68 yo male admitted to combined internal medicine/psychiatry unit with hallucinations & confusion PMH: Dx w/parkinson s disease 3 yrs ago; HTN; HLD; CAD (s/p MI & stent) Parkinson s treatment history Managed solely by PCP No meds for 1 st yr, started on carbidopa/levodopa for 1 yr before visual hallucinations began Hallucinations prompted switch to ropinirole, titrated up to 0.75 mg TID Ropinirole discontinued at an outside hospital 2 days earlier due to worsening hallucinations DLB Patient Case (cont.) Additional information from patient interview Patient has had progressive confusion since his Parkinson s disease diagnosis per wife Patient able to remember and tell about the multiple jobs he has had throughout his life Physical findings Masked facies; very mild tremor; mild cogwheel rigidity in upper extremities; micrographia; mildly hypophonic speech; unsteadiness transitioning from sitting to standing and walks with walker DLB Patient Case (cont.) Hospital course Neurology consulted. Concerned for possible DLB vs Parkinson s. Recommended starting low dose of carbidopa/levodopa (1/2 tab of 25/100 TID). Neuropsych testing conducted. No evidence of REM behavior disorder but marked fluctuations in level of alertness. Hx progressive visual hallucinations. Marked deficits in executive function based on completed tests. Findings appear to be broadly consistent with Lewy Body Dementia. Neurology recommended donepezil based on DLB diagnosis and to consider low-dose quetiapine if hallucinations and agitation became a significant problem. DLB Patient Case (cont.) Medication Interventions Carbidopa/levodopa started & increased to one 25/100 mg tab TID by discharge Donepezil started at 5 mg HS Quetiapine was not initiated Sertraline started at 25 mg daily and increased to 50 mg daily to target significant anxiety symptoms Treatment Targets for DLB & PDD Parkinsonian symptoms Cognitive impairment Psychosis Depression Management of Parkinsonian Symptoms in DLB & PDD PDD: patients generally already treated since dementia manifests long after motor symptoms DLB: only treat if symptoms interfere with function Response to levodopa in DLB & PDD impaired compared to Parkinson s patients without dementia Suggested that falls may be reduced even in patients without optimal motor response Dodel et al. J Neurol, 2008; Poewe Mov Disord, 2005; Lucetti et al. Parkinsonism Relat Disord, 2010; Ballard et al. Drugs Aging,

3 Antiparkinsonian Agents Dopamine precursor Levodopa Dopamine precursor extenders Carbidopa (decarboxylase inhibitor) Catacholamine O-methyltransferase (COMT) inhibitors Entacapone Tolcapone Anticholinergics Benztropine Trihexyphenidyl Dopamine agonists Ropinirole Pramipexole Bromocriptine Rotigotine (transdermal) Apomorphine (subcutaneous) Amantadine Monoamine oxidase B (MAO-B) inhibitors Selegiline Rasagaline Antiparkinsonian Agents May exacerbate psychotic symptoms RCT data: psychosis more common with dopamine agonists than levodopa May exacerbate cognitive impairment Anticholinergics can further impair attention Generally avoid anticholinergics in patients with dementia Carbidopa/levodopa is mainstay of treatment Start low and titrate slowly Parkinson Study Group JAMA, 2000; Troster Neuropsychol Rev, 2008; Horstink et al. Eur J Neurol, 2006 Management of Cognitive Impairment in DLB & PDD Evidence exists for cholinesterase inhibitors and memantine Treatment effects on cognition are modest Must weigh potential benefits of the cognitive enhancers against the adverse effects Cholinesterase Inhibitors Cholinergic deficits greater in DLB & PDD than in Alzheimer s disease May have added benefit of improving hallucinations Horstink et al. Eur J Neurol, 2006 Rivastigmine McKeith 2000 (DLB) 120 pts, rivastigmine (mean dose 9.4 mg/d) vs. placebo for 20 wks Improvements in Neuropsychiatric Inventory subscale score (NPI-4, including apathy & psychosis) significant for observed cases but not intent-to-treat MMSE scores not statistically different, though mean 1.6-pt improvement vs. placebo for rivastigmine completers More adverse events with rivastigmine (92% vs. 75%); no differences in motor symptom scores Rivastigmine Emre 2004 (PDD) 541 pts, rivastigmine (mean dose 8.6 mg/d) vs. placebo for 24 wks Mean 2.1-point improvement in ADAS-cog vs. placebo; clinically meaningful improvement in 19.8% vs. 14.5% for placebo 17% of pts receiving rivastigmine left the study due to adverse effects vs. 8% for placebo; no differences in motor symptom scores but significantly more tremor with rivastigmine McKeith et al. Lancet, 2000 Emre et al. NEJM,

4 Rivastigmine Emre 2014 (PDD) Long-term, open-label safety study of rivastigmine capsules (n = 295, mean dose 8.86 mg/d) or patch (n = 288, mean dose 9.22 mg/d) for 76 wks Incidence of adverse events due to worsening parkinsonism was 36.1% with capsules and 31.9% with patch (tremor most common, less with patch); falls ~20% in both groups 26% of pts overall withdrew due to adverse effects (nausea worse with capsules) Donepezil Mori 2012 (DLB) 140 pts, donepezil (3, 5, or 10 mg) vs. placebo for 12 wks Significantly greater mean improvement on MMSE in 5 mg (3.4) and 10 mg (2.0) groups vs. placebo NPI-4 scores significantly improved with 10 mg group No differences in study withdrawals due to adverse effects; no significant differences in nausea, vomiting, or parkinsonian symptoms between donepezil & placebo Emre et al. NEJM, 2004 Mori et al. Ann Neurol, 2012 Donepezil MMSE score increased ~2 pts in two small placebocontrolled crossover trials in PDD Dubois 2012 (PDD) 550 pts, donepezil (5 or 10 mg) vs. placebo for 24 wks Mean 1.45-point improvement in ADAS-cog vs. placebo (not significant); significant improvement in MMSE ~1.5 pts with donepezil Significant improvement in scores of global function for 10 mg but not 5 mg vs. placebo More pts withdrew due to adverse effects with donepezil; no differences in motor symptom scores but more tremor with donepezil Aarsland et al. J Neurol Neurosurg Psychiatry, 2002; Ravina et al. J Neurol Neurosurg Psychiatry, 2005; DuBois et al. Mov Disord, 2012 Cochrane Reviews of Cholinesterase Inhibitors PDD Studies support positive impact on global assessment, cognitive function, behavioral disturbance, and activities of daily living LBD Effect remains unclear Weak evidence for benefit on neuropsychiatric symptoms; may be an alternative to antipsychotics Tolerability More dropouts & adverse events for rivastigmine vs. donepezil Rolinski et al. Cochrane Database Syst Rev, 2012; Wild et al. Cochrane Database Syst Rev, 2003 Memantine Leroi 2009 (PDD) 25 pts, memantine 20 mg daily vs. placebo for 16 wks (plus 6-wk washout) No significant difference in cognitive impairment or NPI scores, though deterioration of function after 6 wks off drug worse with memantine MMSE scores at end of drug treatment not better than placebo Tolerability similar to placebo Memantine Aarsland 2009 (DLB & PDD) 72 pts (32 DLB, 40 PDD), memantine 20 mg daily vs. placebo for 24 wks (cholinesterase inhibitors allowed) Significant mean difference in global change at week 24 (Cohen s d = 0.52) 27% of pts achieved moderate or substantial improvement with memantine vs. 17% with placebo Improvement in MMSE 1.9 pts with memantine (not significant); no differences in change on NPI Study withdrawals due to adverse effects similar to placebo; no differences in motor symptom scores Separate secondary analysis showed significantly improved quality of life in memantine group Leroi et al. Mov Disord, 2009 Aarsland et al. Lancet Neurol, 2009; Larsson et al. Dement Geriatr Cogn Disord,

5 Memantine Emre 2010 (DLB & PDD) 199 pts (78 DLB, 121 PDD), memantine 20 mg daily vs. placebo for 24 wks No significant difference in global change or NPI scores at week 24 for total population, but significant for DLB pts alone Adverse effects similar to placebo Overall for memantine: inconsistent data for benefits though well tolerated Clinician s Global Impression of Change: Continuous Data Meta-Analysis of Cognitive Enhancers Emre et al. Lancet Neurol, 2010 Wang et al. J Neurol Neurosurg Psychiatry, 2014 Meta-Analysis of Cognitive Enhancers Meta-Analysis of Cognitive Enhancers Mini-Mental State Examination: Continuous Data Neuropsychiatric Inventory: Continuous Data Wang et al. J Neurol Neurosurg Psychiatry, 2014 Wang et al. J Neurol Neurosurg Psychiatry, 2014 Cognitive Enhancer Adverse Effects Cholinesterase inhibitors Nausea/vomiting, anorexia, somnolence, dizziness, tremor (in pts with PDD) May increase falls with long-term treatment Memantine No significant difference from placebo in clinical trials for DLB & PDD Most common in prescribing info: dizziness, confusion, headache, constipation Management of Psychosis in DLB & PDD Identify and treat any infections, metabolic disorders, electrolyte abnormalities Discontinue any nonessential medications that could contribute to mental impairment e.g. anxiolytics/sedatives, anticholinergic antidepressants Attempt to reduce antiparkinsonian drugs before adding antipsychotics Stop anticholinergics and amantadine, then reduce/stop dopamine agonists, then reduce/stop MAOIs & COMT inhibitors, then reduce carbidopa/levodopa as last resort Choose antipsychotic medications least likely to exacerbate parkinsonian symptoms and use low doses Weintraub & Hurtig Am J Psychiatry, 2007; Horstink et al. Eur J Neurol,

6 Antipsychotics Avoid typical antipsychotics Clozapine and quetiapine are considered best choices (use LOW doses!), but risk of adverse effects must still be considered Risperidone and olanzapine clearly worsen parkinsonism Aripiprazole also shown to worsen parkinsonism despite being a D 2 partial agonist Mechanistic Considerations for Antipsychotics Blockade of dopamine D 2 receptor in the mesolimbic dopamine tract leads to antipsychotic activity Blockade of D 2 receptors in the nigrostriatal dopamine tract can cause or exacerbate parkinsonian symptoms Agents with faster dissociation ( fast-off ) from D 2 receptors have lower risk for parkinsonism Weintraub & Hurtig Am J Psychiatry, 2007; Horstink et al. Eur J Neurol, 2006 Seeman Can J Psychiatry, 2002 % of D 2 Receptors Occupied Seeman Can J Psychiatry, 2002 Brief D 2 Occupation by Clozapine & Quetiapine D2 threshold for antipsychotic effect Hours after oral dose Evidence for Clozapine & Quetiapine Three well-designed placebo-controlled studies found clozapine effective for reducing psychosis with no worsening of parkinsonism or cognition in patients with Parkinson s psychosis Two negative placebo-controlled trials for quetiapine in Parkinson s psychosis; one negative trial specifically in patients with dementia (23 DLB, 9 PDD, 8 AD) Weintraub & Hurtig Am J Psychiatry, 2007; Ballard et al. Drugs Aging, 2011 Clozapine vs. Quetiapine Clinical trial comparison Small (N = 45) comparative study of quetiapine (mean dose 91 mg) & clozapine (mean dose 26 mg) in patients with Parkinson s psychosis (dementia excluded) Both agents led to statistically similar reductions in Brief Psychiatric Rating Scale scores with no significant increases in ratings of parkinsonism Clinical differences Quetiapine generally preferred over clozapine because of tolerability Antipsychotic Adverse Effects Can exacerbate parkinsonism Associated with severe sensitivity reaction in DLB & PDD patients Both olanzapine & quetiapine cause sedation, orthostasis, anticholinergic effects, and adverse metabolic effects (worse with clozapine) Clozapine also associated with rare risk of myocarditis, seizures, and agranulocytosis Weekly CBC/ANC monitoring required for first 6 mos, then every 2 wks for 6 mos, then monthly throughout treatment Monitor for constipation with clozapine; may also develop sialorrhea Morgante et al. Clin Neuropharmacol, 2004 McKeith et al. BMJ, 1992; Aarsland et al. J Clin Psychiatry,

7 Increased Mortality in Elderly with Dementia-Related Psychosis Elderly patients with dementia related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo Analysis of 17 RCTs revealed a risk of death with atypical APs 1.6 to 1.7 times that seen with placebo Rate of death 4.5% with drug vs. 2.6% with placebo Majority of deaths were cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) Initial 2005 warning for atypical APs, but extended to all antipsychotics in 2008 (risk is similar with typical APs) Management of Depression in DLB & PDD No studies of antidepressants for depression in DLB, though some evidence for ECT and rtms in treatment-resistant depression Evidence in patients with Parkinson s disease is limited and results are mixed Gill et al. Ann Intern Med, 2007; Ray et al. NEJM, 2009 Aarsland et al. Curr Neurol Neurosci Rep, 2012; Connolly & Lang JAMA, 2014 Antidepressants May have poorer response than elderly patients without Parkinson s disease Limited evidence supports TCAs and SSRIs in patients with Parkinson s disease; stronger evidence for TCAs, though SSRIs are associated with fewer adverse effects Anticholinergic effects of TCAs may exacerbate cognitive dysfunction in DLB & PDD; also a concern for orthostasis & falls Start low and titrate slowly Back to Patient Case Carbidopa/levodopa a better choice than most recent trial of ropinirole; used lower dose than in patient s previous carbidopa/levodopa trial Donepezil vs. rivastigmine Best to avoid antipsychotics if unnecessary, though QTP would be a reasonable choice if needed Sertraline has no supporting evidence in this population, but anxiety a significant concern for this patient & his wife Dodel et al. J Neurol, 2008; Horstink et al. Eur J Neurol, 2006; Connolly & Lang JAMA, 2014 Summary Carbidopa/levodopa is generally preferred for management of parkinsonian symptoms in DLB & PDD, though symptoms may not respond as well as in patients with Parkinson s disease without dementia Anticholinergic agents worsen cognitive impairment and dopamine agonists have a higher propensity to exacerbate psychotic symptoms Cholinesterase inhibitors show modest improvement in cognition and may also reduce psychotic symptoms, but tolerability is an issue Unclear benefit of memantine, but better tolerated than cholinesterase inhibitors Summary Reduction of antiparkinsonian agents and discontinuation of potentially cognitively impairing medications should come before initiating antipsychotics when managing psychosis in DLB & PDD Quetiapine and clozapine are preferred if antipsychotics are needed due to low potential to exacerbate parkinsonism Antidepressants are poorly studied in DLB & PDD populations, though SSRIs are usually first choice in clinical practice Avoid antidepressants with anticholinergic effects 7