Medication Treatments for Dementia Stephen Thielke Treatment is a MORAL decision. Facts can help you determine HOW to accomplish something. Facts cannot tell you WHAT YOU WANT to accomplish. Dementia Meds (Thielke), NWGEC WInter 2015 1
IS Factual Scientific X SHOULD OUGHT Moral Values- Based The Good Diminished symptoms? Cure? Years of life? Quality-adjusted years of life? Patient autonomy? Public safety? They would thank me later? I wouldn t want to live like that? Long-term ends or the means? Intentions or results? Dementia Meds (Thielke), NWGEC WInter 2015 2
Possible Treatment Advice We have FDAapproved treatments for dementia. They treat the disease. You should use one. FDA-approved treatments exist. They improve symptoms, but produce no difference in caregiver burden or nursing home Do you want to use one? Treatments exist, but they do not modify the disease course, and provide only symptomatic benefit in about 1/3 of patients. Do you want to use one? Medications for dementia do not fix the problem. They are unlikely to help you and are expensive and dangerous. You should not take one. Official and Unofficial Indications FDA-approved does not mean should be prescribed for everyone. Medication giving and taking are complex behaviors. Your reasons for prescribing a medication are less important than the patient s or family s reasons for using it. Why might families want to give medications, regardless of their direct effects? Dementia Meds (Thielke), NWGEC WInter 2015 3
One of the first duties of the physician is to educate the masses not to take medicine. Far too large a section of the treatment of disease is today controlled by the big manufacturing pharmacists, who have enslaved us in a plausible pseudo-science. Evidence-Based Outcomes The outcome is supposed to be what matters to people who would use the treatment. What outcomes were chosen? Were they chosen before or after the study? Did all outcomes improve? Dementia Meds (Thielke), NWGEC WInter 2015 4
OVERVIEW: Alzheimer s Dementia Cholinesterase Inhibitors Memantine Other Dementias Behavioral Symptoms Definition of Dementia A significant chronic loss in memory and/or mental functions, involving structural damage to the brain. DEMENTIA IS NOT CURABLE. Dementia Meds (Thielke), NWGEC WInter 2015 5
THE NEURONS HAVE DIED Why would you want to give a medication for an incurable disease? How much risk would you undertake in order to accomplish certain benefits? Dementia Meds (Thielke), NWGEC WInter 2015 6
Cognitive Symptoms Memory problem plus one of: Aphasia Apraxia Agnosia Executive dysfunction Causes significant functional impairments Problematic Behaviors Wandering Agitation Verbal or motor Inappropriate or repetitive Poorly timed bodily needs Unsafe tasks Driving Cooking Aggression Screaming Sexuality Repetition Following Destruction Stereotypy Dementia Meds (Thielke), NWGEC WInter 2015 7
Neuropsychiatric Symptoms Hallucinations Delusions Paranoia Depression Apathy Emotional incontinence Restlessness Frequency and Course of Symptoms Cache County Study: 20% of communitydwelling patients with Alzheimer s dementia have behavioral symptoms. Lyketsos et al, Am J Psy 2000 Cognitive decline is steady during the course of dementia, but behavioral symptoms fluctuate. Psychomotor agitation is the most persistent. Devanand et al, Arch Gen Psy 1997 Dementia Meds (Thielke), NWGEC WInter 2015 8
Categories of Medication with an FDA Indication to Treat Cognitive Symptoms of Dementia: 2 Medications with an FDA Indication to Treat Behavioral Symptoms of Dementia: 0 Dementia Meds (Thielke), NWGEC WInter 2015 9
Medications with an FDA Indication to Prevent Dementia: 0 Medications used in at least one trial to prevent or treat dementia or its symptoms: >50 Dementia Meds (Thielke), NWGEC WInter 2015 10
Tricyclics SSRIs SNRIs Bupropion Mirtazapine Trazodone Typical antipsychotics Atypical antipsychotics Buspirone Alpha blockers Beta blockers Antihistamines Dementia Meds (Thielke), NWGEC WInter 2015 11
Cannabinoids Opioids Methylphenidate Lamotrigine Antiepileptic drugs Lithium Estrogen Vitamin E Homocysteine B Vitamins Resveratrol Ginseng Dementia Meds (Thielke), NWGEC WInter 2015 12
Acetylcholinesterase inhibitors Nicotine NMDA antagonists Lisuride Racetams Methylene blue Intranasal insulin Cyproterone NSAIDs COX2 Inhibitors H2 blockers Thiazide diuretics Calcium channel blockers ACE inhibitors Statins Dementia Meds (Thielke), NWGEC WInter 2015 13
CONCLUSION: Acupuncture at Baihui (GV 20), Shenshu (BL 23), Geshu (BL 17), and the points selected according to the midnight-noon, ebb-flow eight methods of the intelligent turtle combined with the drug nimodipine can yield definite therapeutic effects in vascular dementia. Zhong 2009 Cholinesterase Inhibitors Galantamine (Razadyne, Reminyl) Donepezil (Aricept) Rivastigmine (Exelon) Tacrine (Cognex) Increase levels of acetylcholine more acetylcholine in brain, more parasympathetic activity in periphery Dementia Meds (Thielke), NWGEC WInter 2015 14
Cholinesterase Inhibitors Cholinesterase Inhibitors Side effects: usually transitory GI upset, diarrhea Reduced heart rate Interactions Effects are BLOCKED by anticholinergic drugs No significant drug-drug interactions Dementia Meds (Thielke), NWGEC WInter 2015 15
MMSE Score Winblad, 2001 ADAS-Cog Score Corey-Bloom, 2000 Dementia Meds (Thielke), NWGEC WInter 2015 16
MMSE Score Tariot, 2000 But Over 2 years, patients on donepezil showed 0.8 points improvement in MMSE and a one-point improvement in ADLs n=565 Courtney, 2004 Dementia Meds (Thielke), NWGEC WInter 2015 17
Cholinesterase Inhibitors no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths Courtney, 2004 Dementia Meds (Thielke), NWGEC WInter 2015 18
Cost Effectiveness: Cost of cholinesterase inhibitor is roughly $5 per day Cost-effectiveness ratio of the most cost-effective medication: $400 per unit decline in the ADAS-cog subscale over 6 months The ADAS-cog has 70 points Although statistical improvements were noted in the analyses, they do not necessarily translate into clinically relevant benefits for the patients receiving these drugs or for their caregivers. Perras C, Shukla VK, Lessard C, Skidmore B, Bergman H, Gauthier S. Cholinesterase inhibitors for Alzheimer s disease: a systematic review of randomized controlled trials [Technology report no 58]. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2005. Dementia Meds (Thielke), NWGEC WInter 2015 19
Memantine Partially reversible NMDA antagonist Approved for moderate to severe dementia Most studies evaluated combination of memantine with cholinesterase inhibitors Few side effects: headache, constipation, confusion FDA Indications Generic Trade FDA Indication (Alzheimer s Stage) donepezil Aricept All stages galantamine Razadyne Mild to moderate rivastigmine Exelon Mild to moderate tacrine Cognex Mild to moderate memantine Namenda Moderate to severe This does NOT mean that everyone with a certain stage of dementia should or must be taking the corresponding medication! Dementia Meds (Thielke), NWGEC WInter 2015 20
Pharmacologic therapeutic interventions of the 5 FDA-approved drugs discussed in the review have shown statistically significant improvement in scores on various instruments to evaluate changes in patients with dementia. Most of these outcomes are not used in routine clinical practice, and interpretation of the clinical importance of improvements is challenging. Many of the improvements demonstrated in the trials, although statistically significant, were not clinically important or their relative importance cannot be determined at this time. Qaseem et al, Current Pharmacologic Treatment of Dementia: A Clinical Practice Guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148:370-378 Vascular Dementia No FDA-indicated treatments No consistent results from treatment trials of cholinesterase inhibitors Dementia Meds (Thielke), NWGEC WInter 2015 21
Lewy Body Dementia AVOID ANTIPSYCHOTICS No FDA-indicated treatments for Lewy Body dementia Rivastigmine has an indication for treating dementia associated with Parkinson s disease AVOID ANTIPSYCHOTICS Frontotemporal Dementia No FDA-approved treatments Many small trials, many of them negative Difficult to conduct good trials Dementia Meds (Thielke), NWGEC WInter 2015 22
Stopping Medications Patients often seem worse after they have stopped a medication. This may have nothing to do with the medication. Other medical events Other changes in treatment Changes in caregiving and environment Cause and effect What are the effects of stopping a medication that can be attributed to the medication? Double-blind, placebo-controlled discontinuation trial Dementia Meds (Thielke), NWGEC WInter 2015 23
Agitation CONSIDER Unmet needs Conditioning Natural response to environmental cues BEFORE turning to medications Common Triggers Change in caregiver Change in living arrangements Travel Hospitalization Houseguests Bathing / toileting Dressing / undressing Dementia Meds (Thielke), NWGEC WInter 2015 24
High-Yield Behavioral Strategies Distraction Empathetic attention Comforting stimuli Return home Antipsychotics In small studies, typical and atypical agents show modest aggregate improvements in behavioral symptoms compared to placebo on clinician-defined rating scales. Devenand et al, Am J Psy 1998 Street et al, Arch Gen Psy 2000 BLACK BOX WARNING Elderly patents with dementia-related psychosis treated with atypical or typical antipsychotic drugs are at an increased risk of death compared to placebo. All-cause mortality is increased by 1.6x Dementia Meds (Thielke), NWGEC WInter 2015 25
Prescribing an Antipsychotic Have an informed consent discussion whenever possible. Monitor the response Use the lowest dose possible to achieve the response. Stop the drug if there is no positive response. Continue to consider the causes of agitation. Continue to apply behavioral approaches. Prazosin Alpha-1 adrenergic antagonist (opposes adrenaline): counters fight or flight Not a very effective antihypertensive (needs doses of about 20mg per day). Generally very safe. Used for PTSD symptoms, especially nightmares. Off-label for dementia-related agitation. The one published trial (Wang 2009) suggested effectiveness and safety. Dementia Meds (Thielke), NWGEC WInter 2015 26
Prazosin rough dosing guidelines Start at 1mg at bedtime. Increase to 1mg twice a day in 3-4 days. Increase in 1mg increments until agitation improves. Maximum target dose about 5mg twice a day (10mg total). Dosing recommendations being developed. Other possible treatments Trazodone SSRIs Antiepileptic medications Benzodiazepines (be careful) Dementia Meds (Thielke), NWGEC WInter 2015 27
AVOID ANTICHOLINERGICS SOME of the most powerful: -Oxybutynin (Ditropan) -Diphenhydramine (Benadryl) -Doxylamine (Unisom) -Hydroxyzine (Vistaril) -Dimenhydrinate (Dramamine) Caregiver Interventions vs Pills Mittelman 2004 Dementia Meds (Thielke), NWGEC WInter 2015 28
What is the right advice? We have FDAapproved treatments for dementia. They treat the disease. You should use one. FDA-approved treatments exist. They improve symptoms, but produce no difference in caregiver burden or nursing home Do you want to use one? Treatments exist, but they do not modify the disease course, and provide only symptomatic benefit in about 1/3 of patients. Do you want to use one? Medications for dementia do not fix the problem. They are unlikely to help you and are expensive and dangerous. You should not take one. Dementia Meds (Thielke), NWGEC WInter 2015 29