1. Place in Therapy of SSRI’s in Agitation of Dementia Karen McGee, Pharm.D. CDE SC College of Pharmacy USC campus March 2008 mcgee@sccp.sc.edu

2. Objectives Review Pathophysiology and Etiology of Dementia Describe Behavior Problems Associated with Dementia Discuss Place in Therapy of SSRI’s in Agitation of Dementia Decide Place in Therapy of Anti-psychotics in Agitation of Dementia

3. Introduction Types of dementia Alzheimers (>60%) Vascular (Multi Infarct) Mixed Lewy Body

4. Alzheimers: Etiology Alzheimers Early onset 40- 64 years Usual > 65 yrs > 50% incidence > 85 yrs 100,000 deaths yearly due to Aspiration Pneumonia Trauma Nutritional deficiency

5. Alzheimers: Pathophysiology Beta Amyloid Proteins Neurofibrillary Tangles Apo-lipo protein E Inflammatory Mediators Cholinergic system

6. Alzheimers: Symptoms & MMSE Memory Loss Dysphasia Dyspraxia Disorientation Impaired time concepts Cant recognize family Impaired calculation Impaired Judgment or problem solving MMSE (mini mental status exam) common test used to evaluate A.k.a. Folstein

7. Alzheimers: Behavioral Issues Depression Anxiety Psychotic Symptoms Hallucinations Delusions Suspiciousness Non-psych disturbances Physical aggression Verbal aggression Motor hyperactivity Uncooperative Wandering Repetitive mannerisms Common Reason for Nursing Home Placement

8. Alzheimer’s: Differential Diagnosis Insidious onset Progressive decline in cognitive function Deficient in MMSE GDS No acute disturbance of consciousness Age 40-90 Rule out other causes: Hypothyroid B12 and folate deficient Syphilis

9. Purpose/ Controversy of this Discussion To support appropriate use of antipsychotic medications for behavioral problems in dementia New data supports the notion that antipsychotics should be used more sparingly Blackbox Warning implemented in 2007 Warning: Increased Mortality in Elderly Patients with Dementia Related Psychosis Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of 17 placebo controlled trials in these patients revealed a risk of death in the drug treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug treated patients was about 4.5% compared to 2.6% in the placebo group. Most common cause was either cardiovascular (heart failure, sudden death) or infectious (pneumonia).

10. A Pilot, Open-Label Trial of Citalopram for Restless Activity and Abberrant motor behaviors in Alzheimer Disease ( Am J Geriatr Psych 2003;11;6:687-91) Study Overview 12 weeks 19 Caucasian Patients Alzheimers (14 women) 48-87 yrs (average 74) MMSE = 13 (Moderate) Citalopram 10 -40 mg Behavior review at weeks 4,8,12 Restlessness Pacing Hyper-kinesia Rummaging Repetitions Put on / Take off clothes hoarding

11. A Pilot, Open-Label Trial of Citalopram for Restless Activity and Abberrant motor behaviors in Alzheimer Disease (Am J Geriatr Psychiatry 2003;11;6:687-91) Inclusion Stable psychotropics for 4 weeks allowed Sleep aids Quetiapine Valproate ACHE Memantine Exclusions Depression Psychotic disorders

12. A Pilot, Open-Label Trial of Citalopram for Restless Activity and Aberrant motor behaviors in Alzheimer Disease (Am J Geriatr Psych 2003;11;6:687-91) Primary Outcomes Aberrant Motor Subscale of the Neuropsychiatric Inventory (NPI) Scale > 50% decrease in symptoms at week 8 and 12 4 pts had complete resolution of symptoms 2 pts were nonresponders 13 pts had 50-70% improvement after 8 weeks Secondary Outcomes Change in ADAS-cog ( 70 point scale)= NO Change Change in Caregiver stress subscales = Significant CG report decreased agitation, anxiety, aggression and irritability Able to maintain these patients at home

13. A Double Blind Comparison of Citalopram and Risperidone for the Treatment of Behavioral and Psychotic Symptoms Associated with Dementia (Am J Geriatr Psych 2007;15:1-11 ) Positive Points of the Trial Strongest study design to date Clinically useful/ valid Scale for Symptom assessment Duration: 12 weeks (still short) NNT = 103 patients to detect 15% difference with a power of 80% and alpha = 0.05 Pt Population was more varied & matched Less medication allowed Still allowed ACHE or Memantine in stable doses Also, Lorazepam up to 2 mg for acute agitation Study Doses (titrated) Citalopram 10 -40 mg Risperidone 0.5 – 2 mg

14. A Double Blind Comparison of Citalopram and Risperidone for the Treatment of Behavioral and Psychotic Symptoms Associated with Dementia (Am J Geriatr Psych 2007;15:1-11 ) Inclusions Inclusions Pts with dementia hospitalized for behavior controlPts with dementia hospitalized for behavior control Aggression, agitation, hostility, suspiciousness, hallucinations and delusionsAggression, agitation, hostility, suspiciousness, hallucinations and delusions Goal: Discharge back to home, SNF or NHGoal: Discharge back to home, SNF or NH Alzheimer Dz with Moderate to severe behaviorsAlzheimer Dz with Moderate to severe behaviors > 3 on NBRS indicating moderate to severe symptoms> 3 on NBRS indicating moderate to severe symptoms Mixed or Lewy body dementiaMixed or Lewy body dementia Exclusions Exclusions Vascular dementiaVascular dementia SchizophreniaSchizophrenia Major depressionMajor depression Etoh induced dementiaEtoh induced dementia Acute or unstable physical illnessAcute or unstable physical illness

15. A Double Blind Comparison of Citalopram and Risperidone for the Treatment of Behavioral and Psychotic Symptoms Associated with Dementia (Am J Geriatr Psych 2007;15:1-11 ) Primary Outcomes: Change in NBRS scale Change in Agitation score Change in Psychosis score NBRS scale: 0 = No symptoms present 1= Very mild symptoms 2= Mild 3= Moderate 4= Moderate to severe 5= Severe 6= Extremely severe

16. A Double Blind Comparison of Citalopram and Risperidone for the Treatment of Behavioral and Psychotic Symptoms Associated with Dementia (Am J Geriatr Psych 2007;15:1-11 ) Results No significant change in Overall NBRS score Agitation Score: 8.2% decrease in risperidone group and a 12.5% decrease in the citalopram group Psychosis Score: Both groups had a significant decrease! 35.2% decrease in Risperidone group 32.3% decrease in Citalopram group Side effects Risperdone= more somnolence Risperdone and Citalopram = EPSE (rigidity and tremor)

17. F-Tag 329 Pharmacy Assessment & Documentation Document Target Symptoms _____________________________ Appropriate diagnosis Document SE monitoring Elders should be free from unnecessary drugs Free of Chemical Restraint Recommend tapers Eliminate Poly-pharmacy Should not treat the caregivers (75% one study) Threat to self or others Interference with ADL’s Psychosis associated with organic brain disorders or dementia AIMS, CBC, BMP, LFTs Ongoing (quarterly assessments) Chemical restraint orders Trial taper in two separate quarters with at least one month between each taper Taper annually Unless Sx return, must document in progress notes Educate caregivers

18. Medication Classes: Place in Therapy 1 st line- SSRI’s SSRI have the latest trial data Most data with Citalopram 10 mg X 3days then titrate up slowly to a maximum of 40 mg daily Paroxetine, more sedating, may offer benefit for those unable to sleep. Dose at bedtime. Only one study in dementia Monitor Baseline LFT’s and BMP and repeat to assess for hyponatremia 2 nd Line- Valproate Mood Stabilizers Used to treat aggressive, combative behaviors Studies are lacking about place in treatment 3 rd line- Antipsychotics Most useful for harmful hallucinations and delusions Consider last due to new blackbox warning and need for more frequent, intensive monitoring ( Tag F329), AIMS, LFTs, CBC, BMP

19. Thank You! Any Questions?