Differentiating Depression, Delirium and Dementia

Differentiating Depression, Delirium and Dementia
Megg Wheeldon RN, BSN, A/GNP-C Geriatric Educator and Advanced Practice Nurse

Why Differentiate ? Depression - most commonly missed diagnosis in the elderly. Delirium - when missed can be fatal Dementia - symptoms confused with depression and delirium

DSM-IV FOR A MAJOR DEPRESSIVE EPISODE: 1
> 5 symptoms present during the same 2 weeks A change from previous functioning Functional impairment and/or distress Symptoms not due to another cause DSM-IV. Washington, DC: American Psychiatric Association, 1994

DSM-IV CRITERIA FOR A MAJOR DEPRESSIVE EPISODE: 2
The total of five symptoms must include: Depressed mood and/or Loss of interest or pleasure Plus… DSM-IV, Washington DC: American Psychiatric Association, 1994

DSM-IV CRITERIA FOR A MAJOR DEPRESSIVE EPISODE: 3
Physical Symptoms Appetite or weight change Insomnia or hypersomnia Psychomotor agitation or psychomotor retardation Fatigue Psychological Symptoms Depressed mood Loss of interest or pleasure Feelings of worthlessness or guilt Diminished ability to think, concentrate, or make decisions Recurrent thoughts of death or suicide

DIAGNOSIS OF DEPRESSION Special Concerns in Older Patients
Recognizing depression may be more difficult in elderly patients Depressive symptoms may be incorrectly attributed simply to aging Patients may report somatic symptoms rather than depressed mood Coexisting physical conditions and medications complicate diagnosis Coexisting dementia may complicate diagnosis If depression is suspected, all relevant symptoms can be considered related to depression

SELECTED DRUGS ASSOCITED WITH DEPRESSION
Anticonvulsants Antihypertensives Antineoplastic agents Antiparkinsonian drugs Antipsychotics CNS Depressants Corticosteroids Digitalis preparation Histamine (H2)-antagonists Tuberculostatics

RISKS OF NOT TREATING DEPRESSION IN LATER LIFE
Chronic depression Cognitive impairment Medical illness Poor compliance with medical treatment Social dysfunction Suicide

TREATMENT OF DEPRESSION IN ELDERLY PATIENTS WITH ALZHEIMER’S DEMENTIA
20-40% of cognitively impaired elderly persons exhibit depression or depressive symptoms Patients with dementia are more susceptible to anticholinergic adverse effects on memory and attention Antidepressants with lower anticholinergic activity are preferable Norpramin (Desipramine) Trazadone (Desyrel) Wellbutrin (Bupropion)

PROFILE OF THE IDEAL ANTIDEPRESSANT
Rapid onset of action Efficacy in a range of disorders Once0daily dosing Ideal Antidepressant Cost-effective Minimal Side effects Safety in Overdose No drug/food interactions

THE IMPORTANCE OF PHARMACOKINETICS IN DRUG-DRUG INTERACTIONS
The pharmacologic action of a drug may be altered by the coadministration of a second drug. This coadministration may: Increase or decrease a known effect Create an adverse effect Result in a new effect not seen with either drug alone Use of multiple drugs by the elderly increases the probability of drug-drug interactions.

RISK FACTORS FOR DRUG-DRUG INTERACTIONS
Drugs that interfere with the cytochrome P450 system Quinidine Ketoconazole Drugs with a low therapeutic index Multiple drug regimens Patient-specific factors Older age Substance abuse Medical illness Individual factors

Eleanor’s most recent complaint
Tightness in her throat last night. No SOB or pain. Thinks her CHF is acting up. SHX: husband has SDAT, wanders out at night, yells at her, and frightens her.

Distinguishing Delirium From Dementia
Slide 27 Distinguishing Delirium From Dementia Delirium Dementia Psychomotor changes occur late in the illness unless depression or apathy develops Consciousness not clouded until terminal stage Attention span not characteristically reduced Marked psychomotor changes (hyperactive or hypoactive) Altered and changing level of consciousness Strikingly short attention span Distinguishing Delirium From Dementia Although the symptoms of delirium and dementia can overlap considerably, a number of clues to differentiate delirium from dementia are listed on this slide. In particular, one should investigate the timeline of events, the patient’s functional status, and comorbid conditions. Note that clouding of consciousness refers to a patient’s ability to perform higher cognitive functions, not to a patient’s state of wakefulness Source: Adapted with permission from Guttman R et al, eds. Diagnosis, Management and Treatment of Dementia: A Practical Guide for Primary Care Physicians. Chicago, Ill: American Medical Association; 1999. Guttman R, Seleski M, eds. Diagnosis, Management and Treatment of Dementia: A Practical Guide for Primary Care Physicians. Chicago, Ill: American Medical Association; 1999. Lipowski Z. Delirium, clouding of consciousness and confusion. J Nerv Ment Dis. 1967;145:

Distinguishing Delirium From Dementia
Slide 29 Distinguishing Delirium From Dementia Delirium Dementia Acute illness Usually reversible, often completely Chronic illness Generally irreversible, often chronically progressive Distinguishing Delirium From Dementia This slide details other characteristic differences between delirium and dementia Source: Adapted with permission from Guttman R, et al, eds. Diagnosis, Management and Treatment of Dementia: A Practical Guide for Primary Care Physicians. Chicago, Ill: American Medical Association; 1999. Guttman R, Seleski M, eds. Diagnosis, Management and Treatment of Dementia: A Practical Guide for Primary Care Physicians. Chicago, Ill: American Medical Association; 1999.

Possible Contributors to Delirium
Slide 30 Possible Contributors to Delirium UTI Respiratory infection Undiagnosed pain CHF COPD causing hypoxia Renal insufficiency Anemia Hypoperfusion states Recent surgery Sensory impairment Cataract, hearing loss Possible Contributors to Delirium In determining the cause(s) of delirium, it is useful to review the patient’s history with regard to recent onset of illness and chronic illnesses, as well as medication history Studies have shown that the number of diagnoses is positively correlated with agitated behavior. Acute illness of any kind can lead to a perturbation of mental status in elderly persons, with or without an underlying dementia (urinary tract infection [UTI] and pneumonia are classic examples). Similarly, chronic conditions that cause hypoxia, sensory impairment, or metabolic derangement can increase confusion Very often, several of these possible causes are found to be contributing to delirium in a given case (ie, multifactorial in origin) Sources: Lipowski ZJ. JAMA. 1987;258: Lipowski ZJ. Psychiatr Clin North Am. 1992;15: Cohen-Mansfield J, Werner P, Marx MS. Screaming in nursing home residents. J Am Geriatr Soc. 1990;38: Johnson JC. Delirium in the Elderly. In: Rose C, ed. Emerg Med Clin North Am. Philadelphia, Pa; WB Saunders Co; 1990;8: Lipowski ZJ. Delirium (acute confusional states). JAMA. 1987;258: Lipowski ZJ. Update on delirium. Psychiatr Clin North Am. 1992;15:

Possible Contributors to Delirium
Slide 31 Possible Contributors to Delirium Iatrogenic Medications with anticholinergic effects Effects may be additive Medication change Need to rule out withdrawal syndrome (eg, from alcohol or short-acting benzodiazepine) Possible Contributors to Delirium There are several iatrogenic causes of behavioral disturbance and mental status alteration, and these will be addressed in detail in this presentation Cohen-Mansfield J, Werner P, Marx MS. Screaming in nursing home residents. J Am Geriatr Soc. 1990;38: Johnson JC. Delirium in the Elderly. In: Rose C, ed. Emerg Med Clin North Am. Philadelphia, Pa; WB Saunders Co; 1990;8: Lipowski ZJ. Delirium (acute confusional states). JAMA. 1987;258: Lipowski ZJ. Update on delirium. Psychiatr Clin North Am. 1992;15: Sources: Lipowski ZJ. JAMA. 1987;258: Lipowski ZJ. Psychiatr Clin North Am. 1992;15:

Medication with Anticholinergic Effects
Slide 32 Medication with Anticholinergic Effects 14 of 25 most commonly prescribed medications in the elderly have detectable anticholinergic effects Many cannot be avoided Most have modest effects However, anticholinergic effects are cumulative and may be clinically relevant Medications With Anticholinergic Effects Tune et al (1992) demonstrated that 14 of the 25 most frequently prescribed drugs in geriatric medical practice have anticholinergic effects. Some of these drugs (eg, digoxin) may be difficult to avoid and the additive effect from their use in combination puts the patient at risk for delirium and other anticholinergic effects Source: Tune L et al. Am J Psychiatry. 1992;149: Tune L, Carr S, Hoag E, Cooper T. Anticholinergic effects of drugs commonly prescribed for the elderly: potential means for assessing risk of delirium. Am J Psychiatry. 1992;149:

Medication with Anticholinergic Effects
Slide 33 Medication with Anticholinergic Effects Commonly prescribed in the elderly Cimetidine Ranitidine Prednisolone Theophylline Warfarin Dipyridamole Codeine Nifedipine Isosorbide Digoxin Furosemide Triamterene and hydrochlorothiazide Captopril Medications With Anticholinergic Effects The above slide lists examples of medications that are commonly prescribed in the elderly, all of which have been shown by receptor-binding assay to have anticholinergic receptor activity Oxybutynin and tolterodine, which also bind to anticholinergic receptors, are increasingly prescribed for urinary incontinence in elderly patients Again, it may be wise to consider alternatives to medications with anticholinergic properties when such alternatives are available Source: Tune L et al. Am J Psychiatry. 1992;149: Tune L, Carr S, Hoag E, Cooper T. Anticholinergic effects of drugs commonly prescribed for the elderly: potential means for assessing risk of delirium. Am J Psychiatry. 1992;149:

Psychotropic Medications With Anticholinergic Effects
Slide 34 Tricyclic antidepressants Amitriptyline Doxepin Antipsychotics Thioridazine Chlorpromazine Diphenhydramine Imipramine Clozapine Olanzapine Psychotropic Medications With Anticholinergic Effects Tricyclics are frequently prescribed for treatment of depression, chronic pain, and bladder incontinence. However, there are safer alternatives and these alternatives should be considered whenever possible Tertiary amines (eg, amitriptyline, doxepin, imipramine) in particular are difficult for patients to tolerate due to their range of peripheral, as well as CNS (ie, causing delirium) anticholinergic toxicity. However, even the somewhat better-tolerated secondary amines (eg, nortriptyline) can be difficult for older persons to tolerate Other side effects of tricyclics are predictable by a review of their receptor-binding activity, for example:  1-adrenergic receptor blockade leads to orthostatic hypotension  Histaminic receptor blockade causes sedation (and may also be related to weight gain) Both of these side effects have important consequences in elderly patients

Conventional (Typical) vs Atypical Antipsychotics
Slide 50 Conventional (Typical) vs Atypical Antipsychotics Conventional Introduced in 1950s and 1960s Dopamine-receptor blockade Examples Haloperidol Thioridazine Chlorpromazine Atypical Introduced in the 1990s Dopamine and serotonin receptor blockade Examples Clozapine Risperidone Olanzapine Quetiapine Conventional (Typical) vs Atypical Antipsychotics Conventional antipsychotic agents include drugs that have been available since the 1950s (eg, chlorpromazine, the prototype of the low-potency antipsychotics, and haloperidol, the prototype of the high-potency conventional antipsychotics). These agents are presumed to exert their antipsychotic effects (and their significant extrapyramidal side effects) through blockade of CNS dopamine receptors The atypical agents, which were introduced in the 1990s, were added to the antipsychotic drug armamentarium. The atypical antipsychotic drugs block a subset of serotonin receptors in addition to dopamine receptors, which may be the reason for their superior efficacy and safety Source: Jeste DV et al. Am J Geriatr Psychiatry. 1999;7:70-76. Jeste DV, Rockwell E, Harris MJ, Lohr JB, Lacro J. Conventional vs. newer antipsychotics in elderly patients. Am J Geriatr Psychiatry. 1999;7:70-76.

Conventional Antipsychotics in Dementia Meta-Analysis of Controlled Trials
Slide 52 Reviewed 33 controlled studies No individual study demonstrated efficacy Modest efficacy demonstrated only when data combined in meta-analysis Conventional Antipsychotics in Dementia Meta-Analysis of Controlled Trials In a frequently cited paper, Schneider et al (1990) reviewed 33 studies of conventional antipsychotics in elderly patients with dementia Although no individual study demonstrated a conventional antipsychotic to be statistically more effective than placebo, the combined effect of conventional antipsychotic therapy in their meta-analysis was an 18% improvement over placebo These data were confirmed in a subsequent meta-analysis of 16 randomized, controlled, double-blind trials of conventional neuroleptics in patients with dementia. In this analysis, the treatment effect was found to be 26% above placebo Source: Schneider LS et al. J Am Geriatr Soc. 1990;38: Lanctôt KL, Best TS, Mittmann N, et al. Efficacy and safety of neuroleptics in behavioral disorders associated with dementia. J Clin Psychiatry. 1998;59: Schneider LS, Pollock VE, Lyness SA. A metaanalysis of controlled trials of neuroleptic treatment in dementia. J Am Geriatr Soc. 1990;38:

Conventional Antipsychotics Consequences of Acute Side Effects
Slide 53 Conventional Antipsychotics Consequences of Acute Side Effects Side Effect Extrapyramidal symptoms: parkinsonism Cognitive toxicity: delirium Sedation: increased falls Orthostatic hypotension: increased falls Anticholinergic Effects: constipation Conventional Antipsychotics Consequences of Acute Side Effects The side effects of the conventional antipsychotic drugs are problematic and are predictable, given a basic understanding of their receptor-binding profiles The high-potency agents (eg, haloperidol) predictably cause a high rate of extrapyramidal symptoms (EPS) [eg, iatrogenic parkinsonism] due to their dopamine receptor affinity The low-potency agents (eg, thioridazine, chlorpromazine) block 1-adrenergic receptors in smooth muscle cells in the vasculature, causing orthostatic hypotension; block CNS histamine receptors, causing sedation; and block CNS cholinergic receptors, causing confusion and delirium Cognitive impairment is an important issue with conventional antipsychotics in geriatrics. For example, the use of haloperidol may be associated with a nonspecific blunting effect. When haloperidol is used in conjunction with benztropine and trihexyphenidyl, potent anticholinergic medications, there is further iatrogenic cognitive impairment Source: Tune LE et al. In Davidson M, ed. Psychiatric Clinics of North America. Philadelphia, Pa: WB Saunders Co; 1991;14:

Conventional Antipsychotics Consequences of Acute Side Effects
Slide 54 Conventional Antipsychotics Consequences of Acute Side Effects Side Effect Anticholinergic effects Consquences Constipation, urinary retention, tachycardia, blurred vision, dry mouth, confusion, delirium Conventional Antipsychotics Consequences of Acute Side Effects Blockade of muscarinic receptors, a subset of cholinergic receptors, is associated with side effects such as constipation, urinary retention, tachycardia, blurred vision, dry mouth, confusion, and delirium This wide range of side effects makes conventional antipsychotics, which block muscarinic receptors, difficult to tolerate (engendering noncompliance and poor clinical outcome) in patients of all ages. However, these predictable side effects can be particularly toxic in older patients. Hence, the combination of minimal efficacy and poor tolerability explains the burgeoning interest in the atypical antipsychotic agents Source: Richelson E. J Clin Psychiatry. 1996;57(suppl 11):4-11. Richelson E. Preclinical pharmacology of neuroleptics: focus on new generation compounds. J Clin Psychiatry. 1996;57(suppl 11):4-11. Tune LE, Steele C, Cooper T. Neuroleptic drugs in the management of behavioral symptoms of Alzheimer’s disease. In: Davidison M, ed. Psychiatric Clinics of North America. Philadelphia, Pa: WB Saunders Co; 1991;14:

Atypical Antipsychotics
Slide 56 Atypical Antipsychotics Clozapine Risperidone Olanzapine Quetiapine Others in development Atypical Antipsychotics Four agents are currently available in this class: clozapine, risperidone, olanzapine, and quetiapine. Others are in development

Risperidone in the Elderly
Slide 58 Risperidone in the Elderly Most prescribed atypical agent 2 double-blind placebo-controlled trials in elderly patients with dementia (N=969) Better side-effect profile than conventional antipsychotics Recommended dosing regimen in dementia Starting dose: 0.25 mg to 0.5 mg hs Target dose: 0.5 mg to 1.5 mg hs Risperidone in the Elderly Of the 4 available atypical antipsychotics, risperidone has been the most extensively studied in the elderly and is in wide clinical use in the elderly. Risperidone is the preferred antipsychotic in more than 75% of nursing homes When an antipsychotic becomes commercially available, the initial data supporting its use usually come from studies of younger patients with schizophrenia who require higher doses of medication and are better able to tolerate side effects. As the initial experience with risperidone demonstrated, it is a mistake to extrapolate these dosage guidelines to elderly patients When risperidone was first introduced, patients were typically administered 4 mg/d to 6 mg/d. At doses above 2 mg in most elderly patients, increased frequency of side effects was noted. However, since then there have been numerous open trials and at least 2 new well-controlled, double-blind studies suggesting that the ideal final target dose of risperidone in patients with dementia is in the range of 0.5 mg/d to 1.5 mg/d. In patients with dementia, doses above 2 mg/d are seldom needed Sources: Aronson SM. Mental Disorders in the Elderly: New Therapeutic Approaches. 1998;13: De Deyn PP et al. Neurology. 1999;53: Falsetti AE. Am J Health-Syst Pharm. 2000;57: Jeste DV et al. J Clin Psychiatry. 1996;57(suppl 3): IMS NPA data 6/00.

Risperidone in Dementia Psychosis Subscale—BEHAVE-AD
Slide 62 Risperidone in Dementia Psychosis Subscale—BEHAVE-AD 3.0 2.5 † 2.5 2.2 ‡ 2.0 *At end point. †P=.005 vs placebo. ‡P=.01 vs placebo. 1.6 Mean Improvement From Baseline* 1.5 1.5 1.0 Risperidone in Dementia Psychosis Subscale—BEHAVE-AD This graph shows the effect of risperidone on elements of psychosis as measured by the psychosis subscale of the Behavioral Pathology in Alzheimer’s Disease (BEHAVE-AD) Patients receiving the 1 mg and 2 mg daily doses of risperidone had scores statistically superior to those of placebo-treated patients and patients receiving risperidone 0.5 mg/d 0.5 0.0 Placebo n=161 0.5 mg n=146 1.0 mg n=148 2.0 mg n=162 Dose of Risperidone Source: Katz IR et al. J Clin Psychiatry. 1999;60: Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M for the Risperidone Study Group. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. J Clin Psychiatry. 1999;60:

Risperidone in Dementia Mini–Mental State Examination (MMSE)
Slide 64 † † Risperidone in Dementia Mini–Mental State Examination (MMSE) Cognitive function is measured using the Mini–Mental State Examination (MMSE), an 11-item rating scale There was a slight improvement in cognition at risperidone doses of 1 and 2 mg/d; however, differences were not significant compared to placebo Similar results were observed in the De Deyn trial. The least squares mean changes in the risperidone and placebo groups were not significantly different and indicated no cognitive deterioration in response to risperidone † Placebo 0.5 mg 1.0 mg 2.0 mg Dose of Risperidone *Least squares mean. †Not significant vs placebo. Sources: Katz IR et al. J Clin Psychiatry. 1999;60: Data on file, Janssen Pharmaceutica. De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology. 1999;53: Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M for the Risperidone Study Group. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. J Clin Psychiatry. 1999;60:

Quetiapine in the Elderly
151 patients ~65 years of age with psychosis Multicenter, open-label, 52-week safety study; interim analysis at week 12 Population: organic psychotic disorders (n=106), schizophrenia/schizoaffective (n=34), delusional disorder (n=7), bipolar disorder (n=4) Quetiapine median dose, 100 mg/d Improvement noted in BPRS and CGI-S scores Adverse events: somnolence (32%), dizziness (14%), postural hypotension (13%), agitation (11%), constipation (8%) Quetiapine in the Elderly Quetiapine, FDA-approved for marketing in the United States in 1997, was the fourth available atypical antipsychotic. This agent was studied in 151 elderly patients with a variety of diagnoses in an open-label, 52-week trial designed to assess safety and tolerability. An interim analysis was conducted at week 12 The majority of participants were diagnosed with organic psychotic disorders including Alzheimer’s disease, vascular dementia, and Parkinson’s disease (n=106). Also included were patients witih schizophrenia/schizoaffective disorders (n=34), delusional disorder (n=7), and bipolar disorder (n=4) Quetiapine was initiated at a dose of 25 mg/d. Doses were increased in 25 mg to 50 mg increments every 1 tyo 3 days (up to 800 mg/d, depending on clinical response). The median daily dose of quetiapine utilized in the trial was 100 mg/d (range, 13 mg to 400 mg/d) for all patients Although the study was primarily a safety trial, assessments of psychiatric symptomatology were made using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impressions (CGI) scale Source: McManus et al. J Clin Psychiatry. 1999;60:

Quetiapine in the Elderly
Slide 77 Quetiapine in the Elderly Adverse events Somnolence (32%) Dizziness (14%) Postural hypotension (13%) Agitation (11%) Constipation (8%) No placebo-controlled studies available yet Quetiapine in the Elderly The most commonly reported side effects were somnolence (32%), dizziness (14%), postural hypotension (13%), agitation (11%), and constipation (8%) A lingering question regarding quetiapine is whether the lens opacification that develops in laboratory animals administered quetiapine is species-specific or whether humans are also at higher risk of developing cataracts. The package insert recommends examination of the lens at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment Randomized, placebo-controlled studies of quetiapine are needed in order to further define its use in the elderly population with dementia Source: McManus DQ et al. J Clin Psychiatry. 1999;60: McManus DQ, Arvanitis LA, Kowalcyk BB, for the Seroquel Trial 48 Study Group. Quetiapine, a novel antipsychotic: experience in elderly patients with psychotic disorders. J Clin Psychiatry. 1999;60:

Olanzapine in Dementia
Slide 72 Olanzapine in Dementia 238 patients with Alzheimer’s disease and psychosis 8-week, double-blind, placebo-controlled trial Mean dose = 2.4 mg/d (1 to 8 mg/d) There was no difference in efficacy between olanzapine and placebo No differences vs placebo for discontinuation due to adverse effects Olanzapine in Dementia An initial double-blind, placebo-controlled, prospective trial evaluated olanzapine in patients aged 65 or older with psychotic and behavioral symptoms secondary to Alzheimer’s dementia. Two hundred thirty-eight patients received olanzapine (1 to 8 mg/d) or placebo Results showed no difference in efficacy between the olanzapine and placebo groups There were no differences in discontinuation rates due to adverse effects Higher doses of olanzapine lower the seizure threshold; a dose of 4 mg/d increases the occurrence of seizures in the elderly Source: Satterlee WG et al. Psychopharmacol Bull. 1995;31:534. Satterlee WG, Reams SG, Burns PR, et al. A clinical update on olanzapine treatment in schizophrenia and in elderly Alzheimer’s disease patients. Psychopharmacol Bull. 1995;31:534.

Slide 73 Olanzapine in Dementia Study Design N=206 patients with dementia Mean age 82.8 years; 61% female Mean MMSE 6.9/30 6-week multicenter, placebo-controlled study Randomized to (6 weeks) Olanzapine fixed dose (5 mg/d, 10 mg/d, 15 mg/d) Placebo Olanzapine in Dementia A second double-blind, placebo-controlled trial evaluated olanzapine in the treatment of patients with dementia. It was a 6-week trial conducted in 206 patients with AD Mean age was 82.8 years and mean Mini–Mental State Exam (MMSE) score was 6.9/30 Patients were randomized to olanzapine (5 mg/d, 10 mg/d, or 15 mg/d) or placebo Source: Street J et al. Arch Gen Psychiatry. 2000;57: Street J, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities. Arch Gen Psychiatry. 2000;57:

Slide 74 Olanzapine in Dementia Efficacy Results Significant improvement in the combined agitation, delusions, and hallucinations items of the NPI/NH for 5 mg/d and 10 mg/d doses compared to placebo 15 mg/d of olanzapine showed no difference vs placebo on any measure Trend for better response at lower dose Olanzapine in Dementia Olanzapine treatment, at doses of 5 mg/d (P<.001) and 10 mg/d (P=.006), resulted in significant improvement in the combined agitation, delusions, and hallucinations items of the Neuropsychiatric Inventory—Nursing Home version (NPI/NH) compared to placebo. Several measures showed a trend toward greater efficacy at lower doses of olanzapine Source: Street J et al. Arch Gen Psychiatry. 2000;57: Street J, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities. Arch Gen Psychiatry. 2000;57:

Slide 75 Olanzapine in Dementia Safety Results EPS rate similar to placebo Significantly higher incidence of somnolence and gait disturbance vs placebo Higher incidence of abnormal gait in olanzapine-treated patients with somnolence vs those without somnolence Gait disturbance may be linked to increased falls Olanzapine in Dementia Measures of acute extrapyramidal symptoms (EPS) were not statistically different among olanzapine-treated groups and placebo group There was a significantly increased incidence of somnolence and gait disturbance in patients treated with olanzapine. (EPS and gait disturbance were measured using the Simpson-Angus Scale, Abnormal Involuntary Movement Scale, and Barnes Akathisia Scale) – The risk of somnolence was 5 to 8 times higher for the olanzapine-treated patients vs placebo-treated patients – Higher incidence of abnormal gait was noted in olanzapine-treated patients with somnolence (28%) vs those without somnolence (12%) [P=.02] – Incidence of falls was not reported Gait disturbance may be linked to an increased risk of falling. One third of the elderly population (>65 years of age) suffers a fall each year, with 1% of the falls resulting in a fracture Source: Street J et al. Arch Gen Psychiatry. 2000;57: Rubenstein. Ann Long-Term Care. 2000;8:61-64

Ziprasidone No studies in elderly patients with dementia
Slide 78 Ziprasidone No studies in elderly patients with dementia Efficacy shown in patients with schizophrenia Symptoms associated with schizophrenia or schizoaffective disorder improved Safety Prolonged QTc interval Potential risk for ventricular arrhythmias/sudden death Psychopharmacologic Drugs Advisory Committee recommended approval with caveats Ziprasidone All trials with published data focus on the use of ziprasidone in the treatment of schizophrenia There are no published trials using ziprasidone in the elderly for the treatment of psychosis and agitation associated with dementia In short-term and long-term (1-year) double-blind, placebo-controlled studies, ziprasidone was effective in reducing the positive, negative, and depressive symptoms associated with acute exacerbation of schizophrenia or schizoaffective disorder Ziprasidone was well tolerated with a low incidence of adverse effects in both short-term and long-term studies Ziprasidone was originally denied approval by the FDA in 1998 because of concerns of a greater risk of potentially fatal ventricular arrhythmia due to a prolonged QTc interval Sources: Reuters Health. July 20, Available at Minutes of the meeting of the Psychopharmacologic Drugs Advisory Committee to the FDA, July 19, Available at Accessed September 20, 2000.

Atypical Antipsychotics Development of Diabetes
Slide 84 Are independent pathways used? Increased adiposity Diabetes Atypical Antipsychotics Development of Diabetes Weight gain, abnormal glucose metabolism, and elevated triglycerides are often associated with diabetes. Increases in adiposity can lead to weight gain, which in turn can result in decreased insulin sensitivity, increased glucose intolerance, and, ultimately, diabetes. Analysis of large numbers of case reports of patients receiving atypical antipsychotics suggest, however, that weight, triglycerides, and glucose metabolism independently influence the development of diabetes The reported emerging data demonstrate that not all new onset diabetes in patients receiving atypical antipsychotics is associated with weight gain, suggesting that changes in glucose metabolism can occur independently of increase in adiposity. Changes in glucose metabolism have been noted within the first 6 weeks of treatment. One controlled study showed that clozapine- and olanzapine-treated patients had elevated fasting plasma glucose levels vs risperidone-treated patients and nontreated controls. Similar trends were observed for glucose and insulin levels after administration of an oral glucose load in the same study Elevated triglycerides Abnormal glucose metabolism Sources: Wirshing DA et al. Biol Psychiatry. 1998;44: Meyer JM. Presented at: 38th Annual Meeting of the American College of Neuropsychopharmacology; December 12-16, 1999; Acapulco, Mexico. Newcomer JW et al. Presented at: 38th Annual Meeting of the American College of Neuropsychopharmacology; December 12-16, 1999; Acapulco, Mexico. Wilson DR et al. Presented at: 38th Annual Meeting of the American College of Neuropsychopharmacology; December 12-16, 1999; Acapulco, Mexico.

Atypical Antipsychotic Agents New Onset Diabetes Risk
Slide 85 Atypical Antipsychotic Agents New Onset Diabetes Risk Case studies show a correlation between the use of atypical antipsychotics and diabetes onset, as well as glucose dysregulation including ketoacidosis in people with diabetes Atypical Antipsychotic Agents New Onset Diabetes Risk Growing numbers of case reviews report a link between the use of atypical agents and the emergence of treatment-induced diabetes mellitus and diabetic ketoacidosis. The majority of reports associate the particular use of clozapine or olanzapine to new onset diabetes. To date, fewer reports link quetiapine to diabetes development, whereas no reports have yet connected risperidone use with the onset of diabetes It is likely that mechanisms through which atypical antipsychotics provoke diabetes are rooted in well-known diabetic risk factors. Weight gain, which is especially significant with clozapine and olanzapine and less signficant with quetiapine, is known to lead to obesity and diabetes. Many diabetic case reviews noted a substantial weight gain prior to the discovery of atypical antipsychotic-dependent diabetes. Similarly, increased insulin resistance, glucose intolerance, and elevated triglyceride levels are characteristic of the pathogenic progression of diabetes Multiple mechanisms may induce diabetes Aberrant glucose metabolism Weight gain Hypertriglyceridemia

Divalproex: Clinically Attractive for Behavioral Disturbance in Dementia
Preliminary animal and human data suggest antiagitation effects Antiagitation effects often apparent within 1 to 3 weeks May be effective as monotherapy or combination therapy May be effective in agitation nonresponsive to or worsened by antipsychotics or benzodiazepines OBRA Guidelines do not require monitoring forms Divalproex: Clinically Attractive for Behavioral Disturbance in Dementia Preliminary data from animal and human studies suggest that divalproex sodium has antiagitation effects, which are often apparent within 1 to 3 weeks of beginning treatment with the drug. Divalproex may be effective as monotherapy or in combination with another agent, such as an antipsychotic.

Divalproex Sodium Possible Mechanism of Action
Enhancement of central GABA transmission Augmentation of 5HT function Inhibition of limbic kindling Neuroprotection (Hussini Manji, M.D.) No Anticholinergic/ Dopaminergic Effects

Summary of Efficacy in Agitation and Aggression
Data From Trials Using Sodium Valproate or Divalproex Sodium N Design Outcome (No. improved) Mellow et al Open Decreased agitation (3) Sival et al Chart review Decreased aggression (6) Lott et al Open Decreased agitation (9) Horne & Lindley, Open Decreased agitation (1) Sandborne et al Open Decreased partial agitation (2) Decreased partial aggression (2) Narayan et al Chart review Decreased agitation (13) Porsteinsson et al Open Decreased aggression (10) Summary of Efficacy in Agitation and Aggression To date, 14 open trials with a total of 169 patients have indicated probable efficacy of valproate in the treatment of agitation and/or aggression. These studies were predominantly open-label or chart-review studies, and their results are summarized above.

Summary of Efficacy in Agitation and Aggression (cont.)
Data From Trials Using Valproate N Design Outcome Haas et al Open Decreased aggression (12) Kaskow et al Open Decreased agitation (5) Kunick et al Chart review Decreased agitation (9) Herrmann Open Decreased agitation (8) Gardner et al Open Decreased aggression(8) Gupta et al Chart review Decreased agitation (4) Goldberg Chart review Decreased agitation (16) Porsteinsson et al Placebo Decreased agitation (38) controlled Summary of Efficacy in Agitation and Aggression (cont.) As mentioned previously, 14 open trials with a total of 169 patients have indicated probable efficacy of valproate in the treatment of agitation and/or aggression. One recent placebo-controlled study by Porsteinsson et al. reported that divalproex effectively decreased agitation in 68% of patients receiving the drug versus 52% of patients receiving placebo, a significant difference.

Rochester Divalproex Study
N=56 agitated dementia patients in nursing homes Randomized, double-blind, placebo-controlled Best dose (mean 826 mg/d) vs. placebo for 6 weeks 5 Socially inappropriate 93 Aggression Physical agitation Verbal agitation % Target Symptoms Porsteinsson & Tariot, 2001

Clinical Global Impression Therapeutic Effect
Marked Unchanged/ Improvement Worse Divalproex (n=28) 40% 32% Placebo (n=28) 11% 50% Overall Improvement with Divalproex was 68% P = 0.07 Porsteinsson AP, et al. Presented at the International Psychogeriatrics Association annual meeting. August Vancouver, British Columbia.

Goldberg Study The Use of Adjunctive Divalproex for Neuroleptic Unresponsive Behavioral Disturbances in Nursing Home Residents with Dementia, by Richard Goldberg, MD; Annals of Long-Term Care,Vol. 7,#2, 2/99 22 residents, unacceptable response to 2 to 4mg of Risperdal for at least 8 wk. Divalproex (Depakote®) 375mg mg/day, serum level mean 67.2 g/ml, 6 to 12 wk., Global Rating Scale

Goldberg - Residents receiving Psychoactive Medications
Med. # at start # at end Trazodone Antidepressant Anticonvulsant Lithium Benzodiazepine Neuroleptic (typ.) Atypical

Results - Goldberg Study
Divalproex well tolerated - 6 pts (27%) much improved; 6 (27%) more improved; 4 pts (18%) minimally improved; 4 pts (18%) not improved; 2 pts(9%) worse Neuroleptic dose was reduced in 3 of 10 residents

Lorazepam and Divalproex in Nursing Facilities
Methods Retrospective chart review Documented dementia and behavioral disturbance Improvement defined by reduced frequency of behavior, and observations recorded by nursing staff. Frenchman IB et al. Curr Ther Res Clin Exp 2000;61:621-9.

Lorazepam and Divalproex in Nursing Facilities
146 patient charts reviewed 81 patients (55.5%) received lorazepam; 65 patients (44.5%) received divalproex 37 patients (56.9%) treated with divalproex showed improvement 25 patients (30.9%) treated with lorazepam showed improvement Frenchman IB et al. Curr Ther Res Clin Exp 2000;61:621-9.

NH Residents: Experiencing Falls
Frenchman IB et al. Curr Ther Res Clin Exp 2000;61:621-9.

Residents Experiencing Weight Gain/ Loss
41 patients receiving lorazepam (50.6%) experienced weight loss; average 1.68 pounds (unknown how this average was calculated, all patients or only those experiencing weight loss) 32 patients receiving divalproex (49.2%) experienced weight gain; average gain 2.68 pounds (unknown how this average was calculated, all patients or only those experiencing weight gain) Frenchman IB et al. Curr Ther Res Clin Exp 2000;61:621-9.

Initiating Divalproex
Initiate mg q hs or 125 mg BID Increase by mg every 3-7 days or until desired clinical response Usual range mg/day Usual total level g/mL Divalproex is an enteric-coated formulation to minimize gastrointestinal side effects Sprinkle capsules for patients who have difficulty swallowing pills Consider Extended Release tablets once stable dosing, reduces frequency of dosing. 500mg ER now available. 250mg ER available in one month. Beginning a Patient on Divalproex Patients should be started on divalproex sodium at a dosage of mg qhs or 125 mg BID. This dosage can then be increased by mg every 3-7 days or until a desired clinical response is seen. The usual dosing range of divalproex is between mg/day, and serum levels typically range between g/mL. In order to avoid some of the gastrointestinal side effects commonly associated with valproate use, divalproex is enteric coated. Also, sprinkle capsules are available for patients who have difficulty swallowing pills.

Divalproex Sodium Adverse Effects Rare Over-dosed patients
Hepatotoxicity Pancreatitis Over-dosed patients Sedation Gait disturbance Tremors Common bothersome Alopecia Weight gain GI distress (less with divalproex)  Platelets (usually mild) Grosssman F, Pharmacotherapy. 1998;18:

Benzodiazepines Minimal efficacy data
Slide 93 Benzodiazepines Minimal efficacy data Highly sedating and may increase risk of falls Further inhibit learning and memory Paradoxical disinhibition Commonly used Lorazepam Oxazepam Benzodiazepines Benzodiazepines are widely used in the elderly, although data supporting their use for the management of agitation and psychosis in this population are very limited, and side effects are of great concern Benzodiazepine use in older adults carries the risk of further cognitive impairment, sedation, falls, and paradoxical behavioral disinhibition Benzodiazepines should be used only if absolutely necessary, at the lowest effective dose, and for a short period of time, until the primary pharmacotherapy (antipsychotic or other agent) begins to work. Short-acting agents (lorazepam, oxazepam) are preferred Source: Coccaro EF et al. Am J Psychiatry. 1990;147: Alexopoulos GS, Silver JM, Kahn DA, et al, eds. The expert consensus guideline series: treatment of agitation in older persons with dementia. Postgrad Med. 1998;103(suppl):1-88. American Psychiatric Association. Practice guideline for the treatment of patients with Alzheimer’s disease and other dementias of late life. Am J Psychiatry. 1997;154(suppl):1-39. Coccaro EF, Kramer E, Zemishlany Z, et al. Pharmacologic treatment of noncognitive behavioral disturbances in elderly demented patients. Am J Psychiatry. 1990;147:

Carbamazepine Dementia-Related Agitation
Slide 90 Carbamazepine Dementia-Related Agitation Three controlled studies – Two showed efficacy – One showed no efficacy Autoinduction of P450 enzymes Need for CBC monitoring for hematologic risks Blood levels of drug may be irrelevant Recommended starting dose in the elderly: 100 to 200 mg given at bedtime Carbamazepine Dementia-Related Agitation Three placebo-controlled studies were conducted to assess the efficacy of carbamazepine in the treatment of dementia-related agitation. Two studies indicated that carbamazepine may be beneficial in some patients with dementia-related agitation, while 1 showed no benefit (Chambers et al, 1982; Tariot et al, 1994; Tariot et al, 1998) Carbamazepine can be difficult to use because it induces its own hepatic metabolism, often making frequent dose changes necessary. Carbamazepine also induces the metabolism of many other drugs, making dose adjustments of these other drugs necessary as well Frequent CBC monitoring is required because of the potential effects of carbamazepine on red blood cell and white blood cell lines (aplastic anemia and agranulocytosis) There may be little or no correlation between clinical response and blood levels of the drug. The doses often used in elderly patients may not produce robust blood levels even though they improve in regard to agitation and aggression The recommended starting dose in the elderly is 100 mg to 200 mg given at bedtime Sources: Chambers CA et al. IRCS Med Sci. 1982;10: Tariot PN et al. J Am Geriatr Soc. 1994;42: Tariot PN et al. Am J Psychiatry. 1998;155: Tariot PN et al. J Clin Psychiatry. 1999;60:

Antidepressant Agents
Slide 91 Antidepressant Agents Agitation in a patient with dementia may be a “masked depression” Carefully selected antidepressant may have a role Caveat: Avoid agents with anticholinergic or sedating effects Antidepressant Agents Depression is common in patients with dementia and may be manifested as agitation. Treatment with a properly chosen antidepressant may alleviate agitation Antidepressants with significant anticholinergic and sedating properties should be avoided Many physicians prefer the selective serotonin reuptake inhibitors (SSRIs) because they may be better tolerated, especially in the elderly population American Psychiatric Association. Practice guideline for the treatment of patients with Alzheimer’s disease and other dementias of late life. Am J Psychiatry. 1997:154(suppl):1-39. Aronson SM. Treatment of behaviorally disturbed elderly patients: a clinical approach. In: Brunello N, Langer SZ, Racagni G, eds. Mental Disorders in the Elderly: New Therapeutic Approaches. Basel, Switzerland: S Karger AG; 1998;13: Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA. 1997;278:

Citalopram 98 patients with moderate AD/SDAT or VD
Slide 92 Citalopram 98 patients with moderate AD/SDAT or VD Combined double-blind and open-label trial with placebo and citalopram Analysis conducted after 4 weeks of double-blind treatment Citalopram resulted in significant improvement in emotional bluntness, confusion, irritability, anxiety, fear/panic, depressed mood, and restlessness compared to baseline Incidence of side effects similar to placebo Citalopram The selective serotonin reuptake inhibitor (SSRI), citalopram, has been studied in the treatment of emotional disturbances in dementia In a study that examined the effects of citalopram in the treatment of moderate Alzheimer’s disease (AD), senile dementia of the Alzheimer’s type (SDAT) or vascular dementia (VD), 98 patients were treated with 2 double-blind periods of 20 mg citalopram or placebo daily for 4 weeks with an open-label period of citalopram for 8 weeks between the double-blind periods. Doses were titrated up or down 10 mg/d according to patient response At 4 weeks, patients who received citalopram had significant improvement in emotional bluntness, anxiety and fear/panic (P<.05), as well as confusion, irritability, depressed mood, and restlessness (P<.01) compared to baseline. These improvements were not seen in placebo-treated patients Incidence of side effects was similar between the citalopram-treated and placebo-treated patients Source: Nyth AL et al. Br J Psychiatry. 1990;157: Nyth AL and Gottfries CG. The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. A Nordic multicentre study. Br J Psychiatry ;157:

Projected Prevalence of AD
4 Million AD Cases Today— Over 14 Million Projected Within a Generation 16 14.3 14 11.3 12 10 8.7 Millions 8 6.8 5.8 6 4 4 2 2000 2010 2020 2030 2040 2050 Year Evans DA et al. Milbank Quarterly. 1990;68:

Cholinergic Changes in AD
The most prominent neurotransmitter abnormalities are cholinergic Reduced activity of choline acetyltransferase (synthesis of acetylcholine)1 Reduced number of cholinergic neurons in late AD (particularly in basal forebrain)2 Selective loss of nicotinic receptor subtypes in hippocampus and cortex1,3 1. Bartus RT et al. Science. 1982;217: 2. Whitehouse PJ et al. Science. 1982;215: 3. Guan ZZ et al. J Neurochem. 2000;74:

Indications for Evaluation of AD
Difficulty in learning and retaining new information Difficulty in performing complex tasks Impaired reasoning ability Problems with orientation and spatial abilities Language difficulties Depression Behavioral changes Costa PT et al AHCPR Pub. # 19.

Risk Factors for AD Advanced age Genetic factors Female gender
Family history of dementia APOE-epsilon4 genotype Female gender Small GW et al. JAMA. 1997;278: Flier JS et al. N Engl J Med. 1991;325:

AD Is Often Misdiagnosed
Patient initially diagnosed with AD Patient’s first diagnosis other than AD 35% 14% 14% No 72% 9% Yes 28% 7% 21% Dementia (not AD) Stroke Depression No diagnosis Normal aging Other Source: Consumer Health Sciences, LLC. Alzheimer’s Caregiver Project

Standard Medical Evaluation of AD
Patient history and complete physical examination Neurologic evaluation Psychologic evaluation Laboratory tests Brain imaging

Identifying Causes of Dementia: Laboratory Tests
Complete blood count Serum electrolytes (including calcium) Liver function tests Blood urea nitrogen and creatinine Thyroid-stimulating hormone Serum vitamin B12 level Fillit H, Cummings J. Manag Care Interface. 2000;13: Geldmacher DS, Whitehouse PJ. Neurology. 1997;48(suppl 6):S2-S9.

Summary of AD Diagnosis
AD can be mistaken for normal aging, depression, and other conditions Early diagnosis and treatment of AD will benefit both the patient and the caregivers The established criteria* provide a high degree of certainty of diagnosis * NINCDS/ADRDA criteria.

Current Medications Used to Treat AD
*Paxil 3% Other 25% *Zyprexa 3% *Zoloft 3% Vitamin E 3% *Ativan 4% Aricept 44% *Haldol 6% Cholinergics are the most commonly used drugs to treat AD Tacrine (Cognex®) is still available, but is no longer actively marketed Donepezil (Aricept®) was the only acetylcholinesterase inhibitor available at the time these data were collected Rivastigmine (Exelon®) was introduced in April 2000 Galantamine (Reminyl®) approval is pending The remainder are medications primarily used to treat behavioral symptoms *Risperdal 9% *These uses are investigational. Source: National Disease and Therapeutic Index, 1998.

Current Treatment Summary
Cholinergic agents initially improve and transiently maintain cognitive abilities in patients with mild-to-moderate AD Cognitive abilities worsen over time, indicating treatment does not stop (but may delay) the progression of AD New treatments that maintain cognitive ability and stop the progression of AD are needed Although current cholinergic treatments improve or maintain cognitive abilities, there is no evidence that treatment slows the progression of AD Current drug development research is focused on slowing the progression of AD and on maintaining cognitive abilities over a longer period of time

Tacrine (Cognex®) Half-life of 3–5 hours (variable, affected by food intake) 4-times-daily dosing of 10 to 40 mg (40 to 160 mg/day) Metabolized by the cytochrome P450 isoenzyme CYP1A2 Associated with hepatotoxicity (monthly liver testing suggested) Concomitant food intake decreases tacrine absorption (half-life may be prolonged with concomitant food intake), and interindividual absorption of tacrine is variable Due to its associated hepatotoxicity, tacrine is no longer actively marketed Davis KL, Powchik P. Lancet. 1995;345: Crimson ML. Pharmacotherapy 1998;18(2 pt 2):47S-54S.

Tacrine Safety Adverse gastrointestinal effects (somewhat alleviated by concomitant food intake) Elevated liver transaminase levels (ALT) 25%–30% of patients with ALT > 3 times the upper limit of normal Monitoring of liver function required In addition to adverse events related to elevated liver transaminase (ALT) levels, there were frequent occurrences of nausea and/or vomiting, diarrhea, abdominal pain, dyspepsia, and skin rash Farlow M et al. JAMA. 1992;268: Knapp MJ et al. JAMA. 1994;271:

Donepezil (Aricept®) The first second-generation cholinesterase inhibitor Half-life of 70 hours Once-a-day dosing of 5 to 10 mg Metabolized by cytochrome P450 isoenzymes CYP3A and CYP2D6 Higher doses associated with cholinergic side effects, but generally well tolerated This slide summarizes the pharmacokinetic profile of donepezil Bryson HM, Benfield P. Drugs Aging. 1997;10: Aricept® package insert.

Donepezil ADAS-cog Scores After Washout (Burns)
-3.0 **** **** **** -2.0 **** *** **** -1.0 **** *** Mean change (± SE) from baseline in ADAS-cog scores 0.0 * ** 1.0 Improvement 2.0 Placebo Endpoint Donepezil 5 mg/day Donepezil 10 mg/day 3.0 This slide shows the change in ADAS-cog scores during for the LOCF patient population for the 24-week treatment period (donepezil 5 or 10 mg) and after the single-blind, 6-week washout phase Following the washout phase, patient ADAS-cog scores were similar to placebo, indicating efficacy was not maintained when treatment was discontinued (scores for other efficacy measures, including CIBIC-plus, CDR-SB, and IDDD, were also similar to placebo after the washout phase) Treatment with donepezil is most likely compensatory and does not stop the progression of the disease 4.0 6 12 18 24 30 Week Placebo washout * p < ** p < *** p < **** p < Reprinted with permission from Burns A et al. Dement Geriatr Cogn Discord. 1999;10:

Donepezil Summary Donepezil (5* and 10 mg) improves cognition and global function in patients with mild-to-moderate AD Long-term efficacy is maintained for up to 38 weeks ADL may be partially maintained by donepezil Donepezil is generally safe and well tolerated This slide summarizes the key results from Phase III donepezil trials * In the largest trial, donepezil 5 mg was significantly better than placebo using the ADAS-cog scale, but scores worsened from baseline.

Rivastigmine (Exelon®)
Newer second-generation cholinesterase inhibitor Half-life of 1.5 hours Dosing (bid) of 3 to 12 mg/day Metabolism is almost totally independent of the hepatic cytochrome P450 system Gastrointestinal adverse events are common, including weight loss This slide presents the key pharmacokinetic features of donepezil First-pass metabolism converts rivastigmine to a metabolite that is 10-fold less active than the parent drug Exelon® package insert.

Rivastigmine Safety (cont)
Rivastigmine was generally safe and well tolerated There was no evidence of hepatotoxicity Fewer adverse events were observed with concomitant food administration versus administration without food In addition to nausea and vomiting, rivastigmine was associated with significant weight loss This slide summarizes rivastigmine safety Although rivastigmine is generally well tolerated, the package insert warnings include: Nausea and vomiting (47% of patients receiving rivastigmine mg/day versus 12% receiving placebo) Weight loss (26% of women and 18% of men receiving rivastigmine 6-12 mg/day lost 7% of their weight compared to 6% and 4%, respectively, for those receiving placebo) Anorexia (17% of those receiving rivastigmine 6-12 mg/day vs 3 % of those receiving placebo developed anorexia) Exelon [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2000.

Rivastigmine Summary Rivastigmine (6–12 mg) improves cognition and global function in patients with mild-to-moderate AD Positive effects on ADL have been observed in some studies Rivastigmine is generally safe and well tolerated, although cholinergic side effects occur at high doses This slide summarizes rivastigmine efficacy and safety

Galantamine (Reminyl®)
Galantamine has a dual mechanism of action Competitive inhibition of acetylcholinesterase1 Allosteric modulation of presynaptic and postsynaptic nicotinic receptors2 Galantamine improves major aspects of AD (eg, cognition, behavior, function)1 Galantamine is generally safe and well tolerated1 This slide summarizes the characteristics of galantamine (Reminyl®) Galantamine was originally isolated from the snowdrop, Galanthus woronowi (Amaryllidaceae), and currently is extracted from daffodils Galantamine acts on both the nicotinic acetylcholine receptor and acetylcholinesterase In clinical trials, galantamine has been shown to treat major aspects of AD (cognition, behavior, function) Maintains efficacy for at least 12 months Consistent results in all double-blind, placebo-controlled trials Galantamine is safe and well tolerated Side effects are typical of cholinergic agents No sleep disturbances No major safety issues Recommended dosage escalation: 8 mg/day for 4 weeks, 16 mg/day for 4 weeks (maintenance), 24 mg/day maximum recommended dose Available as an oral solution and in tablet form 1. Tariot PN et al. Neurology. 2000;54: 2. Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:

Outcome Scales Used in Galantamine Phase III Trials
Cognition Cognitive subscales of the Alzheimer’s Disease Assessment Scale (ADAS-cog) Global change Clinician Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) Activities of Alzheimer’s Disease Cooperative Study- daily living Activities of Daily Living Inventory (ADCS-ADL) Disability Assessment for Dementia (DAD) Behavioral Neuropsychiatric Inventory (NPI) disturbances A wide range of outcomes was measured in galantamine pivotal trials The primary outcome measures (described in Module 4) ADAS-cog/11 CIBIC-plus Secondary outcomes were: Alzheimer’s Disease Cooperative Study—Activities of Daily Living Inventory (ADCS-ADL), Disability Assessment for Dementia (DAD), Neuropsychiatric Inventory (NPI), and resource utilization (including caregiver burden)

Comedication Minimal potential for clinically relevant drug interactions No effect on kinetics of digoxin or warfarin As with other cholinergics, galantamine should be used with caution in patients with heart block or sick sinus syndrome Galantamine has a low potential for drug-drug interactions due to: Low plasma protein binding Short half-life Dual hepatic metabolism (CYP 2D6, CYP 3A4) No individual adverse events or classes of adverse events were found to be directly related to the medications commonly used in this patient population

Do Cholinesterase Inhibitors Treat More Than Just Symptoms?
Cholinesterase inhibitors are effective for treating the symptoms of AD Even with therapy, the symptoms of AD will eventually progress Cholinergic therapy may slow the progression of symptoms Possible special relevance of nicotinic receptor modulation Most cholinergic agents used in the treatment of AD act by inhibiting acetylcholinesterase These agents affect the symptoms of AD (eg, cognitive deficiencies, behavioral abnormalities), but do not appear to have an effect on the pathological progression of AD Agents that modulate the nicotinic receptor may have a neuroprotective effect by stimulating target neurons, and indirectly stimulating neighboring neurons.1 There is evidence that increased cholinergic activity may slow the deposition of -amyloid and, thus, slow neuronal cell death2,3 1. Maelicke A and Albuquerque EX. Eur J Pharmacol. 2000;393: 2. Court JA and Perry EK. CNS Drugs. 1994;2: 3. Kihara T et al. Brain Res. 1998;792: Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:

Discrimination Between Disease Modification and Symptomatic Benefit
Withdrawal design Staggered-start design Randomized phase Placebo phase Randomized phase Placebo phase Active Active Disease-modifying effect Performance Performance Placebo Placebo Symptomatic effect Symptomatic effect Since there are no definitive diagnostic criteria for following the progression of AD, 2 study designs were conceived by Paul Leber at the Food and Drug Administration to distinguish between disease-modifying and symptomatic effects The study design on the left demonstrates 2 potential outcomes after treatment is withdrawn: Performance rapidly deteriorates to the same level as those that had received placebo; this would indicate that only the symptoms had been treated Performance declines, but does not deteriorate to the same level as those that had received placebo; this would indicate that the progression of the disease had been slowed The study design on the right demonstrates 2 outcomes when patients on placebo are treated If the effect of treatment is symptomatic, patients will immediately improve If the effect of treatment is disease modifying, patients will decline at a slower rate over time than they did while they were receiving placebo Disease-modifying effect Time Time Leber P. Alzheimer Dis Assoc Disord. 1997;11(suppl 5):S10-S39.

Max Max comes in for his CPE. Dx are SDAT, HTN, DM. His wife complains that he has anxiety and mood changes. He is angry most of the time. His wife denies he has any psychotic episodes. Pt is on ACI. What would you do?

Treatment CPE and psych/social exam Treat any physical findings
Add Depakote 125mg at night, increase to BID if needed.

Mary 85 yr old NH pt with Dx dementia, OP,OA and Depression. Pt is on Zoloft, ACI, and Ca. Nurses complain that she won’t leave her room and that she is increasingly hostile with care. What would you do and what would you recommend to the nursing staff?

Mary CPE and psych/social exam - reassess depressive symptoms
Evaluate for pain from vertebral fractures. Add Fosamax or Miacalcin

Differentiating Depression, Delirium and Dementia

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