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RECOGNITION AND TREATMENT OF PSYCHIATRIC DISORDERS:A PSYCHOPHARMACOLOGY HANDBOOK FOR PRIMARY CARE PHYSICIANS

First Edition

Authored by:Charles B. Nemeroff, MD, PhD

Professor and ChairmanDepartment of Psychiatry and Behavioral Sciences

Emory University School of MedicineAtlanta, Georgia

andAlan F. Schatzberg, MD

Chairman, Department of PsychiatryStanford Medical CenterStanford, California

Developed by:Diane M. Coniglio, PharMD

Sally K. Laden, MSScientific Therapeutics Information, Inc

Springfield, New Jersey

Developed under an educational grant from:SmithKline Beecham Pharmaceuticals

Philadelphia, Pennsylvania

PRELIMINARY DRAFT/February 25, 1997

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NOTE: The views expressed in this publication are those of theparticipating individuals. It should not be inferred or assumed thatthey represent the views of Scientific Therapeutics Information, Inc, orany manufacturer of pharmaceuticals.Before prescribing any medication, review the complete prescribinginformation, including indications, contraindications, warnings,precautions, and adverse effects.This publication is prepared under an educational grant from SmithKlineBeecham Pharmaceuticals by Scientific Therapeutics Information, Inc,505 Morris Avenue, Springfield, New Jersey 07081, U SA; telephone(201) 376-5655; FAX (201) 376-0611. Copyright 19 97 by American Psychiatric Press, Inc. All rightsreserved, including that of translation into other languages. No partof this publication may be reproduced or transmitted in any form or byany means. electronic or mechanical, including photocopying, recording,or any information storage or retrieval systems, without permission inwriting from the copyright holder.

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TABLE OF CONTENTS

Under development


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PRICFACZ

tinder development


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INTRODUCTION

Under development; will include overview on how to use the handbook,format/contents. Will state that the book focuses on psychopharmacologyrather than psychotherapy and only adults are considered. Focus is onpsychiatric disorders most commonly seen in primary care.


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OVERVIEW OF PSYCHIATRIC DISORDERS

ALZHEIMER'S DISEASE

Alzheimer's Disease (AD) is the most common primary, progressivedegenerative dementia in the elderly and the fourth leading cause ofdeath in the United States (Keefover, 1996; Raskind, 1993). At anannual cost of more than $67 billion in the US alone, AD has importantpublic health implications, especially in concert with the unparalleledgrowth of the aged population (Keefover, 1996).

EpidemiologyAlzheimer's disease afflicts up to 4 million US adults (Keefover, 1996),a figure that may double by the year 2000 (Price et al, 1995). Theprevalence of AD clearly increases with advancing age and some estimatethat up to 50% of US adults older than 85 years of age have the disorder(Evans et al, 1989). Overall estimates of the incidence of AD (11/y)are hindered by a lack of reliable data (Keefover, 1996). The presenceof AD greatly reduces life expectancy; median survival is 5 to 8 yearsafter diagnosis (Keefover, 1996) but the illness can persist up to20 years until death (Cohen. 1995). Life expectancy is lower in menwith AD than in women with AD and in also those with significantlyimpaired cognition at the time of diagnosis. Risk factors for AD areshown in Table 1 (Keefover, 1996).


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Table 1. Possible risk factors for AD (Keefover, 19 96 ; Sandson et al,1995)

Risk factorommentsAluminum ingestion

Apolipoprotein S4

Diet

Education levelEstrogen deficiency

Head injury

Unresolved; f aluminosilicate concentrations found in NF Tand plaques of persons with AD but aluminum inhalation oringestion (including aluminum-containing antacids) doesnot produce ADPresence of the E4 allele i s a strong risk factor forlate-onset AD but not a diagnostic testPossible trend toward delayed onset of dementia invegetarians versus heavy meat eatersAD occurs more often in undereducated personsPostmenopausal women not using estrogen supplements maybe at risk for ADPositive family history 1 ' risk of ADUnresolved whether females are at greater risk for ADthan malesHead injury causing loss of consciousness or retrogradeamnesia has been associated with t risk of AD in men inlater life

Family historyFemale gender

maternal ageate maternal age may T risk of AD in offspringThyroid diseasenconfirmed association between thyroid disease and ADSee Glossary for abbreviations.PathophysiologyAlthough the cause of AD is unknown, a genetic component is likely(Small, 1996). The primary degenerative central nervous system (CNS)


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changes in AD include prominent cerebral atrophy in cortical associationareas, neuronal losses, neurofibrillary tangles [g"FT], and neuritic orsenile plaques. The latter two are hallmark neurohistologic lesions ofAD and were first described in the early 19 00$ by Alois Alzheimer.

Because of these degenerative changes, patients with AD have deficits ofseveral neurotransmitters, primarily acetylcholine (ACH) , but also ofmonoamines (eg, dopamine, norepinephrine, serotonin), somatostatin, andgamma aminobutyric acid (GABA). Low ACS levels may be caused by reducedactivity of enzymes (eg, choline acetyltransferase [ChAT],acetylcholinesterase) involved in ACS synthesis (Schneider and Tariot,

1994).

PresentationInsidious memory loss is the hallmark feature of AD (Table 2); short-term memory loss occurs in the early stages of AD and is eventuallyfollowed by long-term memory loss (Price et al, 1995; Raskind, 19 95 ).


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Table 2. Typical presentation of AD

Appears usually after 65 years of age41. Reduced cognitive abilities

- memory, performance speed, problem-solving skills Language disorders (word-finding difficulties, aphasia) Altered spatial perceptions, judgment (eg, personal safety) Progressive inability to perform or inattentiveness toward activities

of daily living and personal hygiene Disruptive behavioral changes

- nonpsychotic (eg, physical and verbal abuse, aggression, agitation,screaming. wandering, uncooperativeness)- psychotic (eg hallucinations, simple paranoid delusions)

At least 40% of patients with AD develop disruptive, agitated behaviorduring the course of the disorder; this behavior may adversely affectcognitive function by interfering with motivation or attentiveness(Raskind, 1993).

Hallucinations and delusions often appear in a patient with AD usuallyduring the early or middle stages of the disorder. In contrast to themore complex, grandiose delusions of schizophrenia, delusions of AD areusually simple, paranoid beliefs related to memory loss. Typicaldelusions of AD might Include perceived theft of money or personalitems, a belief that a long-deceased acquaintance is still alive, or a


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belief that one's spouse is an imposter. These differences betweendelusions of schizophrenia and those of AD may explain why antipsychoticdrugs are less effective in the latter disorder.

Depression often coexists with AD and can aggravate simple memory loss.In advanced stages of AD, patients have profound dementia, aphasia, andusually are bedridden, incontinent, and unable to remain alone or in ahome setting without constant care.

DiagnosisDementia is only one possible diagnosis in an older individual withreduced cognitive function. Other causes of impaired memory includethat due to normal aging processes, encephalopathies (eg, from anoxia,head trauma), vascular or multi-infarct dementia, or an acuteconfusional state related to s a metabolic, toxic, or infectious disorder(Sandson et al, 1995). These alternative diagnoses should be ruled out.

The National Institutd of Neurological and Communicative Disorders andStroke and the Alzheimer's Disease and Related Disorders Association(NINCDS-ADRDA) task force has established commonly used diagnosticcriteria for possible, probable, or definite AD (McKhann et al, 1 984).However, a definitive diagnosis of AD can only be made on autopsy.

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To establish progressive deterioration in memory and cognitive skills,the primary care physician must perform a careful patient evaluation,including a detailed family history, medication history, past medicalhistory, and a complete physical, neuropsychologic, and laboratoryworkup (Table 3). Referral for neuroimaging studies may be useful inselected cases (McKhann et al, 1984; Price et al, 1995; Sandson et al, .1995).


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Medical history

Clinical examination

Establish history ofprogressive memorydeterioration andinability to performtasks.

Document diagnosticinclusion and exclusioncriteria

Neuropsychologicalrovide additionalevaluationnformation on diagnosis

of dementia

Table 3. Diagnostic approach to the patient with suspected AD (McKhann et al, 1984; Sandson et al, 1995)

ivaluationoalpproachInterview patient, family, close acquaintances. Obtaindetailed family history, medication history (prescriptionand nonprescription), past medical history (eg, stroke,seizures, head trauma, psychiatric history)

Perform physical examination, mental status testing (eg,MMSE), neurologic testing

Recognition Span Test, Boston Naming Test, Wechsler AdultIntelligence Scale, Continuous Performance Test, GollinIncomplete Pictures Test, Wisconsin Card Sorting Test,Philadelphia Geriatrics Center forms'

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Table 3 (cont'd). Diagnostic approach to the patient with suspected AD (McKhann et al, 19 84; Sandsonet al, 1995)

EvaluationoalpproachLaboratory testingnhance diagnosticbtain routine blood, electrolyte, renal, liver,

accuracyetabolic studies. Also, Vitamin 13 , folic acid, thyroidfunction tests, erythrocyte sedimentation rate, syphilisor HIV (if risk factors present)

Neuroimaging studies Identify potentiallytreatable causes ofdementia leg. tumors,abscess, subduralhematoma)

CT or MRI

Identify 4 regional PET or SPECT (mainly research tools)glucose metabolism andblood flow in parietaland temporal lobes

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Screening Tools: In the office setting, the Mini Mental StateExamination (MMSE) (Foletein et al, 1975), the Blessed Dementia Scale,(Blessed et al, 1968), or the Short Portable Mental Status Questionnaire(Pfeiffer, 1975) may be used to screen a patient in whom dementia is

suspected. On the MMSE, a score of 26 or less is abnormal in a highschool graduate and a score of 27 to 30 with evidence of cognitivedecline should prompt more detailed neuropsychological testing (Peskind,1996). More detailed neuropsychologic testing as outlined by theNINCDS-ADRDA (McKhann et al, 1984) should follow if clinical suspicionis raised. Patients with AD will show a reduction of 3 to 4 points/y onthe Blessed Memory Concentration Test or a reduction of 2 to 3 points/yon the MMSE (Price et al, 1995).

ReferralsA multidisciplinary approach that addresses medical, social,psychological, and environmental issues is needed not only for thepatient's benefit, but also for the family or caregiver's sake (Cohen,1995; Sky and Grossbeig, 1994). Alzheimer's disease extracts asubstantial burden on the patient's family and caregivers; theseindividuals often become the second patients. It has been estimatedthat up to 80% of spousal caregivers experience clinically significantsymptoms of anxiety or depression as well as more frequent medicalillness associated with chronic stress during the course of thepatient's disorder (Cohen, 1995). Thus, the primary care physician


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plays an important role in referring family members or caregivers tolocal support servi ces (see Glossary) that may alleviate some of thesestresses. For example, having the patient attend an "adult day care'setting once or twice weekly may provide the caregiver with sorely

needed personal time.

ANXIETY DISORDERS

Panic DisorderAgoraphobiaObsessive-Compulsive Disorder (0CD)Posttraumatic Stress Disorder (PTSD)Generalized Anxiety Disorder (GAD)Social Phobia

EATING DISORDERS

Anorexia Nervosa (with subtypes)Bulimia Nervosa (with subtypes)


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MOOD DISORDERS

Depressive DisordersManiaBipolar Disorder

SCHIZOPHRENIA

SLEEP DISORDERS

Primary Insomnia

SOMATIZATION DISORDER

SUBSTANCE USE/ABUSE DISORDERS

Cocaine AbuseAlcohol AbuseOpiate/Opioid Abuse


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PSYCHOPHARMACOLOGIC AGENTS

Before prescribing any drug to a patient, readers are encouraged to

consult a current and more complete source of prescribing i nformation,such as the Physician's Desk Reference (1997), AHFS Drug Information(1997), or other similar source. Unless otherwise cited, information inthis chapter has been compiled from these and similar secondaryresources.

ANTIDEPRESSANTS

BENIODIAZEPINES

NONBENZODIAIEP/NE ANEIOLYTICS

ANTIPSYCHOTICS

TraditionalAtypical (olanzapine, risperidone, clozapine)

DRUGS FOR EXTRAPYRAMIDAL SYMPTOMS

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DRUGS FOR BIPOLAR DISORDER

COGNITIVE ENHANCERS

Irgoloid MesylateErgoloid mesylates (Hydergine,e Sandoz Pharmaceuticals Corporation;dihydroergotoxine, dihydrogenated ergot alkaloids) are indicated forsymptomatic relief of age-related mental capacity decline (in persons>60 years of age), such as that which might occur in AD (Table 4).

Table 4. Overview of ergoloid mesylate therapy

FeatureommentsMechanismnknown , may t cerebral blood flowPharmacokineticsapid oral absorption, extensive hepaticmetabolism, drug interactions notreported

Efficacyodest T in cognitionSafetyransient nausea, GI disturbancesDosingtart with 1 mg TID; titrate up to1 2 mg/d in divided doses; responseusually requires 2 6 mg/d for 6 monthsPaychopharmacology Randbook.11 12(5 109 7)/Page 1 8

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Mechanism: Ergoloid mesylates may increase cerebral blood flow althoughthe exact mechanism is unknown. Unlike natural ergot alkaloids, thisproduct does not have vasoconstrictive properties.

Pharmacokinetics: Ergoloid mesylates are rapidly absorbed in thegastrointestinal (GI) tract after oral administration and are quicklyand extensively metabolized in the liver. Drug interactions have notbeen reported.

Efficacy: In 1 2-week studies using the Sandoz Clinical AssessmentGeriatric Rating Scale, modest but statistically significantimprovements have been observed in mental alertness, confusion,orientation, emotional lability, recent memory, self-care, depression,anxiety, cooperation, sociability, appetite, dizziness, fatigue, andoverall improvement in clinical status.

Safety: Ergoloid mesylates are generally well tolerated but can causetransient nausea or other GI disturbances.

Warnings/Precautions: Reversible and potentially treatable causes ofdementia should be ruled out before ergoloid mesylate therapy isprescribed. Periodically reevaluate any perceived benefit of therapy tothe patient.


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Dosing Guideli nes: The usual starting dose is 1 mg TID; doses may beincreased up to 12 mg/d ( divided). Results may not be detected for 3 or4 weeks and treatment with a minimal dose of 6 mg/d may be needed for atleast 6 months to detect any benefit. This product is available intablet, liquid, and liquid capsule formulations.

Cholinesterase InhibitorsBecause of the known deficit of cortical ACH in persons with AD (ie, thecholinergic hypothesis), drug development research has focused on agentsthat will restore levels of this neurotransmitter either directly (ie,cholinergic agonists) or indirectly (i e, cholinesterase inhibitors). In1993, the first cholinesterase inhibitor, tacrine (Cognexo, Parke-Davis;,tetrahydroaminoacridine, TEA), was approved for the treatment of mild tomoderate cognitive impairment of AD. Although tacrine is only modestlyeffective and carries a relatively signi ficant adverse effect profile,it may offer respite (albeit temporary) for selected patients with AD(Table 5).


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Table S. Overview of tacrine therapy

FeatureommentsMechanismACH concentrations via nonspecific

inhibition of brain cholinesterasePharmacokineticsapid oral absorption, extensive hepaticmetabolismEfficacyinimal but significant improvement in ADAScog, and global impressions in trials

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Pharmacokinetics: Taken orally, tacrine is rapi dly absorbed and has aduration of action of 4 to 6 hours- Food does not affect tacrineabsorption if the drug is taken at least 1 hour before meals (ie, on anempty stomach, between meals if possible). Tacrine is extensivelymetabolized by hepatic cytochrome P450 enzymes, primarily CYPIA2 (seeTable 6) but not CYPIID6. Advanced age and renal disease have noclinically important influence on tacrine elimi nation. However, liverdisease may reduce the elimi nation of tacrine and its metabolites.Tacrine serum concentrations are 50t higher in females than in males andabout 33t lower in smokers than in nonsmokers.


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Table 6. Drug and food interactions with tacrine

Substanceffect of tacrineAnticholinergics

Cholinergic agonists (eg,bethanechol), cholinesteraseinhibitors (eg, physostigmine),succinylcholineTheophylline

Cimetidine

Food

May interfere with activity ofanticholinergicsMay have a synergistic effectwith these drugs

Prolongs elimination oftheophylline and T plasma

concentrations. Monitortheophylline concentrations and1 dose accordinglyCimetidine I concentrations oftacrine by inhibiting itsmetabolismFood plasma tacrine levels byone-third; take tacrine betweenmeals if possible

Efficacy: Tacrine has been shown to be effective in placebo-controlledtrials in patients with mild to moderate probable AD. In two keystudies of up to 30 weeks' duration, most patients taking tacrine (20 to

160 mg/d) showed minimal but statistically significant improvement inthe Alzheimer's Disease Assessment Scale (ADAS cog; Rosen et al, 1984)


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and clinician's global impression measures (Davis et al, 1992; Farlow etal, 19 9 2; Knapp et al, 19 9 4). The ADAS cog examines memory attention,reason, language, and praxis- However, there were a wide range ofresponses and a substantial number of patients were unable to toleratetacrine therapy and withdrew from the trials- Importantly, thebeneficial effects of tacrine tended to diminish with time, even inpatients who experienced an initial beneficial response

Safety: Tacrine has an extensive adverse effect profile. Commonadverse events are nausea, vomiting, diarrhea, dyspepsia, and other GIsymptoms, elevated LFTs (see Warnings/Precautions), myalgia, anorexia,and ataxia. Except for LFT abnormalities and myalgia, these effects are ,dose related. The safety and efficacy of tacrine have not been testedin demented children; tacrine should not be given to pregnant orlactating women (Pregnancy Category C; see Glossary).

Warnings/Precautions: Use tacrine carefully in patients with current orpast liver dysfunction (ie, elevated LFTs). Tacrine commonly increasesLFTs in persons without a prior history of liver disease and may causeclinically significant sequelae (eg, jaundice). However, promptwithdrawal of tacrine in such circumstances will only rarely result inliver injury and LFTs should return to normal limits within 4 to6 weeks. Patients who develop clinical jaundice (total bilirubin>3 mg/dL) or those with clinical signs or symptoms of hypersensitivity


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with elevated LFTs should permanently stop tacrine therapy (see DosingGuidelines below and prescribing information for LFT monitoring advice).Tacrine stimulates cholinergic activity and should be used cautiously inselected patients (Table 7)-

Table 7- Cautions related to cholinergic activity of tacrine

Tacrine may cause:se with caution in:BradycardiaSick sinus syndrome," conduction

abnormalities, bradyarrhytmia

T Gastric acidatients at risk for ulcers (eg, historysecretionf ulcer disease, current NSAID users).Monitor for active or occult GI bleedingBladder outflowladder dysfunctionobstructionSeizuresimited potential; seizures also may be

due to AD itselfAsthmaistory of asthmaDosing Guidelines: Prescribe tacrine only when a caregiver can monitorpatient compliance with drug administration at regular intervals.Usual starting dose: 10 mg QID; do not increase dose for at least6 weeks to observe potential delayed LFT elevation. Tacrine isavailable in 10-, 20-. 30-, and 40 -mg capsules.


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Dose titration: Increase to 20 mg QID if LFTs are normal and patient istolerating therapy- Higher doses (eg, 30 to 40 mg QID) may be given at6-week intervals unless side effects appear- It may take up to 6 monthsto see any benefit and if none is seen within this time, tacrine shouldbe discontinued.

LFTs: After tacrine therapy is initiated, monitor LFTs every other weekfor at least the first 16 weeks, monthly for 2 months, every 3 monthssubsequently. The dose of tacrine should be reduced by 40 mg/d if LFTsare between three and five times the upper limit of normal (ULN)-Tacrine should be discontinued if LFTs are greater than five times ULN.If treatment is stopped and restarted for any reason, resume weeklymonitoring as described above.

Cholinsrgic AgonistsAlthough theoretically appealing, no commercially available drugs ofthis class have provided clinical utility in patients with AD. Althoughpatients with AD taking bethanechol have shown some improvement on theMMSE, the drug must be given intracerebroventricularly because it doesnot cross the blood-brain barrier. Other oral agents (eg, pilocarpine)have been ineffective or have required frequent intravenousadministration (eg, arecoline). A number of newer orally activecholinergic agonists are under study (Schneider and Tariot, 1 99 4).


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MiscellaneousSelegiline (Eldepryl,e Somerset Pharmaceuticals, Inc; formerly known asL-deprenyl) is currently indicated for adjunctive use in Parkinson'sdisease to prolong the efficacy of levodopa. However, this drug hasbeen shown to be effective in improving cognitive function and disturbedbehavior (eg, anxiety, cooperation, agitation) in patients with AD(Schneider and Tariot, 1994) (Table 8).

Table 8. Overview of selegiline therapy

FeatureommentsMechanismrreversible selective inhibition of MAO-Bat low doses (


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vivid dreams, dyskinesia, and headache have been reported. Selegilinehas not been studied in children. Selegiline is rated as PregnancyCategory C (see Glossary).

Warnings/Precautions/Drug Interactions: Do not increase the doseselegiline higher than 1 0 mg/d. CNS toxicity (including hyperpyrexia,severe agitation, hallucinations, and death) has occurred in somepatients taking selegiline with TCAs, SSRIs, or meperidine.Hypertensive crises have occurred in patients taking selegiline and thesympathomimetic agent, ephedrine.

Dosing Guidelines: The dose of selegiline is 5 mg administered BID,with breakfast and lunch. Higher doses are not more effective andshould be avoided to prevent side effects. In trials of AD patients,any clinical benefit was evident within a few weeks.

SEDATIVE-HYPNOTICS

S T IAIIILA.NTS


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PHARMACOTHERAPY OF PSYCHIATRIC DISORDERS IN PRIMARY CARE

OVERVIEW OF DRUG THERAPY: GENERAL PRINCIPLES

ElderlyPregnancy/Lactation (see Glossary for FDA definitions)

TREATMENT ALGORITHMS FOR COMMON PSYCHIATRIC DISORDERS

Alzheimer's DiseaseBecause AD is a chronic, progressive disorder, by necessity, treatmentapproaches must be continually customized and adjusted according to thepatient's current situation. A multidisciplinary approach shouldinvolve both nonpharmacologic and pharmacologic avenues for the patientwith AD and his or her family (Figure 1). Nonpharmacologic approachesinclude behavioral counseling (for patients and caregivers) and homesafety evaluation (eg, providing living arrangements on a single levelof the home to eliminate need to use stairs, enhance lighting in darkhallways to reduce disorientation, lower hot water temperature, etc).

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DepressionAntidepressants (as above)

MONIToRtherapeutic benefit, tolerability

REEVALUATEbenefit and need for continued drug therapyneed to change therapeutic approach for emergence of new sym ptoms

EVALUATE patient:Family/medical/drug historyClinical examinationLaboratory/neurologic testingINTERVIEW rel iable family mem ber/acquaintance

IMPLEME NT nonpharmacologic intervention:BehavioralEnvironmentalSocial

INITIATE pharmacologic therapyto restore neurotransm itter imbalance (tacrine, selegiline) or improve cog nition (ergoloid mesylates)

ASSESS bothersome secondary behavioral disturbances:PsychosisAntipsychoticstraditional (eg. haloperidol. thioridazine)atypical (eg. clozapine, risperidone)AgitationAntipsychotics (as above)Anticonvulsants (eg. carbamezepine, sodium valproate)Antimanic (eg. lithium)Anxiolytics (eg. buspirone. benzodiazepines)Antidepressants (eg, SSR ls. trazodone. nortriptyline)

Figure 1. Treatment approach to the patient with AD.


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Pharmacotherapy cannot delay or prevent the onset of AD but can bedirected at restoring primary underlying neurotransmitter deficits (ie,low central ACE levels). Currently, only tacrine (see Page 19 ) isindicated in the US for the treatment of the dementia of AD. Ergoloidmesylates (see Page 1 8) have been used in elderly demented patients butwith little clinical success. A number of new compounds are activelybeing studied (Schneider and Tariot, 1994; Schneider, 1996).

Pharmacotherapy for patients with AD also can be directed at managingsecondary behavioral disturbances such as aggression or agitation,depression, or psychosis (Tables 9 and 10) (Raskind, 1995).


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Table 9. Secondary behavioral symptoms of AD and the expected responseto drug therapy (Sky and Grossberg, 19 94 )

More likely to respond:

Less likely to respond:

Nonspecific hyperactivity, physicalor verbal agitation, classicpsychoses or delusions, depressivesymptoms, hallucinationSWandering, public disrobing,hoarding or hiding objects andpossessions, repetitive questioning,social inappropriateness

Antipsychotics: Data supporting the use of antipsychotics andantidepressants in patients with AD are limited; much of the data havebeen extrapolated from studies in younger, demented patients. Moretrials are needed in elderly patients with strictly defined AD.

Antipsychotics have demonstrated limited efficacy and only a marginalbenefit over placebo in AD (Table 10) (Raskind, 1995; Schneider et al,19 90) . According to a meta-analysis, no antipsychotic drug offerssubstantial clinical advantage over another. Antipsychotics are mosteffective for managing classic psychotic symptoms (eg, grandiose,

complex delusions) and less effective in patients who are not agitated,

hyperactive. or not experiencing hallucinations or delusions (Raskind,

1 9 9 3).

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Table 10. Pharmacotherapy of behavioral disturbances in patients with AD (Raskind, 1993; Schneider and

Tariot, 1994; Sky and Grossberg. 1994; Tariot, 1996)

Drug claim Behavioral feature Typical regimen Caution. Comments

Antipsychotic Symptomsresembling

Haloperidol 1 mg,

thioridazine 20 mg;

EPS more common with

high -potency drugs

Only marginal benefit

vs placebo.ostclassic psychosis t dose every 3 days (eg, haloperidol) effective in those(eg,hyperactivity,grandiose or

as tolerated untiltherapeutic effect.Divide higher doses

whereasanticholinergiceffects (eg, urinary

with classic psychoticsymptoms.xcesssedation and EPS limit

complexhallucinations,delusions)

(eg, haloperidol upto 4.6 mg/d orthioridazine up to

retention,constipation, drymouth. blurry

clinical utility.Emerging data withclozapine and

150 mg/d) BID or TID.Discontinue ( t a p e r )regimen after3 months to avoidlong-term drugexposure and EPS

vision,edation,orthoatatichypotension,delirium) morecommon with low-potency drugs leg.thioridazine)

risperidone.

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Serotonlnergic symptomsresemblingclassic psychosis( e g ,hyperactivity.hallucinations,delusions

Trazodone 25 to400 mg/ddivided)Buspirone 10 to45 mg/ddivided) Trazodone:orthostatichypotension, sedationBuspirone:izziness,

sedation. headache

Uncontrolled,anecdotal data

Benzodiazepines Anxiety.agitation.wandering.restlessness

tine low dose of ashort- orintermediate-actingagent with inactivemetabolitese g ,oxazepam 20 to

Tolerance ordependence withchronic use. ataxia,sedation,mpairedcognition, confusion

No large, wellcontrolled studies

80 mg/d.orezepam,1 to 1.5 mg/d)

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Mtimanic drugs Violent behavior.impulsiveness

Carbamezepine 50 to100 mg BiD (up to1000 mg/dmaintenance)

Sodium valproateplasma levels of30 to 90 ug/mLreported beneficial

Lithium 25 0 to1200 mg/d

carbamezepine:sedation,taxia.leukopenia.kinrash, hepatotoxicity

Lithium:PS.confusion, ataxia

Controlled dataneeded; therapeuticserum level monitoringmust be implemented

Antidepressants Apathy.leep orappetite changes.psychomotoragitation orretardation

Select agent with lowanticholinergicactivity (eg. SSRI,trazodone. secondaryamine)

Very limitedcontrolled clinicaltrial data

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11 Blocker Agitation.hostility

Propranolol 40 to520 mg/ddivided)Pindolol 60 to100 mg/ddivided) Use with caution inheart failure,obstructivepulmonary disease.asthma, diabetes,hyperthyroidism/

drug interactionscommon


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Because functional improvements are often limited by excess sedation andsubstantial EPS, clinicians should consider the impact of drug therapyon the quality of life of the AD patient and their caregivers. If thepatient and caregiver can tolerate certain disruptive behavior,

antipsychotic drug therapy could be withheld, at least temporarily. Onthe other hand, however, some evidence indicates that psychotic symptomsmay be associated with faster cognitive deterioration (Raskind, 1 99 5) .Thus, outcome trials are needed to determine usefulness of antipsychoticdrugs in patients with AD.

Antidepressants: Antidepressants have not been well studied indepressed patients with AD and the response to placebo is very high(Table 10) ( Alexopoulos, 19 96 ). Thus, early "response" to anantidepressant may forecast an early 'relapse." These drugs may improvemood or disturbed sleep-wake cycles but have no effect on cognitivefunctioning. Clinicians should select a low dose of an antidepressant

with few anticholinergic properties such as an SSRI, a secondary amine

(eg, nortriptyline, desipramine) and increase the dose gradually. Ifimprovement is not noted, select another agent. Some evidence indicates

that plasma levels considered therapeutic in nondemented depressed

individuals may not apply to demented depressed patients (Alexopoulos,

1996).

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RESOURCES

MENTAL HEALTH ORGANIZATIONS

Alzheimer's Disease (Cohen, 1995)Alzheimer's Association (AA)70 E Lake Street, Chicago, IL 60601TEL: 312-85 3-3 060 or 800-272-3900National organization with extensive family-oriented information and

newsletter. Local chapters are an excellent resource for information oncommunity services (eg, adult day care, respite programs).

American Association of Retired Persons (AARP)TEL: 800-424-3410Provides literature on services and programs for older adults.

Area Agency on AgingTEL: Check local listing for nearest Area Agency on Aging.Division of the US Department of Health and Human Services; coordinatesa large network of offices on aging to provide information andreferrals.


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Alzheimer's Disease Education and Referral Program (ADEAR)TEL: 800-438-4380.Sponsored by the National Institute on Aging. ADEAR performs freeliterature searches for clinicians and researchers on AD.

Alzheimer's Disease Centers (ADC)Offers diagnosis and management services (costs are variable),information about AD and local resources, opportunities to participatein drug trials. Contact ADEAR (above) for nearest center.

PATIENT ADVOCACY GROUPS

PUBLICATIONS

INTERNET RESOURCES


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GLOSSARY

ACH: acetylcholine.AD: Alzheimer's disease.ADAS cog:BID: twice daily.ChAT: choline acetyltransferase.CNS: central nervous system.CT: computed tomography.Cytochrome P450 system (CYP450): Proteins that catalyze oxidative drugmetabolism. Many families and subfamilies of isoenzymes. Cytochromes(CYP) IA2, IIC, IID6, and IIIA4 are relevant to metabolism of manypsychotherapeutic agents and clinically important drug interactions.BPS: Extrapyramidal side effects; common with antipsychotic therapy.Includes acute dystonic reactions (eg, facial grimacing, oculogyriccrisis), akathisia (ie, subjective feeling of restlessness),pseudoparkinson features (eg, slowed movement, masked facies, rigidity,resting tremor) and tardive dyskinesia (ie, irregular facial movements).EPS are treatable with antiparkinsonian drugs.GABA: gamma aminobutyric acid.GI: gastrointestinal.HIV: human immunodeficiency virus.


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LFTe: liver function tests such as alanine aminotransferase (ALT[formerly SGPT)), aspartate aminotransferase (AST [formerly SGOT)),gamma-glutamyl transpeptidase (GGT), bilirubin.MAOI: monoamine oxidase inhibitor.MBE: Mini Mental State Examination: a short (


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Category A: Adequate studies in pregnant women have notdemonstrated fetal risk in the first trimester and there is noevidence of risk in later trimesters.Category B: No fetal risk in animal studies but no adequate

studies in pregnant women. OR, animal studies have shown adverseeffect but adequate studies in pregnant women have notdemonstrated fetal risk during the first trimester and no evidenceof risk in later trimesters.Category C: No adverse effect in animal studies but no adequatestudies in humans. Benefits from use of the drug by pregnantwoman may be acceptable despite these risks. Or, no animalreproduction studies and no adequate studies in humans.Category D: Evidence of human fetal risk but potential benefitsfrom the drug in a pregnant women may be acceptable despite theserisks.Category X: Studies in animals or humans demonstrate fetalabnormalities or evidence of fetal risk; the risk of use clearlyoutweighs any passible benefit.

QID: four times daily.SPRCT: single positron emission computed tomography.SSRI: selective serotonin reuptake inhibitor. Class of antidepressantsincludes fluoxetine, paroxetine. sertraline.TCA: tricyclic antidepressant.TID: three times daily.


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BIBLIOGRAPHY

Alexopoulos GS. The treatment of depressed demented patients. J din

Psychiatry. 19 96;5 7(suppl 14):14-20.

American Hospital Formulary Service (AHFS). ARFS Drug Information.Bethesda, MD: American Society of Health Systems Pharmacists; 19 96 .

Blessed G, Tomlinson BE, Roth M. The association between quantitative

measures of dementia and of senile change in the cerebral grey matter ofelderly subjects. Br J Psychiatry. 1968;114:797-811.

Cohen GD. Management of Alzheimer's disease. Adv Intern Med.1995;40:31-67.

Davis KL, Thal LJ, Gamzu ER, et al, for the Tacrine Collaborative StudyGroup. A double-blind. placebo-controlled multicenter study of tacrinefor Alzheimer's disease. N Engl J Med. 1992;327:1253-1259.

Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer'sdisease in a community population of older persons. Higher thanpreviously reported. JAMA. 1989;262:2551-2556.

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Farlow M, Gracon SI, Hershey LA, Lewis KW, Sadowsky CH, Dolan-Ureno J,for the Tacrine Study Group. A controlled trial of tacrine inAlzheimer's disease. JAMA. 1992;268:2523-2529.

Folstein M, Folstein S, McHugh PR. Mini-Mental State: a practicalmethod for grading the cognitive state of patients for the clinician.J Psychiatr Res. 1975;12:189-198.

Keefover RW. The clinical epidemiology of Alzheimer's disease. NeurolClin. 1996;14:337-351 .

Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI,for the Tacrine Study Group. A 3 0-week, randomized controlled trial ofhigh-dose tacrine in patients with Alzheimer's disease. JAMA.1994;271:985-991.

McKhann G, Drachman D; Folstein M, Katzman R, Price D, Stadlan EM.Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDAWork Group under the auspices of the Department of Health and HumanServices Task Force on Alzheimer's disease. Neurology. 1984;34:939-944.


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Peskind ER. Question and answer session, In: Clinical developments in

Alzheimer's disease. J Clin Psychiatry. 19 96;57(suppl 1 4):39-44.

Pfeiffer E. A short, portable mental status questionnaire for the

assessment of organic brain deficit in elderly patients. J Am GeriatrSoc. 1975;23:433-441.

Physicians' Desk Reference- 51" ed. Montvale, NJ: Medical EconomicsCompany, Inc; 199 7.

Price DL, Walker LC, Martin LJ, Borchelt DR, Wong PC, Sisodia SS.Biology of Alzheimer's disease and animal models. In: Textbook ofPsychopharmacology. Washington, DC: American Psychiatric Press Inc;1995;523-535.

Raskind MA. Treatment of Alzheimer's disease and other dementias. In:Textbook of Psychopharmacology. Washington, DC: American PsychiatricPress Inc; 19 95 ;657-667.

Raskind MA. Management of late-life depression and the noncognitivebehavioral disturbances of Alzheimer's disease. Psych Clin North Am.1993;16:815-827.


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Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer'sdisease. Am J Psychiatry. 1984;141:1356-1364-

Sandson TA, Sperling RA, P rice BH. Alzheimer's disease: an update.Compr Ther. 1995;21:480-485.

Schneider LS. New therapeutic approaches to Alzheimer's disease.J Clin Psychiatry. 19 96;57(suppl 14):30-36.

Schneider LS, Tariot PN. Emerging drugs for Alzheimer's disease.Mechanisms of action and prospects for cognitive-enhancing medications.Med Clin North Am. 1994;78:911-934.

Schneider LS, Tariot PN, Goldstein B. Therapy with 1- deprenyl(selegiline) and relation to abuse liability. Clin Pharmacol Ther1994;56:750-756.

Schneider LS, Pollock 'VE, Lyness SA. A meta-analysis of controlledtrials of neuroleptic treatment in dementia. J Am Geriatr Soc.1990;38:553-563.

Sky AJ, Grossberg GT. The use of psychotropic medication in themanagement of problem behaviors in the patient with Alzheimer's disease.Med Clin North Am. 1 994;78:811-822.


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Small GW. Neuroimaging and genetic assessment for early detection ofAlzheimer's disease. J din Psychiatry. 1996;57(suppl 14):9-13.

Tariot PN. Treatment strategies for agitation and psychosis indementia. J Clin Psychiatry. 19 96;57(suppl 14):21-29.

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