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`in
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`
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`Eighth Edition
`
`
`Paul J. Perry
`Bruce Alexander
`
`Barry I. Liskow
`C. Lindsay DeVane
`
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`7 .4,
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`@ Lippincott Williams 8:Wlkans
`Wlters Klijer busin
`y.anV nssen ffimzozo00440) EX 1044 p 001
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`; " Eighth Edition
`
`
`. PhD, BCPP. FCCP
`Paul 1. Fe
`Emeritus Pro essor of Psychiatry, Carver College of Medicine
`University of lowa. Iowa City, Iowa
`Professor of Pharmacy. College of Pharmacy
`Touro University, Vallejo, California
`Bruce Alexander. PhannD. BCPP
`Clinical Pharmacist Specialist
`Pharmacy and Psychiatry Services
`Department of Veterans Affairs Medical Center
`Iowa City. Iowa
`Professor (Clinical) of Psychiatry, College of Medicine
`Professor Emeritus (Clinical), College of Pharmacy
`University of Iowa. Iowa City. Iowa
`Barry I. Llskow, MD
`Professor and Vice Chair, Department of Psychiatry and Behavioral Sciences
`School of Medicine, University of Kansas Medical Center
`Kansas City, Kansas
`
`C. Lindsay DeVane, PharmD, BCPP. FCCP
`ProfeSsor and Vice Chair for Research
`Department of Psychiatry and Behavioral Sciences
`Director. Laboratory of Drug Disposition and Phatmacogenetics
`Medical University of South Carolina, Charleston, South Carolina
`
`3 Lippincott Williams & Wilkins
`a Walters KluWer business
`W-4d“!Harm Lam
`mm-mm-W-mn
`
`Mylan V. Janssen (IPR2020-00440) EX. 1044, p. 002
`
`

`

`Acquisitions Editor: David Troy
`Managing Editor: Meredith Brittain
`Marketing Manager: Marisa O'Brien
`Production Editor: lulie Montalbano
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`Copyright 0 2007 Lippincott Williams & Mlkins
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`All rights reserved. This book is protected by copyright. No part of this book
`may be reproduced in any form or by any means, including photocopying, or
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`The publisher is not responsible (as a matter of product liability, negligence,
`or otherwise) for any injury resulting from any material contained herein. 1his
`publication contains information relating to general principles of medical care
`that should not be construed as specific instructions for individual patients.
`Manufacturers' product information and package inserts should be reviewed
`for current information. including contraindications, dosages, and precautions.
`Printed in the United States of America
`Seventh edition published in 1997 by American Psychiatric Press. Inc.
`Library of Congress Cataloging-in-Publlcation Data
`Psychotropic drug handbook / Paul 1. Perry
`[et al]. — 8th ed.
`.
`; cm.
`Rev? ed. of: Psychotropic drug handbook / Paul I. Perry, Bruce
`Alexander. Barry I. Liskow. 7th ed. c1997.
`Includes bibliographical references and index
`ISBN 0-7317‘6273-1
`
`I.
`
`l. Psychotropic drugs—Handbooks, manuals, etc.
`II. Perry, Paul 1'. Psychotropic drug handbook.
`[DNLM:
`1. Psychotropic Drugs—Handbooks.
`2006]
`RM315.P44 2006
`615'.783—dc22
`
`I. Perry, Paul
`
`QV 39 P9743
`
`2005029938
`
`The publishers have made every effort to trace the copyright holders for borrowed
`material. If they have inadvertently overlooked arty. they will be pleased to make the
`my arrangements at the first opportunity.
`To purchase additional copies of this book, cali our customer service
`department at {800) 638-3030 or fax orders to [301) 824-7390. International
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`Mylan V. Janssen (IPR2020-00440) EX. 1044, p. 003
`
`

`

`Contents
`
`chapter
`
`I
`
`Anfipsyehoties
`Second-Generation Antipsychotics
`First-Generation Antipsychotics
`References
`
`Chapter 2
`
`Antidepressants
`Selective Serotonin Reuptake Inhibitors
`Third-Generation Antidepressants
`Tricydic Antidepressants
`Monoarnine Oxidase Inhibitors
`
`Benzodiazepines
`CNS Stimulants
`
`References
`
`Chapter 3
`
`Mood Stabilizers
`Lithium
`
`Valproate
`Carbarnazepine
`Lamotrigine
`Miscellaneous Treatments
`
`Benzodiazepines
`Clonidine
`
`Gabapentin
`Omega-3 Fatty Acids
`Oxcarbazepine
`Topiramate
`Verapamil
`References
`
`Chapter 4
`
`Antianxiety Agents (Anxiolytics)
`Benzodiazepines
`Antidepressants
`B-Adrenergic Blocking Drugs
`Buspirone
`Miscellaneous Agents
`References
`
`I
`6
`55
`l 1 6
`
`no
`142
`166
`132
`199
`
`210
`211
`
`212
`
`225
`227
`
`256
`265
`277
`282
`
`283
`283
`
`284
`284
`285
`285
`285
`286
`
`296
`296
`312
`323
`329
`334
`337
`
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`

`xii
`
`Contents
`
`chapter 5
`
`Chapter 6
`
`Chapter 7
`
`Hypnotic:
`Definition and Evaluation of Insomnia
`Nonpharmacologic Treatment of Insomnia
`Pharmacologic Treatment of Insomnia
`Benzodiazepine Receptor Agonists
`Non-Bemdiazepine Receptor Agonists
`Rational Prescribing of Hypnotics for
`Insomnia
`
`Dietary Supplements for Treatment of insomnia
`Valerian
`Melatonin
`Tryptophan
`Rational Prescribing of Dietary
`Supplements for insomnia
`Narcotherapy
`References
`
`Psychotropic Drug Treatment of Alcohol
`and Drug Dependence
`Disuifiram
`Naitrexone
`
`Acamprosate
`Methadone and L—a-Acetyi Methadol
`Buprenorphine
`Promising Drugs for Treatment of
`Substance Dependence
`References
`
`Drug Interactions
`Types of Drug Interactions
`Opportunities for Drug Interactions
`Evidence for Drug interactions
`Explanations for Minimal Expression of
`Adverse Drug interactions
`References
`
`Chapter 8
`
`Management at Acute Drug Withdrawal
`Ethanol Withdrawal
`
`552
`352
`356
`357
`360
`376
`
`382
`
`383
`383
`385
`388
`
`389
`389
`394
`
`404
`404
`4 14
`
`4 21
`424
`428
`
`432
`433
`
`44o
`441
`442
`448
`
`451
`452
`
`454
`454
`
`465
`Anxioiytic— Hypnotic Withdrawal
`481
`Opiate Withdrawal
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`

`

`
`Contents
`
`Nicotine Withdrawal
`
`Central Nervous System Stimulant
`Withdrawal
`'
`
`References
`
`chapter 9
`
`Electroconvulsive Therapy
`Indications
`
`Efficacy
`Mechanism of Action
`Treatment-Related Variables
`Adverse Effects
`Devices Used in ECT
`Method of Administration
`Medications Used in ECI‘
`
`Rational Prescribing
`References
`
`Chapter
`
`1 0 Phannacotherapy of Childhood and
`Adolescent Psychiatric Disorders
`Psychostimulants
`Antidepressants
`Antipsychotics
`Mood Stabilizers
`
`a1-Adrenergic Agonists
`Artxiolytics
`References
`
`Chapter
`
`1 I Geriatrics
`Introduction
`
`Challenges and Guidelines of Psychotropic Drug
`Prescribing to the Geropsychiatric Patient
`Pharmacokinetic and Dynamic Changes
`Occurring with Normal Aging
`Mental Disorders and Other Treatabie Conditions
`
`in the Elderly
`Dementia
`
`Overview of Drugs Used for the Treatment
`of Dementia
`
`xiii
`
`491
`
`496
`
`499
`
`506
`506
`
`507
`512
`514
`520
`526
`526
`532
`
`535
`536
`
`548
`548
`560
`57 1
`576
`
`578
`581
`583
`
`591
`59 i
`
`595
`
`596
`
`600
`602
`
`602
`
`606
`Acctyldtolinesterase Inhibitors
`609
`NMDA Antagonist: Memantine
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`

`

`xiv
`
`Contents
`
`Depression
`Nonpharmacologic Treatment
`Pharmacotherapy of Depression in AD
`Phannacotherapy of Late-Life Depression
`Pharmacolherapy of Depression with
`Medical Illness
`
`Anxiety. Agitation, and Behavioral Problems
`Sleep Problems
`Summary
`References
`
`Appendix A Psychotropic Drug Product List
`
`Appendix B Pregnancy Risk and Lactation Categories
`
`Appendix C Psychotropic Drug Pharmacoldnetic
`Parameters
`
`Appendix D Psychotropic Drug Interactions
`
`Index
`
`6 l 0
`610
`61 l
`612
`
`614
`
`615
`617
`618
`618
`
`625
`
`643
`
`641
`
`651
`
`671
`
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`

`74
`
`Psychotropic Drug Handbook
`
`typically required less than 100 mg/day of each drug, some significantly
`agitated patients required haloperidol and lorazepam 240 mg each per
`day. The combination has been given for more than 2 weeks without
`adverse effects.
`
`Oral-Parenteral Dose Equivalents—Hydrochloride or
`Lactate Salts
`
`Some antipsychotics are available for intramuscular use; therefore, it is
`important to know the bioavailability of the oral versus intramuscular
`dosage forms for proper dosing. For example, the intramuscular form
`of chlorpromazine hydrochloride is four times more bioavailable than
`an equivalent oral dose, so 25 mg or less intramuscularly would be
`required to yield the same blood level as chlorprornazine 100 mg orally
`(Hollister, Kanter, «St Wright, 1963).
`
`Long-Acting Parenteral Antipsychotics—Decanoate Esters
`Products available in the United States include fluphenazine decanoate
`and haloperidol decanoate (Hollister et al., 1963; Van Praag 89 Dols,
`1973).
`
`ORAL-TO-DECANOATE CONVERSION. Most clinicians recommend that
`
`patients being considered for a decanoate dosage form have their treat~
`merit initiated with an oral antipsychotic (Del Giudice, Clark, 62 Codes,
`1975; Johnson, 1984). The rationale is that the oral form allows flexibil-
`ity in daily dosing and the ability to quickly withdraw the drug if ”signifi-
`cant" side effects occur. However, this practice requires the patient to be
`converted from oral to decanoate after clinical improvement. Patients
`receiving antipsychotics other than fluphenazine or haloperidol should
`have their oral antipsychotic converted to the respective drug on the
`basis of relative oral potency. Typically, patients are treated with the oral
`antipsychotic for 1 to 2 weeks before being administered the decanoate
`(Kane, 1993). A patient who responds to the oral drug will be given one
`or two injections of the decanoate as an inpatient, with plans to taper
`the oral dose as an outpatient over the course of some variable time
`period. No specific guidelines are available for tapering the oral dose. It
`is possible that the patient, once discharged to an outpatient setting,
`may be noncompliant with the oral drug. This noncompliance may sig-
`nificantly affect the total serum level of the antipsychotic and may poten-
`tially lead to relapse (Kane, 1993). In addition, the long-term use of the
`combination of dosage forms is not recommended, as noncompliance
`with the oral drug may lead to confusion about the required maintenance
`dose (Johnson, 1985).
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`

`Antipsychotics o First-Generation Antipszchotics
`
`75
`
`Oral Fluphenazine—to-Decanoate Conversion. The literature on conver-
`sion of oral fluphenazine to decanoate indicates a wide variability in
`recommended doses (Nair. Suranyi-Cadotte, Schwartz, et at, 1986; Ya-
`dalam at Simpson, 1988). Recommendations for conversion doses for
`decanoate and oral doses. as well as for management of the oral drug
`during the change to the decanoate, are summarized in Table 1.6 (Yada-
`lam & Simpson, 1988). This information is based on clinical experience
`rather than on comparative serum-level data. Because of assay technical
`difficulties and significant interpatient variability in oral fluphenazine
`”first-pass" metabolism. serum-level data comparing oral with decanoate
`doses indicate a poor correspondence (Ereshefsky, Saldad. lann. et al..
`1984; Yadalam 52 Simpson, 1988). Therefore, these recommendations
`should be viewed as guidelines only. The oral dose can be tapered for 1
`month or a shorter period if EPS are present or worsen after fluphenazine
`decanoate is started.
`
`Although loading doses of fluphenazine decanoate might alleviate
`the need for continuing oral fluphenazine during the conversion. this
`approach has not been extensively investigated. One open-design study
`suggested that patients receiving initial fluphenazine decanoate closes
`greater than 25 mg (i.e., "loading doses") administered biweekly re—
`quired a longer time for their psychotic symptoms to be stabilized
`(Weiden, Schooler, Severe. et 31., 1993). The reason for this finding is
`unclear.
`
`Oral Haloperidol-to-Decanoate Conversion. Patient conversion from
`oral haloperidol to maintenance doses has been accomplished with and
`without the use of a haloperidol decanoate loading dose.
`The no—loading-dose approach involves administering a calculated
`maintenance dose while the oral dose is tapered. A review of US. studies
`indicated that a maintenance dose of decanoate [milligrams per month)
`
`
`conversion Schedule for Oral Fluphenazine to Decanoate
`
`Fluphenuine Oral Dose
`(mg/day)
`
`Fluphenazine Decanoate Dose
`(mg/2 weeks)
`
`5
`10
`- 20
`30
`40
`
`6.25
`12.5
`12.5
`25.0
`25.0
`
`i
`
`’
`
`Some: Ereshefslty st nl., 1934; Yndulum s Simpson, 1988; Weider! at d. W93.
`
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`76
`
`Psychotropic Drug Handbook
`
`to oral (milligrams per day) dose ratio of 10 to 15 was more reasonable
`than the European literature’s ratio of 20 (Kane. 1986). For example.
`using the US. studies‘ recommendations, if a patient was stabilized on
`20 mg/day orally, the decanoate dose would be 200 mg administered
`every month. One review reported that 48% ofpatients received a supple-
`mental oral haloperidol dose of 15 mg/day during the first month of
`decanoate treatment (Ereshefsky et al., 1984). This dose declined to an
`average of 13 mg/day in 21% of patients after 4 months. Considering
`that steady-state haloperidol concentrations are not reached for 3
`months with the decanoate. a tapering schedule of oral haloperidol dur-
`ing a 1-month period might be attempted. If side effects occur during
`this period, acceleration of the oral taper might be considered.
`Loading doses of haloperidol decanoate of 20 and 40 times the oral
`dose have also been investigated (Kane, 1986; Ereshefsky, Toney, Saklad,
`et al.. 1993). Although both doses were effective in maintaining antipsy-
`chotic control. the higher loading dose was associated with more EPS.
`A loading dose protocol for initiating haloperidol decanoate after
`reviewing the previous literature has been recommended (Kane, 1993).
`In the elderly (i.e., persons older than 65 years of age) and in patients
`stabilized on 10 mg/day or less of oral haloperidol, the recommended
`loading dose is 10 to 15 times the oral dose (Kane. 1993). If a patient
`is receiving more than 10 mg/day of oral haloperidol, the total loading
`dose is 20 times the oral dose. Although an initial maximum decanoate
`dose of 100 mg is recommended, higher initial doses can be used (De
`Cuyper. Bollen, van Praag et al, 1985; Ereshefsky et al., 1993; Ram,
`1993). For example. a BOO—mg total loading dose would be administered
`as 100 mg with the ZOO-mg dose administered 3 to 7 days later. The
`oral haloperidol is discontinued at the time of the first injection of the
`loading dose or, more conservatively. at the time of the final loading
`dose. The target maintenance dose is 50% of the loading dose. To achieve
`the maintenance dose, the second month’s dose can be reduced by 25%
`and the third month's dose by an additional 25%. in older patients, the
`target maintenance dose would still be 50% of the loading dose.
`Although typical haloperidol decanoate maintenance doses are 75 to
`300 mg/month. 500 mg/month has been used. However. one author
`recommends that the maximum haloperidol decanoate dose is 450 mg]
`month (Kane, 1993).
`Haloperidol serum levels have been used to calculate a loading dose.
`because haloperidol's metabolism is less complicated titan that of flu-
`phenazine. A nomogram using data from two reports of oral haloperidol
`and haloperidol decanoate serum-level monitoring has been constructed
`and is illustrated in Table 1.7). For illustration, a patient's symptoms
`are well controlled on oral haloperidol with a steadyvstate senirn level
`of 9.3 ng/mL. Achieving a level close to this would require haloperidol
`decanoate 250 mg/month (column 1) to be administered for 3 to 4
`months (column 3). However. a haloperidol decanoate loading dose of
`400 mg (column 1) would achieve a serum level of 9.3 ng/mL (column
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`

`Antipgchotics a First-Generation Antipsychorics
`
`77
`
`
`. Projected Plasma Steady-State Haloperidol Plasma Concentrations
`from Oral Steady-state Levels
`
`Haloperidol
`Halopefidol
`Haloperidol
`Decanoate Dose
`Concentration (ng/mL),
`Concentration (ng/rnL).
`
`(mg/month)
`Month I
`Month 3'
`
`50
`100
`150
`200
`250
`300
`350
`400
`
`1.1
`2.2
`3.3
`4.5
`5.7
`6.9
`8.1
`9.3
`
`1.8
`3.6
`5.5
`1.5
`9.4
`I 1.4
`l 3.4
`l 5.4
`
`.
`’
`’
`‘—
`‘
`t
`:
`
`'me I119 fulowing amnion: huloperidol (nu/ml) = [1.0291 ldose‘wl.
`Suite: Regimes al at, 1982; Nu'l at at, 1986; Perry & Alermder, 1991.
`
`2) in 1 month. The 400mg dose could be divided and administered in
`three weekly iniections (e.g., 100 mg, 150 mg, 150 mg; see haloperidol
`loading-dose protocol under Dosing Intervals below). To determine the
`maintenance dose required to achieve a serum level of 9.3 ng/mL after
`a loading dose, examine column 3. A level of 9.4 ng/mL would be pro-
`duced by 250 mg (column 1) administered every month. This dose
`would start 1 month after the first loading—dose injection. Note: This
`dosing nomogram is only a guideline. The patient must be continuously
`monitored for therapeutic response and adverse effects.
`
`DOSING INTERVALS. Historically, fluphenazine decanoate was adminis-
`tered on a weekly or a biweekly (i.e.. every other week) schedule. How—
`ever, subsequent studies reported that 30% of patients could be success-
`fully maintained on iniections at 3-week intervals and 30% on monthly
`injections for up to 1 year, whereas another report indicated that 76%
`of patients could be maintained on monthly injections for up to 2 years
`(Wistedt e1 3]., 198] ). In a later study, 30% of patients were managed
`with monthly injections for an 8-month period (Chouinard et al., 1989).
`One study demonstrated that no relapses were experienced in patients
`who had their fluphenazine decanoate discontinued for 6 weeks (Be-
`langer & Chouinard, 1982). A more recent double-blind study reported
`no difference in relapse, symptom, or side-effect measures between flu-
`phenazine decanoate 25 mg administered every 2 weeks or every 6 weeks
`for 54 weeks in patients stabilized on fluphenazine decanoate [Carpen-
`ter, Buchanan, Kirkpatrick, et al., 1999). Therefore, patients stabilized
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`