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ATTACHMENT A


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PAXIL ADVISORY BOARD MEETINGA PROPOSAL FOR O NE PSYCHIATRIST ADVISORY BOARD MEETING

Program Date: November 5-7, 1993

Proposed to:Bonnie Rossello

SmithKline Beecham

Proposed by:John A. Romankiew icz, PharmD

Scientific Therapeutics Information, Inc

RevisedOctober 1, 1993

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TABLE OF CONTENTS

PagePurposeCost SummaryDescription Agenda and FacultyAdvisory Board MembersServices0Meeting Editorial Costs 1Meeting Report3Background Papers4Payment Schedule5

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1PURPOSE

The purpose of this proposal is to outline a description, services,timing, and costs for organizing and running one psychiatrist advisoryboard meeting with members of the PAXIL Advisory Board. The firstmeeting will be held from November 5-7, 1993 in Palm Beach Florida.

The purpose of the Advisory Board Meeting is to assemble the members ofthe PAXIL Advisory Board to provide an exchange of scientific andmarketing information regarding PAXIL and related topics. Comments onthe information concerning quality, application, and practicalsuggestions on the best vehicle for distribution, will be solicited. Inaddition, helpful ideas and advice on issues faced by the PAXILMarketing Team will be sought.

The information obtained at these meetings will be recorded in a reportthat will highlight key points and will serve as a reference source forfuture use.

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COST SUMMARY

Developmental fees, attendanceexpenses for STI. time, estimated travel $37,400

Meeting with Chairman, October 11 $2,800 Slide development, estimated $13,000 Advisory Board airfares, estimated $40,000 Meeting Report $12,500 Background paper preparation: 4 topics $12,000

TOTAL: $117,700

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DESCRIPTION

A description of the key components of the Advisory Board Meetinginclude:

1. The meeting will be held over a three-day period. Day I will be atravel day with a dinner reception held in the evening. Day IIand Day III will each have a half-day session held in the morning,concluding with lunch. Departure will be scheduled for theafternoon of Day III.

2. The meeting program will consist of a combination of lectures anddiscussions. Ample opportunity will be provided for discussion ofconcepts, new research, and new areas of direction for PAXIL .

3. Selected Advisory Board members may be asked to prepare apresentation relevant to the specific meeting.

4. Each meeting will be a closed meeting. The audience will consistof the Advisory Board members (up to 15), individuals fromSmithKline Beecham, and two editors from STI.

5 .ach Advisory Board member will receive an honorarium.WB 085324

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4AGENDA AND FACULTY

A formal agenda for each meeting will be prepared in advance of eachmeeting after consultation with SmithKline Beecham. The agenda includedbelow is a sample agenda for the 1993 Advisory Board Meeting. Topics areincluded without faculty. Briefings on the data available with PAXILand issues that SmithKline Beecham wants to address are necessary. Thisagenda will be completed after consultation with the sponsor.

SM1TH K LINE BEECHAM PSYCHIATRIST ADVISORY BOARD MEETINGNovember 5 - 7, 1993

Ritz Carlton HotelPalm Beach , Florida

Friday, November 5Afternoon Arrival and Hotel Check-in7:00 PMocktail Reception8:00 PMinnerWelcoming Remarks byDavid Brand, Vice President,

SmithKline Beecham

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AGENDA AND FACULTY (continued)

Saturday, November 67:00 AMreakfast8:00 AMgenda and ObjectivesCharles B. INImeroff, MD, PhD, Chairman8:10 AM

Strengthen Paxil profile Identify competitor deficits/strengths Evaluate clinical research/promotionalprograms Generate information for use inpromotion/education Strategize to reach primary care physiciansOverview of Paxil Market Experience and SuccessBonnie Rossello, Paxil SeniorProduct Manager, SmithKline Beecham

8:30 AMomparison of Paxil with Marketed and Investigational SSRIsJerrold F. Rosenbaum, MD (suggested) Pharmacology Pharmacokinetics Indications/efficacy Adverse effects9:00 AM Advisory Board Reaction and CommentCharles B. Nemeroff, MD, PhD, Chairman, Moderating

Comments Controversies Summarize strengths/weaknesses of all agents9:30 AMoffee Break

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Saturday, November 6 (continued)10:00 AM Review of Paxil Clinical Research ProgramDavid E. Wheadon, MD, Vice President,SmithKline Beecham

Recently completed studies Ongoing studies Future studies11:00 AM Advisory Board Reaction and Comment

Charles B. Nemeroff, MD, PhD, Chairman, Assessment of research program

Moderating

Suggestions for use of data Recommendations for future studies,indications11:30 AM Review of Paxil Promotion

Brian Lortie, Paxil Product Manager,SmithKline Beecham

Overview of Paxil promotional program compare/contrast with competitors' promotionalefforts12:00 PM Advisory Board Reaction and CommentCharles B. Nemeroff, MD, PhD, Chairman,

Assessment of promotional program - bypsychiatrists versus primary care physicians

Moderating

Assessment of competitors' promotion Suggestions for additional programs/futuredirections12:30 PM Luncheon

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7AGENDA AND FACULTY (continued)

Saturday, Novem ber 6 (continued)1:30 PM Open Forum:ong-Term Outlook for Depression TreatmentCharles B. Nemeroff, MD, PhD,0 Unmet needs in therapy Chairman0 Impact of health care reformRole of psychiatrists, primary care physicians

What is industry involvement?0 Future treatment of depression2:15 PM Adjourn2:30 PM Afternoon at leisure7:00 PM Cocktails8:00 PM Dinner

Sunday, November 77:00 AMreakfast8:00 AMreakout into WorkshopsWorkshop 1 Paxil versus Competitors

Facilitated by Charles B. Nemeroff, MD, PhDGoals: Differentiate Paxil from competitors onbasis of P450 , dose titration, sedation,activation, weight loss/gain, sexual dysfunctionWorkshop 2 Profile of Paxil Patients

Facilitated by James C. Ballenger, MDGoals: Identify 4 or 5 patient subtypessuitable for treatment with Paxil

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Sunday, Novem ber 7 (continued)Workshop 3 Reaching the Primary Care Physician

Facilitated by *Psychiatrist with knowledge ofprimary care and presentation of depression inthis settingGoals: Generate recommendations for educatingprimary care physicians about depression,appropriate treatment, and use of Paxil

8:00 AM

9:15 AM9:30 AM

10:45 AM11:00 AM

12:15 PM1:30 AM

Workshop 1: Paxil versus Competitors (Group A)Workshop 2: Profile of Paxil Patients (Group B)BreakWorkshop 3: Reaching the Primary Care Physician (Group A)Workshop 1: Paxil versus Competitors (Group B)BreakWorkshop 2: Profile of Paxil Patients (Group A)Workshop 3: Reaching the Primary Care Physician (Group B)LuncheonDeparture for all

* For these sessions, STI in conjunction with SmithKline Beecham andthe Moderator will develop a series of questions on key issues withPAXIL that are aimed at acquiring information.

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9ADVISORY BOARD MEMBERS*

ADVISORY BOARD OF PSYCHIATRISTS(confirmed as of September 29, 1 993 )James C. Ballenger, MDChairman, Dept of PsychiatryDirector, Institute ofPsychiatryMedical University of SouthCarolinaCharleston, SC 29425John G. Csernansky, MDGregory B. Couch AssociateProfessorDepartment of PsychiatryWashington University MedicalSchoolSt. Louis, MO 6311 0Joseph Deltito, MDDirector, Anxiety andMood Disorders ProgramAssoc Professor of ClinicalPsychiatryNew York HospitalCornell Medical CenterWhite Plains, NY 10 605David L. Dunner, MDProfessor and Vice Chairmanfor Clinical ServicesDept of Psychiatry andBehavioral SciencesUniversity of WashingtonSeattle, WA 9810 5Robert Hirschfeld, MD /ChairmanDept of Psychiatry andBehavioral SciencesUniversity of Texas -Medical BranchGalveston, TX 77555

Charles B. Nemeroff, MD, PhDProfessor and ChairmanDept of Psychiatry andBehavioral SciencesEmory University School of MedicineAtlanta, GA 30322Charles F- Reynolds, III, MDDirector, Sleep Evaluation CenterProfessor of Psychologyand NeurologyWestern Psychiatric Instituteand ClinicPittsburgh, PA 1 521 3Jerrold F- Rosenbaum, MDAssociate Professor of PsychiatryHarvard Medical SchoolChief, ClinicalPsychopharmacotherapy UnitMassachusetts G eneral HospitalBoston, MA 0211 4Steven Schleifer, MDProfessor and ChairmanDept of PsychiatryUMDNJNewark, NJ 0710 3David V. Sheehan, MDProfessor of PsychiatryDirector, Clinical ResearchUniversity of South FloridaPsychiatry CenterTampa, FL 3 6613

* Additional Advisory Board Members are being recruited.

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10SERVICES

The services and costs for this Advisory Board meeting assume thatSmithKline Beecham will provide all logistical arrangements. STI willprovide program design and content, editorial development, and facultyliaison services.

STI Editorial Services

STI will work in conjunction with SmithKline Beecham to provide thefollowing:

Identify and develop program content/agenda.

Identify and recruit Advisory Board Members

Research and prepare background material for mailing to AdvisoryBoard prior to meeting.

Provide slide services as needed for presenters.

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1 1MEETING EDITORIAL COSTS

Our costs are based on program development work, editorial activity,writing, proofreading, correspondence (usually express mail) withAdvisory Board members, SmithKline Beecham and others as needed toinsure a high quality, credible, and useful program for SmithKlineBeecham and Advisory Board members. Costs are as follows:

EditorialDevelopment:Liaison with board members including recruitment andtravel arrangements of board members and SmithKlineBeecham, content outline development, preparation ofmoderator for meeting, authoring one presentation(Rosenbaum) and discussion questions (fee).

COST:30,000STI Airfarewo STI editors (coach).Expenses:OST:2,000tPer Diemwo STI editors: 3 days each.Expenses:OST:1,500STI Meetingwo editors onsite, plus travel time (fee).Attendance andssumes three days.Travel Time:OST:3,900Consultingp to 20 Advisory Board members as follows:Fee:hairman - $5,000; 3 presenters/moderators@ $4,0 00 each; 16 (estimated) a $2,500 each.(SB TO PAY)SlideTI will work with the faculty to develop highDevelopmentuality and professional presentation slides. Ourcosts for slides are $130 .00 per slide if we have 2weeks or more to work with and $170.00 if we have lessthan two weeks to work. We estimate 10 0 slides for

this program. COST:13,000*t Pass through cost* STI will bill for the actual number of slides developed.WB 085332

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12MEETING EDITORIAL COSTS (continued)

Meeting withne visit with Chairman in Atlanta on October 11,Chairman:993. Two editors @ $650 each (fee) plus travelexpenses estimated at $1,500 (air and groundtransport)2,800Board Travelirst Class air travel for 20 Advisory BoardExpenses:embers.40,000t93,200

t Pass through cost.

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13MEETING REPORT

STI will transcribe the audiotapes (meeting plus one of each workshop)and provide a synopsis of the key points from the meeting. The reportwill be issued within one month of the meeting. We estimate the reportto be up to 50 doublespaced typewritten pages. An executive summarywill be included.

COSTS:12,500WB 085334

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14

BACKGROUND PAPERS

Purpose:e propose to develop succinct background papers that willprovide a literature based review of the facts regardingissues associated with Paxil. These papers will outline theinformation needed to come to a consensus on the specificissues that will be discussed in the workshops.

Description:

Costs:

Each background paper will be up to 10 typewritten, doublespaced pages in length and will include pertinentreferences. A statement of the issue will initiate thepaper with a detailed analysis of data supporting orrefuting the issue to follow. Background papers will bedeveloped on the following topics:1. P45 0 and drug interactions with SSRIs2. Identification of patient types for Paxil therapy3. Dose titration needs with SSRIs4. Sedation and SSRIs

The costs associated with development of these backgroundpapers include literature research, technical writing andediting, client review and comments, preparation of twodrafts, timing (one month), word processing, copy editingand proofreading, distribution to advisory board members inadvance of meeting, and management needed to develop thesebackground papers on a timely schedule.3,500OST (4 papers):12,000** A discount is provided for development of all four developedsimultaneously because we can take advantage of economies of scale.

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PAYMENT SCHEDULE

To be invoiced immediately $58,850To be invoiced upon completion of the meetingNovember 4-5, 1993 $58,850

$117,700

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ATTACHM ENT B


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From:ally Laden To:[email protected]:roposal for 2 review articlesDate:7/28/2003 09:40:30 (GMT-05:00)

Dear Eric:

Thank you for thinking of me for the Safety in Breast Feeding and the Tolerability ofPaxilCR review articles. A proposal for both is attached. Please review and contact mewith questions. As we discussed on Friday, I am not able to start work on these papersuntil September, but if we decide to move forward, I will reserve that month for theseprojects.

Two other questions:

1) Lydia L ewisfrom the DBSA asked me to be the writer for their upcoming dual diagnosisconsensus meeting this November. She mentioned that Scott committed GSK to funding thewriting costs for the consensus statement. Lydiais asking if GSK will be able to payingme directly rather than offering the DBSA a grant for the cost of the writing. I amhaving problems connecting with Scott. If you see him in the near future, would youinquire about this? I would submit the proposal directly to GSK and bill GSK directly.(Thanks)

2) Is there a problem with my invoice for writing Dwight Evans , editorial for the DBSA,scomorbidity issue to Biological Psychiatry? I submitted it over a month ago and waswondering about the status.f the payment cycle >30 days, so be it. I was justwondering.Thanks again Eric. I look forward to working with you again.

Sally Laden MSE Communications

898 Cahill Court Cheshire, CT0641 0T 203 y271-1047 F 203 [email protected] New business proposals.docAttachments:ew business proposals.doc;embedded picture.bmp

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ATTACHM ENT C


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EDITORIALMood Disorders and Medical Illness: A Major PublicHealth ProblemDespite efficacious and widely available antidepressantsand psychotherapeutic interventions, the psychosocial andmedical burden of depression is increasing. In fact, theWo rld Health Organization projects that depression willcontinue to be prevalent, and by the year 2 020, will remaina leading cause o f disability, second on ly to cardiovasculardisease (Michaud et al 2001). Although we do not knowwith certainty why rates and disability associated withdepression are increasing, it is likely that this mooddisorder continues to be remarkably under-recognized andunder-treated. Depression frequently occurs in the contextof chron ic medical illness, and it is only relatively recentlythat the research community has turned its attention to therelationship between depression and chronic medical con-ditions. However, there is much work yet to be done. Therecently released Institute of Medicine report (2003) ac-knowledged dep ression as one of a number of chronicconditions that requires priority action, but did not addressthe importance of com orbid depression and medical ill-ness.The relationship between depression and medical ill-nesses is complex. A chronically ill patient who also isclinically depressed may experience enhanced morbidity,a poorer prognosis, and even increased mortality from themedical diagnosis. Simply put, depression makes every-thing worse. But the association with depression goesbeyond the effects of comorbidity on the course andoutcome of a medical illness. A burgeoning body ofevidence has now demonstrated that the relationship be-tween depression and certain medical illnesses may indeedbe bidirectional in nature. Depression may be both a causeand a consequence of some medical illnesses, such ascardiovascular disease, stroke, HIV/AID S, cancer, andepilepsy.In recognition of the need to increase awareness aboutthis topic and improve the quality of life for persons withdepression, the Depression and B ipolar Support Alliance,the w orld's largest patient advocacy organization, con-vened a two-day, multidisciplinary consensus conferenceon November 12, 20 02 in W ashington, DC. Nearly 50experts in the fields of psychiatry, cardiology, immunol-ogy, oncology, neurology, endocrinology, internal medi-cine, family medicine, federal health care agency p olicyand research, and patient advocacy participated in thisprocess. Formal presentations centered around the per-spectives and goals of the N ational Institutes of Health andthe Food and Drug Administration, the personal and

societal burden of depression and medical illness, and theepidemiology, mechanisms, diagnosis, treatment, andprognosis of depression in the context of cardiovasculardisease, cancer, HIV/AIDS , stroke, neurologic diseases,diabetes, osteoporosis, obesity, and chronic pain. Work-groups met to discuss specific issues related to these topicsand on the second day, work group leaders presented theirfindings and facilitated open discussions from the group.

Burden of Mood Disorders and MedicalIllnessThe fun ctional impairment associated with depressioncontributes significantly to the economic burden ofchronic medical illness. Depression also is becomingrecognized as a cause of increased morbidity and mortalityin chronic medical illness. As reviewed by Katon (2003),medical costs for patients with major depression areapproximately 50% higher than the costs of chronicmedical i l lness alone. In addition, Katon (20 03) und er-scores the equ ally important, but often less appreciated,effects of depression on adverse h ealth behaviors, such assmoking, unhealthy diet, sedentary lifestyle, and pooradherence to medical regimens (e.g., cardiac rehabilita-tion). The findings from a number of studies have estab-lished that major dep ression is associated w ith significantfunctional impairment, lost work produ ctivity, occupa-tional disability, and increased h ealth care resource utili-zation, and that effective treatment restores functioning.Simon (2003) reviews these data in the context of evi-dence from recent cross-sectional, longitudinal, and treat-ment studies of depressed patients with and withoutarthritis, chronic obstructive pulmonary disease, diabetes,or heart disease. This emerging body of evidence de mon-strates that depression significantly increases the burden offunctional impairment in medical illness, and that treat-ment reduces disability and health service costs. The effectof other mood d isorders, such as dysthym ia or bipolardisorder, on the burden of chronic medical illness isremarkably understudied.

Cardiovascular DiseaseIt is now recognized that m ajor depression and bipolardisorder are associated with increased rates of death from

2003 Society of Biological Psychiatry006-3223/03/$30.00doi:10.1016/S0006-3223(03)00639-5


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17 8IOL PSYCHIATRYditorial2003;54:177-180coronary heart disease (CHD), and that major depressionor depressive symptoms increase the risk of incident CHD(Musselman et al 1998). As reviewed by Rudisch andNemeroff (2003), as many as 27% of patients with CH Dhave m ajor depression, but a substantially larger numberof cardiac patients have subsyndromal depressive symp-toms. Depression is a particularly lethal develop ment forpatients with acute myocardial infarction (MI). In theUnited States, there are approximately 150,000 deaths inthe first year after an initial MI, and Carney an d Freedland(2003) estimate that at least 90,000 of these deaths may berelated to post-MI depression. The cum ulative body ofevidence in support of an association between dep ressionand cardiovascular disease is large and impressive; Carneyand Freedland (2003) evaluate this literature and outlinefuture directions for research, including studies that willbetter elucidate the role of depression in the developm entand progression of atherosclerosis, ischemia, and arrh yth-mias.One p articularly diverse and robust field of research isdedicated to better understanding the mechanism s thatunderlie the relationship between depression and cardio-vascular disease. In their paper, Joynt and colleagues(2003) overview seven probable mechanisms associatedwith depression that may be related to cardiovasculardisease: noncompliance w ith cardiac rehabilitation andmedical regimens; risk factor clustering (e.g., smo king,hypertension, diabetes, hy percholesterolemia, obesity);hypothalamic-pituitary-adrenal (HPA) axis hyperactivityand cortisol elevation; decreased heart rate variability;elevated plasma levels of pro-inflammatory cytokinesleading to atherosclerosis; platelet activation and h yperco-agulability; and psychological stress.The demonstrated adverse effect of depression on therisk of new and progression of established CHD hasspurred the nex t emergent area of clinical study in thisfield: the conseq uences of depression treatment on cardio-vascular morbidity and survival. As noted in the p aper byRoose (200 3), findings from the few o pen-label or ran-dom ized, controlled clinical trials suggest that the selec-tive serotonin reuptake inhibitors (SSRIs), bupropion, andcertain psychotherapeutic interventions are safe and effec-tive treatment of depression in patients with CH D. Th etricyclic antidepressants (TCAs) increase heart rate, causeorthostatic hypotension and conduction delays, have beenshown to increase the risk of cardiac mortality, and shouldbe avoided in this patient population. There is one pub -lished placebo-controlled trial, which suggests that SSRItreatment of depressed post-MI patients may improveoutcome and increase survival, but this study was notadequately powered to find significant changes in thesecardiac disease outcomes. Thus, it is still not known

wheth er treatment of depression enhances the outcom e ofthe cardiac disease. Further study is clearly needed.CancerAs with cardiovascular disease, there is a large andgrowing body of evidence in support of a relationshipbetween depression and cancer. Research efforts havefocused on depression as a risk factor for cancer, depres-sion as a consequence of cancer, and the dynamics ofcomorbid depression and cancer. Large population studiessuggest that depressed mood or stressful life events mayincrease the risk of cancer. Although it is acknow ledgedthat these observations of increased risk may be due in partto earlier, undetected malignancies or factors other thandepression (Lillberg et al 200 3; Penninx et al 199 8), thesefindings are compelling and further study is w arranted.Depression also is a common occurrence in patientswith a wide range of different malignancies and oftenprevents patients from complying with treatment regimensand other h ealth-promoting behaviors, thus worsening theprognosis. A diagnosis of cancer represents a significantlife stressor, which in vulnerable person s can precipitatean episode of depression. In addition, patients with cancermay develop "sickness behavior" or depressive syndromesdue to proinflamm atory cytokine activation that is theresult of tumor cell burden , tissue destruction, radiationtreatments, and chemotherapy. The papers by Raison andMiller (2003) and Spiegel and Giese-Davis (2003) reviewthe relationships between depression and cancer and offerinsight into disease progression and treatment. Of imme-diate clinical util ity are th e findings of stud ies show ingthat pretreatment with serotonergic antidepressants canprevent neurotoxicity and clinical depression in patientstreated with interferon-alpha.HIV/AIDSMood disorders, including depression and mania, areprevalent in persons with human immunodeficiency virus(HIV) disease and may be associated with impairedquality of life, neurocognitive and functional impairment,and poor ad herence to antiretroviral therapy. In addition,emerging data suggest that dep ression is associated withdeclining CD4 cell counts, accelerated disease p rogres-sion, and increased mortality. In their paper, Cruess andcolleagues (2003) discuss the negative impact of mooddisorders on HIV/AIDS and review evidence for safetyand efficacy of antidepressants, mood stabilizers, andnovel pharmaco therapies in this population (Evans et al200 2a). Leserman (200 3) also reviews this topic, but witha focus on the biological mechanisms underlying therelationship between m ood disorders and HIV d isease


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EditorialIOL PSYCHIATRY792003;54:177-ISOand the immune effects that result from this comorbid-ity (Leserman et al 1997; Evans et al 2002b). Patientswith HIV/AIDS and comorbid depression are a signif-icantly underserved and understudied population. Fur-ther epidemiologic, biological, and therapeutic studiesare urgently needed to better understand the nature ofthis comorbidity, increase case-finding, and developeffective treatment strategies.Neurologic DiseaseThis special issue also includes papers devoted to thetopics of depression and comorbid neurologic disorders,such as stroke, Parkinson's disease, Alzheimer's disease,and epilepsy. Of these neurologic disorders, the relation-ship between mood disorders and cerebrovascular acci-dents is particularly well-studied. As reviewed by Robin-son (200 3), depression is comm on in poststroke patients,with reported prevalence rates of approximately 20%;bipolar disorder is less common. There is no standardizeddiagnostic approach for poststroke depression, and thecontroversies surrounding various approaches are summa-rized by Robinson (2003). The findings of treatmentstudies showing efficacy of antidepressants, electrocon-vulsive therapy, psychostimulants, and cognitive behav-ioral therapy in patients with p oststroke depression are ofconsiderable clinical importance. Importantly, treatmentof depression improves measures of function and cogni-tion and may result in improved survival. Evidence thatantidepressants may prevent poststroke depression offershope. As with m any other medical comorbidities, depres-sion may increase the risk of stroke, and the findings oftwo large epidemiologic studies support the role of depres-sion as a risk factor for stroke. These findings furtherunderscore the importance of identifying the underlyingbiological mechanisms associated with depression comor-bidity.Depression occurs in roughly half of patients withParkinson's disease and is associated with significantimpairment, including reduction in fine motor skills andcognitive function. In their paper, McDonald and col-leagues (2003) review th e distinct presentation of depres-sion in this population, discuss the challenges associatedwith diagnosis, and highlight the need for more sensitivescreening and d iagnostic tools.Depression in this population may not be due simply tothe disability and added life stressors associated withParkinson's disease. Rather, emerging evidence suggeststhat depression in th ese patients may be a consequence ofneurodegeneration. Treatment of depression in Parkin-son's disease is complicated by variable responses, sensi-tivity to adverse effects, and drug interactions. Random-ized, placebo-controlled trials, particularly of the SSRIs

and dopamine agents, are needed. The findings of func-tional neuroimaging studies are presented, which mayeventually lead to the improved understanding of theneurocircuitry of depression in Parkinson's disease.Even though depression occurs in as many as 50% ofpatients with Alzheimer's disease, contributing to accel-erated functional and cognitive decline, impaired qualityof life, care-giver depression, and earlier institutionaliza-tion, surprisingly little evidence-base d data are available toinform diagnosis and treatment. The diagnosis of depres-sion in this cohort is particularly challenging becausesymptoms, such as psychomotor retardation, insomnia,and emotional liability, which occur in nondepressedpatients with Alzheimer's disease may be difficult todifferentiate from a true depressive episode. Moreover,symptoms of dementia may mask an underlying depres-sive disorder. In an effort to guide research and betterinform clinical care, the National Institute of MentalHealth has undertaken the task of developing diagnosticcriteria for depression in Alzheimer's disease. Lee andLyketsos (2003) review these developm ents and describean ongoing longitudinal study of depression and otherneuropsychiatric comorbidities in new cases of Alzhei-mer's disease, which will provide valuable information onthe epidemiology, natural course, and diagnosis of depres-sion in this population.Epilepsy is another neurologic disorder that often iscomplicated by como rbid depression. As many as 50% ofepileptic patients seen in tertiary treatment centers mayhave depression, and suicidality among depressed epilep-tics have been reported to be as h igh as 10 times the ratethan in the general population. Kanner (20 03) reviews thechallenges related to diagnosing depression in epilepsy:patients often present with atypical depressive symptoms(e.g., anxiety, irritability, hypomania, pain); the peri-ictalperiod often is associated with a recurrent and short-liveddysphoria that is clinically significant but does not con-form to standard diagnostic criteria; and antiepilepticdrugs and su rgical intervention can be iatrogenic cause s ofdepression. Clearly, epilepsy is a risk factor for depres-sion; however, recent evidence suggests that depressionmay increase the risk for epilepsy by 4- to 6-fold. Furtherstudies are needed to better characterize this complexrelationship.

Call for ActionThe con tributions made by this conference and th e paperspublished in this special issue of Biological Psychiatryshould not simply be measured by th e quality and quantityof the data, wh ich are impressive. Rather, the strength ofthis publication also lies in the fact that the views ofexperts from widely divergent fields of clinical and scien-


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18 0IOL PSYCHIATRYditorial2003;54:177-180tific endeavor resonate along 4 basic themes: 1) Depres-sion is very common in chronic medical illness; 2)Comorbidity with depression inevitably hinders recoveryand worsens prognosis; 3) Medical illness is a risk factorfor depression because of psychosocial stressors, func-tional impairment, and oth er biological mechanisms (e.g.,Parkinson's disease); and 4) Depression may figure prom-inently as an etiologic factor in the onset and course ofmedical illness, particularly cardiovascular disease, stroke,HIV/ AIDS, cancer, and epilepsy. The latter observation istruly remarkable. Much more research is needed to betterunderstand this bidirectional relationship and identifypossible common pathogenic, mechanistic pathways thatlink depression and serious medical illness.These are pow erful messages that must no t be ignored.The w eight of evidence is so persuasive that there shou ldnever again be a valid reason for not aggressively seekingout and treating depression in medically ill patients.Increasing aw areness, reducing stigma, and maintaining ahigh level of vigilance for depression in medically illpatients must beco me a p riority for clinicians. In addition,the efforts of the research comm unities must continue tobetter elucidate the prevalence, risk profile, diagnosticcriteria, treatment, and biological underpinnings of thecomorbid relationship between depression and medicalillness. Only by furthering research efforts and aggres-sively diagnosing and treating depression, will we be ableto achieve substantive gains in health care and in ourpatients' quality of life.

Dwight L. EvansDepartment of PsychiatryUniversity of Pennsylvania School of Medicine3 Blockley Hall423 G uardian DrivePhiladelphia, PA 19104-6021Dennis S. CharneyMood and Anxiety Disorders Research ProgramNational Institute of Mental HealthBethesda, Maryland

We acknowledge Sally K. Laden for editorial support.

ReferencesCarney RM, Freedland KE (2003): Depression, mortality, andmedical morbidity in patients with coronary heart disease.

Biol Psychiatry 54:241-247.Cruess DG, Evans DL, Repetto MJ, Gettes D, Douglas SD,Petitto JM (2003): Prevalence, diagnosis, and pharmacologi-cal treatment of mood d isorders in H IV disease. Biol Psychi-

atry 54:307-316.Evans DL, Mason K, Bauer R, Leserman J, Petitto J (2002a):Neuropsychiatry manifestations of HIV-1 Infection andAIDS. In: Charney D, Coyle J, Davis K, N emeroff C, editors.

Neuropsychopharmacology: The Fifth Generation ofProgress. New York, NY: Raven Press, 1281-1300.Evans DL, Ten Have TR, Dou glas SD, Gettes DR, Morrison M,Chiappini MS, et al (2002b): Association of depression withviral load, CD8 T lymphocytes, and natural killer cells in

women with H IV infection. A m .1 Psychiatry 159:1752-1759.Institute of Med icine (2003): Priority A reas for National A ction:Transforming Health Care Quality. In: Adams K, CorriganJM, editors. Washington, DC: Th e National Academies Press.

Joynt KE, Whellan DJ, O'Connor CM (2003): Depression andcardiovascular disease: Mechanisms o f interaction. Biol Psy-chiatry 54:248-261.Kanner AM (2003): Depression in epilepsy: Prevalence, clinicalsemiology, pathogenic mechanisms, and treatment. Biol Psy-chiatry 54:388-398.Lee HB, Lyketsos CG (2003): Depression in Alzheimer's dis-ease: Heterogeneity and related issues. Biol Psychiatry 54:353-362.Leserman J (2 003): H IV disease progression: Depression, stress,and possible mechanisms. Biol Psychiatry 54:295-306.Leserman J, Petitto JM, Perkins DO, Folds JD, Golden RN,Evans DL (1997): Severe stress, depressive symptoms, andchanges in lymphocyte subsets in h uman imm unodeficiencyvirus-infected men: A 2-year follow-up study. Arch GenPsychiatry 54:279-285.Lillberg K, Verkasalo PK, Kaprio J, Teppo L, Helenius H,Koskenvuo M (2003): Stressful life events and risk of breastcancer in 10,808 women: A cohort study. A m .1 Epidemiol157:415-423.Katon WJ (2003): Clinical and health services relationshipsbetween major depression, depressive symptoms, and generalmedical illness. Biol Psychiatry 54:216-226.Michaud CM , Murray CJ, Bloom BR (2001): Burden of disease:Implications for future research. J A M A 285:535-539.McDonald WM, Richard IH, DeLong MR (2003): The preva-lence, etiology, and treatment of depression in Parkinson'sdisease. Biol Psychiatry 54:363-375.Musselman DL, Evans D L, Nemeroff CB (1998): The relation-ship of depression to cardiovascular disease: epidemiology,biology, and treatment. Arch Gen Psychiatry 55:580-592.Penninx BW, Guralnik JM, Pahor M, Ferrucci L, Cerhan .TR,Wallace RB, et al (1998): Chronically depressed mood andcancer risk in older persons. J Natl Cancer bast 90:1888-1893.Raison CL, Miller AH (2003): Depression in cancer: Newdevelopments regarding diagnosis and treatment. Biol Psy-chiatry 54:283-294.Robinson RG (2003): Poststroke depression: Prevalence, diag-nosis, treatment, and disease progression. Biol Psychiatry54:376-387.Roose SP (20 03): Treatment of depression in patients with heartdisease. Biol Psychiatry 54:262-268.Rudisch B, N emeroff CB (200 3): The epidemiology of comorbidcoronary artery disease and depression. Biol Psychiatry 54:227-240.Simon GE (2003): Social and economic burden of mood disor-ders. Biol Psychiatry 54:208-215.Spiegel D, Giese-Davis J (2003): Depression and cancer: Mech-anisms and disease progression. B iol Psychiatry 54:269-282.


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ATTACHM ENT D


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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 ex pressed 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,50 5 Morris Avenue, Springfield, New Jersey 07081 , USA; telephone(201) 376-5655; FAX (201) 376-0611. Copyright 199 7 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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Table 1. Possible risk factors for AD (Keefover, 1 996; 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 is 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, 199 6). 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 1900 $ 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). L ow 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, 1995 ).


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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 i mpaired 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, 19 95 ). 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, 1984).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). D iagnostic approach to the patient with suspected AD (McKhann et al, 1984 ; 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 services (see Glossary) that may alleviate some of thesestresses. For example, having the patient at tend 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 information,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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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. D rug interactions have notbeen reported.

Efficacy: In 12 -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 Guidelines: 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 produc t 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 (ie, 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 t acrine is only modestlyeffective and carries a relatively significant ad verse effect profile,it may offer respite (albeit temporary) for selected patients w ith 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

lasting


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Pharmacokinetics: Taken orally, tacrine is rapidly 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 stomac h, 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 elimination. However, liverdisease may reduce the elimination of tacrine and its metabolites.Tacrine serum concentrations are 50t higher in females than in males andabout 33t low er in smokers than in nonsmokers.

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and clinician's global impression measures (Davis et al, 19 92; Farlow etal, 1992; Knapp et al, 1994). 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 LF Ts). Tacrine commonly increasesLFTs in persons without a prior history of liver disease and may causeclinically significant sequelae (eg, j aundice). 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 QI D 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- I t 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 c linical 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, 1994).


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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, 1 994) (Table 8).

Table 8. Overview of selegiline therapy

FeatureommentsMechanismrreversible selective inhibition of MAO-Bat low doses (


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higher doses, the drug loses its selectivity and also inhibits MAO-A.Monoamine oxidase is responsible for the breakdown of dopamine,serotonin, and norepinephrine and the B type is found primarily in thebrain- selegiline also may increase dopaminergic activity by otherunknown mechanisms. Emerging evidence indicates that selegiline mayretard the progression of AD by reducing oxidative stress in neurons(Schneider and Tariot, 1994).

Pharmacokinetics: The bioavailability of selegiline increases up tofour times when the drug is taken with food. Selegiline is extensively

metabolized in the liver and one metabolite has clinical activity. Dataare not available regarding the pharmacokinetic fate of selegiline orits metabolite in patients with renal or hepatic impairment. It is notknown if selegiline is excreted in breast milk.

Efficacy: Results of several randomized, placebo-controlled trialsindicate that selegiline (10 mg/d) appears to impart beneficial effectson cognition and behaVior in patients with AD (Schneider et al, 1994).Additional trials are needed to confirm these findings. Whether thebenefit of selegiline is related to increased MAO-B activity that hasbeen reported in AD or related to improvement in mood is not clear.

Safety: Safety data from controlled clinical trials is limited butnausea. dizziness, abdominal pain, confusion, hallucinations, dry mouth,


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vivid dreams, dyskinesia, and headache have been r eported. 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 10 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 symptoms

EVALUATE patient:Family/medical/drug historyClinical examinationLaboratory/neurologic testingINTERVIEW reliable family member/acquaintance

IMPLEM ENT nonph armacologic intervention:BehavioralEnvironmentalSocial

INITIATE ph armacologic therapyto restore neurotransmitter imbalance (tacrine, selegiline) or improve cognition (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. benzod iazepines)Antidepressants (eg, SSRls. 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 1 9) isindicated in the US for the treatment of the dementia of AD. Ergoloidmesylates (see Page 18) have been used in elderly demented patients butwith little clinical success. A number of new compounds are activelybeing studied (Schneider and Tariot, 1994 ; Schneider, 199 6).

Pharmacotherapy for patients with AD also can be directed at managingsecondary behavioral disturbances such as aggression or agitation,depression, or psychosis (Tables 9 and 1 0) (Raskind, 199 5).


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Table 9. Secondary behavioral symptoms of AD and the expected responseto drug therapy (Sky and Grossberg, 1994)

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,

1993).

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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 withhigh -potency drugs

Only marginal benefitvs placebo.ost

classic 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 valproate

plasma levels of30 to 90 ug/mLreported beneficial

Lithium 250 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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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: Ex trapyramidal 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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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. 1996;57(suppl 14):14-20.

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

Blessed G, Tomlinson BE, Roth M. The association between quantitativemeasures 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 30 -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 Alz heimer'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. 1996;57(suppl 14):39-44.

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

assessment of organic brain deficit in e lderly 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; 1995;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, Price BH. Alzheimer's disease: an update.Compr Ther. 1995;21:480-485.

Schneider LS. New therapeutic approaches to Alzheimer's disease.J Clin Psychiatry. 1996;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, G oldstein 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 G T. The use of psychotropic medication in themanagement of problem behaviors in the patient with Alzheimer's disease.Med Clin North Am. 1994;78:81 1-822.


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Small GW. Neuroi maging 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. 1996;5 7(suppl 14 ):21-29.

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INDEX

OPTIONAL; need decision regarding its inclusion after review of Draft I-


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Scientific Therapeutics Information, IncFebruary 4, 19 97Charles B- Nemeroff, MD, PhDProfessor and ChairmanDept of Psychiatry and Behavioral SciencesEmory University School of MedicinePO Drawer AFAtlanta, GA 30322-4990RE: PRIMARY CARS HANDBOOK OF PSYCHOPHARMACOLOGY

I am pleased to provide an update on the status of this project- Wehave begun development of the text, and Diane Coniglio, PharmD is theprimary technical writer and project manager. I will be working closelywith Diane at all times and will serve as technical editor. You andAlan are in good hands with Diane; she has many years of experience andis a creative and accomplished technical writer.We have developed a timeline for completion of work as follows: Sample text for preliminary comment Draft I to co-authors/APPI/sponsor Comments to STI Draft II to co-authors/sponsor Comments to STI Draft III to co-authors/sponsor forsign-off Production begins Page proofs to co-authors/APPI/sponsor for final approval Disk to publisher for printing

Feb 21May 2May 30June 20July 11July 25August 1August 15September 1

A complete content outline is enclosed for your comment. We have madeseveral key content assumptions as listed below. Please comment onthese issues.1. Investigational drugs will not be discussed2. Only oral formulations will be discussed3. Somatization disorder and general treatment guidelines for elderlyand pregnant/lactating patients have been added- OK?4. The benzodiazepine-, antipsychotic-, and barbiturate-classes contain

many drugs. Should we select representative agents from each ofthese classes rather than discussing the entire class?5. Should thyroid hormone augmentation of resistant depression beincluded or is this an issue not commonly encountered in primarycare?

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505 Motris Avenue. Springfield NJ 07081 *Telephone: (201) 376-5655 Fax: (201) 376-0611 or (201) 376-5567



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Charles B. Nemeroff, MD, PhDFebruary 4, 1997Page 2

I hope that our progress to date meets with your approval. DianeConiglio will be in touch with you in the near future to discuss theissues addressed in this letter and to gain the benefit of your input-In the meantime, please do not hesitate to call me if you have questionsor require additional information.Siney,Sallyaden, MSAssociate Editorial Directorenclcc: C ReinburgB Brand

J ArmsonJ RomankiewiczM PhilipsD ConiglioJ Leib.1112

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Note: The authors have worked to ensure that all information in this book concerning drugdosages, sche dules, and routes of administration is accurate as of the time of publication andconsistent with standards set by the U.S. Food and D rug Ad ministration and the gene ral medicalcommunity. As med ical research and practice advance, howeve r. therapeutic standards may change.For this reason and because human and m echanical errors sometimes occur. we rec ommend thatreaders follow the advice of a physician who is directly involved in their care or the care of amembe r of their family.Books published by the Ame rican Psychiatric Press, Inc., represent the views and opinions of theindividual authors and do not nece ssarily represent the policies and opinions of the Press or theAmerican Psychiatric Association.This text reviews the use of pharmacologic agents, not all of which are cleared for marketing bythe FDA for the psychiatric disorders discussed in this publication.In keeping with good clinical practice. before prescribing any medication, review the completeprescribing information. including indications, contraindications, warnings, precautions, andadverse effects.First Ed itionCopyright 1999 A merican Psychiatric Press. Inc.02 01 00 99 4 3 2 1A LL R IG H TS RE S E RV E DManufactured in the United States of America on acid-free paperAmerican Psyc hiatric Press, Inc.1400 K S treet , NWWashington, DC 20005www.appi.orgLibrary of Congress Cataloging-in-Publication DataNemeroff, Charles B.Rec ognition and treatment of psychiatric d isorders : a

psychopharmacology handbook for primary care / C harles B. Neme roff,Alan F. Schatzberg ; 1st ed.

p. cm.Includes bibliographical references and index.ISBN 0-88048-990-11. Mental i l lnessTreatment H andbooks. manuals, etc .

2. Psychopharmacology Handbooks, manuals. etc. 3. Primary care(Medicine) Handbooks. manuals, etc.. Schatzberg. Alan F.II. Title.[DNLM: 1. Mental Disordersdrug therapy Handbooks. 2. MentalDisordersdiagnosis Handbooks. 3. Psychotropic Drugs Handbooks.WM 34 N433r 19991RC454.4.N46 1999616.89' .18dc21DNLM/DLCfor Library of Congress . 99-15420C IP

British Library Cataloguing in Publication DataA CLP record is available from the British Library.


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Mental health is an important public health issue, as e videnced by theprevalence of psyc hiatric problems that are associated with tremendous d is-ability, imme nse personal suffering, and a heavy e conomic burden. 1 2 Nationalsurvey data indicate that 48% of a representative US adult sample populationhave reported a psychiatric d isorder at one time or another and that about30% have reported a disorder during the past 12 months. Less than half ofthose with a li fetime history of a psychiatric d isorder e ver received treatment.interestingly, 14% of the sample reported a li fetime history of three or morecomorbid psychiatric d isorders. ' These findings speak d irectly to the impor-tance of screening, identifying, and treating patients with mental illness.

The primary care setting has been called a de facto mental healthcaresystem in the US' and the hidden mental health network.' About 60% ofpatients with a psychiatric disorder are identified and rece ive treatment in aprimary care setting.' With the changing healthcare environment in the US,more and more patients are entering the primary care network, creating everlarger, busier, and m ore closely regulated practices. Thus, primary c are physi-cians are be ing forced to de velop or refine strategies for screening and ide nti-fying patients with psychiatric disorders.

This handbook, Recognition and Treatment of Psychiatric Disorders:A Psychopharmacology Handbook for Primary Care, was deve loped to add ressthese issues and meet some of these needs. Another factor that led to thede velopment of this handbook is the continually growing number of newdrugs being introduced for the treatment of mental disorders and of currentlyavailable d rugs being used for new psyc hiatric indications. Although manypsychiatric disorders are suitable for treatment in the primary care setting,issues for referral to psychiatric c olleagues are germane to contemporary prae-tice and are d iscussed in this text . We rec ognize that primary care physicianshave little extra time to read the voluminous psychiatric literature and distill itdown to practical yet timely and acc urate treatment strategies, and we hopethis handbook will aid in that e ndeavor.

We thank SmithKline Be echam P harmaceuticals for providing an unre-stricted educational grant to Scientific Therapeutics Information, Inc, for thede velopment of this handbook. The ed itorial assistance of D iane M. Coniglio,PharmD, and the staff of Scientific Therapeutics Information, Inc, is gratefullyacknowledged. We also appreciate the support of our publisher, AmericanPsychiatric P ress, Inc.

Charles B. Nemeroff, MD , PhDlan F. Schatzberg, MDPrefaceii


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(STI Cover Page - To be removed before submis .sion)

PAROXETINE TREATMENT OF MOOD DISORDERS IN WOMEN:PREMENSTRUAL DYSPHORIC DISORDER AND HOT FLASHES

Authored by:Kimberly A. Yonkers, M D

Associate Professor ofPsychiatryYale University School of'Medicine

New Haven, CT

For submission as part of a supplement to:Psychopharmacology Bulletin

Prepared by:C. dloria Mao, PharmDSally K. Laden, RPh, MS

Scientific Therapeutics Information, IncSpringfield, New- Jersey

Draft IMarch 24, 200 3

2007 Yonkers PMDD ms (103 41 2)/Page 1

CONFIDENTIAL - SUBJECT TO PRO TECTIVE ORD ER - PRODUC ED BY GSK IN CRO OKS VS. SMITHKLINE AR014831413BEECHAM (NO. 07 L 004934, COOK COUNTY, IL )


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Spring 2003 Volume 37 Supplement 1Psychopharmaco logyULLETIAdvancing the Treatment of Mood

and Anxiety Disorders:The First 10 Years' Experiencewith ParoxetineIntroduct ionBy C harles B. Nem eroff MD , PhDNeuropharmacology of ParoxetineBy Michael j: Ow ens, PhD, andCharles B. Nem erof M D, PhDIn Vivo N enroimaging Correlates of theEfficacy of Paroxetine in the Treatm entof Mood a nd Anxiety DisordersBy Clinton K ilts, PhDPharnutcokinetics, Drug Interactions, andTolerabllityof Partncetine and Paroxetine CRBy C. Lindsay DeV ane, PharmDParoxetine Treatment of M ajor DepressiveDisorderBy M artin B. Keller, MDTreatment of Pa nic Disorder:Focus on ParoxetineBy Mark H. Pollack, M A and A licia C. Doyle, BAParoxetine Treatment o f General izedAnxiety DisorderBy D avid V Sheehan, MD, MB

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