Treatment of Depression Treatment of Depression and Schizophreniaand Schizophrenia

Presented by:Presented by:

Charles B. Nemeroff, MD, PhDCharles B. Nemeroff, MD, PhDReunette W. Harris Professor and ChairmanReunette W. Harris Professor and Chairman

Department of Psychiatry & Behavioral SciencesDepartment of Psychiatry & Behavioral SciencesEmory University School of MedicineEmory University School of Medicine

Atlanta, GAAtlanta, GA

Annotated for Bi 1by Henry Lester May 21, 2002

MACBETHMACBETH

Canst thou not minister to a mind diseased?Pluck from the memory a rooted sorrow,

Raze out the written troubles of the brain,And with some sweet oblivious antidote

Cleanse the stuffed bosom of that perilousStuff which weighs upon the heart?

William Manchester,William Manchester,The Last Lion, Winston Spencer Churchill, Vol. I: Visions of GloryThe Last Lion, Winston Spencer Churchill, Vol. I: Visions of Glory

(New York: Little, Brown & Company, 1989, p. 23)(New York: Little, Brown & Company, 1989, p. 23)

All his life he suffered spells of depression, sinking into the brooding depths of melancholia, an emotional state which, though little understood, resembles the passing sadness of the normal man as a malignancy resembles a canker sore.

Major Depressive Episode:Major Depressive Episode: DSM-IVDSM-IV Diagnostic Criteria Diagnostic Criteria

• Characterized by clinically significant distress and/or impairment in social, occupational, or other important areas of functioning

• Symptoms must persist for most of day, nearly every day, for 2 consecutive weeks

DSM-IV. 1994.

Poi

nt P

reva

lenc

eof

Maj

or D

epre

ssio

n (%

)

0

5

10

15

20

25

Prevalence of Depression in United StatesPrevalence of Depression in United States

Community Primary CareClinic

MedicalInpatientSetting

Nursing Home

Katon W. Schulberg H. Gen Hosp Psychiatry. 1992; 14: 237-247

2%- 4%

5%-10%

10%-14%

6%-25%

DSM-IVDSM-IV Diagnostic Criteria for Diagnostic Criteria for Major DepressionMajor Depression

5 symptoms including depressed mood and/or anhedonia

- Other symptoms may include:

- Significant weight change

- Psychomotor agitation/retardation

- Pervasive loss of energy/fatigue

- Feelings of worthlessness/excessive or inappropriate guilt

- Difficulty concentrating

- Sleep disturbance

- Recurrent thoughts of death/suicide

• Symptoms present for 2 weeksDSM-IV. 1994.

Epidemiology of Major DepressionEpidemiology of Major Depression

• 17% of US population reported a major depressive episode in their lifetime

• Average age of onset: late 20s

- >50% of patients have first episode by age 40

• Duration: 6 months – 2 years if left untreated

- Episodes continue in up to 80% of untreated patients

Depression Guideline Panel. Depression in Primary Care: Vol 1. Detection and Diagnosis. Clinical Practice Guideline No. 5. 1993.

“He asked me if I was suicidal, and I reluctantly told him yes. I did not particularize -- since there seemed no need to -- did not tell him that in truth many of the artifacts of my house had become potential devices for my own destruction: the attic rafters (and an outside maple or two) a means to hang myself, the garage a place to inhale carbon monoxide, the bathtub a vessel to receive the flow form my open arteries. The kitchen knives in their drawers had but one purpose for me. Death by heart attack seemed particularly inviting, absolving me as it would of responsibility, and I had toyed with the idea of self-induced pneumonia -- a long, frigid, shirt sleeved hike through the rainy woods. Nor had I overlooked an ostensible accident, a la Randall Jarrell, by walking in front of a truck on the highway nearby. These thoughts may seem outlandishly macabre -- a strained joke -- but they are genuine. They are doubtless especially repugnant to healthy Americans, with their faith in self-improvement. Yet in truth such hideous fantasies, which cause well people to shudder, are to the deeply depressed mind what lascivious daydreams are to persons of robust sexuality.”

William Styron, Darkness Visible: A Memoir of Madness, 1990.

Global Burden of Disease and Injury Series

THE GLOBAL BURDENOF DISEASE

A comprehensive assessment of mortality and disability from diseases, injuries, and risk

factors in 1990 and projected to 2020

EDITED BY

CHRISTOPHER J. L. MURRAYHarvard UniversityBoston, MA, USA

ALAN D. LOPEZWorld Health Organization

Geneva, Switzerland

Published by The Harvard School of Public Health on behalf of The World Health Organization and The World Bank

Distributed by Harvard University Press

Leading Causes of Disability, World, 1990Leading Causes of Disability, World, 1990

All CausesAll Causes

TotalTotal(millions)(millions)

472.7472.7

Per cent Per cent of totalof total

1) Unipolar major depression 50.8 10.7

2) Iron-deficiency anaemia 22.0 4.7

3) Falls 22.0 4.6

4) Alcohol Use 15.8 3.3

5) Chronic obstructive pulmonary disease 14.7 3.1

6) Bipolar Disorder 14.1 3.0

7) Congenital anomalies 13.5 2.9

8) Osteoarthritis 13.3 2.8

9) Schizophrenia 12.1 2.6

10) Obsessive-compulsive disorders 10.2 2.2

The leading causes of disease burden for women, aged 15-44, 1990

Percent of all causes in developed or developing regionsCAUSES

Unipolar major depression

Obstructed labour

Maternal sepsis

War

Abortion

Alcohol use

Osteoarthritis

Chlamydia

Self-inflicted injuries

Rheumatoid arthritis

Tuberculosis

Iron-deficiency anaemia

Schizophrenia

Road traffic accidents

Bipolar disorder

Obsessive-compulsive disorder

The burdens of mental illness, such as depression, alcohol dependence, and schizophrenia, have been seriously underestimated by traditional approaches that take account only of deaths and not disability. While psychiatric conditions are responsible for little more than one per cent of deaths, they account for almost 11 per cent of disease burden worldwide.

In 1990, suicide was the number-one cause of death and disability for women ages 15 to 44 worldwide. By the year 2020, it will rank second only to heart disease as the world’s leading cause of death and disability for men and women of all ages, predicts a five-year study by the World Health Organization, the World Bank and the Harvard School of Public Health.

Depression harms more women than AIDS or cancer

Among adults aged 15 – 44 worldwide, road traffic Among adults aged 15 – 44 worldwide, road traffic accidents were the leading cause of death for men and the accidents were the leading cause of death for men and the fifth most important for women. For women aged between fifth most important for women. For women aged between 15 – 44, suicide was second only to tuberculosis as a 15 – 44, suicide was second only to tuberculosis as a cause of death. In China alone, more than 180,000 women cause of death. In China alone, more than 180,000 women killed themselves in 1990. In India, women face an killed themselves in 1990. In India, women face an appallingly high risk of dying in fires: in 1990 alone, more appallingly high risk of dying in fires: in 1990 alone, more than 87,000 Indian women died this way. In Sub-Saharan than 87,000 Indian women died this way. In Sub-Saharan Africa, by contrast, the most important cause of injury Africa, by contrast, the most important cause of injury deaths for both women and men is war.deaths for both women and men is war.

Depressive Disorders in ChildrenDepressive Disorders in Children

Prevalence of Depressive Disorders in Children*• Preschool children – 0.8%• School-aged prepubertal children – 2.0%• Adolescents – 4.5%

Key Issues†

• Distinguish between depressive disorders and behavioral disorders

• Depressive disorders before age 20 often associated with recurrent mood disorders in adulthood

• 30% of adolescents hospitalized with severe major depressive disorder develop bipolar disorder

*Weller EB, Weller RA. In: Psychiatric Disorders in Children and Adolescents. 1990: 3-20.†Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. 1993: 1-65.Giles DE, Jarrett RB, Biggs MM, et al. Am J Psychiatry. 1989; 146: 765-767.Strober M, Carlson G. Arch Gen Psychiatry. 1982; 39: 549-555.

0

10

20

30

40

50

60

70

8010

-14

15-1

920

-24

25-2

930

-34

35-3

940

-44

45-4

950

-54

55-5

960

-64

65-6

970

-74

75-7

980

-84

>85

Tota

l

Male

Female

No. ofSuicides

Per 100,000

*In the United States, 1994.Reproduced with permission from Hirschfeld RMA and Russell JM. N Engl J Med. 1997;337:910-915.© Copyright 1997, Massachusetts Medical Society. All rights reserved.

Age (years)

Rates of Completed Suicide*

Postpartum Depression (PPD)Postpartum Depression (PPD)

• 10% to 15% in adults*

• 26% of adolescents†

• Second in frequency only to C-section

*Stowe and Nemeroff. Am J Obstet Gynecol. 1995; 173: 639-645.†Troutman and Cutrona. J Abnorm Psychol. 1990; 99: 69.

Depressive Disorders After MiscarriageDepressive Disorders After Miscarriage

• >33% severely depressed*

duration of pregnancy = risk of depressive disorder*

• Treat depressive disorders if reaction beyond expected grief and bereavement

*from Janssen et al. Am J Psychiatry. 1996; 153: 226-30.

Anxiety DisordersAnxiety Disorders

PanicDisorder

SpecificPhobias

SocialPhobia

GeneralizedAnxietyDisorder

PosttraumaticStress

Disorder

Obsessive-Compulsive

Disorder

Comorbid Depressive Disorder

Depressive Disorders in Older AgeDepressive Disorders in Older Age

• Occur in approximately 15% of population >65 years old

• May mimic dementia

• Comorbid somatic symptoms

• Not due to “old age”

• Require appropriate treatment

Data from NIH Consensus Development Panel on Depression in Late Life. JAMA. 1992; 288: 1018-24.

Current Treatment OptionsCurrent Treatment Optionsfor Depressionfor Depression

Nonpharmacologic

• Psychotherapy

- Cognitive behavioral therapy

- Interpersonal therapy

- Psychodynamic therapy

• Electroconvulsive therapy

• PhototherapyDepression Guideline Panel. Depression in Primary Care: Vol 1. Detection and Diagnosis. Clinical Practice Guideline No. 5. 1993.

Pharmacologic

•Antidepressant medications

Goal = reduce symptoms of depression and return patient to full, active life

STEPS: Factors to Consider inSTEPS: Factors to Consider inAntidepressant SelectionAntidepressant Selection

• Safety- Drug-drug interaction potential

• Tolerability- Acute and long term

• Efficacy- Onset of Action- Treatment and prophylaxis

• Payment (cost-effectiveness)• Simplicity

- Dosing- Need for monitoring

Preskorn SM. J Clin Psychiatry. 1997; 58(suppl 6): 3-8.

Pharmacotherapy of DepressionPharmacotherapy of Depression

Antidepressant agent classes

• Monoamine oxidase inhibitors (MAOIs)• Tricyclic (TCAs) and tetracyclic

antidepressants• Selective serotonin reuptake inhibitors

(SSRIs)• Atypical antidepressants

- Bupropion- Venlafaxine- Nefazodone- Mirtazapine

Rossen EK, Buschmann MT. Arch Psychiatr Nurs. 1995; 9: 130-136.

Evidence for the Undertreatment of Evidence for the Undertreatment of Depressive DisordersDepressive Disorders

Adapted from Wells KB, Katon W, Rogers B, et al. Am J Psychiatry. 1994; 151: 694-700.

Medical Outcomes StudyN = 634

19%

12%

11%

59%

Minor tranquilizeronly

Antidepressant*only

Antidepressant*and minor tranquilizer

No antidepressantor tranquilizer

*39% of patients using antidepressants were receiving subtherapeutic dosesData are rounded to nearest percentage

Reproduced with permission from Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34. Copyright 2002, Physicians Postgraduate Press.

Remission

x

xx

Symptoms

Syndrome

Response

RelapseRecovery

Recurrence

Treatment Phases AcuteAcute6-12 Weeks6-12 Weeks

ContinuationContinuation4-9 Months4-9 Months

MaintenanceMaintenance?1 Year?1 Year

Outcome of Depression TreatmentOutcome of Depression TreatmentThe Five RsThe Five Rs

Depression Guideline Panel. Depression in Primary Care, Volume 2: Treatment of Major Depression. Clinical Practice Guidelines, Number 5. 1993.Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34.

3 Episodes3 Episodes>90%>90%

1 Episode1 Episode50%50%

2 Episodes2 Episodes80% - 90%80% - 90%

Depression: Recurrence Risks

Recurrent Recurrent Depression:Depression:Treatment Treatment

ImplicationsImplications

Depression Guideline Panel. Depression in Primary Care, Volume 2: Treatment of Major Depression. Clinical Practice Guidelines, Number 5. 1993.Schulberg HC et al. Arch Gen Psychiatry. 1998;55:1121-1127.

Continue antidepressant Continue antidepressant for for first 4 - 9 months first 4 - 9 months

Continue antidepressant Continue antidepressant indefinitely after indefinitely after 3 episodes or3 episodes or2 episodes in patients 2 episodes in patients with risk factorswith risk factors

0

20

40

60

80

100

0 to 3 3 to 6 6 to 9 9 to 12

Usual Care

Intervention Group

Time Period (months)

% of Patients

* P<.001; statistical significance assessed only at 1 year. Katon W et al. Arch Gen Psychiatry. 2001;58:241-247.

Primary Care Patients with Depression% of Patients Who Filled Antidepressant % of Patients Who Filled Antidepressant

PrescriptionsPrescriptions

*

% ofPatients

DiscontinuingMedication

Weeks After Medication Initiation

Adapted with permission from Lin EHB et al. Med Care. 1995;33:67-74.

Primary Care Patients with DepressionDiscontinuation Rate of Antidepressant

Medication

0

20

40

60

80

100

0 4 8 12 16

SSRIs Available for Treatment of SSRIs Available for Treatment of Depression in the United StatesDepression in the United States

• Fluoxetine: Prozac®, Eli Lilly

• Paroxetine: Paxil®, GlaxoSmithKline

• Sertraline: Zoloft®, Pfizer

• Citalopram: CelexaTM, Forest & Parke-Davis

Physicians’ Desk Reference. 1998.Celexa Package Insert. Forest Pharmacueticals, Inc.

SSRI StructuresSSRI Structures

ClCl

ClCl

CHCH33

HNHN

NN

CHCH22

OO

OO

OO

ParoxetineParoxetine

CitalopramCitalopram

OO

NCNC

CHCH22CHCH22CHCH22N(CHN(CH33))22 HBr HBr

FF

SertralineSertralineOO

HHCC

CHCH22CHCH22NNCHCH33

HHFluoxetineFluoxetine

FF33CC CC CHCH22 CHCH22 CHCH22 CHCH22 CHCH33OO

NN

OO CHCH22 CHCH22 NHNH22FluvoxamineFluvoxamine

Celexa package insert, Forest Laboratories, Inc.Celexa package insert, Forest Laboratories, Inc.Physicians’ Desk ReferencePhysicians’ Desk Reference. 1998.. 1998.

Response to Paroxetine and Fluoxetine Response to Paroxetine and Fluoxetine in Patients with Major Depressionin Patients with Major Depression

0

10

20

30

40

50

60

70

Wk 1 Wk 3 Wk 4 Wk 6

Paroxetine(N=37)

Fluoxetine(N=41)

% P

ati

ents

wit

h >

50

% R

ed

uc

tio

n

in B

ase

line

HA

MD

To

tal S

co

re

*P<.05DeWilde et al. Acta Psychiar Scand. 1993; 87: 141

*

Doogan et al. Br J Psychiatry. 1992; 160: 217

Relapse of Depression During Continuation Study of Sertraline

Days of Continuation Treatment

Pro

po

rtio

n R

em

ain

ing

We

ll

SSRIs: SSRIs: Tolerability Tolerability

IssuesIssues

Early-onset effects Early-onset effects (headache, GI)(headache, GI)

Sexual dysfunctionSexual dysfunction

Weight changeWeight change

DiscontinuationDiscontinuation

Drug interactionsDrug interactions

Most Common Adverse EffectsMost Common Adverse Effects

Paxil(N=4126)

Prozac(N=2938)

Zoloft(N=4126)

•Nausea 23%•Headache 18%•Somnolence 17%•Dry Mouth 17%• Insomnia 13%

•Nausea 23%•Headache 18%•Nervousness 17%• Insomnia 16%•Anxiety 13%

•Nausea21%

•Headache18%

•Dry Mouth16%

•Diarrhea/Loose Stools15%

• Insomnia14%

Boyer et al. J Clin Psychiatry. 1992; 53 (suppl 2):61.Doogan. Int Clin Psychopharmacol. 1991; 6(suppl 2): 47.Stokes. Clin Ther. 1993; 15: 216.

Keller Ashton A et al. J Sex Marital Ther. 1997;23:165-175.Segraves RT. J Clin Psychiatry. 1998;59(suppl 4):48-54.

SSRIs and Sexual Dysfunction

Common, class effectCommon, class effect

Affects men and womenAffects men and women

Reduced libidoReduced libido

Orgasmic dysfunctionOrgasmic dysfunction– delayed ejaculationdelayed ejaculation– anorgasmiaanorgasmia

Erection difficulties minimalErection difficulties minimal

Associated with anxiety/depressionAssociated with anxiety/depression

Strategies forStrategies forAntidepressant NonresponseAntidepressant Nonresponse

Optimization: Full Doseand Duration

Augmentation:Addition of

Second Agent(Not an

Antidepressant)

Combination: Additionof Second

Antidepressant AgentDrug Substitution

Electroconvulsive Therapy

Antipsychotic Indications and Antipsychotic Indications and UsesUses

– Schizophrenia/PsychosisSchizophrenia/Psychosis– Bipolar DisorderBipolar Disorder

ManiaMania

DepressionDepression

– Unipolar DepressionUnipolar DepressionPsychoticPsychotic

Treatment ResistantTreatment Resistant

– DementiaDementiaAgitation/psychosisAgitation/psychosis

SchizophreniaSchizophrenia

Chronic, “lifelong” conditionChronic, “lifelong” condition

Very high morbidityVery high morbidity

Very high mortalityVery high mortality

High personal/family impactHigh personal/family impact

High societal/medical system costHigh societal/medical system cost

The Course of SchizophreniaThe Course of Schizophrenia

Affects approximately 1.3% of the population*Affects approximately 1.3% of the population*

Onset generally occurs during young adulthood*Onset generally occurs during young adulthood*

Early treatment predicts better long-term outcomes*Early treatment predicts better long-term outcomes*

Majority of patients experience at least one relapseMajority of patients experience at least one relapse††

Higher incidence of comorbid conditions including Higher incidence of comorbid conditions including hypertension, diabetes, cardiac concern, STDs, hypertension, diabetes, cardiac concern, STDs, substance abuse disorders, smoking*substance abuse disorders, smoking*‡‡

Mortality higher than in the general populationMortality higher than in the general population‡‡

– 10% incidence of suicide10% incidence of suicide‡‡

*Mental health: a report of the surgeon general. Department of Health and Human Services. December 1999.

†Robinson D, Woerner MG, Alvir JMJ, et al. Arch Gen Psychiatry. 1999;56:241-247.‡Goldman LS. J Clin Psychiatry. 1999;60(suppl 21):10-15.

Risk of Relapse in Patients With SchizophreniaRisk of Relapse in Patients With SchizophreniaRate of relapse among patients treated with Rate of relapse among patients treated with conventionalconventional

antipsychotics for first-episode schizophrenia and antipsychotics for first-episode schizophrenia and schizoaffective disorderschizoaffective disorder– 16% at 1 year16% at 1 year– 54% at 2 years54% at 2 years– 82% at 5 years82% at 5 years

Stable patients were allowed the option to discontinue Stable patients were allowed the option to discontinue antipsychotic medication after 1 year of treatmentantipsychotic medication after 1 year of treatmentThe risk for a first and second relapse was almost 5 times The risk for a first and second relapse was almost 5 times greater than when not taking medication*greater than when not taking medication*– Risk is diminished by maintenance Risk is diminished by maintenance

antipsychotic drug treatmentantipsychotic drug treatment*Based on a survival analysis of relapse using medication status as a time-dependent covariate.Source:Robinson D, Woerner MG, Alvir JMJ, et al. Arch Gen Psychiatry. 1999;56:241-247.

Barriers to Adherence to Barriers to Adherence to Antipsychotic TherapyAntipsychotic Therapy

Cognitive impairmentCognitive impairment

Complex drug regimen (eg, BID dosing)Complex drug regimen (eg, BID dosing)

Adverse events (eg, weight gain, EPS, diabetes, QTc Adverse events (eg, weight gain, EPS, diabetes, QTc prolongation)prolongation)

Monitoring of selected adverse events (eg, ECG, blood, Monitoring of selected adverse events (eg, ECG, blood, glucose, liver functioning, electrolyte, slit-lamp testing)glucose, liver functioning, electrolyte, slit-lamp testing)

Cost of medicationCost of medication

Substance abuseSubstance abuse

Source: Perkins DO. J Clin Psychiatry. 1999;60(suppl 21):25-30.

All All AntipsychoticsAntipsychotics

Efficacious, but not perfectEfficacious, but not perfect

High side effect burdenHigh side effect burden

Potential catastrophic adverse eventsPotential catastrophic adverse events

Acceptable in the balance between Acceptable in the balance between treatment vs no treatmenttreatment vs no treatment

Typical AntipsychoticsTypical Antipsychotics

Discovered by accidentDiscovered by accident– ChlorpromazineChlorpromazine

All cause same side effectsAll cause same side effects– Byproduct of drug discovery processByproduct of drug discovery process

Not ObsoleteNot Obsolete

Atypical AntipsychoticsAtypical Antipsychotics

Discovered by accidentDiscovered by accident– Clozapine (Clozaril)Clozapine (Clozaril)

Significant improvement over typicalSignificant improvement over typical

Improved “effectiveness”Improved “effectiveness”

Typical vs. AtypicalTypical vs. Atypical

TypicalTypical– High DHigh D22

– Low 5-HTLow 5-HT2A2A

– DD11=D=D22

– Increases neurotensin in caudate and nucleus accumbensIncreases neurotensin in caudate and nucleus accumbens

AtypicalAtypical– High 5-HTHigh 5-HT2A2A

– Lower DLower D22

– Low DLow D11

– Increases neurotensin in nucleus accumbens onlyIncreases neurotensin in nucleus accumbens only

a peptide neurotransmitter

Atypical AntipsychoticsAtypical Antipsychotics

Clozapine (Clozaril)Clozapine (Clozaril)

Risperidone (Risperdal, Consta)Risperidone (Risperdal, Consta)

Olanzapine (Zyprexa)Olanzapine (Zyprexa)

Quetiapine (Seroquel)Quetiapine (Seroquel)

Ziprasidone (Geodon)Ziprasidone (Geodon)

Atypical AntipsychoticsAtypical AntipsychoticsAll efficaciousAll efficacious

Differing levels of effectivenessDiffering levels of effectiveness– Patient response characteristicsPatient response characteristics– Side effectsSide effects– Use limitations (Clozapine)Use limitations (Clozapine)

All have significant side effectsAll have significant side effects– Similar magnitudeSimilar magnitude– Different specificsDifferent specifics

Significant Improvement Across a Full Range Significant Improvement Across a Full Range of Symptoms*of Symptoms*

P<0.02

P<0.001

P<0.001 P<0.001

P<0.025

PositivePositivesymptomssymptoms

Hostility/Hostility/excitementexcitement

NegativeNegativesymptomssymptoms MoodMood CognitionCognition

Imp

rove

me

nt

0.1

0.5

0.0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

Risperidone (n=85) Placebo (n=86)

*The Positive and Negative Syndrome Scale (PANSS) is a composite scale consisting of items used to assess overall psychopathology. Conclusions as to efficacy outcomes of individual items should not be drawn.

†6 mg/day.Source: Marder SR, Davis JM, Chouinard G. J Clin Psychiatry. 1997;58:538-546.

PANSS=Positive and Negative Syndrome Scale.

-3.29-3.29

-2.56-2.56

-3.16-3.16

-1.23-1.23

-3.07-3.07

-0.19

-1.28-1.28

-0.28-0.28

0.470.47

-0.65-0.65

Mea

n P

AN

SS

ch

ang

e sc

ore

at

Wee

k 1†

Risperidone Provides Rapid and Sustained Efficacy*Risperidone Provides Rapid and Sustained Efficacy*

1-year, double-blind trial (n=365)1-year, double-blind trial (n=365)– Average dose was 4.9 mg/day at 1 yearAverage dose was 4.9 mg/day at 1 year

*Data on file, 2000. Submitted for publication.

Significant improvement in symptom scores at week 1Significant improvement in symptom scores at week 1

Significant improvement maintained through 1 yearSignificant improvement maintained through 1 year

Mea

n T

ota

l P

AN

SS

ch

ang

e sc

ore 0

-1.0

-2.0

-3.0

-4.0

-5.0

-6.0

-7.0

Imp

rove

me

nt

1 2 4 12 28 52Week

P<0.001

P<0.001

PANSS=Positive and Negative Syndrome Scale.

Reduction of Hostility in SchizophreniaReduction of Hostility in Schizophrenia

Week 1Week 1

*Change from baseline to weeks 6 and 8 (last observation carried forward).†6 mg/day.PANSS=Positive and Negative Syndrome Scale. Source: Marder SR, Davis JM, Chouinard G. J Clin Psychiatry. 1997;58:538-546.

Placebo (n=86) Risperidone (n=85)†

Mea

n P

AN

SS

ch

ang

e sc

ore

*

Week 8Week 8

Imp

rove

me

nt

0.5

0.4

0.3

0.2

0.1

0.0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

P<0.001P<0.001

Imp

rove

men

t

0.10

0.00

-0.05

-0.10

-0.15

-0.20

-0.25

-0.30

-0.35

-0.40

-0.45

-0.50

-0.55

-0.60

-0.65

P<0.001

P<0.001

*Symptoms of disorganized thought from the PANSS scale.†Change from baseline to weeks 6 and 8 (last observation carried forward).‡6 mg/day.PANSS=Positive and Negative Syndrome Scale.Source: Marder SR, Davis JM, Chouinard G. J Clin Psychiatry. 1997;58:538-546.

Placebo (n=86) Risperidone (n=85)‡

Week 1 2 3 4 5 6 7 8

Improvement of Symptoms Associated With Cognition*Improvement of Symptoms Associated With Cognition*

Mea

n P

AN

SS

ch

ang

e sc

ore

†

Improvement of Mood* Symptoms in SchizophreniaImprovement of Mood* Symptoms in Schizophrenia

Imp

rove

men

t

Mea

n P

AN

SS

ch

ang

e sc

ore

†0.10

0.00

-0.05

-0.10

-0.15

-0.20

-0.25

-0.30

-0.35

-0.40

-0.45

-0.50

-0.55

-0.60

-0.65

P<0.025

P<0.001

*Symptoms of anxiety/depression from the PANSS scale.†Change from baseline to weeks 6 and 8 (last observation carried forward).‡6 mg/day.PANSS=Positive and Negative Syndrome Scale. Source: Marder SR, Davis JM, Chouinard G. J Clin Psychiatry. 1997;58:538-546.

Placebo (n=86) Risperidone (n=85)‡

Week 1 2 3 4 5 6 7 8

Emerging Safety Concerns With Emerging Safety Concerns With Selected AntipsychoticsSelected Antipsychotics

DiabetesDiabetes

– Glucose elevationsGlucose elevations

Weight GainWeight Gain

Cardiac SafetyCardiac Safety

– QTc prolongationQTc prolongation

Weight Change After 10 Weeks on Standard Drug Weight Change After 10 Weeks on Standard Drug Doses, Estimated From a Random Effects ModelDoses, Estimated From a Random Effects Model

nonp

harm

acol

ogi

nonp

harm

acol

ogi

c co

ntro

l

c co

ntro

l

thio

rida

zine

/

thio

rida

zine

/

mez

orid

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e

mez

orid

azin

e

66

95

% c

on

fid

en

ce

inte

rval

for

weig

ht

ch

an

ge (

kg

)

95

% c

on

fid

en

ce

inte

rval

for

weig

ht

ch

an

ge (

kg

)

5544

33

22

11

00

–1–1

–2–2

–3–3

PlaceboPlaceboConventional antipsychoticsConventional antipsychotics

Novel antipsychoticsNovel antipsychotics

Nonpharmacologic controlsNonpharmacologic controls

plac

ebo

plac

ebo

mol

indo

ne

mol

indo

nezipr

asid

one

zipr

asid

one

fluph

enaz

ine

fluph

enaz

ine

halo

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l

halo

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lpo

lyph

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poly

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mac

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risp

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Allison et al. Am J Psychiatry 156:1686-1696, 1999