Schizophrenia:An overview of diagnosis

and treatment

• A disease process with multiple signs and symptoms involving thoughts, perceptions, emotions, and behavior1

• Most catastrophic mental illness1,2

• Peak incidence in males at 15 to 25 years of age and in females at 25 to 35 years of age1

• Global incidence: 1% in all societies3

• Course of illness is extremely variable, often chronic, and sometimes episodic1

• Florid symptoms may diminish with age, although years of dysfunction are rarely overcome1

Epidemiology of Schizophrenia

Epidemiology of Schizophrenia• Associated with heavy emotional burden4

• Often requires long-term caregiving4

• 50% of patients exhibit comorbid substance abuse

Economic impact

• 22% of all mental illness costs in the United States5

• Annual direct and indirect costs estimated at $65 billion (1991)5

• Annual treatment costs may range from $10,000 to $70,000per patient6-9

Behavioral Symptoms

Positive SymptomsDelusions

HallucinationsDisorganized speech

SuspiciousnessExaggerated thoughts

CognitionAttention / MemoryOrganized ThinkingJudgment / Insight

Negative SymptomsAffective flatteningAlogia / Avolition

AnhedoniaSocial withdrawal

MoodDepression

ManiaAnxiety / Aggression

Impact of Mood Symptoms

• Depressive symptoms present in up to 65% of patients

• Affect all other core symptoms

• Affect all outcomes, including compliance

• Higher suicide rate 40% Attempt / 10% Completion

Clinical IssuesInterplay of Depressive and Other

Symptoms of Illness in SchizophreniaNegative

Symptoms

FunctionalImpairment

ProlactinEffects

CognitiveDysfunctio

n

PositiveSymptoms

EPS

Mood Symptoms

Illness Related Symptoms

Medication Related Side Effects

Causes of Psychosis

• Dopamine Hypothesis

• Neurotransmitter Interaction

• Structural Abnormalities

• Prenatal or Perinatal Trauma

Brain Pathways

From:Risch SC. Pathophysiology of schizophrenia and the role of newer antipsychotics. Pharmacotherapy 1996;15(1 pt 2):12S

9

WorkingMemory

(D1 receptors)

Prefrontal Cortex

Sensory Data

Motor Data

AffectiveData

Behavior

Cognition

Personality

Role of Prefrontal Cortex

Schizophrenia

Dopamine Activity Overview

• Psychotic Symptoms: – Caused by too much Dopamine activity

in the limbic system

• Extrapyramidal Symptoms: – Not enough Dopamine activity

Efficacy = Dopamine Blockade

• All Anti-psychotic medications MUST:

– BLOCK DOPAMINE RECEPTORS

• For Superior Efficacy:

– SELECTIVE DOPAMINE BLOCKING

• Degree of dopamine blocking

• Activity in selective areas of the brain (A9, A10)

Degree of Blockade

• Agent must block 50% of D2 receptors to begin controlling positive symptoms

• Blocking > 70% of D2 receptors may cause dose-dependant EPS

• PUBLISHED DATA SHOWS:

– Zyprexa & Clozaril

• 50-60% D2 Blockade

– Risperdal & Haldol

• 80-90% D2 Blockade

Selective Dopamine Blockade

• A-10 (Mesolimbic) PATHWAY– The "Efficacy Pathway"– ZYPREXA is theorized to have strong

activity here

• A-9 (Nigral Striatal) PATHWAY– The "EPS Pathway"– Typicals and Risperdal are theorized to be

more active here (vs.. A-10)

A-10 = GOOD A-9 = BAD

Psychosocial

Pharmacologic

Patient CareThe "Team Approach"

Psychiatrist

Psychiatric Nurse / DON

Psychologist

Medical Director

Primary care physician

Physician Assistant (PA)

Nurse Practitioner (NP)

Consultant / Clinical Pharmacist

Case Manager / Social worker

Family and friends

Psychological Rehabilitation

Considerations in Choosing Antipsychotics: Acute vs.Continuation

• Time to response: significant response may take 4 to 5 weeks of therapy with conventional agents12

• Symptom control/level of function: persistence of positive, negative, cognitive, or affective symptoms may indicate need to switch

• Incidence of adverse effects: EPS/TD, sedation, cognitive impairment, hypotension, sexual dysfunction (Risks vs. Benefits)

• Cost of therapy, including acquisition price and cost of necessary adjunctive meds or inpatient treatment

• Available formulations: Dosing Flexibility

• Previous experience with an agent or class

Chemical StructuresCH3

HCH3

Olanzapine QuetiapineClozapine

CH3

CH3

FRisperidone

O

N

N

H

Cl

N

N

N

NN

N

S

O

N

N

N

ON

N

HO

Cl

O

F

Haloperidol

ON

NN

S

OH

17

ClozapineOlanzapine Haloperidol

Risperidone

H1

21

Musc

5-HT2C

5-HT2A

D4

Quetiapine Ziprasidone

D1

Bymaster FP, et al. Neuropsychopharmacology. 1996;14(2):87-96. Schotte A, et al. Psychopharmacology (Berl). 1996;124(1-2):57-73.

Receptor Binding Profiles

Aripiprazole

D2

Anti-Psychotic Side Effects:

• Extrapyramidal Symptoms (EPS)– Akathisia: Severe inner restlessness– Dystonia: Involuntary muscle spasms– Parkinsonism: Rigidity of the

muscles, Tremor, Shuffling of feet

"It can be argued that EPS are the most troublesome side effects…a major reason why patients discontinue their drug therapy"*

*Source: Casey DE. International Clinical Psychopharmacology. 1997;12 (suppl 1):S19-S27

Anti-Psychotic Side Effects:

• TD (Tardive Dyskinesia)– Involuntary muscle movements of the face,

body and/or trunk– Often Irreversible: Patient is disfigured,

"looks like a psych patient"– Typicals carry 5% risk of developing TD

per year of exposure• 85% risk after 25 years of continuous

exposure

*Source: Casey DE. International Clinical Psychopharmacology. 1997;12 (suppl 1):S19-S27

• Prolactin Related Side-Effects– Short Term

• Amenorrhea• Galactorrea• Gynecomastia• Sexual Dysfunction

– Long Term• Increased risk for Osteoporosis• Increased risk for Breast Cancer

Anti-Psychotic Side Effects:

Other Limitations ofConventional Anti-Psychotics:• Extrapyramidal symptoms (EPS)

• Tardive dyskinesia (TD)

• Prolactin elevation

• Sedation

• QTc prolongation

• Cognitive impairment

• Orthostatic hypotension

• Compliance / Relapse

Typical Antipsychotics Haldol, Mellaril, Thorazine, Prolixin, etc.

• Available since the mid - '50s

• Proven positive symptom efficacy

• Formulations:– Short acting ( I.M.)– Long acting (Depot)

• Generics available ($)

• Incomplete symptom efficacy (compared to atypicals)– Negative– Mood– Cognition

• High incidence of EPS• Increased risk for TD• Prolactin-related side effects

The Bipolar patient...

“My thoughts ran with lightning-like rapidity from one subject to another. All the problems of the universe came crowding in my mind, demanding instant discussion and solution--- mental telepathy, hypnotism, women’s right, all the problems of medical science, religion and politics

Months later……...

Bipolar Patient cont…..

“I seem to be in a perpetual fog and darkness. I cannot get my mind to work. Instead of associations clicking into place, everything is an inextricable jumble. I could not feel more ignorant, undecided or inefficient. It is appallingly difficult to concentrate, and writing is a pain and grief to me”

Classifications of Bipolar

• Bipolar I– 1 or more manic or mixed episodes– May be followed by 1 or more depressive

episodes

• Bipolar II– 1 or more depressive episodes– accompanied by at least 1 hypomanic episode

• mania not severe enough to cause “marked impairment”

Subtypes: Rapid Cycling

– 4 or more mood episodes in 1 year– Occurs in 12-20% of bipolar patients– Occurs later in the illness– Difficult to treat– More common in women– Inducible by antidepressants

• Racing Thoughts• Distractibility• Poor Insight• Disorganization• Inattentiveness• Confusion

• Delusions• Hallucinations• Sensory Hyperactivity

Symptom Domains in Bipolar I Disorder

Cognitive SymptomsCognitive Symptoms

Psychotic SymptomsPsychotic Symptoms

• Euphoria• Grandiosity• Pressured Speech• Impulsivity• Excessive Libido• Recklessness• Diminished Need

for Sleep

• Depression• Anxiety• Irritability• Hostility• Violence or Suicide

Manic Mood and Manic Mood and BehaviorBehavior Dysphoric Mood Dysphoric Mood

and Behaviorand Behavior

Symptom Descriptors for Bipolar

Manic Episodes• inflated self-esteem or

grandiosity• decreased need for

sleep• excessive talkativeness• racing thoughts• distractibility• increased physical

activity • pursuit of pleasurable

but risky activities• psychotic features

Depressive Episodes• depressed mood• diminished interests or

pleasure • fatigue• worthlessness or guilt• poor concentration• suicidal thoughts

Increase or decrease in:• weight/appetite• physical activity• sleep

HypomanicEpisode

BIPOLAR II

Depressive Episode

Manic Episode BIPOLAR I

Mixed Episode

Mood WithinNormal Range

Classifications of Bipolar

Subtypes of Bipolar

RapidCycling

Epidemiology of Bipolar Disorder

• Psychotic symptoms occur in 47-75% of all patients at some point in the disease cycle

• 2/3 of bipolar episodes present as depression• No differences in race or gender• 50% have a family history• Women with postpartum depression at higher risk• Symptoms usually first appear between the ages of

15-24• Prevalence rates from 1.2% - 1.6%

*Compared to an 18% rate for those without bipolar

Effect on Social Functioning

• Ability to work declines in 66% of patients• Social functioning declines in 50% of patients• Represents a high divorce rate• 60% suffer from substance abuse issues

– May be self medicating– Masks illness in early stages – Predictor of early onset (before age of 20)

• Significant impact on expected life span and personal health

Morbidity of Bipolar Disorder

• Recurrent illness in 85-95% of patients

• Functional recovery often lags behind symptomatic and syndrome recovery

• Recurrent episodes may lead to progressive deterioration in functioning

• Number of episodes may affect subsequent treatment response and prognosis

Mortality in Bipolar Disorder

• 25%-50% attempt suicide

• Suicide completion rate ~19%

• 50% suicidal ideation in mixed mania

Schizophrenia vs. Bipolar

Schizophrenia Bipolar

Thinking Disorder which can affect mood

Primarily a mood disorder that can affect thinking & judgment

Psychotic disorder

Affective Disorder

Contrasts of Schizophrenia and Bipolar Disorder

Key Similarities• Generally treated by psychiatrists

• Psychotic symptoms are frequent during mania

• Antipsychotics were drugs of choice through 1960s

– lithium as a "mood stabilizer"

– Awareness of TD risk (greater risk in bipolar ?)

• High utilization of health care system

• Problems with treatment compliance

Key Differences• Different core symptoms

• Different courses of illness

– Bipolar patients are less consistently "sick" and outcomes get closer to "well”

– Bipolar patients are more likely to commit suicide

• Treatment paradigms

– therapeutic setting

– treatment goals

– medication choices

While some similarities exist, mostly a different patient population with different treatment paradigms

level of

functioning

Bipolar Schizoaffective Schizophrenia

Schizoaffective: has features of both schizophrenia and mood disorders. Best diagnosis for patients whose clinical syndrome would be distorted if it were considered as only schizophrenia or only a mood disorder. (Kaolin and Sadock, 1996)

Related Disease Outcomes

Diagnosis of Bipolar Disorder

• High rates of misdiagnosis - Important to determine longitudinal course– May be diagnosed as unipolar depression– May be mischaracterized as adolescent behavior– May be masked by substance abuse

• A psychiatrist is most often the one who ultimately makes the correct diagnosis

• Involvement from various members of the health care team (Psychologist, Psych Nurse, etc.)

Olanzapine Data Suggest Effects AcrossMultiple Neurotransmitter Systems

SYSTEM Olanzapine ActionRelevance to Bipolar

Dopamine Direct DA receptor antagonist

DA antagonists reduce psychotic symptoms

Serotonin Multiple, balanced 5HT receptor antagonist

5HT may affect mood, violence, suicide

AcetylcholineIndirect Ach agonist

Cholinomimetics may reduce mania, improve cognition

GABA Indirect GABA agonist

May help reduce manic symptoms

Glutamate Modulates and stabilizes glutamate transmission

May help regulate mood stability

Current Treatment Paradigm for Psychiatrists

A/P

Antipsychotics are currently not considered a standardtherapy for long term treatment of bipolar

(For psychosis associated with acute mania)

Maintenance Treatment

MOOD STABILIZER

A/D

For recurrent psychotic features

For recurrent depressive

features

A/P

M/S

A/D

M/S

Attributes of Ideal Mood Stabilizer for Mania

Adapted from Keck Jr. PE, McElroy SL. In: Nathan PE, Gorman JM, eds.A Guide to Treatment that Works. New York: Oxford University Press, 1997

Rapid efficacy for mania

Treats psychotic symptoms of mania

Broad efficacy (e.g., mixed, rapid cycling)

Reduces depressive elements in mania

Favorable cognitive effects

Long-term usefulness

Safe & well-tolerated

Ease of use

Young Mania Rating Scale (Y-MRS)

• Elevated mood

• Hypersexuality

• Irritability

• Racing thoughts / flight of ideas

• Disruptive behavior

• Increased activity

• Decreased sleep• Abnormal thought

content• Rapid/pressured

speech• Inappropriate

appearance• Poor insight

Y-MRS was the primary efficacy variable for both studies

Psychosis in Bipolar Disorder

• Prevalence– 55% of patients had at least one psychotic symptom by

clinician evaluation– 90% of patients had at least one psychotic symptom by

self-report

• More common in mania than in depression

• Stabilized bipolar patients with history of psychotic features have relapse rates two to three times those without history of psychosis

Goodwin FK, Jamison KR, 1990; Keck Jr. PE et al, 1998; Pope HG, Lipinski JF, 1978; Tohen et al, 1990

Reasons for Non-Compliance

• Symptoms of the illness– Patients don't want to “lose the high”– Feelings of Grandiosity

• Blood monitoring• Stigma of a medication

– Fear of taking an “antipsychotic”

• Unwanted Side Effects – Higher functioning pts - more sensitive?

• Co-morbid substance abuse– Considered the most consistent predictor of poor

compliance• Partial efficacy• Multiple daily dosing

More unique to bipolar disorder

• Racing Thoughts• Distractibility• Poor Insight• Disorganization• Inattentiveness• Confusion

• Delusions• Hallucinations• Sensory Hyperactivity

Symptom Domains in Bipolar I Disorder

Cognitive SymptomsCognitive Symptoms

Psychotic SymptomsPsychotic Symptoms

• Euphoria• Grandiosity• Pressured Speech• Impulsivity• Excessive Libido• Recklessness• Diminished Need

for Sleep

• Depression• Anxiety• Irritability• Hostility• Violence or Suicide

Manic Mood and Manic Mood and BehaviorBehavior Dysphoric Mood Dysphoric Mood

and Behaviorand Behavior