Treatment of Schizophrenia

(and Related Psychotic Disorders)

Scott Stroup, MD, MPH
2004

Psychosis
Generally equated with positive
symptoms and disorganized or bizarre
speech/behavior
Impaired reality testing
A syndrome present in many illnesses
remove known cause or treat underlying
illness
treat symptomatically with antipsychotic
medications

Schizophrenia is a
heterogeneous illness
Defined by a constellation of symptoms,
including psychosis
Multifactorial etiology, variable course
Social/occupational dysfunction a
required diagnostic criterion
Good treatment must address
symptoms and social/occupational
dysfunction

DSM-IV Schizophrenia
2 or more of the following for most of 1 month:

Delusions
Hallucinations
Disorganized speech
Grossly disorganized or catatonic behavior
Negative symptoms

Social/occupational dysfunction
Duration of at least 6 months
Not schizoaffective disorder or a mood disorder
with psychotic features
Not due to substance abuse or a general
medical disorder

Features of Schizophrenia
Positive symptoms
Delusions
Hallucinations
Functional Impairments
Work/school
Interpersonal relationships
Self-care
Cognitive deficits
Attention
Memory
Verbal fluency
Executive
function
(eg, abstraction)

Disorganization
Speech
Behavior

Negative symptoms
Anhedonia
Affective flattening
Avolition
Social withdrawal
Alogia

Mood symptoms
Depression/Anxiety
Aggression/Hostility
Suicidality

Common needs of people with

schizophrenia

Symptom control
Housing
Income
Work
Social skills
Treatment of comorbid conditions

Challenges in the Treatment

of Schizophrenia

Stigma
Impaired insight no agreement on problem
Treatment compliance
Substance abuse very common
Violence risk
Suicide risk
Medical problems common, often
unrecognized

Schizophrenia Treatment
Therapeutic Goals
minimize symptoms
minimize medication side effects
prevent relapse
maximize function
recovery

Types of Treatment
pharmacotherapy
psychosocial/psychotherapeutic

Treatments for schizophrenia:

Strong evidence for effectiveness
Antipsychotic medications
Family psychoeducation
Assertive Community Treatment
(ACT teams)

The First Modern Antipsychotic

Chlorpromazine (Thorazine)
Antipsychotic properties discovered in
1952
Studied originally for usefulness as a
sedative
Found to be useful in controlling
agitation in patients with schizophrenia
Introduced in U.S. in 1953

Show Video Tape

Augustine

The Dopamine Hypothesis of

Schizophrenia
All conventional antipsychotics block
the dopamine D2 receptor
Conventional antipsychotic potency is
directly proportional to dopamine
receptor binding
Dopamine enhancing drugs can induce
psychosis (e.g., chronic amphetamine
use)

Typical antipsychotic medications

(aka first-generation, conventional,
neuroleptics, major tranquilizers)
High Potency (2-20 mg/day)
(haloperidol, fluphenazine)
Mid Potency (10-100 mg/day)
(loxapine, perphenazine)
Low Potency (300-800+ mg/day)
(chlorpromazine, thioridizine)

Dopamine blockade effects

Limbic and frontal cortical regions:
antipsychotic effect
Basal ganglia: Extrapyramidal side
effects (EPS)
Hypothalamic-pituitary axis:
hyperprolactinemia

Typical Antipsychotic limitation:

Extrapyramidal side effects (EPS)

Parkinsonism
Akathisia
Dystonia
Tardive dyskinesia (TD)-- the worst form
of EPS-- involuntary movements

Parkinsonian side effects

Rigidity, tremor, bradykinesia, masklike
facies
Management:
Lower antipsychotic dose if feasible
Change to different drug (i.e., to an atypical
antipsychotic)
Anticholinergic medicines:
benztropine (Cogentin)
trihexylphenidine (Artane)

Akathisia
Restlessness, pacing, fidgeting; subjective
jitteriness; associated with suicide
Resembles psychotic agitation, agitated depression
Management:
lower antipsychotic dose if feasible
Change to different drug (i.e., to an atypical
antipsychotic)
Adjunctive medicines:
propanolol (or another beta-blocker)
benztropine (Cogentin)
benzodiazepines

Acute dystonia
Muscle spasm: oculogyric crisis,
torticollis, opisthotonis, tongue
protrusion
Dramatic and painful
Treat with intramuscular (or IV)
diphenhydramine (Benadryl) or
benztropine (Cogentin)

Show Tardive Dyskinesia

Videotape
Abnormal Involuntary Movement
Scale (AIMS) training tape

Tardive Dyskinesia (TD)

Involuntary movements, often
choreoathetoid
Often begins with tongue or digits,
progresses to face, limbs, trunk
Etiologic mechanism unclear
Incidence about 3% per year with
typical antipsychotics
Higher incidence in elderly

Tardive Dyskinesia (TD)-2

Major risk factors:
high doses, long duration, increased age,
women, history of Parkinsonian side effects,
mood disorder

Prevention:
minimum effective dose, atypical meds,
monitor with AIMS test

Treatment:
lower dose, switch to atypical, Vitamin E (?)

Neuroleptic Malignant Syndrome

(NMS)

Fever, muscle rigidity, autonomic instability,

delirium
Muscle breakdown indicated by increased CK
Rare, but life threatening
Risk factors include:
High doses, high potency drugs, parenteral
administration

Management:
stop antipsychotic, supportive measures (IV fluids,
cooling blankets, bromocriptine, dantrolene)

Typical Antipsychotic limitation:

Other common side effects
Anticholinergic side effects: dry mouth,
constipation, blurry vision, tachycardia
Orthostatic hypotension (adrenergic)
Sedation (antihistamine effect)
Weight gain
Neuroleptic dysphoria

Typical Antipsychotic limitation:

Treatment Resistance
Poor treatment response in 30% of
treated patients
Incomplete treatment response in
an additional 30% or more

The First Atypical Antipsychotic:

Clozapine (Clozaril)
FDA approved 1990
For treatment-resistant schizophrenia
30% response rate in severely ill,
treatment-resistant patients (vs. 4%
with chlorpromazine/Thorazine)
Receptor differences: Less D2 affinity,
more 5-HT
10

Clozapine Helps
Treatment-Resistant Patients

BPRS Schizophrenia
Factor

Double Blind, Randomized Trial of Clozapine vs

Chlorpromazine in Treatment Resistant Patients
16
14
12
10

clozapine
chlorpromazine

8
6
4
2
0
0

3
Weeks in Trial

6
11

Clozapine: pros and cons

Superior efficacy for positive symptoms

Possible advantages for negative symptoms
Virtually no EPS or TD
Advantages in reducing hostility, suicidality
Associated with agranulocytosis (1-2%)
WBC count monitoring required

Seizure risk (3-5%)

Warning for myocarditis
Significant weight gain, sedation, orthostasis, tachycardia,
sialorrhea, constipation
Costly
Fair acceptability by patients

Atypical antipsychotics
(aka second-generation, novel)
FDA approval
Generic Name
(Brand Name)
1990
clozapine
(Clozaril)

1994
1996
1997
2001
2002

risperidone
olanzapine
quetiapine
ziprasidone
aripiprazole

2003

risperidone MS

(Risperdal)
(Zyprexa)
(Seroquel)
(Geodon)
(Abilify)
(Consta)

Defining atypical antipsychotic

Relative to conventional drugs:
Lower ratio of D2 and 5-HT2A receptor
antagonism
Lower propensity to cause EPS
(extrapyramidal side effects)

Atypical Antipsychotics:
Efficacy
Effective for positive symptoms
(equal or better than typical antipsychotics)

Clozapine is more effective than

conventional antipsychotics in treatmentresistant patients
Atypicals may be better than
conventionals for negative symptoms

Relapse Rates in 1 Year Studies:

Atypical vs. Typical Antipsychotics
CA

n/N
Marder, 2002 (risperidone)
2/33
%
10%
Csernansky, 2002 (risperidone)
41/177
Risperidone pooled
35
Daniel, 1998 (sertindole)
43/210
Speller, 1997 (amisulpride)
31
2/94
Tamminga, 1993 (clozapine)
11
Essock, 1996 (clozapine)
5/29
Rosenheck, 1999 (clozapine)
29
Clozapine pooledd
Tran, 1998a (olanzapine)
1/25
Tran, 1998b (olanzapine)
0
Tran, 1998c (olanzapine)
13/76
Olanzapine pooled
31
10/35
Total
29
24/136
p=0.0001 in favor of atypical drugs;
25
Leucht S et al. Am J Psychiatry.10/45
2003

NA

Risk Difference (95% CI fixed)

%
6%

n/N
3/30

23

65/188

21

68/218

12/109

17

9/31

0/14

17

15/48

29

4/14

18

19/76

22

-0.5

Favors
Atypical Antipsychotic
2/10

0.5
Favors
Conventional Drug

Atypical Antipsychotics:
Efficacy for Cognitive and Mood
Symptoms
Atypical antipsychotics may improve
cognitive and mood symptoms
(Typical antipsychotics tend to worsen
cognitive function)
Dysphoric mood may be more
common with typical antipsychotics

Atypical Antipsychotics:
Side Effects
Atypical antipsychotics tend to have
better subjective tolerability (except
clozapine)
Atypical antipsychotics much less likely to
cause EPS and TD, but may cause more:
Weight gain
Metabolic problems (lipids, glucose)
ECG changes

Weight gain at 10 weeks

6
5
4

Kg

3
2
1

Allison et al 1999

CLOZ

CPZ

OLZ

RISP

ZIP

HAL

-1

PLB

Summary of Antipsychotic Side Effects

Side Effect

Highest Liability

Low Liability

EPS

Conventional
antipsychotics
Conventional
antipsychotics

CLZ, OLZ, QTP

TD

Hyperprolactinemia Conventional
antipsychotics, RIS
Sedation
CPZ, CLZ, QTP, OLZ
Anticholinergic
CPZ, CLZ
effects
QTc prolongation

ZIP, thioridazine,
mesoridazine

Weight gain

CPZ, CLZ, OLZ

Hyperglycemia, DM

Atypical antipsychotics

CLZ, OLZ, QTP

CLZ, OLZ, QTP
RIS
RIS

HAL, ZIP

Why worry about side effects?

May cause secondary symptoms,
illnesses
Contribute to noncompliance and thus
relapse

Current consensus on
antipsychotics
Atypical antipsychotics (other than clozapine)
are first choice drugs:
-superiority on EPS and TD
-at least equal efficacy on + and symptoms
-possible advantages on mood and cognition

BUT:

-long-term consequences of weight gain and

metabolic effects may alter recommendation
-atypicals are very expensive

Real and Projected Global Sales of

Antipsychotics 1990-2009 ($ millions)

Common factors associated

with psychotic relapse
antipsychotics not completely effective
noncomplianceinconsistent
antipsychotic medication use
stressful life events/home environment
(Expressed EmotionEEhostility,
criticism, overinvolvement)
alcohol use
drug use

Antipsychotic medication
reduces relapse rates
Risk of relapse in one year:
Consistently taking medications:

20-30%

Not taking medications consistently: 65-80%

Relapse in Schizophrenia
Hogarty et al., N = 374

% Not Relapsed

Prien et al., N 630

100
90
80
70

Caffey et al., N = 259

Neuroleptics

60
50
40

Placebo

30
20
10
0

12

15

18

21

24

27

30

Months
Baldessarini RJ et al: Tardive Dyskinesia: APA Task Force Report 18, 1980

Consequences of relapse
Disruptive to patients lives
(hospitalizations, lost jobs, lost apartments,
estranged family and friends)
Risk of dangerous behaviors
May worsen course of illness
Increased costs

Long-acting injectable (depot)

antipsychotics
Until late 2003, only haloperidol and fluphenazine
available in the U.S.
Long-acting risperidone introduced late 2003
Injections approximately every 2 weeks (fluphenazine
and risperidone) or 4 weeks (haloperidol)
Goal is to decrease noncompliance and thus
relapse--widely used but less commonly in last 10
years
Not yet clear if long-acting risperidone will reverse the
trend

Schizophrenia Treatment
Assertive Community Treatment
Multidisciplinary teams: MDs, RNs,
social workers, psychologists,
occupational therapists, case managers
Staff:patient ratio about 1:10
Outreach, contact as needed
Effective at reducing hospitalizations
Cost-effective when targeted at high
hospital users

Schizophrenia Treatment
Family Psychoeducation
Provides information about
schizophrenia: course, symptoms,
treatments, coping strategies
Supportive
One aim is to decrease expressed
emotion (hostility, criticism, etc.)
Not blaming

Other interventions for schizophrenia:

Some evidence for effectiveness

Some types of psychotherapy

Case management
Vocational rehabilitation
Outpatient commitment
ECT (for catatonia)

Schizophrenia Treatment
Psychotherapy (individual or group)
Supportive
Cognitive-behavioral
Compliance therapy
Psychoeducational
Not regressive / psychoanalytic

Schizophrenia Treatment
Psychosocial Remedial Therapies
To improve social and vocational skills
Clubhouse model offers opportunities to
socialize, transitional employment
Vocational rehabilitationespecially
supported employment

Schizophrenia Treatment:
Case management
Case manager helps coordinate
treatments, provides support
Help navigating life, such as managing
every day activities, transportation, etc.
Helps broker access to available services
Benefits:
improves compliance, reduces stressors,
helps identify and treat problems with
substance use

Deinstitutionalization
Mid-1950s: >500,000 people in state psychiatric
hospitals
Now: <<100,000
Antispychotic medications
Civil (patients) rights movement
Community Mental Health Acts (1963-64)
Medicaid (1965-allows states to share costs with
federal government)
Still an active issue in N.C.adequacy of
community-based services remain in doubt

Recommended books on
schizophrenia
Is there no place on earth for me?,
Susan Sheehan
Imagining Robert,
Jay Neugeboren
Nightmare: a schizophrenia narrative,
Wendell Williamson
The Quiet Room, Lori Schiller