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
Double Blind, Randomized Trial of Clozapine vs
Chlorpromazine in Treatment Resistant Patients
BPRS Schizophrenia
Factor
16
14
12
10
clozapine
chlorpromazine
8
6
4
2
0
0
1
2
3
Weeks in Trial
4
5
6
11
Clozapine: pros and cons
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•
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•
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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
•
1990
Generic Name
clozapine
(Brand Name)
(Clozaril)
•
•
•
•
•
1994
1996
1997
2001
2002
risperidone
olanzapine
quetiapine
ziprasidone
aripiprazole
(Risperdal)
(Zyprexa)
(Seroquel)
(Geodon)
(Abilify)
•
2003
risperidone MS
(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
n/N
NA
%
CA
n/N%
3/30 10%
65/188 35
68/218 31
12/109 11
9/31 29
Marder, 2002 (risperidone)
Csernansky, 2002 (risperidone)
Risperidone pooled
Daniel, 1998 (sertindole)
Speller, 1997 (amisulpride)
2/33
41/177
43/210
2/94
5/29
6%
23
21
2
17
Tamminga, 1993 (clozapine)
Essock, 1996 (clozapine)
Rosenheck, 1999 (clozapine)
Clozapine pooledd
Tran, 1998a (olanzapine)
Tran, 1998b (olanzapine)
Tran, 1998c (olanzapine)
Olanzapine pooled
1/25
13/76
10/35
24/136
10/45
6/48
71/534
87/627
4
17
29
18
22
13
13
14
161/1096
15
Total
p=0.0001 in favor of atypical drugs;
Leucht S et al. Am J Psychiatry. 2003
0/14
15/48
4/14
19/76
2/10
3/14
29/156
34/180
Risk Difference (95% CI fixed)
0
31
29
25
20
21
19
19
142/61423
-0.5
Favors
Atypical Antipsychotic
0
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
0
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
• “noncompliance”—inconsistent
antipsychotic medication use
• stressful life events/home environment
(Expressed Emotion—EE—hostility,
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
3
6
9
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
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•
•
•
•
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 rehabilitation—especially
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