1. Treatment of Schizophrenia
(and Related Psychotic Disorders)
Scott Stroup, MD, MPH
2004

2. 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

3. 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

4. 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

5. Features of Schizophrenia
Positive symptoms Negative symptoms
Delusions Anhedonia
Hallucinations Affective flattening
Avolition
Social withdrawal
Functional Impairments
Work/school Alogia
Interpersonal relationships
Self-care
Cognitive deficits
Attention
Memory Disorganization Mood symptoms
Verbal fluency Depression/Anxiety
Speech Aggression/Hostility
Executive
function Behavior Suicidality
(eg, abstraction)

6. Common needs of people with
schizophrenia
• Symptom control
• Housing
• Income
• Work
• Social skills
• Treatment of comorbid conditions

7. 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

8. Schizophrenia Treatment
• Therapeutic Goals
• minimize symptoms
• minimize medication side effects
• prevent relapse
• maximize function
• “recovery”
• Types of Treatment
• pharmacotherapy
• psychosocial/psychotherapeutic

9. Treatments for schizophrenia:
Strong evidence for effectiveness
• Antipsychotic medications
• Family psychoeducation
• Assertive Community Treatment
(ACT teams)

10. 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

11. Show Video Tape
Augustine

12. 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)

13. Conventional Antipsychotics
FDA approval Generic Name Brand Name
• 1953 chlorpromazine (Thorazine)
• 1958 trifluoperazine (Stelazine)
• 1958 perphenazine (Trilafon)
• 1959 fluphenazine (Prolixin)
• 1959 thioridazine (Mellaril)
• 1967 haloperidol (Haldol)
• 1967 thiothixene (Navane)
• 1970 mesoridazine (Serentil)
• 1975 loxapine (Loxitane)
• 1977 molidone (Moban)
• 1984 pimozide (Orap)

14. “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)

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

16. Typical Antipsychotic limitation:
Extrapyramidal side effects (EPS)
• Parkinsonism
• Akathisia
• Dystonia
• Tardive dyskinesia (TD)-- the worst
form of EPS-- involuntary movements

17. 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)

18. 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

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

20. Show Tardive Dyskinesia
Videotape
Abnormal Involuntary Movement
Scale (AIMS) training tape

21. 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

22. 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 (?)

23. 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)

24. 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”

25. Typical Antipsychotic limitation:
Treatment Resistance
• Poor treatment response in 30% of
treated patients
• Incomplete treatment response in
an additional 30% or more

26. 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

27. Clozapine Helps
Treatment-Resistant Patients
Double Blind, Randomized Trial of Clozapine vs
Chlorpromazine in Treatment Resistant Patients
16
14
BPRS Schizophrenia
12
10 clozapine
Factor
8 chlorpromazine
6
4
2
0
0 1 2 3 4 5 6
Weeks in Trial
11

28. 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

29. Atypical antipsychotics
(aka second-generation, novel)
FDA approval Generic Name (Brand Name)
• 1990 clozapine (Clozaril)
• 1994 risperidone (Risperdal)
• 1996 olanzapine (Zyprexa)
• 1997 quetiapine (Seroquel)
• 2001 ziprasidone (Geodon)
• 2002 aripiprazole (Abilify)
• 2003 risperidone MS (Consta)

30. Defining “atypical” antipsychotic
Relative to conventional drugs:
• Lower ratio of D2 and 5-HT2A receptor
antagonism
• Lower propensity to cause EPS
(extrapyramidal side effects)

31. Atypical Antipsychotics:
Efficacy
• Effective for positive symptoms
• (equal or better than typical antipsychotics)
• Clozapine is more effective than
conventional antipsychotics in treatment-
resistant patients
• Atypicals may be better than
conventionals for negative symptoms

32. New Antipsychotics and Haloperidol vs
Placebo: ‘Pooled’ Data
Mean BPRS Changes
Olanzapine pooled
r=.23*; n=574
(2 studies)
Quetiapine pooled
r=.23*; n=991
(4 studies)
Risperidone pooled
r=.28*; n=686
(3 studies)
Haloperidol pooled
r=.28*; n=814
(6 studies)
-0.4 -0.3 0.2 0.1 0 0.1 0.2 0.3 0.4 0.5 r (95% CI)
*Statistically significant.
Modified from Leucht S, et al. Schizophr Res. 1999;35:51-68.

33. New Antipsychotics and Haloperidol
vs Placebo: ‘Pooled’ Data
Change in Negative Symptoms
Olanzapine pooled
r=.21*; n=582
(2 studies)
Quetiapine pooled
r=.19*; n=823
(4 studies)
Risperidone pooled
r=.20*; n=686
(2 studies)
Haloperidol pooled
r=.17*; n=796
(5 studies)
-0.4 -0.3 0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 r (95% CI)
*Statistically significant.
Modified from Leucht S, et al. Schizophr Res. 1999;35:51-68.

34. Relapse Rates in 1 Year Studies:
Atypical vs. Typical Antipsychotics
NA
CA Risk Difference (95% CI fixed)
Marder, 2002 (risperidone) n/N
2/33 %
6% n/N
3/30
%
Csernansky, 2002 (risperidone) 10%
Risperidone pooled 41/177 23 65/188
Daniel, 1998 (sertindole) 35
Speller, 1997 (amisulpride) 43/210 21 68/218
31
Tamminga, 1993 (clozapine) 2/94 2 12/109
Essock, 1996 (clozapine) 11
Rosenheck, 1999 (clozapine) 5/29 17 9/31
Clozapine pooledd 29
Tran, 1998a (olanzapine)
Tran, 1998b (olanzapine) 1/25 4 0/14
Tran, 1998c (olanzapine) 0
Olanzapine pooled 13/76 17 15/48
31
10/35 29 4/14
Total 29
24/136 18 19/76
p=0.0001 in favor of atypical drugs; -0.5 Favors 0 Favors 0.5
25
Leucht S et al. Am J Psychiatry. 2003 Atypical Antipsychotic Conventional Drug
10/45 22 2/10

35. 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

36. 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

37. Weight gain at 10 weeks
6
5
4
Kg 3
2
1
0
-1
HAL
OLZ
CPZ
CLOZ
PLB
ZIP
RISP
Allison et al 1999

38. Summary of Antipsychotic Side Effects
Side Effect Highest Liability Low Liability
EPS Conventional CLZ, OLZ, QTP
antipsychotics
TD Conventional CLZ, OLZ, QTP
antipsychotics
Hyperprolactinemia Conventional CLZ, OLZ, QTP
antipsychotics, RIS
Sedation CPZ, CLZ, QTP, OLZ RIS
Anticholinergic CPZ, CLZ RIS
effects
QTc prolongation ZIP, thioridazine,
mesoridazine
Weight gain CPZ, CLZ, OLZ HAL, ZIP
Hyperglycemia, DM Atypical antipsychotics

39. Why worry about side effects?
• May cause secondary symptoms,
illnesses
• Contribute to “noncompliance” and thus
relapse

40. 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

41. Real and Projected Global Sales of
Antipsychotics 1990-2009 ($ millions)

42. 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

43. Antipsychotic medication
reduces relapse rates
Risk of relapse in one year:
Consistently taking medications: 20-30%
Not taking medications consistently: 65-80%

44. Relapse in Schizophrenia
Hogarty et al., N = 374
Prien et al., N ≈ 630
100
90 Caffey et al., N = 259
80
70 Neuroleptics
% Not Relapsed
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

45. 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

46. 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

47. 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

48. 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

49. Other interventions for schizophrenia:
Some evidence for effectiveness
• Some types of psychotherapy
• Case management
• Vocational rehabilitation
• Outpatient commitment
• ECT (for catatonia)

50. Schizophrenia Treatment
Psychotherapy (individual or group)
• Supportive
• Cognitive-behavioral
• “Compliance” therapy
• Psychoeducational
• Not regressive / psychoanalytic

51. Schizophrenia Treatment
Psychosocial Remedial Therapies
• To improve social and vocational skills
• Clubhouse model offers opportunities to
socialize, transitional employment
• Vocational rehabilitation—especially
supported employment

52. 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

53. Course of Schizophrenia
Stages of Illness
premorbid prodromal onset/ residual/
deterioration stable
More symptoms
Higher Function
Gestation/Birth 10 20 30 40 50

54. “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

55. 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