Schizophrenia Update:

Treatment Options and Side Effects

Jonathan M. Meyer, M.D
Assistant Professor
Department of Psychiatry
University of California San Diego

Outline
Recent Data from the NIMH
Sponsored CATIE Schizophrenia
Study
Medical Issues in Schizophrenia
Side Effect Concerns With
Antipsychotics
Whats New?
Timeline of Major
Antipsychotic Therapies
Ziprasidone
1950 1960 1970 1980 1990 2001 2003 2007
ECT, etc.
Chlorpromazine
Fluphenazine
Thioridazine
Haloperidol
Clozapine
Risperidone

Olanzapine
Quetiapine
Aripiprazole


Consta
Paliperidone
Consta = Long-acting injectable risperidone
The CATIE
Schizophrenia Trial
CATIE Study Phase 1:
Time to Discontinuation for Any Cause
Lieberman JA et al. N Engl J Med. 2005;353:1209-1223.
Olanzapine (N=330) Risperidone (N=333)
Ziprasidone (N=183)
Quetiapine (N=329) Perphenazine (N=257)
0.8
0.9
0.7
0.6
0.4
0.3
0.1
0.5
0.2
0.0
0 3 6 9 12 15 18
1.0
Time to Discontinuation for Any Cause (months)
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Stroup TS et al. Am J Psychiatry. 2006; 163:611-622.
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Time to Phase 2 Discontinuation (months)
1.0
0.8
0.6
0.4
0.2
0 3 6 9 12 15 18
Olanzapine (N=66) Quetiapine (N=63) Risperidone (N=69) Ziprasidone (N=135)
CATIE Study Phase 2T:
Time to Discontinuation for Any Cause
Average Monthly Symptom
Scores
Rosenheck R et al. Cost Effectiveness of Second-Generation Antipsychotics and Perphenazine in a
Randomized Trial of Treatment for Chronic Schizophrenia Am J Psychiatry 2006; 163:2080-89
Medical and Safety
Issues During
Antipsychotic
Treatment
Recent Multi-State Study Mortality Data:
Years of Potential Life Lost
Compared with the general population, persons with major mental illness
typically lose more than 25 years of normal life span
Colton CW, Manderscheid RW. Preventing Chronic Disease. Apr 2006;3:1-14
Miller BJ, et al. Psych Services Oct 2006; 57: 1482-87
Year AZ MO OK RI TX UT OH
1997 26.3 25.1 28.5
1998 27.3 25.1 28.8 29.3
1999 32.2 26.8 26.3 29.3 26.9
2000 31.8 27.9 24.9
1998 -
2002
32.0
Factor Prevalence in
Schizophrenia
Prevalence in Bipolar Prevalence in
General Population
Smoking 75% 43-75% 25%
Obesity 50% 58% 33%
Diabetes Mellitus 13-14% 9.9-26% 7%
HIV 3% ? 0.3%
Hepatitis C 20% ? 1.8%
Other:
-inactivity, poor nutrition
-substance use
Medical Issues in Schizophrenia
and Bipolar Disorder
Meyer JM and Nasrallah H eds. Medical Illness and Schizophrenia. APPI 2003
Regenold WT, et al. Increased prevalence of type 2 diabetes mellitus among psychiatric inpatients with bipolar I affective and
schizoaffective disorders independent of psychotropic drug use. Journal of Affective Disorders. 2002 Jun;70(1):19-26
Undertreatment of Common Disorders in the
CATIE Schizophrenia Trial at Enrollment
69.8
37.6
12.0
30.2
62.4
88.0
0
25
50
75
100
Diabetes
Mellitus
Hypertension Dyslipidemia
Treated Untreated
Nasrallah HA, Meyer JM et al. Schiz Res 2006.
Side Effects of Atypical Antipsychotics
CLOZ = clozapine; RIS = risperidone; OLZ = olanzapine; QUET = quetiapine; ZIP = ziprasidone; ARIP =
aripiprazole; Adapted from: Nasrallah HA, Mulvihill T. Ann Clin Psychiatry. 2001(Dec);13(4):215-227
0 0 ++ +++ + +++
Blood sugar
0 0 ++ +++ + +++
Lipids
-/+ -/+ ++ ++++ + ++++
Weight gain
0 0 +++ ++ +/- +++
Sedation
0 +/0 0 0/+ +/++ 0
Tremors, stiffness,
endocrine problems
0

0 0 +/++ 0 +++
Dry mouth,
constipation
0/+ 0/+ ++ +/0 + +++
Low Blood Pressure
INVEGA/
CLOZARIL RISPERDAL ZYPREXA SEROQUEL GEODON ABILIFY
Past Areas of
Concern
Current Medical Realities
Shift in Risk Perception
of Antipsychotics
Sedation
Weight
Gain
Insulin
Resistance
CHD
Hyper-
lipidemia
Weight Gain
Diabetes
Prolactin
Insulin
Resistance
Sedation
Hyperlipidemia
Coronary Heart
Disease
Tardive
Dyskinesia
TD
Prolactin
Drug Weight Gain Risk for
Diabetes
Worsening
Lipid Profile
Clozapine (Clozaril) +++ ++ ++
Olanzapine (Zyprexa) +++ ++ ++
Risperidone (Risperdal)
Paliperidone (Invega)
++ +/- +/-
Quetiapine (Seroquel) ++ +/- +
Aripiprazole* (Abilify) +/- - -
Ziprasidone* (Geodon) +/- - -
ADA/APA Consensus Conference on Antipsychotic
Drugs and Obesity and Diabetes
Summary

+ = increase effect; - = no effect; D = discrepant
results. *Newer drugs with limited long-term data.
Inquiry
Personal or family history:
Diabetes
Hypertension
CHD (MI or Stroke)
Cigarette smoking
Diet
Physical Activity
Measure
Height
Weight
Waist circumference
Blood Pressure
Lab
Fasting Glucose
Fasting Lipids
What We Should Be Doing
And - trying to use medications which have fewer
metabolic side effects!
Equipment
Clinical Issues
Lack of access to medical care for
patients with severe mental illnesses
Switching to more metabolically neutral
medications may reverse many
problems, but requires careful attention
by the psychiatrist and motivation by the
client
Change in Body Weight Following
Switch to Aripiprazole-8 Wk Study
-3
-2
-1
0
1
Olanzapine Risperidone Haloperidol
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*p<0.001;

p=0.077
LOCF analysis.
Casey, et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S187.
n = 169 106 14
Prior antipsychotic
Estimated Weight Change (lb)
After Switch to Ziprasidone

Repeated measures analysis

Conventionals Olanzapine Risperidone
-25
-20
-15
-10
-5
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5
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49 53 58 45 40 36 32 27 23 19 14 10 6
Weeks
*
***
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*P<0.05
**P<0.001
***P<0.0001
Switched from
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Presented at APA 2004, New York, NY
Whats New?
Newer Antipsychotics
Paliperidone (Invega) - Risperdal metabolite
Very similar side effect profile to Risperdal
Very similar effectiveness to Risperdal
Bifeprunox - similar in mechanism to Abilify
More nausea than Abilify -> Long titration (8 days) - not for acute use
Questions about effectiveness - awaiting FDA decision
Asenapine - another atypical antipsychotic
No major efficacy or safety benefits - awaiting FDA decision
Iloperidone - another atypical antipsychotic
No major efficacy benefits, QTc concerns - awaiting FDA decision
Long-Acting Injectables (Not Yet Approved)
Olanzapine Pamoate: 2-4 wks, effective, major safety concerns
Paliperidone Palmitate: 4 wks, not yet filed with FDA (?2009)

On the Horizon
Some features of schizophrenia may be due to
decreased levels of activity at a certain type of receptor
(NMDA glutamate receptors)
Glycine can stimulate those receptors and might prove
useful as a treatment for schizophrenia
Glycine Transport Inhibitors (GlyT1 Blockers)
The GlyT1 transporter is localized to important areas of the brain
Interesting data in animal models of psychosis induced by PCP
How A Reuptake Inhibitor Works
Glycine Reuptake Pump
Postsynaptic
Neuron
Presynaptic
Nerve Ending
NMDA Receptors
Synaptic
vesicles with
Glycine
Glycine
Conclusions
Except for clozapine, most of the
currently available agents, and those
on the horizon, are more alike than
different in terms of effectiveness
Safety and avoidance of metabolic
side effects are major reasons to
choose certain medications
Providers have a duty to monitor
weight, blood pressure, blood sugar
and cholesterol (lipids)
Long-acting injectable medications
are useful, will have more options in
the next few years
Ongoing research may help
identify newer classes of medications