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Schizophrenia Update:
Treatment Options and Side Effects
Jonathan M. Meyer, M.D
Assistant Professor
Department of Psychiatry
University of California San Diego
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Outline
Recent Data from the NIMHSponsored CATIE SchizophreniaStudy
Medical Issues in Schizophrenia
Side Effect Concerns WithAntipsychotics
Whats New?
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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
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The CATIESchizophrenia Trial
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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
0.00 3 6 9 12 15 18
1.0
Time to Discontinuation for Any Cause (months)
Proportiono
fPatients
ContinuingTreatment
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Stroup TS et al.Am J Psychiatry. 2006; 163:611-622.
ProportionofPatients
Continuing
Treatment
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
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Average Monthly Symptom
Scores
Rosenheck R et al. Cost Effectiveness of Second-Generation Antipsychotics and Perphenazine in aRandomized Trial of Treatment for Chronic SchizophreniaAm J Psychiatry 2006; 163:2080-89
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Recent Multi-State Study Mortality Data:
Years of Potential Life Lost
Compared with the general population, persons with major mental illnesstypically lose more than 25 years of normal life span
Colton CW, Manderscheid RW. Preventing Chronic Disease.Apr 2006;3:1-14Miller 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
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Factor Prevalence inSchizophrenia
Prevalence in Bipolar Prevalence inGeneral 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 andschizoaffective disorders independent of psychotropic drug use. Journal of Affective Disorders. 2002 Jun;70(1):19-26
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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.
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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
00+++++++++Blood sugar
00+++++++++Lipids
-/+-/++++++++++++Weight gain
00++++++/-+++Sedation
0+/000/++/++0Tremors, stiffness,endocrine problems
000+/++0+++Dry mouth,
constipation
0/+0/++++/0++++Low Blood Pressure
INVEGA/CLOZARIL RISPERDAL ZYPREXA SEROQUEL GEODON ABILIFY
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Past Areas ofConcern
Current Medical Realities
Shift in Risk Perception
of Antipsychotics
SedationWeight
Gain InsulinResistance
CHD
Hyper-lipidemia
Weight Gain
Diabetes
Prolactin
Insulin
Resistance
Sedation
Hyperlipidemia
Coronary Heart
Disease
Tardive
Dyskinesia
TD
Prolactin
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InquiryPersonal or family history:
Diabetes
Hypertension
CHD (MI or Stroke)
Cigarette smoking
Diet
Physical Activity
MeasureHeight
Weight
Waist circumference
Blood Pressure
LabFasting Glucose
Fasting Lipids
What We Should Be Doing
And - trying to use medications which have fewer
metabolic side effects!
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Equipment
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Clinical Issues
Lack of access to medical care for
patients with severe mental illnesses
Switching to more metabolically neutralmedications may reverse many
problems, but requires careful attention
by the psychiatrist and motivation by theclient
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Change in Body Weight FollowingSwitch to Aripiprazole-8 Wk Study
-3
-2
-1
0
1
Olanzapine Risperidone Haloperidol
Meanchangei
nweight(kg)
*
*p
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Estimated Weight Change (lb)
After Switch to Ziprasidone
Repeated measures analysis
Conventionals Olanzapine Risperidone
-25
-20
-15
-10
-5
0
5
LS
MeanChange,lb
49 53 584540363227231914106
Weeks
*
***
***
**
**
***
*P
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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)
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On the Horizon
Some features of schizophrenia may be due todecreased levels of activity at a certain type of receptor(NMDA glutamate receptors)
Glycine can stimulate those receptors and might proveuseful 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
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How A Reuptake Inhibitor Works
Glycine Reuptake Pump
Postsynaptic
Neuron
PresynapticNerve Ending
NMDA Receptors
Synaptic
vesicles with
Glycine
Glycine
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Conclusions Except for clozapine, most of thecurrently available agents, and those
on the horizon, are more alike thandifferent in terms of effectiveness
Safety and avoidance of metabolicside effects are major reasons tochoose certain medications
Providers have a duty to monitorweight, blood pressure, blood sugarand cholesterol (lipids)
Long-acting injectable medications
are useful, will have more options inthe next few years
Ongoing research may helpidentify newer classes of medications