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Schizophrenia Update:Treatment Options and Side Effects
Schizophrenia Update:Treatment Options and Side Effects
Jonathan M. Meyer, M.D
Assistant Professor
Department of Psychiatry
University of California San Diego
Jonathan M. Meyer, M.D
Assistant Professor
Department of Psychiatry
University of California San Diego
OutlineOutline
Recent Data from the NIMH Recent Data from the NIMH Sponsored CATIE Schizophrenia Sponsored CATIE Schizophrenia StudyStudy
Medical Issues in SchizophreniaMedical Issues in Schizophrenia
Side Effect Concerns With Side Effect Concerns With AntipsychoticsAntipsychotics
What’s New?What’s New?
Timeline of Major Antipsychotic Therapies
Ziprasidone
1950 1960 1970 1980 1990 2001 2003 2007
ECT, etc.
Chlorpromazine
Fluphenazine
ThioridazineHaloperidol Clozapine
Risperidone
OlanzapineQuetiapine
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
0.00 3 6 9 12 15 18
1.0
Time to Discontinuation for Any Cause (months)
Pro
po
rtio
n o
f P
ati
ents
Co
nti
nu
ing
Tre
atm
en
t
Stroup TS et al. Am J Psychiatry. 2006; 163:611-622.
Pro
po
rtio
n o
f P
ati
ents
C
on
tin
uin
g T
rea
tme
nt
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 Average Monthly Symptom ScoresScores
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;3:1-14Miller 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
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 2003Regenold 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
DiabetesMellitus
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
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
Past Areas of Concern
Current Medical Realities
Shift in Risk Perception of Antipsychotics
SedationWeight Gain
Insulin Resistance
CHD
Hyper-lipidemia
Weight Gain
Diabetes
Prolactin
Insulin Resistance
Sedation
Hyperlipidemia
Coronary HeartDisease
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.
InquiryInquiry• Personal or family history:Personal or family history:
– Diabetes Diabetes
– Hypertension Hypertension
– CHD (MI or Stroke)CHD (MI or Stroke)
– Cigarette smokingCigarette smoking
– Diet Diet
– Physical ActivityPhysical Activity
MeasureMeasure• HeightHeight
• WeightWeight
• Waist circumferenceWaist circumference
• Blood PressureBlood Pressure
LabLab• Fasting GlucoseFasting Glucose
• Fasting LipidsFasting Lipids
What We Should Be DoingWhat We Should Be Doing
And - trying to use medications which have fewer metabolic side effects!
EquipmentEquipment
Clinical IssuesClinical Issues
• Lack of access to medical care for Lack of access to medical care for patients with severe mental illnessespatients with severe mental illnesses
• Switching to more metabolically neutral Switching to more metabolically neutral medications may reverse many medications may reverse many problems, but requires careful attention problems, but requires careful attention by the psychiatrist and motivation by the by the psychiatrist and motivation by the clientclient
Change in Body Weight Following Change in Body Weight Following Switch to Aripiprazole-8 Wk StudySwitch to Aripiprazole-8 Wk Study
-3
-2
-1
0
1
Olanzapine Risperidone Haloperidol
Mea
n c
han
ge
in w
eig
ht
(kg
)
*
†
*p<0.001; †p=0.077LOCF 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
0
5
LS
Mea
n C
han
ge,
lb
49 53 584540363227231914106
Weeks
*
***
***
**
**
***
*P<0.05 **P<0.001***P<0.0001
Switched from
Imp
rovem
ent
Presented at APA 2004, New York, NY
What’s New?
Newer AntipsychoticsNewer 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 HorizonOn 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
PostsynapticNeuron
PresynapticNerve 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