Schizophrenia%20Update:%20Treatment%20Options%20and%20Side%20Effects

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Schizophrenia UpdateTreatment 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 NIMH Sponsored CATIE
  Schizophrenia Study
• Medical Issues in Schizophrenia
• Side Effect Concerns With Antipsychotics
• Whats New?

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Timeline of Major Antipsychotic Therapies
Paliperidone
ECT, etc.
Olanzapine Quetiapine
Aripiprazole
Consta
Chlorpromazine
Fluphenazine
Risperidone
Thioridazine
Ziprasidone
Haloperidol
Clozapine
1950 1960 1970 1980 1990 2001
2003 2007
Consta Long-acting injectable risperidone
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The CATIE Schizophrenia Trial
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(No Transcript)
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CATIE Study Phase 1 Time to Discontinuation for
Any Cause
Olanzapine (N330)
Risperidone (N333)
Quetiapine (N329)
Perphenazine (N257)
1.0
Ziprasidone (N183)
0.9
0.8
0.7
Proportion of Patients Continuing Treatment
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
Time to Discontinuation for Any Cause (months)
Lieberman JA et al. N Engl J Med.
20053531209-1223.
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CATIE Study Phase 2T Time to Discontinuation
for Any Cause
1.0
0.8
Proportion of Patients Continuing Treatment
0.6
0.4
0.2
0
3
6
9
12
15
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Time to Phase 2 Discontinuation (months)
Olanzapine (N66)
Quetiapine (N63)
Risperidone (N69)
Ziprasidone (N135)
Stroup TS et al. Am J Psychiatry. 2006
163611-622.
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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 1632080-89
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Medical and Safety Issues During Antipsychotic
Treatment
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Recent Multi-State Study Mortality Data Years of
Potential Life Lost
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

• 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 200631-14 Miller BJ, et al. Psych
Services Oct 2006 57 1482-87
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Medical Issues in Schizophrenia and Bipolar
Disorder
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
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 Jun70(1)19-26
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Undertreatment of Common Disorders in the CATIE
Schizophrenia Trial at Enrollment
Nasrallah HA, Meyer JM et al. Schiz Res 2006.
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Side Effects of Atypical Antipsychotics

INVEGA/ CLOZARIL
RISPERDAL ZYPREXA SEROQUEL GEODON
ABILIFY
0/
0/

/0


Low Blood Pressure
Dry mouth, constipation
0
0
0
/
0

Tremors, stiffness, endocrine problems
0
/0
0
0/
/
0
0
0


/-

Sedation
-/
-/




Weight gain
0
0




Lipids
0
0




Blood sugar
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
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Shift in Risk Perception of Antipsychotics
Past Areas of Concern
Current Medical Realities
Diabetes
TD
Weight Gain
Prolactin
Tardive Dyskinesia
Hyperlipidemia
Insulin Resistance
Sedation
Weight Gain
Insulin Resistance
Hyper- lipidemia
Coronary Heart Disease
Sedation
CHD
Prolactin
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ADA/APA Consensus Conference on Antipsychotic
Drugs and Obesity and Diabetes Summary
Drug Weight Gain Risk for Diabetes Worsening Lipid Profile
Clozapine (Clozaril)
Olanzapine (Zyprexa)
Risperidone (Risperdal) Paliperidone (Invega) /- /-
Quetiapine (Seroquel) /-
Aripiprazole (Abilify) /- - -
Ziprasidone (Geodon) /- - -
increase effect - no effect D
discrepant results. Newer drugs with limited
long-term data.
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What We Should Be Doing
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
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 neutral
  medications may reverse many problems, but
  requires careful attention by the psychiatrist
  and motivation by the client

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Change in Body Weight Following Switch to
Aripiprazole-8 Wk Study


n 169 106 14
Prior antipsychotic
plt0.001 p0.077 LOCF analysis. Casey, et
al. Int J Neuropsychopharmacol. 20025(suppl
1)S187.
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Estimated Weight Change (lb) After Switch to
Ziprasidone
Improvement
Repeated measures analysis
Presented at APA 2004, New York, NY
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Whats New?
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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 -gt 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 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

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How A Reuptake Inhibitor Works
Synaptic vesicles with Glycine
PresynapticNerve Ending
Glycine Reuptake Pump
Glycine
PostsynapticNeuron
NMDA Receptors
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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