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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. Outline. Recent Data from the NIMH Sponsored CATIE Schizophrenia Study Medical Issues in Schizophrenia

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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

outline
Outline
  • Recent Data from the NIMH Sponsored CATIE Schizophrenia Study
  • Medical Issues in Schizophrenia
  • Side Effect Concerns With Antipsychotics
  • What’s New?
timeline of major antipsychotic therapies
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

slide6

CATIE Study Phase 1: Time to Discontinuation for Any Cause

Olanzapine (N=330)

Risperidone (N=333)

Perphenazine (N=257)

Quetiapine (N=329)

1.0

Ziprasidone (N=183)

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. 2005;353:1209-1223.

catie study phase 2t time to discontinuation for any cause
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

18

Time to Phase 2 Discontinuation (months)

Olanzapine (N=66)

Quetiapine (N=63)

Risperidone (N=69)

Ziprasidone (N=135)

Stroup TS et al. Am J Psychiatry. 2006; 163:611-622.

average monthly symptom scores
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

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 spanRecent Multi-State Study Mortality Data: Years of Potential Life Lost

Colton CW, Manderscheid RW. Preventing Chronic Disease. Apr 2006;3:1-14

Miller BJ, et al. Psych Services Oct 2006; 57: 1482-87

slide11

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
Undertreatment of Common Disorders in the CATIE Schizophrenia Trial at Enrollment

Nasrallah HA, Meyer JM et al. Schiz Res 2006.

side effects of atypical antipsychotics
Side Effects of Atypical Antipsychotics

INVEGA/

CLOZARIL RISPERDAL ZYPREXA SEROQUEL GEODON ABILIFY

Low Blood Pressure

+++

+

+/0

++

0/+

0/+

Dry mouth, constipation

+++

0

+/++

0

0

0

Tremors, stiffness,

endocrine problems

0

+/++

0/+

0

+/0

0

Sedation

+++

+/-

++

+++

0

0

Weight gain

++++

+

++++

++

-/+

-/+

Lipids

+++

+

+++

++

0

0

Blood sugar

+++

+

+++

++

0

0

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

shift in risk perception of antipsychotics
Shift in Risk Perception of Antipsychotics

Past Areas of Concern

Current Medical Realities

Diabetes

TD

Weight Gain

Tardive Dyskinesia

Prolactin

Hyperlipidemia

Insulin

Resistance

Sedation

Weight Gain

Insulin

Resistance

Hyper-

lipidemia

Coronary Heart

Disease

Sedation

CHD

Prolactin

ada apa consensus conference on antipsychotic drugs and obesity and diabetes summary
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.

what we should be doing
What We Should Be Doing

And - trying to use medications which have fewer metabolic side effects!

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

*

n = 169 106 14

Prior antipsychotic

*p<0.001; †p=0.077

LOCF analysis.

Casey, et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S187.

slide20

Weeks

19

27

58

14

32

49

53

6

23

36

40

45

10

5

0

*

***

-5

**

LS Mean Change, lb

-10

***

**

-15

*P<0.05

**P<0.001

***P<0.0001

-20

***

-25

Switched from

Conventionals

Olanzapine

Risperidone

Estimated Weight Change (lb) After Switch to Ziprasidone†

Improvement

†Repeated measures analysis

Presented at APA 2004, New York, NY

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)

Newer Antipsychotics
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

On the Horizon
how a reuptake inhibitor works
How A Reuptake Inhibitor Works

Synaptic vesicles with Glycine

PresynapticNerve Ending

Glycine Reuptake Pump

Glycine

PostsynapticNeuron

NMDA Receptors

slide25

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