Schizophrenia Update

8/11/2019 Schizophrenia Update

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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

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-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

Documents

Schizophrenia Update