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

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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

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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