Schizophrenia as a progressive brain disorder

1
Schizophrenia as a progressive brain disorder

• René S. Kahn, MD, PhD
• University Medical CentreUtrecht, the Netherlands

2
Natural History of Schizophrenia
Stages of Illness
Premorbid
Prodromal
Onset/Deterioration
Residual/Stable
Healthy ? ? WorseningSeverity ofSigns
andSymptoms
10
20
30
40
50
Gestation/Birth
Puberty
Years
3
Time to Remission by Prior Duration of Psychosis
Cumulative Responding to Treatment
Weeks in Treatment
Lieberman JA, et al. Neuropsychopharmacology.
199614(3 suppl)13S-21S.
4
Cumulative Relapse Ratesby Episode of Illness
Relapse Rate(95 Confidence Interval)
Patients Remaining at Risk at End of Year (n)
Relapse
Year
Refers to year(s) after recovery from the
previous episode.Robinson D, et al. Arch Gen
Psychiatry. 199956(3)241-247.
5
Background

• Brain imaging studies have consistently
  demonstrated brain volume abnormalities in
  patients with schizophrenia
• Since illness course is progressive, are brain
  changes progressive?
• If so, early treatment may be particularly
  important to prevent (or reverse) early brain
  changes

6
Brain Structure Changes Across the Life Span
mL
Gray matter White matter
15
45
75
Age (Years)
7
Brain Structure Changes Across the Life Span
8
Brain Structure Changes Across the Life Span
Progressive Brain Changes in Schizophrenia
mL
Gray matter White matter
15
45
75
Age (Years)
9
Brain Volume Changes in First-Episode
Schizophrenia A 1-Year Follow-Up Study

• First-episode schizophrenia (n34) and matched
  healthy comparison subjects (n36)
• MRI obtained at inclusion and after 1 year
• Outcome was measured at 2 years
• Total brain volume and cerebral gray volume
  significantly decreased and lateral ventricle
  volume significantly increased in patients
  compared with controls
• The decrease in global gray matter volume
  significantly correlated with outcome and,
  independent of that, with higher cumulative
  dosage of antipsychotic medication

Cahn W, et al. Arch Gen Psychiatry.
200259(11)1002-1010.
10
Brain Volume Changes and Outcome
60
40
20
0
Total Brain Volume Changein 1 Year (cm3)
-20
-40
-60
-80
10
8
6
4
2
0
Total Number of Needs
4
3
2
1
Lateral Ventricle VolumeChange in 1 Year (cm3)
0
-1
-2
-3
-4
10
8
6
4
2
0
Total Number of Needs
Measured by Camberwell Assessment of Need
(CAN).Cahn W, et al. Arch Gen Psychiatry.
200259(11)1002-1010.
11
Brain Measurements in the First Year of Illness
Predict 5-Year Clinical and Global Outcome
8
40
6
20
4
0
Lateral Ventricle Volume Change (cm3) T1-T0
Gray Matter Volume Change (cm3) T1-T0
2
-20
0
-40
-2
-60
-4
-80
1.4
1.0
.8
.4
0
.2
.6
1.2
40
30
20
10
0
Mean Total Number of Needs at T5
Negative Symptoms at T5
r-0.54, df27, p.002. r0.54, df27,
p.003.Cahn W, et al. Schizophr Res. 2004.
12
Antipsychotic Treatment Effects on Symptomatic
Outcome and Progression of Brain Pathomorphology
in First-Episode Schizophrenia

• Dr. Jeffrey A. Lieberman, University of North
  Carolina School of Medicine, NC, USADr. Charles
  B. Nemeroff, Emory University School of Medicine,
  GA, USADr. Bruce Cohen, McLean Hospital, MA,
  USADr. Joseph P. McEvoy, John Umstead Hospital,
  NC, USADr. Wayne K. Goodman, University of
  Florida, FL, USADr. Alan I. Green, Massachusetts
  Mental Health Center, MA, USADr. Anthony J.
  Rothschild, University of Massachusetts Medical
  Center, MA, USADr. Raquel E. Gur, University of
  Pennsylvania Medical Center, PA, USADr. Robert
  Zipursky, Clarke Institute of Psychiatry,
  CanadaDr. Stephen M. Strakowski, University of
  Cincinnati, OH, USADr. Ira Glick, Stanford
  University School of Medicine, CA, USADr. John
  De Quardo, University of Michigan Medical Center,
  MI, USAProf. Dr. R.S. Kahn, University Hospital,
  Utrecht, The Netherlands Prof. Robin Murray and
  Dr. Tonmoy Sharma, Institute of Psychiatry, UK

13
Summary of Study Design

• Double-blind, randomised, multicentre,
  international study over 104 weeks comparing
  olanzapine(5-20 mg/day) and haloperidol (2-20
  mg/day)
• Acute treatment phase 12 weeks
• Follow-up continuation phase 92 weeks
• Cognitive and MRI/MRS assessments performed at
  baseline and weeks 12, 24, 52, and 104
• DSM-IV criteria for first-episode psychotic
  disorder (including schizophrenia,
  schizophreniform disorder, and schizoaffective
  disorder)
• Duration of illness lt60 months, duration of prior
  treatment lt16 weeks

Lieberman JA, et al. Am J Psychiatry.
2003160(8)1396-1404.
14
Study Hypotheses

• Olanzapine would be more effective than
  haloperidol on measures of psychopathology,
  treatment response, and treatment continuation
• Olanzapine would be associated with greater
  improvement on measures of neurocognition
• Greater rates of EPS would be associated with
  haloperidol
• Olanzapine would be associated with
  neuroprotective effects as measured on biomarkers
  of brain ROI volume measured by quantitative MRI
  and NAA, CHO, CREATon 1H-MRS

EPSextrapyramidal symptoms ROIregion of
interest NAAN-acetylaspartateCHOcholine
CREATcreatine 1H-MRS1H Magnetic Resonance
Spectroscopy
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Baseline Demographics

Lieberman JA, et al. Am J Psychiatry.
2003160(8)1396-1404.
16
Treatment of First-Episode Psychosis Modal Dose
Over 2 Years
Lieberman JA, et al. Am J Psychiatry.
2003160(8)1396-1404.
17
Efficacy Time toAll-Cause Discontinuation
Time to Discontinuation Due to Any Reason to 2
Years
Haloperidol median time to dropout118
days Olanzapine median time to dropout229
daysp.004
Survival Distribution Function
0
100
200
300
400
500
600
700
800
Days
Strata
Haloperidol therapy
Censored haloperidol therapy
Olanzapine therapy
Censored olanzapine therapy
Lieberman JA, et al. Am J Psychiatry.
2003160(8)1396-1404.
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Whole Brain Gray (SE)
Relative Week of Therapy
19
Mean Change of Whole Brain Gray Volume (OC)
plt.05p.056
Week 0 12 24 52 104 Olanzapine (n)
122 78 68 45 27 Haloperidol (n) 126 72 50 35 13
OCobservational case analysis.Lieberman JA, et
al. Presented at 156th APA Annual Meeting May
17-22, 2003San Francisco, Calif.
20
(No Transcript)
21
Relative volume loss in patients Controlled for
intracranial volume, initial volume, sex and age
Relative volume loss in patients (n96)
b
SE (b)
t (df203)
p
Whole brain
-14.71
3.61
-4.07
lt0.001
Cerebral grey
-16.43
3.34
-4.93
lt0.001
Cerebral white
2.39
2.87
0. 83
0.407
Cerebellum
-0. 43
0.49
-0.90
0.371
Lateral ventricles
0.69
0.32
2.16
0.032
Third ventricle
0.07
0.03
2.78
0.006
Peripheral CSF
5.97
3.17
1.88
0.061
p lt 0.05 p lt 0.01 plt 0.001
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Change in grey matter volume at T0 and T5 in
patients and controls
23
Cerebral volume change with age
24
Cerebral gray matter volume change with age
25
Third ventricle volume change with age
26
Lateral ventricle volume change with age
27
Change in cerebral volume during scan-interval
and olanzapine intake in mg per year
scan-interval
28
Excessive grey matter density decrease during the
scan-interval in patients with schizophrenia
Talairach coordinate (axial) z15
Talairach coordinate (sagittal) x11
29
Decreases in grey matter density in patients with
schizophrenia as compared to healthy individuals
at baseline and follow-up
30
Regression of excessive grey matter density
change on number of hospitalizations and
medication intake in patients
 
 
 
Superior frontal gyrus (anterior and medial, area
9 and 10)
-7 -9   -21
58 63   51
25 17   31
Cumulative olanzapine medication /
year Cumulative olanzapine medication /
year Cumulative clozapine medication /
year Number of hospitalizations Cumulative
clozapine medication / year
5.53E-06 7.59E-06 2.32E-07 -6.01E-03 3.50E-07
2. 20 2.63 2.07 -2.21 2.42
0.05 0.01 0.04 0.03 0.02
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Caudate nucleus
13 11
-2 10
27 17
Cumulative typical medication / year Cumulative
typical medication / year
2.22E-05 3.42E-05
2.29 2.19
0.03 0.03
31
Regression of excessive grey matter density
change on number of hospitalizations in patients
N92 p0.03
32
Regression of excessive grey matter density
change on cumulative clozapine intake (mg) per
day during scan interval
N58 p0.02
33
Regression of excessive grey matter density
change on cumulative olanzapine intake (mg) per
day during scan interval
N37 p0.01
34
Regression of excessive grey matter density
change on cumulative typical medication intake
(haloperidol eq.) per day during scan interval
N53 p0.14
35
Conclusions

• Gray matter decreases progressively across the
  course of the illness
• This loss is most pronounced in frontal and
  temporal areas
• The progression in frontal tissue loss is related
  to the number of psychotic relapses,
• but is attenuated (reversed?) by clozapine and
  olanzapine not by typical antipsychotics