1. The Role of Cognition in Treatment Resistance
Philip D. Harvey, PhD
University of Miami Miller School of Medicine

2. Concept of Treatment Resistance
• Classically defined as failure to manifest an
adequate response of clinical symptoms to
antipsychotic treatment
• About 35% of patients meet strict criteria for
treatment resistance
• This discussion will focus on treatment
response of other features of the illness

3. Dynamics of Treatment Resistance
• Treatment resistance is rarely present at the time of the first
episode, but tends to develop over time
• Negative symptoms and cognitive deficits may be present
prior to the onset of psychosis, but may appear to respond to
treatment at the first admission
• It may be that treatment response at the time of the first
episode suggests “secondary negative symptoms
• However, this whole issue is not yet settled

4. Successive Relapses Prolonged
Time to Remission
7.0
4.0
First episode
Second episode
Third episode
*
*P=.001
24.3
Successive Episodes
0 5 10 15 20 25 30
Median Time to Remission (Weeks)
Lieberman JA, et al. Neuropsychopharmacology. 1996;14(suppl 3):13S-21S.
3-Episode Group (n=6)

5. Psychosis and Brain Volume Changes During the First
5 Years of Schizophrenia
Gray Matter Lateral Ventricle 3rd Ventricle
Duration of Psychosis (months) Duration of Psychosis (months) Duration of Psychosis (months)
Cahn W, et al. Eur Neuropsychopharm. 2009;19:147-151.
N = 48

6. Gray Matter Loss in Patients With Schizophrenia at
Baseline and 5-Year Follow-Up
-5.05
-6.00
-6.52
Baseline
Talairach coordinate (axial): z=3
van Haren NE, et al. Neuropsychopharmacology. 2007;32(10):2057-2066.
-5.05
-6.00
-7.00
-7.60
Follow-Up
Talairach coordinate (axial): z=3

7. What else does not respond to
treatment?
• Antipsychotic treatment does not influence
many other aspects of the illness
– Everyday functioning
– Cognition
– Negative symptoms

8. What is the prevalence of different
outcomes?
100
90
80
70
60
50
40
30
20
10
0
Percentage of Cases
Remission First Episode Remission Multi-Episode Full Time work Independent Living

9. Poor Psychosocial Outcomes Are Very
Common
• Present in multiple domains
– Everyday activities
– Social Outcomes
– Work
• Not related to current symptomatic status
• Related to other features of schizophrenia that
are not improved by antipsychotic treatment

10. Is poor adherence to treatment
associated with poor outcomes?

11. Comparative Study of Adherence oriented vs. Functionally
oriented treatment
• Cognitive adaptation therapy (Velligan, 2008)
– Prosthetic intervention
– Aimed at increasing organization and functioning
without necessarily increasing the cognitive
performance
– Can aimed at global life skills or medication
management

12. Effect on Adherence

13. Effect on Relapse

14. But Adherence does not improve functioning

15. Cognition and Everyday outcomes
• Multiple studies have shown correlations
• Treatment of cognitive deficits with CRT
improves outcomes in some circumstances
• Other ability variables are important
– Functional Capacity
– Social Skills

16. Neg Sx
Processing
Speed
Verbal
Memory
Working
Memory
Prediction of Community
Activities
SSPA
Community
Activities
.40*
-.47*
.43*
.-27*
R2=0.48
.41*
UPSA
Executive
Functioning
.38*
.34*
.43*
.50*
*p<.01