without early (subjective) improvement by antipsychotic treatment, only low chance for remission...
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Without early (subjective) improvement by antipsychotic treatment, only low chance for
remission
Dieter Naber
Department of Psychiatry
University of Hamburg
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How many weeks of antipsychotic treatment do we need to predict its success or when
should we change treatment?
• Most guidelines or textbooks recommend to wait several weeks before switching the antipsychotic should be considered.
• With 6 - 8 pharmacologically rather different atypical antipsychotics available, is this recommendation still valid?
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Early Response to Antipsychotics as Predictor of Later Response in the Naturalistic Treatment of
Schizophrenia (Ascher-Svanum et al., 2007)
• PANSS total score data of a randomised open-label trial (n=664) were analysed. Early (non-)response (at least 20% reduction) after 2 weeks predicted late (non-) response after 8 weeks with high accuracy (73%), moderate sensitivity (42%) and high specificity (90%).
• Early response/non-response appears to accurately predict subsequent response /non-response. Findings suggest that early non-responders may benefit from change in antipsychotic treatment.
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Early Prediction of Antipsychotic Non-response among Patients with Schizophrenia
(Leucht et al., 2007)
• Individual patient data from 7 randomized, controlled antipsychotic drug trials including 1708 patients were pooled.
• Patients with no improvement of psychopathology (less than 3-7% BPRS score reduction) during the first two weeks of treatment are unlikely to respond at week 4 and may benefit from a change of treatment.
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Relationship between SWN and Psychopathology (Karow et al., 2005)
PANSS syndromes
Baseline (n=84)
Discharge 42±28 days (n=84)
Follow-up 6 months (n=39)
Hostile Excitement
- .01 - .37* - .15
Negative Syndrome
- .34* - .22 - .43*
Cognitive Syndrome
- .12 - .26 - .10
Positive Syndrome
- .13 - .33* - .09
Depression - .30* - .38* - .67*
Correlation Coefficient *p<.01
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Subjective effects of antipsychotics
• Many schizophrenic patients treated with typical antipsychotics report not only motor effects, but also emotional and affective restrictions – ‘I feel like a zombie’. These patients benefit particularly from atypicals.
• Complaints are well known (pharmacogenic depression, akinetic depression, pharmacogenic anhedonia, neuroleptic-induced deficit syndrome), but barely investigated. They are often too subtle to be detected by objective examination and the common rating scales.
• Symptoms are often difficult to differentiate from negative symptoms of schizophrenia.
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Animal data on affective changes with (typical) antipsychotics
• Extensive animal data indicate the importance of mesocortical dopamine (mostly D2) systems in mediating reward behaviour
• Several animal studies have demonstrated that typical antipsychotics strongly and negatively affect reward system(s) in a variety of models
• Less or none inhibition of reward systems by atypical antipsychotics ?
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Subjective wellbeing under neuroleptics
• A self-report scale has been constructed to evaluate Subjective Well-being under Neuroleptics (SWN)
• The revised short from of 20 items shows sufficient internal consistency (Cronbach’s α .92), good construct validity and does not require more than 5-10 minutes to be filled out
• SWN data indicate relevance for compliance as well as significant and relevant superiority of atypical vs typical antipsychotics
• Correlations to Heinrichs QLS (n=1462): baseline r=.49, 3 months r=.61, 6 months r=.66, 12 months r=.71.
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• All statements refer to the past 7 days.• Total score, 5 subscores (e.g. physical functioning)
My body is a burden to me
I feel very comfortable with my body
I feel weak and exhausted
My body feels familiar
Not at all A little Somewhat Noticeable Much Very much
Self-report of well-being by schizophrenic patients
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Improvement of Psychopathology and Subjective Well-Being under
Atypical Neuroleptics
• Relationship between individual changes of SWN and PANSS in 97 schizophrenic in-patients treated with olanzapine (n=36), risperidone (n=28) or clozapine (n=36) for 30-58 days
• r=-0.29, p<0.006
Naber D, et al. Schizophr Res. 2001;50(1-2):79-88.
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Double-blind Comparison of Olanzapine and Clozapine
olanzapine [N=49] clozapine [N=50]
Treatment week
0 2 4 6 14 26
SW
N s
co
re 70
75
80
85
90
SWN
Tot
al S
core
SWN - PANSS, r = -.45, p=.003
Naber et al., Acta Psychiat Scand 2005
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European SOHO Study
• Comparison at baseline, 3, 6 and 12 months of patients initiating / changing to / adding treatment with olanzapine, risperidone, quetiapine, amisulpride, clozapine, oral typicals (PO Typical), depot typicals
• Treatment cohorts were defined based on the drug newly initiated or added at baseline documentation
• Prospective non-interventional/observational study over 3 years, all patient care is at the discretion of the participating psychiatrists
• 10,972 patients enrolled across 10 countries, 3.499 in Germany, where the SWN was used
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1. Lambert et al. in preparation
62
71,6
77,280
81,883,4 84,4
62,5
7072,3
73,9 75 74,5 74
60
70
80
90
Baseline 3months
6months
12months
24months
30months
36months
Olanzapine
Risperidone
Quetiapine
Amisulpride
Clozapine
Typicals oral
Typicals depot
Atypicals total
Typicals total
Effects of atypicals vs. typicals on SW• 36-month results of the SOHO study (N=2960)1
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Early change of subjective wellbeing as predictor of compliance 1
1. Karow et al. J Clin Psychiatry 2006.
• 1669 patients with schizophrenia assessed for compliance over 12 months
SWN-K: Subjective Well-being under Neuroleptics; CGI-S: Clinical Global Impressions-Severity; EPS: Extrapyramidal side effects
16
13
8
0
5
10
15
20
Improvedcompliance
(n=225)
Unchangedcompliance
(n=1366)
Worsenedcompliance
(78)
Median change of SWN-K total score
0,83
0,77
0,81
1,37
0 0,5 1 1,5
Change of EPS
CGI positive symptomchange
CGI positive symptomscore at baseline
SWN total scoreimprovement ( 20 points)
Odds ratios Odds ratios for compliancefor compliance
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1. Lambert et al. J Psychiatr Res, in preparation.
• 631 patients with schizophrenia, 4 & 12 weeks follow-up
• PANSS pos & neg, CGI-S, SOFAS, and SWN-K were transformed into measures ranging from 0-100 and added to a combined outcome variable (=OUT)
Measure Beta T p
PANSS T0 ,14 3,28 ,001
CGI T0 ,13 3,11 ,002
SOFAS T0 ,22 5,12 ,000
SWN-K T0 ,06 1,45 ,15
Linear regression of baseline scores with OUT at
3 months
Measure Beta T pChange TO to T4 (overall reduction)PANSS ,09 2,21 ,027CGI ,19 4,99 ,000SOFAS ,15 4,08 ,000SWN ,44 10,69 ,000Change TO to T4 (response category)PANSS (Change > 20%) ,085 2,532 ,012CGI (Change > 2) ,176 4,694 ,000SOFAS (Change > 20%) ,195 5,275 ,000SWN-K (Change > 20%) ,409 11,807 ,000Linear regression of change scores and response
categories scores with OUT at 3 months
Early change of subjective wellbeing as predictor of response and outcome 1
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1. Lambert et al. J Clin Psychiatry, 2006.
Early change of subjective wellbeing as predictor of outcome (recovery) 1
• Single remission rates (≥ 2 years), composite recovery rate (≥ 2 years), and predictors of composite recovery in 586 drug-naive patients with schizophrenia
Symptomatic remission: Positive, negative, and cognitive symptoms (CGI-S ≤ 3); Functional remission: Employment, independent living, social contacts; Quality of Life: SWN-K total score ≥ 80 points; Composite recovery: Concurrent achievement of all three outcome domains for ≥ 2 years.
49
35
40
16
0
10
20
30
40
50
Symptomaticremission (³
2 years)
Functionalremission (³
2 years)
AdequateQuality of Life
(³ 2 years)
Compositerecovery (³ 2
years)
0,14
3
3,18
3,91
4,94
0 1 2 3 4 5
Increasing age
Early symptomaticremission (at 3 months)
Early functional remission(at 3 months)
Independent living atbaseline
Early SWN remission (at 3months)
Odds ratios Odds ratios for composite for composite recoveryrecovery
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Definition of remission in the SOHO study in Germany 1
2960 patients with schizophrenia for more than 2 years 1
1. Lambert et al. J Clin Psychiatry, 2006.
Remission was defined as at least 6 months of :
Symptomatic remission: CGI-Severity total score ≤ 3; CGI-Severity positive and cognitive subscore ≤ 3; CGI-Severity negative subscore ≤ 4
Functional remission: Work: full or part time, student or housekeeping Ability to lead an independent life (lives alone, with partner or friends)
Remission of subjective quality of life: Subjective well-being (SWN-K) ≥ 80 points (range 20-120 points) Shows good subjective wellbeing
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Predictors for Remission at 24 Months1
• Predictors for complete remission OR p-Value– Young age– Functioning at baseline– Early symptomatic remission 2.36 <.001– Early functional remission 2.92 <.001– Early adequate subjective well-being 2.47 <.001
• Consistent predictors across all remission criteria– Receiving first-time antipsychotic treatment 2.3 - 2.7 <.001– Initial treatment with atypicals 2.4 - 2.8 <.001
1. Lambert et al. J Clin Psychiatry 2006; 67: 1690-1697.
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Prediction of 2-year remission
• Complete Remission was mainly predicted by early (3 months) symptomatic remission, functional remission and remission of subjective well-being (OR 2.5-2.8).
• First-line treatment with atypical antipsychotics increased the likelihood of Complete Remission compared to conventional antipsychotics (OR 2.6).
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Early detection of incomplete remission with the SWN-K 1
1. Lambert et al. Acta Psychiatrica Scand, 2006.
40
50
60
70
80
90
SWN total scoreat baseline
SWN total scoreat week 4
SWN total scoreat week 12
SW responder (n=507)
SW non-responder (n=220)
4
4,5
5
5,5
6
6,5
7
CGI-S score atbaseline
CGI-S score atweek 4
CGI-S score atweek 12
40
45
50
55
60
65
70
SOFAS scoreat baseline
SOFAS scoreat week 4
SOFAS scoreat week 12
8
9,5
11
12,5
14
15,5
17
PANSSpositive score
at baseline
PANSSpositive at
week 4
PANSSpositive at
week 12
13
15
17
19
21
PANSSnegative score
at baseline
PANSSnegative at
week 4
PANSSnegative at
week 12
727 patients with SWN-K ≤ 60 at admission, treated with amisulpride for 12 weeks
CGI-S SOFAS
PANSS pos
PANSS negSWN-K response = increase ≥ 20%
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Subjective Experience and Striatal Dopamine D2 Receptor Occupancy
in Patients with Schizophrenia Stabilised by Olanzapine or Risperidone
• After a stable dose of olanzapine (N=15, 14.7 ± 5.8 mg) or risperidone (N=7, 4.1±0.9 mg), subjective well-being was assessed with the SWN, dopamine D2 receptors’ occupancy with 123I-IBZM-SPECT.
• In addition, PANSS, MADRS, and EPMS were assessed• Dopamine D2 receptor occupancy was related to subjective
experience (p=-.03/-.05), depression (p=.02), and negative symptoms (p=.02), but not to extrapyramidal symptoms.
de Haan L, et al. Am J Psychiatry. 2000;157(6):1019-1020.
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Relationships between SWN and Dopamin D2 Receptor Occupancy: Striatal r =-.66, p=.01, temporal, r =-.76, p=.003 (Mizrahi et al., 2007)
12 patients received 2,5 or 15 mg olanzapine vs. 1 or 4 mg risperidone
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Conclusion
If antipsychotic treatment does not result in marked improvement of psychopathology and particularly of subjective quality of life within 2-4 weeks (depends on number of previous antipsychotic trials), later improvement and remission is rather doubtful and switching the antipsychotic should seriously be considered.