Without early (subjective) improvement by antipsychotic treatment, only low chance for remission Dieter Naber Department of Psychiatry University of Hamburg

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 pharmacologically rather different atypical antipsychotics available, is this recommendation still valid?

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.

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.

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 *-.15 Negative Syndrome -.34* * Cognitive Syndrome Positive Syndrome *-.09 Depression-.30*-.38*-.67* Correlation Coefficient *p<.01

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.

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 ?

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 (Cronbachs α.92), good construct validity and does not require more than 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.

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

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 days r=-0.29, p<0.006 Naber D, et al. Schizophr Res. 2001;50(1-2):79-88.

Double-blind Comparison of Olanzapine and Clozapine SWN Total Score SWN - PANSS, r = -.45, p=.003 Naber et al., Acta Psychiat Scand 2005

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, in Germany, where the SWN was used

1. Lambert et al. in preparation Effects of atypicals vs. typicals on SW 36-month results of the SOHO study (N=2960) 1

Early change of subjective wellbeing as predictor of compliance 1 1. Karow et al. J Clin Psychiatry 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 Median change of SWN-K total score Odds ratios for compliance

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 and added to a combined outcome variable (=OUT) MeasureBetaTp PANSS T0,143,28,001 CGI T0,133,11,002 SOFAS T0,225,12,000 SWN-K T0,061,45,15 Linear regression of baseline scores with OUT at 3 months MeasureBetaTp Change TO to T4 (overall reduction) PANSS,092,21,027 CGI,194,99,000 SOFAS,154,08,000 SWN,4410,69,000 Change TO to T4 (response category) PANSS (Change > 20%),0852,532,012 CGI (Change > 2),1764,694,000 SOFAS (Change > 20%),1955,275,000 SWN-K (Change > 20%),40911,807,000 Linear 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

1. Lambert et al. J Clin Psychiatry, 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. Odds ratios for composite recovery

Definition of remission in the SOHO study in Germany patients with schizophrenia for more than 2 years 1 1. Lambert et al. J Clin Psychiatry, 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 points) Shows good subjective wellbeing

Predictors for Remission at 24 Months 1 Predictors for complete remissionORp-Value –Young age –Functioning at baseline –Early symptomatic remission2.36<.001 –Early functional remission2.92<.001 –Early adequate subjective well-being2.47<.001 Consistent predictors across all remission criteria –Receiving first-time antipsychotic treatment <.001 –Initial treatment with atypicals < Lambert et al. J Clin Psychiatry 2006; 67:

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 ). First-line treatment with atypical antipsychotics increased the likelihood of Complete Remission compared to conventional antipsychotics (OR 2.6).

Early detection of incomplete remission with the SWN-K 1 1. Lambert et al. Acta Psychiatrica Scand, patients with SWN-K 60 at admission, treated with amisulpride for 12 weeks CGI-SSOFAS PANSS pos PANSS neg SWN-K response = increase 20%

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):

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

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.