1. Treatment of Schizophrenia: Remission, Functioning, Quality of Life and the Patients‘ Perspective
Dieter Naber
Department of Psychiatry and Psychotherapy
University Medical Center, Hamburg-Eppendorf
Hamburg, Germany

2. Disclosures: Dieter Naber
I have an interest in relation with one or more organisations that could be perceived as a possible conflict of interest in the context of this presentation. The relationships are summarised below:
Interest
Name of organisation
Paid positions, honoraria and advisory boards
AstraZeneca, Eli Lilly, Johnson & Johnson, Lundbeck, Otsuka, Servier, Takeda
Lectures
AstraZeneca, Eli Lilly, Johnson & Johnson, Lundbeck, Otsuka, Takeda

3. More ambitious treatment goals over the past 50 years
Reduction of (positive) psychotic symptoms
Long-term treatment
Negative symptoms
Neuropsychological deficits
Quality of life (QoL)/Subjective well-being (SW)
Early detection/delay of transition to psychosis
Remission/recovery (functional outcome)
1960
1980
1990
2000
2005

4. Interest in quality of life in schizophrenia
Number of publications from 1988 to 2014
Data obtained March 2015 using the Medline, PubMed search: schizophrenia AND “quality of life” OR “subjective well being” OR “subjective wellbeing”

5. Main reasons for neglecting QoL and subjective well-being (SW) in schizophrenia
Lack of agreement on definition, on essential components of QoL or SW and on rating scales1
Self-rated judgment of QoL or SW is often disqualified as unreliable1
Before availability of atypicals, only limited ways to consider patient’s complaints
QoL=quality of life; SW=subjective well-being
1. Lambert et al. Pharmacopsychiatry 2003;36(Suppl3):181–190

6. HRQoL and SW in schizophrenia: Overview on definitions 1,2,3,4,5
Health Related Quality of Life (HRQoL)1
Patient's self-reported bio-psychosocial perception of the disorder and of the health status including capacity to function physically, mentally and socially
Subjective well-being (SW) 2,3,4,5
All experiences in patients’ report, whether positive or negative, at the physical, emotional and cognitive levels under treatment with antipsychotic medication, causality (illness or drug effects) not questioned
1. Bullinger and Hasford. Control Clin Trials 1991;12(4 Suppl):91-105
2. Lambert M et al. Pharmacopsychiatry 2003; 36 Suppl 3:
3. Naber D. Int Clin Psychopharmacology 1995;10 (suppl 3):
4. De Haan et al. Psychopharmacology (Berl) 2002;162(1):24-8.
5. Singh MM. Dis Nerv Syst 1976;37:

7. Quantifying Clinical Relevance in the Treatment of Schizophrenia (Corell et al, 2011)
Increasing attention has been focused in recent years on the importance of patient-reported outcomes in informing research and clinical practice. Given the subjective nature of many aspects of psychopathology, it is particularly important in psychiatry to have this perspective. Yet, in schizophrenia there are concerns about insight, cognitive dysfunction, reality testing and communicative ability, which must be recognized in the acquisition and interpretation of such data.

8. Are schizophrenic patients able to self-rate?
The wide majority of schizophrenia patients, if no more acutely psychotic and without severe cognitive deficits (and not living under socially deprived conditions),
is able to reliably self-rate their quality of life /　　 subjective well-being
Naber et al, 1995; Voruganti et al, 1998; Khatri et al., 2001; de Haan et al., 2002; Voruganti et al., 2002; Liraud et al., 2004; Baumstarck et al., 2013; Hayhurst et al. 2014 12

9. A theory of social comparison processes (Festinger 1954)
Do we assess with subjective QoL the result of an adaptation process?
A theory of social comparison processes (Festinger 1954)
Persons compare themselves to others in order to evaluate their own situation.
Lateral and downward comparisons increase satisfaction, while upward comparisons decrease satisfaction
Hamburg 2008

10. Quality of Life and Duration of Hospitalization
N = 266, Patients suffering from chronic Schizophrenia
satisfied 6 5
Neither /nor 4
Beschreibe: Lebensbedingungen bei Jahr 30 (3-Bett-Zi, kein Eigentum, Tagesablauf + Freizeit = vorgegeben, .....)
Response shift: Karzinom. Brickman.
Wir unstersucht: zentralen, immer wieder monierten Befund. Gab einige theoretische, fast keine empirisch belegten Erklärungsversuche. Was passiert zwischen Jahr 10 und Jahr 30? 3
dissatisfied
< 10
10-20
20-30
30-40
> 40 J.
Duration of Hospitalization
Franz et al. 1998, 1999, 2001
Hamburg 2008

11. Quality of life measurement in schizophrenia
Numerous scales are available (generic versus disease-specific, self- versus expert-rated).
Disease-specific scales seem to be more sensitive than generic scales, self-rated scales are less time consuming and might be more useful than interview- based scales.
Quality of Life scale (Heinrichs et al., 1984) is most widely used. 21-item semi-structured interview to access QOL in relation to deficit symptoms and impaired functioning. Total score and 4 subscores, 45 minutes.

12. Subjective effects of antipsychotics
Many schizophrenic patients, particularly if treated with typical antipsychotics, report not only motor effects, but also emotional and affective restrictions – ‘I feel like a zombie’
Complaints are well known (pharmacogenic depression, akinetic depression, pharmacogenic anhedonia, neuroleptic- induced deficit syndrome), but barely investigated
Symptoms are often difficult to differentiate from negative symptoms of schizophrenia
Clinical experience: when patients were switched from typical antipsychotics to clozapine, they reported major improvement 6

13. Subjective well-being under neuroleptics (SWN)
The self-report of 20 items (10 positive, 10 negative, Likert scale) shows sufficient internal consistency (Cronbach‘s  .92) and good construct validity.
Most patients do not need more than 5-10 minutes to fill it out.
There are 5 subscores (emotional regulation, self-control, social integration, mental and physical functioning).
SWN improvement is rather relevant for adherence
(more than improvement of psychopathology) and also
for the chance to reach remission. 9

14. Self-report of well-being by schizophrenic patients
All statements refer to the past 7 days.
Total score, 5 subscores (e.g. physical functioning)
Not at all A little Somewhat Noticeable Much Very much
My body is a burden to me
I feel very comfortable with my body
I feel weak and exhausted
My body feels familiar 10

15. Improvements of Psychopathology and Subjective Well-Being under Atypical Neuroleptics are not strongly related
Relationship between individual changes of SWN and PANSS in 97 in-patients with schizophrenia 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. 18

16. Double-blind Comparison of Olanzapine and Clozapine
SWN Total Score
D SWN - D PANSS, r = -.45, p=.003
Naber et al., Acta Psychiat Scand 2005 23

17. Relationships among SWN and other outcome measures in schizophrenia (Chen et al. 2010)
Data of a randomised multi-centre study of chronic schizophrenia patients (n=628) were examined to investigate the relationship among several outcome measures, including PANSS, MADRS, Schizophrenia Objective Functioning Instrument (SOFI), Quality of Life Scale (QLS), and the SWN.
Two analytic approaches were used:
1) pairs analysis and 2) factor analysis.
Findings suggest some redundancy, particularly among the clinician-rated functional and quality of life measures. Only a small proportion of the variance in SWN was explained by the clinician-rated measures, suggesting that the SWN captures unique information.

18. Negative subjective well-being
Relationships between SW/QoL and expert-rated psychopathology
high
Negative Symptoms
Negative subjective well-being
Meltzer et al. (1990) r = -.3 bis -.4 (< 0.01)
Browne et al. (1990) r = -.69 (< 0.01)
Naber et al. (1994) r = -.3 bis -.4 (< 0.01)
Gervin et al. (1999) r = -.5 (< 0.001)
Bow-Thomas et al. (1999) r = -.45 (p<0.05)
Naber et al. (2001) r = -.4 (< 0.01)
Depressive Symptoms
Carpiniello et al. (1997) r = -.3 bis -.4 (< 0.01)
Dickerson et al. (1998) r = -.45 (< 0.01)
Franz et al. (1997) r = -.35 (<0.01)
Karow et al. (in press) = r = -.4 (<0.01)
Meltzer et al. (1990) r = -.2 bis -.3 (ns)
Browne et al. (1990) r = -.21 (ns)
Naber et al. (1994) r = .1 bis -.2 (ns)
Naber et al. (2001) r = -.1 (ns)
Positive Symptoms
less high
1. Lambert M et al., Pharmacopsychiatry 2003; 36 Suppl 3: 18

19. The Neuroleptic Strategy Study (NeSSy):
Randomized double-blind 6-months comparison of two first generation antipsychotics (Haloperidol, Flupentixole: conventional strategy) versus three second generation antipsychotics (Aripiprazole, Olanzapine, Quetiapine: „atypical“ strategy) Six substance pairs: Haloperidol/Aripiprazole Flupentixole/Aripiprazole Haloperidol/Olanzapine Flupentixole/Olanzapine Haloperidol/Quetiapine Flupentixole/Quetiapine Choice of both „the best“ typical or atypical,based on characterics of patient and substance Randomization: either the typical or the atypical antipsychotic

20. Primary endpoint: CGI-I

21. Primary endpoint: SF-36 Health Survey
The doctors did not see a difference,but the patients did!
Moreover, cognition improved under atypicals but worsened under typicals

22. Impact of Side Effects on SWN
Under treatment with typical AP: EPS are most disturbing
Under atypical AP: sexual SE, weight gain and sedation
1. Putzhammer et al. Pharmacopsychiatry 2005; 38: 132-8

23. Prediction of 5-year Remission by early Improvement of SWN , but not of PANSS 1
110 patients with first episode of schizophrenia
Continuous symptomatic remission between month 6 and month 60
p=.095
Change of SWN-K and PANSS
values in the first 6 weeks
p=.0004
SWN-K
PANSS
1. DeHaan et al. Pharmacopsychiatry, 2008

24. Early detection of incomplete remission with the SWN-K 1
727 patients with SWN-K ≤ 60 at admission, treated with amisulpride for 12 weeks
CGI-S
SOFAS
PANSS pos
SWN-K response = increase ≥ 20%
PANSS neg
1. Lambert et al. Acta Psychiatrica Scand, 2006.

25. Linear regression of baseline scores with OUT at 3 months
SWN-K as predictor of response 1
631 patients, 12 weeks follow-up PANSS pos & neg, CGI-S, SOFAS, and SWN-K were transformed into measures ranging from and combined to total outcome
Measure
Beta T p
Change TO to T4
PANSS
,09
2,21
,027
CGI
,19
4,99
,000
SOFAS
,15
4,08
SWN
,44
10,69
Linear regression of baseline scores with OUT at 3 months
1. Karow et al. J Clin Psychiatry, in preparation.

26. 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 antipsychotics strongly and negatively affect reward system(s) in a variety of models
Dopamine agonists (cocaine, crack) are abused, dopamine antagonists (antipsychotics) never!
Less inhibition of reward systems by some atypical antipsychotics (a.o. aripiprazole, olanzapine, and clozapine) 7

27. High D2 receptor blockade results in reduced subjective well-being: a PET study in schizophrenia
In 12 patients, treated with 1 mg RIS (n=2), 4 mg RIS (n=3), 2.5 mg OLA (n=3), or 15 mg OLA (n=4) striatal and extrastriatal dopamine D2 occupancy (50–91%, 4–95% respectively) as well as PANSS, SWN and motor symptoms were assessed
SWN and PANSS positive symptom scores were not significantly correlated (r=0.11, p=0.78) but SWN and Simpson-Angus Rating Scale scores were (r=- 0.71, p=0.047)
SWN and D2 occupancy were significantly correlated in the striatum (r=-0.66, p=0.01) as well as in the temporal lobe (r=-0.76, p=0.003)
OLZ=olanzapine; PANSS=Positive and Negative Syndrome Scale; PET=positron emission tomography; RIS=risperidone; SWN=Subjective Well-being Under Neuroleptic Treatment Scale
Mizrahi et al. Am J Psychiatry 2007;164(4):630–637

28. Relationships between SWN and Dopamin D2 Receptor Occupancy:
Striatal r =-.66, p=.01, temporal, r =-.76, p=.003 (Mizrahi et al., 2007) 28

29. How to Balance Subjective Quality of Life and Antipsychotic Efficacy?
What is the right antipsychotic dosage (dopaminergic blockade)?
PET studies indicate a „right“ dopaminergic blockade of %
If the blockade is too high: motor side effects and reward inhibition
If the blockade is too low: insufficient antipsychotic efficacy
For most antipsychotics, particularly for typicals, the range is small
A good balance (broad range) of QoL vs. efficacy was found for atypical antipsychotics such as aripiprazole, clozapine, olanzapine and quetiapine-
Clozapine! Low dopaminergic blockade ( 60%), but good antipsychotic efficacy

30. Non-Adherence is still the Major Problem in the Treatment of Schizophrenia
Reasons for Non-Adherence: a.o. lack of insight , side effects , cognitive problems, alcohol/substance abuse
Atypical/second generation antipsychotics have not markedly increased adherence
Most relevant factor to improve adherence: Quality of therapeutic alliance
How to increase adherence?
- Psychoeducation, involvement of caregivers / relatives
dopaminergic blockade as high as necessary - as low as possible
- ”peer patients”
- long-acting injection (LAI)

31. Attitude towards antipsychotic medication1
228 patients with schizophrenia assessed with:
Psychopathology (PANSS)
Antipsychotic side effects (LUNSERS)
Attitude towards antipsychotic medication (DAI)
Knowledge about antipsychotics
Insight (Birchwood Insight scale, PANSS item G12)
Therapeutic alliance with clinicians (CALPAS, PEESS)
Experience during first admission (McArthur Admission Experience Survey)
Key points:
Diese Folie zeigt die Ergebnisse einer Befragung von 450 Patienten in 12 europäischen Ländern
Diese Befragung wurde durch eine Markt- und Meinungsforschungsinstitut im Jahre 2000 durchgeführt.
Gründe für das Ablehnen der Medikation liesen sich bei 369 Patienten dokumentieren.
EPMS-Nebenwirkungen wie schweres Zittern und Krämpfe wurde von den Patienten mit ca 65 % als häufigste Nebenwirkung genannt.
Attitudes towards antipsychotics and subsequent compliance were best predicted by the quality of the therapeutic alliance and a positive experience during first admission
CALPAS=California Psychotherapy Alliance Scale; DAI=Drug Attitude Inventory; LUNSERS=Liverpool University Neuroleptic Side Effect Rating Scale; PANSS=Positive and Negative Syndrome Scale; PEESS=Perceived Expressed Emotion in Staff Scale
1. Day et al. Arch Gen Psychiatry 2005;62:717–724

32. What is special about LAI formulations of antipsychotics?
Immediate transparency of non-adherence and the chance of interventions (from calling the patient or his/her caregivers to home treatment)
Questions of carers and doctors “Have you taken your medication? ” is not necessary anymore
Improvement of the therapeutic alliance by regular contact with the therapeutic team (setting, what happens in addition to the injections?)
Surveys: Doctors: “My patients refuse the injection!”
　　　　　Patients: “My doctor never offered me this formulation!”
In the past: Negative image of LAIs (stigma, highly negatively selected patients, “control?”)　

33. Patients are willing to accept LAI antipsychotic when properly informed (despite their negative reputation!)
In a survey of psychiatrists:
Approximately 80% cited patient refusal as a primary reason for not prescribing LAI antipsychotics1
In a survey of patients with/without LAI antipsychotic experience:
79% of patients without LAI experience cited having never been informed about the option by their psychiatrist2
75% of psychiatrists felt that they informed the patient, but only 33% of patients felt informed2
In a survey of patients with ≥3 months of LAI antipsychotic experience:
Injectable antipsychotics were the preferred formulation3
70% of patients felt better supported in their illness by virtue of regular contact with the doctor or nurse who administered their injection3
350 Psychiatrists were asked to rate the influence of 16 statements on long-acting injectable antipsychotics on their decision against the prescription of a long-acting formulation in the treatment of a patient diagnosed with schizophrenia or schizoaffective disorder1
Factors negatively influencing a psychiatrist’s decision to prescribe LAI therapy included1:
Presumed sufficient adherence to oral antipsychotic treatment
Patient refusal
Lack of available LAI choices
In a survey of 82 patients with schizophrenia, 61 had no experience with long-acting injectable antipsychotics2
Only 21% of these patients had been informed of the option by their psychiatrist
Only 9% of these patients’ psychiatrists had recommended a change to long-acting injectable therapy
A survey of patients with schizophrenia who had at least 3 months’ experience using LAI antipsychotics (N=206) was conducted3
Among patients who had received at least 2 different formulations, injections were the favored formulation, being preferred by 47% of the patients
70% of patients felt better supported in their illness by virtue of regular contact with the doctor or nurse who administered their injection
The most frequently cited reasons for patients’ preferring injections were that the doses were spread out over time and there was no risk of forgetting a dose
Participants were selected from a community mental health setting in a Swedish urban area. Patients receiving depot treatment visited the setting regularly to have their injections. The selection strategy was that all patients who had ongoing depot treatment and had received it for at least 2 years were informed about the study by their key workers and asked if they wanted to participate4
Eleven patients voluntarily agreed to participate
Open-ended interviews were chosen for data collection to allow participants to freely talk about their experiences of depot treatment in relation to the aim of the study
Depot treatment made it possible for them to take control over situations, and, above all, it protected them from relapsing into eventual psychosis. It also made it possible for them to take part in “ordinary” life as people able to function and to improve personal relations. They hoped for a cure, but, even so, they expressed apprehension that their dependency on depot treatment would be lifelong
References
Heres S, Hamann J, Kissling W, Leucht S. Attitudes of psychiatrists toward antipsychotic depot medication. J Clin Psychiatry. 2006;67(12):
Jaeger M, Rossler W. Attitudes towards long-acting depot antipsychotics: a survey of patients, relatives and psychiatrists. Psychiatry Res. 2010;175(1-2):58-62.
Caroli F, Raymondet P, Izard I, Plas J, Gall B, Delgado A. Opinions of French patients with schizophrenia regarding injectable medication. Patient Prefer Adherence. 2011;5:
Svedberg B, Backenroth-Ohsako G, Lützén K. On the path to recovery: patients' experiences of treatment with long-acting injections of antipsychotic medication. Int J Ment Health Nurs. 2003;12(2):
LAI=long-acting injectable antipsychotic
1. Heres et al. J Clin Psychiatry 2006;67(12):1948–1953; 2. Jaeger & Rossler. Psychiatry Res 2010;175(1–2):58–62; 3. Caroli et al. Patient Prefer Adherence 2011;5:165–171

34. Efficacy of LAIs versus oral antipsychotics
Randomised controlled trials
No differences in study-defined relapse/all-cause discontinuation between LAIs and oral antipsychotics1
Mirror image studies
LAIs reduce risk of hospitalisation compared with oral antipsychotics2
Cohort study
LAI antipsychotics significantly improve treatment outcomes (risk of discontinuation or rehospitalisation) in patients with schizophrenia3
LAI=long-acting injectable
1. Kishimoto et al. Schizophr Bull 2014;40(1):192–213; 2. Kishimoto et al. J Clin Psychiatry 2013;74(10):957–965; 3. Tiihonen et al. Am J Psychiatry 2011;168(6):603–609

35. Real-world studies favour the use of LAI antipsychotics
As study design shifts toward real-world populations, LAI formulations display significant advantages
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
2.2
Adjusted risk ratio
RR=0.62
RR=0.89
RR=0.56
Favours oral
Relapsea
Hospitalisationa
All-cause discontinuationa
Overalla
Favours LAI
A PubMed literature review targeted English-language articles published since 2000 with efficacy information for LAI and oral antipsychotic treatment arms in schizophrenia, which also reported relapse, hospitalization, or all-cause discontinuation as end points
Within each study design grouping, meta-analysis with random effects was used to estimate the pooled RR and 95% confidence interval (CI) of all end points combined. In turn, average conversion factors between study designs were calculated as the ratios of pooled RR
There were a total of 13 relevant studies (5 RCTs, 4 prospective, 4 retrospective) that included information on 19 comparisons of LAI vs oral medications
Meta-analysis of adjusted end points resulted in RR (CI, P value) of 0.88 ( , P=0.416) for RCTs
In contrast, there was a significant advantage for LAI formulations in both prospective (RR=0.62 [ , P<0.001]) and retrospective (RR=0.56 [ , P<0.001]) studies, implying conversion factors of 1.41 and 1.57 between RCTs and prospective and retrospective designs, respectively
In tightly controlled RCTs, the benefits of LAI antipsychotics were not significantly superior to oral formulations. In contrast, as study design shifts toward prospective and retrospective studies in real-world clinical settings, LAI formulations display significant advantage
Reference
Kirson NY, Wong B, Yermakov S, et al. The impact of study design in comparative effectiveness research in schizophrenia. Presented at: 52nd Annual Meeting of New Research Approaches for Mental Health Interventions; May 29-June 1, 2012; Phoenix, AZ.
Randomised clinical studies
Prospective studies
Retrospective studies
RCT Real-world
aRisk ratio of LAI to oral antipsychotic; LAI=long-acting injectable antipsychotic; RCT=randomised controlled trial; RR=risk ratio
Kirson et al. J Clin Psychiatry 2013;74(6):568–575

36. Mirror-Image Studies [Hospitalizatio Risk]
LAI vs. OAP
Mirror-Image Studies [Hospitalizatio Risk]
16 studies, 4066 patients
Risk Ratio=0.43, 95%CI: , p<0.0001
NNT=3
Kishimoto et al. Journal of Clinical Psychiatry 2013

37. Cohort Studies [Hospitalization Risk]
LAIs vs. OAPs
Cohort Studies [Hospitalization Risk]
Kishimoto et al. Scz Bull in press

38. LAI antipsychotics approved for the treatment of schizophrenia in the EU – the more the better, to individualise treatment
Conventional LAIs
Second generation LAIs
Flupentixol
Aripiprazole
Fluphenazine
Olanzapine
Haloperidol
Paliperidone
Perphenazine
Risperidone
Pipotiazine
Zuclopenthixol
LAI antipsychotics are designed to deliver a gradual release of active antipsychotic from a single deep-tissue injection1
All agents listed in the table may also have additional indications, and local variations may apply
1. Weiden et al. Psychiatr Ann 2011;41(5):271–278

39. Effectiveness study – study design
Screening (<2 weeks)a
Period A
Oral conversion (3 weeks)
Period B
LAI treatment initiation
(5 weeks)c,d
Period C LAI treatment continuation, once-monthly
(20 weeks)
Safety follow-up
(4 weeks)
Patients were randomised 1:1
1 week oral aripiprazole (10–30 mg/day)
Injection 1 (Day 28): 400 mg aripiprazole-OM with 2 weeks oral aripiprazole (10–20 mg/day)
Patients were converted from a previous antipsychoticb
Injection 1: 150 mg as PAL [EU and Canada] or 234 mg as PP [US] (Day 21) Injection 2: 100 mg as PAL [EU and Canada] or 156 mg as PP [US] (Day 28)
50–150 mg/month as PAL [EU and Canada] or 78–234 mg/month as PP [US]
Baseline
Two visits (Weeks 2 & 3)
Two visits (Weeks 4 & 8)
Five monthly visits (starting Week 8)
Oral aripiprazole 5–30 mg/day (n=143)
Aripiprazole-OM 400 mg
Aripiprazole-OM 400/300 mg R
5 injections
Oral paliperidone 3–12 mg/day (n=143)
Paliperidone IM injection
Paliperidone IM injection
aPatients undergo screening for eligibility (7–14 days); patients stratified according to age >35 or ≤35 years with expected ratio of 1:2; IM=intramuscular; LAI=long-acting injectable; OM=once-monthly; PAL=paliperidone; PP=paliperidone palmitate; R=randomisation
Naber et. al. Schiz. Res. 2011

40. QUALIFY Study: effectiveness endpoints
Primary
Mean change from baseline to Week 28 in the Quality of Life Scale (QLS) total score
Secondary
Mean change from baseline to Week 28 in:
Investigator Assessment Questionnaire (IAQ) total score
Clinical Global Impression-Severity of Illness (CGI-S) score
Subjective Well-being under Neuroleptics-short version (SWN-S) score
Tolerability and Quality of Life (TooL) score
Other
Readiness for Work Questionnaire (WoRQ)
Arizona Sexual Experience Scale (ASEX)
Clinical Global Impression-Improvement (CGI-I) score at Week 28
Naber et. al. Schiz. Res. 2011

41. Quality of Life Scale (Heinrichs-Carpenter QLS)
Rater
Clinician
Domains
Interpersonal relations
Instrumental role
Intrapsychic foundationsa
Common objects and activities
Purpose
To examine a patient’s social experience
To assess a patient’s work functioning
To assess a patient’s sense of purpose and motivation
To evaluate a patient’s level of participation in the community
Items
1. Household
2. Friends
3. Acquaintances
4. Social activity
5. Social network
6. Social initiative
7. Withdrawal
8. Sociosexual
9. Occupational role
10. Work functioning
11. Work level
12. Work satisfaction
13. Sense of purpose
14. Motivation
15. Curiosity
16. Anhedonia
17. Aimless inactivity
20. Empathy
21. Emotional interaction
18. Commonplace objects
19. Commonplace activities
Scoring
Each item is rated on a 7-point scale, ranging from 0 (severe impairment) to 6 (normal or unimpaired functioning); higher scores indicate a better quality of life and functioning
aThe items within the ‘Intrapsychic foundations’ domain are considered to be the building blocks for interpersonal and instrumental role functioning
Heinrichs et al. Schizophr Bull 1984;10(3):388–398

42. QUALIFY Study: primary effectiveness variable – LS mean change from baseline in QLS total score (FAS) * * *
LS mean difference at Week 28: 4.67 (95% CI: 0.32, 9.02) p=0.036
Required for baseline values and data: Data on file, Table , Table
Treatment week
LS mean change from baseline at endpoint for QLS total score was significantly greater with aripiprazole-OM compared with paliperidone IM injection
*p<0.05 versus paliperidone IM injection
Based on MMRM, FAS; mean baseline QLS score (FAS): aripiprazole-OM (n=136) 66.1, paliperidone IM injection (n=132) 62.5; FAS=full analysis set; IM=intramuscular; LS=least squares; MMRM=mixed-model repeated measures; OM=once-monthly; QLS=Quality of Life Scale; SE=standard error
Naber et. al. Schiz. Res. 2011

43. QLS scores by age groups
Significant improvements for aripiprazole-OM vs paliperidone-IM on QLS total scores in patients ≤35 years (FAS) * *
*p<0.05 vs paliperidone-IM patients ≤35 years; LSM changes from baseline are based on MMRM; in treated patients ≤35 years, baseline mean (±SD) QLS total scores were 67.5±21.6 for aripiprazole-OM and 64.1±24.6 for paliperidone-IM; in patients >35 years: 65.7±21.3 for aripiprazole-OM and 61.9±20.1 for paliperidone-IM; IM=intramuscular; LSM=least squares mean; MMRM=mixed-model repeated measures; OM=once-monthly; QLS=Heinrichs–Carpenter Quality of Life Scale; SE=standard error
Naber et. al. Schiz. Res. 2011

44. Effect of aripiprazole once-monthly on quality of life may be more pronounced in early schizophrenia
≤35 years
>35 years * * *
*p<0.05 vs PP; mixed model for repeated measures, full analysis set; mean baseline QLS domain scores for AOM 400 mg and PP, respectively: ≤35 years (AOM, n=41; PP, n=37): common objects and activities, 7.3 and 7.4; intrapsychic foundations, 23.7 and 23.1; interpersonal relations, 25.3 and 23.8; instrumental role, 11.0 and >35 years (AOM, n=95; PP, n=95): common objects and activities, 7.7 and 7.5; intrapsychic foundations, 23.5 and 22.6; interpersonal relations, 23.4 and 22.7; instrumental role, 10.8 and 9.6; AOM=aripiprazole once-monthly, LS=least squares, PP=paliperidone palmitate, QLS=Quality of Life Scale, SE=standard error
1. Naber et al. Poster presented at 11th Annual NEI Congress. 2015; Orlando, FL. Poster 160

45. CGI-S scores by age groups
Significant improvements for aripiprazole-OM vs paliperidone-IM on CGI-S scores in patients ≤35 years (FAS) * * * ** * * *
*p<0.05, **p<0.01 vs paliperidone-IM; LSM changes from baseline are based on MMRM; in treated patients ≤35 years: baseline CGI-S scores were 3.95±0.62 for aripiprazole-OM and 4.00±0.57 for paliperidone-IM; in patients >35 years: 4.01±0.67 for aripiprazole-OM and 3.96±0.68 for paliperidone-IM; CGI-S=Clinical Global Improvement – Severity; IM=intramuscular; LSM=least squares mean; MMRM=mixed-model repeated measures; OM=once-monthly; SE=standard error
Naber et. al. Schiz. Res. 2011

46. Other secondary endpoints – IAQ, SWN-S and TooL
Significant or numerical improvements for aripiprazole-OM vs paliperidone-IM treatment on IAQ, SWN-S, and TooL total scores (FAS) *
*p<0.05 vs paliperidone-IM; LSM changes from baseline are based on MMRM; IAQ=Investigator’s Assessment Questionnaire; IM=intramuscular; LSM=least squares mean; MMRM=mixed-model repeated measures; OM=once-monthly; SE=standard error; SWN-S=Subjective Well-Being under Neuroleptic Treatment – Short version; TooL=Tolerability and quality of life questionnaire
Naber et al. Poster at ASCP; Miami, Florida, June 22–25, 2015

47. Sexual dysfunction-change from baseline to week 28 AOM vs PP- Patients 18-35 years%
* p =0,0036
Potkin SG Reduced sexual dysfunction with aripiprazole once-monthly versus paliperidone palmitate: results from QUALIFY Int Clin Psychpharmacol Mar 1. doi: /YIC

48. Other secondary endpoints – WoRQ
Significant improvements for aripiprazole-OM vs paliperidone-IM on WoRQ total and numbers of patients shifting in work readiness status from baseline to Week 28 (FAS)
Shift in status on ‘Readiness for work’ (WoRQ Item 8)
Aripiprazole-OM (n=110)
Paliperidone-IM (n=98)
Baseline:
Yes No
Week 28
29 (26.4%)
20 (20.4%)
12 (12.2%)
7 (6.4%)
45 (40.9%)
9 (9.2%)
57 (58.2%) **
The odds at Week 28 of being rated ready for work were higher for aripiprazole-OM vs paliperidone-IM (adjusted odds ratio: 2.67, 95% CI: 1.39, 5.14; p=0.003)
**p<0.01 vs paliperidone-IM; LSM change from baseline based on MMRM; IM=intramuscular; LSM=least squares mean; MMRM=mixed-model repeated measures; OM=once-monthly; SE=standard error; WoRQ=Readiness to work questionnaire
Naber et al. Poster at ASCP; Miami, Florida, June 22–25, 2015

49. Correlations between Outcomes
QLSb
IAQ
CGI-I
WoRQ
TooL
-0,431
0,529
-0,365
0,226
0,387
-0,558
-0,362
0,247
0,345
0,037
SWN
0,343
-0,281
-0,316
-0,132
-0,616

50. Remission and Recovery: New Hopes- Realistic Aims in the Treatment of Schizophrenia
Providing hope : a difficult balance !
Too much optimism might lead to non-compliance and unrealistic expectations,
Too much scepticism might lead to refusal of treatment and despair
Regarding necessity of antipsychotic long-term treatment, many patients, families and doctors hope that in first episode patients, psychosis is „only drug-induced“

51. Remission: Definition and Relationships
Symptomatic remission as defined by Andreasen et al. (2005):
Only mild degree of severity in 8 PANSS items for at least 6 months
Functional remission?
(Cognition, ability to work, independent living)
Subjective remission?
(Quality of life, self-reported)

52. How can we bridge these differences?
Correlation of assessments of remission by patients, relatives and psychiatrists with clinical scales (n=131)
Most important outcome for remission
Patients: SWN-K
Relatives: SWN-K, PANSS
Psychiatrists: PANSS, FROGS
Concordance of estimates of remission:
Remission assessed by patients (%)
Remission assessed by psychiatrist (%) 26 61 39 18 20 24
All views correlate to some extent with clinical scales, but relative importance differs between stakeholder groups
How can we bridge these differences? 32
Remission assessed by relative (%)
PANSS, Positive and Negative Syndrome Scale; FROGS, Functional Recovery Scale in Schizophrenia; SWN-K, Subjective Well-being under Neuroleptics scale
Reproduced with permission
Karow et al. Eur Psychiatry 2011 52

53. The relationship between symptomatic and functional or subjective remission is weak
In 77 first-episode patients, 36% reached symptomatic and 25% functional remission. No significant relationship between both domains (Ventura et al., 2011)
Similar data in 177 patients, of whom 70 reached symptomatic remission ( Oorschot et al., 2012)
In a review of 21 articles, relationships between symptomatic remission, cognition, functioning and quality of life were investigated.
Only 30-38% of symptomatically remitted patients had adequate functioning and only % satisfying quality of life. In 2 of 3 trials, no difference in cognition between symptomatically remitted and non- remitted patients ( Lambert et al, 2010).

54. Important questions to the patients
What is currently your biggest problem?
What is your most relevant treatment goal?
What do you enjoy?
How would you describe your relationship with your
family/relatives/partner?
What about treatment with a LAI?

55. Conclusions
Evaluating the effects of treatment, the assessment should not only include expert-rated psychopathology, but also self-rated quality of life
Both domains are not strongly related
Compared to psychopathology, subjective quality of life is more closely related to adherence
LAI antipsychotics are a valuable treatment option for patients with schizophrenia (not only after 2-3 relapses, but already for first episode patients)
Remission and even recovery should be treatment goals