1 EFFECTIVENESS OF ANTIPSYCHOTIC DRUGS IN FIRST-EPISODE SCHIZOPHRENIA AND SCHIZOPHRENIFORM DISORDER. René S. Kahn*, W. Wolfgang Fleischhacker*, Han Boter, Michael Davidson, Diederick E. Grobbee, Yvonne Vergouwe, Ireneus P.M. Keet, Mihai D. Gheorghe, Janusz K. Rybakowski, Silvana Galderisi, Jan Libiger, Martina Hummer, Sonia Dollfus, Juan J. López-Ibor, Luchevar G. Hranov, Wolfgang Gaebel, Jozef Peuskens, Nils Lindefors and Anita Riecher- Rössler for the EUFEST study group *These authors contributed equally to the study René S. Kahn, MD, PhD; Han Boter, PhD. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, the Netherlands W. Wolfgang Fleischhacker, MD, PhD; Martina Hummer, MD, PhD. Department of Biological Psychiatry, Medical University Innsbruck, Innsbruck, Austria. Michael Davidson, MD, PhD. Sheba Medical Center, Tel Hashomer, Israel Diederick E. Grobbee, MD, PhD; Yvonne Vergouwe, PhD Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands Ireneus P.M. Keet, MD, PhD, GGZ Mentrum, Amsterdam Mihai D. Gheorghe, MD, PhD Department of Psychiatry, Central Military Hospital, Bucarest, Romania Janusz K. Rybakowski, MD, PhD Department of Adult Psychiatry, University of Medical Sciences, Poznan, Poland,
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1
EFFECTIVENESS OF ANTIPSYCHOTIC DRUGS IN FIRST-EPISODE
SCHIZOPHRENIA AND SCHIZOPHRENIFORM DISORDER.
René S. Kahn*, W. Wolfgang Fleischhacker*, Han Boter, Michael Davidson, Diederick E.
Grobbee, Yvonne Vergouwe, Ireneus P.M. Keet, Mihai D. Gheorghe, Janusz K. Rybakowski,
Silvana Galderisi, Jan Libiger, Martina Hummer, Sonia Dollfus, Juan J. López-Ibor,
Luchevar G. Hranov, Wolfgang Gaebel, Jozef Peuskens, Nils Lindefors and Anita Riecher-
Rössler for the EUFEST study group
*These authors contributed equally to the study
René S. Kahn, MD, PhD; Han Boter, PhD. Department of Psychiatry, Rudolf Magnus
Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, the Netherlands
W. Wolfgang Fleischhacker, MD, PhD; Martina Hummer, MD, PhD. Department of
Biological Psychiatry, Medical University Innsbruck, Innsbruck, Austria.
Michael Davidson, MD, PhD. Sheba Medical Center, Tel Hashomer, Israel
Diederick E. Grobbee, MD, PhD; Yvonne Vergouwe, PhD Julius Center for Health Sciences
and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
p=0.002). Also, as a group the SGAs showed a longer time to the LOR event compared to
haloperidol (HR 0.39; 95% CI 0.29-0.53; p<0.001; results not presented in a table or figure).
14
Secondary outcomes
Loss of Retention
The SGAs did not differ from each other on time to LOR for any cause, except that patients
on olanzapine stayed longer on their assigned study drug than those on quetiapine (HR 0.50;
p<0.01).
Comparing time to LOR because of lack of efficacy (figure 2b and table 2) showed that
patients on haloperidol dropped out sooner than those on olanzapine (HR 0.17; p<0.001),
amisulpride (HR 0.22; p<0.001), and ziprasidone (HR 0.51; p=0.04) but not quetiapine
(p=0.13). Also, analyzing the time to treatment discontinuation between the SGAs revealed
that patients stayed longer on olanzapine (HR 0.26; p<0.001) and on amisulpride (HR 0.36;
p<0.01) than on quetiapine.
The time to a LOR event because of side effects (figure 2c and table 2) in the haloperidol
group was shorter than in the quetiapine group (HR 0.12; p<0.01) and the olanzapine group
(HR 0.23; p<0.01).
Finally, table 2 and figure 2d show that patients on haloperidol did not differ in time to the
LOR event due to antipsychotic non-adherence.
15
PANSS
The decrease of the total PANSS score was statistically significant in all treatment groups
(p<0.001; Figure 3). After circa six months the change in PANSS total scores compared with
baseline leveled off. Compared with haloperidol, the other four medications showed a lower
PANSS score after 12 months of treatment (56.0, 54.2, 53.8, 51.4, and 53.7 for haloperidol,
olanzapine, quetiapine, amisulpride and ziprasidone, respectively).
CGI
All treatment groups showed statistically significant reductions on the CGI compared to
baseline (p<0.001).
Safety and tolerability
Table 3 shows the outcomes of safety and tolerability. Two patients died during the follow up
(suicide). About 20% of the patients were admitted to hospital after randomization, but the
proportions did not differ significantly for the five groups.
Differences were found on the prevalence of neurological side effects: higher proportions of
patients on haloperidol or ziprasidone experienced akathisia as compared with patients on the
other antipsychotics (26-28% vs. 10-16%; p<0.01) and more patients on haloperidol showed
signs of Parkinsonism than patients assigned to any of the SGAs (34% vs. 6-17%; p<0.001).
Though the proportions of patients being overweight were high (34-54%) and did not differ
between treatment arms, weigh gain (>7% from baseline) and weight change (overall and per
month) were highest for patients on olanzapine and lowest for patients on haloperidol or
ziprasidone (e.g. 86% on olanzapine showed >7% weight gain vs. 39-53% for the other drugs
16
[p<0.001]; +1.7 kg/month on olanzapine vs. +0.8-1.0 kg/month for the other drugs
[p<0.001]).
We found no differences between treatment arms on fasting glucose, cholesterol, high- and
low-density lipoprotein, fasting insulin, and triglycerides, except for 89% of patients on
amisulpride having hyperprolactinemia, versus 41-50% in patients on other antipsychotics
(p<0.001), and amisulpride showing greater increases in prolactin values per month (p<0.001;
data not shown in table).
High proportions of patients used concomitant medication with more patients on haloperidol
or olanzapine taking antidepressants (15-18% vs. 6-7%; p<0.01). Additionally, higher
proportions of patients on haloperidol or amisulpride received anticholinergics (28-36% vs.
17-21%; p<0.01) than the other patients.
Post-hoc analyses
Comparing males and females revealed no differences in time to the LOR event.
Additionally, analyses excluding patients who did not take the assigned antipsychotic or who
- after all - did not meet the inclusion criteria did not change the results.
17
DISCUSSION
The main finding is that effectiveness, expressed as continued use of the assigned study
medication, of SGAs was significantly greater than that of a low dose of haloperidol in first-
episode schizophrenia and schizophreniform patients. This superior effectiveness could be
attributed to both the improved therapeutic efficacy and better tolerability of olanzapine;
larger therapeutic efficacy of amisulpride and ziprasidone; and superior tolerability of
quetiapine as compared to haloperidol. The overall discontinuation rate varied widely, from
61% for haloperidol to 28% for olanzapine. Patients who completed the entire study on their
allotted medication did equally well symptomatically at the end of the 12 months follow-up.
About 20% of all patients were (re)admitted to hospital during the follow-up period, but this
percentage was not different for the study drugs. Side-effects varied: haloperidol showed
more Parkinsonism than the SGAs, while weight gain was most pronounced in patients on
olanzapine, and lowest on those on haloperidol and ziprasidone. A higher proportion of
patients on haloperidol and amisulpride was prescribed anticholinergic medication.
This is the first study comparing long-term effectiveness of various SGAs with that of a first-
generation antipsychotic in a large group of unselected first-episode schizophrenia patients.
Indeed, 40% of the patients at baseline were diagnosed as schizophreniform, and a third had
never been exposed to prior antipsychotic treatment. Exceptionally for most antipsychotic
treatment trials, 40% of the sample was female, reflecting as it does the male to female
distribution of this illness in the population.32 Finally, consistent with the unrestrictive
inclusion criteria, a quarter of the patients exhibited suicidal thoughts, 9% suffered from co-
morbid depression and almost one in five met criteria for current substance dependence or
abuse. Therefore, it is difficult to compare its results to those of earlier studies.
18
One large study (n=555) compared the effects of risperidone (modal dose 3.3 mg), a SGA, to
a low dose of haloperidol (2.9 mg) in a double blind randomized design. Primary outcome
was number of relapses, but discontinuation rates were also reported, and were not
significantly different for the two groups, i.e. around 36.5% for haloperidol, and 42% for the
risperidone group. However, patients with drug (ab)use and concomitant medications were
excluded and prior antipsychotic treatment was allowed for up to 12 weeks. Nevertheless
these results may suggest that under double-blind conditions dropout rates on haloperidol
may be lower than in our study. Similar to our results, akathisia and parkinsonism were more
pronounced on haloperidol than on the SGAs.15
In another double-blind study in 263 first-episode schizophrenia patients haloperidol (modal
dose 4.8 mg) was compared to olanzapine (10.2 mg) over a two year follow-up period. This
sample was predominantly male (82%) and prior treatment was maximized at 16 weeks. Drug
abuse was excluded. In this study, estimated discontinuation rates at one year (data
extrapolated) were considerably higher than in our study: approximately 75% for the
haloperidol group and around 65% for olanzapine, with a significantly larger group
continuing treatment on olanzapine than on haloperidol at two years.33
Low completion rates of around 30% were also found in a one-year study comparing
effectiveness, defined as completion rates on the assigned drug, between three SGAs
(olanzapine, quetiapine and risperidone, n=400) in patients in the early course of
schizophrenia. In contrast to our findings, discontinuation rates did not differ among the
compounds tested.34 Whether the large difference in discontinuation rates between studies can
solely be explained by the difference in open versus double blind design remains open to
debate.
19
In chronic schizophrenia, effectiveness of SGAs has been compared to that of the low
potency first-generation antipsychotic, perphenazine. In that study, 1493 chronic
schizophrenia patients were randomized to olanzapine, quetiapine, risperidone, ziprasidone
and perphenazine.8 Similar to the results in our study, olanzapine was found superior in
effectiveness as compared to quetiapine (and versus risperidone, which was not tested in this
study). Also consistent with our results, when lack of efficacy was the reason for
discontinuation, time to discontinuation was longer in the olanzapine group than in the
patients on perphenazine and quetiapine but, as we found, similar to that of ziprasidone. In
contrast to that study, overall discontinuation rates in our study were considerably lower,
even when groups are compared with the lowest discontinuation rates in both studies: in our
study 28% of patients on olanzapine discontinued treatment within a year versus 64% in the
other study. It could be argued that this difference may be due to the patient groups studied,
since first-episode patients respond better and faster than chronic patients. Also, patients in
our study were unlikely to have failed prior treatments (since their prior exposure in the year
prior to enrolment was maximized at two weeks), whereas in the study in chronic patients this
may have been a reason for inclusion.
It could be argued that results of our study are biased by the open nature of the design.
Physicians could have been motivated to discontinue patients on haloperidol earlier than
when the study would have been double-blind. However, such a bias contrasts with the high
rates of first-generation antipsychotics still being prescribed in Europe. The discontinuation
on the patients on haloperidol and quetiapine due to lack of efficacy occurred mostly within
the first two months of the study. Whether this is attributable to investigator bias or to a lack
of efficacy early in the treatment, or dosing issues, remains unclear.
20
Interestingly, even though haloperidol was given in a low dose it induced Parkinsonism more
than the SGAs; also more patients were prescribed anticholinergic medication while on
haloperidol than patients on olanzapine and quetiapine. Indeed, the side-effects observed in
this study are generally consistent with those published in other studies and meta-analyses
with weight gain most pronounced in patients on olanzapine and least in those on haloperidol
and ziprasidone. Interestingly, dystonia was hardly observed, even in the haloperidol group,
suggesting that the low dose used in this study is well-tolerated in this regard.
In conclusion, this study found that one year discontinuation rates in an unselected sample of
first-episode schizophrenia patients varied widely (between 28 and 61%) and were
significantly larger on a low dose of haloperidol than on several of the SGAs. This effect
could be explained by improved efficacy and tolerability of olanzapine, increased efficacy of
amisulpride and ziprasidone and better tolerability of quetiapine. If patients continued their
medication they did equally well on all drugs. Encouragingly, in contrast to most earlier
studies in first-episode and chronic schizophrenia, continuation rates on several of the SGAs
in this pragmatic trial were high (around 70%) suggesting that effective and clinically
meaningful long-term antipsychotic treatment is achievable in the first stages of
schizophrenia.
21
TABLES AND FIGURES
Figure 1 Trial profile Randomisation to Ziprasidone was blocked between December 2003 and October 2004. Patients who dropped out within 14 days have not been at risk for a Loss of Retention event.
641 eligible
103 assigned to haloperidol 1 did not take drug
104 assigned to amisulpride 0 did not take drug
105 assigned to olanzapine 1 did not take drug
82 assigned to ziprasidone 0 did not take drug
498 randomized
143 not randomized 121 declined 22 other reasons
103 included in prim.analyses
104 included in prim.analyses
105 included in prim.analyses
104 included in prim.analyses
82 included in prim.analyses
40 continued study drug 63 Loss Of Retention 34 lack of efficacy 13 side effects 15 non- compliance 1 other reason
72 continued study drug 32 Loss Of Retention 11 lack of efficacy 12 side effects 9 non- compliance 0 other reason
52 continued study drug 30 Loss Of Retention 17 lack of efficacy 7 side effects 6 non- compliance 0 other reason
54 continued study drug 50 Loss Of Retention 36 lack of efficacy 2 side effects 11 non- compliance 1 other reason
76 continued study drug 29 Loss Of Retention 10 lack of efficacy 5 side effects 13 non- compliance 1 other reason
67 completed follow up 36 dropped out (10 within 2 weeks) 33 withdrew consent/no show 3 other reason
71 completed follow up 33 dropped out (5 within 2 weeks) 33 withdrew consent/no show 0 other reason
82 completed follow up 23 dropped out (3 within 2 weeks) 21 withdrew consent/no show 2 other reason
70 completed follow up 34 dropped out (4 within 2 weeks) 31 withdrew consent/no show 3 other reason
53 completed follow up 29 dropped out (5 within 2 weeks) 25 withdrew consent/no show 4 other reason
1047 patients screened
406 did not meet inclusion criteria
Mean 4.5 (4.7 sd) months follow up for sec. analyses
Mean 7.0 (4.9 sd) months follow up for sec. analyses
Mean 8.4 (4.6 sd) months follow up for sec. analyses
Mean 6.3 (5.0 sd) months follow up for sec. analyses
Mean 6.0 (5.0 sd) months follow up for sec. analyses
* Denominators fluctuate due to differences in response. Because of rounding, proportions may not sum up to 100. 1 Years in school from 6 years of age onwards. 2 According to the Mini International Neuropsychiatric Interview Plus (MINI+); ‘Depression’ includes ‘major depressive episode (with or without melancholic features)’ and ‘dysthemia’. 3 Positive and Negative Syndrome Scale (PANSS); theoretical scores range from 30-210 (total scale), 7-49 (positive scale), 7-49 (negative scale), 16-112 (general psychopathology scale); higher scores indicate more severe psychopathology. 4 Clinical Global Impression (CGI); theoretical scores range from 1-7; higher scores indicate greater severity of illness. 5 Global Assessment of Functioning (GAF); theoretical scores range from 1-100; higher scores indicate better functioning. 6 St Hans Rating Scale (SHRS). 7 Cases scored moderate/severe on selected items of the Udvalg for Kliniske Undersøgelser (UKU); for men: increased/decreased libido, orgastic dysfunction, gynaecomastia, or erectile/ejaculatory dysfunction (6 items); for women: increased/decreased libido, orgastic dysfunction, menorrhagia, amenorrhoea, galactorrhoea, or dry vagina (7 items). 8 Body Mass Index (kg/m2); Interquartile Range. 9 QTc prolongation: men >450 mseconds, women >470 mseconds
23
0,00 2,00 4,00 6,00 8,00 10,00 12,00
survival time (in months)
0,0
0,2
0,4
0,6
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1,0
Cu
m S
urv
ival
Randomised study medication
amisulpride
haloperidol
olanzapine
quetiapine
ziprasidone
Survival Functions
0,00 2,00 4,00 6,00 8,00 10,00 12,00
survival time (in months)
0,0
0,2
0,4
0,6
0,8
1,0
Cu
m S
urv
ival
Randomised study medication
amisulpride
haloperidol
olanzapine
quetiapine
ziprasidone
Survival Functions
Figure 2a Time to LOR-event for any reason Figure 2b Time to LOR-event for lack of efficacy
0,00 2,00 4,00 6,00 8,00 10,00 12,00
survival time (in months)
0,0
0,2
0,4
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1,0
Cu
m S
urv
ival
Randomised study medication
amisulpride
haloperidol
olanzapine
quetiapine
ziprasidone
Survival Functions
0,00 2,00 4,00 6,00 8,00 10,00 12,00
survival time (in months)
0,0
0,2
0,4
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1,0
Cu
m S
urv
ival
Randomised study medication
amisulpride
haloperidol
olanzapine
quetiapine
ziprasidone
Survival Functions
Figure 2c Time to LOR-event for side effects Figure 2d Time to LOR-event for non-adherence
24
Table 2 Loss Of Retention (LOR) according to allocated treatment1
Haloperidol (N=103)
Amisulpride (N=104)
Olanzapine (N=105)
Quetiapine (N=104)
Ziprasidone (N=82)
P value1
Mean dose before LOR-event (mg/d, SD) 2.9 (1.2) 448.5 (175.1) 12.5 (4.9) 501.3 (201.4) 114.2 (61.8) ≥ maximum dose before LOR-event 54/92 (59%) 25/96 (26%) 54/102 (53%) 36/99 (36%) 36/78 (46%) <0.001 LOR for any cause 63/103 (61%) 32/104 (31%) 29/105 (28%) 50/104 (48%) 30/82 (37%) Months to LOR – 25th percentile (95% CI)2 0.5 (0.5-0.9) 5.3 (3.0-12+) 6.4 (3.8-12+) 1.2 (7.0-2.0) 1.1 (0.8-8.5) Cox-model treatment comparisons3 Haloperidol Hazard Ratio (95% CI) 0.36 (.23-.55) 0.27 (.17-.42) 0.49 (.33-.73) 0.47 (.29-.76) <0.001 P value <0.001 <0.001 <0.001 0.002 Quetiapine Hazard Ratio (95% CI) 0.74 (.45-1.19) 0.50 (.33-.87) 0.95 (.57-1.59) P value 0.21 0.01 0.85 Amisulpride Hazard Ratio (95% CI) 0.72 (.43-1.22) 1.21 (.69-2.14) P value 0.23 0.51 Ziprasidone Hazard Ratio (95% CI) 0.65 (.34-1.25) P value 0.65 LOR for lack of efficacy 34/103 (33%) 11/104 (11%) 10/105 (10%) 36/104 (35%) 17/82 (21%) Cox-model treatment comparisons3 Haloperidol Hazard Ratio (95% CI) 0.22 (.11-.45) 0.17 (.08-.34) 0.68 (.41-1.12) 0.51 (.27-0.96) <0.001 P value <0.001 <0.001 0.13 0.04 Quetiapine Hazard Ratio (95% CI) 0.36 (.18-.76) 0.26 (.13-.55) 0.83 (.43-1.61) P value 0.01 <0.001 0.58 Ziprasidone Hazard Ratio (95% CI) 0.52 (.22-1.23) 0.39 (.15-.98) P value 0.14 0.05 Amisulpride Hazard Ratio (95% CI) 0.71 (.29-1.74) P value 0.45 LOR for side effects 13/103 (13%) 12/104 (12%) 5/105 (5%) 2/104 (2%) 7/82 (9%) Cox-model treatment comparisons3 Haloperidol Hazard Ratio (95% CI) 0.55 (.25-1.23) 0.23 (.08-.65) 0.12 (.03-.54) 0.45 (.16-1.27) 0.02 P value 0.14 0.01 0.01 0.13 Amisulpride Hazard Ratio (95% CI) 0.38 (.13-1.11) 0.21 (.05-.99) 0.90 (.30-2.66) P value 0.08 0.05 0.84 Ziprasidone Hazard Ratio (95% CI) 0.68 (.18-2.51) 0.26 (.05-1.49) P value 0.56 0.13 Olanzapine Hazard Ratio (95% CI) 0.35 (.06-2.00) P value 0.24 LOR for non-adherence 15/103 (15%) 9/104 (9%) 13/105 (12%) 11/104 (11%) 6/82 (7%) Cox-model treatment comparisons3 Haloperidol Hazard Ratio (95% CI) 0.52 (.22-1.24) 0.52 (.24-1.12) 0.40 (.17-.91) 0.46 (.16-1.31) 0.27 P value 0.14 0.10 0.03 0.14 Amisulpride Hazard Ratio (95% CI) 1.01 (.41-2.45) 0.84 (.32-2.18) 0.77 (.25-2.32) P value 0.99 0.72 0.64 Ziprasidone Hazard Ratio (95% CI) 1.32 (.45-3.91) 0.91 (.30-2.81) P value 0.61 0.87 Olanzapine Hazard Ratio (95% CI) 0.59 (.24-1.46) P value 0.25 LOR for other reason 1/103 (1%) - 1/105 (1%) 1/104 (1%) - 1 Standard Deviation (SD); Confidence Interval (CI). 2 Kaplan Meier; months at risk for the LOR event, excluding the first 14 days after randomization. For amisulpride and olanzapine no upper limit for the CI could be estimated because of low event rates. 3 Cox proportional-hazards regression models, adjusted for gender and country.
* Denominators fluctuate due to differences in response. To calculate p-values we did not yet adjust for gender and country. 1 Percentages are based on the number of patients with at least one follow-up assessment (SHRS and UKU: 1, 3, 6, 9, 12 months) - cases scored positive at at least one evaluation; UKU: cases scored moderate/severe on severity of sexual dysfunction. 2 Percentages and change scores are based on the data of patients with at least one post-baseline assessment (3, 6, 9, 12 months) - the maximum weight measured during follow-up was selected for the analyses. To convert weight to lb, multiply by 2.2. Body Mass Index (kg/m2); Interquartile Range. 3 QTc prolongation at 12 months: men >450 mseconds, women >470 mseconds.
27
APPENDIX
EUFEST (European First Episode Schizophrenia Trial) Study Group
Author contributions:
Financial disclosures:
Principal investigators (PI’s): RS Kahn and WW Fleischhacker.
Executive committee: RS Kahn, IPM Keet (trial coordinator until July 2004), H Boter (trial
coordinator since July 2004).
Management group: RS Kahn, WW Fleischhacker, H Boter, C Brugman, H Burger, DE
Grobbee, MC Hafkamp, IPM Keet, K Nijssen.
Steering Committee: RS Kahn, WW Fleischhacker, H Boter, IPM Keet, C Brugman, M
Davidson, S Dollfus, W Gaebel, S Galderisi, M Gheorghe, DE Grobbee, LG Hranov, M
Hummer, J Libiger, N Lindefors, JJ López-Ibor, K Nijssen, J Peuskens, A Riecher-Rössler, JK
Rybakowski, G Sedvall, M Wilmsdorff.
Office manager: PC Ywema.
Julius Centre Study Team: Datamanagement: N Boekema, H den Breeijen, M van den Haak, P
Huizinga, R Veen; Project managers: C Brugman, MC Hafkamp, KM Nijssen; Site monitoring: P
Berackova, A Blizanowska, C Brugman, MC Hafkamp, T Huizinga, H van Gelderen, M Gordat,
S Lorteau, G Makhanlal, H Moqadar.
Tangent Data Study Team (co-monitoring Romania): I Gonen, A Mihailescu, R Radici, C
Zus.
28
Participating investigators (CC: Country coordinator; SC: Site coordinator), centres, and
countries: Austria: M Hummer (CC and SC Innsbruck), M Muhlbacher (SC Salzburg), H
Widmoser (SC Hall in Tirol); Belgium: J Peuskens (CC), J Hulselmans (SC Antwerpen), C
Mertens (SC Gent), E Thijs (SC Kortenberg); Bulgaria: L G Hranov (CC and SC Sofia), S
Georgiev (SC Plovdiv), L Sayan (SC Bourgas); Czech Republic: J Libiger (CC and SC Hradec
Králové), E Češková (SC Brno), D Seifertová (SC Praha-Bohnice); France: S Dollfus (CC and
SC Caen I), G Allio (SC Rouen), B Chabot (SC Caen II), A Navarre Coulaud (SC Dieppe), P
Thomas (SC Lille); Germany: W Gaebel (CC), M Krebs (SC Berlin), R Lencer (SC Lübeck), K
Leopold (SC Berlin), T Wobrock (SC Homburg); Israel: M Davidson (CC), Y Abramovitch (SC
Beer-Yaakov), D Amital (SC Ness Ziona), A Caspi (SC Ramat Gan), A Kaplan (SC Beer Sheva),
I Treves (SC Shalvata), P Zipris (SC Pardessiya); Italy: S Galderisi (CC), M Casacchia (SC
L’Aquila), G Invernizzi (SC Milano II), A Mucci (SC Naples), E Novelli (SC Melzo), S Scarone
(SC Milano I), A Vita (SC Melzo); Netherlands: H Boter (CC and SC Utrecht), IPM Keet (CC
and SC Utrecht); Poland: J K Rybakowski (CC and SC Poznan), M Jarema (SC Warsaw), M
Masiak (SC Lublin), J Rabe-Jablonska (SC Lodz); Romania: M Gheorghe (CC), V Burtea (SC
Brasov), P Boisteanu (SC Iasi), C Friedman (SC Constanta), M Ienciu (SC Timisoara), A Ionescu
(SC Buzau), I Miclutia (SC Cluj), T Mihai (SC Tulcea), D Prelipceanu (SC Bucuresti II), T
Udistroiu (SC Craiova), D Vasile (SC Bucuresti I); Spain: J J López Ibor (CC), J L Carrasco (SC
Madrid); Sweden: N Lindefors (CC and SC Stockholm), G Sedvall (CC), F A Wiesel (SC
Uppsala); Switzerland: A Riecher-Rössler (CC), U Gschwandtner (SC Basel).
29
ACKNOWLEDGEMENTS
The three pharmaceutical industries that indirectly funded EUFEST are AstraZeneca, Pfizer, and
Sanofi whose representatives were permitted to comment on the manuscript, but the final
approval of content was exclusively retained by the authors. We thank all patients who
participated in the study and M Edlinger from the Julius Centre, who advised on the statistical
analyses.
30
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