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ORIGINAL ARTICLES
MAINTAINING SYMPTOMS CONTROL IN
SCHIZOPHRENIA: A NATURALISTIC
6 MONTHS OBSERVATION
ªerban Turliuc1, Beatrice Costea 2, on behalf of SECURE investigators+.
Abstract:
Background:
Schizophrenia is a serious psychiatric condition that has a
detrimental impact on patients functioning and quality of
life. Therefore effective control of schizophrenia symptoms
is essential in the long term management of patients with
this disease .Considering the lack of published data
observing local population in a naturalistic setting, this
non-interventional project aimed to analyze quetiapine XR
efficacy in relapse prevention in schizophrenia, observing
an unselected group of patients being already treated, as
part of routine practice.
Aim: This study focus on observing schizophrenia patients
in real life practice, in different clinical settings in order to
draw conclusions regarding long term symptoms
management and quality of life impact.
Method: The patients have been diagnosed with
schizophrenia and have been receiving treatment,
including quetiapine XR, before study observation started.
Study length was six months and during that interval
patients received medical assistance according to usual
practice.
Results: 578 patients (37% males and 63% females) have
been observed, most of them being diagnosed with
different types of schizophrenia but also with other
schizophrenia-related diseases, such as schizoaffective
disorder. Over the six months of observation a significant
improvement in symptoms has been noticed with an
average decrease in BPRS score (Brief Psychiatric
Rating Scale) score of 26.3 points (1).Quetiapine XR
average dose (SD- standard deviation) at study entry was
600 (+/- 148) mg/day with a minimum dose of 200 mg/day
and a maximum of 1000 mg/day.
Conclusions: Quetiapine XR is a valuable treatment both
in young patients at the first schizophrenia episode and for
those with a long disease history, as well. It provides longterm, high quality symptoms control after disease
stabilization and prevents efficiently relapses at an
average dose reaching 622 mg/day with SD 150mg/day.
Treatment satisfaction and overall sense of well being, as
perceived by the patients, shows gradual improvement
with long term-treatment.
Key words: psychotic disorders, quality of life, long-term
management.
Rezumat:
Premise:
Schizofrenia este o tulburare psihiatricã severã cu impact
negativ considerabil asupra funcþionalitãþii sociale ºi
caliãþii vieþi pacienþilor. Controlul simptomatic eficient
este esenþial pentru managementul adecvat al bolii pe
termen lung. Numãrul redus al publicaþiilor locale ca
rezultat al observãrii unui grup populaþional autohton, pe
termen lung, în condiþiile practicii curente, zilnice, a
constituit premisa iniþierii acestui studiu nonintervenþional. Proiectul ºi-a propus observarea
eficacitãþii quetiapinei XR în prevenirea recãderilor pe
termen lung la un lot neselecþionat de pacienþi cu
schizofrenie aflaþi déjà în tratament, ca parte a unei
decizii terapeutice de rutinã.
Obiective: Observarea managementului terapeutic la un
lot reprezentativ de pacienþi neselecþionaþi dupã criterii
stricte, caracteristice studiilor randomizate,
diagnosticaþi cu schizofrenie ºi trataþi în unitãþi medicale
cu profil diferit conform practicilor uzuale a permis
formularea unor concluzii cu privire la calitatea
controlului simptomatic ºi efectul acesteia asupra
calitãþii vieþii.
Metoda: S-a observat evoluþia unor pacienþi
diagnosticaþi cu schizofrenie, în ordinea consecutivã a
prezentãrii la consultaþii, care primeau tratament
conform deciziei medicului psihiatru, inclusiv quetiapina
XR,îinainte de fi parte a lotului de studiu. Pe parcursul
celor aproximativ 6 luni de observaþie subiecþii au primit
asistenþã medicalã de specialitate conform practicii
psihiatrice uzuale.
Rezultate: Lotul a cuprins 578 pacienþi (37% de sex
masculin ºi 63% de sex feminin) cei mai mulþi cu diferite
tipuri de schizofrenie dar ºi cu alte tulburãri din spectrul
schizofreniei, inclusiv tulburare schizoafectivã.. La
finalul celor 6 luni s-a remarcat o ameliorare
semnificativã a tabloului simptomatic cu o scãdere medie
a scorului BPRS (Brief Psychiatric Rating Scale) de 26.3
puncte (1). Doza medie (DS) de quetiapina XR la
începutul observaþiei a fost 600 mg/zi (+/- 148), cu un
minim de 200 mg/zi ºi un maxim de 1000 mg/zi.
Concluzii: Quetiapina XR reprezintã o alternativã
terapeuticã valoroasã atât la pacienþii tineri aflaþi la
primele episoade de boalã cât ºi la cei cu istoric
îndelungat al afecþiunii. Controlul simptomatic este unul
de calitate, se menþine pe termen lung dupã stabilizare, cu
prevenirea apariþiei recurenþelor episodice în condiþiile
unei doze medii de pânã la 622 mg/zi cu DS +/- 150mg/zi.
Percepþia pacienþilor cu privire la tratament ºi senzaþia
generalã de bine fizicºsi psihic este una pozitivã, cu
ameliorarea progresivã a acestor parametri pe termen
lung.
Cuvinte cheie: tulburãri psihotice, calitatea vieþii,
management pe termen lung.
1
Professor Assistant, Universitatea de Medicina si Farmacie“ Gr.T.Popa”Iasi, Romania, Contact:
[email protected];
2
Medical Adisor CNS, AstraZeneca Romania,Contact:[email protected]; + Members listed at the end.
27
ªerban Turliuc, Beatrice Costea : Maintaining Symptoms Control In Schizophrenia: A Naturalistic 6 Months
Observation
INTRODUCTION
Schizophrenia is a serious psychiatric condition
that has a detrimental impact on patients functioning
and quality of life. Therefore effective control of
schizophrenia symptoms is essential in the long term
management of patients with this disease. While
atypical antipsychotics have proven efficacy in reducing
acute symptoms and preventing or delaying relapse in
some studies, relapse rates are still high, resulting in an
increased economic burden and poor prognosis.
Since the main objective of antipsychotic treatment, aside
from the initial management of symptoms, is to prevent
relapse without increasing the potential for adverse
effects, this indicates a continuing unmet need in the
treatment of schizophrenia. Predictors of relapse include
poor adherence to treatment, severe residual
psychopathology, lack of insight into illness, co morbid
substance abuse, and inadequate relationships with family
and care providers. Of these, poor or nonadherence to
treatment is often the major contributory cause. This can
be a result of many factors related to the patient
( p s y c h o p a t h o l o g y, c o g n i t i v e
impairment,age,comorbidity, gender, personality traits,
insight), the treatment (tolerability,
route of
administration, pattern and complexity of dosing, length
of treatment, cost of treatment, polypharmacy, onset of
action, efficacy), and the treatment context (therapeutic
relationship, social support, attitude of both patient and
physician toward treatment, supervision of treatment,
social rank of illness, location of treatment
provision).When compared with conventional
antipsychotics, the lower levels of extrapyramidal
symptoms (EPS) and adverse events generally
experienced by patients
prescribed atypical
antipsychotics can be expected to result in improved
adherence to treatment and, consequently, lower levels of
relapse (2).
Quetiapine XR is an atypical antipsychotic drug with a
receptor-binding profile predictive of clozapine-like
antipsychotic activity and low extra-pyramidal symptoms
potential. There is an increasing body of evidence
supporting quetiapine XR effectiveness for patients with
schizophrenia, with efficacy across a broad symptoms
range (3-8). Quetiapine a first-line treatment for
schizophrenia and is comparable in this respect with other
atypical antipsychotics (9). Quetiapine XR has shown
efficacy in treating anxiety symptoms in bipolar disorder
and agitation in schizophrenia In addition, early evidence
suggests efficacy in treating major depressive disorder.
Extended release quetiapine XR is a new, once daily
formulation based on a gel matrix technology to control
the release of quetiapine XR. It relies on delayed drug
release from the formulation to maintain plasma drug
concentrations at higher levels for a longer time period
than is possible with an IR formulation. Characteristics of
the quetiapine XR formulation result in less frequent
dosing being required to maintain therapeutic drug
concentration.
Quetiapine XR has a predictable and reproducible
pharmacokinetic profile and is formulated to be
administered once daily. It has been developed to provide
patients and physicians with a more convenient dosage
and a simpler dose-administration regimen. In
schizophrenia a therapeutically effective dose should be
28
achieved with this formulation by Day 2 without
compromising the safety and tolerability profile of the
treatment.
Results of randomised clinical trials showed that oncedaily quetiapine XR (400–800mg/day) is effective in
preventing relapse in patients with clinically stable
schizophrenia (2, 10).
Considering the lack of published data observing
local population in a naturalistic setting, this noninterventional project aimed to analyze quetiapine XR
extended release efficacy in relapse prevention in
schizophrenia, observing an unselected group of patients
being already treated, as part of the routine practice. As
complexity of dosing is a major contributor to treatment
nonadherence and publications generally acknowledge
an estimate of 50% of patients not adhering to their
prescribed regimen that could lead to treatment failure,
relapse and consequences, such as hospitalization or
suicide we intended to observe clinical aspects for an
unselected sample of schizophrenia patients observed for
6 months in real life setting. Beside once daily
administered quetiapine XR extended release physicians
were allowed to use any drug considered according to
needs and daily practice.
PRIMARY OBJECTIVE
To assess the efficacy of Quetiapine XR in maintaining
symptoms control in schizophrenia over 6 months
interval.
SECONDARY OBJECTIVE
To assess the quality of life, using self-administered
Quality of Life Enjoyment & Satisfaction Questionnaire
(Q-LES-Q-SF) at the beginning and end of observation
time (11).
METHOD
6 months observational study on Romanian patients with
schizophrenia, assessed according to usual treatment
practice during 7 visits.
Eligible patients already diagnosed with schizophrenia, as
per DSM IV TR and have been receiving quetiapine XR
for approximately one month before study. Therapeutic
plan, including quetiapine XR and any other drug was
fully decided by treating physician and reflected daily
practice. Study protocol included quetiapine XR
administration according to manufacturer's prescription
recommendations. Decisions to modify treatment
(quetiapine XR and associated therapy) during the course
of the 6-months observation belonged entirely to the
treating physician with no restrictions imposed by study
protocol.
The study protocol set forth the doctors' responsibility to
record the adverse reactions that were spontaneously
reported during treatment, according to routine clinical
practice.
RESULTS
578 patients (37% males and 63% females), over 18 years
of age, were enrolled, most of them being diagnosed with
different types of schizophrenia, but also with other
schizophrenia-related diseases, such as schizoaffective
disorder. The mean age (SD) at diagnosis confirmation
was 31 years (+/- 10) while mean longitudinal history was
Romanian Journal of Psychiatry, vol. XIII, No.1, 2011
11 years. It is to be noticed that many patients had been ill
since approximately 2 years, so they were experiencing
the first 2- 4 episodes of the disease. Therapeutic history of
the group observed showed a large variety of choices that
have been used with 60 % of patients being treated with
second generation antipsychotics (14 % olanzapine, 11 %
amisulpride, 10 % risperidone, 5 % aripiprazole, 16 %
quetiapine instant release, 4 % various combinations)
while the remaining of 38% had first generation
antipsychotics (13%haloperidole, 10%flupentixole, 15%
haloperidole and flupentixole) and almost 2 % had
clozapine. At study entry 54% of patients have been
receiving quetiapine XR, monotheraphy and 46 % had
been receiving add on therapy with levomepromazine +/trihexifenidil, valproic acid +/- clonazepame,
escitaloprame, carbamazepine and benzodiazepines,
mainly diazepam. A gradual change of therapeutic
approach toward monotherapy has been observed for most
of the cases by the end of the 6 month.
The average dosage (SD) at study entry was 600 mg/day
(+/- 148) quetiapine XR with a minimum of 200 mg/day
and a maximum of 1000 mg/day. During the study
minimum dose remained 200 mg/day while the maximum
rose at 1200 mg/day. The mean dose along the whole study
length varied between 600 - 622 mg/day and over 55%
patients were noticed on these doses at every consultation
that occurred during 6 months interval.
A significant symptoms improvement was not noticed at
endpoint with an average decrease in the BPRS score of
26.3 points: BPRS v1-v7= 26.3 (CI 95% 24.7 - 27.8;
p<0.001) (Figure 1A).
BPRS mean baseline V1 =56, 4; BPRS mean end point V7 = 30, 1;
BPRS v1-v7 = 26, 3; IC 95% 24.7- 27, 8; *p<0,001
Figure 1.A. Symptoms control. BPRS changes
The long-lasting treatment effect was sustained by the
significant decline in symptoms severity, as illustrated by
CGI-S sub-scale (Clinical Global Impression - Severity
sub-scale) score evolution, from an average value of 4.7 at
baseline to 2.8 at endpoint: CGI-S v1-v7= 1.9 (CI 95%
“1.7 - 2.0, p <0.001). In other words, cases severity
declined, on the average, from “marked” to “mild”(Figure
1B).
CGI–I figures (Clinical Global Impression - Improvement
sub-scale) showed significant improvement since the
observation reference time, with an average variation of
CGI-I v2-v7 = 1.1 (CI 95% 1.01 - 1.18, p<0.001). After the
first assessment, “a minimal improvement” (modal value
3) was noticed in most patients, an effect consolidated at
the end when most patients had a “very high level of
improvement” (modal value 1) on CGI-I sub-scale.
The most frequent adverse reactions that caused dose
changes were mainly drowsiness in 0.8% of cases and
irritability in 1.03% of cases. In 1.6% of cases suboptimal
efficacy triggered increase of the dose. Adverse events
remission was generally complete at the next consultation
approximately one month later.
All cause hospitalizations rate was 1, 5% (90/578 patients)
out of that 1, 2 %( 72/90 patients) being determined by
disease relapses and remaining 0, 3% (18/90) triggered by
administrative reasons not related to the medical condition
under observation. These figures confirm the results of
randomized clinical studies showing quetiapine XR
efficacy in preventing schizophrenia relapses.
Quality of life, as seen by the patients based on Q-LES-Q
SF improved in many aspects, especially for a series of
items such as: physical health, mood, routine household
activities, social relationships, family relationships, daily
life functioning, sexual drive / interest / performance,
satisfaction with the current treatment. Every item was
rated on a scale from 1 to 5 and referred to last week status.
(Very poor = 1, poor = 2, fair = 3, good = 4, very good = 5).
49 % of patients reported their physical health as good at 6
months endpoint vs. only 19% at baseline. Mood was
rated as good by 46 % of patients at 6 months vs. 16% only
at baseline. Ability to work was rated as good at 6 months
end point by 36% of patients vs. 17% at baseline. Ability to
perform household activities was rated as good and very
good in 54 % of cases at 6 months vs. 24% at baseline.
29
ªerban Turliuc, Beatrice Costea : Maintaining Symptoms Control In Schizophrenia: A Naturalistic 6 Months
Observation
CGI-S mean baseline v1= 4, 7; CGI-S mean end point v7= 2, 8
CGI-S v1-v7 = 1, 91; IC 95% 1, 7-2, 0 *p<0,001;
Figure 1. B. Symptoms control.CGI-S changes
Overall sense of well being rating was fair, good and very
good in 95 % of cases vs. 67 % at baseline. Treatment
satisfaction rating was good and very good at 79 % of
patients vs. 35 % at baseline. Overall life satisfaction and
contentment rating was good and very good in 74% of
cases vs. 24 % at baseline.
A more detailed look at treatment satisfaction shows that
patients' rating was good and very good in 81 % of cases
that received first generation antipsychotics in the past and
76 % of cases treated with other drugs, including atypical
or not treated at all (Figure 2A).
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
antipsihotic tipic
+
foarte putin
putin
mediu
antipsihotic tipic
-
mult
antipsihotic tipic
+
foarte putin
putin
mult
foarte mult
antipsihotic tipic
-
mediu
foarte mult
Figure 2.A. Quality of life. Treatment satisfaction changes. Patients previously treated with first generation
antipsychotic. Left graph shows V1 results; Right graph shows v7 results
This evaluation confirm patients perspective from
published literature related to better quality of life as a
consequence of using second generation
antypsychotics.Additionaly at baseline overall quality of
life rating as good and very good occurred with higher
frequency in patients that received quetiapine instant
release formulation in the past comparing with others
treatments, including typical and atypical antipsychotics.
This rating was maintained and consolidated during the
observation for all the items described before. Treatment
30
satisfaction rating was upgraded to good and very good for
30 % more patients that received quetipine immediate
release formulation and at some point in time it have been
changes to extended release formulation (Figure 2B).
Along the same line at 6 months endpoint treatment
satisfaction was upgraded to good and very good at all
items mentioned before in subgroups of patients that
received other second generation antipsychotics, except
quetipine and first generation antipsychotics, as well.
Romanian Journal of Psychiatry, vol. XIII, No.1, 2011
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
quetiapina +
foarte putin
putin
mediu
quetiapina mult
foarte mult
quetiapina +
foarte putin
putin
mediu
quetiapina mult
foarte mult
Figure 2.B.Quality of life. Treatment satisfaction changes. Patients previously treated with second generation
antipsychotic, including quetiapine.
Left graph shows V1 results; Right graph shows v7 results.
CONCLUSIONS
Quetiapine XR is a valuable treatment alternative both in
young patients at the first schizophrenia episode and for
those with a long disease history, as well.
This observational study conducted in a naturalistic
setting shows that quetiapine XR provides long-term, high
quality symptoms control after disease stabilization and
prevents efficiently relapses at an average dosage
reaching 622 mg/day with SD 150mg/day. Dose
individualization remains the clue
for reaching
quantifiable clinical benefit in terms of short, long term
efficacy and patients safety that ultimately ensure
treatment adherence.
Patients' positive perception of their general health status
and quality of life has been validated by the results of this
naturalistic observation.
DISCUSSIONS
Clinical data obtained by the recording of daily practice in
a representative group of local schizophrenia patients
shows that quetiapine XR is a valuable treatment both in
young patients who are at their first disease episodes and
in those with a long psychotic disorder history.
This observational study confirms the results of published
randomized clinical trials with regards to quetiapine XR
clinical effectiveness that include an optimal mix between
efficacy on symptoms, good tolerability profile on long
term and patient acceptability that ultimately ensure
reasonable treatment adherence.
Large scale observational studies that could provide more
insight regarding pharmacological and nonpharmacological interventions and cost efficiency outputs
derived from all kind of health units profile at country
level would probably give a more accurate sense on
schizophrenia spectrum disorder management in
Romania
Acknowledgements:
This study was sponsored by AstraZeneca Romania. It is
registered at www.ClinicalTrials.gov under the title “Noninterventional Study to Observe Treatment Efficacy in
Maintaining Symptoms Control in Patients With
Schizophrenia, Treated With Seroquel XR” (govidentifier: NCT00750087, Study ID/ NIS-NRO-SER2008/1 ).Special thanks to SECURE study investigators.
Special thanks for consultancy to Irina Dan, MD and
Prof.Assist.Radu Mihailescu, Prof. Dr. Obregia Clinic
Psych Hospital, Bucuresti. The authors acknowledge the
assistance of Iosif Ionel, MD for statistical programming
Participating Investigators: Serban Turliuc (Iasi), Dorina
Donciu (Iasi), Nicoleta Cartas (Iasi), Virginia Marinescu
(Iasi), Madalina Miclos (Bucuresti), Anisoara Toncu
(Bucuresti), Alma Carstoiu (Bucuresti),Rodica Botan
(Bucuresti), Florica Blacioti (Bucuresti),Mihaela Rosca
(Bucuresti), George Cristian Bellu Bengescu (Bucuresti),
Anca Dragan (Bucuresti), Adela Ciobanu (Bucuresti),
Ana- Maria Trifan (Bucuresti), Ana Roxana Mischianu
(Bucuresti), Anca Danciu (Bucuresti),Carlig Raisa
(Bucuresti), Mariana Sima (Bucuresti), Bogdan Jianu (
Campina), Ana-Maria Stoian (Ploiesti), Florescu
Lorentina (Targoviste), Elena Camelia Hriban (Bacau),
Andreia Gociu (Bacau), Mircea Blajovan (Galati),
Eufrosina Cotoranu (Galati), Liliana Mihalache (Galati),
Nicolae Vlad (Botosani),Diana Decu (Braila),Iuliana
Magda Gheorghiu (Siret), Catalina Petrescu( Slobozia),
Mihaela Fadgyas Stanculete (Cluj),Traian Neamtu (Cluj),
Horea Coman (Cluj), Horatiu Salvan (Cluj),Diana Ilies
(Sibiu), Boesan Monica Bianca (Brasov),Diana Ionica
Dascalu(Horezu), Dan Alexandru Ilies (Bistrita), Liliana
Enescu (Calarasi), Corina Marta (Zalau),Monica Oiegar
(Deva),Luminita Iarca (Timisoara), Magdolna Gordan
(Timisoara), Felicia Giurgi Oncu (Timisoara),Olimpia
Cudalb (Timisoara), Anca Cirstea (Timisoara),Dan Silviu
Stefanescu (Giurgiu), Marius Stefanescu (Rm. Valcea),
Mihai Ardelean (Tg.Mures), Adriana Mihai (Tg.Mures),
Eli Morman (Pitesti), Diana Pascu (Pitesti),Catalin
Zarioiu (Pitesti), Izabela Dora Paunica (Craiova), Viorica
Diosteanu (Craiova), Stefan Codruta (Vedea).
Abbreviations list
BPRS, Brief Psychiatric Rating Scale
SD, Standard deviation
EPS, Extrapyramidal symptoms
Q-LES-Q-SF, Quality of Life Enjoyment & Satisfaction
Questionnaire
CGI-S scale, Clinical Global Impression - Severity subscale
CGI-I scale, Clinical Global Impression - Improvement
sub-scale
31
ªerban Turliuc, Beatrice Costea : Maintaining Symptoms Control In Schizophrenia: A Naturalistic 6 Months
Observation
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