The "Seroquel" Outcomes Study (SOS): Efficacy and tolerability oí

I
International
Journal
oi Psychiatry
in Clinical Practice, 2007; 11(3): 222-232
informa
healthcare
ORIGINAL ARTICLE
The "Seroquel" Outcomes Study (SOS): Efficacy and tolerability oí
quetiapine in a long-term, naturalistic study oí patients with
schizophrenia
JUAN GIBERT1, JosÉ GINER2, JULIO BOBES3, MÓNICA TAFALl.A\
SANTIAGO HERRANZ\ CARMEN OVEJER05 & FERNANDO RICO-VIllADEMOROS5
for the SOS GROUP*
1Facultad de Medicina,
Departamento de Farmacología, Cádiz, Spain, 2Departamento de Psiquiatría, Hospital Universitario
"Virgen Macarena", Universidad de Sevilla, Sevilla, Spain, 3Departamento de Psiquiatría, Facultad de Medicina,
Universidad de Oviedo, Oviedo, Spain, 4Departamento Médico, AstraZeneca, Madrid, Spain, and 5Biométrica, Madrid,
Spain
Abstraet
Objective. The "Seroquel" Outcomes Study (SOS) aimed to assess the efficacy and tolerability of quetiapine in patients with
schizophrenia in the clinical practice setting. Methods. A 6-month, non-comparative, open-label study in adults with
schizophrenia in a standard care setting in Spain. Outpatients received tlexibly dosed quetiapine. Efficacy was evaluated
using the BriefPsychiatry Rating Scale (BPRS) and the Clinical Globallmpression (CGI) scale. BPRS response was defined
as ~30% decrease from baseline. Tolerability was assessed using the Simpson-Angus Scale (SAS) and a modified Udvalg
for Kliniske Undersogelser (UKU) side-effeets scale. Results. A total of 2029 patients enrolled. Significant changes from
baseline to Month 6 were recorded for BPRS total and subscale scores (P <0.001). Compared with doses of~600 mg/day,
doses of <400 mg/day were a strong predictor of a lower response rate (OR 0.62; 95% CI: 0.48, 0.82) and higher
withdrawal rate (OR 3.3; 95% CI; 2.5, 4.4). Mean change in weight was minimal (+0.4 kg). Somnolence (26.7%), asthenia
(12.5%), and constipation (9.8%) were the most common adverse events. Conclusion. Quetiapine was found to improve
symptoms of schizophrenia, as indicated by a significant decrease in BPRS scores, and was well tolerated by patients in
clinical practice.
Key Words:
Quetiapine,
antipsychotics, schizophrenia,
naturalistic, outpatient
Introduction
Schizophrenia is a chronic and debilitating illness
that impacts on the cognitive, affective, behavioural,
and motivational functioning of patients [1]. The
World Health Organization has reported a worldwide prevalence rate of 0.1-1.7% [2], while in the
US, the lifetime prevalence of the disease is estimated at 1% [3].
The development
of the so-caBed "atypical"
antipsychotics in the 1990s extended the treatment
options for patients with schizophrenia. In addition
to effectively treating the positive symptoms of
schizophrenia,
these agents are effective against
negative, affective and cognitive symptoms. Their
* See Appendix for tbe complete list of SOS Group members.
broad therapeutic profile and improved tolerability
compared with the conventional
antipsychotics,
particularly with regard to extrapyramidal symptoms
(EPS), means that the atypical antipsychotics are
considered first-line treatment for schizophrenia in
most clinical situations [4].
The modero standard for evaluating new medicines is the randomised clínical tríal [5]. Although the
use of proper controls, randomisation and blinding
decreases bias and the potential for error, the conditions under which such trials are conducted differ
from everyday clínical practice [6,7]. In the "reallife" setting, the typical patient often presents with
comorbid disorder(s), has not responded to previous
treatment efforts, and may require a number of
different treatments.
Further,
trial patients are
usually carefully selected and must meet strict study
Correspondence: Mónica Tafalla, MD, Medical Department, AstraZeneca, Parque Norte, Edificio Roble, Serrano Galvache 56, 28033 Madrid, Spain. Tel.:
+34 91 301 9647. Fax: +3491 301 9104. E-mail: [email protected]
(Received 10 February 2006; accepted 7 December 2006)
ISSN 1365-1501 print/lSSN 1471-1788 online iD 2007 Taylor & Francis
DOI: 10.1080/13651500601176963
NaturaJistic study of quetiapine for schizophrenia
inclusion/exclusion criteria. Naturalistic studies closely mirror daily clinical practice, but have the
disadvantage of being uncontrolled and as they are
observational are potentially open to bias. How a new
medicine performs in clinical practice is a proper
indication of its ttue benefit to risk ratio [8]. It is,
therefore, important for the prescribing clinician to
consider clinical trial data in conjunction with data
from naturalistic studies as well as his/her own
experience when selecting an atypical antipsychotic
for a given patient [9].
Quetiapine is a dibenzothiazepine atypical antipsychotic with affinity for various neurotransmitter
receptors including serotonin, dopamine, histamine,
and adrenergic receptors and its chemical strueture
is similar to that of clozapine [10]. Three pivotal,
randomised, double-blind clinical trials demonstrated that quetiapine efIectively reduces psychotic
symptoms in patients with schizophrenia as indicated by significant difIerences between quetiapine
and placebo on the Brief Psychiatty Rating Scale
(BPRS) total, BPRS positive-symptom, Scale for the
Assessment of Negative Symptoms (SANS) and
Clinical Global Impression (CGI) severity of illness
scales [11-13]. Quetiapine has shown comparable
efficacy to chIorpromazine [14] and haloperidol
[15,16]. The main objective of the "Seroquel"
Outcomes Study (SOS) was to assess the efficacy
and tolerability of the atypical antipsychotic, quetiapine ("Seroquel"), in a large representative group of
patients with schizophrenia under naturalistic conditions. It also assessed factors relevant to the use of
quetiapine in the clinical setting, such as the reduction of side efIects in patients who had switched to
quetiapine from previous antipsychotic medications.
Methods
Patients
Male or female outpatients aged ~ 18 years with a
DSM-IV diagnosis of schizophrenia or schizophreniform disorder for whom study investigators prescribed quetiapine as part of their normal clinical
practice were included in the study. Patients were
excluded if contraindicated by the quetiapine product label, for example, known hypersensitivity to
the medication or any of its ingredients.
This study was conducted in accordance with the
Declaration of Helsinki [17]. Written informed
consent was obtained from all patients prior to
enrolment and the study was reported to the
Ministty of Health in accordance with Spanish
regu1ations at the time of the trial.
Study design and dosing
This was a non-comparative, open-Iabel, naturalistic, multicentre study conducted in Spain and
223
involved 279 investigators (see Appendix). Eligible
patients received open treatment with quetiapine
(flexiblydosed according to the clinical judgement of
the study investigator) and were followed for 6
months (Figure 1). The use of concomitant medications was permitted at the discretion of the clinician.
Patients were categorised into two groups at
baseline: (1) patients not currently receiving antipsychotic treatment (first or breakthrough episode);
(2) patients currently receiving antipsychotic treatment and requiring combination treatment with
quetiapine or a switch to quetiapine due to an
inadequate response or intolerable adverse events.
Inadequate response was defined as persistent positive, negative, cognitive or severe depressive symptoms, persistent agitation, or treatment-refractory
schizophrenia. Intolerable adverse events were determined by the psychiatrist and included sedation,
weight gain, EPS, cognitive, anticholinergic, cardiovascular or sexual/reproductive adverse events, tardive dyskinesia or neuroleptic malignant syndrome.
Efficacy assessments
The primary efficacy assessments were changes from
baseline on the BPRS [18] total and subscale scores
and the CGI [19] severity of illness scale at Months
1,3 and 6. The BPRS comprises 16 items covering
general, positive and negative symptoms and is
scored on a severity scale of 1-7 (higher scores
indicate more severe symptoms). The CGI severity
of illness scale has a seven-point scale (1 is normal
and 7 is extremely ill). Secondary efficacy variables
included the BPRS response rate (response was
defined as a ~ 30% decrease from baseline in BPRS
score) and the CGI improvement scale, which
measures the change in the state of the patient's
illness relative to baseline scored from 1 (very much
improved) to 7 (very much worse) and was completed at each visitoIn addition, a CGI improvement
of side efIects scale (a scale identical to the CGI
improvement scale used for the efficacy assessment)
was fulfilled at each visit for patients with intolerable
adverse efIects to previous antipsychotic treatment.
A CGI global improvement rating of at least "much
improved" constituted a therapeutic response for
both an improvement in the illness and an improvement in side efIects. Investigators also recorded if
patients exhibited any of the following: aggression/
violence, agitation/excitement, insomnia, dysphoria,
suicidal behaviour, comorbid substance abuse, cognitive difficulties or other problems. Categories were
primarily based on those described in the Expert
Consensus Guideline for the Treatment of Schizophrenia [19].
At the end of the study, patients completed a
Likert-type scale (7 points) to report their satisfaction with treatment, where 1 indicated "extremely
224
J Gibert et al.
Excluded N=109
Missing baseline
visit 3 (0.1 %)
Missing post-baseline
visit 68 (3.3%)
No post-basaline efficacy
evaluation 38 (1.9%)
Withdrawn N=120:
Lost to follow-up, N=3
Adversa event, N=40
Lack of efficacy, N=22
Patient withdrew cansen!, N=42
Other, N=13
5 pis not available at Month 1
Withdrawn N=155:
Lost to follow-up, N=15
Adversa event, N=46
Lack of efficacy, N=22
Palient withdrew consen!, N=52
Other, N=20
5 PIs not available at Month 1
Withdrawn N=174:
Lost to follow-up, N=45
Adversa event, N= 18
Lack of efficacy, N=43
Patient withdrew cansent, N=40
Other, N=28
Withdrawn N=175:
Lost to follow-up, N=46
Adverse event, N=18
Lack of efficacy, N--43
Palient withdrew cansent, N=40
Other, N=28
Withdrawn N=l42:
Lost to follow-up, N=48
Adversa event, N=5
Lack of efflcacy, N=46
Patient withdrew cansent, N=27
Other, N=16
Withdrawn N=142:
Lost to follow-up, N=48
Adversa event, N=5
Lack of efflcacy, N=46
Palient withdrew consent, N=27
Other, N=16
5 pis not available at Month 3
but available al Month 6
5 PIs not available at Month 3
but avaiJable at Month 6
Figure l. Patient disposition.
satisfied", 4 "neither satisfied nor dissatisfied", and
7 "extremely dissatisfied" with treatment.
Tolerability assessments
Medical and psychiatric histories were taken at
base1ine and a physical examination was carried
out. Vital signs and weight were measured by the
investigators using their normal clinical practice
methods (non-standardised procedures) at baseline
and at Months 1,3 and 6. Body mass index (BMI)
was calculated. Weight gain was defmed as any
increase in weight (kg) from baseline. The
Simpson-Angus Scale (SAS), a 10-point scale
measuring EPS using standardised clinical assessment of parkinsonian side-effects including tremor,
rigidity and salivation, was completed at baseline
and at each follow-up visito Treatment-emergent
adverse events, including sedation and cognitive
side effects, were identified by patient report through
open questioning ("Have you had any discomfort
that could be related to the antipsychotic medication?") and categorised by the investigator using a
modified Udvalg for K1iniskeUndersogelser [UKU]
Side Effect Rating Scale [20], a 23-point scale
covering cognitive, whole body abnormalities and
sexual dysfunction, at baseline and each follow-up
visitoThe investigators used their own judgement to
determine the probability of a causal relationship of
an adverse event to the medication as "absent",
"possible", or "probable". In addition, adverse
events classed as "intolerable", such as tardive
dyskinesia, were evaluated by the clinician using
the CGI improvement of side effects scale as
described above.
Statistical analysis
Al1efficacy analyses were performed on the intention
to treat (fIT) sample using a last observation carried
forward approach (LOCF). The ITT population
comprised patients who met the study entry criteria,
were prescribed quetiapine and had at least one postbaseline efficacy evaluation. For inclusion of patient
data in the ITT sample for multi-item scales such as
the BPRS, data for at least 80% of all items was
required. Logistic regression analysis was carried out
to determine the relationship between patients'
clinical characteristics, dose of quetiapine at endpoint (categorised as low, <400; intermediate,
~400 to <600; and high, ~600 mglday) and
response rateo A Student's paired t-test was used to
analyse changes from baseline to endpoint in the
BPRS total and clusters scores. AlI statistical tests
were two-tailed with a P value of ~0.05 considered
statistically significant [21].
Descriptive statistics were used to summarise
modified UKU and SAS total score data for the
tolerability population (all patients who entered
the study and had at least one follow-up visit).
Any increase from the baseline severity score in a
UKU item rated as possibly or probably related to
n more than one medication.
Naturalistic study of quetiapine for schizophrenia
quetiapine was considered to be an adverse event;
missing evaluations of causal relationship were also
considered possibly related to quetiapine. For the
SAS, changes from baseline scores were assigned to
three categories: "improved" (change <O), "no
change" (change =0) and "worsened" (change
>0), and the frequency distributions of the categories calculated for each study visito
A logistic regression analysis was performed to
investigate the relationship between patients' clínical
characteristics and quetiapine dose with regard to
response rateo The following risk factors were included: age, sex, first episode, breakthrough episode,
inadequate response to previous treatment, intolerable adverse reactions to previous treatment, inadequate response and intolerable adverse reactions to
previous treatment, treatment -refractory schizophrenia, dose (categorised as "low", "intermediate" and
"high"; see definitions above), prominent depression
(BPRS item #9 score > 4), prominent hostility symptoms (BPRS item #10 score >4), prominent anxiety
symptoms (BPRS item #2 score >4), diagnostic
complications as defined above were introduced as
dichotomous variables, and finally the total BPRS
score at baseline.
Results
A total of 2029 patients were enrolled in the study.
Demographic and clínical characteristics are pre-
sented in Table 1. Overall, 109 patients were
excluded from the ITT analyses (n = 1920) due to
missing base1ine visit (n =3), missing post-baseline
visit (n = 68) or no post-baseline efficacy evaluation
(n =38).
At study entry, 78% of patients (n = 1575) were
already receiving antipsychotic treatment: 63.3%
were switched from their existing medication to
quetiapine monotherapy and 14.7% received quetiapine as adjunctive therapy. Of the patients
switched from previous antipsychotics to quetiapine,
9% had previously been treated with two or more
antipsychotics (n = 68) and 91 % with one antipsychotic (n = 717). Of the patients treated with one
previous antipsychotic (n = 717), 35.4% had received risperidone, 27.1 % olanzapine, 2.8% clozapine, 15.5% haloperidol, 0.4% other atypicals and
19.3% other conventional antipsychotics. The most
common therapies in the adjunctive group were
risperidone (23.2%), zuclopenthixol (15.2%), olanzapine (14.3%), fluphenazine (14.3%) and haloperidol (10.3%). Of those previously on antipsychotic
medication, 42.5% had an inadequate response to
previous treatment, 17.3% had experienced intolerable adverse events and 40.2% cited both reasons.
Agitation (25.3%), dysphoria (25.1 %), insomnia
(19.1%), cognitive deficits (18.8%) and aggression/
violence (15.3%) were among the most common
diagnostic complications (occurring in ~ 15% patients) reported by the investigators.
Table I. Patient charaeteristics.
2.9
7.4
13
7.4
14.7
0.2
0.5
4.7
24.1
58.8
%7.1
0.4
0.3
0.9
28.1
33.2
2.3
11.8
1.0
1.1
1.4
11.9
8.0
6.1
10.4
6.9
61.1
8.7
16.2
Lithium
Anticonvulsants
Co-morbidities
0.6
0.8
31.2
21.8
38.4
2.4
12.2
59.7
66.8
Mean
SD
55.7
12.6
Mean (SD) weight, kg
1239
Nsystem
10
1194
488
177
95
4
59
328
A1zheimers
Parkinsons
Other
Cardiovascuiar
Diabetes
Other 1212
1354
163
571
442
283
240
247
780
633
124
21
19
9
abnormalities
241
673
150
46
47
22
48
29
16
12
6
12.4
N76.1
141
Cataraets
1130
151
264
36.8
24.1
Nerwus
abnormalities
Antidepressants
Hypertension
Anxiolyticslhypnotics
Ischemic
Obesity
cardiopathy
Optical
Antiparkinsonians
abnormalities
225
Endocrinelnutritionallmerabolic
Cardiac
insufficiency
Other
circulatory
abnormalities abnormalities
Existing
medication'
226
J
Gibert et al.
Overall, 541 (26.7%) patients withdrew from the
study: 162 (8%) were lost to follow-up, 131 (6.5%)
withdrew consent; 112 (5.5%) withdrew due to lack
of efficacy; 69 (3.4%) withdrew due to adverse
events and 67 (3.3%) withdrew for other reasons.
At study endpoint, the mean (SD) dose of
quetiapine was 449 (206.7) mg/day; 24.7% of
patients received <400 mg/day quetiapine; 44.3%
received ~400 to <600 mg/day and 31.0% received ~ 600 mg/day.
·6.0
•
Monlh1
•
Monlh3
O Monlh6
·5.0
.s
j~ ~
li
-
CI)
~
f~
·4.0
·3.0
-1.0
~
-1.2.0
.É
0.0
Bfficacy
Quetiapine significantly improved symptoms from
Month 1 through to study end. Mean BPRS total
score decreased significantly by 17.3 points from
base1ineto endpoint (from 51.5 to 34.2, respective1y;
p <0.001; Figure 2). Significant decreases from
baseline to Month 6 in BPRS positive, negative
and Factors I-V (thought disturbance, anergia,
anxiety, activation, hostility/suspicion) subscale
scores were also observed (P <0.001; Figure 3).
After 1 month of quetiapine treatment, 22.6%
(95% CI: 20.7, 24.4) of patients were c1assified as
responders (~30% decrease from baseline in BPRS)
with this proportion increasing to 46.1 % at Month 3
(95% CI: 43.8, 48.3), and to 55.8% (95% CI; 53.5,
58.0) at Month 6, the study endpoint. Similarly, the
CGI global improvement response rates increased
over the 6-month study period with responses of
22.3% (95% CI: 20.4, 24.2), 44.1% (95% CI; 41.8,
46.3) and 52.8% (95% CI: 50.6, 55.0) at Months 1,
3 and 6, respectively. Both the BPRS and CGI
response rates were statistically significant at Months
3 and 6 (P <0.001) versus Month 1. The factors
that were the strongest predictors of a lower response
to treatment (< 30% decrease from baseline in
BPRS) were the use of quetiapine at a dose of
<400 mg/day compared with ~600 mg/day (odds
ratio [OR] 0.62; 95% CI; 0.48, 0.82), and initiating
treatment because of an inadequate response to
previous therapy (OR: 0.63; 95% CI: 0.51, 0.79).
A substantial number of patients initiated treatment with quetiapine monotherapy because of
-20.0
Month 1
"'1><0.001
vs b8se1ine
Figure 2. Mean change froro baseline in BPRS total score.
"·p<O.OOl
F~Qr$I·V
Figure 3. Mean change froro baseline in BPRS positive, negative
and Factor 1-V subscale scores.
intolerable adverse events with their previous antipsychotic treatment. By Month 6, a CGI improvement of side efIects score of:::;;2 ("much" or "very
much" improved) was achieved for more than 80%
of those who switched due to experiencing EPS with
their previous antipsychotic therapy, for 78.2% of
patients who switched due to sexual side efIects and
for two-thirds of patients who experienced adverse
cognitive efIects with their previous medication
(Table 11). For patients who experienced tardive
dyskinesia during previous treatment, more than half
(58%) of the 24 evaluable patients were "much" or
"very much" improved after 6 months of quetiapine
treatment.
At the end of the study, two-thirds of the lIT
population were satisfied with their treatment, with
41.6% of these noting that they were either "very
satisfied" or "extreme1y satisfied". Of the 1485
patients who completed the 6-month study, 86.9%
were satisfied with treatment, of whom 55.3% were
"very satisfied" or "extremely satisfied".
1blerability
The tolerability population comprised 1961 patients
(who had at least one follow-up visit). In general,
quetiapine was well tolerated. Patients experienced
considerable improvements in EPS on quetiapine
treatment, as indicated by reductions in SAS scores.
Mean SAS scores decreased significantly from a
baseline score of6.8 (95% CI: 6.5, 7.1) to 2.8 (95%
CI: 2.6, 3.0) at Month 6 (P <0.05).
Weight changes that occurred durlng the study
were mínimal, with a mean weight increase from
baseline to Month 6 of 0.4 kg. Analysis according to
baseline BMI showed that patients with a normal
BMI (Le. 20-25 kglm2) had only a modest mean
increase of 1.6 kg while those who were clinically
obese or severely obese (BMI categories ~30 kglm2)
had mean weight reductions at the end of the study
,
Naturalistic study 01quetiapine lor schizophrenia
Table II. Improvement of adverse reactions according to CGI-I at Month 6 in patients with intolerable
antipsycbotic treatment.
No. of patients
AlI" N=1575
Side effect
EPS
Tardive dyskinesia
Sexual dysfunctions
Weight gain
Sedation
Cognitive
Anticholinergic
Cardiovascular
Other reproductive
Other side effeets
effects
CGI score:S;2 (%) "Much"
Switcbedb
N = 1276
323
24
270
88
325
79
281
94
79
91
40
74
AlI" N=1575
7
33
5
26
27
26
23
(Figure 4). A weight change of>7% was reported
for 10.1% ofpatients (n= 1718).
The most common side effects (~5% patients)
according to the UKU Side Effects Rating Scale were
somnolence (25.7%; 95% CI: 23.8, 27.6), asthenia/
lassitude (12.0%; 95% CI: 10.6, 13.4) constipation
(9.3%; 95% CI: 8.0, 10.6), orthostatic hypotension
(7.8%; 95% CI: 6.6, 9.0), dry mouth (6.9%; 95%
CI: 5.8, 8.0), difficulty concentrating (5.6; 95% CI:
4.6,6.6) and reduced libido (5.0%; 95% CI: 5.0,6.0)
(Table lII). Spontaneously reported adverse events
followed a similar pattern with the only event
reported in over 5% of patients being somnolence
(18.5%). There was a reduction in the severity of
somnolence in 52.0 and 69.7% of the patients
presenting with this adverse event at the first evaluation (n = 300) after 3 and 6 months, respectively,
indicating that tolerance to somnolence developed
during the study. The effect of concomitant psychotropic medications on somnolence and sexual function was analysed. Treatment with antipsychotics
other than quetiapine was associated with a significant increase in orgastic dysfunction (P=0.035) (this
analysis could not be conducted for individual
antipsychotic agents due to small numbers). In
addition, treatment with anxiolyticsJhypnotics was
associated with a significant decrease in the incidence
3.0
2.5
BMI(kglm'l
2.0
.!
.<20
1.5
J-
1.0
.20-25
.2S-30
~30-40
0>40
Adverse event
3
·1.0
·1.5
Somnolence
Asthenia/lassitude
-3.5
Month3
Figure 4. Mean change in weight according
baseline.
Monlh 6
to BMI category at
81.6
57.9
78.2
54.0
67.1
66.2
54.5
40.0
69.2
63.6
(Le. switching or combination).
Table III. Adverse events recorded for ;?:5% of patients using the
UKU Side Effeets Rating Scale
.o.S
0.0
·3.0
N = 1276
In a naturalistic clínical setting, patients treated with
quetiapine experienced significant reductions in
symptoms of schizophrenia and improvements in
overall functioning. Over the 6-month treatment
period, quetiapine was well tolerated with over half
le
s.f.
-2.5
improved
Discussion
0.5
-2.0
Switcbedb
to previous
ofsomnolence (P=0.006) and a significant increase
in reports ofincreased sexual desire (P=0.015). Five
deaths occurred during the study and none of these
were considered related to the study drug in the
investigator's opínion. Deaths were due to suicide
(n = 2) and myocardial infarction, pneumonia, and
following laryngeal surgery.
Using the logistic regression model with "withdrawal due to any cause" as the dependent variable,
the strongest predictor of withdrawal was the use of
a lower dose of quetiapine (mean final dose <400
mg/day) with an OR of 3.3 (95% CI: 2.5, 4.4).
Patients who received a mean final dose of ~ 400
to <600 mg/day were also slightly more likely to
withdraw (OR: 1.12; 95% CI: 0.9, 1.5) than those
who received a mean final dose of>600 mg/day.
When crude withdrawal rates were analysed according to dosage group, the proportions were 49.7%
(272/485), 18.5% (161/867) and 17% (103/607)
for the <400, ~400 to <600 and ~600 mg/day
quetiapine categories, respectively.
j~
i-
or "very much"
79.5
58.4
77.0
52.9
68.9
67.1
52.5
57.1
69.2
61.5
19
'Patients with intolerable adverse events (ITT sample) who initiated treatment with quetiapine
bpatients who were switcbed to quetiapine from previous antipsychotic treatment.
Monlh 1
adverse reactions
227
Constipation
Orthostatic hypotension
Drymouth
Difficulty concentrating
Reduced libido
No. (%) of patients
(n =1961)
503
235
182
153
136
110
(25.7)
(12.0)
(9.3)
(7.8)
(6.9)
(5.6)
98 (5.0)
95% CI
23.8,27.6
10.6, 13.4
8.0, 10.6
6.6,9.0
5.8,8.0
4.6,6.6
5.0,6.0
I
228
J. Gibert et al.
the population of patients who completed the study
indicating a high degree of satisfaction (very or
extremely satisfied) with the treatment that they
received.
The response rate of 55.8% obtained in the study
was very similar to that reported in trials by Arvanitis
et al (51% with 300 mg/day quetiapine) and Small
et al (50% with <250 mg/day quetiapine and 53%
with ~250 to :::;;750mg/day quetiapine) using the
same criteria of a ~ 30% reduction in BPRS total
score [11,13]. However, it is important to note that
a substantial proportion of patients in our study
ínitiated treatment with quetiapine solely because of
the presence of intolerable side efIects with previous
antipsychotics. In addition, our study included a
greater proportion of patients with comorbidities
and, possibly, more treatment-refractory patients.
Over 30% of patients who were classed as nonresponders (:::;;30%decrease in BPRS score) reported that they were satisfied with treatment. This
suggests that it is important to use both objective and
subjective measures to assess patient response to
treatment in a naturalistic clínical setting.
A low withdrawal rate of26. 7% was observed. This
is comparable with the 26.5% withdrawal rate
encountered with olanzapine in the same setting
with a 6-month study duration [22] but substantially
lower than that observed elsewhere [23]. A Cochrane
Group review of 42 trials of quetiapine reported
dropout rates of 36-64%, despite the fact that most
ofthe trials were short term [23]. More recently, the
CATIE [24] (Clínical Antipsychotic Trials of Intervention EfIectiveness) study, reported that 74% of all
patients discontinued antipsychotic treatment before
18 months; in the quetiapine group 82% of patients
discontinued treatment (the mean modal dose of
quetiapine was 543.4 mg/day). Although a naturalistic design, CATIE was a double-blind clínical trial
and the design and duration of follow-up may have
impacted on withdrawal rates. In addition, it was
relatively easy for patients to switch treatments. One
can only speculate about the reasons for this difIerence in withdrawal rates, since many factors afIect
treatment compliance. Logistic regression analysis
undertaken in the present study indicated that
dropouts were associated with the use of quetiapine
at doses of <400 mg/day when controlling the baseline difIerences between dose groups. This is an
important finding because, in clínical practice, withdrawal from treatment could be considered to be a
measure of treatment efIectiveness.
In clinical practice, addressing adverse events that
may occur with antipsychotics is problematic. Several therapeutic strategies are available for the
management of adverse events, including adjusting
the dose, using an antidote (e.g., antiparkinsonian
medications, amantadine, nizatidine, bromocriptine)
or switching to another antipsychotic [1,25]. The
actual management of antipsychotic-induced side
efIects in the clinical setting is therefore an interesting matter to investigate. In the present naturalistic
study, we found that more than two-thirds of
patients who experienced EPS, sexual side efIects,
other hormonal efIects (e.g., amenorrhoea), cognitive side efIects or sedation with their previous
antipsychotic medication experienced considerable
improvement in these adverse events when switched
to quetiapine. Significant improvements in EPS have
also been reported in a previous naturalistic study in
patients with schizophrenia switched from other
antipsychotics to quetiapine [26]. Significant increases in weight have been reported for clozapine
and olanzapine [27,28]. While there was a slight
increase in mean patient weight of 0.4 kg during the
6-month treatment period in our study, this is a
mínimal change compared with that observed with
clozapine and olanzapine [29,30]. In addition, in
patients who were switched to quetiapine from other
antipsychotics, weight gain was improved or very
much improved in over 50% of patients. Furthermore, when weight gain was stratified by baseline
BMI, most weight gain occurred in those who were
underweight, whereas there was an overall reduction
in weight in patients who were clínically obese.
Greater increases in weight were reported in a
retrospective analysis of weight change in 661
patients treated with quetiapine for at least 26 weeks
(mean duration of treatment = 17.8 months) [31];
the mean weight change in this analysis was 2.3 kg.
As observed in the present study, the greatest weight
gain occurred in patients who were underweight at
base1ine, with no significant change in those who
were clínically obese. The prevalence of obesity in
the studied population would afIect the mean weight
change and could be an indirect reflection of
selective prescribing pattems in the observational
studies.
The incidences of somnolence and asthenia in our
study were slightly higher than previously reported
in placebo-eontrolled trials [13,15,32], although a
recent pooled analysis of eight placebo-controlled
studies reported a similar rate of somnolence
(25.6%) [33]. No concomitant psychotropic medication appeared to be significantly associated with an
increase in somnolence but, as this was an uncontrolled trial, a clear relationship to quetiapine treatment could not be ascertained. Reduced libido was
the only common (~5% of patients) sexual side
efIect reported, despite the use of concomitant drugs
that are associated with a significant increase in
sexual desire (anxiolytics) and orgastic dysfunction
(other antipsychotics). A similar rate of reduced
libido (3.7%) was reported in another Spanish
naturalistic study in patients with schizophrenia
using a difIerent evaluation method, the Psychotropic-Related Sexual Dysfunction Questionnaire [34].
Numerous naturalistic studies have been carried
out with the atypical antipsychotics, and used to
Naturalistic study 01quetiapine lor schizophrenia
(
supplement and expand on the data from randomised controlled trials [35]. The open-Iabel QUEST
study compared the efficacy and tolerability of
3 months' treatment with quetiapine or risperidone
in 728 patients with psychosis [36]. The results
suggest that overall, both agents have similar efficacy
and tolerability, but that quetiapine has a more
favourable EPS profile. Similarly, in a naturalistic
study comparing risperidone and olanzapine in
patients with first-episode schizophrenia, there were
significant reductions in the severity of illness and
patient functioning with both agents, but the incidence of EPS was significantIy higher in the risperidone group [37]. In a large, pan-European study of
8400 outpatients with schizophrenia, patients treated
with risperidone were significantIy more likely to
experience EPS and sexual dysfunction, while patients treated with olanzapine and elozapine had
significantIy greater weight gain [38].
Naturalistic studies have a number of limitations.
An open-Iabe1, uncontrolled, non-randomised design means that caution must be exercised when
interpreting results and drawing conelusions. In the
present study, investigators were requested to inelude consecutive patients; however, selection bias
exists due to the lack of randomisation and because
the study aimed to elose1yreflect elinical practice in a
"real-life setting" [39]. In addition, the uncontrolled
design of the study limits defmitive conclusions, as
effects such as regression to the mean cannot be
discounted.
Conversely, an important strength of our study is
that it is representative of clinical practice, or at the
very least, of clinical practice in Spain (the demographics and clinical characteristics of our patients
are very similar to those included in another large,
naturalistic Spanish study of olanzapine [40]). In
addition, by looking at patient characteristics (e.g.,
psychiatric comorbidity, use of concomitant medications) it appears that most patients would not have
been included in clinical trials of quetiapine nor any
other antipsychotic due to strict enrolment criteria.
Our study not only supports the effectiveness of
quetiapine (measured by scales such as the BPRS,
CGI, SAS and UKU, previously reported in randomised, controlled clinical trials), but also suggests
that the efficacy and tolerability results obtained with
quetiapine in carefully selected trial populations
remain valid in a naturalistic setting.
Conclusions
This study demonstrated that quetiapine was well
tolerated and improved symptoms in patients during
a 6-month study in a naturalistic care setting in
Spain. A quetiapine dose of <400 mglday was a
strong predictor of lower BPRS changes « 30%
decrease) and higher withdrawals than a dose of
;::;:600mglday, suggesting that higher doses are
229
associated with increased benefits. The results from
this open-Iabel, naturalistic study indicated that
patients with schizophrenia who were treated with
quetiapine experienced symptom improvement and
reduced side effects.
Key points
• The main objective of the study was to assess
the efficacy and tolerability of the atypical
antipsychotic, quetiapine, in a large representative group of patients with schizophrenia under
naturalistic conditions
• Quetiapine treatment was associated with significant and progressive improvement in overall
symptomatology at 1,3 and 6 months
• Quetiapine < 400 mglday was a strong predictor
of lower BPRS changes «30% decrease) and
higher withdrawals than doses ;::;:600mglday,
suggesting that higher doses are associated with
increased benefits
• Patients experienced considerable improvements in EPS on quetiapine treatment, as
indicated by reduetions in SAS scores
• Weight changes that occurred during the study
were minimal, with a mean weight increase
from baseline at 6 months of 0.4 kg
Acknowledgements
We thank Jocelyn Woodcock, MPhil, from CMC,
who provided editing assistance funded by AstraZeneca.
Statement of interest
This study was supported by AstraZeneca, Madrid,
Spain.
References
[1] Kane JM. Management issues in schizophrenia. London:
Taylor & Francis (A Martín Dunitz Book); 2000.
[2] Barbato A. Schizophrenia and public health. World Health
Organization, Geneva, 1998. Accessed 27 May 2005 [available at: http://www.who.intlmentaChealth!mediaJen/55.pdf).
[3] National Institute of Clínical Excellence. Schizophrenia:
core interventions in the treatment and management of
schizophrenia in primary and secondary careo 2002. Accessed 27 May 2005 [available at: http://www.nice.org.uk].
[4] McEvoy ]P, Scheifler PL, Frances A. Expert Consensus
Guideline Series. Treatment of schizophrenia. J Clin Psychiatry 1999;60(Suppl 11):8-80.
[5] Friedman LM, Furberg CD, DeMets DL. Fundamentals of
c1ínicaltrials. New York: Springer-Verlag; 1998.
[6] Fleischhacker WW, Hummer M. Do phase In trials have
c1ínicalvalue? J Clin PsychopharmacoI1999;19:391-2.
[7] Norquist G, Lebowitz B, Hyman S. Expanding the frontier
of treatment research. Prevention and treatment. Vol. 2,
Article OOOla, 1999, posted 21 March. Accessed 27 May
2005 [available at: http://www.journals.apa.org/prevention/
volume2/pre002000 1a.htm1].
230
(
J
Gibert et al.
[8) Awad AG. Quality of life of schizophrenic patients on
medications and implications for new drug trials. Hosp
Cornmunity Psychiatry 1992;43:262-5.
[9) Stahl SM. Selecting an atypical antipsychotic by combining
clinical experience with guidelines from clinical trials. J Clin
Psychiatry 1999;60(Suppll0):31-41.
[10) Nemeroff CB, Kinkead B, Goldstein J. Quetiapine: preclinical studies, pharmacokinetics, drug interactions, and
dosing. J Clin Psychiatry 2002;63(SuppI13):5-1 1.
[11) Arvanitis LA, Miller BG, and the Seroquel Trial 13 study
group. Multiple fixed doses of "Seroquel" (quetiapine) in
patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biol Psychiatry
1997;42:233-46.
[12) Borison RL, Arvanitis LA, Miller BG, and the US Seroquel
Study Group. ICI 204,636, an atypical antipsychotic:
efficacy and safety in a multicenter, placebo-controlled trial
in patients with schizophrenia. J Clin Psychopharmacol
1996;16:158-69.
[l3) Small JG, Hirsch SR, Arvanitis LA, Miller BG, Link CGG,
and the Seroquel Study Group. Quetiapine in patients with
schizophrenia. A high- and low-dose double-blind comparison with placebo. Arch Gen Psychiatry 1997;54:549-57.
[14) Peuskens J, Link CGG. A comparison of quetiapine and
chlorpromazine in the treatment of schizophrenia. Acta
Psychiatr Scand 1997;96:265-73.
[15) Copolov DL, Link CGG, Kowalcyk B. A multicentre,
double-blind, randomized comparison of quetiapine (ICI
204,636, "Seroquel") and haIoperidol in schizophrenia.
Psychol Med 2000;30:95-105.
[l6) Emsley RA, Raniwalla J, Bailey PJ, Jones AM, on behalf of
the PRIZE Study Group. A comparison of the effeets of
quetiapine ("Seroquel") and haloperidol in schizophrenic
patients with a history of and a demonstrated, partial
response to conventional antipsychotic treatment. Int Clin
PsychopharmacoI2000;15:121-31.
[17) World Medical Association Declaration of Helsinki: ethical
principies for medical research involving human subjeets
(revised 7 Oetober 2000). HIV Clin Trials 2001;2:92-5.
[l8) Overall]E, Gorham DR The Brief Psychiatric Rating Scale.
Psychol Rep 1962;10:799-912.
[19) Guy W ECDEU. Assessment Manual for Psychopharmacology -Revised (DHEW Publ No ADM 76-338). Rockville,
MD: US Department of Health, Education, and Welfare,
Public Health Service, Alcohol, Drug Abuse, and Mental
Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Ptograms;
1976. p 218-22.
[20) Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, EIgen K.
The UKU side effeet rating scale. A new comprehensive
rating scale for psychotropic drugs and a cross-sectional
study of side effeets in neuroleptic-treated patients. Acta
Psychiatr Scand 1987;334:1-100.
[21) A1tman DG. Practical statistics for medical research. London: Chapman and Hall; 1991.
[22) Gomez JC, Sacristan JA, Hemandez J, et al. The safety of
olanzapine compared with other antipsychotic drugs: results
of an observational prospective study in patients with
schizophrenia (EFESO Study). Pharmacoepidemiologic
Study of Olanzapine in Schizophrenia. J Clin Psychiatry
2000;61 :335-43.
[23) Srisurapanont M, Disayavanish C, Taimkaew K. Quetiapine
for schizophrenia. Cochrane Database ofSystematic Reviews
2000; CD000967.
[24) Lieberman JA, Stroup TS, McEvoy]P, et al. Effectiveness of
antipsychotic drugs in patients with chronic schizophrenia.
New Engl J Med 2005;353:1209-23.
[25) Wirshing DA, Danovitch 1, Erhart SM, Pierre JM, Wirshing
WC. Update on atypicals: practical tips to manage cornmon
side effects. Curr Psychiatry (accessed 3 April 2004) [http://
www.currentpsychiatry.coml2003_03/0303_antipsych.asp).
[26) De Nayer A, Windhager E, lrmansyah, et al. Efficacy and
tolerability of quetiapine in patients with schizophrenia
switched from other antipsychotics. Int J Psychiatry Clin
Praet 2003;7:59-66.
[27) AIlison DB, Mentore JL, Heo M, et al. Antipsychoticinduced weight gain: a comprehensive research synthesis.
Am J Psychiatry 1999;156:1686-96.
[28) Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin
Psychiatry 1999;60:358-63.
[29) Eli Lilly and Company. Zyprexa® olanzapine tabletsIUS
prescribing information. 2005 [http://pi lilIycomluslzyprexapipdf].
[30) Lamberti JS, Bellnier T, Schwarzkopf SB. Weight gain
among schizophrenic patients treated with clozapine. Am J
Psychiatry 1992;149:689-90.
[31) Brecher M, Leong R, Osterling-Koskinen L, Jones M. Longterm weight change with quetiapine in schizophrenia: data
review. Poster presented at the American Psychiatric Association Annual Meeting, Atlanta, GA, USA; 2005. Poster
NR262.
[32) Buckley PF. Efficacy of quetiapine for the treatment of
schizophrenia: a combined analysis of three placebo-controlled trials. Curr Med Res Opin 2004;20:1357-63.
[33) Goldstein J, Paulsson B, Sweitzer D, Zhong K. A review of
the evidence for somnolence with quetiapine treatment.
158th Annual Meeting of the American Psychiatric Association, Atlanta, GA, USA, 21-26 May; 2005. NR 259.
[34) Montejo Gonzalez AL, Rico-VilIademoros F, Tafalla M,
Majadas S, Spanish Working Group for the Study of
Psychotropic-related Sexual Dysfunction. A 6-month prospective observational study on the effeets of quetiapine on
sexual functioning. J Clin Psychopharmacol 2005;25:533538.
[35) Sebastian CS, Glazer W, Buckley PE Naturalistic studies of
second generation antipsychotics in the treatment of schizophrenia. Curr Med Chem 2004;11:329-42.
[36) MullenJ,Jibson MD, Sweitzer D, the QUEST StudyGroup.
A comparison of the rclative safety, efficacy, and tolerability
of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the Quetiapine
Experience with Safety and Tolerability (QUEST) study.
Clin Ther 2001;23:1839-54.
[37) Montes JM, Ciudad A, Gascon J, Gomez JC, EFESO Study
Group. Safety, effcctiveness, and quaiity of life of olanzapine
in first-episode schizophrenia: a naturalistic study. Prog
Neuropsychopharmacol Biol Psychiatry 2003;27:667 -74.
[38) Lambert M, Haro JM, Novick D, et al. Olanzapine vs. other
antipsychotics in actual out-patient settings: six months
tolerability results from the European Schizophrenia Outpatient Health Outcomes study. Acta Psychiatr Scand 2005;
111:232-43.
[39) Tognoni G, Laporte ]R. From clinical trails to drug
utiJization. In: Dukes MNG, editor. Drug utiJization studies.
Methods and uses. WHO Regional Publications European:
World Health Organization; 1993.
[40) Gomez JC, Sacristan JA, Hemandez J, et al. The safety of
olanzapine compared with other antipsychotic drugs: results
of an observational prospective study in patients with
schizophrenia (EFESO Study). Pharmacoepidemiologic
Study of Olanzapine in Schizophrenia. J Clin Psychiatry
2000;61 :335 -43.
Appendix
SOS Group members
Antonio Agüera Fernández, MD; Cristina del
Álamo Jiménez, MD; Mercedes Alba Vallejo, MD;
Ángeles Albarrán Barrado, MD; Jesús Alberdi Sudupe, MD; Beatriz Allue Torra, MD; Luis Almenar
Naturalistic study o/ quetiapine /or schizophrenia
(
Gay, MD; Yolanda Alonso de Armiño Fernandez,
MD; Susana Álvarez Avelló, MD; Luis Miguel
Alvárez Carmona, MD; Pablo Álvarez Lobato,
MD; César Antón Saiz, MD; Enrique Aragués Ortiz
de Zárate, MD; Juan José Arechederra Aranzadi,
MD; José Ramón Arteaga Darías, MD; Javier
Aztarain Diez, MD; José Vicente Baeza Alemán,
MD; Maria Montserrat Bañuelos Piñol, MD; Iván
Baques Rebull, MD; Concepció Bardoleti Casas,
MD; Ignacio Basurte Villamor, MD; Miguel Bautista Parraga, MD; Francisco Bellver Fradas, MD;
CarIes Berche Cruz, MD; José Manuel Bertolin
Guillén, MD; José Javier Blanco Blanco, MD; Joan
Manuel Blanqué López, MD; Moisés Bolívar Peralvarez, MD; Antonio Bordallo Aragón, MD; Juan
F. Bort Ruiz, MD; David Busse i Olivé, MD; Pedro
Bustos de Abajo, MD; Carmen Busuldo Vega, MD;
Arturo Cabezas Sánchez, MD; Rodrigo Cabrera
Gárate, MD; Joan Cadevall Dieguez, MD; Román
Calabuig Crespo, MD; Manuel Camacho Muñoz,
MD; José María Cámara Teruel, MD; Manuel
Camarero Candela, MD; Rossend Camon Solsona,
MD; Mateo Campillo Agusti, MD; Salustiano
Campos Velázquez, MD; Jose Cañete Crespillo,
MD; José Carmona Calvo, MD; Carlos Carmona
Palau, MD; Esther Carrasco Parrado, MD; Alfonso
Casas Losada, MD; Ma Rosario Cejas Méndez,
MD; Ramón Collado Bayona, MD; Jesús M. Cuesta
Bascones, MD; Pastora Cuevas Muñoz, MD; Miguel Ángel Cuquerella Benavent, MD; Amando de
Bernardo Barrio, MD; José de BIas Soto, MD;
Consuelo de Dios Perrino, MD; Jaime de La Torre
Hernández, MD; Ma Teresa de Lucas Taracena,
MD; Miguel Ángel de Uña Mateos, MD; Tomás de
Vicente Muñoz, MD; José Francisco Delgado González, MD; Antonio Delgado Martel, MD; Juan
Carlos Diaz del Valle, MD; Marina Diaz Marsá,
MD; Francisco Doce Feliz, MD; Jordi Domingo
Ribas, MD; María Echeveste Portugal, MD; Nabil
El Jada Qawashi, MD; Vicente Elvira Cruañes, MD;
Ma Luisa Embid Martin, MD; BIas Erkizia Amiliria,
MD; Manuel Espiñeira Álvarez, MD; José Vicente
Estalrich Canet, MD; Jose Antonio Fernández
Benítez, MD; Juan Fernández Hierro, MD; Luis
Fernández Menéndez, MD; José Luis Fernández
Sastre, MD; Andrés Fernández-Cuevas Vicario,
MD; Isabel Florez Fernández, MD; Eva Fontova
Carbonell, MD; Joan Franch Barcelo, MD; Isabel
Freire Santos, MD; Ma Asunción Fresno Gonzalez,
MD; Javier Frometa Pérez, MD; Antonio Galbis
Olivares, MD; José Mariano Galletero López, MD;
Alberto Gangoiti Gurtubay, MD; Juan Carlos García Álvarez, MD; Javier García Campayo, MD; Juan
Antonio García Mellado, MD; Blanca García Montañez, MD; Gorka García Serrano, MD; Ma Jesús
Garrido Machiñena, MD; Jose Gascon Barrachina,
MD; Francisco Gazquez Martinez, MD; Miguel
Gelabert Camarasa, MD; Susana Gil Flores, MD;
Patxi Gil López, MD; Mar Gil Villa, MD; Angel
231
Gilabert Senar, MD; José Manuel Giménez García,
MD; Juan Carlos Giménez Morales, MD; José
Gimillo Asensio, MD; Josep M. Giralt Coll, MD;
María José Gómez del Castillo, MD; Isidro Gómez
Pérez, MD; Felisa Gómez Robina, MD; Esther
Gómez Rodriguez, MD; Gixane González García,
MD; Antonio P. González González, MD; Felix
Andrés González Lorenzo, MD; Emilio González
Pablos, MD; Lidia González Segura (Residente),
MD; Ana Isabel González Vázquez, MD; Micaela
González-Quiros Menéndez de Luarca, MD; Eva
Gracia Peligero, MD; Oded Graizer Rebhuhn, MD;
Basilia Guerra Amador, MD; Antonio Guerrero
Romero, MD; Joaquin Guinart Prados, MD; Albert
Guiral Torner, MD; Miguel ÁngelHaza Duaso, MD;
Miguel Ángel Hernández Lasheras, MD; Jose Luis
Hernández Fleta, MD; Cristina Hernández Herrero,
MD; Miguel Hernández Viadel, MD; Jose Herrera
Arroyo, MD; Oscar Herreros Rodriguez, MD; Carmen Hidalgo Moratal, MD; Raúl Guillermo Ibáñez
Corrales, MD; Lorenzo Iglesias, MD; Celso Iglesias
García, MD; Ma Laura Iglesias Victor, MD; Jose
Manuel Jaquotot Arnaiz, MD; Fernando Jiménez
Mazo, MD; Luis María Larrazabal Salazar, MD; Ma
Teresa Lázaro Casasus, MD; Jon Lizárraga Sobrino,
MD; Patricia Uorens Rodríguez, MD; Francisco J
López Ibor Aliño, MD; Ángeles López López, MD;
Juan José López Plaza, MD; Luis López Sánchez,
MD; Rufino Losantos Pascual, MD; Elena Lozano
San Martin, MD; José Ángel Macías Fernández,
MD; Iñaki Madariaga Zamalloa, MD; Pedro Malabia Lieb, MD; Juan José Mancheño Barba, MD; José
Felix Marcos Frías, MD; Enrique Marcos González,
MD; José Luis Marín Morales, MD; Manel Márquez Rowe, MD; Félix Martin Herguedas, MD;
Rafael Martin Muñoz, MD; Sara Martinez Barrondo, MD; Antonio Martinez Fernández, MD; José
Luis Martinez Fernández, MD; Ricardo Martinez
Gallardo, MD; Manuel Martinez García de Castro,
MD; Miguel Martinez Roig, MD; Adolf Mas-Yebra i
Reverter, MD; Teresa Mayans Vázquez, MD; Sacramento Mayoral Moyano, MD; Pedro Antonio
Megia López, MD; Desiderio Mejias Verdú, MD;
Roger Mercade Sales, MD; María Jesús Merino
García, MD; Luis Minguez Martin, MD; Ramón
Mira Sempere, MD; Juan José Molina Castillo, MD;
José María Mongil San Juan, MD; Ángel Luis
Montejo González, MD; Jose Luis Montero Horche,
MD; José Manuel Montes Rodríguez, MD; María
Isabel Montes Santana, MD; Ma Virtudes Morales
Contreras, MD; Carmen Rosa Morales García, MD;
José Luis Morell Ocaña, MD; Crístina Moreno
Corona, MD; Pablo Luis Moreno Flores, MD; Jesús
Morillas Ariño, MD; Carlos Morillo-Velarde Quintero, MD; José Antonio Muñoz Martinez, MD; J.
Javier Mz. de Morentin Barajoan, MD; Maria Carmen Natividad Hernández, MD; Rafael Navarro
Pichardo, MD; Sergio Ocio León, MD; José Manuel
Olivares Diez, MD; Jorge Alejandro Oliver Paez,