BJP 2001 Adams 290 9

10.1192/bjp.179.4.
290 Access the most recent version at DOI:

2001, 179:290-299. BJP
CLIVE E. ADAMS, MARK K. P. FENTON, SEEMA QURAISHI and ANTHONY S. DAVID
with schizophrenia
Systematic meta-review of depot antipsychotic drugs for people
References
http://bjp.rcpsych.org/content/179/4/290#BIBL
This article cites 0 articles, 0 of which you can access for free at:
permissions
Reprints/
permissions@rcpsych.ac.uk write to
To obtain reprints or permission to reproduce material from this paper, please
to this article at
You can respond
http://bjp.rcpsych.org/letters/submit/bjprcpsych;179/4/290
from
Downloaded
The Royal College of Psychiatrists Published by
on June 10, 2014 http://bjp.rcpsych.org/
http://bjp.rcpsych.org/site/subscriptions/
go to: The British Journal of Psychiatry To subscribe to
Background Background Long-actingdepot Long-actingdepot
antipsychotic medicationis a widelyused antipsychotic medicationis a widelyused
treatment for schizophrenia. treatment for schizophrenia.
Aims Aims To synthesiserelevant systematic To synthesiserelevant systematic
Cochranereviews. Cochranereviews.
Method Method The Cochrane Database was The Cochrane Database was
searched and summarydata were searched and summarydata were
extracted fromrandomisedcontrolled extracted fromrandomisedcontrolled
clinical trials of depots. clinical trials of depots.
Results Results Standard dose depot Standard dose depot v v. .
placeboresultedin significantlyless placeboresultedin significantlyless
relapse but more movement disorders. relapse but more movementdisorders.
Those on depots ( Those on depots (v v. oral drugs) showed . oral drugs) showed
more global change on one outcome more global change on one outcome
measure; relapse and adverse effects measure; relapse and adverse effects
showedno difference.Comparisons showedno difference.Comparisons
showedno convincingadvantages for one showedno convincingadvantages for one
depot over another. depot over another.
Conclusions Conclusions Depot antipsychotics are Depot antipsychotics are
safe and effective.Theymayconfer a small safe and effective.Theymayconfer a small
benefitoveroral drugs onglobal outcome. benefitoveroral drugs onglobal outcome.
Those for whomdepots are most Those for whomdepots are most
indicatedmaynot berepresented. Large indicatedmaynot berepresented. Large
studies arerequiredto discern differences studies arerequiredto discern differences
inrelapserates andlong-termadverse inrelapserates andlong-termadverse
effects, and data on satisfaction, qualityof effects, and data on satisfaction, qualityof
life and economics. life and economics.
Declaration of interest Declaration of interest Fundedby Fundedby
the NHSHealthTechnology Assessment the NHSHealthTechnology Assessment
programme. A.S.D. is participatingin a programme. A.S.D. is participatingin a
trial fundedby Janssen-Cilagandhas been trial fundedby Janssen-Cilagandhas been
an advisor for them.The Cochrane an advisor for them.The Cochrane
Schizophrenia Grouphas receivedfunding Schizophrenia Grouphas receivedfunding
frompharmaceutical companies, the NHS frompharmaceutical companies, the NHS
and Department of Health. and Department of Health.
Antipsychotic medication is the mainstay in Antipsychotic medication is the mainstay in
the effective management of schizophrenia. the effective management of schizophrenia.
These drugs reduce symptoms and, when These drugs reduce symptoms and, when
used as a maintenance treatment, prevent used as a maintenance treatment, prevent
relapse (Davis & Andriukaitis, 1986). relapse (Davis & Andriukaitis, 1986).
Translation of this success into clinical Translation of this success into clinical
practice is attenuated by poor compliance practice is attenuated by poor compliance
(Weiden & Olfson, 1995), reasons for (Weiden & Olfson, 1995), reasons for
which include adverse effects, level of which include adverse effects, level of
insight, severity of illness, complexity of insight, severity of illness, complexity of
treatment regimen and the relationship that treatment regimen and the relationship that
patients have with mental health practi- patients have with mental health practi-
tioners (Fenton tioners (Fenton et al et al, 1997; Kemp & David, , 1997; Kemp & David,
1997). Long-acting depot antipsychotics 1997). Long-acting depot antipsychotics
were developed in the 1960s, to promote were developed in the 1960s, to promote
compliance in people with chronic psy- compliance in people with chronic psy-
chotic illnesses (Simpson, 1984). They chotic illnesses (Simpson, 1984). They
generally consist of an ester of the anti- generally consist of an ester of the anti-
psychotic drug in an oily solution injected psychotic drug in an oily solution injected
intramuscularly every 16 weeks. Depots intramuscularly every 16 weeks. Depots
simplify the treatment process by requiring, simplify the treatment process by requiring,
for example, the person to attend for injec- for example, the person to attend for injec-
tion at a specific clinic, thus guaranteeing tion at a specific clinic, thus guaranteeing
the delivery of a known quantity of medi- the delivery of a known quantity of medi-
cation (Barnes & Curson, 1994; Davis cation (Barnes & Curson, 1994; Davis et et
al al, 1994). Apart from overcoming covert , 1994). Apart from overcoming covert
non-compliance, the pharmacological non-compliance, the pharmacological
advantages for depots include the avoid- advantages for depots include the avoid-
ance of problems associated with absorp- ance of problems associated with absorp-
tion and hepatic biotransformation. tion and hepatic biotransformation.
Disadvantages include concerns over Disadvantages include concerns over
adverse effects, including tardive dyskinesia adverse effects, including tardive dyskinesia
and those associated with parenteral and those associated with parenteral
administration administration per se per se (Johnson, 1984). (Johnson, 1984).
Many clinicians have promoted the use of Many clinicians have promoted the use of
depots (Glazer & Kane, 1992; Gerlach, depots (Glazer & Kane, 1992; Gerlach,
1995; Kane 1995; Kane et al et al, 1998), yet patient and , 1998), yet patient and
clinician acceptance is variable, with the clinician acceptance is variable, with the
mode of delivery being a major stumbling mode of delivery being a major stumbling
block (reviewed in companion paper block (reviewed in companion paper
Walburn Walburn et al et al, 2001, this issue). Figures , 2001, this issue). Figures
on the use of depots are sparse but a UK on the use of depots are sparse but a UK
national household survey found that national household survey found that
approximately 29% of 390 non-hospitalised approximately 29% of 390 non-hospitalised
patients with psychotic disorders were patients with psychotic disorders were
prescribed depots (Foster prescribed depots (Foster et al et al, 1996). , 1996).
Davis undertook meta-analyses, incor- Davis undertook meta-analyses, incor-
porating several methodologies (Davis porating several methodologies (Davis et et
al al, 1994) including `mirror image' and in- , 1994) including `mirror image' and in-
fluential discontinuation trials (e.g. Hirsch fluential discontinuation trials (e.g. Hirsch
et al et al, 1973), and concluded that depots , 1973), and concluded that depots
were superior to oral drugs in many were superior to oral drugs in many
respects. Similarly, Glazer & Kane (1992) respects. Similarly, Glazer & Kane (1992)
combined several studies comparing the combined several studies comparing the
incidence of tardive dyskinesia for people incidence of tardive dyskinesia for people
on depots with those on oral agents. They on depots with those on oral agents. They
concluded that depots were no more harm- concluded that depots were no more harm-
ful than oral drugs in this respect. Because ful than oral drugs in this respect. Because
non-randomised evaluative studies, includ- non-randomised evaluative studies, includ-
ing before and after (`mirror image') trials, ing before and after (`mirror image') trials,
repeatedly have been shown to over- repeatedly have been shown to over-
estimate the effect of experimental inter- estimate the effect of experimental inter-
ventions (Chalmers ventions (Chalmers et al et al, 1983; Schulz , 1983; Schulz et et
al al, 1995), these have not been included in , 1995), these have not been included in
Cochrane schizophrenia reviews (see Cochrane schizophrenia reviews (see
Adams & Eisenbruch, 2000; Coutinho Adams & Eisenbruch, 2000; Coutinho et et
al al, 2000; Quraishi & David, 2000 , 2000; Quraishi & David, 2000a a e e; ;
Quraishi Quraishi et al et al, 2000). , 2000).
Objective Objective
The aim of this paper is to provide a The aim of this paper is to provide a
synthesis and quantitative summary of the synthesis and quantitative summary of the
findings of Cochrane depot reviews. findings of Cochrane depot reviews.
METHOD METHOD
Search Search
The search strategy, methods of selection, The search strategy, methods of selection,
quality assessment, data extraction and quality assessment, data extraction and
assimilation within each review are assimilation within each review are
published in published in The Cochrane Library The Cochrane Library. The . The
reader is referred to these reviews for reader is referred to these reviews for
explicit details. explicit details.
Selection Selection
All reviews of long-acting depot anti- All reviews of long-acting depot anti-
psychotics for schizophrenia were obtained psychotics for schizophrenia were obtained
from from The Cochrane Library The Cochrane Library (Issue 1, (Issue 1,
2000) by searching using the term 2000) by searching using the term
SCHIZOPHRENIA and scanning the titles SCHIZOPHRENIA and scanning the titles
of completed reviews. The pre-stated of completed reviews. The pre-stated
comparisons of interest were of any long- comparisons of interest were of any long-
acting depot antipsychotic medication acting depot antipsychotic medication v v. .
placebo or placebo or v v. oral medication and, finally, . oral medication and, finally,
high-dose depot high-dose depot v v. low-dose depot, for . low-dose depot, for
people with schizophrenia or schizo- people with schizophrenia or schizo-
phrenia-like illnesses. Outcomes of phrenia-like illnesses. Outcomes of a priori a priori
interest were intention-to-treat data on interest were intention-to-treat data on
death, improvement in global functioning, death, improvement in global functioning,
mental state, behaviour, social functioning, mental state, behaviour, social functioning,
quality of life, carer burden and incidence quality of life, carer burden and incidence
of attrition and adverse effects. of attrition and adverse effects.
Quality assessment Quality assessment
There was no quality assessment of the There was no quality assessment of the
primary reviews from which these data primary reviews from which these data
2 9 0 2 9 0
BRI TI S H J OURNAL OF P SYCHI ATRY BRI TI S H J OURNAL OF P SYCHI ATRY ( 2 0 0 1) , 17 9, 2 9 0 ^ 2 9 9 ( 2 0 0 1) , 17 9, 2 9 0 ^ 2 9 9 R E V I E W AR T I C L E R E V I E W AR T I C L E
Systematic meta-reviewof depot antipsychotic Systematic meta-reviewof depot antipsychotic
drugs for people with schizophrenia drugs for people with schizophrenia
{ {
CLIVE E. ADAMS, MARK K. P. FENTON, SEEMA QURAISHI CLIVE E. ADAMS, MARK K. P. FENTON, SEEMA QURAISHI
and ANTHONY S. DAVID and ANTHONY S. DAVID
{ {
See pp. 300^307, this issue. See pp. 300^307, this issue.
SYS TEMATI C META- REVI EW OF DEPOT ANTI P SYCHOTI CS SYS TEMATI C ME TA- REVI EW OF DEPOT ANTI PSYCHOTI CS
were extracted but the empirical-evidence- were extracted but the empirical-evidence-
based Cochrane reviews have, in general, based Cochrane reviews have, in general,
been shown to be of higher quality than been shown to be of higher quality than
others (Jadad others (Jadad et al et al, 1998). , 1998).
Data extraction Data extraction
Data were extracted from reviews by Data were extracted from reviews by
M.K.P.F. and re-extracted by either M.K.P.F. and re-extracted by either
C.E.A. or A.S.D. Where disagreement C.E.A. or A.S.D. Where disagreement
arose, this was resolved through discussion. arose, this was resolved through discussion.
Data analysis Data analysis
All intention-to-treat data were binary out- All intention-to-treat data were binary out-
comes. Risk ratios (RRs, random) and their comes. Risk ratios (RRs, random) and their
95% confidence intervals (CI) were ex- 95% confidence intervals (CI) were ex-
tracted from the original review and entered tracted from the original review and entered
into RevMan 4.1 (http://www.update- into RevMan 4.1 (http://www.update-
software.com/ccweb/cochrane/revman.htm). software.com/ccweb/cochrane/revman.htm).
These were calculated in preference to odds These were calculated in preference to odds
ratios because they are robust to hetero- ratios because they are robust to hetero-
geneity and more intuitive to clinicians geneity and more intuitive to clinicians
(Boissel (Boissel et al et al, 1999). In turn, where appro- , 1999). In turn, where appro-
priate, summary data from each review priate, summary data from each review
were summated and an overall RR and were summated and an overall RR and
the summary 95% CI were calculated. the summary 95% CI were calculated.
Where possible, we calculated the numbers Where possible, we calculated the numbers
needed to treat (NNT) or harm (NNH). For needed to treat (NNT) or harm (NNH). For
a test of heterogeneity we visually inspected a test of heterogeneity we visually inspected
graphs as well as employing the graphs as well as employing the w w
2 2
test. test.
There are some dangers in this overall There are some dangers in this overall
approach. Because it was not possible to approach. Because it was not possible to
avoid spurious results by counting partici- avoid spurious results by counting partici-
pants twice in the `specific depot pants twice in the `specific depot v v. other . other
depots' comparison, totals are not depots' comparison, totals are not
produced. Totalling across different produced. Totalling across different
pharmacological classes of antipsychotics pharmacological classes of antipsychotics
is statistically attractive. Power to demon- is statistically attractive. Power to demon-
strate outcomes of interest afforded by strate outcomes of interest afforded by
summation is increased so that any import- summation is increased so that any import-
ant effects that the small source trials and ant effects that the small source trials and
reviews would have missed may be high- reviews would have missed may be high-
lighted. Clinically and pharmacologically, lighted. Clinically and pharmacologically,
however, such totalling may not make however, such totalling may not make
sense. Clinicians who choose to prescribe sense. Clinicians who choose to prescribe
a specific depot may not be interested in a a specific depot may not be interested in a
summary statistic across all depots. In some summary statistic across all depots. In some
circumstances effects could cancel out in an circumstances effects could cancel out in an
overall summary statistic and causative and overall summary statistic and causative and
protective effects could be masked or can- protective effects could be masked or can-
celled out. Data using summated totals celled out. Data using summated totals
must therefore be interpreted with caution. must therefore be interpreted with caution.
RESULTS RESULTS
The original reviews The original reviews
Details of the studies included and excluded Details of the studies included and excluded
in specific reviews can be found in the in specific reviews can be found in the
individual Cochrane publications. Overall, individual Cochrane publications. Overall,
composite data for some compounds were composite data for some compounds were
sparse (see Table 1). Only 111 people have sparse (see Table 1). Only 111 people have
been randomised within trials of perphena- been randomised within trials of perphena-
zine and 117 in bromperidol decanoate zine and 117 in bromperidol decanoate
studies. On the other hand, 3348 people studies. On the other hand, 3348 people
have been randomised in trials of fluphena- have been randomised in trials of fluphena-
zine decanoate. The duration of studies in zine decanoate. The duration of studies in
the reviews ranged from 2 weeks to 3 years. the reviews ranged from 2 weeks to 3 years.
Most of the included studies employed Most of the included studies employed
operationalised definitions of schizo- operationalised definitions of schizo-
phrenia, which covered several phrenia, which covered several classifi- classifi-
cation systems and their revisions. Doses cation systems and their revisions. Doses
of depots varied from the very low of depots varied from the very low
(1.25 mg of fluphenazine every 2 weeks) (1.25 mg of fluphenazine every 2 weeks)
to the very high (2501100 mg of fluphena- to the very high (2501100 mg of fluphena-
zine weeklymonthly), although analysis zine weeklymonthly), although analysis
was undertaken only between comparable was undertaken only between comparable
dose ranges where appropriate, with most dose ranges where appropriate, with most
falling within falling within British National Formulary British National Formulary
ranges (British Medical Association & ranges (British Medical Association &
Royal Pharmaceutical Society of Great Royal Pharmaceutical Society of Great
Britain, 1999). Reviewers sought clinically Britain, 1999). Reviewers sought clinically
relevant outcomes but only a limited range relevant outcomes but only a limited range
were recorded consistently or presented in a were recorded consistently or presented in a
usable form. Overall, study attrition was usable form. Overall, study attrition was
remarkably low. For example, only about remarkably low. For example, only about
14% of those randomised to the compari- 14% of those randomised to the compari-
sons of one depot with another left the sons of one depot with another left the
trials early. Trials of oral atypical anti- trials early. Trials of oral atypical anti-
psychotic agents have rates of attrition of psychotic agents have rates of attrition of
4060% (Thornley & Adams, 1998). 4060% (Thornley & Adams, 1998).
Depot antipsychotics Depot antipsychotics v v. placebo . placebo
depots depots
Understandably, few people have been Understandably, few people have been
randomised within this comparison. Three randomised within this comparison. Three
reviews compared depot medication against reviews compared depot medication against
placebo (bromperidol, fluphenazine and placebo (bromperidol, fluphenazine and
haloperidol decanoate). Only one small haloperidol decanoate). Only one small
trial within the fluphenazine review trial within the fluphenazine review
reported mortality, with no clear differ- reported mortality, with no clear differ-
ences between groups ( ences between groups (n n54, RR 54, RR5, 5,
CI CI0.2599). One review reported on re- 0.2599). One review reported on re-
lapse (fluphenazine decanoate lapse (fluphenazine decanoate v v. placebo), . placebo),
with the results favouring the active drug with the results favouring the active drug
( (n n415, RR 415, RR0.3, CI 0.3, CI0.220.4; NNT 0.220.4; NNT2, 2,
CI CI1.82.6; see Fig. 1). Three reviews pre- 1.82.6; see Fig. 1). Three reviews pre-
sented data for the numbers leaving the sented data for the numbers leaving the
studies early. Significantly more people studies early. Significantly more people
taking depot medication stayed in the taking depot medication stayed in the
studies than those receiving placebo studies than those receiving placebo
( (n n152, RR 152, RR0.43, CI 0.43, CI0.270.71). Two 0.270.71). Two
reviews reported on the adverse effects of reviews reported on the adverse effects of
blurred vision or dry mouth. Curiously, blurred vision or dry mouth. Curiously,
these symptoms were more frequent in the these symptoms were more frequent in the
placebo group ( placebo group (n n52, RR 52, RR0.16, 0.16,
CI CI0.030.8; NNT 0.030.8; NNT3, CI 3, CI29). When 29). When
data were reported in the review as `move- data were reported in the review as `move-
ment disorders general', ment disorders general', statistical signifi- statistical signifi-
cance was achieved in favour of those taking cance was achieved in favour of those taking
placebo ( placebo (n n51, RR 51, RR20.5, 20.5, CI CI1.3338; 1.3338;
NNH NNH3, CI 3, CI6.51.9). 6.51.9).
Depot antipsychotics Depot antipsychotics v v. oral . oral
antipsychotics antipsychotics
Death is a rare, inconsistently reported out- Death is a rare, inconsistently reported out-
come. One review presented limited data come. One review presented limited data
and there is no clear effect of either depot and there is no clear effect of either depot
or oral antipsychotic ( or oral antipsychotic (n n156, RR 156, RR2, 2,
CI CI0.1921). Three reviews present data 0.1921). Three reviews present data
on global change. Significantly fewer on global change. Significantly fewer
numbers of people allocated to depot numbers of people allocated to depot
preparations had no clinically meaningful preparations had no clinically meaningful
change ( change (n n127, RR 127, RR0.7, CI 0.7, CI0.50.9; 0.50.9;
NNT NNT4, 4, CI CI2.49; see Fig. 2). For out- 2.49; see Fig. 2). For out-
comes comes such as relapse, study attrition, such as relapse, study attrition,
needing adjunctive anticholinergic medi- needing adjunctive anticholinergic medi-
cation and incidence of tardive dyskinesia, cation and incidence of tardive dyskinesia,
no clear differences were demonstrated no clear differences were demonstrated
between between those taking depot and people those taking depot and people
allocated to oral antipsychotics (relapse, allocated to oral antipsychotics (relapse,
n n844, RR 844, RR0.96, CI 0.96, CI0.81.1). 0.81.1).
Specific depot antipsychotic Specific depot antipsychotic
v v. another depot . another depot
All nine depot reviews contributed to at All nine depot reviews contributed to at
least one of the outcomes in this compari- least one of the outcomes in this compari-
son. No data were pooled because it was son. No data were pooled because it was
impossible to avoid counting data twice: impossible to avoid counting data twice:
one review's experimental group was one review's experimental group was
another's control. For all outcomes (see another's control. For all outcomes (see
Fig. 3) there were few convincing data that Fig. 3) there were few convincing data that
any real differences exist between depots. any real differences exist between depots.
All data from reviews that compared the All data from reviews that compared the
depot antipsychotic of interest with depot antipsychotic of interest with
another, for the outcome of `no important another, for the outcome of `no important
improvement in global functioning' as improvement in global functioning' as
indexed by Clinical Global Impression indexed by Clinical Global Impression
(CGI) scores (Guy, 1976), included the (CGI) scores (Guy, 1976), included the
possibility that there were no differences possibility that there were no differences
between depots. This also applies to the between depots. This also applies to the
outcome of leaving the study early (25% outcome of leaving the study early (25%
attrition attrition in the experimental groups). The in the experimental groups). The
outcome of `mental state relapse' outcome of `mental state relapse'
showed that zuclopenthixol decanoate showed that zuclopenthixol decanoate
was statistically superior to the control was statistically superior to the control
depots (largely fluphenazine decanoate) depots (largely fluphenazine decanoate)
( (n n296, RR 296, RR0.64, CI 0.64, CI0.40.9, NNT 0.40.9, NNT8, 8,
CI CI553), but this could be a function of 553), but this could be a function of
publication bias (see Discussion). publication bias (see Discussion).
High-dose depot High-dose depot v v. .
standard dose, and standard dose, and
standard dose standard dose v v. lowdose . low dose
There are limited data, but reviews found There are limited data, but reviews found
no differences between high-dose (250 mg no differences between high-dose (250 mg
of fluphenazine weekly; 200 mg of flupen- of fluphenazine weekly; 200mg of flupen-
tixol every 2 weeks) tixol every 2 weeks) v v. standard-dose . standard-dose
2 91 2 91
ADAMS E T AL ADAMS E T AL
2 9 2 2 9 2
T
a
b
l
e
1
T
a
b
l
e
1
S
u
m
m
a
r
y
o
f
i
n
c
l
u
d
e
d
r
e
v
i
e
w
s
S
u
m
m
a
r
y
o
f
i
n
c
l
u
d
e
d
r
e
v
i
e
w
s
R
e
v
i
e
w
R
e
v
i
e
w
M
e
t
h
o
d
s
M
e
t
h
o
d
s
P
a
r
t
i
c
i
p
a
n
t
s
P
a
r
t
i
c
i
p
a
n
t
s
I
n
t
e
r
v
e
n
t
i
o
n
I
n
t
e
r
v
e
n
t
i
o
n
O
u
t
c
o
m
e
s
O
u
t
c
o
m
e
s
B
r
o
m
p
e
r
i
d
o
l
B
r
o
m
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
d
e
c
a
n
o
a
t
e
A
l
l
o
c
a
t
i
o
n
:
a
l
l
4
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
A
l
l
o
c
a
t
i
o
n
:
a
l
l
4
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
D
u
r
a
t
i
o
n
:
6
m
o
n
t
h
s
^
1
y
e
a
r
D
u
r
a
t
i
o
n
:
6
m
o
n
t
h
s
^
1
y
e
a
r
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
A
g
e
:
r
a
n
g
e
2
0
^
6
5
y
e
a
r
s
A
g
e
:
r
a
n
g
e
2
0
^
6
5
y
e
a
r
s
G
e
n
d
e
r
:
G
e
n
d
e
r
:
44
5
5
M
;
5
5
M
;
44
4
2
F
4
2
F
NN
4
,
4
,
nn
1
1
7
1
1
7
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
s
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
s
1
.
B
r
o
m
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
5
0
^
2
4
2
m
g
/
m
o
n
t
h
(
1
.
B
r
o
m
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
5
0
^
2
4
2
m
g
/
m
o
n
t
h
(
nn
5
8
)
5
8
)
2
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
1
6
.
7
^
3
0
0
m
g
/
m
o
n
t
h
(
2
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
1
6
.
7
^
3
0
0
m
g
/
m
o
n
t
h
(
nn
3
9
)
3
9
)
3
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
1
1
9
m
g
/
m
o
n
t
h
(
3
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
1
1
9
m
g
/
m
o
n
t
h
(
nn
1
0
)
1
0
)
4
.
P
l
a
c
e
b
o
(
4
.
P
l
a
c
e
b
o
(
nn
1
0
)
1
0
)
G
l
o
b
a
l
e
f
f
e
c
t
(
C
G
I
)
G
l
o
b
a
l
e
f
f
e
c
t
(
C
G
I
)
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
M
e
n
t
a
l
s
t
a
t
e
(
u
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
)
M
e
n
t
a
l
s
t
a
t
e
(
u
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
)
S
i
d
e
-
e
f
f
e
c
t
s
(
D
O
T
E
S
)
S
i
d
e
-
e
f
f
e
c
t
s
(
D
O
T
E
S
)
F
l
u
p
e
n
t
i
x
o
l
F
l
u
p
e
n
t
i
x
o
l
d
e
p
o
t
d
e
p
o
t
A
l
l
o
c
a
t
i
o
n
:
a
l
l
1
5
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
A
l
l
o
c
a
t
i
o
n
:
a
l
l
1
5
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
D
u
r
a
t
i
o
n
:
8
w
e
e
k
s
^
2
y
e
a
r
s
D
u
r
a
t
i
o
n
:
8
w
e
e
k
s
^
2
y
e
a
r
s
I
n
f
o
r
m
e
d
c
o
n
s
e
n
t
f
r
o
m
p
a
r
t
i
c
i
p
a
n
t
s
I
n
f
o
r
m
e
d
c
o
n
s
e
n
t
f
r
o
m
p
a
r
t
i
c
i
p
a
n
t
s
i
n
5
s
t
u
d
i
e
s
i
n
5
s
t
u
d
i
e
s
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
1
^
2
9
y
e
a
r
s
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
1
^
2
9
y
e
a
r
s
NN
1
5
,
1
5
,
nn
6
1
5
6
1
5
G
e
n
d
e
r
:
G
e
n
d
e
r
:
44
3
7
3
M
;
3
7
3
M
;
44
1
9
3
F
,
u
n
k
n
o
w
n
1
9
3
F
,
u
n
k
n
o
w
n
i
n
1
t
r
i
a
l
i
n
1
t
r
i
a
l
A
g
e
:
r
a
n
g
e
1
7
^
7
9
y
e
a
r
s
A
g
e
:
r
a
n
g
e
1
7
^
7
9
y
e
a
r
s
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
1
.
F
l
u
p
e
n
t
i
x
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
9
m
g
/
2
^
3
w
e
e
k
s
t
o
3
0
0
m
g
/
1
.
F
l
u
p
e
n
t
i
x
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
9
m
g
/
2
^
3
w
e
e
k
s
t
o
3
0
0
m
g
/
2
^
3
w
e
e
k
s
(
2
^
3
w
e
e
k
s
(
nn
3
5
9
)
3
5
9
)
2
.
C
l
o
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
5
0
^
6
0
0
m
g
/
2
^
4
w
e
e
k
s
2
.
C
l
o
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
5
0
^
6
0
0
m
g
/
2
^
4
w
e
e
k
s
((
nn
4
8
)
4
8
)
3
.
F
l
u
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
2
5
m
g
/
3
w
e
e
k
s
,
r
a
n
g
e
3
.
F
l
u
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
2
5
m
g
/
3
w
e
e
k
s
,
r
a
n
g
e
1
0
^
5
0
m
g
(
1
0
^
5
0
m
g
(
nn
1
3
9
)
1
3
9
)
4
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
1
5
1
m
g
/
i
n
j
e
c
t
i
o
n
(
4
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
1
5
1
m
g
/
i
n
j
e
c
t
i
o
n
(
nn
1
6
)
1
6
)
5
.
P
e
n
f
l
u
r
i
d
o
l
:
m
e
a
n
d
o
s
e
2
0
m
g
/
w
e
e
k
(
5
.
P
e
n
f
l
u
r
i
d
o
l
:
m
e
a
n
d
o
s
e
2
0
m
g
/
w
e
e
k
(
nn
3
0
)
3
0
)
6
.
P
i
p
o
t
h
i
a
z
i
n
e
:
m
e
a
n
d
o
s
e
1
0
0
m
g
/
m
o
n
t
h
(
6
.
P
i
p
o
t
h
i
a
z
i
n
e
:
m
e
a
n
d
o
s
e
1
0
0
m
g
/
m
o
n
t
h
(
nn
2
3
)
2
3
)
D
e
a
t
h
D
e
a
t
h
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
R
e
l
a
p
s
e
R
e
l
a
p
s
e
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
M
e
n
t
a
l
s
t
a
t
e
(
B
P
R
S
,
C
P
R
S
,
H
R
S
D
)
M
e
n
t
a
l
s
t
a
t
e
(
B
P
R
S
,
C
P
R
S
,
H
R
S
D
)
S
i
d
e
-
e
f
f
e
c
t
s
(
S
A
S
)
S
i
d
e
-
e
f
f
e
c
t
s
(
S
A
S
)
F
l
u
p
h
e
n
a
z
i
n
e
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
d
e
c
a
n
o
a
t
e
A
l
l
o
c
a
t
i
o
n
:
a
l
l
4
8
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
A
l
l
o
c
a
t
i
o
n
:
a
l
l
4
8
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
B
l
i
n
d
i
n
g
:
v
a
r
y
i
n
g
d
e
g
r
e
e
s
o
f
d
o
u
b
l
e
B
l
i
n
d
i
n
g
:
v
a
r
y
i
n
g
d
e
g
r
e
e
s
o
f
d
o
u
b
l
e
b
l
i
n
d
i
n
g
b
l
i
n
d
i
n
g
D
u
r
a
t
i
o
n
:
2
w
e
e
k
s
^
2
y
e
a
r
s
D
u
r
a
t
i
o
n
:
2
w
e
e
k
s
^
2
y
e
a
r
s
T
w
o
s
t
u
d
i
e
s
u
s
e
d
a
c
r
o
s
s
o
v
e
r
T
w
o
s
t
u
d
i
e
s
u
s
e
d
a
c
r
o
s
s
o
v
e
r
m
e
t
h
o
d
m
e
t
h
o
d
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
a
n
d
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
a
n
d
s
c
h
i
z
o
a
f
f
e
c
t
i
v
e
d
i
s
o
r
d
e
r
s
c
h
i
z
o
a
f
f
e
c
t
i
v
e
d
i
s
o
r
d
e
r
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
r
a
n
g
e
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
r
a
n
g
e
55
2
^
3
9
2
^
3
9
y
e
a
r
s
y
e
a
r
s
NN
4
8
,
4
8
,
nn
3
3
4
8
3
3
4
8
G
e
n
d
e
r
:
G
e
n
d
e
r
:
44
1
3
1
8
M
;
1
3
1
8
M
;
44
1
0
5
4
F
1
0
5
4
F
A
g
e
:
r
a
n
g
e
2
4
^
7
0
y
e
a
r
s
A
g
e
:
r
a
n
g
e
2
4
^
7
0
y
e
a
r
s
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
1
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
5
1
.
7
3
m
g
,
r
a
n
g
e
(
l
o
w
1
.
2
5
^
1
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
5
1
.
7
3
m
g
,
r
a
n
g
e
(
l
o
w
1
.
2
5
^
6
.
2
5
m
g
)
s
t
a
n
d
a
r
d
^
h
i
g
h
d
o
s
e
2
5
^
1
1
0
0
m
g
/
2
^
4
w
e
e
k
s
(
6
.
2
5
m
g
)
s
t
a
n
d
a
r
d
^
h
i
g
h
d
o
s
e
2
5
^
1
1
0
0
m
g
/
2
^
4
w
e
e
k
s
(
nn
1
9
6
3
)
1
9
6
3
)
2
.
B
r
o
m
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
2
4
2
m
g
/
m
o
n
t
h
,
r
a
n
g
e
2
.
B
r
o
m
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
2
4
2
m
g
/
m
o
n
t
h
,
r
a
n
g
e
6
4
^
4
0
0
m
g
(
6
4
^
4
0
0
m
g
(
nn
2
3
)
2
3
)
3
.
C
h
l
o
r
p
r
o
m
a
z
i
n
e
:
d
o
s
e
r
a
n
g
e
5
0
^
1
0
0
m
g
/
d
a
y
(
3
.
C
h
l
o
r
p
r
o
m
a
z
i
n
e
:
d
o
s
e
r
a
n
g
e
5
0
^
1
0
0
m
g
/
d
a
y
(
nn
3
6
)
3
6
)
4
.
C
l
o
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
2
2
0
m
g
/
3
^
4
w
e
e
k
s
,
r
a
n
g
e
4
.
C
l
o
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
2
2
0
m
g
/
3
^
4
w
e
e
k
s
,
r
a
n
g
e
2
0
0
m
g
/
4
w
e
e
k
s
t
o
6
0
0
m
g
/
2
w
e
e
k
s
(
2
0
0
m
g
/
4
w
e
e
k
s
t
o
6
0
0
m
g
/
2
w
e
e
k
s
(
nn
1
9
)
1
9
)
5
.
F
l
u
p
e
n
t
i
x
o
l
:
d
o
s
e
r
a
n
g
e
3
0
^
4
0
m
g
/
2
^
4
w
e
e
k
s
(
5
.
F
l
u
p
e
n
t
i
x
o
l
:
d
o
s
e
r
a
n
g
e
3
0
^
4
0
m
g
/
2
^
4
w
e
e
k
s
(
nn
4
8
)
4
8
)
6
.
F
l
u
p
h
e
n
a
z
i
n
e
h
y
d
r
o
c
h
l
o
r
i
d
e
(
o
r
a
l
)
:
m
e
a
n
d
o
s
e
1
8
.
9
m
g
,
d
o
s
e
6
.
F
l
u
p
h
e
n
a
z
i
n
e
h
y
d
r
o
c
h
l
o
r
i
d
e
(
o
r
a
l
)
:
m
e
a
n
d
o
s
e
1
8
.
9
m
g
,
d
o
s
e
r
a
n
g
e
2
.
5
^
6
0
m
g
/
d
a
y
(
r
a
n
g
e
2
.
5
^
6
0
m
g
/
d
a
y
(
nn
3
9
6
)
3
9
6
)
7
.
F
l
u
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
:
d
o
s
e
r
a
n
g
e
2
.
5
^
3
8
7
.
5
m
g
/
2
^
4
w
e
e
k
s
7
.
F
l
u
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
:
d
o
s
e
r
a
n
g
e
2
.
5
^
3
8
7
.
5
m
g
/
2
^
4
w
e
e
k
s
((
nn
9
6
)
9
6
)
8
.
F
l
u
s
p
i
r
i
l
e
n
e
d
e
c
a
n
o
a
t
e
:
3
^
2
0
m
g
/
w
e
e
k
(
8
.
F
l
u
s
p
i
r
i
l
e
n
e
d
e
c
a
n
o
a
t
e
:
3
^
2
0
m
g
/
w
e
e
k
(
nn
9
3
)
9
3
)
9
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
1
0
9
.
4
m
g
,
r
a
n
g
e
1
5
^
9
0
0
m
g
/
9
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
1
0
9
.
4
m
g
,
r
a
n
g
e
1
5
^
9
0
0
m
g
/
2
^
4
w
e
e
k
s
(
2
^
4
w
e
e
k
s
(
nn
1
4
2
)
1
4
2
)
1
0
.
P
e
n
f
l
u
r
i
d
o
l
:
d
o
s
e
r
a
n
g
e
2
0
^
1
6
0
m
g
(
1
0
.
P
e
n
f
l
u
r
i
d
o
l
:
d
o
s
e
r
a
n
g
e
2
0
^
1
6
0
m
g
(
nn
2
7
)
2
7
)
1
1
.
P
i
m
o
z
i
d
e
:
d
o
s
e
8
m
g
/
d
a
y
^
w
e
e
k
,
r
a
n
g
e
1
0
^
6
0
m
g
(
1
1
.
P
i
m
o
z
i
d
e
:
d
o
s
e
8
m
g
/
d
a
y
^
w
e
e
k
,
r
a
n
g
e
1
0
^
6
0
m
g
(
nn
7
0
)
7
0
)
1
2
.
P
i
p
o
t
i
a
z
i
n
e
p
a
l
m
i
t
a
t
e
:
m
e
a
n
d
o
s
e
8
8
.
3
m
g
,
d
o
s
e
r
a
n
g
e
1
2
.
P
i
p
o
t
i
a
z
i
n
e
p
a
l
m
i
t
a
t
e
:
m
e
a
n
d
o
s
e
8
8
.
3
m
g
,
d
o
s
e
r
a
n
g
e
6
.
2
5
^
4
0
0
m
g
/
2
^
5
w
e
e
k
s
(
6
.
2
5
^
4
0
0
m
g
/
2
^
5
w
e
e
k
s
(
nn
1
8
4
)
1
8
4
)
1
3
.
P
l
a
c
e
b
o
(
1
3
.
P
l
a
c
e
b
o
(
nn
7
5
)
7
5
)
1
4
.
T
r
i
f
l
u
o
p
e
r
a
z
i
n
e
:
d
o
s
e
1
0
m
g
/
d
a
y
(
1
4
.
T
r
i
f
l
u
o
p
e
r
a
z
i
n
e
:
d
o
s
e
1
0
m
g
/
d
a
y
(
nn
1
7
)
1
7
)
G
l
o
b
a
l
i
m
p
r
o
v
e
m
e
n
t
(
C
G
I
)
G
l
o
b
a
l
i
m
p
r
o
v
e
m
e
n
t
(
C
G
I
)
M
e
n
t
a
l
s
t
a
t
e
(
B
P
R
S
,
C
P
R
S
)
M
e
n
t
a
l
s
t
a
t
e
(
B
P
R
S
,
C
P
R
S
)
B
e
h
a
v
i
o
u
r
(
N
O
S
I
E
)
B
e
h
a
v
i
o
u
r
(
N
O
S
I
E
)
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
S
i
d
e
-
e
f
f
e
c
t
s
S
i
d
e
-
e
f
f
e
c
t
s
2 93 2 93
F
l
u
p
h
e
n
a
z
i
n
e
F
l
u
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
e
n
a
n
t
h
a
t
e
A
l
l
o
c
a
t
i
o
n
:
a
l
l
1
4
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
A
l
l
o
c
a
t
i
o
n
:
a
l
l
1
4
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
D
u
r
a
t
i
o
n
:
2
w
e
e
k
s
^
1
y
e
a
r
D
u
r
a
t
i
o
n
:
2
w
e
e
k
s
^
1
y
e
a
r
O
n
e
s
t
u
d
y
u
s
e
d
a
c
r
o
s
s
o
v
e
r
d
e
s
i
g
n
O
n
e
s
t
u
d
y
u
s
e
d
a
c
r
o
s
s
o
v
e
r
d
e
s
i
g
n
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
a
c
u
t
e
t
o
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
a
c
u
t
e
t
o
h
o
s
p
i
t
a
l
i
s
e
d
h
o
s
p
i
t
a
l
i
s
e
d
44
2
y
e
a
r
s
2
y
e
a
r
s
NN
1
4
,
1
4
,
nn
4
5
1
4
5
1
A
g
e
:
r
a
n
g
e
1
7
^
6
5
y
e
a
r
s
A
g
e
:
r
a
n
g
e
1
7
^
6
5
y
e
a
r
s
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
1
.
F
l
u
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
:
d
o
s
e
r
a
n
g
e
3
.
5
^
3
8
7
.
5
m
g
/
2
^
4
w
e
e
k
s
1
.
F
l
u
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
:
d
o
s
e
r
a
n
g
e
3
.
5
^
3
8
7
.
5
m
g
/
2
^
4
w
e
e
k
s
((
nn
2
7
9
)
2
7
9
)
2
.
C
h
l
o
r
p
r
o
m
a
z
i
n
e
:
m
e
a
n
d
o
s
e
3
8
8
m
g
/
d
a
y
(
2
.
C
h
l
o
r
p
r
o
m
a
z
i
n
e
:
m
e
a
n
d
o
s
e
3
8
8
m
g
/
d
a
y
(
nn
1
5
)
1
5
)
3
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
2
.
5
^
5
0
0
m
g
/
2
^
4
w
e
e
k
s
3
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
2
.
5
^
5
0
0
m
g
/
2
^
4
w
e
e
k
s
((
nn
2
8
4
)
2
8
4
)
4
.
F
l
u
s
p
i
r
i
l
e
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
1
^
1
4
m
g
/
w
e
e
k
(
4
.
F
l
u
s
p
i
r
i
l
e
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
1
^
1
4
m
g
/
w
e
e
k
(
nn
3
1
)
3
1
)
5
.
P
i
p
o
t
i
a
z
i
n
e
p
a
l
m
i
t
a
t
e
:
d
o
s
e
r
a
n
g
e
2
5
^
2
5
0
m
g
/
2
^
4
w
e
e
k
s
5
.
P
i
p
o
t
i
a
z
i
n
e
p
a
l
m
i
t
a
t
e
:
d
o
s
e
r
a
n
g
e
2
5
^
2
5
0
m
g
/
2
^
4
w
e
e
k
s
((
nn
4
2
)
4
2
)
G
l
o
b
a
l
e
f
f
e
c
t
(
C
G
I
)
G
l
o
b
a
l
e
f
f
e
c
t
(
C
G
I
)
M
e
n
t
a
l
s
t
a
t
e
(
B
P
R
S
)
M
e
n
t
a
l
s
t
a
t
e
(
B
P
R
S
)
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
S
i
d
e
-
e
f
f
e
c
t
s
(
B
o
r
d
e
l
e
a
u
S
c
a
l
e
,
H
R
S
D
)
S
i
d
e
-
e
f
f
e
c
t
s
(
B
o
r
d
e
l
e
a
u
S
c
a
l
e
,
H
R
S
D
)
F
l
u
s
p
i
r
i
l
e
n
e
F
l
u
s
p
i
r
i
l
e
n
e
A
l
l
o
c
a
t
i
o
n
:
a
l
l
7
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
A
l
l
o
c
a
t
i
o
n
:
a
l
l
7
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
D
u
r
a
t
i
o
n
:
4
w
e
e
k
s
^
6
m
o
n
t
h
s
D
u
r
a
t
i
o
n
:
4
w
e
e
k
s
^
6
m
o
n
t
h
s
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
2
^
3
9
y
e
a
r
s
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
2
^
3
9
y
e
a
r
s
NN
7
,
7
,
nn
2
9
0
2
9
0
A
g
e
:
r
a
n
g
e
1
6
^
8
0
y
e
a
r
s
A
g
e
:
r
a
n
g
e
1
6
^
8
0
y
e
a
r
s
G
e
n
d
e
r
:
G
e
n
d
e
r
:
44
9
8
M
;
9
8
M
;
44
1
3
7
F
1
3
7
F
S
e
t
t
i
n
g
:
i
n
-
p
a
t
i
e
n
t
a
n
d
c
o
m
m
u
n
i
t
y
S
e
t
t
i
n
g
:
i
n
-
p
a
t
i
e
n
t
a
n
d
c
o
m
m
u
n
i
t
y
1
.
F
l
u
s
p
i
r
i
l
e
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
1
^
2
3
m
g
/
1
^
2
w
e
e
k
s
1
.
F
l
u
s
p
i
r
i
l
e
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
1
^
2
3
m
g
/
1
^
2
w
e
e
k
s
((
nn
1
6
0
)
1
6
0
)
2
.
C
h
l
o
r
p
r
o
m
a
z
i
n
e
:
d
o
s
e
r
a
n
g
e
3
7
0
^
7
2
0
m
g
/
d
a
y
(
2
.
C
h
l
o
r
p
r
o
m
a
z
i
n
e
:
d
o
s
e
r
a
n
g
e
3
7
0
^
7
2
0
m
g
/
d
a
y
(
nn
2
0
)
2
0
)
3
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
2
5
^
1
5
0
m
g
/
2
^
3
w
e
e
k
s
3
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
2
5
^
1
5
0
m
g
/
2
^
3
w
e
e
k
s
((
nn
7
1
)
7
1
)
4
.
F
l
u
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
:
m
e
a
n
d
o
s
e
7
.
5
5
m
g
/
w
e
e
k
(
4
.
F
l
u
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
:
m
e
a
n
d
o
s
e
7
.
5
5
m
g
/
w
e
e
k
(
nn
2
6
)
2
6
)
5
.
P
i
p
o
t
i
a
z
i
n
e
u
n
d
e
c
y
l
e
n
a
t
e
:
m
e
a
n
d
o
s
e
1
0
3
.
8
m
g
/
2
w
e
e
k
s
5
.
P
i
p
o
t
i
a
z
i
n
e
u
n
d
e
c
y
l
e
n
a
t
e
:
m
e
a
n
d
o
s
e
1
0
3
.
8
m
g
/
2
w
e
e
k
s
((
nn
1
3
)
1
3
)
G
l
o
b
a
l
e
f
f
e
c
t
(
C
G
I
)
G
l
o
b
a
l
e
f
f
e
c
t
(
C
G
I
)
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
S
i
d
e
-
e
f
f
e
c
t
s
(
U
K
U
)
S
i
d
e
-
e
f
f
e
c
t
s
(
U
K
U
)
H
a
l
o
p
e
r
i
d
o
l
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
d
e
c
a
n
o
a
t
e
A
l
l
o
c
a
t
i
o
n
:
a
l
l
1
1
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
A
l
l
o
c
a
t
i
o
n
:
a
l
l
1
1
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
D
u
r
a
t
i
o
n
:
1
6
^
6
0
w
e
e
k
s
D
u
r
a
t
i
o
n
:
1
6
^
6
0
w
e
e
k
s
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
o
r
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
o
r
s
c
h
i
z
o
a
f
f
e
c
t
i
v
e
d
i
s
o
r
d
e
r
s
c
h
i
z
o
a
f
f
e
c
t
i
v
e
d
i
s
o
r
d
e
r
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
0
^
3
8
y
e
a
r
s
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
0
^
3
8
y
e
a
r
s
NN
1
1
,
1
1
,
nn
4
5
5
4
5
5
A
g
e
:
r
a
n
g
e
1
8
^
6
6
y
e
a
r
s
A
g
e
:
r
a
n
g
e
1
8
^
6
6
y
e
a
r
s
G
e
n
d
e
r
:
G
e
n
d
e
r
:
44
2
6
4
M
;
2
6
4
M
;
44
1
7
5
F
1
7
5
F
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
1
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
1
5
^
9
0
0
m
g
/
2
^
4
w
e
e
k
s
1
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
1
5
^
9
0
0
m
g
/
2
^
4
w
e
e
k
s
((
nn
2
3
8
)
2
3
8
)
2
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
2
.
5
^
3
0
0
m
g
/
2
^
4
w
e
e
k
s
2
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
2
.
5
^
3
0
0
m
g
/
2
^
4
w
e
e
k
s
((
nn
1
2
5
)
1
2
5
)
3
.
H
a
l
o
p
e
r
i
d
o
l
(
o
r
a
l
)
:
d
o
s
e
n
o
t
s
p
e
c
i
f
i
e
d
(
3
.
H
a
l
o
p
e
r
i
d
o
l
(
o
r
a
l
)
:
d
o
s
e
n
o
t
s
p
e
c
i
f
i
e
d
(
nn
1
1
)
1
1
)
4
.
P
i
p
o
t
i
a
z
i
n
e
p
a
l
m
i
t
a
t
e
:
d
o
s
e
r
a
n
g
e
5
0
^
1
2
5
m
g
/
m
o
n
t
h
(
4
.
P
i
p
o
t
i
a
z
i
n
e
p
a
l
m
i
t
a
t
e
:
d
o
s
e
r
a
n
g
e
5
0
^
1
2
5
m
g
/
m
o
n
t
h
(
nn
2
0
)
2
0
)
5
.
P
l
a
c
e
b
o
(
5
.
P
l
a
c
e
b
o
(
nn
3
9
)
3
9
)
6
.
Z
u
c
l
o
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
2
8
4
m
g
/
m
o
n
t
h
(
6
.
Z
u
c
l
o
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
m
e
a
n
d
o
s
e
2
8
4
m
g
/
m
o
n
t
h
(
nn
2
3
)
2
3
)
D
e
a
t
h
D
e
a
t
h
G
l
o
b
a
l
i
m
p
r
e
s
s
i
o
n
(
C
G
I
)
G
l
o
b
a
l
i
m
p
r
e
s
s
i
o
n
(
C
G
I
)
M
e
n
t
a
l
s
t
a
t
e
(
B
P
R
S
,
C
P
R
S
,
d
e
p
r
e
s
s
i
o
n
,
M
e
n
t
a
l
s
t
a
t
e
(
B
P
R
S
,
C
P
R
S
,
d
e
p
r
e
s
s
i
o
n
,
K
r
a
w
i
e
c
k
a
S
c
a
l
e
,
M
A
D
R
S
)
K
r
a
w
i
e
c
k
a
S
c
a
l
e
,
M
A
D
R
S
)
B
e
h
a
v
i
o
u
r
(
W
i
n
g
W
a
r
d
S
c
a
l
e
)
B
e
h
a
v
i
o
u
r
(
W
i
n
g
W
a
r
d
S
c
a
l
e
)
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
S
i
d
e
-
e
f
f
e
c
t
s
(
A
I
M
S
,
B
o
r
d
e
l
e
a
u
S
c
a
l
e
,
S
A
S
,
S
i
d
e
-
e
f
f
e
c
t
s
(
A
I
M
S
,
B
o
r
d
e
l
e
a
u
S
c
a
l
e
,
S
A
S
,
U
K
U
)
U
K
U
)
P
e
r
p
h
e
n
a
z
i
n
e
P
e
r
p
h
e
n
a
z
i
n
e
d
e
p
o
t
d
e
p
o
t
A
l
l
o
c
a
t
i
o
n
:
b
o
t
h
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
A
l
l
o
c
a
t
i
o
n
:
b
o
t
h
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
B
l
i
n
d
i
n
g
:
d
o
u
b
l
e
,
n
o
f
u
r
t
h
e
r
d
e
t
a
i
l
s
D
u
r
a
t
i
o
n
:
r
a
n
g
e
6
w
e
e
k
s
^
6
m
o
n
t
h
s
D
u
r
a
t
i
o
n
:
r
a
n
g
e
6
w
e
e
k
s
^
6
m
o
n
t
h
s
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
o
r
a
c
u
t
e
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
o
r
a
c
u
t
e
p
s
y
c
h
o
s
i
s
p
s
y
c
h
o
s
i
s
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
55
2
^
2
5
y
e
a
r
s
2
^
2
5
y
e
a
r
s
NN
2
,
2
,
nn
2
3
6
2
3
6
A
g
e
:
r
a
n
g
e
1
8
t
o
A
g
e
:
r
a
n
g
e
1
8
t
o
44
6
0
y
e
a
r
s
6
0
y
e
a
r
s
G
e
n
d
e
r
:
G
e
n
d
e
r
:
44
1
3
5
M
;
1
3
5
M
;
44
8
7
F
8
7
F
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
1
.
P
e
r
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
2
0
^
6
0
0
m
g
/
2
w
e
e
k
s
1
.
P
e
r
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
2
0
^
6
0
0
m
g
/
2
w
e
e
k
s
((
nn
1
1
1
)
1
1
1
)
2
.
C
l
o
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
5
0
^
8
0
0
m
g
/
2
w
e
e
k
s
2
.
C
l
o
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
5
0
^
8
0
0
m
g
/
2
w
e
e
k
s
((
nn
8
7
)
8
7
)
3
.
P
e
r
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
:
m
e
a
n
d
o
s
e
1
0
8
.
5
m
g
/
2
w
e
e
k
s
3
.
P
e
r
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
:
m
e
a
n
d
o
s
e
1
0
8
.
5
m
g
/
2
w
e
e
k
s
((
nn
2
4
)
2
4
)
D
e
a
t
h
D
e
a
t
h
G
l
o
b
a
l
i
m
p
r
e
s
s
i
o
n
(
C
G
I
)
G
l
o
b
a
l
i
m
p
r
e
s
s
i
o
n
(
C
G
I
)
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
S
i
d
e
-
e
f
f
e
c
t
s
S
i
d
e
-
e
f
f
e
c
t
s
C
o
n
t
i
n
u
e
d
C
o
n
t
i
n
u
e
d
2 9 4 2 9 4
T
a
b
l
e
1
T
a
b
l
e
1
C
o
n
t
i
n
u
e
d
C
o
n
t
i
n
u
e
d
R
e
v
i
e
w
R
e
v
i
e
w
M
e
t
h
o
d
s
M
e
t
h
o
d
s
P
a
r
t
i
c
i
p
a
n
t
s
P
a
r
t
i
c
i
p
a
n
t
s
I
n
t
e
r
v
e
n
t
i
o
n
I
n
t
e
r
v
e
n
t
i
o
n
O
u
t
c
o
m
e
s
O
u
t
c
o
m
e
s
P
i
p
o
t
i
a
z
i
n
e
P
i
p
o
t
i
a
z
i
n
e
d
e
p
o
t
d
e
p
o
t
A
l
l
o
c
a
t
i
o
n
:
a
l
l
1
4
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
A
l
l
o
c
a
t
i
o
n
:
a
l
l
1
4
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
B
l
i
n
d
i
n
g
:
v
a
r
y
i
n
g
d
e
g
r
e
e
s
o
f
d
o
u
b
l
e
B
l
i
n
d
i
n
g
:
v
a
r
y
i
n
g
d
e
g
r
e
e
s
o
f
d
o
u
b
l
e
b
l
i
n
d
i
n
g
b
l
i
n
d
i
n
g
D
u
r
a
t
i
o
n
:
r
a
n
g
e
1
1
w
e
e
k
s
^
3
y
e
a
r
s
D
u
r
a
t
i
o
n
:
r
a
n
g
e
1
1
w
e
e
k
s
^
3
y
e
a
r
s
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
r
a
n
g
e
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
r
a
n
g
e
55
3
^
3
4
y
e
a
r
s
3
^
3
4
y
e
a
r
s
NN
1
4
,
1
4
,
nn
7
7
1
7
7
1
A
g
e
:
r
a
n
g
e
1
8
^
6
9
y
e
a
r
s
A
g
e
:
r
a
n
g
e
1
8
^
6
9
y
e
a
r
s
G
e
n
d
e
r
:
G
e
n
d
e
r
:
44
3
8
0
M
;
3
8
0
M
;
44
2
0
5
F
2
0
5
F
I
n
f
o
r
m
e
d
c
o
n
s
e
n
t
g
i
v
e
n
i
n
2
s
t
u
d
i
e
s
I
n
f
o
r
m
e
d
c
o
n
s
e
n
t
g
i
v
e
n
i
n
2
s
t
u
d
i
e
s
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
1
.
P
i
p
o
t
i
a
z
i
n
e
p
a
l
m
i
t
a
t
e
a
n
d
u
n
d
e
c
y
l
e
n
a
t
e
(
1
.
P
i
p
o
t
i
a
z
i
n
e
p
a
l
m
i
t
a
t
e
a
n
d
u
n
d
e
c
y
l
e
n
a
t
e
(
nn
3
6
5
)
3
6
5
)
2
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
(
2
.
F
l
u
p
h
e
n
a
z
i
n
e
d
e
c
a
n
o
a
t
e
(
nn
1
9
8
)
1
9
8
)
3
.
F
l
u
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
(
3
.
F
l
u
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
(
nn
8
7
)
8
7
)
4
.
F
l
u
s
p
i
r
i
l
e
n
e
(
4
.
F
l
u
s
p
i
r
i
l
e
n
e
(
nn
1
3
)
1
3
)
5
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
(
5
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
(
nn
2
1
)
2
1
)
6
.
O
r
a
l
a
n
t
i
p
s
y
c
h
o
t
i
c
s
(
v
a
r
i
o
u
s
)
(
6
.
O
r
a
l
a
n
t
i
p
s
y
c
h
o
t
i
c
s
(
v
a
r
i
o
u
s
)
(
nn
8
7
)
8
7
)
G
l
o
b
a
l
i
m
p
r
e
s
s
i
o
n
(
C
G
I
)
G
l
o
b
a
l
i
m
p
r
e
s
s
i
o
n
(
C
G
I
)
M
e
n
t
a
l
s
t
a
t
e
(
B
P
R
S
,
H
R
S
D
)
M
e
n
t
a
l
s
t
a
t
e
(
B
P
R
S
,
H
R
S
D
)
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
S
i
d
e
-
e
f
f
e
c
t
s
(
A
I
M
S
,
B
o
r
d
e
l
e
a
u
S
c
a
l
e
,
S
i
d
e
-
e
f
f
e
c
t
s
(
A
I
M
S
,
B
o
r
d
e
l
e
a
u
S
c
a
l
e
,
D
O
T
E
S
)
D
O
T
E
S
)
Z
u
c
l
o
p
e
n
t
h
i
x
o
l
Z
u
c
l
o
p
e
n
t
h
i
x
o
l
d
e
p
o
t
d
e
p
o
t
A
l
l
o
c
a
t
i
o
n
:
a
l
l
4
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
A
l
l
o
c
a
t
i
o
n
:
a
l
l
4
s
t
u
d
i
e
s
r
a
n
d
o
m
i
s
e
d
B
l
i
n
d
i
n
g
:
v
a
r
y
i
n
g
d
e
g
r
e
e
s
o
f
d
o
u
b
l
e
B
l
i
n
d
i
n
g
:
v
a
r
y
i
n
g
d
e
g
r
e
e
s
o
f
d
o
u
b
l
e
b
l
i
n
d
i
n
g
b
l
i
n
d
i
n
g
D
u
r
a
t
i
o
n
:
1
2
w
e
e
k
s
^
1
y
e
a
r
D
u
r
a
t
i
o
n
:
1
2
w
e
e
k
s
^
1
y
e
a
r
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
D
i
a
g
n
o
s
i
s
:
s
c
h
i
z
o
p
h
r
e
n
i
a
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
D
u
r
a
t
i
o
n
o
f
i
l
l
n
e
s
s
:
44
2
y
e
a
r
s
2
y
e
a
r
s
NN
4
,
4
,
nn
3
3
2
3
3
2
A
g
e
:
r
a
n
g
e
2
0
^
6
5
y
e
a
r
s
A
g
e
:
r
a
n
g
e
2
0
^
6
5
y
e
a
r
s
G
e
n
d
e
r
:
G
e
n
d
e
r
:
44
1
9
7
M
;
1
9
7
M
;
44
7
1
F
7
1
F
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
S
e
t
t
i
n
g
:
c
o
m
m
u
n
i
t
y
a
n
d
i
n
-
p
a
t
i
e
n
t
1
.
Z
u
c
l
o
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
1
0
0
^
6
0
0
m
g
/
1
.
Z
u
c
l
o
p
e
n
t
h
i
x
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
1
0
0
^
6
0
0
m
g
/
2
^
4
w
e
e
k
s
(
2
^
4
w
e
e
k
s
(
nn
1
7
)
1
7
)
2
.
F
l
u
p
e
n
t
i
x
o
l
p
a
l
m
i
t
a
t
e
:
d
o
s
e
r
a
n
g
e
2
5
^
3
0
0
m
g
/
4
w
e
e
k
s
2
.
F
l
u
p
e
n
t
i
x
o
l
p
a
l
m
i
t
a
t
e
:
d
o
s
e
r
a
n
g
e
2
5
^
3
0
0
m
g
/
4
w
e
e
k
s
((
nn
4
8
)
4
8
)
3
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
3
9
^
2
0
0
m
g
/
4
w
e
e
k
s
3
.
H
a
l
o
p
e
r
i
d
o
l
d
e
c
a
n
o
a
t
e
:
d
o
s
e
r
a
n
g
e
3
9
^
2
0
0
m
g
/
4
w
e
e
k
s
((
nn
2
8
)
2
8
)
4
.
P
e
r
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
:
d
o
s
e
r
a
n
g
e
2
0
^
6
0
0
m
g
/
2
w
e
e
k
s
4
.
P
e
r
p
h
e
n
a
z
i
n
e
e
n
a
n
t
h
a
t
e
:
d
o
s
e
r
a
n
g
e
2
0
^
6
0
0
m
g
/
2
w
e
e
k
s
((
nn
8
5
)
8
5
)
D
e
a
t
h
D
e
a
t
h
G
l
o
b
a
l
i
m
p
r
e
s
s
i
o
n
(
C
G
I
)
G
l
o
b
a
l
i
m
p
r
e
s
s
i
o
n
(
C
G
I
)
R
e
l
a
p
s
e
R
e
l
a
p
s
e
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
L
e
a
v
i
n
g
t
h
e
s
t
u
d
y
e
a
r
l
y
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
U
s
e
o
f
a
d
d
i
t
i
o
n
a
l
m
e
d
i
c
a
t
i
o
n
S
i
d
e
-
e
f
f
e
c
t
s
(
U
K
U
)
S
i
d
e
-
e
f
f
e
c
t
s
(
U
K
U
)
D
i
s
c
h
a
r
g
e
D
i
s
c
h
a
r
g
e
NN
,
n
u
m
b
e
r
o
f
t
r
i
a
l
s
;
,
n
u
m
b
e
r
o
f
t
r
i
a
l
s
;
nn
,
n
u
m
b
e
r
o
f
p
a
r
t
i
c
i
p
a
n
t
s
;
M
,
m
a
l
e
s
;
F
,
f
e
m
a
l
e
s
;
A
I
M
S
,
A
b
n
o
r
m
a
l
I
n
v
o
l
u
n
t
a
r
y
M
o
v
e
m
e
n
t
S
c
a
l
e
(
G
u
y
,
1
9
7
6
)
;
B
P
R
S
,
B
r
i
e
f
P
s
y
c
h
i
a
t
r
i
c
R
a
t
i
n
g
S
c
a
l
e
(
O
v
e
r
a
l
l
&
G
o
r
h
a
m
,
1
9
6
2
)
;
B
o
r
d
e
l
e
a
u
S
c
a
l
e
(
B
o
r
d
e
l
e
a
u
,
n
u
m
b
e
r
o
f
p
a
r
t
i
c
i
p
a
n
t
s
;
M
,
m
a
l
e
s
;
F
,
f
e
m
a
l
e
s
;
A
I
M
S
,
A
b
n
o
r
m
a
l
I
n
v
o
l
u
n
t
a
r
y
M
o
v
e
m
e
n
t
S
c
a
l
e
(
G
u
y
,
1
9
7
6
)
;
B
P
R
S
,
B
r
i
e
f
P
s
y
c
h
i
a
t
r
i
c
R
a
t
i
n
g
S
c
a
l
e
(
O
v
e
r
a
l
l
&
G
o
r
h
a
m
,
1
9
6
2
)
;
B
o
r
d
e
l
e
a
u
S
c
a
l
e
(
B
o
r
d
e
l
e
a
u
e
t
a
l
e
t
a
l
,
1
9
6
7
)
;
C
G
I
,
C
l
i
n
i
c
a
l
,
1
9
6
7
)
;
C
G
I
,
C
l
i
n
i
c
a
l
G
l
o
b
a
l
I
m
p
r
e
s
s
i
o
n
(
G
u
y
,
1
9
7
6
)
;
C
P
R
S
,
C
o
m
p
r
e
h
e
n
s
i
v
e
P
s
y
c
h
o
p
a
t
h
o
l
o
g
i
c
a
l
R
a
t
i
n
g
S
c
a
l
e
(
s
b
e
r
g
G
l
o
b
a
l
I
m
p
r
e
s
s
i
o
n
(
G
u
y
,
1
9
7
6
)
;
C
P
R
S
,
C
o
m
p
r
e
h
e
n
s
i
v
e
P
s
y
c
h
o
p
a
t
h
o
l
o
g
i
c
a
l
R
a
t
i
n
g
S
c
a
l
e
(
s
b
e
r
g
e
t
a
l
e
t
a
l
,
1
9
7
8
)
;
D
O
T
E
S
,
D
o
s
a
g
e
R
e
c
o
r
d
a
n
d
T
r
e
a
t
m
e
n
t
E
m
e
r
g
e
n
t
S
y
m
p
t
o
m
S
c
a
l
e
(
G
u
y
,
1
9
7
6
)
;
H
R
S
D
,
H
a
m
i
l
t
o
n
R
a
t
i
n
g
S
c
a
l
e
f
o
r
D
e
p
r
e
s
s
i
o
n
(
H
a
m
i
l
t
o
n
,
,
1
9
7
8
)
;
D
O
T
E
S
,
D
o
s
a
g
e
R
e
c
o
r
d
a
n
d
T
r
e
a
t
m
e
n
t
E
m
e
r
g
e
n
t
S
y
m
p
t
o
m
S
c
a
l
e
(
G
u
y
,
1
9
7
6
)
;
H
R
S
D
,
H
a
m
i
l
t
o
n
R
a
t
i
n
g
S
c
a
l
e
f
o
r
D
e
p
r
e
s
s
i
o
n
(
H
a
m
i
l
t
o
n
,
1
9
6
0
)
;
K
r
a
w
i
e
c
k
a
S
c
a
l
e
(
M
a
n
c
h
e
s
t
e
r
S
c
a
l
e
)
(
K
r
a
w
i
e
c
k
a
1
9
6
0
)
;
K
r
a
w
i
e
c
k
a
S
c
a
l
e
(
M
a
n
c
h
e
s
t
e
r
S
c
a
l
e
)
(
K
r
a
w
i
e
c
k
a
e
t
a
l
e
t
a
l
,
1
9
7
7
)
;
M
A
D
R
S
,
M
o
n
t
g
o
m
e
r
y
^
s
b
e
r
g
D
e
p
r
e
s
s
i
o
n
R
a
t
i
n
g
S
c
a
l
e
(
M
o
n
t
g
o
m
e
r
y
,
1
9
7
7
)
;
M
A
D
R
S
,
M
o
n
t
g
o
m
e
r
y
^
s
b
e
r
g
D
e
p
r
e
s
s
i
o
n
R
a
t
i
n
g
S
c
a
l
e
(
M
o
n
t
g
o
m
e
r
y
e
t
a
l
e
t
a
l
,
1
9
7
8
)
;
N
O
S
I
E
,
N
u
r
s
e
s
'
O
b
s
e
r
v
a
t
i
o
n
S
c
a
l
e
f
o
r
I
n
-
p
a
t
i
e
n
t
E
v
a
l
u
a
t
i
o
n
(
H
o
n
i
g
f
e
l
d
,
1
9
7
8
)
;
N
O
S
I
E
,
N
u
r
s
e
s
'
O
b
s
e
r
v
a
t
i
o
n
S
c
a
l
e
f
o
r
I
n
-
p
a
t
i
e
n
t
E
v
a
l
u
a
t
i
o
n
(
H
o
n
i
g
f
e
l
d
e
t
a
l
e
t
a
l
,
1
9
6
2
)
;
S
A
S
,
,
1
9
6
2
)
;
S
A
S
,
S
i
m
p
s
o
n
^
A
n
g
u
s
S
c
a
l
e
(
S
i
m
p
s
o
n
&
A
n
g
u
s
,
1
9
7
0
)
;
U
K
U
,
U
K
U
S
i
d
e
E
f
f
e
c
t
s
R
a
t
i
n
g
S
c
a
l
e
(
L
i
n
g
j
a
e
r
d
e
S
i
m
p
s
o
n
^
A
n
g
u
s
S
c
a
l
e
(
S
i
m
p
s
o
n
&
A
n
g
u
s
,
1
9
7
0
)
;
U
K
U
,
U
K
U
S
i
d
e
E
f
f
e
c
t
s
R
a
t
i
n
g
S
c
a
l
e
(
L
i
n
g
j
a
e
r
d
e
e
t
a
l
e
t
a
l
,
1
9
8
7
)
;
W
i
n
g
W
a
r
d
S
c
a
l
e
(
W
i
n
g
,
1
9
6
1
)
.
,
1
9
8
7
)
;
W
i
n
g
W
a
r
d
S
c
a
l
e
(
W
i
n
g
,
1
9
6
1
)
.
(12.550 mg of fluphenazine every 2 weeks; (12.550 mg of fluphenazine every 2 weeks;
40 mg of flupentixol biweekly) depot anti- 40 mg of flupentixol biweekly) depot anti-
psychotics for global outcome, mental psychotics for global outcome, mental
state, adverse effects or attrition. The state, adverse effects or attrition. The
estimates of effect all had wide confidence estimates of effect all had wide confidence
intervals. Within the standard dose intervals. Within the standard dose v v. low . low
dose comparison, most data were available dose comparison, most data were available
for the outcome of relapse ( for the outcome of relapse (n n638). Pooled 638). Pooled
data across three phenothiazine prepara- data across three phenothiazine prepara-
tions (flupentixol, fluphenazine decanoate tions (flupentixol, fluphenazine decanoate
and enanthate) suggest that the standard and enanthate) suggest that the standard
dose (12.5 dose (12.550 mg every 2 weeks) is more 50 mg every 2 weeks) is more
effective than the low doses (1.2525 mg effective than the low doses (1.2525 mg
every 2 weeks) (RR every 2 weeks) (RR2.5, CI 2.5, CI1.15.9; 1.15.9;
NNT NNT7, CI 7, CI512). Although no clear 512). Although no clear
differences were demonstrated between differences were demonstrated between
the standard dose and low dose on global the standard dose and low dose on global
functioning, attrition and adverse effects functioning, attrition and adverse effects
(movement disorders), data are limited. (movement disorders), data are limited.
DISCUSSION DISCUSSION
Generalisability Generalisability
This overview collates a great deal of trial This overview collates a great deal of trial
data. All trial populations were slightly data. All trial populations were slightly
different and this clinical heterogeneity different and this clinical heterogeneity
may mean that at least some participants, may mean that at least some participants,
treatment regimens and circumstances treatment regimens and circumstances
should resemble those seen in everyday should resemble those seen in everyday
practice. Whether those patients for whom practice. Whether those patients for whom
a depot is most indicated were included, a depot is most indicated were included,
however, is less certain. It would be however, is less certain. It would be
problematic to recruit those who are reluc- problematic to recruit those who are reluc-
tant with a prescription for oral antipsy- tant with a prescription for oral antipsy-
chotics into any clinical trial. The reviews chotics into any clinical trial. The reviews
mostly comprised those who were stable mostly comprised those who were stable
on oral medication. Some participants on oral medication. Some participants
whose course of illness had not been helped whose course of illness had not been helped
previously by a variety of medications were previously by a variety of medications were
included, but it is unclear whether these included, but it is unclear whether these
people were non-compliant or unresponsive people were non-compliant or unresponsive
to treatment. Studies that compared people to treatment. Studies that compared people
who were stable on oral medication and who were stable on oral medication and
then were randomised to receive either then were randomised to receive either
depot or inactive placebo, such that the depot or inactive placebo, such that the
comparison group are undergoing discon- comparison group are undergoing discon-
tinuation of treatment, were not included tinuation of treatment, were not included
in this overview. in this overview.
Depot antipsychotics Depot antipsychotics
v v. placebo depots . placebo depots
Currently, it would be difficult to undertake Currently, it would be difficult to undertake
a trial comparing placebo to neuroleptic a trial comparing placebo to neuroleptic
depot depot in the treatment of schizophrenia, in the treatment of schizophrenia,
given the availability of effective treat- given the availability of effective treat-
ments. Even with the limited data ments. Even with the limited data
( (n n415), fluphenazine decanoate clearly 415), fluphenazine decanoate clearly
reduces relapse between 12 weeks and 2 reduces relapse between 12 weeks and 2
years (NNT years (NNT2). That significantly more 2). That significantly more
people stayed in the study if allocated to people stayed in the study if allocated to
depot (21% depot (21% v v. 49% over the same time . 49% over the same time
period) can be interpreted as a positive period) can be interpreted as a positive
outcome, assuming that those who left outcome, assuming that those who left
early were unlikely to be well. Data from early were unlikely to be well. Data from
within this comparison suggest that the within this comparison suggest that the
adverse effects of blurred vision or dry adverse effects of blurred vision or dry
mouth are not good indicators of anti- mouth are not good indicators of anti-
psychotic activity because they are more psychotic activity because they are more
frequent in the placebo group. Unsurpris- frequent in the placebo group. Unsurpris-
ingly, drugs such as fluphenazine decanoate ingly, drugs such as fluphenazine decanoate
are associated with movement disorders. are associated with movement disorders.
We have calculated that, on average, be- We have calculated that, on average, be-
tween two and seven people have to be tween two and seven people have to be
given depot for one person to suffer sig- given depot for one person to suffer sig-
nificant general movement disorders nificant general movement disorders
(NNH (NNH3, CI 3, CI26.5), which is admittedly 26.5), which is admittedly
a crude index. a crude index.
Depot antipsychotics Depot antipsychotics
v v. oral antipsychotics . oral antipsychotics
An underlying assumption in psychiatric An underlying assumption in psychiatric
therapeutics is that people with serious therapeutics is that people with serious
mental illnesses may not take oral medi- mental illnesses may not take oral medi-
cation reliably, resulting in relapse. If this cation reliably, resulting in relapse. If this
assumption is correct, then the comparison assumption is correct, then the comparison
of relapse rates should demonstrate an of relapse rates should demonstrate an
advantage for those on depots advantage for those on depots v v. oral drugs. . oral drugs.
Although the advantage on one outcome Although the advantage on one outcome
measure in favour of depots was statisti- measure in favour of depots was statisti-
cally significant (global improvement: cally significant (global improvement:
2 9 5 2 9 5
Fig. 1 Fig. 1 Depot antipsychotic Depot antipsychotic v v. placebo depot: all outcomes. . placebo depot: all outcomes.
3
3
^
^
^
3
Study Study
Depot Depot
( (n/N n/N) )
Placebo Placebo
( (n/N n/N) )
RR RR
(95% CI random) (95% CI random)
Weight Weight
(%) (%)
RR RR
01 01 Mental state: General ^ relapse Mental state: General ^ relapse
Fluphenazine decanoate Fluphenazine decanoate 38/210 38/210 122/205 122/205 100.0 100.0 0.30 (0.22^0.41) 0.30 (0.22^0.41)
Subtotal (95% CI) Subtotal (95% CI) 38/210 38/210 122/205 122/205 100.0 100.0 0.30 (0.22^0.41) 0.30 (0.22^0.41)
Test for overall effect Test for overall effect z z7 77.55, 7.55, P P5 50.00001 0.00001
02 02 Leaving the study early Leaving the study early
Bromperidol decanoate Bromperidol decanoate 2/10 2/10 5/10 5/10 12.5 12.5 0.40 (0.10^1.60) 0.40 (0.10^1.60)
Haloperidol decanoate Haloperidol decanoate 5/20 5/20 16/22 16/22 37.5 37.5 0.34 (0.15^0.77) 0.34 (0.15^0.77)
Test for heterogeneity Test for heterogeneity w w
2 2
0.65, d.f. 0.65, d.f.2, 2, P P0.72 0.72
Test for overall effect Test for overall effect z z7 73.33, 3.33, P P0.0009 0.0009
03 03 Side-effects: 1. Dry mouth/blurred vision Side-effects: 1. Dry mouth/blurred vision
Bromperidol decanoate Bromperidol decanoate 0/10 0/10 3/10 3/10 33.1 33.1 0.14 (0.01^2.45) 0.14 (0.01^2.45)
2 2
0.01, d.f. 0.01, d.f.1, 1, P P0.93 0.93
04 04 Side-effects: 2. Movement disorders ^ general Side-effects: 2. Movement disorders ^ general
2 2
0.0, d.f. 0.0, d.f.0 0
Test for overall effect Test for overall effect z z2.12, 2.12, P P0.03 0.03
0.01 0.01 0.1 0.1 1 1 10 10 100 100
Favours depot Favours depot Favours placebo Favours placebo
NNT NNT4, CI 4, CI29), other important out- 29), other important out-
comes such as relapse, attrition and adverse comes such as relapse, attrition and adverse
effects were not. Reviews involving over effects were not. Reviews involving over
800 participants did not demonstrate a 800 participants did not demonstrate a
statistically significant difference between statistically significant difference between
depots and oral medications (RR depots and oral medications (RR0.9, 0.9,
CI CI0.81.2) in terms of relapse, despite 0.81.2) in terms of relapse, despite
good statistical power. It could be argued good statistical power. It could be argued
that those participating in trials were that those participating in trials were
reasonably compliant with oral medi- reasonably compliant with oral medi-
cations so that the demonstration of cations so that the demonstration of any any
advantages to depot (and absence of disadvantages to depot (and absence of dis-
advantages) is noteworthy. Trials suggest advantages) is noteworthy. Trials suggest
that adverse effects, reported as the proxy that adverse effects, reported as the proxy
outcome of `needing additional anti- outcome of `needing additional anti-
cholinergic medication', occur in about cholinergic medication', occur in about
two-thirds of people on antipsychotics, two-thirds of people on antipsychotics,
whether administered by depot or given whether administered by depot or given
orally. orally.
Specific depot antipsychotic Specific depot antipsychotic
v v. another depot . another depot
Many of these comparisons can be seen as Many of these comparisons can be seen as
fulfilling the need to market a new fulfilling the need to market a new
substance rather than answering any rele- substance rather than answering any rele-
vant clinical question. No differences were vant clinical question. No differences were
seen on any global measures of change. seen on any global measures of change.
All nine reviews reported data on relapse. All nine reviews reported data on relapse.
One found a statistically significant result One found a statistically significant result
in favour of zuclopenthixol decanoate in favour of zuclopenthixol decanoate
(NNT (NNT8, CI 8, CI553). Unlike the other 553). Unlike the other
depots, this finding in favour of zuclo- depots, this finding in favour of zuclo-
penthixol was consistent across the out- penthixol was consistent across the out-
comes of leaving the study early and comes of leaving the study early and
needing additional anticholinergic drugs. needing additional anticholinergic drugs.
It is feasible that zuclopenthixol decanoate It is feasible that zuclopenthixol decanoate
is indeed a better depot in terms of the out- is indeed a better depot in terms of the out-
comes comes measured, although relapse rates in measured, although relapse rates in
the comparator drugs were high and, the comparator drugs were high and,
pharmacologically, pharmacologically, there are no grounds to there are no grounds to
suspect any superiority. On the other hand, suspect any superiority. On the other hand,
being one of the newest preparations, it has being one of the newest preparations, it has
not been used as the comparator depot in not been used as the comparator depot in
any other trial (Gilbody & Song, 2000). any other trial (Gilbody & Song, 2000).
By the same token, this may explain, to By the same token, this may explain, to
some extent, the poor results for fluphena- some extent, the poor results for fluphena-
zine compounds, at least when it comes to zine compounds, at least when it comes to
adverse effects. These compounds have adverse effects. These compounds have
been used more than any other as the been used more than any other as the
control drugs and these data may be the control drugs and these data may be the
summation of a publication/reporting summation of a publication/reporting bias. bias.
High-dose depot High-dose depot
v v. standard dose, and . standard dose, and
standard dose standard dose v v. low dose . low dose
Data from trials support the clinical Data from trials support the clinical
impression that there is no clear advantage impression that there is no clear advantage
2 9 6 2 9 6
Fig. 2 Fig. 2 Depot antipsychotic Depot antipsychotic v v. oral antipsychotic: all outcomes. . oral antipsychotic: all outcomes.
^
^
^
^
^
3
^
3
3
3
Study Study
Depot Depot
( (n/N n/N) )
Oral Oral
( (n/N n/N) )
RR RR
Weight Weight
(%) (%)
RR RR
01 01 Death Death
02 02 Global functioning: No important global change Global functioning: No important global change
Fluphenazine enanthate Fluphenazine enanthate 5/16 5/16 7/15 7/15 6.6 6.6 0.67 (0.27^1.66) 0.67 (0.27^1.66)
2 2
1.85, d.f. 1.85, d.f.2, 2, P P0.40 0.40
Fluspirilene decanoate Fluspirilene decanoate 2/20 2/20 2/20 2/20 0.9 0.9 1.00 (0.16^6.42) 1.00 (0.16^6.42)
Pipotiazine palmitate Pipotiazine palmitate 15/61 15/61 10/63 10/63 6.2 6.2 1.55 (0.76^3.18) 1.55 (0.76^3.18)
2 2
1.88, d.f. 1.88, d.f.2, 2, P P0.39 0.39
Flupentixol decanoate Flupentixol decanoate 3/30 3/30 1/30 1/30 1.2 1.2 3.00 (0.33^27.24) 3.00 (0.33^27.24)
2 2
0.89, d.f. 0.89, d.f.3, 3, P P0.83 0.83
05 05 Side-effects: 1. Movement disorders ^ general ^ needing anticholinergic medication Side-effects: 1. Movement disorders ^ general ^ needing anticholinergic medication
Flupentixol decanoate Flupentixol decanoate 19/30 19/30 16/30 16/30 13.4 13.4 1.19 (0.77^1.83) 1.19 (0.77^1.83)
2 2
6.46, d.f. 6.46, d.f.4, 4, P P0.17 0.17
06 06 Side-effects: 2. Movement disorders ^ tardive dyskinesia Side-effects: 2. Movement disorders ^ tardive dyskinesia
2 2
0.39, d.f. 0.39, d.f.1, 1, P P0.53 0.53
0.1 0.1 0.2 0.2 1 1 5 5 10 10
Favours depot Favours depot Favours oral Favours oral
in the use of high-dose depot preparations in the use of high-dose depot preparations
introduced for treatment-resistant cases, introduced for treatment-resistant cases,
and that ultralow doses are little more than and that ultralow doses are little more than
placebo. placebo.
Limitations Limitations
Many outcomes, stated by trialists to Many outcomes, stated by trialists to
have been recorded, were lost owing to have been recorded, were lost owing to
poor reporting. Modern trialists recom- poor reporting. Modern trialists recom-
mend mend that all outcome measures should that all outcome measures should
be reported (Begg be reported (Begg et al et al, 1996). Data from , 1996). Data from
often poorly reported, small trials of often poorly reported, small trials of
limited generalisability, when taken limited generalisability, when taken
together with larger trials, support the together with larger trials, support the
value of depot antipsychotic preparations. value of depot antipsychotic preparations.
This complements information from less This complements information from less
methodologically rigorous studies (Davis methodologically rigorous studies (Davis
et al et al, 1994). There is little convincing , 1994). There is little convincing
evidence that one depot is clearly better evidence that one depot is clearly better
than another, and none that high or ultra- than another, and none that high or ultra-
low doses have advantages. low doses have advantages.
Direct data on economic outcomes, Direct data on economic outcomes,
quality of life and satisfaction were not quality of life and satisfaction were not
found. Such outcomes were scarcely consid- found. Such outcomes were scarcely consid-
ered in randomised trials from the 1960s to ered in randomised trials from the 1960s to
early 1980s. A review of what limited early 1980s. A review of what limited
evidence there is relating to satisfaction evidence there is relating to satisfaction
with depot antipsychotics suggests that with depot antipsychotics suggests that
patients on depots are, on average, reason- patients on depots are, on average, reason-
ably satisfied (see companion paper ably satisfied (see companion paper
Walburn Walburn et al et al, 2001, this issue). , 2001, this issue).
Future studies Future studies
Clinicians and recipients of care could Clinicians and recipients of care could
still benefit from thorough evaluation of still benefit from thorough evaluation of
any one of these widely used compounds any one of these widely used compounds
within a large, long, simple and clinically within a large, long, simple and clinically
relevant randomised trial (Hotopf relevant randomised trial (Hotopf et al et al, ,
1999). Further research should, ideally, 1999). Further research should, ideally,
focus on those living outside of hospital focus on those living outside of hospital
in community settings, whose non-adherence in community settings, whose non-adherence
to treatment and follow-up is thought to to treatment and follow-up is thought to
contribute to relapses in their condition. contribute to relapses in their condition.
Such studies are, by their very nature, dif- Such studies are, by their very nature, dif-
ficult to perform. Those designing evalua- ficult to perform. Those designing evalua-
tive studies of depots in the future, tive studies of depots in the future,
including `atypical' compounds, should including `atypical' compounds, should
learn from the limitations and strengths learn from the limitations and strengths
seen in depot trial design over the past seen in depot trial design over the past
three decades. Such studies would have three decades. Such studies would have
to be of longer duration than the majority to be of longer duration than the majority
conducted to date, in order to capture a conducted to date, in order to capture a
sufficient number of relapses. Long-term sufficient number of relapses. Long-term
2 9 7 2 9 7
Fig. 3 Fig. 3 Specific depot antipsychotic Specific depot antipsychotic v v. control depot: all outcomes, no summations. . control depot: all outcomes, no summations.
3
3
"
3
"
3
Study Study
Named Depot Named Depot
( (n/N n/N) )
Control depot Control depot
( (n/N n/N) )
RR RR
RR RR
01 01 Death Death
Fluphenazine decanoate Fluphenazine decanoate 1/19 1/19 0/19 0/19 3.00 (0.13^69.32) 3.00 (0.13^69.32)
Haloperidol decanoate Haloperidol decanoate 0/45 0/45 1/52 1/52 0.38 (0.02^9.20) 0.38 (0.02^9.20)
Perphenazine decanoate Perphenazine decanoate 0/85 0/85 1/87 1/87 0.34 (0.01^8.26) 0.34 (0.01^8.26)
Zuclopenthixol decanoate Zuclopenthixol decanoate 2/123 2/123 0/113 0/113 4.60 (0.22^94.74) 4.60 (0.22^94.74)
02 02 Global functioning: No important improvement Global functioning: No important improvement
Bromperidol decanoate Bromperidol decanoate 3/15 3/15 2/16 2/16 1.60 (0.31^8.29) 1.60 (0.31^8.29)
Fluspirilene decanoate Fluspirilene decanoate 2/25 2/25 5/25 5/25 0.40 (0.09^1.87) 0.40 (0.09^1.87)
Pipotiazine palmitate Pipotiazine palmitate 86/92 86/92 91/95 91/95 0.98 (0.91^1.05) 0.98 (0.91^1.05)
Flupentixol decanoate Flupentixol decanoate 39/131 39/131 34/149 34/149 1.30 (0.88^1.94) 1.30 (0.88^1.94)
Fluphenazine enanthate Fluphenazine enanthate 7/42 7/42 5/47 5/47 1.57 (0.54^4.57) 1.57 (0.54^4.57)
05 05 Side-effects: Movement disorders ^ general ^ needing anticholinergic medication Side-effects: Movement disorders ^ general ^ needing anticholinergic medication
0.1 0.1 0.2 0.2 1 1 5 5 10 10
Favours named depot Favours named depot Favours control Favours control
trials specifically designed to examine out- trials specifically designed to examine out-
comes such as tardive dyskinesia also are comes such as tardive dyskinesia also are
required. The definition of relapse requires required. The definition of relapse requires
careful consideration and would need to careful consideration and would need to
be operationalised. Obtaining useful cost- be operationalised. Obtaining useful cost-
effectiveness data and data on quality of effectiveness data and data on quality of
life, satisfaction, disability, etc. is a life, satisfaction, disability, etc. is a
research priority. research priority.
REFERENCES REFERENCES
Adams, C. E. & Eisenbruch, M. Adams, C. E. & Eisenbruch, M. (2000) (2000) Depot Depot
fluphenazine for schizophrenia. fluphenazine for schizophrenia. Cochrane Library Cochrane Library, issue 3. , issue 3.
Oxford: Update Software. Oxford: Update Software.
sberg, M., Montgomery, S., Perris, C., sberg, M., Montgomery, S., Perris, C., et al et al (1978) (1978)
The comprehensive psychopathological scale. The comprehensive psychopathological scale. Acta Acta
Psychiatrica Scandinavica Supplementum Psychiatrica Scandinavica Supplementum, , 271 271, 5^27. , 5^27.
Barnes, T. R. & Curson, D. A. Barnes, T. R. & Curson, D. A. (1994) (1994) Long-termdepot Long-termdepot
antipsychotics. A risk^benefit assessment. antipsychotics. A risk^benefit assessment. Drug Safety Drug Safety, ,
10 10, 464^479. , 464^479.
Begg, C., Cho, M., Eastwood, S., Begg, C., Cho, M., Eastwood, S., et al et al (1996) (1996)
Improving the quality of reporting of randomised Improving the quality of reporting of randomised
controlled trials. The CONSORTstatement. controlled trials. The CONSORTstatement. Journal of the Journal of the
American Medical Association American Medical Association, , 276 276, 637^639. , 637^639.
Boissel, J. P., Cucherat, M., Li, W., Boissel, J. P., Cucherat, M., Li, W., et al et al (1999) (1999) The The
problemof therapeutic efficacy indices. 3.Comparison of problemof therapeutic efficacy indices. 3.Comparison of
the indices and their use. the indices and their use. Therapie Therapie, , 54 54, 405^411. , 405^411.
Bordeleau, J. M., Albert, J. M., Killer, J., Bordeleau, J. M., Albert, J. M., Killer, J., et al et al (1967) (1967)
Medication antiparkinsonienne et bilan extrapyramidal. Me dication antiparkinsonienne et bilan extrapyramidal.
Etude du trihexyphenidyl. E
tude du trihexyphenidyl. Canadian Psychiatric Canadian Psychiatric

Association Journal Association Journal, , 12 12, 585^595. , 585^595.
British Medical Association & Royal British Medical Association & Royal
Pharmaceutical Society of Great Britain Pharmaceutical Society of Great Britain (1999) (1999)
British National Formulary British National Formulary. London & Wellingford: BMJ . London & Wellingford: BMJ
Books & Pharmaceutical Press. Books & Pharmaceutical Press.
Chalmers, T. C., Celano, P., Sacks, H. S., Chalmers, T. C., Celano, P., Sacks, H. S., et al et al (1983) (1983)
Bias in treatment assignment in controlled clinical trials. Bias in treatment assignment in controlled clinical trials.
New England Journal of Medicine New England Journal of Medicine, , 309 309, 1358^1361. , 1358^1361.
Coutinho, E., Fenton, M. & Quraishi, S. Coutinho, E., Fenton, M. & Quraishi, S. (2000) (2000)
Zuclopenthixol decanoate for schizophrenia and other Zuclopenthixol decanoate for schizophrenia and other
serious mental illnesses. serious mental illnesses. Cochrane Library Cochrane Library, issue 2. , issue 2.
Davis, J. M. & Andriukaitis, S. Davis, J. M. & Andriukaitis, S. (1986) (1986) The natural The natural
course of schizophrenia and effective maintenance drug course of schizophrenia and effective maintenance drug
treatment. treatment. Journal of Clinical Psychopharmacology Journal of Clinical Psychopharmacology, , 6 6, ,
2S^10S. 2S^10S.
_ _ , Matalon, L., Watanabe, M. D., , Matalon, L.,Watanabe, M. D., et al et al (1994) (1994) Depot Depot
antipsychotic drugs. Place in therapy. antipsychotic drugs. Place in therapy. Drugs Drugs, , 47 47, 741^773. , 741^773.
Fenton, W. S., Blyler, C. R. & Heinssen, R. K. Fenton, W. S., Blyler, C. R. & Heinssen, R. K. (1997) (1997)
Determinants of medication compliance in Determinants of medication compliance in
schizophrenia: empirical and clinical findings. schizophrenia: empirical and clinical findings.
Schizophrenia Bulletin Schizophrenia Bulletin, , 23 23, 637^651. , 637^651.
Foster, K., Meltzer, H., Gill, B., Foster, K., Meltzer, H., Gill, B., et al et al (1996) (1996) Adults Adults
with a psychotic disorder living in the community. with a psychotic disorder living in the community. OPCS OPCS
Surveys of Psychiatric Morbidity in Great Britain Surveys of Psychiatric Morbidity in Great Britain, Report 8. , Report 8.
London: HMSO. London: HMSO.
Gerlach, J. Gerlach, J. (1995) (1995) Depot neuroleptics in relapse Depot neuroleptics in relapse
prevention: advantages and disadvantages. prevention: advantages and disadvantages. International International
Clinical Psychopharmacology Clinical Psychopharmacology, , 9 9 (suppl. 5), 17^20. (suppl. 5), 17^20.
Gilbody, S. M. & Song, F. Gilbody, S. M. & Song, F. (2000) (2000) Publication bias and Publication bias and
the integrity of psychiatry research. the integrity of psychiatry research. Psychological Psychological
Medicine Medicine, , 30 30, 253^258. , 253^258.
Glazer, W. M. & Kane, J. M. Glazer, W. M. & Kane, J. M. (1992) (1992) Depot neuroleptic Depot neuroleptic
therapy: an underutilized treatment option. therapy: an underutilized treatment option. Journal of Journal of
Clinical Psychiatry Clinical Psychiatry, , 53 53, 426^433. , 426^433.
Guy, W. Guy, W. (1976) (1976) ECDEU Assessment Manual for ECDEU Assessment Manual for
Psychopharmacology Psychopharmacology. Revised DHEW Pub. (ADM). . Revised DHEW Pub. (ADM).
Rockville, MD: National Institute for Mental Health. Rockville, MD: National Institute for Mental Health.
Hamilton, M. Hamilton, M. (1960) (1960) A rating scale for depression. A rating scale for depression.
Journal of Neurology, Neurosurgery and Psychiatry Journal of Neurology, Neurosurgery and Psychiatry, , 23 23, ,
56^62. 56^62.
Hirsch, S. R., Gaind, R., Rohde, P. D., Hirsch, S. R., Gaind, R., Rohde, P. D., et al et al (1973) (1973)
Outpatient maintenance of chronic schizophrenic Outpatient maintenance of chronic schizophrenic
patients with long-acting fluphenazine: double-blind patients with long-acting fluphenazine: double-blind
placebo controlled trial. placebo controlled trial. British Medical Journal British Medical Journal, , i i, ,
633^637. 633^637.
Honigfeld, G., Gillis, R. D. & Klett, C. J. Honigfeld, G., Gillis, R. D. & Klett, C. J. (1962) (1962) NOSIE- NOSIE-
30: a treatment sensitive ward behavior scale. 30: a treatment sensitive ward behavior scale.
Psychological Reports Psychological Reports, , 10 10, 799^812. , 799^812.
Hotopf, M., Churchill, R. & Lewis, G. Hotopf, M., Churchill, R. & Lewis, G. (1999) (1999)
Pragmatic randomised controlled trials in psychiatry. Pragmatic randomised controlled trials in psychiatry.
British Journal of Psychiatry British Journal of Psychiatry, , 175 175, 217^223. , 217^223.
Jadad, A. R., Cook, D. J., Jones, A., Jadad, A. R., Cook, D. J., Jones, A., et al et al (1998) (1998)
Methodology and reports of systematic reviews and Methodology and reports of systematic reviews and
meta-analyses: a comparison of Cochrane reviews with meta-analyses: a comparison of Cochrane reviews with
articles published in paper-based journals. articles published in paper-based journals. Journal of the Journal of the
Johnson, D. A. Johnson, D. A. (1984) (1984) Observations on the use of long- Observations on the use of long-
acting depot neuroleptic injections in the maintenance acting depot neuroleptic injections in the maintenance
therapy of schizophrenia. therapy of schizophrenia. Journal of Clinical Psychiatry Journal of Clinical Psychiatry, , 45 45, ,
13^21. 13^21.
Kane, J. M., Aguglia, E., Altamura, A. C., Kane, J. M., Aguglia, E., Altamura, A. C., et al et al
(1998) (1998) Guidelines for depot antipsychotic treatment in Guidelines for depot antipsychotic treatment in
schizophrenia. European Neuropsychopharmacology schizophrenia. European Neuropsychopharmacology
Consensus Conference in Siena, Italy. Consensus Conference in Siena, Italy. European European
Neuropsychopharmacology Neuropsychopharmacology, , 8 8, 55^66. , 55^66.
Kemp, R. A. & David, A. S. Kemp, R. A. & David, A. S. (1997) (1997) Insight and Insight and
compliance. In compliance. InTreatment Compliance and theTherapeutic Treatment Compliance and theTherapeutic
Alliance Alliance (ed. B. Blackwell), pp. 61^84. Newark, NJ: (ed. B. Blackwell), pp. 61^84. Newark, NJ:
Harwood Academic. Harwood Academic.
Krawiecka, M., Goldberg, D. & Vaughn, M. Krawiecka, M., Goldberg, D. & Vaughn, M. (1977) (1977)
Standardised psychiatric assessment scale for chronic Standardised psychiatric assessment scale for chronic
psychiatric patients. psychiatric patients. Acta Psychiatrica Scandinavica Acta Psychiatrica Scandinavica, , 36 36, ,
25^31. 25^31.
Lingjaerde, O., Ahlfors, U. G., Bech, P., Lingjaerde, O., Ahlfors, U. G., Bech, P., et al et al (1987) (1987)
The UKU side effects rating scale. The UKU side effects rating scale. Acta Psychiatrica Acta Psychiatrica
Scandinavica Scandinavica, , 76 76 (suppl. 334), 1^100. (suppl. 334), 1^100.
Montgomery, S. A., Taylor, P. & Montgomery, D. Montgomery, S. A., Taylor, P. & Montgomery, D.
(1978) (1978) Development of a schizophrenia scale sensitive to Development of a schizophrenia scale sensitive to
change. change. Neuropharmacology Neuropharmacology, , 78 78, 1061^1062. , 1061^1062.
Overall, J. E. & Gorham, D. R. Overall, J. E. & Gorham, D. R. (1962) (1962) The Brief The Brief
Psychiatric Rating Scale. Psychiatric Rating Scale. Psychological Reports Psychological Reports, , 10 10, ,
799^812. 799^812.
Quraishi, S. & David, A. Quraishi, S. & David, A. (2000 (2000a a) ) Depot flupenthixol Depot flupenthixol
decanoate for schizophrenia or other similar psychotic decanoate for schizophrenia or other similar psychotic
disorders. disorders. Cochrane Library Cochrane Library, issue 3. Oxford: Update , issue 3. Oxford: Update
Software. Software.
_ _ & & _ _ (2000 (2000b b) ) Depot fluspirilene for schizophrenia. Depot fluspirilene for schizophrenia.
Cochrane Library Cochrane Library, issue 3. Oxford: Update Software. , issue 3. Oxford: Update Software.
_ _ & & _ _ (2000 (2000c c) ) Depot haloperidol decanoate for Depot haloperidol decanoate for
schizophrenia. schizophrenia. Cochrane Library Cochrane Library, issue 3. Oxford: Update , issue 3. Oxford: Update
Software. Software.
2 9 8 2 9 8
CLINICAL IMPLICATIONS CLINICAL IMPLICATIONS
& &
Depot neuroleptic medication is an effective maintenance therapy for Depot neuroleptic medication is an effective maintenance therapy for
schizophrenia. schizophrenia.
& & There may be a slight therapeutic advantage (and no obvious disadvantage) of There may be a slight therapeutic advantage (and no obvious disadvantage) of
depot over oral medication, but the evidence is weak. depot over oral medication, but the evidence is weak.
& & There are few advantages of one depot over another. There are few advantages of one depot over another.
LIMITATIONS LIMITATIONS
& &
Data on patients for whomdepots are most indicated are lacking. Data on patients for whomdepots are most indicated are lacking.
& & Patient satisfaction, cost-effectiveness and other outcomes have not been studied Patient satisfaction, cost-effectiveness and other outcomes have not been studied
in controlled trials. in controlled trials.
& &
There may be unforeseen methodological problems in meta-analyses of several There may be unforeseen methodological problems in meta-analyses of several
systematic reviews. systematic reviews.
CLIVE E. ADAMS, MRCPsych, MARKK. P. FENTON, RMN, Cochrane Schizophrenia Group, Summertown CLIVE E. ADAMS, MRCPsych, MARKK. P. FENTON, RMN, Cochrane Schizophrenia Group, Summertown
Pavilion, Oxford; SEEMAQURAISHI, MSc, ANTHONY S. DAVID, FRCPsych, Institute of Psychiatry & Guy's, Pavilion, Oxford; SEEMAQURAISHI, MSc, ANTHONY S. DAVID, FRCPsych, Institute of Psychiatry & Guy's,
King's and St Thomas' School of Medicine, London King's and St Thomas' School of Medicine, London
Correspondence: Professor Anthony S. David, Institute of Psychiatry & GKT School of Medicine, Correspondence: Professor Anthony S. David, Institute of Psychiatry & GKT School of Medicine,
Denmark Hill, London SE5 8AF,UK. Tel: 020 7848 0138; Fax: 020 7848 0572; e-mail: Denmark Hill, London SE5 8AF,UK. Tel: 020 7848 0138; Fax: 020 7848 0572; e-mail:
a.david a.david@ @iop.kcl.ac.uk iop.kcl.ac.uk
(First received 6 September 2000, final revision 5 February 2001, accepted 8 February 2001) (First received 6 September 2000, final revision 5 February 2001, accepted 8 February 2001)
_ _ & & _ _ (2000 (2000d d) ) Depot perphenazine decanoate and Depot perphenazine decanoate and
enanthate for schizophrenia. enanthate for schizophrenia. Cochrane Library Cochrane Library, issue 3. , issue 3.
_ _ & & _ _ (2000 (2000e e) ) Depot pipothiazine palmitate and Depot pipothiazine palmitate and
undecylenate for schizophrenia. undecylenate for schizophrenia. Cochrane Library Cochrane Library, issue 3. , issue 3.
_ _ , , _ _ & Adams, C. E. & Adams, C. E. (2000) (2000) Depot bromperidol Depot bromperidol
decanoate for schizophrenia. decanoate for schizophrenia. Cochrane Library Cochrane Library, issue 3. , issue 3.
Schulz, K. F., Chalmers, I., Hayes, R. J., Schulz, K. F., Chalmers, I., Hayes, R. J., et al et al (1995) (1995)
Empirical evidence of bias. Dimensions of Empirical evidence of bias. Dimensions of
methodological quality associated with estimates of methodological quality associated with estimates of
treatment effects in controlled trials. treatment effects in controlled trials. Journal of the Journal of the
Simpson, G. M. Simpson, G. M. (1984) (1984) A brief history of depot A brief history of depot
neuroleptics. neuroleptics. Journal of Clinical Psychiatry Journal of Clinical Psychiatry, , 45 45, 3^4. , 3^4.
Simpson, M. & Angus, J. W. Simpson, M. & Angus, J. W. (1970) (1970) A rating scale for A rating scale for
extrapyramidal side effects. extrapyramidal side effects. Acta Psychiatrica Acta Psychiatrica
Scandinavica Scandinavica, , 212 212, 11^19. , 11^19.
Thornley, B. & Adams, C. Thornley, B. & Adams, C. (1998) (1998) Content and quality Content and quality
of 2000 controlled trials in schizophrenia over 50 years. of 2000 controlled trials in schizophrenia over 50 years.
British Medical Journal British Medical Journal, , 317 317, 1181^1184. , 1181^1184.
Walburn, J., Gray, R., Gournay, K., Walburn, J., Gray, R., Gournay, K., et al et al (2001) (2001)
Systematic review of patient and nurse attitudes to Systematic review of patient and nurse attitudes to
depot antipsychotic medication. depot antipsychotic medication. British Journal of British Journal of
Psychiatry Psychiatry, , 179 179, 300^307. , 300^307.
Weiden, P. J. & Olfson, M. Weiden, P. J. & Olfson, M. (1995) (1995) Cost of relapse in Cost of relapse in
schizophrenia. schizophrenia. Schizophrenia Bulletin Schizophrenia Bulletin, , 21 21, 419^429. , 419^429.
Wing, J. K. Wing, J. K. (1961) (1961) A simple and reliable subclassification A simple and reliable subclassification
of chronic schizophrenia. of chronic schizophrenia. Journal of Mental Science Journal of Mental Science, , 107 107, ,
862^876. 862^876.
2 9 9 2 9 9

BJP 2001 Adams 290 9

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

BJP 2001 Adams 290 9

Uploaded by

Copyright:

Available Formats

10.1192/bjp.179.4.

290 Access the most recent version at DOI:

tude du trihexyphenidyl. Canadian Psychiatric Canadian Psychiatric

You might also like