ARTICLE OPEN
De e minan s o pa ien sa is ac ion in clozapine use s: esul s
om he Clozapine In e na ional Conso ium (CLOZIN)
Ma e Z. an de Ho s
1,2
✉, Nini de Boe
1
, CLOZIN collabo a o s*, Cyn hia Okhuijsen-P ei e
1
and Ju jen J. Luykx
3,4,5,6,7
Clozapine is highly e ec i e o ea men - esis an schizoph enia bu is unde u ilized due o pa ien and clinician- ela ed conce ns.
Li le is known abou he gene al le el o pa ien sa is ac ion wi h clozapine and de e minan s he eo . We he e o e explo ed
de e minan s o pa ien sa is ac ion wi h clozapine in indi iduals diagnosed wi h schizoph enia spec um diso de s (SSDs). C oss-
sec ional da a om 480 clozapine use s we e used o examine demog aphic and clinical ac o s, including symp om se e i y,
ea men esponse, and ad e se d ug eac ions (ADRs). Pa ien sa is ac ion was sel - a ed on a scale o 1 o 10. Resul s showed a
mean sa is ac ion sco e o 7.4 (SD =1.9), wi h significan associa ions be ween sa is ac ion and ea men esponse (B=0.42,
R² =0.19, p=3.9 × 10⁻¹⁸), symp om se e i y (B=0.10, R² =0.05, p=2.06 × 10
-9
), occu ence o ADRs (B=−0.16, R² =0.06,
p=3.2 × 10
-5
), and ec ea ional d ug use (B =−1.32, R² =0.05, p=2.09 × 10
-4
). Hype sali a ion and p olonged sleep du a ion we e
he only ADRs linked o lowe sa is ac ion (B=−0.72, R² =0.06, p=3.5 × 10
-5
and B=−0.57, R² =0.04, p=1.4 × 10
-3
, espec i ely).
Despi e conce ns abou ADRs, ea men e ec i eness showed a s onge associa ion wi h pa ien sa is ac ion among clozapine
use s han he occu ence o ADRs. In conclusion, ou findings sugges ha s a egies aimed a bols e ing clozapine’s e ec i eness
may help coun e wo ldwide unde p esc ip ion a es o clozapine in pa ien s wi h SSDs.
Schizoph enia (2025) 11:28 ; h ps://doi.o g/10.1038/s41537-025-00570-9
INTRODUCTION
T adi ionally, ea men success in schizoph enia esea ch has
elied mos ly on symp om alle ia ion asce ained by a e s o he
han he pa ien . O e ecen yea s, howe e , pa ien pe spec i es
a e inc easingly ecognized as c i ical in he e alua ion o
ea men ou comes o indi iduals diagnosed wi h schizoph enia
spec um diso de (SSD)
1
. In his con ex , he ecogni ion o
pa ien sa is ac ion as a aluable ool o e alua ing ea men
ou comes and e ec i eness has gained momen um
2
. Pa ien s’
iewpoin s and judgmen s may di e om ha o heal hca e
p o essionals o amily membe s, pa icula ly when pa ien s ha e
limi ed insigh in o hei illness, as is o en he case in indi iduals
diagnosed wi h ea men - esis an schizoph enia (TRS)
3,4
. Fo
ins ance, indi iduals wi h TRS o en a e he se e i y o hei
symp oms much lowe han hei ea ing physicians do
4
. This
disc epancy also ex ends o conce ns abou ad e se d ug
eac ions (ADRs): heal hca e p o essionals a e o en mos con-
ce ned abou a e, po en ially li e- h ea ening ADRs (such as
ag anulocy osis) and abou he need o egula blood moni o ing,
while pa ien s a e p ima ily wo ied abou common ADRs (such as
weigh gain, sleepiness, and hype sali a ion) and less so abou
unde going egula blood es s
5–8
. These di e ences be ween
use s o clozapine and p esc ibe s unde sco e he impo ance o
conside ing pa ien sa is ac ion in e alua ing ea men success.
Se e al s udies ha e explo ed he subjec i e expe iences o
clozapine ea men om he pe spec i e o clozapine use s.
When compa ing pa ien sa is ac ion be ween clozapine use s and
use s o o he an ipsycho ic medica ions, clozapine consis en ly
ecei es highe a ings
9,10
. Clozapine is also deemed supe io
when use s compa ed i o hei p e ious an ipsycho ic
ea men s
11,12
. In all s udies, he majo i y o pa icipan s seem
gene ally sa isfied wi h clozapine ea men
11–16
. Pa icipan s on
a e age epo a high le el o sa is ac ion wi h he posi i e e ec s
o clozapine, such as he educ ion o posi i e symp oms and
imp o ed social unc ioning and quali y o li e, ou weighing he
side e ec s hey expe ience
11,15
. Howe e , o he bes o ou
knowledge, he la ges s udy on pa ien sa is ac ion among
clozapine use s published o da e was based on 130 pa icipan s.
Mo eo e , li le esea ch has been conduc ed on he specific
ac o s con ibu ing o pa ien sa is ac ion among clozapine use s,
and p e ious s udies ha e p ima ily linked sa is ac ion o pa ien s’
subjec i e assessmen s o clozapine ea men ou comes, such as
esponse, while lacking analyses linking he clinician’s pe spec i e
o pa ien sa is ac ion
10,11,13,15,16
. Fu he mo e, p e ious s udies
ha e no examined he explained a iance o he con ibu ing
ac o s and ha e in es iga ed ela i ely ew ADRs. Thus, i is
unclea which a iables con ibu e mos o pa ien sa is ac ion in
people using clozapine. This issue is o pa icula impo ance
because o he con inued high a es o unde u iliza ion o
clozapine ac oss indus ialized coun ies, e en hough i emains
he mos e ec i e an ipsycho ic a ailable
17–19
.
He e, we he e o e e alua ed pa ien sa is ac ion in a comp e-
hensi ely asce ained in e na ional da ase o 480 pa ien s
diagnosed wi h SSD using clozapine. We explo ed he sa is ac ion
le els o pa ien s unde going clozapine ea men and examined
which demog aphic a iables (such as sex, age, educa ion le el,
and ma i al s a us) and clinical ac o s (including illness du a ion,
insigh , ADRs, symp om se e i y, and ea men esponse) a e
associa ed wi h pa ien sa is ac ion abou clozapine. We hus
aimed o deepen he unde s anding o a iables con ibu ing o
1
Depa men o Psychia y, Uni e si y Medical Cen e U ech , U ech Uni e si y, U ech , The Ne he lands.
2
GGNe , Wa ns eld, The Ne he lands.
3
Depa men o Psychia y,
Ams e dam Uni e si y Medical Cen e , Ams e dam, The Ne he lands.
4
GGZ inGees Men al Heal h Ca e, Ams e dam, The Ne he lands.
5
Neu oscience Mood, Anxie y, Psychosis,
S ess & Sleep Resea ch P og am, Ams e dam Uni e si y Medical Cen e , Ams e dam, The Ne he lands.
6
Depa men o Psychia y and Neu opsychology, School o Men al
Heal h and Neu oscience, Maas ich Uni e si y Medical Cen e , Maas ich , The Ne he lands.
7
Public Heal h Men al Heal h Resea ch P og am, Ams e dam Uni e si y Medical
Cen e , Ams e dam, The Ne he lands. *A lis o au ho s and hei a filia ions appea s a he end o he pape . ✉email: m.z. ande ho s -[email p o ec ed]
Published in pa ne ship wi h he Schizoph enia In e na ional Resea ch Socie y
1234567890():,;
pa ien sa is ac ion in clozapine use s o clinicians as well as
pa ien s, so ha hese a iables can be measu ed and i needed
add essed p io o and du ing ea men wi h clozapine, hus
po en ially inc easing chances o success ul ea men .
METHODS
S udy design and pa ien popula ion
We used da a om he ongoing CLOZapine IN e na ional (CLOZIN)
s udy
20–22
, a la ge c oss-sec ional in e na ional s udy. Fo his
s udy, pa icipan s we e ec ui ed om inpa ien and ou pa ien
men al heal h ca e se ings in 7 di e en coun ies be ween 2017
and 2024: 166 pa icipan s we e ec ui ed in he Ne he lands; 76 in
Ge many; 110 in Spain; 9 in Finland; 50 in Se bia; 27 in Aus ia, and
42 in I aly. We complied wi h he Decla a ion o Helsinki (2013).
W i en in o med consen was ob ained om all pa icipan s and
he s udy ecei ed app o al om he espec i e local Ins i u ional
Re iew Boa ds in all pa icipa ing coun ies.
Pa icipan s we e included when hey we e aged 18 yea s o
olde , had been diagnosed wi h an SSD acco ding o he ou h o
fi h edi ion o he Diagnos ic and S a is ical Manual o Men al
Diso de s, and we e using clozapine. To accu a ely ep esen he
eal-wo ld clozapine use popula ion, we did no se a minimum
du a ion o clozapine ea men . Fu he mo e, we explained o
po en ial pa icipan s ha gaining a comp ehensi e unde s and-
ing o he ac o s associa ed wi h pa ien sa is ac ion and
dissa is ac ion was c ucial, encou aging pa icipa ion om bo h
indi iduals who we e sa isfied wi h he ea men and hose who
we e no . Pa icipan s we e excluded i da a ega ding hei
sa is ac ion wi h he ea men we e una ailable o analysis.
Exposu es and ou comes
Dependen a iables. In he cu en s udy, he p ima y ou come
measu e was pa ien sa is ac ion wi h clozapine ea men .
Pa icipan s we e asked o a e hei sa is ac ion wi h clozapine
ea men du ing he single s udy isi using a scale anging om
1 o 10. A a ing o 1 indica ed ‘ e y unsa isfied wi h clozapine,’
while a a ing o 10 deno ed ‘ e y sa isfied wi h clozapine’, wi h a
sco e o 5 ep esen ing ‘neu al sa is ac ion.’Pa icipan s we e
explained he meanings o hese sco es be o e hey a ed hei
sa is ac ion. They we e ins uc ed o choose one o hese sco es o
a sco e in be ween hese a ings ha bes ma ched hei
sa is ac ion wi h clozapine du ing he en i e use pe iod.
Independen a iables. Demog aphic and clinical cha ac e is ics
we e ga he ed h ough pa icipan in e iews, wi h supplemen-
a y in o ma ion ob ained om hei ea ing physicians in cases
o unce ain y. The ollowing a iables we e included as indepen-
den a iables in he analysis based on p io li e a u e o hei
po en ial associa ion wi h pa ien sa is ac ion: age, sex, diagnosis,
ela ionship s a us, highes educa ional a ainmen , smoking
s a us, body mass index (BMI), use o ec ea ional d ugs, illness
du a ion, clozapine dose, clozapine dose equency, and he use o
an ipsycho ic poly he apy compa ed o clozapine mono he -
apy
9–13,15,16
. Fu he mo e, pa icipan s we e asked i hey expe i-
enced common ADRs associa ed wi h clozapine; and i so, which
ADRs hey expe ienced (no es ic ions o he numbe o ADRs
hey could lis ). This was done using a s anda dized ques ionnai e
(Supplemen a y Fig. 1, u he explained in e .
22
). The ini ial
esponses o his ques ionnai e abou he occu ence o
expe ience o ADRs we e p o ided by he pa icipan s hemsel es.
I a pa icipan was unsu e abou hei answe o i he esea che
had doub s abou he eliabili y o he esponse, he ea ing
physician was consul ed o e ifica ion. As explained p e iously
22
,
he o al numbe o clozapine-associa ed ADRs expe ienced by
each pa icipan was hen summed o c ea e a new a iable: ‘ o al
numbe o ADRs’.
Se e i y o schizoph enia symp oms was assessed by he
ea ing physician o ained esea che using he Clinical Global
Imp ession-Se e i y (CGI-S) scale, anging om 1 (indica ing
no mal, no ill) o 7 (indica ing he mos se e e le el o illness;
Supplemen a y Fig. 2), as also explained be o e
23
. Addi ionally, he
ea ing physician e alua ed he ea men esponse le el using a
10-poin scale, as pe c i e ion A o he Alda scale
24,25
. This
c i e ion en ails assessing he ex en o esponse (ac i i y o he
illness unde adequa e clozapine ea men ) on a scale anging
om 0 (no change o wo sening o symp oms) o 10 (comple e
esponse; Supplemen a y Fig. 3)
24,25
.
Mo eo e , ea men adhe ence was assessed du ing s able
pe iods based on c i e ion B4 o he Alda scale
24,25
. A sco e o 0
indica es excellen compliance, wi h all documen ed clozapine
blood le els wi hin he he apeu ic ange, while a sco e o 1
indica es good compliance, wi h 80–99% o blood le els wi hin
he he apeu ic ange. A sco e o 2 indica es poo compliance,
wi h <80% o blood le els wi hin he he apeu ic ange
(Supplemen a y Fig. 3). The e m ‘ he apeu ic ange’ e e s o
he a ge clozapine se um le el conside ed app op ia e o he
pa ien , as de e mined by he ea ing physician.
Finally, he ea ing physician eco ded he use o any addi ional
medica ion du ing s able pe iods by a ing c i e ion B5 o he Alda
scale
24,25
. He e, a sco e o 0 indica es no addi ional medica ion use
excep o occasional sleep medica ion (1 pe week o less), a sco e
o 1 indica es he use o low-dose o occasional an idep essan s o
an ipsycho ics, o p olonged use o sleep medica ion, and a sco e
o 2 indica es sys ema ic use o an idep essan s o an ipsycho ics
(Supplemen a y Fig. 3).
S a is ical analysis
Baseline demog aphics we e summa ized using desc ip i e
s a is ics. Con inuous a iables a e p esen ed as mean ± s anda d
de ia ion (SD), median, minimum, and maximum. Ca ego ical
a iables a e epo ed as equencies and pe cen ages.
Fi s , o ou p ima y analyses, o assess which a iables we e
associa ed wi h sa is ac ion wi h clozapine, we examined he
associa ions be ween pa ien sa is ac ion and he ollowing
independen a iables: age, sex, diagnosis, ela ionship s a us,
highes educa ional a ainmen , smoking s a us, BMI, use o
ec ea ional d ugs, illness du a ion, clozapine dose, clozapine dose
equency, he use o an ipsycho ic poly he apy compa ed o
clozapine mono he apy, he o al numbe o ADRs, he specific
ADRs, symp om se e i y, and esponse. To ha end, a linea
eg ession model was employed, wi h pa ien sa is ac ion
designa ed as he dependen a iable, and age and sex included
as co a ia es. In he model wi h ‘age’as he independen a iable,
only ‘sex’was added as a co a ia e, and ice e sa.
Fo ou seconda y analyses, o assess he a iance in pa ien
sa is ac ion explained by all significan ly associa ed independen
a iables (in he p ima y analyses), we employed mul iple linea
eg ession wi h pa ien sa is ac ion as he dependen a iable. Thus,
all a iables significan ly (a e Bon e oni co ec ion) associa ed
wi h pa ien sa is ac ion in ou p ima y analysis (p<1.9×10
-3
)we e
included as independen a iables in he model, along wi h age
and sex. As desc ibed abo e, he ‘ o al numbe o ADRs’was
calcula ed by summing he occu ences o all specificADRs.
The e o e, ‘ o al numbe o ADRs’and he occu ences o specific
ADRs (such as hype sali a ion) we e assessed in sepa a e models.
Va iables demons a ing collinea i y, iden ified by a a iance
infla ion ac o (VIF) exceeding 10, we e also analyzed indepen-
den ly o mi iga e he isk o mul icollinea i y.
To mi iga e he isk o ype 1 e o s, we applied Bon e oni
co ec ion o mul iple es ing. Specifically, we adjus ed he
significance le el (alpha) o accoun o he numbe o indepen-
den es s conduc ed, which o aled 26. This esul ed in a
co ec ed significance h eshold o p< 0.05/26 =1.92 × 10
-3
.
M.Z. an de Ho s e al.
2
Schizoph enia (2025) 28 Published in pa ne ship wi h he Schizoph enia In e na ional Resea ch Socie y
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The ou comes a e p esen ed using he explained a iance (R
2
)
o he model, wi h he uns anda dized eg ession coe ficien s (B)
o each a iable, hei espec i e 95% confidence in e als, and p
alues.
All s a is ical analyses we e conduc ed using IBM SPSS S a is ics
Ve sion 29.0.1.0.
RESULTS
Demog aphic and clinical cha ac e is ics
Baseline cha ac e is ics a e shown in Table 1and Supplemen-
a y Table 1. The s udy included 480 pa icipan s, o whom 149
(31.1%) we e emale. The mean age o he pa icipan s was 43.9
yea s (SD 11.9). The majo i y o pa icipan s (41.2%) we e a ed
as demons a ing a mode a e esponse o clozapine ea men
by hei ea ing physicians, and 33.2% we e classified as
‘mode a ely ill’on he CGI-S scale du ing clozapine ea men .
The mean du a ion o clozapine ea men was 7.6 yea s (SD
7.3). On a e age, pa icipan s expe ienced 3.6 clozapine-
associa ed ADRs (SD 2.2). The op 3 mos p e alen
clozapine-associa ed ADRs in ou s udy popula ion we e
weigh gain (68.3%), hype sali a ion (55.2%), and p olonged
sleep du a ion (50.2%; Supplemen a y Table 2). Pa ien
sa is ac ion, assessed on a scale o 1 o 10, showed a mean
Table 1. Baseline demog aphic and clinical cha ac e is ics o he s udy popula ion.
N(%) Mean (SD) Median ( ange)
Sex
Female 149 (31.1)
Male 330 (68.9)
Unspecified 1 (0.0)
Age 43.9 (11.9) 45 (19–76)
Diagnosis
Schizoph enia 333 (72.9)
Schizoa ec i e diso de 68 (14.9)
Schizoph eni o m diso de 5 (1.1)
Psychosis NOS 51 (11.2)
Body Mass Index (BMI; kg/m
2
)
<18.5 1 (0.2)
18.5–24.9 111 (23.1)
>25.0 342 (71.3)
Illness du a ion (yea s) 17.0 (9.8) 17(0–52)
Du a ion o clozapine ea men (yea s) 7.6 (7.3) 5(0–35)
Response since s a o clozapine
a
Minimal 13 (3.3)
Mild 62 (15.8)
Mode a e 162 (41.2)
Good 101 (25.7)
Ve y good 55 (14.0)
Compliance du ing pe iod(s) o s abili y
b
Poo 18 (5.2)
Good 108 (31.5)
Excellen 217 (63.3)
Mono he apy s. Poly he apy
Clozapine mono he apy 219 (52.4)
Clozapine +≥1 o he an ipsycho ic 199 (47.6)
Use o addi ional medica ion du ing pe iod o s abili y
c
None o i egula use o sleep medica ion 96 (23.5)
Low dose an idep essan s, mood s abilize s o an ipsycho ics, o p olonged use o sleep medica ion 72 (17.6)
Sys ema ic use o an idep essan s, mood s abilize s o an ipsycho ics 240 (58.8)
To al numbe o clozapine-associa ed ADRs 3.6 (2.2) 3 (0–10)
Pa ien sa is ac ion
d
7.4 (1.9) 8 (1–10)
SD S anda d De ia ion, NOS No O he wise Specified, ADR ad e se d ug eac ion.
a
As measu ed by he Alda-scale A c i e ium
24,25
. A sco e o 1–2 is labeled as ‘minimal’ esponse, 3–4as‘mild’ esponse, 5–6as‘mode a e’ esponse, 7–8as
‘good’ esponse, and 9–10 as ‘ e y good’ esponse.
b
As measu ed by he Alda-scale B4 c i e ium
24,25
.
c
As measu ed by he Alda-scale B5 c i e ium
24,25
.
d
Pa ien sa is ac ion a ed on a scale o 1 o 10, whe e 1 indica ed ‘ e y unsa isfied wi h clozapine’and a sco e o 10 indica ed ‘ e y sa isfied wi h clozapine’.
N < 480 poin owa ds missing da a.
M.Z. an de Ho s e al.
3
Published in pa ne ship wi h he Schizoph enia In e na ional Resea ch Socie y Schizoph enia (2025) 28
sco e o 7.4 (SD 1.9; median 8; ange 1 o 10; Supplemen a y
Fig. 4).
P ima y analyses
We es ed independen a iables oge he wi h age and sex as
co a ia es in a linea eg ession model o hei associa ions wi h
pa ien sa is ac ion. We ound ha be e esponse (B=0.42, 95%
CI 0.33 o 0.51, R² =0.19, p=3.9 × 10⁻¹⁸; Fig. 1A) was associa ed
mos significan ly wi h highe pa ien sa is ac ion. In addi ion and
in descending o de o significance, g ea e symp om se e i y
(B=−0.10, 95% CI −0.57 o −0.29, R² =0.050, p=2.1 × 10⁻⁹;
Fig. 1B), a highe o al numbe o clozapine-associa ed ADRs
(B=−0.16, 95% CI −0.24 o −0.09, R² =0.057, p=3.2 × 10⁻⁵), and
ec ea ional d ug use (B=−1.32, 95% CI −2.01 o −0.62,
R² =0.050, p=2.1 × 10⁻⁴) we e associa ed wi h lowe pa ien
sa is ac ion.
Rega ding clozapine-associa ed ADRs, hype sali a ion
(B=−0.72, 95% CI −1.07 o −0.39, R² =0.056, p=3.5 × 10⁻⁵)
and p olonged sleep du a ion (B=−0.57, 95% CI −0.92 o −0.22,
R² =0.042, p=1.4 × 10⁻³) we e significan ly associa ed wi h lowe
pa ien sa is ac ion (Supplemen a y Table 3).
Seconda y analyses
As seconda y analyses, we an wo mul iple linea eg ession
models, wi h pa ien sa is ac ion as he dependen a iable: one
model included ‘ o al numbe o ADRs’as an independen
a iable, along wi h sex, age, and all a iables wi h s a is ically
significan associa ions wi h pa ien sa is ac ion iden ified in he
p ima y analysis; he o he model included ‘hype sali a ion’and
‘p olonged sleep du a ion’as independen a iables, along wi h
sex, age, and all a iables wi h s a is ically significan associa ions
wi h pa ien sa is ac ion iden ified in he p ima y analysis.
Mul icollinea i y was no de ec ed among any o he independen
Fig. 1 Associa ion o pa ien sa is ac ion wi h ea men esponse and symp om se e i y. Ba cha s illus a ing he associa ion o mean
pa ien sa is ac ion a ing wi h esponse as a ed using he Alda-A c i e ium (A) and wi h symp om se e i y a ed using he CGI-scale (B). The
numbe s deno ed in each ba e e o he mean pa ien sa is ac ion a ing o ha g oup. C i e ium A o he Alda scale was used o de e mine
an associa ion be ween clinical imp o emen and he ea men on a scale o 0 (no change o wo sening) o 10 (comple e esponse)
24,25
.Fo
illus a i e pu poses, a sco e o 1–2 is labeled as 'minimal' esponse, 3–4 as 'mild' esponse, 5–6as‘mode a e’ esponse, 7–8 as 'good' esponse,
and 9–10 as ' e y good' esponse. Abb e ia ions: CGI Clinical Global Imp ession.
M.Z. an de Ho s e al.
4
Schizoph enia (2025) 28 Published in pa ne ship wi h he Schizoph enia In e na ional Resea ch Socie y
a iables (all had a VIF < 5). The model including he o al numbe
o ADRs as an independen a iable demons a ed an R² o 0.24
(24%), wi h esponse and he o al numbe o ADRs showing
significan con ibu ions o he model (B=0.37, 95% CI 0.25 o
0.48, p=1.5 × 10⁻⁹and B=−0.14, 95% CI −0.21 o −0.06,
p=6.1 × 10⁻
4
; Table 2). Simila ly, he model including hype sali a-
ion and p olonged sleep du a ion as independen a iables
yielded an R² o 0.24, wi h esponse and hype sali a ion showing
significan con ibu ions (B=0.66, 95% CI 0.45 o 0.88, R² =0.088,
p=5.9 × 10⁻⁹and B=−0.59, 95% CI −0.95 o −0.22, R² =0.033,
p=1.8 × 10⁻
3
, espec i ely; Table 3).
DISCUSSION
To he bes o ou knowledge, his is he la ges s udy o da e
examining pa ien sa is ac ion among clozapine use s. We
quan ified he mean pa ien sa is ac ion a ing wi h clozapine a
7.4 (SD =1.9) on a scale om 1 o 10 (10 deno ing maximum
sa is ac ion sco es). 82% o pa icipan s s a ed o be sa isfied wi h
clozapine ea men (sco e > 6). In uni a iable analyses, we ound
se e al a iables o be associa ed wi h he le el o pa ien
sa is ac ion, including ea men esponse, symp om se e i y, o al
numbe o ADRs, hype sali a ion, p olonged sleep du a ion, and
ec ea ional d ug use. In mul i a iable analyses we ound ha
ea men esponse con ibu ed mos o pa ien s’sa is ac ion
(explained a iance R² =0.079), wi h hose expe iencing minimal
esponse a e aging a sa is ac ion sco e o only 5.0, compa ed o a
mean sco e o 8.6 among hose showing e y good esponse o
clozapine ea men . Hype sali a ion and p olonged sleep du a-
ion we e he only ADRs linked o lowe sa is ac ion.
In line wi h p e ious esea ch, clozapine use s we e gene ally
sa isfied wi h hei ea men , wi h symp om educ ion being he
key con ibu o . Despi e clozapine’s associa ion wi h nume ous
and bo he some ADRs, use s epo ed high sa is ac ion. Ea lie
s udies simila ly ound ha clozapine yields highe sa is ac ion
a es compa ed o o he an ipsycho ics
9,10
. As clozapine is
ypically p esc ibed o ea men - esis an symp oms, many
pa ien s likely unde wen mul iple unsuccess ul an ipsycho ic
ials be o e s a ing clozapine. Expe iencing a significan educ-
ion in symp oms and he eby a educ ion in su e ing, some imes
a e yea s o unsuccess ul medica ion ials, could he e o e esul
in ela i ely high pa ien sa is ac ion. Consis en wi h ou findings,
Li e al. obse ed ha pa ien s emain posi i e abou clozapine
ea men despi e i s ADR p ofile and consequen ly posi ed ha
symp om-le el and quali y o li e imp o emen s may esul in
accep ance o ADRs
26
. As many iew clozapine as a ‘las - eso ’
op ion ha finally elie es he dis ess associa ed wi h ea men -
esis an symp oms, his may boos hei commi men o
ea men . G o e e al. u he no ed ha clozapine o en
imp o es dep essi e symp oms, psychosocial unc ioning, and
quali y o li e wi hin h ee mon hs o ea men and sugges ed
ha his ela i ely swi amelio a ion o well-being plays a ole in
pa ien sa is ac ion, ou weighing conce ns abou ADRs
27,28
.
Rega ding he associa ion be ween pa ien sa is ac ion and
specific clozapine-associa ed ADRs, we ound ha people
expe iencing hype sali a ion and p olonged sleep du a ion we e
gene ally less sa isfied wi h clozapine. In p e ious wo k by Mahe
e al. hype sali a ion was ound o be he mos p e alen ad e se
e ec nega i ely impac ing he quali y o li e in people ea ed
wi h clozapine
29
. This may be due o he ac ha hype sali a ion
is a isible ADR, which can be s igma izing and unc ionally
disabling, o en leading o eelings o emba assmen and social
impai men . Howe e , despi e expe iencing hype sali a ion, pa i-
cipan s in ou s udy epo ed a ela i ely high le el o sa is ac ion
wi h clozapine, wi h an a e age pa ien sa is ac ion sco e o 7.0
(compa ed o 7.8 in hose who did no expe ience his side e ec ).
This finding aligns wi h ea lie esea ch, which also ound ha
use s epo ed benefi s o ea men and in ended o con inue
aking clozapine despi e he p esence o hype sali a ion
15,30
.
When compa ing pa ien sa is ac ion be ween hose wi h and
wi hou p olonged sleep du a ion in ou s udy popula ion, he
g oup expe iencing his ADR had an a e age sa is ac ion sco e o
7.1, while hose wi hou i sco ed an a e age o 7.7. I is well
documen ed ha clozapine is associa ed wi h imp o emen s in
insomnia and sleep quali y
11
. A he same ime, a significan
p opo ion o pa ien s expe ience an inc eased need o sleep,
excessi e seda ion, and ex ended sleep du a ion
31
. G o e e al.
ound ha excessi e seda ion was pe cei ed as he mos
dis essing side e ec epo ed by pa ien s and an impo an
eason o discon inuing clozapine ea men
28
. G o e & Naska
addi ionally ound ha hype sali a ion and excessi e seda ion
eme ged as he wo impo an ac o s leading o p ema u e
discon inua ion o clozapine he apy
27
. O e all, ou and p e ious
findings highligh he nuanced ela ionship be ween clozapine’s
he apeu ic benefi s and i s ADRs, sugges ing ha while ADRs like
hype sali a ion and p olonged sleep du a ion may impac pa ien
sa is ac ion, hey do no jeopa dize he o e all accep ance o
clozapine among pa ien s.
In ea lie esea ch by No don e al., an associa ion was ound
be ween pa ien sa is ac ion and age; we ound a simila di ec ion
o e ec wi h highe age being associa ed wi h highe sa is ac ion
le els (B=0.019, 95% CI .004 o .033, R2 =0.15, p=0.011;
Supplemen a y Table 3 and Supplemen a y Fig. 5), bu his
associa ion did no mee he Bon e oni-co ec ed significance
le el
9
. In e es ingly -and simila ly o ou s udy-, No don e al.
ound no clea associa ion be ween pa ien sa is ac ion and BMI o
Table 3. Resul s o he mul iple linea eg ession model wi h pa ien
sa is ac ion as he dependen a iable and sex, age, esponse,
hype sali a ion, use o ec ea ional d ugs, and symp om se e i y
included as independen a iables.
B95% CI p alue
Sex 0.25 −0.12 0.62 0.20
Age 0.01 −0.01 0.02 0.18
Response 0.36 0.24 0.47 3.03 × 10
−9
Hype sali a ion −0.58 −0.94 −0.21 2.01 × 10
−3
P olonged sleep du a ion −0.24 −0.62 0.13 0.20
Use o ec ea ional d ugs −0.88 −1.57 −0.20 0.01
Symp om se e i y 0.10 −0.09 0.28 0.31
Bold alues indica e s a is ically significan esul s (p< 1.9 × 10
-3
).
The explained a iance o his model was also 0.24.
ADR ad e se d ug eac ion, Buns anda dized be a, CI confidence in e al.
Table 2. Resul s o he mul iple linea eg ession model wi h pa ien
sa is ac ion as he dependen a iable and sex, age, esponse, o al
numbe o ADRs, use o ec ea ional d ugs, and symp om se e i y
included as independen a iables.
B95% CI p alue
Sex 0.29 −0.08 0.66 0.13
Age 0.01 −0.00 0.03 0.11
Response 0.37 0.25 0.48 1.47 × 10
−9
To al numbe o ADRs −0.14 −0.21 −0.06 6.10 × 10
−4
Use o ec ea ional d ugs −0.93 −1.62 −0.24 0.01
Symp om se e i y −0.07 −0.12 0.26 0.45
Bold alues indica e s a is ically significan esul s (p< 1.9 × 10
-3
).
The explained a iance o his model was 0.24.
ADR ad e se d ug eac ion, Buns anda dized be a, CI confidence in e al.
M.Z. an de Ho s e al.
5
Published in pa ne ship wi h he Schizoph enia In e na ional Resea ch Socie y Schizoph enia (2025) 28
weigh gain
9
. While e idence on his opic is limi ed, one may
hypo hesize ha weigh gain has a lesse impac on sa is ac ion
han p e iously assumed, as many pa ien s ha e al eady
expe ienced significan weigh inc eases om p io an ipsycho ic
ea men s. Consequen ly, he addi ional weigh gain due o
clozapine may no be iewed by pa ien s as nega i ely impac ing
hei o e all wellbeing.
Implica ions o ou wo k include he possibili y o psychoeduca-
ion o pa ien s using clozapine o conside ing i s use. The
findings a e also clinically ac ionable in ha clinicians should
ac i ely enqui e abou hype sali a ion and p olonged sleep
du a ion. Gi en he high p e alence o hype sali a ion in
clozapine use s and he wide a ay o ea men op ions o his
ADR, pa ien sa is ac ion may be boos ed i hype sali a ion and
possibly o he ADRs a e adequa ely managed
22
. Fu he mo e, ou
findings may in o m longi udinal and in e en ion s udies aiming
o op imize use sa is ac ion wi h his las eso ea men . Finally,
ou finding o o e all high sa is ac ion a ings by pa ien s on
clozapine may help cu ail ‘p esc ibe ea ’, which in u n may help
coun e unde u iliza ion
32
. This disc epancy be ween pa ien
sa is ac ion and p esc ibe conce ns unde sco es he impo ance
o in ol ing pa ien s in decisions ega ding clozapine use h ough
sha ed decision-making. P io esea ch has shown ha sha ed
decision-making, ocused on he pa ien ’s pe spec i e, can
inc ease he likelihood o p esc ibe s ecommending a clozapine
ial
33,34
.
No wi hs anding he size and scope o his s udy, conduc ed
ac oss mul iple cen e s and coun ies, we acknowledge se e al
limi a ions. Fi s ly, we canno ully ule ou he possibili y o
selec ion bias as pa icipan s in he s udy had, on a e age, been
using clozapine o an ex ended pe iod and may ha e epo ed
highe sa is ac ion le els and posi i e ea men esponses
ela i e o sho - e m use s. None heless, app oxima ely 20% o
pa icipan s had been on clozapine o less han 2 yea s and we
ound no significan associa ion be ween pa ien sa is ac ion and
he du a ion o clozapine ea men (Supplemen a y Table 3).
Possibly, mo e sa isfied clozapine use s decided pa icipa ing in
his s udy. Howe e , e o s we e made o mi iga e his by ac i ely
encou aging dissa isfied indi iduals o pa icipa e in he ec ui -
men p ocess, ecognizing he alue o hei expe iences.
Secondly, he s udy’s ocus was limi ed o a specific se o ADRs,
no including ce ain possible ADRs, such as pneumonia and
seizu es ( ha may some imes be challenging o link o clozapine
use specifically). Addi ionally, he a e incidence o se e e
clozapine-associa ed ADRs cu ailed s a is ical powe o examine
hei possible associa ions wi h pa ien sa is ac ion. Thi dly, o
he main ou come measu e o pa ien sa is ac ion, we did no use
a alida ed ques ionnai e bu ins ead asked a single ques ion ha
is also easy o implemen in clinical p ac ice. Fo he ou come
measu e o esponse, we used he Alda scale, which is alida ed
o assessing esponse o long- e m ea men wi h mood
s abilize s in bipola diso de
24,25
. We applied his scale o assess
esponse o clozapine because schizoph enia, like bipola
diso de , equi es a long- e m pe spec i e o accu a ely e alua e
ea men e ficacy. This is pa icula ly ue o clozapine, which is
known o i s e ec i eness o e ex ended ea men pe iods.
Fou h and finally, he unde s anding o de e minan s o pa ien
sa is ac ion wi h clozapine could be u he en iched by u u e
s udies collec ing addi ional da a, such as quali a i e da a
cap u ing he pe sonal opinions and expe iences o clozapine
use s. Fu u e s udies may also examine addi ional ac o s o
possible ele ance o pa ien sa is ac ion, such as he p esence o
como bid dep essi e symp oms, he le el o illness insigh , and
he impac o in olun a y clozapine ea men . Fu u e s udies
may also ec ui people who a e hesi an o s a clozapine
ea men , hose who e used i , o hose who discon inued he
agen . This in o ma ion may p o e aluable as i could shed ligh
on he disc epancy be ween he conside able hesi a ion among
pa ien s and clinicians o ini ia e clozapine ea men and he
ela i ely high sa is ac ion wi h i . Fu he mo e, longi udinal
designs addi ionally including pa ien s on o he an ipsycho ics
may allow o assessmen s be o e and a e clozapine ini ia ion
and be o e and a e specific ADR occu ences, as well as
compa a i e d ug analyses. Toge he , hese addi ions may os e
a mo e nuanced pe spec i e on he con ibu o s o pa ien
sa is ac ion and hus help lowe ba ie s o clozapine p esc ibing
and use.
In conclusion, pa ien s diagnosed wi h schizoph enia a e
gene ally sa isfied wi h clozapine ea men , wi h a educ ion in
symp oms showing he s onges associa ion wi h pa ien
sa is ac ion. Ou findings may in o m clinical decision-making
and ha e he po en ial o educe hesi ancy among bo h pa ien s
and heal hca e p o essionals o s a clozapine. This could lead o
mo e imely ini ia ion o clozapine in he disease cou se,
ul ima ely lowe ing unde u iliza ion and imp o ing ea men
ou comes o indi iduals wi h se e e psychosis.
DATA AVAILABILITY
The da a ha suppo he findings o his s udy a e a ailable om he co esponding
au ho , M.Z.H., upon easonable eques .
Recei ed: 31 July 2024; Accep ed: 29 Janua y 2025;
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ACKNOWLEDGEMENTS
UMC U ech is he sponso o his mul icen e s udy. The CLOZIN s udy was unded
by UMC U ech and GGNe , wi h GGNe being in ol ed since 2020. Collabo a ion
wi h o he hospi als was execu ed wi hou financial compensa ion.
AUTHOR CONTRIBUTIONS
M.Z.H. concei ed and designed he analysis, collec ed he da a, pe o med he
analysis, and w o e he manusc ip . N.B., C.O.P., and J.J.L. concei ed and designed he
analysis and supe ised he pape . M.Z.H., C.O.P., and J.J.L. concei ed he s udy
design. The collabo a o s o he CLOZIN s udy collec ed he da a. All au ho s ead
and app o ed he final manusc ip .
COMPETING INTERESTS
The au ho s decla e no compe ing in e es s.
ADDITIONAL INFORMATION
Supplemen a y in o ma ion The online e sion con ains supplemen a y ma e ial
a ailable a h ps://doi.o g/10.1038/s41537-025-00570-9.
Co espondence and eques s o ma e ials should be add essed o
Ma e Z. an de Ho s .
Rep in s and pe mission in o ma ion is a ailable a h p://www.na u e.com/
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© The Au ho (s) 2025
CLOZIN COLLABORATORS
Ahme Müde isoğlu8, Alba Toll P i a 9, Alde Bouhuis10, Alkomie Hasan11, Amy Jongkind12, Ana Gonzalez-Pin o13,
Anna Mane San acana9, A mando D’Agos ino14, Aygün E uğ ul15, A. Eli AnılYağcıoğlu15, Benedic o C espo-Faco o16,
Be nha d T. Baune17,18,19, Bianca Sanchez-Ba be o16, Ca los Spuch20, Ca la Lou Mo gen o h21, Ca men Fe nandez de Pinedo13,
Cecilia Case a14, Chad Bousman22, Ch is a Hoho 17, Ch is os Pan elis22, Claudia O ejas-Ca alán23, Clemen e Ga cia-Rizo24,
Cyn hia Okhuijsen-P ei e 1, Dan Cohen25, D agana Ignja o ic Ris ic26, Edwin Beld25, Eila Repo-Tiihonen27, Elias Wagne 11,
Ellen Jege -Land28, Elisabe Vilella29, Emilio Fe nandez-Egea30, E win Bekema1, Es eban Sepúl eda29, Fede ico Wiedenmann14,
F ancesca Ma ini31, F ancesca Se io14, F ancesca Vai ano14, Giacomo Me cu iali32, Gio anni Boido14, Gökhan Yoca15,
Hanneke an Beek33, Ha m Gijsman10, Heli Tuppu ainen27, Ian E e all22, I ona No ako ic26, Inaki Zo illa13,İ. Me E doğan15,
Jacopo Sapienza31, Jan Boge s33, Ja i Tiihonen27, Ja ie Vázquez-Bou gon23, Jim an Os1, Johannes Schneide -Thoma34,
Ju jen Luykx3,4,5,6,7, Koen G oo ens35, Lo ea Ma -Ba u ia13, Lou des Ma o ell29, Maa en Bak36, Ma co Spanga o31, Ma co Zie hu 21,
Ma ije de Vos37, Ma iken de Koning28, Ma ina Ga iga24, Ma kku Läh een uo27, Ma a Bosia38, Ma e an de Ho s 1,2,
Melih O. Babaoğlu15, Mike Vee eschild37, Mi ko Manchia39, Mishal Qubad40, Monika Edlinge 41, Paloma Fuen es-Pé ez23,
Pasquale Pa ibello39, Pu ificacion Lopez-Pena13, René Kahn1, Robe A. Bi ne 40, Robe o Ca alla o38, Selene Vee man25,
S e an Gu winski21, S e anie Sch ei e 21, S ephan Ripke21, Tania Ri e a Bal anás20, Ta iana O iedo-Salcedo42, Te o Hallikainen27,
Thomas Gö li z11, Wou e Alink10 and Ya uz Ayhan15
M.Z. an de Ho s e al.
7
Published in pa ne ship wi h he Schizoph enia In e na ional Resea ch Socie y Schizoph enia (2025) 28
8
Depa men o Pha macology, Ki ikkale Uni e si y Facul y o Medicine, Ki ikkale, Tu key.
9
Depa men o Psychia y, Ins i u de Neu opsiquia ia i Addiccions, Pa c de Salu
Ma , Ba celona, Spain.
10
P o Pe sona, Wol heze, The Ne he lands.
11
Depa men o Psychia y, Psycho he apy and Psychosoma ics, Medical Facul y, Uni e si y o
Augsbu g, Augsbu g, Ge many.
12
Reinie an A kel, s-He ogenbosch, The Ne he lands.
13
Depa men o Psychia y, Hospi al Uni e si a io de Ala a, BIOARABA, EHU,
CIBERSAM, Vi o ia, Spain.
14
Depa men o Heal h Sciences, San Paolo Uni e si y Hospi al, Uni e si y o Milan, Milano, Milan, I aly.
15
Depa men o Psychia y & Depa men o
Pha macology, Facul y o Medicine, Hace epe Uni e si y, Anka a, Tu key.
16
Depa men o Psychia y, Ins i u o de Biomedicina de Se illa, IBiS-CSIC, CIBERSAM, Uni e si y
Hospi al Vi gen del Rocio, Uni e si y o Se ille, Se ille, Spain.
17
Depa men o Psychia y, Uni e si y o Müns e , Müns e , Ge many.
18
Depa men o Psychia y, Uni e si y o
Melbou ne, Melbou ne, VIC, Aus alia.
19
The Flo ey Ins i u e o Neu oscience and Men al Heal h, Uni e si y o Melbou ne, Pa k ille, VIC, Aus alia.
20
Hospi al Ál a o Cunquei o de
Vigo, Galicia Su Heal h Resea ch Ins i u e, CIBERSAM, Vigo, Spain.
21
Depa men o Psychia y and Psycho he apy, Cha i é - Uni e si ä smedizin Be lin, co po a e membe o F eie
Uni e si ä Be lin, Humbold -Uni e si ä zu Be lin, and Be lin Ins i u e o Heal h, Be lin, Ge many.
22
Depa men o Psychia y, Melbou ne Neu opsychia y Cen e (MNC), The
Uni e si y o Melbou ne & No hWes e n Men al Heal h (RMH), Melbou ne, VIC, Aus alia.
23
Depa men o Psychia y, Uni e si y Hospi al Ma qués de Valdecilla, Ins i u o de
In es igación Sani a ia Valdecilla-IDIVAL, CIBERSAM, Uni e sidad de Can ab ia, San ande , Spain.
24
Hospi al Clinic de Ba celona, Ins i u e o Neu osciences, Hospi al Clínic de
Ba celona, Uni e si y o Ba celona, CIBERSAM, IDIBAPS, Ba celona, Spain.
25
Men al Heal h O ganiza ion No h-Holland No h, Alkmaa , The Ne he lands.
26
Depa men o
Psychia y, Facul y o Medical Sciences, Uni e si y o K aguje ac, Clinic o Psychia y, Uni e si y clinical cen e K aguje ac, K aguje ac, Se bia.
27
Depa men o Fo ensic
Psychia y, Uni e si y o Kuopio, Niu anniemi Hospi al, Kuopio, Finland.
28
A kin, Ins i u e o Men al Heal h, Ams e dam, The Ne he lands.
29
Hospi al Uni e si a i Ins i u Pe e
Ma a, IISPV, URV, CIBERSAM-ISCIII, Reus, Spain.
30
Camb idge Psychosis Cen e, Camb idge, UK.
31
Psycho ic Diso de Uni , IRCSS San Ra aele Scien ific Ins i u e, Milan, I aly.
32
School o Medicine, Vi a-Salu e San Ra aele Uni e si y, Milan, I aly.
33
Men al Heal h Se ices Ri ie duinen, Leiden, The Ne he lands.
34
Depa men o Psychia y and
Psycho he apy, School o Medicine, Technical Uni e si y o Munich, Munich, Ge many.
35
T anzo, TSB, Tilbu g Uni e si y, Tilbu g, The Ne he lands.
36
Mond iaan, Men al Heal h
Ins i u e, Maas ich , The Ne he lands.
37
GGNe Men al Heal h, Wa ns eld, The Ne he lands.
38
Psycho ic Diso de Uni , IRCSS San Ra aele Scien ific Ins i u e, Milan, I aly and
School o Medicine, Vi a-Salu e San Ra aele Uni e si y, Milan, I aly.
39
Depa men o Medical Sciences and Public Heal h, Uni o Psychia y, Uni e si y o Caglia i, Caglia i, I aly.
40
Depa men o Psychia y, Psychosoma ic Medicine and Psycho he apy, Goe he Uni e si y F ank u , Uni e si y Hospi al, F ank u , Ge many.
41
Depa men o Psychia y,
Psycho he apy, Psychosoma ics and Psychological Medicin, Di ision o Psychia y I, Medical Uni e si y Innsb uck, Innsb uck, Aus ia.
42
Depa men o Psychia y and
Psycho he apy, Uni e si y Hospi al, LMU Munich, Munich, Ge many.
M.Z. an de Ho s e al.
8
Schizoph enia (2025) 28 Published in pa ne ship wi h he Schizoph enia In e na ional Resea ch Socie y
