P3d011
Combination of clozapine with paliperidone in
treatment-resistant schizophrenia
Oriolo G,1 Dominguez I,1 Fortea A,1 BernardoM,2 Bioque M,3 ParelladaE.2
1Servicio depsiquiatría
ypsicología, HospitalClínic deBarcelona, Catalunya,España.
2BarcelonaClinic Schizophrenia Unit, HospitalClinic deBarcelona.CIBERSAM,Universitat deBarcelona, IDIBAPS
3BarcelonaClinic Schizophrenia Unit, HospitalClinic deBarcelona.CIBERSAM
OBJECTIVES
METHODS
Combination strategy (CS) with a second antipsychotic
drug is the most frequently employed pharmacological
strategy for the management of treatment - resistant
schizophrenia (TRS) when clozapine (CLZ) is not
effective.1
We conducted a naturalistic observational retrospective non-interventional study of patients
with diagnosis of schizophrenia and related disorders, following criteria reported in the DSMIV-TR.
We selected patients that accomplished TRS criteria following Suzuki et al
treated with CLZ combined with pali-ER or pali-LAI as combination strategy.
Paliperidone, both in extended-release (Pali-ER) or
long-acting injectable (Pali-LAI), could represent a
novelty and effective CS.2 Due to its documented fast
onset of action, delayed time-to-recurrence and good
tolerability.
3
and who were
The study was based on the analysis of registries of computerized medical records from the
database of ≥ 18 years old patients included in the CLZ pharmacovigilance protocol for
hematologic monitoring, from 2009 to 2015.
Socio-demographic and clinical variables were obtained from 23 patients. CLZ and paliperidone
daily dose as well as the basal version of the clinical global impression scale for schizophrenia
(b-CGI-SCH) were calculated before and after treatment combination, as well as the
improvement version obtained of the same scale (i-CGI-SCH).4
The aim of this work is to describe the clinical
outcomes of TRS patients treated with pali-ER or paliLAI in combination with CLZ
RESULTS
Alone
17
Married
3
Divorced
3
12
Unemployed
6
Part-TimeJob
3
TemporalLaboral Inability
2
OriginFamily
14
ProperFamily
4
Alone
4
Residence
1
Diagnosis
Schizophrenia
19
0
Clozapine+
Paliperidone
Positive
Symptoms
Simultaneous
combination
74%
Paliperidone+
Clozapine
Figure 2:CS chronology. In20patients, pali-ER
orPali-LAI was added after CLZtreatment was
initiated
500
ClozapineDose
3…
280
PaliperidoneDose
20
10
Pre-COMBO
Post-COMBO
Negative
Symptoms
Depressive
Symptoms
Cognitive
Symptoms
Global
Symptoms
Figure 4. St atistical significant differences were found in th e
average punctuation of b-CGI calculated before and after
treatment combinat ion for each dimension (Positive
symptoms mean score = 2.78, IC95%=2.35-3.21 t =13.37,
p<0.01. Negative symptoms mean score = 1.04,
IC95%=0.69-1.40, t=6 .07, p<0.01. Depressive sympto ms
mean score = 1.56, IC95%=1.28-1.85, t=11.33, p <0.01.
Cognitive s ympto ms mean score = 0 .74, IC95%=0.41-1.06,
t=4.71, p <0.01. Glob al symp toms mean score = 2.56
IC95%=2.22-2.91, t=15.62, p<0 .01)(*=p <0.01)Statistical
significant improv ement was obtained considerin g the paliER and Pali-LAI subgroups when analysed separately.
5,7
ImprovementCGIValuesafterCS
0
0
*
Pre-COMBO
Post-COMBO
Figure 3 a, b : d aily mg dose of clozapine and p aliperidone after
SchizoaffectiveDisorder
4
CS.
PaliperidoneTreatment
The CLZ dose combin ed with palip eridone was lower [mean =280
mg p er day (SD=+/-145)] than the CL Z dose when used alone
Pali-ER
9
[mean =317,1 mg p er d ay (SD=+/-165,7)], but no stat istical
significance was achiev ed (t =1,325, p=0 .201). Likewise, th e dose
Pali-LAI
14
of paliperidon e wh en combin ed was lower [mean 5,75 mg p er d ay
(SD=+/-2,7)] than its use alone [ mean=10 mg per day (SD =+/-4.1)],
Table 1. Socio-demographic andClinical variables (n=23)
but no statistical significance was achieved (t=1.770, p=0.137).
Statistical significant differences
were found in the average
punctuation of b-CGI and the same
trend was shown by the i-CGI
punctuation (see Fig.4 and 5 for
details).
1
Combination Chronology
13%
*
*
*
2
Figure 1a, b. Reported adverse events after CSandsetting inwhich CS
was begun
Livingenvironment
*
3
8%
13%
EmploymentStatus
PermanentLaboral
Inability
4
CGI_PostCombo
MaritalStatus
61%
Acathisia
CGI_Basal
23
5
30%
CGI_PostCombo
Caucasian
6
CGI_Basal
Ethnicity
8%
7
CGI_PostCombo
5
16%
12%
BasalCGIValuesbeforeandafterCS
CGI_Basal
18
9%
Weight
increment
Shialorrea
28%
DayHospital
CGI_PostCombo
28%
Inpatients
CGI_Basal
Female
Outpatients
Sedation
Sex
Male
SettingofCombination
AdverseEffects
CGI_PostCombo
42,2(+/- 11,9SD)
Max=73,Min=
21
CGI_Basal
Age(averageofyears)
5
4
3
2
1
0
3,3
2,87
2,04
2,48
CGI_IPOSITIVECGI_INEGATIVE
CGI_I
SYMPTOMS
SYMPTOMS
DEPRESSIVE
SYMPTOMS
CGI_I
COGNITIVE
SYMPTOMS
2,35
CGI_IGLOBAL
SYMPTOMS
Figure 5. Th e i-CGI scal e shown the same trend, underlying
at l east a mini mal improv ement in each di mension, which is
considered a clinical response to treatment
CONCLUSIONS
Ø A significant clinical improvement was observed in our cohort of TRS patients by the means of the b-CGI-SCH scale, when
CLZ and paliperidone were used as CS.
Ø The amelioration evidenced by the i-CGI-SCH scale can be considered of great clinical relevance taking in account that in
TRS patients even a slight improvement might represent a clinically significant effect.5
Ø The lower antipsychotic doses during the CS, thought no significant, can reduce the risk and incidence of side effects,
increasing at the same time treatment adherence.
Concerning limitations, the retrospective and naturalistic design of this observational study and the absence of a control
group are two important ones, as well as the small sample included. A larger sample size would have allowed to find bigger
differences and to design new analysis. At last, it is well established that the CGI allows the clinician to look back over the
course of care and identify what interventions did or did not work,4 but it could be influenced by the inter-observer bias.
The daily CLZ and paliperidone doses
were lower when used in CS than
alone, but no statistical significance
was achieved (see Fig. 3 a,b).
An average of 3.8 times of
hospitalization was calculated among
patients before the CS. 3 patients had
a
hospitalization
during
the
combined treatment due to positive
psychotic
symptoms
relapse,
whereas
the months
without
symptoms relapses median after CS
was 15 (max=47 months, min=1
month). 3 patients discontinued
medication, 2 due to a unilateral
decision and 1 due to agranulocytosis
(for other details, see Table 1, Fig. 1
a,b and Fig.2).
References
1 Dold M, Leucht S. Pharmacotherapy of treatment-resistant
schizophrenia: a clinical perspective. Evid Based Mental Health
2014; 17(2):33-37.
2 Esslinger C, Inta D, Englisch S, Essert A, Zink M. Clozapine
combined with paliperidone observations in schizophrenic patients
with insufficient responses to clozapine monotherapy. German J
Psychiatry 2010; 13:37-40.
3 Suzuki T, Remington G, Mulsant BH, Uchida H, Raji T, GraffGuerrero A. Defining treatment-resistant schizophrenia and
response to antipsychotics: A review and recommendation.
Psychiatry Res 2012;197:1-6.
4 Haro JM, Kamath SA, Ochoa S, Novick D, Rele K, Fargas A et al.
The clinical global impression-schizophrenia scale: a simple
instrument to measure the diversity of symptoms present in
schizophrenia. Acta psychiatr Scand 2003; 107(S416):16-23
5 Samara MT, Dold M, Gianatsi M et al. Efficacy, acceptability and
tolerability of antipsychotics in treatment-resistant schizophrenia.
A network meta-analysis. JAMA psychiatry. 2016;73(3):199-210.
CONFLICTOFINTEREST
G.Oriolo ,I.Dominguez andA.Fortea have received grant from Ferrer,Pfizer,Lundbeck,andgrants andhonorariafrom Janssenan
MBernardohasbeen aconsultant for,received grant/research support andhonorariafrom,andbeen on the speakers/advisory board ofABBiotics,Adamed,Almirall,AMGEN,Boehringer,EliLilly,Ferrer,Forum Pharmaceuticals,Gedeon,Hersill,Janssen-Cilag,Lundbeck,Otsuka,Pfizer,Roche,Servier andhasobtained
research funding from the Spanish Ministry ofHealth,the Spanish Ministry ofScience andEducation,the Spanish Ministry ofEconomy andCompetiveness,CentrodeInvestigaciónBiomédicaenReddeSaludMental(CIBERSAM),by the Government ofCatalonia,Secretariad’Universitats iRecercadelDepartament
d’Economia iConeixement,Institut d'Investigacions Biomèdiques August PiiSunyer (IDIBAPS),andthe 7thFrameworkProgram ofthe European Union.
MBioque hasbeen aconsultant for,received honorariafrom and/or been on the speakers/advisory board ofAdamed,Ferrer,Janssen-Cilag,Lundbeck,Otsuka,andPfizer.
EParelladahasreceived honorariaand/or research grants from the FondodeInvestigaciónSanitaria(registered number PI080055)ofthe Spanish Ministry ofScience andInnovation,Fundació laMarató deTV3ofCatalonia,Janssen-Cilag,Glaxo-Smith-Kline andFerrer.