P3d011 Combination of clozapine with paliperidone in treatment-resistant schizophrenia Oriolo G,1 Dominguez I,1 Fortea A,1 Bernardo M,2 Bioque M,3 Parellada E.2 1Servicio de psiquiatría y psicología, Hospital Clínic de Barcelona, Catalunya, España. 2Barcelona Clinic Schizophrenia Unit, Hospital Clinic de Barcelona. CIBERSAM, Universitat de Barcelona, IDIBAPS 3Barcelona Clinic Schizophrenia Unit, Hospital Clinic de Barcelona. CIBERSAM

OBJECTIVES METHODS

Combination strategy (CS) with a second antipsychotic We conducted a naturalistic observational retrospective non-interventional study of patients drug is the most frequently employed pharmacological with diagnosis of schizophrenia and related disorders, following criteria reported in the DSM- strategy for the management of treatment - resistant IV-TR. schizophrenia (TRS) when clozapine (CLZ) is not We selected patients that accomplished TRS criteria following Suzuki et al 3 and who were effective.1 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 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 novelty and effective CS.2 Due to its documented fast onset of action, delayed time-to-recurrence and good hematologic monitoring, from 2009 to 2015. tolerability. 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 The aim of this work is to describe the clinical (b-CGI-SCH) were calculated before and after treatment combination, as well as the outcomes of TRS patients treated with pali-ER or pali- improvement version obtained of the same scale (i-CGI-SCH).4 LAI in combination with CLZ

RESULTS

Age (average of years) 42,2 (+/- 11,9 SD) Adverse Effects Setting of Combination Statistical significant differences Outpatients Inpatients Day Hospital Basal CGI Values before and after CS Max = 73, Min = Sedation 7 were found in the average 9% 21 6 28% 28% Weight punctuation of b-CGI and the same Sex increment 5 Shialorrea 30% trend was shown by the i-CGI Male 18 16% 4 61% 12% Acathisia punctuation (see Fig.4 and 5 for Female 5 3 * 8% * 8% * * details). Ethnicity 2 * 1 Caucasian 23 Figure 1 a, b. Reported adverse events after CS and setting in which CS was begun 0 Marital Status The daily CLZ and paliperidone doses

Alone 17 CGI_Basal CGI_Basal CGI_Basal CGI_Basal CGI_Basal Combination Chronology were lower when used in CS than CGI_PostCombo

Married 3 CGI_Post Combo CGI_Post Combo CGI_Post Combo CGI_Post Combo Clozapine + Positive Negative Depressive Cognitive Global alone, but no statistical significance Divorced 3 13% Paliperidone Symptoms Symptoms Symptoms Symptoms Symptoms was achieved (see Fig. 3 a,b). Employment Status 13% Simultaneous combination Figure 4. Statistical significant differences were found in th e Permanent Laboral 74% Paliperidone + average punctuation of b-CGI calculated before and after Inability 12 Clozapine treatment combination for each dimension (Positive Unemployed 6 symptoms mean score = 2.78, IC95%=2.35-3.21 t=13.37, An average of 3.8 times of p<0.01. Negative symptoms mean score = 1.04, Part-Time Job 3 Figure 2: CS chronology. In 20 patients, pali-ER IC95%=0.69-1.40, t=6 .07, p<0.01. Depressive symptoms hospitalization was calculated among or Pali-LAI was added after CLZ treatment was Temporal Laboral Inability 2 mean score = 1.56, IC95%=1.28-1.85, t=11.33, p<0.01. patients before the CS. 3 patients had initiated Cognitive symptoms mean score = 0 .74, IC95%=0.41-1.06, Living environment t=4.71, p<0.01. Global symptoms mean score = 2.56 a hospitalization during the IC95%=2.22-2.91, t=15.62, p<0 .01)(*=p <0.01)Statistical Origin Family 14 Clozapine Dose Paliperidone Dose combined treatment due to positive 500 significant improvement was obtained considering the pali- Proper Family 4 280 ER and Pali-LAI subgroups when analysed separately. 3… 20 10 psychotic symptoms relapse, Alone 4 5,7 Improvement CGI Values after CS whereas the months without Residence 1 0 0 5 symptoms relapses median after CS Pre-COMBO Post-COMBO Diagnosis 4 Pre-COMBO Post-COMBO 3,3 was 15 (max=47 months, min=1 3 2,87 Schizophrenia 19 2,35 2 2,48 Figure 3 a, b: daily mg dose of clozapine and paliperidone after 2,04 month). 3 patients discontinued Schizoaffective Disorder 4 1 CS. 0 medication, 2 due to a unilateral Paliperidone Treatment The CLZ dose combined with paliperidone was lower [mean=280 CGI_I POSITIVE CGI_I NEGATIVE CGI_I CGI_I CGI_I GLOBAL mg per day (SD=+/-145)] than the CLZ dose when used alone SYMPTOMS SYMPTOMS DEPRESSIVE COGNITIVE SYMPTOMS decision and 1 due to agranulocytosis Pali-ER 9 SYMPTOMS SYMPTOMS [mean=317,1 mg per day (SD=+/-165,7)], but no statistical Pali-LAI 14 significance was achiev ed (t=1,325, p=0 .201). Likewise, th e dose (for other details, see Table 1, Fig. 1 Figure 5. Th e i-CGI scale shown the same trend, underlying of paliperidone wh en combined was lower [mean 5,75 mg perday at least a minimal improvement in each dimension, which is a,b and Fig.2). (SD=+/-2,7)] than its use alone [mean=10 mgper day (SD =+/-4.1)], Table 1. Socio-demographic and Clinical variables (n=23) considered a clinical response to treatment but no statistical significance was achieved (t=1.770, p=0.137).

CONCLUSIONS References

1 Dold M, Le ucht S. Pharmacotherapy of treatment-resistant Ø A significant clinical improvement was observed in our cohort of TRS patients by the means of the b-CGI-SCH scale, when schizophrenia: a clinical perspective. Evid Based Me ntal Health CLZ and paliperidonewere used as CS. 2014; 17(2):33-37. 2 Esslinger C, Inta D, En gl i s ch S, Essert A, Zink M. Clozapine Ø The amelioration evidenced by the i-CGI-SCH scale can be considered of great clinical relevance taking in account that in combined withpaliperidone observations in schizophrenic patients TRS patients even a slightimprovement might represent a clinically significant effect.5 with in su f f ic ie n t re sp o nse s to clozapine monotherapy. Ge rman J Psychiatry 2010; 13:37-40. Ø The lower antipsychotic doses during the CS, thought no significant, can reduce the risk and incidence of side effects, 3 Suzuki T, Re min gton G, Muls ant BH, Uchida H, Raji T, Graff- Guerrero A. Defining treatment-res is tan t schizophrenia and increasing at the same time treatment adherence. response to antipsychotics: A re view an d re co mme n d ation . Psychiatry Res 2012;197:1-6. 4 Haro JM, Kamath SA, Ochoa S, Novic k D, Re le K, Fargas A et al. Concerning limitations, the retrospective and naturalistic design of this observational study and the absence of a control The clinical global impression-schizophrenia scale: a simple instrument to measure the diversity of symptoms present in group are two important ones, as well as the small sample included. A larger sample size would have allowed to find bigger schizophrenia. Acta psychiatr Scand 2003; 107(S416):16-23 differences and to design new analysis. At last, it is well established that the CGI allows the clinician to look back over the 5 Samara MT, Dold M, Gianatsi M et al. Efficacy, acceptability and 4 tolerability of antipsychotics in treatment-re s is tan t schizophrenia. courseofcare and identify what interventions did ordid notwork, butit could beinfluenced by the inter-observerbias. A network meta-analysis. JAMA ps ychiatry. 2016;73(3):199-210.

CONFLICT OF INTEREST G. Oriolo , I. Dominguez and A.Forteahave receiv ed grant fromFerrer, Pf izer, Lundbeck, and grants and honoraria fromJanssenan M Bernardo has been a consultant for, received grant/research support and honoraria from, and been on thespeakers/advisory board of ABBiotics, Adamed, Almirall, AMGEN, Boehringer, Eli Lilly, Ferrer, Forum Pharmaceuticals, Gedeon, Hersill, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Roche, Servier and has obtained research funding from theSpanish Ministry of Health, theSpanish Ministry of Science and Education, theSpanish Ministry of Economy and Competiveness, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), by the Government of Catalonia, Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement, Institut d'Investigacions Biomèdiques Aug ust Pi i Sunyer (IDIBAPS), and the 7th Framework Program of theEuropean Union. M Bioque has been a consultant for, received honoraria from and/or been on the speakers/advisory board of Adam ed, Ferrer, Janssen-Cilag, Lundbeck, Otsuka, and Pfizer. E Parellada has received honoraria and/or research grants from the Fondo de Investigación Sanitaria (registered number PI080055) of the Spanish Ministry of Science and Innovation, Fundació la Marató de TV3 of Catalonia, Janssen-Cilag, Glaxo-Smith-Kline and Ferrer.