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AbstractBackground: Clozapine remains the only evidence-based treatment for treatment-resistant schizophrenia, and prediction of clozapine response is important in developing stratified treatment. We studied potential predictors of clozapine response, applying functional assessments as well as service use. Procedures: We performed a nationwide cohort-study among all individuals diagnosed with schizophrenia in Denmark after 1995 (age>=18 years) who initiated clozapine treatment between 2004-2011 with a Global Assessment of Functioning (GAF-F) score registered at clozapine initiation. During up to two years follow-up, clinical response was defined as (i) no further hospitalization with schizophrenia or (ii) improvement in GAF-F score (moderate improvement=increase≥10; substantial improvement=increase≥20 and GAF-F≥50). We performed Cox regression analysis and report adjusted hazard rate ratios (HRR; 95%-confidence intervals (95%-CI)). Results: Among 502 clozapine users with a registered GAF-F score, 232 (46.2%) remained out of hospital, 96 (19.1%) achieved moderate functional improvement, and 29 (5.8%) substantial functional improvement. Of all potential predictors, voluntary status at clozapine initiation showed borderline statistical significance with non-hospitalization (HRR=1.61; 95%-CI=0.97-2.67). Regarding functional improvement, living with a partner was the strongest predictor with an almost threefold increased HRR (2.78; 95%-CI=1.07-7.23). Female gender was only non-insignificantly associated with functional improvement, while the chance of substantial improvement decreased by 15% (HRR=0.85; 95%-CI=0.72-1.00) for each year delay in clozapine initiation among females. Conclusions: Living with a partner was the strongest predictor of functioning after clozapine initiation in this study. Though potentially indicating better pre-morbid functioning, this finding stresses the need and importance of social support during the course of the treatment independent of clinical factors. Key words: schizophrenia; clozapine; treatment response; functional level; global assessment of functioning (GAF); epidemiologyIntroductionApproximately one-third of patients with schizophrenia will not respond to non-clozapine antipsychotic treatment, thus meeting criteria for treatment-resistant schizophrenia (TRS) {{3770 Lally,J. 2015;}}. The criteria for TRS in most guidelines, e.g. the UK National Institute for health and Care Excellence (NICE 2014, ), are failure to respond to two different antipsychotics at therapeutic dosages for a sufficient duration {{3773 Suzuki,T. 2012; 3770 Lally,J. 2015;}}. In the case of TRS, guidelines recommend treatment with clozapine, the antipsychotic with proven superior effectiveness in this patient group {{3856 McEvoy,J.P. 2006;}}. Nevertheless, adherence to these guidelines is poor and varies geographically {{3774 Nielsen,J. 2012; 3954 Stroup,T.S. 2014;}}. Furthermore, recent studies have identified the problems of delays in clozapine initiation and under-use of clozapine in TRS, and there is a concern that delayed use may have a negative impact on long term outcome {{3857 Howes,O.D. 2012; 3770 Lally,J. 2015;}}. The identification of clinical variables predicting clozapine response has the potential to encourage timely treatment with clozapine, particularly in patients who are most likely to benefit. However, to date, the evidence regarding prediction of clozapine response is very limited. Early clozapine treatment initiation after fulfillment of TRS criteria {{3775 Ucok,A. 2015;}}, a lower number of psychiatric hospitalizations and antipsychotic trials prior to clozapine treatment {{3772 Nielsen,J. 2012;}}, and an increase in triglyceride levels {{3771 Lally,J. 2013;}} have all been associated with clozapine response. The results on gender {{3851 Szymanski,S. 1996; 3850 Usall,J. 2007;}} and age {{3853 Hofer,A. 2003; 3859 Kelly,D.L. 2010;}} are conflicting. Furthermore, most studies to date have been underpowered {{3771 Lally,J. 2013; 3775 Ucok,A. 2015;}}. Finally, recent reviews have emphasized the importance of including functional outcomes in the evaluation of the clinical course of treatment {{3776 Lieberman,J.A. 2008; 3773 Suzuki,T. 2012; 3714 Suzuki 2015;}}. We aimed to identify potential predictors of clozapine response based on both a service measure (no hospitalizations) and a functional measure (increments in the global assessment of functioning (GAF-F) score). To our knowledge, this is the first study implementing these two clinically important dimensions in the prediction of the clinical course of clozapine treatment within a large nationwide setting. Materials and MethodsThe registersThe present population-based cohort-study was performed by merging several Danish nationwide registers via the unique personal identification number assigned to all people living in Denmark permanently {{3423 Pedersen,C.B. 2011;}}. The registers represent well-validated resources for research {{3428 Jensen,V.M. 2011; 3423 Pedersen,C.B. 2011; 3424 Mors,O. 2011; 3426 Kildemoes,H.W. 2011; 3646 Uggerby 2013;}}. Danish Psychiatric Central Research Register (DPCRR)The DPCRR has registered all inpatient contacts to psychiatric hospitals in Denmark since 1969, and all outpatient and emergency contacts to psychiatric hospitals since 1995. The information includes dates of contacts and diagnoses, which are coded according to the International Classification of Diseases, 8th edition (ICD-8) up to 1994, and according to ICD-10 since then {{3424 Mors,O. 2011;}}. Danish Schizophrenia Registry (DSR) and the global assessment of functioning (GAF)The DSR {{3604 Mainz 2004; 3752 Pedersen,C.G. 2014;}} was established in the Danish Healthcare System in 2003 and constitutes a registry on selected measures of quality of care in relation to people diagnosed with schizophrenia (ICD-10: F20.0-F20.9). All patients diagnosed with schizophrenia in Denmark since 2004, both inpatients and outpatients, are registered, except those treated in forensic mental health services. Since January 1, 2004, data on approximately 11,000 patients were recorded each year. A recent study documented high internal validity of the variables registered in the DSR when compared to information from medical records {{3752 Pedersen,C.G. 2014;}}. The GAF-scale evaluates both symptom severity (GAF-S) and functioning (GAF-F) {{3713 Jones,S.H. 1995;}}, ranking a patient from 1 (lowest score) to 100 on both scales. Within the DSR, GAF-F is used and is supposed to be registered at various times. Between January 1, 2004 and December 31, 2011, among patients admitted to a hospital, patients were generally GAF-F scored at discharge or after one year if the hospitalization lasted longer than one year. Among outpatient contacts, patients were GAF-F scored once yearly and/or at completion of the outpatient contact. The availability of registration of GAF scoring may therefore vary at defined dates for epidemiological studies during follow up. The internal and external validity of the GAF-F score against measures of severity is good {{3933 K?hler, O 2016;}}. Danish National Prescription Registry (DNPR)The DNPR registers all prescriptions issued at Danish community pharmacies since 1995 and records information, among others, on date of redemption, the Anatomical Therapeutic Chemical (ATC) code, amount and drug name {{3426 Kildemoes,H.W. 2011;}}. Registers used for identification of covariatesThe Danish Civil Registration System (DCR) provides information on date of birth, gender and parents for each resident in Denmark since 1968 {{3423 Pedersen,C.B. 2011;}}. Levels of educational achievements and occupational status are registered in the Danish Education Registers {{3428 Jensen,V.M. 2011;}} and the Danish registers on personal labor market affiliation {{3866 Petersson,F. 2011;}}, respectively. Study populationUsing the DPCRR {{3424 Mors,O. 2011;}}, we identified all adult patients (≥18 years) born after January 1, 1955 and with a diagnosis of schizophrenia (ICD-10: F20.0-F20.9) in an in- or outpatient setting between January 1, 1995 and December 31, 2011. We then used the DNPR {{3426 Kildemoes,H.W. 2011;}} to identify those patients with schizophrenia who redeemed their first prescription of clozapine (ATC-code: N05AH02), i.e. who picked up their clozapine prescription at a Danish pharmacy, between January 1, 2004 and December 31, 2011. Clozapine initiation was defined as the date of redemption of the first clozapine prescription. We used the DSR to identify those patients who had a registered GAF-F score within the 30 days prior to clozapine initiation. This score represented the GAF-F at baseline, i.e. at clozapine treatment initiation. Treatment durationSince prescribed dosage information was not available, the duration of clozapine treatment following each redemption of a clozapine prescription was estimated based on the prescribed number and dose of pills and the Defined Daily Dose (DDD) {{3455 World 2008;}}. We calculated the estimated treatment duration for each prescription as follows: treatment duration (days) = ((Number of packages Number of pills per package dose of pills) / DDD) 1.15 + 90. The multiplication factor of 1.15 and the addition of 90 days were included since these extensions of the treatment period are in closer agreement with actual drug consumption in clinical practice due to poor adherence {{3641 Tiihonen,J. 2011;}}. Hence, if an individual did not redeem a new prescription for clozapine within the calculated time window (including the 90 days grace period, i.e. the extra period to allow for low compliance or delayed redemption of the next clozapine prescription), clozapine treatment was considered discontinued. We followed all individuals for the first two years of clozapine treatment or until discontinuation. Outcome: clinical responseWe assessed the clinical response to clozapine treatment by applying both a service use and a functional outcome measure. The service use outcome measure was defined as non-hospitalization with schizophrenia (ICD-10: F20.0-F20.9), i.e. staying out of hospital during clozapine treatment {{3424 Mors,O. 2011;}}. The functional outcome measure was based on a recent study, which defined response to clozapine treatment via increments in the level of psychosocial functioning {{3773 Suzuki,T. 2012;}}. Using the DSR {{3604 Mainz 2004; 3752 Pedersen,C.G. 2014;}}, we identified the highest GAF-F score achieved during clozapine treatment. The definition of functional response was {{3773 Suzuki,T. 2012;}}: Moderate improvement: GAF-F increase≥10Substantial improvement: GAF-F increase≥20 and total GAF-F≥50. Assessment of predictorsWe identified information on the following covariates at the time of the first clozapine prescription (baseline): gender and age {{3423 Pedersen,C.B. 2011;}}; education (primary school or higher education) {{3428 Jensen,V.M. 2011;}}; employment status (work force and early retirement pension) {{3866 Petersson,F. 2011;}}; marital status (single or married/cohabiting); and time since first schizophrenia diagnosis {{3424 Mors,O. 2011;}}. Additionally we assessed in- or out-patient contacts to psychiatric hospitals within 30 days of the first clozapine prescription, and among inpatients the length of hospitalization in number of days. Furthermore, we identified whether the hospital contact happened during detainment, i.e. whether any coercive measures were applied during the hospitalization. Statistical analysesConcerning differences between individuals who were GAF scored and individuals without a registered GAF score, we performed logistic regression analyses on potential baseline differences at the time of the first clozapine prescription.We followed all individuals from the day of the first clozapine prescription was redeemed at a community pharmacy until the occurrence of an outcome (until December 31, 2011 for GAF-scores, and until June 30, 2013 for hospitalizations), death, emigration, discontinuation of clozapine treatment or end of follow-up after two years. We performed Cox regression analyses to evaluate the relationship between the different variables at clozapine treatment initiation and clinical response. We report hazard rate ratios (HRR) and 95%-confidence intervals (95%-CI). The basic analytical model included age and gender. The full model included gender, age, marital status, education, work status, calendar year, and time since first schizophrenia diagnosis until first clozapine prescription, in- or outpatient status including length of hospitalization and detainment. Sub-analyses and sensitivity analyses Because prior studies have shown conflicting results on gender {{3851 Szymanski,S. 1996; 3850 Usall,J. 2007;}}, we performed additional analyses stratified by gender. In sensitivity analyses, we tested the robustness of our findings. First, we investigated whether the results changed when we only included GAF-F scores within the first 14 or 7 days before the first redeemed clozapine prescription or when we restricted to individuals with a GAF-F score registered on the day of the clozapine prescription redemption. Second, we investigated whether the results changed when we calculated the clozapine treatment duration applying a grace period of 30 days or when we added no grace period (instead of the 90 days grace period used for the primary analyses). Third, we only used the criterion of GAF-F improvement≥20 as the definition of substantial improvement. ResultsWe identified 502 individuals with a diagnosis of schizophrenia between 1995 and 2011, who initiated clozapine treatment during 2004-2001, and who had a GAF-F scored within 30 days prior to the first clozapine prescription (see Figure 1 for flow-chart). The baseline characteristics of the sample are shown in Table 1. A total of 378 (75.5%) individuals continued clozapine treatment throughout the two year follow-up period. Patients with a GAF score differed from those without in terms of that they were more often males (p=0.09) and more often hospitalized (p=0.06) (supplementary Table 1). Predictors of non-hospitalization Among the 502 patients who initiated clozapine treatment, 232 (46.2%) were not hospitalized due to schizophrenia during the follow-up period (Table 2). In the fully adjusted model, voluntary status (i.e., no act of detainment) at clozapine initiation showed a tendency towards non-hospitalization (HRR=1.61; 95%-CI=0.97-2.67). A hospitalization of more than 90 days prior to the first clozapine prescription, compared to clozapine initiation during an outpatient contact, indicated a lower risk for non-hospitalization (HRR=0.70; 95%-CI=0.49-1.01). We found no associations for the other variables and in gender-specific analyses. Predictors of good functional improvementA total of 96 (19.1%) individuals achieved a moderate functional improvement, and 29 (5.8%) substantial improvement during the study period (Table 3). In the fully adjusted model, marital or cohabiting status was associated with substantial improvement (HRR=2.78; 95%-CI=1.07-7.23) and showed a non-significant association with moderate improvement (HRR=1.56; 95%-CI=0.88-2.76). Female gender showed a trend towards moderate improvement (HRR=1.25; 95%-CI=0.81-1.94) and substantial improvement (HRR=1.30; 95%-CI=0.56-3.01). Voluntary status at the hospitalization within 30 days prior to clozapine initiation was non-significantly associated with moderate (HRR=1.32; 95%-CI=0.59-2.97) and substantial improvement (HRR=2.36; 95%-CI=0.30-18.85). Sub-analyses and sensitivity analyses Gender-specific sub-analyses indicated that a shorter time from schizophrenia diagnosis to clozapine initiation was associated with substantial functional improvement among women. A total of 13 women achieved substantial improvement, and the chance of substantial improvement decreased by 15% (HRR 0.85 (95%-CI=0.72-1.00)) for each year delay in clozapine initiation after first schizophrenia diagnosis. All sensitivity analyses for different time-windows for identification of the GAF-F scores and different grace periods for calculation of clozapine treatment length supported our primary results. Finally, when using GAF-F improvement≥20 as the sole criterion for substantial improvement, 35 (7.0%) individuals were classified with substantial improvement, and the analyses supported our primary findings. DiscussionThe present study investigated a broad range of potential predictors for clozapine response among 502 patients with schizophrenia by evaluating service-based (no hospitalization with schizophrenia) and functional measures (increase in GAF-F). A total of 75% remained on clozapine treatment during the 2-year follow-up period. Of the patient and disease related factors (i.e., gender, age at first clozapine prescription, time from schizophrenia diagnosis to first clozapine prescription, in- or outpatient status at the hospitalization at clozapine initiation including length of hospitalization, detainment, marital status, education, work status, and calendar year), living with a partner was the strongest factor associated with better response to clozapine treatment. In addition, among women, a shorter time from schizophrenia diagnosis to clozapine initiation was associated with better functional improvement. Predictors for clozapine responseA range of potential predictors for clozapine response have been identified to date, yielding conflicting results {{3858 Suzuki,T. 2011;}}. Living with a partner, indicating better premorbid functioning, predicted functional improvement in our study, which is in accordance with other studies associating better premorbid functioning with improved response to clozapine {{3859 Kelly,D.L. 2010;}}. Furthermore, living with a partner may have resulted in a better adherence and thus better improvement. However, a recent review discussed that the level of premorbid functioning may not be particularly useful in clozapine response prediction {{3858 Suzuki,T. 2011;}}. The importance of the differentiation of premorbid functioning during different periods of life, i.e. childhood or adolescence, was suggested to be more important {{3859 Kelly,D.L. 2010; 3858 Suzuki,T. 2011;}}. Regarding gender, several studies have associated women with better response to clozapine {{3860 Ciapparelli,A. 2004;}}, whereas others have reported either worse response compared to men {{3862 Lieberman,J.A. 1994;}} or no gender-differences {{3861 Semiz,U.B. 2007;}}. Our findings suggest that women may have a better functional improvement during clozapine treatment compared to men, although the results did not reach statistical significance. In addition, among women, we associated a shorter time from schizophrenia diagnosis to clozapine treatment initiation with a trend towards better functional improvement. This association was not present among men. The chance of reaching substantial improvement was deceased by 15% for each year delay in clozapine treatment initiation from first schizophrenia diagnosis. This result is in line with previous findings reporting better response among individuals who initiated clozapine treatment early after fulfillment of TRS criteria {{3775 Ucok,A. 2015;}}. However, these authors did not find gender differences {{3775 Ucok,A. 2015;}}, possibly because of low power (n=162). Indeed, it has been documented that clozapine treatment often is delayed for several years among patients with TRS {{3857 Howes,O.D. 2012;}}. In addition, an underuse of clozapine has been emphasized among patients fulfilling TRS-criteria including reluctance to initiate treatment with clozapine, potentially leading to delayed treatment {{3770 Lally,J. 2015;}}. Thus, future studies should investigate the importance of timing of clozapine treatment, i.e. whether early clozapine treatment initiation, e.g. after fulfilment of TRS criteria, is associated with improved response. Furthermore, it seems important to investigate the presence of possible gender differences concerning timing and treatment response patterns. The absence of detainment was not insignificantly associated with better rates of non-hospitalization and functional improvement in the current study. However, we had only information whether the hospital contact happened during detainment, not concerning the actual clozapine treatment initiation. Nevertheless, since clozapine treatment requires good compliance and acceptability due to frequent blood test monitoring, initiation of clozapine treatment during an act of detainment may be less likely to result in a good response pattern. Finally, wWe found no effects of age at clozapine initiation on clozapine response. Finally, future studies need to investigate whether other important factors are associated with clozapine response, such as psychiatric and/or physical comorbidity and substance use. Strengths and limitationsThe strengths are the population-based design and the well validated Danish registers {{3423 Pedersen,C.B. 2011; 3424 Mors,O. 2011; 3646 Uggerby 2013;}}. The DSR has an overall high validity {{3695 Pedersen,C.G. 2012;}}, including good internal validity for GAF-F {{3933 K?hler, O 2016;}}. Furthermore, we included both service-based and psychosocial measures of functioning in response evaluation, thereby trying to meet the high heterogeneity among patients with schizophrenia. Concerning limitations, other measures of psychosocial functioning than the GAF-F, such as Global Impression Scale (CGI) and the Positive and Negative Symptom Scale (PANSS), are used in different clinical psychiatric settings. However, recent studies have found that the GAF-F has a high validity and correlates well with the CGI and PANSS {{3888 Startup,M. 2002; 3696 Samara,M.T. 2014; 3714 Suzuki,T. 2015;}}. Nevertheless, the GAF-F cannot be directly translated to the other scores, and future studies need to investigate other scores of functioning or psychopathology {{3984 Morosini,P.L. 2000; 3985 Suzuki,T. 2008;}}. Secondly, within the Danish Schizophrenia Register, the GAF-F is only registered at specific times. During our study period, among hospitalized patients, every patient was supposed to have a GAF-F score registered at discharge, or after one year if the hospitalization lasted longer than one year. Among outpatient contacts, a GAF-F score was supposed to be performed once yearly and at completion of the outpatient contact. Therefore, the present study included more patients (70%) who had been inpatients within the 30 days before filling their first prescription for clozapine (p=0.06 compared to individuals without a GAF score) and thus, potentially, a cohort of more severely diseased patients. Furthermore, these pre-defined assessment times may have prevented patients to be GAF-F scored during periods of improvement, potentially resulting in an under-reporting of cases with functional improvement. However, our results were robust in sensitivity analyses with different assessments of the baseline GAF-F score. In addition, we found no important baseline differences between individuals with a GAF score and individuals without a registered GAF score (supplementary Table 1). Third, the Danish National Prescription Registry {{3426 Kildemoes,H.W. 2011;}} holds only information on the redemption of prescriptions, not the actual consumption or specific dosage regimen. However, the methods used in the present study regarding calculation of treatment length have been evaluated as clinically relevant {{3641 Tiihonen,J. 2011;}}. Furthermore, we applied different time windows for calculation of clozapine treatment duration, which did not change the results. Fourth, due to lack of information on hospital treatment, we do not know whether clozapine treatment was initiated during an inpatient stay so that the assessed GAF score within 30 days prior to the first clozapine outpatient prescription may not actually represent precise pre-clozapine functioning. Fifth, response to clozapine is at least partly mediated through blood clozapine concentrations {{3858 Suzuki,T. 2011;}}, but we had no information on clozapine blood levels. Sixth, we did not include information on other psychotropic medications which may have confounded our findings; however, the evidence concerning the efficacy of clozapine augmentation strategies is limited {{3983 Muscatello,M.R. 2014;}}. Finally, although applying large databases, we had low power for several of the investigated predictors because of few events. Conclusion and perspectivesLiving with a partner was the strongest predictor of improved functioning after clozapine initiation in this study. 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