Schizophrenia Research 236 (2021) 123–134 Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Predictors of response to pharmacological treatments in treatment-resistant schizophrenia – A systematic review and meta-analysis Annika Seppälä a, b, *, Jenni Pylvänäinen a, b, Heli Lehtiniemi a, b, c, Noora Hirvonen b, d, Iluminada Corripio e, Hannu Koponen f, Jussi Seppälä a, g, Anthony Ahmed h, Matti Isohanni a, Jouko Miettunen a, b, Erika Jääskeläinen a, b, i a Center for Life Course Health Research, University of Oulu, Oulu, Finland b Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland c Arctic Biobank, Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, Finland d Information Studies, Faculty of Humanities, University of Oulu, Oulu, Finland e Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, CIBERSAM G21, U.A.B (Autonomous University of Barcelona), Barcelona, Spain f University of Helsinki and Helsinki University Hospital, Psychiatry, Helsinki, Finland g Department of Mental Health and Substance Use Disorders, South Carelia Social and Health Care District, Lappeenranta, Finland h Department of Psychiatry, Weill Cornell Medicine, Cornell University, White Plains, USA i Department of Psychiatry, University Hospital of Oulu, Finland A R T I C L E I N F O A B S T R A C T Keywords: Background: As the burden of treatment-resistant schizophrenia (TRS) on patients and society is high it is Schizophrenia important to identify predictors of response to medications in TRS. The aim was to analyse whether baseline Treatment-resistant patient and study characteristics predict treatment response in TRS in drug trials. meta-analysis Methods: A comprehensive search strategy completed in PubMed, Cochrane and Web of Science helped identify Predictors Response relevant studies. The studies had to meet the following criteria: English language clinical trial of pharmacological Pharmacological treatment treatment of TRS, clear definition of TRS and response, percentage of response reported, at least one baseline characteristic presented, and total sample size of at least 15. Meta-regression techniques served to explore whether baseline characteristics predict response to medication in TRS. Results: 77 articles were included in the systematic review. The overall sample included 7546 patients, of which 41% achieved response. Higher positive symptom score at baseline predicted higher response percentage. None of the other baseline patient or study characteristics achieved statistical significance at predicting response. When analysed in groups divided by antipsychotic drugs, studies of clozapine and other atypical antipsychotics produced the highest response rate. Conclusions: This meta-analytic review identified surprisingly few baseline characteristics that predicted treat­ ment response. However, higher positive symptoms and the use of atypical antipsychotics – particularly cloza­ pine –was associated with the greatest likelihood of response. The difficulty involved in the prediction of medication response in TRS necessitates careful monitoring and personalised medication management. There is a need for more investigations of the predictors of treatment response in TRS. 1. Introduction with schizophrenia present with a form of the illness resistant to treat­ ment (Conley and Kelly, 2001). Treatment-resistant schizophrenia (TRS) is a severe yet highly The burden of TRS on patients and society is high. Many comor­ prevalent form of schizophrenia (Kennedy et al., 2014). About 1% of the bidities are associated with the disease and the treatment. Unemploy­ global population has schizophrenia and the percentage is even higher ment and suicide risk are also notably increased. The healthcare costs of in some parts of the world, for example, Northern Finland, with its es­ TRS are 3 to 11 times higher than schizophrenia in general (mainly due timate of 1.8% (Perälä et al., 2008). One-fifth to one-third of all patients to the high number of hospitalizations), representing 60% to 80% of the * Corresponding author at: Center for Life Course Health Research, Medical Faculty, PO Box 5000, 90014, University of Oulu, Finland. E-mail address: annika.seppala@oulu.fi (A. Seppälä). https://doi.org/10.1016/j.schres.2021.08.005 Received 5 December 2020; Received in revised form 30 June 2021; Accepted 4 August 2021 Available online 5 September 2021 0920-9964/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). A. Seppälä et al. Schizophrenia Research 236 (2021) 123–134 total economic burden of schizophrenia (Kennedy et al., 2014). the titles and abstracts of the articles. Subsequently, AS and JP evaluated Estimates of the proportion of treatment responders in TRS vary full text articles. For studies that met the inclusion criteria, AS and JP widely. Suzuki et al. (2011) reviewed 33 clinical trials of antipsychotics extracted the data. When questions arose related to full text evaluation on TRS and the response rate varied between 0%–76%. In a systematic and data extraction, study authors (AS, JP, EJ, JM, and JS) resolved review of 65 trials, the average response rate was 41%, ranging from 0% these by consensus. to 74% (Kennedy et al., 2014). Studies have examined the effects of antipsychotic medications and 2.2. Study selection other treatments on the likelihood of response in TRS (Siskind et al., 2016). Meta-analyses on non-pharmacological predictors of response in We wanted to examine trials that studied response to medication in a TRS are rare (Okhuijsen-Pfeifer et al. 2020). A small number of original TRS population. The articles included in the analyses were required to studies have examined predictors of response in TRS. Based on these meet each of the following eligibility criteria: studies, later age of illness onset (Semiz et al., 2007), shorter hospital­ izations (Zito et al., 1993) and less severe symptoms at baseline (Hong 1. The article detailed an original study of people diagnosed with DSM- et al., 1997; Zito et al., 1993; Wirshing et al., 1999) predict better III, DSM-III-R, DSM IV or ICD-9 or ICD-10 schizophrenia or schizo­ treatment response. Remarkably, more severe positive or negative affective disorder adjudged as treatment resistant. symptoms may also predict better treatment response (Wirshing et al., 2. The article presented clear criteria for treatment resistance (for 1999). Shorter delay in clozapine initiation and fewer pre-clozapine further details, see 2.3). hospitalisations have been associated with better clozapine response 3. The study included a sample size of at least 15 individuals at its (Shah et al., 2019). Gender (Lieberman et al., 1994) and age at study initiation. initiation have not predicted treatment response (Zito et al., 1993; Hong 4. The study had at least a 6-week follow up period. et al., 1997; Lindenmayer et al., 2002; Semiz et al., 2007). In a meta- 5. The article detailed a clinical trial analysing the effect of medications analysis of 34 articles, Okhuijsen-Pfeifer et al. (2020) analysed de­ (mostly antipsychotics; in a few studies, mood stabilisers or antide­ mographic and clinical predictors of clozapine response in schizo­ pressants; and in a very few studies, other pharmacological treat­ phrenia. They found that lower age, lower PANSS negative score and ment). Both naturalistic and controlled trials were included. paranoid schizophrenia subtype predicted better response to clozapine. 6. The article presented the response rate of the sample. To our knowledge, there are no systematic reviews or meta-analyses 7. The study presented at least one baseline characteristic (i.e. predictor summarising predictors of response to any psychopharmacological of response in this study). treatment of TRS. 8. The article presented the study characteristics and inclusion criteria The goal of this systematic review and meta-analysis was to deter­ of the sample. mine the average response rate and identify predictors of treatment 9. The articles were in English. response in patients with TRS in drug trials. We focused on putative predictors assessable at the start or switch of antipsychotic treatment – The exclusion criteria included: usually obtained during the baseline or pre-treatment phases in clinical trials. Based on previous literature, we hypothesised that later age of 1. Studies analysing non-pharmacological treatments, for example, illness onset, shorter duration of hospitalisation and less severe symp­ psychotherapies and ECT since these would be difficult to combine toms at baseline will predict better treatment response. There is a with pharmacological trials based on the different kinds of patient negligible number of individual studies analysing whether patient selection and methods. characteristics predict treatment response. It is therefore not possible to 2. Samples including children or adolescents (patients had to be at least perform a patient level meta-analysis. Thus, in this study, we analysed 18 years of age at the study initiation). the associations at study level, i.e. we analysed the associations between 3. Cross-over studies due to the inability to compare them with other patient and study characteristics and the response percentage in the studies. corresponding study. 2.3. Definition of TRS in this review 2. Methods We included all the clinical trials that reported their sample as a TRS We followed the PRISMA (Preferred Reporting Items for Systematic sample, and that defined TRS as a history of use of at least one trial of reviews and Meta-Analyses) guidelines for systematic reviews and meta- antipsychotics without response. analyses (Page et al., 2021) (see Online supplement appendix 1). There are multiple operational definitions of TRS. The original Kane et al. (1988) criteria were very strict and the required medication dose 2.1. Search strategies was high. When developing a consensus for the definition of TRS, Howes et al. (2017) suggested a more specific definition with six points to A comprehensive literature search was performed in November 2016 consider, including use of a symptom questionnaire and performance and updated in March 2019, using the electronic databases ISI Web of evaluation. Table 1 summarizes various definitions of treatment- Science, PubMed (MEDLINE) and Cochrane CENTRAL (Cochrane Cen­ resistant schizophrenia. tral Register of Controlled Trials). An information specialist (NH) con­ We acknowledge that a consistent definition of TRS is important. ducted the search. The search strategy included the keyword However, in the studies identified, there was great variability in the ‘schizophreni*’ in the title of the article linked with an AND operator to operational definition of TRS and in reporting the definition. In order to a set of keywords describing treatment resistance (‘treatment-resistan*’, capture all possible TRS samples, we chose to include all the clinical ‘ultra-resistan*’, ‘treatment-refractory’, ‘clozapine’) in the abstract and/ trials that reported their sample as a TRS sample, and that defined TRS or topic of the article. The search was restricted to articles in English and as a history of use of at least one trial of antipsychotics without response. to clinical trials as a topic or publication type. There was no time re­ The review included a range of TRS definitions. For example, a broader striction. See the online supplement Table 1 for a description of the definition from Scheepers et al. (2001): “All subjects were previously search strategy for each database. Furthermore, articles were searched treated with at least one typical antipsychotic for a minimum of four using a chaining method, i.e. finding interesting articles in the reference weeks”. In contrast, there was a narrower TRS definition from Dos­ lists of included articles. senbach et al. (2000): “BPRS ≥ 45; Score ≥ 4 in 4 BPRS psychotic At least two authors (AS, EJ, JP) evaluated all search results based on symptoms; non-response to ≥ 3 APs from different classes at ≥ 1000 mg 124 A. Seppälä et al. Schizophrenia Research 236 (2021) 123–134 Table 1 Social and Occupational Functioning Scale (SOFAS). In addition, Examples of definitions of treatment resistant schizophrenia. whenever possible, they recommended that investigators ascertain Author Definition response prospectively over at least six weeks and defined as at least a 20% improvement in symptom scores and meeting the absolute Kane et al., 1. The patient should have manifested a failure to respond to three 1988 or more adequate trials of antipsychotic treatment within the thresholds (symptoms rated at no more than mild severity). Suzuki et al. last 5 years, including medication from two distinct classes with (2011) found that the most commonly used criteria for treatment dosing at least the equivalent of 1000 mg per day of response is at least a 20% reduction in PANSS or BPRS. chlorpromazine. Of the 77 studies included in our review, 64 used a 20% reduction in 2. There must be at least moderately severe continuous symptoms in certain psychosis symptoms (conceptual disorganization, symptoms as a definition of response, 18 studies used a 30% reduction, a suspiciousness, hallucinatory behaviour and unusual thought single study used a reduction of 40% and 50%, and eight studies used the content). Kane 1988 criteria. Kane et al. (1988) defined response with ≥20% 3. There must be evidence of substantial current symptoms decrease in the BPRS total score, and either a post-treatment CGI- despite current optimized treatment to which the patient is Severity score of ≤3 (i.e., better than mild) or BPRS of ≤35. Given that adherent: defined as a score of greater than or equal to 45 on the Brief Psychiatric Rating Scale (BPRS) or 90 in the Positive and only one study used a 40% or 50% reduction, we combined the one Negative Syndrome Scale (PANSS). study with those using the reduction of 30%. A small number of studies Suzuki et al., 1. At least two failed adequate trials with different antipsychotics reported more than one response criteria. Based on these figures, we 2012 (at chlorpromazine-equivalent doses of ≥600 mg/day for ≥6 present the results for the response rate of studies using the following consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsy­ response definitions: 1.) reduction in 20% of symptoms, 2.) reduction in chotic trials 30% of symptoms and 3.) the Kane criteria. Since most of the studies 2. Both a score of ≥4 on the Clinical Global Impression-Severity used a reduction in 20% of symptoms as the response criteria, we studied (CGI-S) and a score of ≤49 on the Functional Assessment for the associations between baseline and study characteristics and the Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤ 50 percentage of response among these studies in a meta-analysis. In on the Global Assessment of Functioning (GAF) scales Howes et al., 1. The patient should have at least moderate severity of symptoms addition, as a sensitivity analysis, we performed the analyses in the total 2017 for 12 weeks (using standardised scale) sample regardless of the response criteria. 2. At least moderate functional impairment measured using a validated scale. 2.5. Recorded variables and analysed predictors of response 3. At least two past treatments with different antipsychotic drugs for at least for 6 weeks with a dosage equivalent to 600 mg of chlorpromazine per day Our team (AS and JP) recorded the following variables from each 4. Adherence is followed systematically, at least 80% of article: year of publication, original and final sample size, duration of prescribed doses taken. Antipsychotic plasma levels monitored follow-up, number of drop-outs, type of pharmacological treatment, on at least one occasion. proportion of males, mean age of participants, duration of illness, age of 5. In ideal cases, at least one antipsychotic drug trial to make sure of the treatment resistance onset, age at first hospitalisation, number of hospitalisations, weight, 6. Criteria clearly separating responsive from treatment-resistant BMI, ethnicity, inpatient/outpatient status, duration of current hospi­ patients. talisation, years of education, baseline overall (PANSS, BPRS, or CGI) and positive and negative symptom (PANSS) severity, and proportion of response. BPRS positive and negative symptoms were not studied as for ≥ 4 months; a history of hospitalization for ≥365 days; non-response those were reported only in a few studies. (20% decrease in BPRS) to CLZ for ≥4 months or intolerance to CLZ”. The sample also included studies using the Kane et al. (1988) criteria 2.6. Sensitivity analysis (see Table 1). Most of the identified clinical trials defined TRS based on only the We completed a sensitivity analysis by including only studies that number of failed antipsychotic medication trials. Most studies did not used a more common definition of TRS, i.e. studies that included pa­ report the dosage or treatment duration of each failed antipsychotic tients who had tried at least two different antipsychotic medications (i.e. trial. Moreover, several were missing standard assessments of symptom studies using the average strict and narrow TRS criteria). Given that severity (e.g. PANSS, BPRS) and the level of disability. Therefore, there are differences on the effects of different treatments, we also medication dosage and duration, symptom severity, and disability did analysed the percentage of treatment response in subpopulations clas­ not figure into our classification of TRS criteria. Rather, we classified the sified by the medication that was analysed in the trial. Further, we included studies into three subclasses based on the number of previous examined associations between predictors and treatment response in 1) antipsychotic trials. We conducted the analyses in the total sample and studies that included only atypical or typical antipsychotics as a trial conducted a sensitivity analysis including only studies in groups 2 and 3: treatment and separately in 2) studies that included only atypical anti­ psychotics. Here, we combined the treatment categories in different 1. History of non-response to at least one adequate trial of antipsychotic trials regardless of the comparison treatment. treatment (broad criteria). 2. History of non-response to at least two adequate trials of antipsy­ 2.7. Statistical analysis chotic treatment (average strict criteria). 3. History of non-response to at least three or more adequate trials of We divided predictor variables into three classes based on tertiles or antipsychotic (narrow criteria). into two classes based on median. Based on the expected heterogeneity of the treatment response percentage between studies, we used a 2.4. Definition of response random effects meta-analysis to pool overall estimates of response. In the random effects analysis, we weighted each study by the inverse of its There was also heterogeneity across studies regarding the definition variance and the between-studies variance. We used random effects of response. Howes et al. (2017) suggested the following criteria for meta-regression to explore the influence of potential predictor variables adequate treatment response: on response proportion. We assessed the heterogeneity of the studies 1.) Symptoms are rated no more than mild severity; 2.) Duration of using I2 statistics, and adjudged the statistical significance of heteroge­ response sustained for a minimum of 12 weeks; and 3.) Functional neity using a chi-square test. The values of I2 ranged from 0% to 100%, impairment rated as mild or better on a standardised scale such as the reflecting the proportion of the total variation across studies beyond 125 A. Seppälä et al. Schizophrenia Research 236 (2021) 123–134 chance. A value of 25% describes low heterogeneity, 50% moderate six of them; the proportion of schizoaffective patients was less than 20% heterogeneity and 75% high heterogeneity or major excessive variation of the whole sample. The highest proportion of schizoaffective patients across studies (Higgins et al., 2003). We completed all analyses using in an individual study was 40%. Stata 13 (StataCorp, L, 2013). 3.3. Response percentage 3. Results In all the studies, 41.3% (95% CI: 36.8, 45.8) of the patients achieved 3.1. Search results response. When only analysing studies using a 20% reduction in symptoms as the response criteria (n = 61), 40.8% (36.1, 45.5) achieved The initial literature search produced 1373 references, and after the response and 40.6% (31.9, 49.3) achieved response when the criteria removal of duplicates, 1148 unique publications were identified (Fig. 1). was 30% of decrease of symptoms (n = 18). In studies using the Kane After inspecting the abstracts, 160 original articles were included for criteria for the response (n = 8), 35.0% (19.3, 50.7) of the patients review against the above-mentioned eligibility criteria. 77 articles were experienced response. When only including studies using the most included in the systematic review. The overall sample included 7546 commonly used TRS criteria (groups 2 and 3, i.e. TRS history of at least 2 TRS patients. AP medications) (n = 60), 42.6% (37.4–47.7) achieved response. When using a 20% reduction in symptoms as the response criteria and 3.2. Study characteristics excluding studies using the broad TRS criteria (n = 44), 42.6% (36.8–47.6) achieved response (Figs. 2–5). In the included studies (online supplement Table 2), the median age at onset was 21.8 years (range 20.5–22.9), median baseline PANSS was 3.4. Association between baseline and study characteristics and treatment 94.0 (81.6–104.4), BPRS 50.6 (42.6–57.5) and the majority 69.3% response (62.0–74.0) of the samples were male. Table 2 includes a summary of the characteristics of included samples. 40 samples were from North Table 3 includes response percentages by baseline and study char­ America (35 from the USA), 20 from Europe, 17 from Asia, two from acteristic variables. Of the included variables only baseline positive Africa and one from Australia. Three of the studies included patients symptoms associated statistically significantly with response from two different countries. Most of the studies had used DSM-IV as a (p = 0.008). Among those studies with highest mean of positive symp­ diagnostic system (n = 48), 19 had used DMS-III-R, six studies DSM-III, toms (highest tertile), median response was 50.0%, whereas in the two studies ICD-10 and two studies did not report the used diagnostic lowest tertile response was 17.8%. None of the other baseline and study system. Regarding the strictness of the definition of TRS, 31 of the characteristics achieved statistical significance. In the studies of the studies required a history of at least three antipsychotics, 29 of the youngest age at baseline, the median response rate was 50.7%, in the studies required a history of at least two antipsychotics and 12 studies middle tertile the response rate was 44.4% and in the oldest tertile it was had a broad definition of history of at least one antipsychotic. It was not 39.4%. Among the studies in which the age at time of first hospital­ possible to classify the strictness of the definition of TRS for five studies. isation was low, only 18.2% achieved response, whereas in the older Nine studies also included schizoaffective patients in the sample and in group the rate was 59.0%. When the cumulative number of Records identified through database searching (N =1422 ) Records after duplicates removed (N = 1148) Records excluded by abstract and title (N=988) Records screened by full text (N = 160) Records excluded by Full text (N=83) Full-text articles included in qualitative synthesis (N =77) Fig. 1. Flow diagram of the selection of studies. 126 A. Seppälä et al. Schizophrenia Research 236 (2021) 123–134 Table 2 treatment response. Summary characteristics of the included studies (n = 77). We also analysed the response percentage in the baseline and study n % characteristic variables in all 77 studies, i.e. including studies with a variable response criteria. Only higher positive symptom score at Country US 35 45.5 baseline was associated with higher response percentage, and no other Canada 5 6.5 statistically significant associations occurred (see Table 2 in the Europe 20 26.0 Supplement). Asia 17 22.1 South-Africa 2 2.6 Australia 1 1.3 3.5. Response in subpopulations to antipsychotic medication Time of the publication Before 1990 2 2.6 Table 4 summarizes the proportion of responders to antipsychotic 1990–1999 22 28.6 medications in several subpopulations. Of patients using typical anti­ 2000–2009 41 53.2 psychotics, 25.0% achieved response whereas of those using atypicals, 2010 or later 12 15.6 Design of the study 41.5% achieved response. Patients using clozapine monotherapy had Double blind RCT 51 66.2 the highest response rate, 50.0%, and patients on chlorpromazine had Open label study or descriptive/naturalistic study 26 33.8 the lowest, 10.3% (although the number of studies was low). There were Size of the sample no significant associations in baseline or study characteristics and the Under 50 44 57.1 50–99 17 22.1 response rate in subgroups by type of medication (analysed separately 100–199 7 9.1 for 1: studies including both typical and atypical antipsychotics and 2: 200–299 6 7.8 studies including atypicals only). Over 300 3 3.9 Used diagnostic system 4. Discussion DSM-III 6 7.8 DSM-III-R 19 24.7 DSM-IV 48 62.3 4.1. Main results ICD-10 2 2.6 Not reported 2 2.6 In this systematic review of medication trials of TRS, 41% of patients Studies reported to include also schizoaffective patients Yes 9 11.7 achieved response defined as a 20% reduction in symptoms. Rather No 68 88.3 surprisingly, none of the baseline or study characteristics other than Length of the study positive symptoms predicted response. Studies of clozapine and other 6 weeks 10 atypical antipsychotics produced the largest proportion of responders. >6 weeks–8 weeks 10 Given that there were no significant difference in the percentage of re­ >8–12 weeks 24 >12–20 weeks 13 sponders by publication year, we can assume that the efficacy of med­ >20–50 weeks 9 ications for TRS has remained unchanged for 30 years. >50–100 weeks 8 There was no statistically significant association between the num­ Over 100 weeks 2 ber of hospitalisations and treatment response. However, there were Used scale for analysing responseb BPRS 43 55.8 some differences in the response percentages. Surprisingly, samples with PANSS 39 50.6 a higher cumulative number of hospitalisations had better treatment CGI 9 11.7 response (46% compared to a response rate of 28% in samples with a SANS 3 3.9 lower number of hospitalisations). One possibility is that patients with a SAPS 2 2.6 fewer hospitalisations had more severe symptoms; thus, they may have BPRS = Brief Psychiatric Rating Scale. spent longer periods in hospital and long-stay institutions and had fewer PANSS = Positive And Negative Syndrome Scale. discharges. It is also possible that patients with fewer hospitalisations SANS=Scale for the Assessment of Negative Symptoms. received less follow-up care. SAPS = Scale for the Assessment of Positive Symptoms. Response rates varied relatively little by the strictness of TRS criteria, a Three of the studies included patients from two different continents, why the nor by different response criteria. However, among studies using the total percentage exceeds 100%. b Kane et al. (1988) criteria, the response percentage was slightly lower Some studies used several different scales for analysing response, why the than in other studies (35% vs. 41%). total percentage exceeds 100%. When analysed in strata by antipsychotic drugs, the highest response rate was in studies with patients using clozapine. The response per­ hospitalisations was lower, the median response rate was 27.6%, and centage was also high in studies analysing injections, although the re­ when it was higher, it was 46.2%. In studies with low proportion of sults remains unsure due to the very low number of studies (n = 3). The inpatients at baseline, the response rate was 44.0%, and in studies with difference in response rate between typical and atypical antipsychotic higher proportion of inpatients, it was 31.9%. In the samples with drugs was notable, whereas response rates did not vary greatly among shorter duration of current hospitalisation, 41.2% achieved response, individual atypical antipsychotic agents. whereas in the samples with longer duration, only 23.9% achieved response. There was no trend in response rates regarding year of pub­ 4.2. Comparison with previous results and clinical implications lication. Using the TRS classification previously described, in the studies with a broad definition of TRS, 37.4% achieved response, in studies with The current meta-analysis obtained a response rate (40.8%) equiv­ a moderately strict definition, 45.2% achieved response and in studies alent to Kennedy et al.’ (2014) estimate of 41%. The response rates were with a narrow definition, 46.7% achieved response. very similar regardless of TRS criteria, which supports the reliability of In the sensitivity analysis, when only studies that used a more the result. As a comparison, in general schizophrenia the response rates common definition of TRS were included, i.e. studies that included pa­ range from 23%–51% (Haddad and Correll, 2018). tients who had tried at least two different antipsychotic medications, the The association between higher baseline positive symptom score and results did not change: Only positive symptoms achieved statistical higher probability of response did not support our hypothesis of lower significance and there was no other statistically significant associations symptoms at baseline and better response. However, the result that between any of the baseline and study characteristics and percentage of higher positive symptoms specifically, but not negative symptoms, 127 A. Seppälä et al. Schizophrenia Research 236 (2021) 123–134 Fig. 2. Percentage of response in all studies. 20%: reduction in 20% of symptoms in PANSS or BPRS, 30%: reduction in 30% of symptoms in PANSS or BPRS, Kane: ≥20% decrease in the BPRS total score, and either a post-treatment CGI-Severity score of ≤3 (i.e., better than mild) or BPRS of ≤35. predicts better response is understandable, since antipsychotics are associated with better treatment response also in original study with effective in the treatment of positive, but less so in the treatment of treatment-refractory schizophrenia patients (Wirshing et al., 1999). negative symptoms. Earlier meta-analysis of clozapine response had We found no statistically significant difference between patient somewhat different results, showing that fewer negative symptoms gender or age at the study moment and response. This result is similar to predicted clozapine response, but positive symptoms were not statisti­ previous original studies that analysed the associations at patient level cally significant (Okhuijsen-Pfeifer et al., 2020). The differences in our (Zito et al., 1993; Lieberman et al., 1994; Hong et al., 1997; Linden­ study and the study by Okhuijsen-Pfeifer et al. (2020) may be explained mayer et al., 2001; Semiz et al., 2007). Age of illness onset, length of by differences in the inclusion criteria, and the differences in the char­ hospitalisation did not predict response either, and similar results were acteristics (e.g. symptom severity at baseline, analysed medications) of found in previous original studies (Semiz et al., 2007; Hong et al., 1997; included samples. More severe positive symptoms at baseline have been Zito et al., 1993; Wirshing et al., 1999). Predicting response in TRS using 128 A. Seppälä et al. Schizophrenia Research 236 (2021) 123–134 Fig. 3. Percentage of response in studies using 20% of decrease of symptoms as response criteria. patient characteristics is challenging. In comparison, in first-episode treatment-resistant and non-treatment-resistant schizophrenia (Gilles­ psychosis, being female, antipsychotic-naïve, having a more severe pie et al., 2017). Treatment-resistant patients have shown a lack of illness and shorter duration of illness at baseline predicted a higher dopaminergic abnormalities but rather show glutamatergic abnormal­ response rate (Zhu et al., 2017). ities, a significant reduction in brain gray matter, and higher familial It may be that TRS has a complex nature with multiple factors loading compared to treatment-responsive patients (Gillespie et al., affecting the course of the illness. Thus, identifying associations between 2017). Okhuijsen-Pfeifer et al.’s (2020) meta-analysis showed that certain patient characteristics and response is challenging. There has younger age (35,9 years in responders, 37,2 in non-responders), few been some tentative evidence of etiological differences between negative symptoms, and paranoid schizophrenia subtype were 129 A. Seppälä et al. Schizophrenia Research 236 (2021) 123–134 Fig. 4. Percentage of response in studies using 30% of decrease of symptoms as response criteria. Fig. 5. Percentage of response in studies using Kane criteria as response. associated to better clozapine response. It may be that the more ho­ antipsychotic medications, Leucht et al. (2013) found only minor dif­ mogenous sample of their study (only clozapine users) associated to the ferences in efficacy in schizophrenia patients. They identified 212 trials fact that significant predictors were found. involving 43,049 participants. All drugs were significantly more effec­ To our knowledge, this is the first systematic study of the predictors tive than placebo. Their findings challenge the straightforward classifi­ of response to any pharmacological treatment in TRS. The number of cation of antipsychotics into typical and atypicals and the idea that individual investigations of predictors of treatment response in TRS is atypical antipsychotics are more effective than typicals. Our finding of rather few. It was therefore not possible to perform a patient-level meta- different response percentage between typicals and atypicals is inter­ analysis. Thus, in this study, we analysed the associations in a study esting. Despite criticism for classifying antipsychotics into typicals and level, as did Okhuijsen-Pfeifer et al. (2020). We examined the associa­ atypicals, it may be that TRS patient response differently to these two tions between sample and study characteristics and the response rates in classes and one reason behind this could be differences in etiology of the the corresponding study using a relatively crude method. Our meta- illness in TRS and schizophrenia in general. analysis generally did not support the few previous findings in which Samara et al. (2015) found no major differences in the efficacy of baseline characteristics predicted treatment response. different antipsychotic agents in TRS, or when comparing clozapine In our study, of patients using typical antipsychotics, 25.0% achieved with other atypicals. However, clozapine was more effective than typical response, whereas among patients using atypicals (not including clo­ antipsychotics. Several studies that support the efficacy of clozapine in zapine), the response rate was 41.5%. In a meta-analysis of 15 the treatment of TRS, and the earlier initiation of clozapine may improve 130 A. Seppälä et al. Schizophrenia Research 236 (2021) 123–134 Table 3 Table 3 (continued ) Percentage of response in subpopulations. Among studies using 20% of decrease Number of Median IQR Statistical of symptoms as criteria for response. studies response % test Number of Median IQR Statistical Predictor studies response % test Baseline positive Predictor PANSS Proportion of males in 57 Under 19.4 7 17.8% 12.0–42.0 t = 3.20, the sample p = 0,008 Less than 64% 19 37.5% 18.2–50.0 t = − 0.27, 19.4–24.0 8 39.4% 18.5–57.1 t = 1.10, p = 0.79 p = 0.29 64–73% 20 49.5% 42.0–60.3 t = 1.75, Over 24.0 7 50.0% 37.5–66.0 Ref. p = 0.09 Baseline negative More than 73% 18 39.2% 18.2–57.8 Ref. PANSS Publication year 61 Under 22.1 7 37.5% 16.3–45.7 t = 0.91, Before year 2000 19 42.6% 27.6–53.7 t = − 0.82, p = 0.38 p = 0.41 22.1–25.7 7 48.5% 13.0–60.0 t = -0.05, 2000–2009 30 42.4% 18.2–57.8 t = − 0.83, p = 0.96 p = 0.41 Over 25.7 7 39.0% 20.0–66.0 Ref. 2010 or later 12 44.8% 36.3–55.0 Ref. Weight 9 t = − 0.43, Proportion of white 19 t = − 0.11, p = 0.68 persons in the p = 0.91 Under 79 kg 4 50.7% 32.7–61.4 sample 79 kg or over 5 49.0% 22.1–49.5 Less than 66% 9 45.7% 36.0–54.2 BMI 8 t = − 0.72, Equal or more than 10 45.3% 27.9–57.0 p = 0.50 66% Under 30 4 46.0% 32.1–60.7 Age at baseline 46 30 or over 4 40.3% 25.7–49.9 Under 38 years 18 50.7% 27.6–60.0 t = 0.87, TRS classification 72 p = 0.39 Has used at least 1 12 37.4% 18.0–46.9 t = − 1.13, 38–40 years 18 44.4% 32.1–49.5 t = − 0.04, AP p = 0.26 p = 0.97 Has used at least 2 24 45.2% 25.0–56.0 t = − 0.22, 41 years or older 20 39.4% 21.1–59.5 Ref. APs p = 0.83 Age of onset 26 t = 0.34, Has used at least 3 20 46.7% 27.6–58.7 Ref. p = 0.74 APs Under 20 years 13 42.6% 22.5–49.0 Attrition 57 t = 1.28 20 years or older 13 43.8% 27.6–57.8 p = 0.207 Age at time of first 10 t = 2.24, Under 15.4% 28 38.1% 21.3–53.7 hospitalisation p = 0.06 15.4% or over 29 44.8% 36.0–57.8 Under 23 years 5 18.2% 18.2–22.5 IQR, inter quartile range. 23 Years or older 5 59.0% 46.6–64.7 Duration of illness 32 t = 0.08, p = 0.94 16 or under 16 50.0% 22.8–55.6 Table 4 Over 16 16 44.1% 21.3–58.7 Response in subpopulations by antipsychotic medication. Among studies using Cumulative number of 17 t = 0.78, 20% of decrease of symptoms as criteria for response. hospitalizations p = 0.45 Number of Median percentage of IQR Under 7 7 27.6% 16.3–60.0 Studies persons meeting 7 or over 10 46.2% 22.1–53.7 response criteria % Proportion of 9 t = − 1.13, inpatients of the p = 0.30 Medication class sample at baseline Typical 20 25.0 9.75–39.0 Under 43% 5 44.0% 42.6–71.4 Atypical (excluding 36 41.5 24.0–52.0 43% or more 4 31.9% 19.1–46.9 clozapine)a Proportion of 10 t = 0.12, Injection 3 45.8 45.5–60.0 outpatient of the p = 0.91 Combination of two 4 45.6 38.1–59.5 sample at baseline medications Under 59% 5 43.8% 20.0–50.0 Clozapine monotherapy 39 50.0 35.7–60.0 59% and over 5 42.6% 23.1–60.0 Clozapine combined to 3 35.0 21.0–50.0 Duration of current 8 t = − 1.27, second medication hospitalisation p = 0.25 Risperidone 14 33.5 20.0–57.0 Under 6.4 months 4 41.2% 28.6–57.4 Chlorpromazine 6 10.3 0.00–31.6 6.4 and over 4 23.9% 10.9–43.0 Haloperidol 10 36.5 25.0–40.0 Baseline total PANSS 36 Olanzapine 11 45.0 38.0–50.0 Under 88 12 40.9% 15.4–53.9 t = − 0.71, Quetiapine 5 25.0 16.3–52.0 p = 0.48 Other psychiatric 8 19.0 17.7–52.0 88–101.9 12 43.9% 32.7–47.8 t = − 0.41, medication than p = 0.69 antipsychoticb 102 and over 12 39.5% 21.3–57.8 Ref. Other than psychiatric 3 42.0 39.0–63.0 Baseline total BPRS 21 medicationc Under 43 7 49.0% 27.6–71.4 t = 0.60, Placebo 16 11.5 6.50–27.5 p = 0.56 a 43–51 7 36.0% 22.5–57.0 t = − 0.23, This class included studies analysing risperidone, amisulpride, aripiprazole, p = 0.82 olanzapine, quetiapine, sertindole, ziprasidone. b Over 51 7 43.4% 22.1–58.3 Ref. This class included studies analysing lamotrigine, lithium mirtazapine, val­ Baseline CGI 23 t = 0.28, proic acid, topiramate, mianserin, topiramate, Lamotrigine, study subjects p = 0.78 might have ongoing other antipsychotic treatment. Under 5 11 44.8% 20.0–54.0 c This class included D-serine, ondansetron, raloxifene, study subjects might 5 and over 12 44.2% 22.3–60.8 have ongoing other antipsychotic treatment. 131 A. Seppälä et al. Schizophrenia Research 236 (2021) 123–134 the outcomes in TRS (Haddad and Correll, 2018). Early recognition and search terms and databases, and was comprehensive enough to identify treatment of TRS are important because for as many as 84% of patients at least most of the published drug trials on TRS. with treatment resistance may be present from the illness onset (Dem­ jaha et al., 2017). 4.4. Conclusions Our study revealed that the prediction of medication response in TRS is difficult to tease out. In such a situation, careful monitoring, follow-up In this systematic review, we identified that higher positive symp­ and personalised medicine should be applied. In practice, this means toms at baseline predicts higher response, but no other baseline char­ tailored antipsychotic medication. When providers start, switch, taper acteristics predicted treatment response in TRS. The response rate or terminate antipsychotics, a one–three-month experimental period remained relatively similar across studies with different definitions of with well-planned medication management (Isohanni et al., 2020) is TRS and response criteria. It also appears that the percentage of re­ often useful. In practice this stresses good collaboration with the patient sponders has remained static from earlier to recent studies. Our results and relatives and follow-up of clinical responses and efficacies, side ef­ support the complex nature of TRS and the need for more effective fects, and patients’ experiences and beliefs about antipsychotics (Iso­ pharmacological and non-pharmacological treatments of TRS. In future hanni et al., 2018, 2020). TRS poses a challenge to the treatment system, studies, it would also be important to study predictors of treatment where standard treatment recommendations and algorithms tend often response at patient level and studies should specifically focus on ana­ to fail. Unfortunately, there are no anticipated breakthroughs in near lysing predictors of treatment response and other outcomes in TRS. To future in antipsychotic medication efficacy of TRS. In such situation, help the future studies on this subject, the patient material should be non-pharmacological efforts designed by sophisticated professional more homogenous and researchers should rule-out pseudoresistance in team must be activated. clinical trials. The field would also benefit from coherent criteria for TRS In addition, in TRS, especially in non-responders, it is important to and treatment response. ascertain diagnostic accuracy and the impact of comorbid conditions on Supplementary data to this article can be found online at https://doi. response and efficacy. For instance, it is reasonable to consider the effect org/10.1016/j.schres.2021.08.005. of neurological or metabolic disorders given that these may complicate the overall treatment course (Lally and Gaughran, 2019). CRediT authorship contribution statement 4.3. Strengths and limitations AS, JS, JM and EJ designed this study. NH performed literature search. AS, JP and EJ extracted the data. HL analysed data. AS wrote the There are several important caveats related to this review. The first draft of the manuscript. All authors contributed to and have protocol of this study was not pre-published. We included only English approved the final manuscript. language articles so we may have missed some non-English publications. We included studies with variable definitions of TRS and this may have Declaration of competing interest caused some heterogeneity and noise in the results. On the other hand, the results did not change in sensitivity analyses restricted to studies that There are no conflicts of interests. only had stricter TRS criteria. The broad inclusion of TRS studies was necessary, as we wanted to have a large number of studies in order to Acknowledgement study potential predictors. There are multiple definitions of TRS as indicated in Online supplement Table 4. When developing a consensus We thank all authors of the included studies. This work was sup­ for the definition of TRS, Howes et al. (2017) suggested a much more ported by grants from the Finnish Cultural Foundation, Grant number specific definition, including a symptom questionnaire and the evalua­ 2DC49079, Jalmari and Rauha Ahokas’ Foundation, the Academy of tion of functioning capacity. However, studies have rarely adopted this Finland, Grant number 316563 and Oulu University Hospital funding. TRS standard. We acknowledge that the field remains in a state of flux with respect to the conceptual validity of treatment resistance, as well as Role of the funding source the definition of response. It is important to consider pseudoresistance when analysing the The funders had no role in the study design, data collection, data response to treatment (Howes et al., 2017). Unfortunately, most of the analysis, interpreting the results or the decision to publish the article. studies included in this meta-analysis did not separately mention pseudo-resistant subjects, and this may have caused additional hetero­ Further Reading geneity in the sample. In addition, we did not separate the ultra-resistant patients since this would have led to a small number of studies in the Agarwal, A.K., Sharma, M., Srivastava, S., Mullick, M., Kumar, A., 1997. An open clinical analyses. trial with clozapine in treatment-resistant schizophrenics. Indian J. Psychiatry 39 77 studies were included. However, the eventual number of studies (1), 70–75. Anil Yagcioglu, A.E., Kivircik Akdede, B.B., Turgut, T.I., Tumuklu, M., Yazici, M.K., in the analyses of different predictors varied notably, and for some Alptekin, K., Ertugrul, A., Jayathilake, K., Gogus, A., Tunca, Z., Meltzer, H.Y., 2005. predictors the number of studies was very low. Studying these predictors A double-blind controlled study of adjunctive treatment with risperidone in at study level and not at patient level is not very powerful statistically schizophrenic patients partially responsive to clozapine: efficacy and safety. J. Clin. Psychiatry 66 (1), 63–72. and there is a need for original studies that focus on individual pre­ Azorin, J., Spiegel, R., Remington, G., Vanelle, J., Péré, J., Giguere, M., Bourdeix, I., dictors. Our analyses on the response rate in the categories of used 2001. A double-blind comparative study of clozapine and risperidone in the medications are crude and do not reflect a standard analyses of efficacy. management of severe chronic schizophrenia. Am. J. Psychiatry 158 (8), 1305–1313. Barnes, T.R., Leeson, V., Paton, C., Marston, L., Osborn, D.P., Kumar, R., Keown, P., Regarding analysing of response, it is possible that some original studies Zafar, R., Iqbal, K., Singh, V., 2018. Amisulpride augmentation of clozapine for may have not correctly subtracted minimum points (30 in PANSS and 18 treatment-refractory schizophrenia: a double-blind, placebo-controlled trial. Ther. in some versions of BPRS) before calculating the response (Obermeier Adv. Psychopharmacol. 8 (7), 185–197. Bitter, I., Dossenbach, M.R., Brook, S., Feldman, P.D., Metcalfe, S., Gagiano, C.A., et al., 2010; Thompson et al., 1994). In other words some studies may Füredi, J., Bartko, G., Janka, Z., Banki, C.M., 2004. Olanzapine versus clozapine in have used e.g. the original 1–7 scale of PANSS without subtraction. treatment-resistant or treatment-intolerant schizophrenia. Prog. Neuro- A strength of this study was that we were able to analyse predictors Psychopharmacol. Biol. Psychiatry 28 (1), 173–180. of treatment response by utilising a meta-analysis, which has not been Bogers, J.P., Schulte, P.F., Broekman, T.G., Moleman, P., de Haan, L., 2018. Dose reduction of high-dose first-generation antipsychotics or switch to ziprasidone in done before. Several plausible predictors that could be utilized in clin­ long-stay patients with schizophrenia: a 1-year double-blind randomized clinical ical practice were included. Our search strategy included multiple trial. Eur. Neuropsychopharmacol. 28 (9), 1024–1034. 132 A. Seppälä et al. Schizophrenia Research 236 (2021) 123–134 Bondolfi, G., Dufour, H., Patris, M., May, J., Billeter, U., Eap, C., Baumann, P., 1998. Higgins, J.P., Thompson, S.G., Deeks, J.J., Altman, D.G., 2003. Measuring inconsistency Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a in meta-analyses. BMJ 327 (7414), 557–560. randomized double-blind study. Am. J. Psychiatry 155 (4), 499–504. Honer, W.G., Thornton, A.E., Chen, E.Y., Chan, R.C., Wong, J.O., Bergmann, A., Breier, A., Hamilton, S.H., 1999. Comparative efficacy of olanzapine and haloperidol for Falkai, P., Pomarol-Clotet, E., McKenna, P.J., Stip, E., 2006. Clozapine alone versus patients with treatment-resistant schizophrenia. Biol. Psychiatry 45 (4), 403–411. clozapine and risperidone with refractory schizophrenia. n.engl. J. Med. 354 (5), Breier, A., Buchanan, R.W., Irish, D., Carpenter, W.T., 1993. Clozapine treatment of 472–482. outpatients with schizophrenia: outcome and long-term response patterns. Psychiatr. Hong, C., Chen, J., Sim, C., 1997. A double-blind comparative study of clozapine versus Serv. 44 (12), 1145–1149. chlorpromazine on Chinese patients with treatment-refractory schizophrenia. Int. Breier, A., Buchanan, R.W., Kirkpatrick, B., Davis, O.R., Irish, D., Summerfelt, A., Clin. Psychopharmacol. 12, 123–130. Carpenter, W.T., 1994. Effects of clozapine on positive and negative symptoms in Howes, O.D., McCutcheon, R., Agid, O., De Bartolomeis, A., Van Beveren, N.J., outpatients with schizophrenia. Am. J. Psychiatry 151, 20–26. Birnbaum, M.L., Bloomfield, M.A., Bressan, R.A., Buchanan, R.W., Carpenter, W.T., Breier, A.F., Malhotra, A.K., Su, T., Pinals, D.A., Elman, I., Adler, C.M., Lafargue, R.T., 2017. Treatment-resistant schizophrenia: treatment response and resistance in Clifton, A., Pickar, D., 1999. Clozapine and risperidone in chronic schizophrenia: psychosis (TRRIP) working group consensus guidelines on diagnosis and effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am. J. terminology. Am. J. Psychiatry 174 (3), 216–229. Psychiatry 156 (2), 294–298. Isohanni, M., Miettunen, J., Jaaskelainen, E., Moilanen, J., Hulkko, A., Huhtaniska, S., Buchanan, R.W., Breier, A., Kirkpatrick, B., Ball, P., Carpenter Jr., W.T., 1998. Positive 2018. Under-utilized opportunities to optimize medication management in long- and negative symptom response to clozapine in schizophrenic patients with and term treatment of schizophrenia. World Psychiatry 17 (2), 172–173. without the deficit syndrome. Am. J. Psychiatry 155 (6), 751–760. Isohanni, M., Jääskeläinen, E., Miller, B., Hulkko, A., Tiihonen, J., Möller, H., Buckley, P.F., 2004. Efficacy of quetiapine for the treatment of schizophrenia: a Hartikainen, S., Huhtaniska, S., Lieslehto, J., 2021. Medication management of combined analysis of three placebo-controlled trials. Curr. Med. Res. Opin. 20 (9), antipsychotic treatment in schizophrenia – a narrative review. Hum. 1357–1363. Psychopharmacol. 36 (2), e2765. Chiu, N.Y., Yang, Y.K., Chen, P.S., Chang, C., Lee, I.H., Lee, J., 2003. Olanzapine in Joffe, G., Terevnikov, V., Joffe, M., Stenberg, J., Burkin, M., Tiihonen, J., 2009. Add-on chinese treatment-resistant patients with schizophrenia: an open-label, prospective mirtazapine enhances antipsychotic effect of first generation antipsychotics in trial. Psychiatry Clin. Neurosci. 57 (5), 478–484. schizophrenia: a double-blind, randomized, placebo-controlled trial. Schizophr. Res. Ciaparelli, A., Dell’Osso, L., Pini, S., Chiavacci, M.C., Fenzi, M., Cassano, G.B., 2000. 108 (1–3), 245–251. Clozapine for treatment-refractory schizophrenia, schizoaffective disorder, and Josiassen, R.C., Joseph, A., Kohegyi, E., Stokes, S., Dadvand, M., Paing, W.W., psychotic bipolar disorder: a 24-month naturalistic study. J. Clin. Psychiatry. 61, Shaughnessy, R.A., 2005. Clozapine augmented with risperidone in the treatment of 329–334. schizophrenia: a randomized, double-blind, placebo-controlled trial. Am. J. Ciapparelli, A., Dell’Osso, L., Bandettini di Poggio, A., Carmassi, C., Cecconi, D., Psychiatry 162 (1), 130–136. Fenzi, M., Chiavacci, M.C., Bottai, M., Ramacciotti, C.E., Cassano, G.B., 2003. Kane, J., Honigfeld, G., Singer, J., Meltzer, H., 1988. Clozapine for the treatment- Clozapine in treatment-resistant patients with schizophrenia, schizoaffective resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch. Gen. disorder or psychotic bipolar disorder: a naturalistic 48-month follow-up study. Psychiatry 45 (9), 789–796. J. Clin. Psychiatry. 64, 451–458. Kane, J.M., Marder, S.R., Schooler, N.R., Wirshing, W.C., Umbricht, D., Baker, R.W., Conley, R.R., Kelly, D.L., 2001. Management of treatment resistance in schizophrenia. Wirshing, D.A., Safferman, A., Ganguli, R., McMeniman, M., 2001. Clozapine and Biol. Psychiatry 50 (11), 898–911. haloperidol in moderately refractory schizophrenia: a 6-month randomized and Conley, R.R., Schulz, S.C., Baker, R.W., Collins, J.F., Bell, J.A., 1988. Clozapine efficacy double-blind comparison. Arch. Gen. Psychiatry 58 (10), 965–972. in schizophrenic nonresponders. Psychopharmacol. Bull. 24 (2), 269–274. Kane, J.M., Khanna, S., Rajadhyaksha, S., Giller, E., 2006. Efficacy and tolerability of Conley, R.R., Tamminga, C.A., Bartko, J.J., Richardson, C., Peszke, M., Lingle, J., ziprasidone in patients with treatment-resistant schizophrenia. Int. Clin. Hegerty, J., Love, R., Gounaris, C., Zaremba, S., 1998. Olanzapine compared with Psychopharmacol. 21 (1), 21–28. chlorpromazine in treatment-resistant schizophrenia. Am. J. Psychiatry 155 (7), Kane, J., Canas, F., Kramer, M., Ford, L., Gassmann-Mayer, C., Lim, P., Eerdekens, M., 914–920. 2007. Treatment of schizophrenia with paliperidone extended-release tablets: a 6- Conley, R.R., Kelly, D.L., Nelson, M.W., Richardson, C.M., Feldman, S., Benham, R., week placebo-controlled trial. Schizophr. Res. 90 (1–3), 147–161. Steiner, P., Yu, Y., Khan, I., McMullen, R., 2005. Risperidone, quetiapine, and Kane, J.M., Potkin, S.G., Daniel, D.G., Buckley, P.F., 2010. A double-blind, randomized fluphenazine in the treatment of patients with therapy-refractory schizophrenia. study comparing the efficacy and safety of sertindole and risperidone in patients Clin. Neuropharmacol. 28 (4), 163–168. with treatment-resistant schizophrenia. J. Clin. Psychiatry. 72 (2), 194–204. Demjaha, A., Lappin, J., Stahl, D., Patel, M., MacCabe, J., Howes, O., Heslin, M., Kennedy, J.L., Altar, C.A., Taylor, D.L., Degtiar, I., Hornberger, J.C., 2014. The social and Reininghaus, U.A., Donoghue, K., Lomas, B., 2017. Antipsychotic treatment economic burden of treatment-resistant schizophrenia: a systematic literature resistance in first-episode psychosis: prevalence, subtypes and predictors. Psychol. review. Int. Clin. Psychopharmacol. 29 (2), 63–76. Med. 47 (11), 1981–1989. Kim, J., Yi, S.H., Lee, J., Kim, Y.S., 2013. Effects of clozapine on heart rate dynamics and Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory their relationship with therapeutic response in treatment-resistant schizophrenia. Schizophrenia, Cramer, J., Rosenheck, R., Xu, W., Henderson, W., Thomas, J., J. Clin. Psychopharmacol. 33 (1), 69–73. Charney, D., 2001. Detecting improvement in quality of life and symptomatology in Kishi, T., Fujita, K., Furukawa, O., Suzuki, T., Moriwaki, M., Nitta, M., Hattori, M., schizophrenia. Schizophr. Bull. 27 (2), 227–234. Tsunoka, T., Chekuri, R., Kane, J.M., 2013. Efficacy and tolerability of clozapine in Dossenbach, M.R., Beuzen, J., Avnon, M., Belmaker, R.H., Elizur, A., Mark, M., japanese patients with treatment-resistant schizophrenia: results from a 12-week, Munitz, H., Schneidman, M., Shoshani, D., Kratky, P., 2000. The effectiveness of flexible dose study using raters masked to antipsychotic choice. Asian J. Psychiatr. 6 olanzapine in treatment-refractory schizophrenia when patients are nonresponsive (3), 200–207. to or unable to tolerate clozapine. Clin. Ther. 22 (9), 1021–1034. Kremer, I., Vass, A., Gorelik, I., Bar, G., Blanaru, M., Javitt, D.C., Heresco-Levy, U., 2004. Dursun, S.M., Gardner, D.M., Bird, D.C., Flinn, J., 1999. Olanzapine for patients with Placebo-controlled trial of lamotrigine added to conventional and atypical treatment-resistant schizophrenia: a naturalistic case-series outcome study. Can. J. antipsychotics in schizophrenia. Biol. Psychiatry 56 (6), 441–446. Psychiatr. 44 (7), 701–704. Kulkarni, J., Gavrilidis, E., Gwini, S.M., Worsley, R., Grigg, J., Warren, A., Gurvich, C., Emsley, R., Raniwalla, J., Bailey, P., Jones, A., 2000. A comparison of the effects of Gilbert, H., Berk, M., Davis, S.R., 2016. Effect of adjunctive raloxifene therapy on quetiapine (" Seroquel") and haloperidol in schizophrenic patients with a history of severity of refractory schizophrenia in women: a randomized clinical trial. JAMA and a demonstrated, partial response to conventional antipsychotic treatment. Int. Psychiatry 73 (9), 947–954. Clin. Psychopharmacol. 15, 121–131. Kumar, M., Chavan, B., Sidana, A., Das, S., 2017. Efficacy and tolerability of clozapine Ertugrul, A., Volkan-Salanci, B., Basar, K., Oguz, K.K., Demir, B., Ergun, E.L., Senturk, S., versus quetiapine in treatment-resistant schizophrenia. Indian J. Psychol. Med. 39 Erbas, B., Cila, A., Ulug, B., 2009. The effect of clozapine on regional cerebral blood (6), 770–776. flow and brain metabolite ratios in schizophrenia: relationship with treatment Lal, S., Thavundayil, J.X., Nair, N.P., Annable, L., Ng Ying Kin, N.M., Gabriel, A., response. Psychiatry Res. Neuroimaging 174 (2), 121–129. Schwartz, G., 2006. Levomepromazine versus chlorpromazine in treatment-resistant Flynn, S., MacEwan, G., Altman, S., Kopala, L.C., Fredrikson, D.H., Smith, G., Honer, W., schizophrenia: a double-blind randomized trial. J. Psychiatry Neurosci. 31 (4), 1998. An open comparison of clozapine and risperidone in treatment-resistant 271–279. schizophrenia. Pharmacopsychiatry 31 (01), 25–29. Lally, J., Gaughran, F., 2019. Treatment resistant schizophrenia - review and a call to Freudenreich, O., Henderson, D.C., Walsh, J.P., Culhane, M.A., Goff, D.C., 2007. action. Ir. J. Psychol. Med. 36 (4), 279–291. Dec. Risperidone augmentation for schizophrenia partially responsive to clozapine: a Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Örey, D., Richter, F., Samara, M., double-blind, placebo-controlled trial. Schizophr. Res. 92 (1–3), 90–94. Barbui, C., Engel, R.R., Geddes, J.R., 2013. Comparative efficacy and tolerability of Gillespie, A.L., Samanaite, R., Mill, J., Egerton, A., MacCabe, J.H., 2017. Is treatment- 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet resistant schizophrenia categorically distinct from treatment-responsive 382 (9896), 951–962. schizophrenia? A systematic review. BMC Psychiatry 17 (1), 12. Lieberman, J.A., Safferman, A.Z., Pollack, S., Szymanski, S., Johns, C., Howard, A., Goff, D.C., Keefe, R., Citrome, L., Davy, K., Krystal, J.H., Large, C., Thompson, T.R., Kronig, M., Bookstein, P., Kane, J.M., 1994. Clinical effects of clozapine in chronic Volavka, J., Webster, E.L., 2007. Lamotrigine as add-on therapy in schizophrenia: schizophrenia: response to treatment and predictors of outcome. Am. J. Psychiatry results of 2 placebo-controlled trials. J. Clin. Psychopharmacol. 27 (6), 582–589. 151 (12), 1744–1752. Haddad, P.M., Correll, C.U., 2018. The acute efficacy of antipsychotics in schizophrenia: Lilly Resistant Schizophrenia Study Group, Tollefson, G.D., Birkett, M.A., Kiesler, G.M., a review of recent meta-analyses. Ther. Adv. Psychopharmacol. 8 (11), 303–318. Wood, A.J., 2001. Double-blind comparison of olanzapine versus clozapine in Heresco-Levy, U., Javitt, D.C., Ebstein, R., Vass, A., Lichtenberg, P., Bar, G., Catinari, S., schizophrenic patients clinically eligible for treatment with clozapine. Biol. Ermilov, M., 2005. D-serine efficacy as add-on pharmacotherapy to risperidone and Psychiatry 49 (1), 52–63. olanzapine for treatment-refractory schizophrenia. Biol. Psychiatry 57 (6), 577–585. Lindenmayer, J.P., Volavka, J., Lieberman, J., Sheitman, B., Citrome, L., Chakos, M., Parker, B., Iskander, A., 2001. Olanzapine for schizophrenia refractory to typical and 133 A. Seppälä et al. Schizophrenia Research 236 (2021) 123–134 atypical antipsychotics: an open-label, prospective trial. J. Clin. Psychopharmacol. Simpson, G.M., Josiassen, R.C., Stanilla, J.K., de Leon, J., Nair, C., Abraham, G., Odom- 21 (4), 448–453. White, A., Turner, R.M., 1999. Double-blind study of clozapine dose response in Lindenmayer, J.P., Czobor, P., Volavka, J., Lieberman, J.A., Citrome, L., Sheitman, B., chronic schizophrenia. Am. J. Psychiatry 156 (11), 1744–1750. Chakos, M., McEvoy, J.P., 2002. Olanzapine in refractory schizophrenia after failure Siskind, D., McCartney, L., Goldschlager, R., Kisely, S., 2016. Clozapine v. first-and of typical or atypical antipsychotic treatment: an open-label switch study. J. Clin. second-generation antipsychotics in treatment-refractory schizophrenia: systematic Psychiatry. 63 (10), 931–935. review and meta-analysis. Br. J. Psychiatry 209 (5), 385–392. Lindenmayer, J.P., Citrome, L., Khan, A., Kaushik, S., Kaushik, S., 2011. A randomized, Smith, R.C., Chua, J.W., Lipetsker, B., Bhattacharyya, A., 1996. Efficacy of risperidone in double-blind, parallel-group, fixed-dose, clinical trial of quetiapine at 600 versus reducing positive and negative symptoms in medication-refractory schizophrenia: an 1200 mg/d for patients with treatment-resistant schizophrenia or schizoaffective open prospective study. J. Clin. Psychiatry 57, 460–466. disorder. J. Clin. Psychopharmacol. 31 (2), 160–168. StataCorp, 2013. L Stata Multilevel Mixed-effects Reference Manual. StataCorp LP, Llorca, P.M., Lancon, C., Disdier, B., Farisse, J., Sapin, C., Auquier, P., 2002. College Station, TX. Effectiveness of clozapine in neuroleptic-resistant schizophrenia: clinical response Suzuki, T., Uchida, H., Watanabe, K., Nakajima, S., Nomura, K., Takeuchi, H., Tanabe, A., and plasma concentrations. J. Psychiatry Neurosci. 27 (1), 30–37. Yagi, G., Kashima, H., 2008. Effectiveness of antipsychotic polypharmacy for Manschreck, T.C., Redmond, D.A., Candela, S.F., Maher, B.A., 1999. Effects of clozapine patients with treatment refractory schizophrenia: an open-label trial of olanzapine on psychiatric symptoms, cognition, and functional outcome in schizophrenia. plus risperidone for those who failed to respond to a sequential treatment with J. Neuropsychiatry Clin. Neurosci. 11 (4), 481–489. olanzapine, quetiapine and risperidone. Hum. Psychopharmacol. Clin. Exp. 23 (6), Martín, J., Gómez, J., García-Bernardo, E., Cuesta, M., Alvarez, E., Gurpegui, M., 1997. 455–463. Olanzapine in treatment-refractory schizophrenia: results of an open-label study. Suzuki, T., Uchida, H., Takeuchi, H., Nakajima, S., Nomura, K., Tanabe, A., Yagi, G., J. Clin. Psychiatry 58, 479–483. Watanabe, K., Kashima, H., 2009. Augmentation of atypical antipsychotics with Meltzer, H.Y., Bobo, W.V., Roy, A., Jayathilake, K., Chen, Y., Ertugrul, A., Yagcioglu, A., valproic acid. an open-label study for most difficult patients with schizophrenia. Small, J.G., 2008. A randomized, double-blind comparison of clozapine and high- Hum. Psychopharmacol. Clin. Exp. 24 (8), 628–638. dose olanzapine in treatment-resistant patients with schizophrenia. J. Clin. Suzuki, T., Remington, G., Mulsant, B.H., Rajji, T.K., Uchida, H., Graff-Guerrero, A., Psychiatry. 69, 274–285. Mamo, D.C., 2011. Treatment resistant schizophrenia and response to Meltzer, H., Lindenmayer, J., Kwentus, J., Share, D., Johnson, R., Jayathilake, K., 2014. antipsychotics: a review. Schizophr. Res. 133 (1–3), 54–62. A six month randomized controlled trial of long acting injectable risperidone 50 and Suzuki, T., Remington, G., Mulsant, B.H., Uchida, H., Rajji, T.K., Graff-Guerrero, A., 100 mg in treatment resistant schizophrenia. Schizophr. Res. 154 (1–3), 14–22. Mimura, M., Mamo, D.C., 2012. Defining treatment-resistant schizophrenia and MOZART Study Group, Sacchetti, E., Galluzzo, A., Valsecchi, P., Romeo, F., Gorini, B., response to antipsychotics: a review and recommendation. Psychiatry Res. 197 Warrington, L., 2009. Ziprasidone vs clozapine in schizophrenia patients refractory (1–2), 1–6. to multiple antipsychotic treatments: the MOZART study. Schizophr. Res. 113 (1), Thompson, P.A., Buckley, P.F., Meltzer, H.Y., 1994. The Brief Psychiatric Rating scale: 112–121. effect of scaling system on clinical response assessment. J. Clin. Psychopharmacol. Munro, J., Matthiasson, P., Osborne, S., Travis, M., Purcell, S., Cobb, A., Launer, M., 14 (5), 344–346. Beer, M., Kerwin, R., 2004. Amisulpride augmentation of clozapine: an open non- Tiihonen, J., Hallikainen, T., Ryynänen, O., Repo-Tiihonen, E., Kotilainen, I., Eronen, M., randomized study in patients with schizophrenia partially responsive to clozapine. Toivonen, P., Wahlbeck, K., Putkonen, A., 2003. Lamotrigine in treatment-resistant Acta Psychiatr. Scand. 110 (4), 292–298. schizophrenia: a randomized placebo-controlled crossover trial. Biol. Psychiatry 54 Obermeier, M., Mayr, A., Schennach-Wolff, R., Seemüller, F., Möller, H.J., Riedel, M., (11), 1241–1248. 2010. Should the PANSS be rescaled? Schizophr. Bull. 36 (3), 455–460. Tiihonen, J., Halonen, P., Wahlbeck, K., Repo-Tiihonen, E., Hyvarinen, S., Eronen, M., Okhuijsen-Pfeifer, C., Sterk, A., Horn, I., Terstappen, J., Kahn, R., Luykx, J., 2020. Putkonen, H., Takala, P., Mehtonen, O., Puck, M., 2005. Topiramate add-on in Demographic and clinical features as predictors of clozapine response in patients treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, with schizophrenia spectrum disorders: a systematic review and meta-analysis. crossover trial. J. Clin. Psychiatry 66 (8), 1012–1015. Neurosci. Biobehav. Rev. 111, 246–252. Toledo-Romero, F., Molina, J.D., Lopez-Rodriguez, E., Amorin-Diaz, M., Munoz Algar, M. Page, M.J., McKenzie, J.E., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., J., Aparicio-Castro, E., 2015. Augmentation with amisulpride for schizophrenic et al., 2021. The PRISMA 2020 statement: an updated guideline for reporting patients non-responsive to risperidone monotherapy. Pharmacopsychiatry 48 (2), systematic reviews. J. Clin. Epidemiol. 372. 51–57. Perälä, J., Saarni, S.I., Ostamo, A., Pirkola, S., Haukka, J., Härkänen, T., Koskinen, S., Umbricht, D., Baker, R.W., Wirshing, D.A., Safiennan, A., Ganguli, R., McMeniman, M., Lönnqvist, J., Suvisaari, J., 2008. Geographic variation and sociodemographic Borenstein, M., 2001. Clozapine and haloperidol in moderately refractory characteristics of psychotic disorders in Finland. Schizophr. Res. 106 (2–3), schizophrenia. Arch. Gen. Psychiatry 58, 965–972. 337–347. VanderZwaag, C., McGee, M., McEvoy, J.P., Freudenreich, O., Wilson, W.H., Cooper, T. Rodriguez-Pérez, V., López, A., Blanco, C., Pena, C., López, A., Abel, A., Gómez, Y., B., 1996. Response of patients with treatment-refractory schizophrenia to clozapine Ferreiro, M.J., Rego, C., Cudeiro, F., 2002. Olanzapine for the treatment of chronic within three serum level ranges. Am. J. Psychiatry 153 (12), 1579–1584. refractory schizophrenia: a 12-month follow-up naturalistic study. Prog. Neuro- Volonteri, L.S., Cerveri, G., De Gaspari, I.F., Baldi, M.L., Rolandi, M.L., Papa, P., Psychopharmacol. Biol. Psychiatry 26 (6), 1055–1062. Mauri, M.C., Mencacci, C., 2010. Long-acting injectable risperidone and metabolic Rosenheck, R., Cramer, J., Xu, W., Thomas, J., Henderson, W., Frisman, L., Fye, C., ratio: a possible index of clinical outcome in treatment-resistant schizophrenic Charney, D., 1997. A comparison of clozapine and haloperidol in hospitalized patients. Psychopharmacology 210 (4), 489–497. patients with refractory schizophrenia. N. Engl. J. Med. 337 (12), 809–815. Weiner, E., Conley, R.R., Ball, M.P., Feldman, S., Gold, J.M., Kelly, D.L., Wonodi, I., Samara, M.T., Leucht, C., Leeflang, M.M., Anghelescu, I., Chung, Y., Crespo-Facorro, B., McMahon, R.P., Buchanan, R.W., 2010. Adjunctive risperidone for partially Elkis, H., Hatta, K., Giegling, I., Kane, J.M., 2015. Early improvement as a predictor responsive people with schizophrenia treated with clozapine. of later response to antipsychotics in schizophrenia: a diagnostic test review. Am. J. Neuropsychopharmacology 35 (11), 2274–2283. Psychiatry 172 (7), 617–629. Wilson, W.H., 1993. Addition of lithium to haloperidol in non-affective, antipsychotic Scheepers, F.E. de Wied, Gispen, Christine C., Pol, H.E.H., van de Flier, W., van der non-responsive schizophrenia: a double blind, placebo controlled, parallel design Linden, Jeroen A., Kahn, R.S., 2001. The effect of clozapine on caudate nucleus clinical trial. Psychopharmacology 111 (3), 359–366. volume in schizophrenic patients previously treated with typical antipsychotics. Wirshing, D.A., Marshall, J., Green, M.F., Mintz, J., Marder, S.R., Wirshing, W.C., 1999. Neuropsychopharmacology 24 (1), 47–54. Risperidone in treatment-refractory schizophrenia. Am. J. Psychiatry 156 (9), Schooler, N.R., Marder, S.R., Chengappa, K., Petrides, G., Ames, D., Wirshing, W.C., 1374–1379. McMeniman, M., Baker, R.W., Parepally, H., Umbricht, D., 2016. Clozapine and Zhang, X., Zhou, D., Cao, L., Zhang, P., Wu, G., Shen, Y., 2001. Risperidone versus risperidone in moderately refractory schizophrenia: a 6-month randomized double- haloperidol in the treatment of acute exacerbations of chronic inpatients with blind comparison. J. Clin. Psychiatry 77 (5), 628–634. schizophrenia: a randomized double-blind study. Int. Clin. Psychopharmacol. 16 (6), Semiz, U.B., Cetin, M., Basoglu, C., Ebrinc, S., Uzun, O., Herken, H., Balibey, H., 325–330. Algul, A., Ates, A., 2007. Clinical predictors of therapeutic response to clozapine in a Zhang, Z., Kang, W., Li, Q., Wang, X., Yao, S., Ma, A., 2006. Beneficial effects of sample of turkish patients with treatment-resistant schizophrenia. Prog. Neuro- ondansetron as an adjunct to haloperidol for chronic, treatment-resistant Psychopharmacol. Biol. Psychiatry 31 (6), 1330–1336. schizophrenia: a double-blind, randomized, placebo-controlled study. Schizophr. Shah, P., Iwata, Y., Brown, E.E., Kim, J., Sanches, M., Takeuchi, H., Nakajima, S., Res. 88 (1–3), 102–110. Hahn, M., Remington, G., Gerretsen, P., 2019. Clozapine response trajectories and Zhu, Y., Krause, M., Huhn, M., Rothe, P., Schneider-Thoma, J., Chaimani, A., Li, C., predictors of non-response in treatment-resistant schizophrenia: a chart review Davis, J.M., Leucht, S., 2017. Antipsychotic drugs for the acute treatment of patients study. Eur. Arch. Psychiatry Clin. Neurosci. 1–12. with a first episode of schizophrenia: a systematic review with pairwise and network Shiloh, R., Zemishlany, Z., Aizenberg, D., Radwan, M., 1997. Sulpiride augmentation in meta-analyses. Lancet Psychiatry 4 (9), 694–705. people with schizophrenia partially responsive to clozapine: a double-blind, placebo- Zito, J.M., Volavka, J., Craig, T.J., Czobor, P., Banks, S., Vitrai, J., 1993. controlled study. Br. J. Psychiatry 171, 569. Pharmacoepidemiology of clozapine in 202 inpatients with schizophrenia. Ann. Shiloh, R., Zemishlany, Z., Aizenberg, D., Valevski, A., Bodinger, L., Munitz, H., Pharmacother. 27 (10), 1262–1269. Weizman, A., 2002. Mianserin or placebo as adjuncts to typical antipsychotics in resistant schizophrenia. Int. Clin. Psychopharmacol. 17 (2), 59–64. 134