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Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 473 – 481 www.elsevier.com/locate/pnpbp Safety and effectiveness of olanzapine versus conventional antipsychotics in the acute treatment of first-episode schizophrenic inpatients Julio Bobesa,*, Juan Gibertb, Antonio Ciudadc, Enrique Alvarezd, Fernando Cañase, José-Luis Carrascof, Josep Gascóng, Juan-Carlos Gómezc, Miguel Gutiérrezh a Facultad de Medicina, Departamento de Psiquiatrı́a, Universidad de Oviedo, Metropolitan Area of Oviedo, Calle Julián Claverı́a 6, E-33006 Oviedo, Asturias, Spain b Psychopharmacology Department, University of Cádiz, Cádiz, Spain c Clinical Research, Lilly Research Laboratories, Madrid, Spain d Psychiatry Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain e Psychiatry Unit, Hospital Psiquiátrico de Madrid, Madrid, Spain f Psychiatry Unit, Hospital Fundación Jiménez Dı́az, Madrid, Spain g Hospital Mutua de Tarrasa, Barcelona, Spain h Psychiatry Unit, Hospital de Cruces, Baracaldo, Spain Accepted 22 January 2003 Abstract Objective: To assess the safety and effectiveness of olanzapine compared to typical antipsychotics in the treatment of first-episode schizophrenics in acute psychiatric inpatient wards. Methods: Data were collected from a prospective, comparative, nonrandomized, open, observational study of 904 inpatients with schizophrenia. One hundred and fifty-eight patients fulfilled the criteria for first-episode schizophrenia, defined as (1) the International Classification of Diseases: Mental and Behavioral Disorders, 10th ed. (ICD-10) diagnosis of schizophrenia, (2) antipsychotic naı̈ve, and (3) a course of illness of less than 5 years. Eighty-nine (56.3%) of these patients were assigned to the olanzapine treatment group (OLZ) and 69 (43.7%) to the control group that received treatment with conventional antipsychotics (CON). Safety was evaluated in terms of the spontaneous adverse events reported and a specific questionnaire for extrapyramidal symptoms (EPS). Clinical status was measured by means of the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression of Severity (CGI-S). Clinical response was defined as the baseline-endpoint decrease in BPRS > 40% plus an endpoint BPRS < 18 or an endpoint CGI 3. Results: The rate of clinical response to treatment in the OLZ was 76.7%, compared to 54.4% in the CON (c2 = 8.48; P=.003). Olanzapine was significantly more effective than conventional antipsychotics in lowering the total BPRS score ( P=.0003), as well as each of the following BPRS subscales: positive symptoms ( P=.0019), negative symptoms ( P < .0001), depression ( P=.018), and agitation ( P=.007), even after mean scores were adjusted for their baseline value and disease duration. Olanzapine also proved to be significantly superior to conventional antipsychotics in lowering mean CGI scores ( P=.013). The frequency with which new EPS appeared, or previously existing ones worsened, was significantly greater in the CON than in the OLZ (55.1% vs. 13.5%; P < .001). Anticholinergics were needed more frequently in the CON than in the OLZ (58.0% vs. 6.7%; P < .0001). Conclusions: The results of this observational, naturalistic study show that olanzapine is safe and effective in a nonselected sample of acute, first-episode schizophrenic inpatients. D 2003 Elsevier Science Inc. All rights reserved. Keywords: Effectiveness; First episode; Inpatients; Olanzapine; Safety; Schizophrenia Abbreviations: ANCOVA, analysis of covariance; BPRS, Brief Psychiatric Rating Scale; CGI-S, Clinical Global Impression of Severity; CON, conventional antipsychotics; EPS, extrapyramidal symptoms; ICD-10, International Classification of Diseases: Mental and Behavioral Disorders, 10th edition; LOCF, Last Observation Carried Forward; NOSIE, Nurses’ Observation Scale for Inpatient Evaluation; OLZ, olanzapine treatment group; OR, odds ratio; UKU, Udvalg for Kliniske UndersØgelser (Side Effect Rating Scale); WHO, World Health Organization. * Corresponding author. Tel./fax: +34-985-10-35-53; mobile: +34-62987-78-00. E-mail address: [email protected] (J. Bobes). 1. Introduction Schizophrenia is a severe, incapacitating psychiatric disorder that, in most cases, leads to progressive personal deterioration in patients, as well as to a significant burden on family members and society in general (Torrey, 1995). Despite the fact that the overwhelming majority of patients recover from their first episode of schizophrenia (Tohen et al., 1992), they run a high risk of subsequent relapse and the 0278-5846/03/$ – see front matter D 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0278-5846(03)00035-6 474 J. Bobes et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 473–481 chronic persistence of residual positive and negative symptoms, cognitive deterioration, as well as social and employment difficulties (Hegarty et al., 1994; Szymanski et al., 1995). Longitudinal studies have demonstrated that schizophrenia progresses most during the first 5 years following the initial episode of the disease (McGlashan, 1998). Nevertheless, there is currently great controversy regarding the exact progression both of psychotic symptoms and the cognitive deficits associated with schizophrenia (Keefe et al., 1999). In spite of this controversy, early intervention at the very beginning of the disease appears to be one of the most important prognostic factors for the subsequent course of schizophrenia (Loebel et al., 1992; Wyatt, 1995; Linszen et al., 1998; Linszen and Dingemans, 2002; McGlashan et al., 2002; Woods and McGlashan, 2002). Conventional antipsychotics have been the mainstay of the treatment of schizophrenia for several decades. Their introduction in the 1950s allowed for the treatment of this disease to move out of the hospital setting, where it had been administered in the majority of cases, and into the community, reserving hospitalization for those situations in which the severity of psychotic or behavioral symptoms did not allow the patient to undergo treatment in his/her usual environment. Conventional neuroleptics have proven their usefulness in rapidly reducing the intensity of psychotic symptoms, allowing for prompt hospital discharge, as well as establishing the basis for long-term management of the disease in these patients. However, conventional antipsychotics present a series of limitations in when treating patients suffering from a psychotic episode. On the one hand, a high percentage of schizophrenic patients respond poorly when treated with this kind of drug (Brenner et al., 1990) with a relapse rate of up to 60% during the year following admission (Kane, 1996). In addition, conventional antipsychotics have the disadvantage of causing many adverse effects, especially extrapyramidal symptoms (EPS) including parkinsonism, dystonia, akathisia, and tardive dyskinesia (Levinson et al., 1990) that, due to the discomfort they cause, increase the likelihood that patients will abandon medication (Weiden et al., 1986), thereby increasing the risk of relapse. These drugs are also the cause of the so-called ‘‘neuroleptic dysphoria,’’ a behavioral syndrome characterized by flat affect and avolition that make social and occupational rehabilitation more difficult in these patients. Bearing this in mind, the emergence of the atypical antipsychotics represented a ray of hope in the treatment of schizophrenia, in particular because of their improved tolerability profile compared with that of conventional antipsychotics. In this regard, clozapine, the first atypical antipsychotic to be put on the market, proved its superior clinical efficacy in the treatment of refractory schizophrenic patients with a minimal risk of provoking adverse extrapyramidal effects (Weiden et al., 1986). However, its poor safety profile (due to the possibility of causing agranulocy- tosis) has restricted its use, precisely to those patients in whom the disease has been resistant to other types of treatment. For this reason, there are no studies that bear out its use in patients with non-refractory schizophrenia. Olanzapine is a tienobenzodiazepine with a chemical structure similar to clozapine. Receptor-affinity studies have also shown that its affinity characteristics are quite similar to those of clozapine (Bymaster et al., 1996; Moore et al., 1993), while recent pharmacogenetic studies have also discovered a great similarity between the two drugs (Mata et al., 2001). Based on several controlled clinical trials, olanzapine’s clinical efficacy has been shown to be at least similar to (and in some cases even greater than) that of conventional antipsychotics, with a much lesser risk of producing extrapyramidal adverse effects (Beasley et al., 1996a,b, 1997; Tollefson and Sanger, 1997, Tollefson et al., 1997a,b; Tran et al., 1997). A total of 1996 patients (Tollefson et al., 1997b) were enrolled in a multicenter, double blind, 6-week clinical trial comparing olanzapine with haloperidol; of them, those patients suffering their first episode of schizophrenia were selected. Olanzapine was seen to have a better efficacy profile than haloperidol with a lesser risk of causing adverse effects in this subgroup of patients, concluding that olanzapine should be considered a treatment of choice for firstepisode psychoses (Sanger et al., 1999). However, the experimental conditions in which clinical trials are conducted are such that the results cannot always be entirely extrapolated to normal clinical practice. The experimental nature of clinical trials makes it impossible to enroll patients with little understanding of their disease, with a co-morbid physical or psychiatric condition, or with the concomitant use of other psychotropic drugs. If we take into consideration the fact that when facing most schizophrenic patients, we must deal with one or more of the aforementioned circumstances, it becomes clear that naturalistic studies that corroborate a drug’s efficacy in terms of effectiveness in daily clinical practice are a necessity. The objectives of this study were to determine olanzapine’s safety and effectiveness compared to conventional antipsychotics in a cohort of schizophrenic patients with a short course of illness and who had never received prior treatment with antipsychotics. 2. Methodology 2.1. Study design The subjects that participated in this study were taken a phase IV, multicenter, observational, prospective, nonrandomized, comparative pharmacoepidemiological study to assess the effectiveness and safety profile of olanzapine in comparison with other antipsychotics in the hospital setting. The study was conducted in Spain with the participation of 83 centers (Álvarez et al., 2003). Between J. Bobes et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 473–481 January and September of 1999, a total of 910 patients diagnosed with schizophrenia according to the International Classification of Diseases: Mental and Behavioral Disorders, 10th ed. (ICD-10) (F.20 of ICD10, World Health Organization (WHO), 1994) that had been hospitalized for an acute psychotic episode were included. Patients were included in the study when, after admission, treatment was started with oral olanzapine or any conventional antipsychotic drug. Those patients that were participating in any other clinical trial or that were being treated with an atypical antipsychotic other than olanzapine (for example, clozapine, risperidone, sertindol, or quetiapine) were excluded, as were those in whom antipsychotic treatment was contraindicated. Indication for treatment was determined solely by clinical criteria, and there was no restriction placed on the clinical management of the patients, which was left entirely in the hands of each psychiatrist. Patients were allowed to voluntarily drop out of the study at any time. For the purposes of this study, those patients that met the following conditions were selected from the aforementioned sample: (1) they had never received antipsychotic treatment prior to admission, and (2) the investigator considered that the course of the disease had a duration of no more than 5 years. A subgroup of ‘‘naı̈ve’’ schizophrenic patients with a course of disease of less than 5 years was thus defined. The study protocol was developed by the sponsor and an external advisory group created for this study (Drs. Alvarez, Bobes, Carrasco, Cañas, Gascón, Gibert, and Gutierrez). The protocol was submitted to the Spanish National Pharmacovigilance Department in compliance with Spanish legislation applicable to nonexperimental observational studies. In line with this regulation, no approval by Ethics Committees of the participating centers nor patients signed informed consent were required to be obtained prior to the commencement of the study. Nevertheless, investigators informed the patients about the objectives of the study, and then oral consent to participate was obtained. Patients’ confidentiality was kept as no details were reflected in the study documentation. 2.2. Evaluation instruments The instruments used for evaluation were administered at baseline at the beginning of treatment and weekly thereafter, until the patient was discharged or medication was withdrawn. The severity of psychotic symptoms was clinically assessed by means of the Clinical Global Impression of Severity (CGI-S) (Guy, 1976)) that gives a score ranging from 1 (disease-free) to 7 (greatest severity possible), and the Brief Psychiatric Rating Scale (BPRS) (Woerner et al., 1988), which is a Likert-type scale comprised of 18 items that are evaluated by the interviewer, in which each item can be given a score of seven different values ranging from 0 (absence of symptom) to 6 (extreme severity). Apart from the total score, scores were obtained for the subscales of 475 positive symptoms (conceptual disorganization, suspiciousness, hallucinations, thought disorders), negative symptoms (emotional barriers, motor slowness, flat affect), agitation (anxiety, tension, hostility, lack of collaboration, excitement), and depression (guilt feelings, depressed mood, somatic complaints, anxiety). Patients’ behavior was assessed by means of the Nurses’ Observation Scale for Inpatient Evaluation (NOSIE) (Honigfeld and Klett, 1965). Finally, EPS were assessed by means of a simple questionnaire based on the section of EPS of the Udvalg for Kliniske Unders;gelser (UKU; Side Effect Rating Scale) scale (Lingjaerde et al., 1987) that evaluated the presence or absence of dystonia, hypertonia, hypokinesia, tremor, dyskinesia, and akathisia. All adverse events spontaneously reported by patients or taken down by each psychiatrist were recorded and coded. 2.3. Statistical analysis The department of biometrics at Phoenix International carried out the statistical analysis. The SAS computer program, version 8.1 for Windows (SAS Institute, Cary, NC), was used for data processing and statistical analysis. Investigators were asked to include patients consecutively and naturalistically. In that way, two treatment groups were defined: the olanzapine treatment group (OLZ), including patients treated with olanzapine in monotherapy or in combination with conventional antipsychotics, and the control group (CON), that included patients receiving one or more conventional antipsychotic drug. In order to minimize selection bias, the participating psychiatrists were asked to include six patients in each treatment group. As soon as a patient was enrolled in the study, treatment could be modified as seen fit by each psychiatrist, and all medication changes were recorded. Patients could be switched from one group to the other in the event of adverse effects, lack of efficacy, or for any other reason as the psychiatrist saw fit. Each patient was followed up throughout his/her entire hospital stay, although in order to prevent distortions in the scores, this study only includes the analysis of the scores obtained by those patients that changed treatment group, up until the point at which those patients were changed. Analyses were made considering the two treatment groups previously described: patients treated with olanzapine (OLZ) and patients treated with conventional antipsychotics (CON). Statistical analyses were made following the principle of ‘‘intent-to-treat,’’ taking into account all those patients from whom information had been gathered. The incidence of each adverse event in each of the treatment groups was calculated by means of the number of patients that presented the event at any time during the study with respect to the total number of patients. The quantitative variables are described in terms of the mean, median, standard deviation, and range. Discreet variables are described in terms of frequency and percentage. Parametric and nonparametric tests were used for the statistical analysis 476 J. Bobes et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 473–481 of the continuous variables, based on the fulfillment of statistical premises (normality and homocedasticity) and on the nature of the variable. The Wilcoxon test was used to compare age and duration of the course of illness. The change on the BPRS and NOSIE scales was analyzed using an analysis of covariance (ANCOVA) test with the treatment group as a factor and the baseline score and years since diagnosis as covariables. The CGI scale was evaluated by means of a Wilcoxon test, given its ordinal nature. The chisquare test, or Fisher’s exact test in the event that the chisquare test could not be applied, was used to analyze the discreet variables (sex, type of schizophrenia, incidence of EPS and other adverse effects, percentage of patients that responded, dropouts due to adverse effects, and the presence of concomitant treatment). A bilateral signification level of .05 was considered for all analyses. No adjustment was made for those variables in which differences were not found at baseline, given their lack of clinical relevance. A Last Observation Carried Forward (LOCF) approximation was made to analyze the changes in the clinical scales, including those patients with a baseline and at least one post-baseline evaluation. 3. Results The sociodemographic and baseline clinical data of the 158 patients that made up the sample appear in Table 1. Randomization was not carried out due to the naturalistic design of the study. Thus, the data pertaining to the 89 (56.3%) patients assigned to the OLZ were compared with the 69 (43.7%) patients assigned to the control group that was treated with conventional antipsychotics (CON). No clinically significant differences were detected between the two groups in any of the sociodemographic or baseline clinical characteristics. Although more male than female patients were included (73.4% vs. 26.6%), distribution in the two groups was similar. The course of the disease was of less than 1 year in 47 patients (24 in the OLZ group vs. 23 in the CON group), between 1 and 2 years in 37 patients (24 vs. 13), between 2 and 3 years in 31 patients (16 vs. 15), between 3 and 4 years in 22 patients (12 vs. 10), and between 4 and 5 years in 21 patients (13 vs. 8). The percentage of patients that had received some kind of pharmacological treatment since admission but before the initial evaluation was similar in both groups (80.9% vs. 82.6%). Nevertheless, a greater percentage of patients in the control group had received parenteral treatment upon admission, as compared to the olanzapine group (26.3% vs. 13.9%, P=.076). At the time of discharge, a greater percentage of patients from the olanzapine group were receiving concomitant treatment with benzodiazepines (44.9% vs. 33.3%) and antidepressants (4.5% vs. 0.0%). However, anticholinergics were more frequently used in the control group made up of patients treated with conventional antipsychotics as opposed to the olanzapine group (58.0% vs. 6.7%, P < .0001). Upon discharge, 13 (14.6%) of the patients treated with olanzapine were receiving concomitant treatment with highpotency antipsychotics, whereas 6 (6.7%) were receiving low-potency antipsychotics. In the group of patients treated with conventional antipsychotics, although all had received high-potency antipsychotics at some point during hospit- Table 1 Sociodemographic and baseline clinical characteristics of the sample Characteristic Age mean (S.D.) median range Sex (% males) Time of evolution (years) Schizophrenia subtype (%) Number of prior admissions Baseline CGI score Baseline BPRS score BPRS Positive Symptom Subscale BPRS Negative Symptom Subscale BPRS Agitation Subscale BPRS Depression Subscale Baseline NOSIE score Baseline extrapyramidal symptoms (%) a b c Wilcoxon test. Chi-square test. Fisher’s exact test. mean (S.D.) median paranoid undifferentiated disorganized residual mean (S.D.) median mean (S.D.) mean (S.D.) mean (S.D.) mean (S.D.) mean (S.D.) mean (S.D.) mean (S.D.) Olanzapine (n = 89) Control group (n = 69) P-value 28.6 (9.4) 27 16 – 74 77.5 1.6 (1.4) 1 80.7 11.4 6.8 1.1 1 (1.6) 0 5 (0.9) 43.6 (12.8) 14.3 (4.3) 7.3 (4.1) 13.7 (6.2) 8.1 (4.2) 44.2 (12.6) 27.0 26.1 (8.4) 24 17 – 68 68.1 1.5 (1.4) 1 78.3 8.7 11.6 1.4 0.7 (1.2) 0 5.3 (0.7) 46.6 (13.4) 15.9 (3.9) 7.6 (4.5) 14.8 (5.5) 7.9 (4.3) 44.9 (17.1) 18.8 .042a .184b .651a .735c .340a .042a .214a .066a .657a .183a .739a .891a .232b J. Bobes et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 473–481 Table 2 Initial, mean, final, and modal doses of olanzapine and haloperidol during study period Initial doses (mg) Mean doses (mg) Final doses (mg) Modal doses (mg) mean (S.D.) median range mean (S.D.) median range mean (S.D.) median range mean (S.D.) median range Olanzapine (n = 89) Haloperidol (n = 61) 13.8 (6.2) 10 5 – 30 16.4 (6.0) 16.7 5 – 36 17.0 (6.1) 20 5 – 30 15.8 (6.2) 15 5 – 30 14.3 (7.5) 12 2 – 30 15.5 (8.1) 12 3.5 – 42.5 13.6 (7.8) 10.5 2.5 – 30 15.3 (11.7) 12 1.5 – 75 alization, 52 (75.4%) of them were discharged while receiving only the high-potency antipsychotic drugs, 13 (18.8%) were taking only low-potency antipsychotics, and 4 (5.8%) were on a combination of both. Haloperidol was the most frequently prescribed antipsychotic in the control group, with 60 (87%) patients having received this drug at some point during hospitalization, and 46 (66.7%) were receiving it as treatment upon discharge. The doses of olanzapine and haloperidol used throughout the study are shown in Table 2. The initial dose refers to the one prescribed at baseline, whereas the mean dose was calculated based on the mean dose that each patient received throughout the study period. The final dose refers to the one prescribed at the time of discharge or at dropout. Finally, the modal dose is defined as the daily dose of the drug most frequently prescribed throughout the study period. Only one of the 89 patients that were assigned to the olanzapine group at the beginning of the study was changed to the treatment group receiving conventional antipsychotics during the course of hospitalization due to insufficient clinical efficacy. However, of the 69 patients that had started the study in the conventional antipsychotics treatment group, 13 (18.8%) were changed to the OLZ by the investigator. The reasons for switching these patients were the emergence of secondary effects in 10 cases and insufficient clinical efficacy in the remaining 3 cases. A total of 10 (11.2%) patients from the olanzapine group prematurely discontinued their participation in the study, versus a total of 7 (10.1%) in the conventional antipsychotics treatment group. The reasons were the patient’s decision (one case in each treatment group), the investigator’s decision (five cases in the OLZ group; four cases in the CON group), and loss to follow-up (four cases in the OLZ group; two cases in the CON group). 477 the patients in the olanzapine group and those in the control group (27% vs. 18.8%). Considering EPS individually, statistically significant differences were observed only with regard to dystonia, which was observed in four (5.8%) patients belonging to the control group, as compared to none of the patients assigned to the olanzapine group (Fisher’s exact test, P=.035). The frequency with which new EPS appeared, or with which preexisting ones worsened, was significantly greater in the control group as opposed to the olanzapine group (55.1% vs. 13.5%, P < .001). When examined individually, all the EPS considered in this study were significantly more frequent in the control group (conventional antipsychotics) than in the group that was treated with olanzapine, with the exception of dyskinesia that did not attain a level of statistical significance (Table 3). There was a higher percentage of patients with at least one adverse effect in the control group compared to the olanzapine group (60.9% vs. 19.1%, P < .0001). Therefore, the risk of suffering some type of adverse effect in the olanzapine-treated group was three times less than for the group treated with conventional antipsychotics. Not a single case of leukopenia associated with the use of olanzapine was found. 3.2. Effectiveness Olanzapine was significantly superior to conventional antipsychotics in lowering both the total BPRS score, as well as each one of the subscales (positive symptoms, negative symptoms, depression, and agitation), even when the mean values were adjusted for the baseline value and duration of the course of illness. Olanzapine was also shown to be significantly superior to conventional antipsychotics in lowering the mean score on the CGI scale (Clinical Global Impression). With respect to the NOSIE, olanzapine was once again superior to conventional antipsychotics, although Table 3 Presence of extrapyramidal symptoms associated with treatmenta Olanzapine (n = 88) Control group (n = 68) P-value N % N % 13.6 38 55.9 < .001y 0.0 5.7 3.4 3.4 3.4 1.1 2.3 10 12 22 17 17 2 2 14.7 17.6 32.4 25.0 25.0 2.9 2.9 < .001y .021y < .001y < .001y < .001y .581y 1.0a 3.1. Safety Extrapyramidal 12 symptoms Individual symptoms Dystonia 0 Rigidity 5 Hypokinesia 3 Tremor 3 Akathisia 3 Dyskinesia 1 Others 2 No significant differences were observed with respect to the presence of EPS at the beginning of the study between a There is one case in each treatment group that has been omitted owing to insufficient data. y Fisher’s exact test. 478 J. Bobes et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 473–481 in this case the differences observed did not reach a level of statistical significance (Table 4). A more robust measure of treatment efficacy can be obtained by calculating ‘‘clinical response,’’ defined a priori in our study as a decrease of at least 40% in the BPRS score plus a CGI scale score of 3 or less, or a final BPRS score of less than 18. In keeping with these criteria, the treatment response rate in the olanzapine group was 76.7%, compared with a rate of 54.4% in the control group. The difference in the response rate between both groups was statistically significant (c2 = 8.48, P=.003). When applying a logistics regression model adjusted for the baseline CGI and BPRS values and time elapsed since diagnosis, the differences between both treatment groups continue to be significant ( P=.044), with a response rate between two and three times greater for the group that was treated with olanzapine (odds ratio, OR = 2.7). Effectiveness was also measured by the number of patients that improved their BPRS scores at different levels. Thus, 73 patients (84.9%) of the patients in the olanzapine group were seen to have received total BPRS scores that were more than 40% lower, as compared to 46 (67.6%) Table 4 Change in CGI, BPRS, and NOSIE scores in each treatment group Olanzapine (n = 89) CGI mean improvement (S.D.) Total BPRS mean improvement (S.D.) BPRS Positive Symptom Subscale mean improvement (S.D.) BPRS Negative Symptom Subscale mean improvement (S.D.) BPRS Depression Subscale mean improvement (S.D.) BPRS Agitation Subscale mean improvement (S.D.) NOSIE mean improvement (S.D.) a Control group (n = 69) P-value .013a 2.0 (1.2) 1.6 (1.1) 30.0 (14.3) 24.7 (16.3) 30.8 10.0 (5.1) 23.6 8.9 (5.5) .0003b 10.5 3.9 (3.4) 8.3 2.0 (3.7) .0019b 4.0 5.2 (3.5) 1.9 4.2 (3.8) < .0001b 5.2 10.2 (6.2) 4.2 9.2 (6.0) .018 10.5 20.3 (13.2) 8.8 17.4 (15.7) .007b 20.6 16.9 .0671b Wilcoxon Test. ANCOVA with mean values adjusted for baseline value and duration of course of illness. b patients in the control group. This finding was confirmed at reduction levels of 60% (69.8% of the OLZ group versus 45.6% of the CON group) and 80% (34.9% of the OLZ group compared to 19.1% of the CON group). Overall, the differences were statistically significant ( P=.001). 4. Discussion This study was carried out with a subgroup of patients that had participated in large prospective, observational study performed with atypical antipsychotics in the hospital setting and that had a diagnosis of schizophrenia that had not previously been treated with antipsychotics and with a course of disease of less than 5 years. The subgroup of patients that are the subject this work is the largest one we are aware of, in terms of the number of patients with firstepisode schizophrenia studied in this way. Certain limitations, inherent in any observational study, should be mentioned before proceeding with the discussion of the most relevant results: (1) selection bias due to the lack of randomization, (2) problems in establishing causal relationships due to the heterogeneity of the control group and the frequent use of concomitant medications, and (3) the possible decrease in the appreciation of adverse effects as compared to clinical trials. Nevertheless, we must take into account the fact that it would be logical to assume that the latter two limitations mentioned occurred equally in both treatment groups such that the comparisons made between both treatment groups should not therefore be greatly affected. On the other hand, the fact that it was not an experimental clinical trial is, to a certain degree, an advantage, if what we are attempting to study is what truly occurs in normal clinical practice with patients being treating in an inpatient setting and without the limitations imposed by a clinical trial. The main objective of this study was to assess olanzapine’s safety and effectiveness in comparison with conventional antipsychotics in normal clinical practice with patients in whom the course of disease was a short one, that were naı̈ve to antipsychotics, and that were experiencing a first episode of schizophrenia. A relatively high number of patients were studied, considering that they were schizophrenics that had never been previously treated and that were hospitalized in a psychiatric ward. At the same time, we find that the retention rate was high, over 84%. Another advantage to this study, unlike what has occurred in other observational studies that have been published recently with other antipsychotics, is precisely the fact that this study included a control group of patients treated with conventional antipsychotics. The mean dose of olanzapine prescribed was well above that prescribed in the only controlled clinical trial with patients experiencing their first psychotic episode that we are aware of (Sanger et al., 1999). The modal dose (defined as the dose most frequently administered to each patient J. Bobes et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 473–481 throughout the study period) of olanzapine in the aforementioned study was 11.6 mg/day, as compared to the 15.8 mg/ day that we obtained in this study. Similarly, in the aforementioned article, the modal dose of haloperidol was 10.8, whereas in ours, it was 15.3 (for those patients being treated with this antipsychotic in the control group). We can think as explanations for this difference between the mean doses used that the conditions in which a clinical trial take place require that the investigators keep their patients under strict protocol limits, with a tendency to administer lower doses of medication. Nevertheless, we estimate that the value of these data is that they reflect the routine clinical practice where antipsychotics are frequently used in higher doses. This was a naturalistic study that allowed concomitant medication to be administered according to the psychiatrists’ criteria. A high percentage of patients in both treatment groups received concomitant medication throughout the time they were hospitalized, especially benzodiazepines. Insofar as both benzodiazepines and antidepressants or mood stabilizers are concerned, the differences observed between both treatment groups were not statistically significant. On the other hand, it was observed that 72.5% of patients treated with conventional antipsychotics also received anticholinergic drugs during their hospital stay, versus a mere 14.6% of those treated with olanzapine. Only a small number of patients changed treatment group while they were hospitalized, confirming the psychiatrists’ propensity to not change a patient’s treatment during their hospital stay. Whereas only 1 (1.1%) of the patients assigned to the OLZ upon admission had his/her medication modified, 13 (18.8%) of those that started treatment with conventional antipsychotics were switched to the olanzapine group during the course of hospitalization. It is striking to note that none of the patients that initiated treatment with olanzapine had to abandon treatment due to the appearance of adverse effects. 4.1. Safety One of the essential objectives of treating recent onset schizophrenics, once the psychotic symptoms have stabilized, is to assure future treatment compliance, as it has been proven that this is one of the leading prognostic factors in schizophrenia (Loebel et al., 1992; Linszen et al., 1998). In our study, none of the patients that were assigned to the OLZ required a change in medication as the result of adverse effects, whereas 10 (14.5%) of those that were assigned to the conventional antipsychotics treatment group were switched to the OLZ for this reason. There have been no unexpected safety problems of clinical relevance. As for the frequency with which any kind of drug-related adverse effect appeared, a significant difference was also noted between both treatment groups ( P < .0001). Patients treated with conventional antipsychotics presented a relative risk of developing an adverse effect of more than three times that of patients receiving olanzapine. 479 While no significant differences were detected in terms of the presence of EPS at the start of the study, it is noteworthy that the frequency with which they worsened or new symptoms of this type appeared was significantly greater in the group of patients treated with conventional antipsychotics than in the olanzapine-treated group ( P < .0001). If we examine EPS (dystonia, rigidity, hypokinesia, tremor, akathisia, and dyskinesia) individually, all of these symptoms became worse or appeared for the first time significantly more frequently in the group that received treatment with conventional antipsychotics than in the OLZ, with the exception of dyskinesia. These results are compatible with those observed in clinical trials both with firstepisode schizophrenics (Sanger et al., 1999) and with more chronic patients (Beasley et al., 1996a,b). In this study, olanzapine, in comparison to conventional antipsychotics, showed a better safety profile. This is of great relevance in treating schizophrenic patients for the first time, a point at which it is crucial that adverse effects be minimized in order to assure subsequent compliance with the medication. Patients never previously treated in general tend to be more sensitive to antipsychotics, especially as regards the emergence of EPS (McEvoy, 1991), so that when treating this type of patient, we should opt for administering those antipsychotics with a lesser risk of causing them. 4.2. Effectiveness It is of the utmost importance that effective treatment be started as soon as possible in schizophrenia. Many studies have established a clear association between the duration of untreated or ineffectively treated psychosis and a poor prognosis of the disease (Loebel et al., 1992; Wyatt, 1995). In our study, olanzapine demonstrated superior effectiveness in comparison with conventional antipsychotics in the treatment of schizophrenic patients naı̈ve to antipsychotics. If we take the individual measurement instruments into consideration, the improvement observed in olanzapinetreated patients was greater than that achieved by the patients treated with conventional antipsychotics. After making the necessary adjustments for the most relevant baseline variables, a statistically significant improvement was seen in patients treated with olanzapine as measured by all the instruments used. Clinical treatment response, defined either as a decrease of 40% on the BPRS plus a CGI score of 3 or less, or a final BPRS score under 18, was significantly more frequent in the OLZ than in the CON treatment group ( P=.003). This result was corroborated when the different levels of improvements on the BPRS were taken into account. Our results with respect to clinical effectiveness do not appear to present artifacts as a result of the patients’ baseline situation since, on the one hand, no statistically significant differences were observed between both groups at the start 480 J. Bobes et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 473–481 of the study and, on the other hand, the analyses were made conservatively, adjusting the differences for baseline values. 5. Conclusions In short, this observational study found a superior effectiveness of olanzapine, both in terms of efficacy and safety, when compared to conventional antipsychotics in treating hospitalized patients with schizophrenia that had never been previously treated with antipsychotics. Acknowledgements This work was sponsored by Lilly, Madrid, Spain. Psychiatrists who participated in the study as investigators: José Antonio Hernández, Recaredo Cap de Pon, Andrés Sandoval, Concepción Ros, Marı́a Concepción Sáez, Francisco Martı́nez, Francisco Gázquez, Antonio Martı́nez, Ali Abú Taleb, Alfredo de la Rubia, Andrés Simón, Agustina González, Marı́a Antonia Garcı́a, Juan Luis Figuerido, Enrique Daniel Vega, Juan Pedro Jiménez, Alicia Iglesias, Adolfo J. Pellejero, Santiago Parada, Alfonso Casas, José Marı́a Blanco, Jose Civeira, Juan Carlos Dı́az del Valle, Manuel Serrano, Ma. Isabel Gómez del Cid, Marı́a Victoria Ortega, Mercedes Alba, Ernesto Linares, Marina Gómez, César Azpeleta, Alicia González, Mauro Garcı́a, Marcelo Camus, Rosario Gil, Pilar Samada, Avelino de Dios, José Vicente Pozo, Marı́a Remedios Fernández, Julio César Carazo, Rosa Marı́a Alameda, Juan Francisco Guardia, Margarita Silvestre, Pablo Calderón, Leopoldo Elvira, Concepción Merino, Raimundo Muñóz, Leonor Coy, Manuel Delgado, Carlos de Gregorio, Ana Moro, José Valle, Patricia Alcinari, Santiago Pérez, Zoilo Fernández, Rafael Gómez, Federico Wamba, Antonio Sánchez, Jose Manuel Bertolı́n, Juan Petrel, Francisco Moreno, David Simón, Manuel Brito, César Rodrı́guez, Angel Trujillo, Antonio Higueras, Pedro Bustos, Rosario de Arce, Laura Iglesias, Marı́a Pilar Pérez, Marta Torreblanca, Jesús Garcı́a, Marı́a Gulbaharian, Pedro Sopelana, Manuel Franco, Jesús Monforte, Jordi Sanahuja, Maria Elena Alea, Jesús Gómez, Jesús Valle, Pablo Ramos, Pilar Nieves Ureña, Manuel Barceló, Concepción Ciscar, Pilar P. de la Fuente, Josep Ribes, Manuel Camarero, José Vicente Baeza, Enrique Navarro, Eliseo López, Teresa Guilera, Román Calabuig, Jesús Morillas, Yolanda Zapico, José Miguel Segovia, Alfredo Dı́az, Leandro Palicio, Juan José Madrigal, Blanca Garcı́a, J. Fernández, José Ferrer, Ester Gómez, Marı́a Jesús Montes, Santiago Escote, Ramón Coronas, Gemma Garcı́a, César Antón, Pedro Moreno, Carmen Busuldo, Jesús Cobo, Emily Miró, Enrique del Moral, José Horta, Ana Marı́a Fargas, Carlos Martı́n Martı́n, Jesús Derecho, Rafael Iglesias, Imanol Querejeta, Ana Garcı́a, Ana Cristina Sierra, Edith Garcı́a, Ildefonso Mateo, Ma. Angeles Caballero, Ginés Palenciano, Federico Dourdill, David Huertas, Ignacio Tortajada, Jorge Pérez, Javier Sanz, Angel Redondo, José Carlos González, Francisco Ballester, José González, Salvador Sarro, Carmen Sarrı́, José Marı́a Sánchez, Luisa Tifón, Vicenc Vallés, Luis Delgado, Enrique Hernández, Manuel Rodrı́guez, Julio Lequerica, Josefina Pérez, Luis Torremocha, Lucı́a Pérez, Diego Arenas, José Luis Benavente, Ana Robador, Marı́a Jesús Luna, Ignacio Zarranz, José Antonio Sánchez, Javier Casanova, Purificación Salgado, Alejandro David Cabo, Adela Paillissé, Jose Manuel Jaquotot, Roberto Rodrı́guez, Eduardo Pons, Pilar Alvarez, Nieves Casas, Ana Yáñez, Ana Rodrı́guez, Ester Ibarrola, Elena Basurto, José Civeira, Juan Luis Figuerido, Ma Concepción Sáez, Francisco Martı́nez, Concepción Merino, Rosario de Arce, Pedro Sopelana, Jesús Gómez, Juan José Madrigal, Marı́a Jesús Montes, and Carmen Busuldo. 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