A randomized, double-blind, comparison of the efficacy and safety of low-dose olanzapine plus low-dose trifluoperazine versus full-dose olanzapine in the acute treatment of schizophrenia

SCHRES-07109; No of Pages 8 Schizophrenia Research xxx (2017) xxx–xxx

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A randomized, double-blind, comparison of the efficacy and safety of low-dose olanzapine plus low-dose trifluoperazine versus full-dose olanzapine in the acute treatment of schizophrenia Ching-Hua Lin a,b, Fu-Chiang Wang a, Shih-Chi Lin a, Yu-Hui Huang a, Cheng-Chung Chen a,b,⁎ a b

Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan Department of Psychiatry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

a r t i c l e

i n f o

Article history: Received 11 September 2016 Received in revised form 26 November 2016 Accepted 3 January 2017 Available online xxxx Keywords: Schizophrenia Olanzapine Trifluoperazine Antipsychotic polypharmacy Antipsychotic monotherapy

a b s t r a c t Objective: Antipsychotic polypharmacy is common in clinical practice, but not recommended in guidelines for treating schizophrenia patients. This study aimed to compare the efficacy and safety of low-dose olanzapine plus low-dose trifluoperazine (a first-generation antipsychotic [FGA]) to full-dose olanzapine (a second-generation antipsychotic [SGA]) in the treatment of acute schizophrenia. Method: In this 6-week, double-blind, fixed-dose study, patients were randomized to receive 5 mg/day of olanzapine plus 5 mg/day of trifluoperazine or 10 mg/day of olanzapine for 6 weeks. Efficacy measures, including the Positive and Negative Syndrome Scale (PANSS) and other scales, safety measures, side effect measures, and quality of life were assessed regularly. Response was defined as at least a 30% reduction in the PANSS total score. Results: Both groups were similar in: 1) baseline characteristics, 2) score changes in all efficacy measures, safety measures, side effect measures, and quality of life, and 3) response rates at each visit. The polypharmacy group with low-dose olanzapine did not have less weight gain and lower lipid levels than the monotherapy group with full-dose olanzapine. Conclusion: Polypharmacy is as efficacious and safe as, but cheaper than, monotherapy in the acute treatment of schizophrenia. Whether our findings can be generalized to other combinations of an appropriate ratio of one FGA to another SGA dosage, which can achieve favorable clinical responses and side effect profiles, needs further investigation. © 2017 Published by Elsevier B.V.

1. Introduction Antipsychotic medications are the mainstay treatment for schizophrenia. Traditionally, treatment guidelines for schizophrenia recommend using antipsychotic monotherapy (Buchanan et al., 2010; Hasan et al., 2012; Moore et al., 2007). However, the rate of antipsychotic polypharmacy (i.e. co-prescription at least two antipsychotics at the same time) has increased over the last decade. Polypharmacy is more common in Asia than in western countries (Chong et al., 2000; Roh et al., 2014; Xiang et al., 2012). The most common type of polypharmacy has been a combination of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) (Gallego et al., 2012; Roh et al., 2014). Guidelines typically recommend antipsychotic polypharmacy as a last resort (Gallego et al., 2012; Lehman et al., 2004; Moore et al., 2007).

⁎ Corresponding author at: Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, 130, Kai-Syuan 2nd Rd., Ling-Ya District, Kaohsiung 802, Taiwan. E-mail address: [email protected] (C.-C. Chen).

Even though antipsychotic polypharmacy is not recommended by treatment guidelines, a variety of clinical reasons have been reported for prescribing polypharmacy in treating schizophrenia (Barnes and Paton, 2011; Correll and Gallego, 2012; Gallego et al., 2012; Lochmann van Bennekom et al., 2013). One of the common reasons is insufficient trials of monotherapy (Fisher et al., 2014; Fleischhacker and Uchida, 2014). Polypharmacy has been expected to improve effectiveness by reducing the dose-related side effects of single agents, too (Barnes and Paton, 2011; Correll and Gallego, 2012; Correll et al., 2011; Gallego et al., 2012). Olanzapine, a thiobenzodiazepine derivative and a selective dopaminergic (D2), serotonergic, histaminergic, and α-adrenergic receptor, is an SGA (Meltzer and Fibiger, 1996). Olanzapine displays its benefits in antipsychotic activity with fewer extra-pyramidal side effects (EPS) and a low propensity to increase serum prolactin (Bhana et al., 2001). However, olanzapine may lead to weight gain, hyperglycemia, and dyslipidemia (Bhana et al., 2001; Kantrowitz and Citrome, 2008; Lieberman et al., 2005). Trifluoperazine, a phenothiazine derivative, is a selective antagonist of D2 receptor, and a FGA (Marques et al., 2004). EPS are notable, but

http://dx.doi.org/10.1016/j.schres.2017.01.004 0920-9964/© 2017 Published by Elsevier B.V.

Please cite this article as: Lin, C.-H., et al., A randomized, double-blind, comparison of the efficacy and safety of low-dose olanzapine plus low-dose trifluoperazine versus full..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.01.004

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weight gain is unusual. It may cause less weight gain than most SGAs (Allison et al., 1999; Stahl, 2014). The chlorpromazine (CPZ) equivalent of trifluoperazine has been reported to approach that of olanzapine (Andreasen et al., 2010; Gardner et al., 2010). Trifluoperazine and olanzapine are commonly used in Taiwan. The present double-blind, six-week trial aimed to compare a combination of low-dose olanzapine plus low-dose trifluoperazine to fulldose olanzapine antipsychotic monotherapy in terms of efficacy and safety when used for treatment of newly hospitalized schizophrenic patients with acute exacerbation. Polypharmacy may maintain efficacy by additively blocking D2 receptors (Freudenreich and Goff, 2002). FGAs at dosages lower than 600 mg/day CPZ equivalents have also been reported to have no more EPS than SGAs (Leucht et al., 2003). We hypothesize that low-dose olanzapine plus low-dose trifluoperazine has comparable efficacy and EPS to full-dose olanzapine, but leads to less weight gain and dyslipidemia than full-dose olanzapine. 2. Materials and methods 2.1. Ethics This study was approved by the Kai-Syuan Psychiatric Hospital's institutional review board (IRB) and conducted in accordance with Good Clinical Practice procedures, the Declaration of Helsinki, and national legal requirements (Human Subjects Research Act). This study was registered on Clinicaltrials.gov (Identifier number: NCT02704962). 2.2. Patients All newly hospitalized schizophrenic patients with acute exacerbation were screened and evaluated by trained and board-certified psychiatrists. The Structured Clinical Interview for DSM-IV (1994) was used to confirm the diagnosis. Han Chinese patients in Taiwan were enrolled into this study if they: 1) were physically healthy and had all laboratory parameters within normal limits, 2) were aged between 18 and 55 years, 3) satisfied DSM-IV criteria for schizophrenia, 4) had a baseline Clinical Global Impression-Severity of Illness Scale (CGI-S) ≥ 4 (Guy, 1976), 5) had no DSM-IV diagnosis of substance abuse or dependence (including alcohol) in the past 6 months, and 6) had not received depot antipsychotics during the preceding three months. Patients excluded from this study were: 1) those with histories of serious adverse reactions to olanzapine or trifluoperazine, 2) those with histories of tardive dyskinesia or neuroleptic malignant syndrome, 3) female subjects who were pregnant or at risk of pregnancy or lactation, and 4) those diagnosed with treatment-resistant schizophrenia (Kane et al., 1988), or having previously received clozapine or electroconvulsive therapy. Written informed consent was obtained from every patient and his or her legal guardian prior to participation in the study after a full explanation of the study's aims, procedures, and possible side effects. 2.3. Study design and procedures This was a prospective, six-week, randomized, double-blind, fixeddose trial to compare efficacy and safety of polypharmacy of low-dose olanzapine plus low-dose trifluoperazine to full-dose olanzapine alone (Gardner et al., 2010) in schizophrenia patients with acute exacerbation. Patients were recruited from Kai-Syuan Psychiatric Hospital, a major psychiatric center in Taiwan, between January 2012 and February 2016. After a washout period of at least 3 days, patients were randomized to receive 5 mg of trifluoperazine or 5 mg of olanzapine, in a 1:1 ratio. Computer-generated codes were used to create randomized blocks before study start-up. Each block contained 2 olanzapine and 2 trifluoperazine kits. Each kit contained all clinical trial material used by a patient throughout the 6-week study. Patients received a 5 mg tablet of

olanzapine (an unblinded tablet) at daytime and an identical-appearing capsule that contained either 5 mg of trifluoperazine or 5 mg of olanzapine at bedtime. In brief, patients were randomly assigned to a 1:1 ratio of 5 mg/day of olanzapine plus 5 mg/day of trifluoperazine or 10 mg/day of olanzapine alone for 6 weeks. To ensure concealment of the randomization assignment, the research pharmacist implemented random allocation and masked treatment assignment. Patient adherence and safety were closely monitored by the research staff. Benzodiazepine was allowed as needed for insomnia or agitation. Biperiden, up to 6 mg/day, was also allowed to treat motor side effects, but prophylactic use of biperiden was prohibited. No other psychotropic agents were permitted during the study. 2.4. Efficacy assessments The primary efficacy assessment was based on changes in the Positive and Negative Syndrome Scale (PANSS) total scores from baseline to the end of the study. Secondary efficacy assessment included changes, from baseline to the end of the study, in the CGI-S, PANSS positive subscale, negative subscale and general psychopathology subscale (Kay et al., 1987), Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., 1994), and Global Assessment of Functioning (GAF) scores (Moos et al., 2002). The CDSS assesses depressive symptoms using a nine-item scale, with each item rated on a scale from 0 (absent) to 3 (severe). The CGI-S, PANSS, CDSS, and GAF were rated at baseline, and again at weeks 1, 2, 3, 4, and 6 (or on early termination). These scales were assessed regularly by trained and board-certified psychiatrists. The PANSS evaluation included the total score (30 items), the positive subscale (7 items), the negative subscale (7 items), and the general psychopathology subscale (16 items). An intra-class correlation coefficient (ICC) of 0.95 was obtained among the raters. To maintain high inter-rater reliability and prevent rater drift, raters met at least once every 3–6 months for training and reliability re-testing. Clinical response was defined a priori as a 30% or greater reduction in PANSS total score from baseline (Lane et al., 2005). 2.5. Assessments of safety and quality of life The severity of EPS was assessed by the following scales: the Abnormal Involuntary Movement Scale (AIMS) (Guy, 1976), the Barnes Akathisia Scale (BAS) (Barnes, 1989), and the Simpson-Angus Rating Scale (SAS) (Simpson and Angus, 1970). AIMS, BAS, and SAS were administered at baseline and at weeks 1, 2, 3, 4, and 6 (or on early termination) in a double-blind manner. General side effects were evaluated by a standardized 48-item scale, the UKU Side Effect Rating Scale (Lingjaerde et al., 1987), with the score of each item ranging from 0 (none) to 3 (severe). A score of 1, 2 or 3 on any UKU item that first occurred or worsened during treatment indicated a “case”. Therefore, side effects included those absent at baseline and the worsening of a side effect already present at baseline during the trial (Daly et al., 2011). AIMS, BAS, SAS, and UKU were administered at baseline and at weeks 1, 2, 3, 4, and 6 (or on early termination) in a double-blind manner. Body weight, body mass index (BMI), waist circumference, pulse rates, blood pressure (systolic and diastolic), 12-lead electrocardiogram (ECG) for QTc intervals (Bazett's correction of QT interval), and laboratory tests were performed to determine safety. Laboratory tests in the morning on the fasting patient included: fasting glucose, liver function (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), renal function (blood urea nitrogen [BUN], creatinine), fasting lipid profiles (triglycerides, cholesterol, high density lipoprotein [HDL], low density lipoprotein [LDL]), and prolactin levels. Body weight, BMI, waist circumference, pulse rates, and blood pressure were checked at baseline and at weeks 1, 2, 3, 4, and 6 (or on early termination). ECG, laboratory tests and Medical Outcomes Study Short-Form 36 (SF36) (Brazier et al., 1992) were assessed at baseline and week 6. The SF-36,

Please cite this article as: Lin, C.-H., et al., A randomized, double-blind, comparison of the efficacy and safety of low-dose olanzapine plus low-dose trifluoperazine versus full..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.01.004

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with two primary-factor analytic components, the physical component summary and the mental component summary, was used to measure quality of life. Lower scores reflect greater pathology in the SF-36.

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Kaplan-Meier survival analysis was used to determine time to clinical response and time to discontinuation between groups. All tests were two-tailed, and significance was defined as an alpha of b0.05. Data were analyzed with the SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA).

2.6. Statistical analysis Pearson χ2 test or Fisher's exact test was used to compare categorical variables; independent t-test was used for continuous variables (baseline ratings and safety parameters, age, age at onset of the first psychotic symptoms and SF-36). Efficacy analysis was on a modified intent-to-treat (MITT) basis. Patients were included in analyses only if they had both a baseline and at least one post-baseline assessment. Missing data, excluding the baseline, were replaced with the last available valid post-baseline observation, according to the principle of last observation carried forward (LOCF). LOCF assumes that the patient experienced no further improvement from the last assessment to the 6th week. Using the LOCF method to handle missing values is allowed by the U.S. Food and Drug Administration (Streiner, 2014). Results were presented for patients who completed the entire study (completers) and for all patients (LOCF) at week 6. Analyses of group differences were performed by analysis of covariance (ANCOVA), with treatment as a fixed factor and the baseline value as a covariate.

3. Results 3.1. Patients The participant selection process is shown in Fig. 1. A total of 94 newly hospitalized schizophrenia patients with acute exacerbation were randomly assigned for treatment with olanzapine plus trifluoperazine (N = 47) or olanzapine alone (N = 47). Four of the 94 patients, who did not have both a baseline and at least one post-baseline assessment, were excluded. The remaining 90 patients (46 antipsychotic polypharmacy and 44 antipsychotic monotherapy) entered the analysis. The mean age of the patients was 39.2 ± 8.0 (SD) years, and 44.4% (N = 40) were males. The mean PANSS score of 96.3 ± 16.8 at baseline reflected a fairly severe population. There were no between-group differences in any of pre-treatment demographic data, laboratory measures, and scores of rating instruments (Table 1).

224 Screened

123 Excluded

101 At least 3-day washout

3 Withdrew consent 2 Haloperidol IM for agitation 2 Discharge before randomization

94 Randomized

47 Allocated to Olanzapinne 5 mg/d + trifloperazine 5 mg/d

47 Allocated to olanzapinne 10 mg/d

2 Withdrew consent 1 Intolerance to drug

1 Withdrew consent

46 At least 1 post-baseline observation (ITT) 9 Discontinued

44 At least 1 post-baseline observation (ITT)

14 Discontinued 37 Completed

30 Completed Fig. 1. Flow chart of study participants.

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Table 1 Comparison of groups in baseline demographics and clinical characteristics. Total

O+T

O

Variable

N

n

n

Sex Male, n (%) Female, n (%) Age, mean (SD), year Age at onset, mean (SD), year CGI-S score, mean (SD) PANSS total score, mean (SD) Positive, mean (SD) Negative, mean (SD) General psychopathology, mean (SD) CDSS score, mean (SD) GAF score, mean (SD) AIMS score, mean (SD) SAS score, mean (SD) BAS score, mean (SD) Pulse rate, mean (SD), beat/min Systolic BP, mean (SD), mm Hg Diastolic BP, mean (SD), mm Hg QTc interval, mean (SD), ms Body weight, mean (SD), kg BMI, mean (SD), kg/m2 Waist circumference, cm Fasting glucose, mean (SD), mg/dL ALT(GPT), mean (SD), U/L AST (GOT), mean (SD), U/L BUN, mean (SD), mg/dL Creatinine, mean (SD), mg/dL Cholesterol, mean (SD), mg/dL Triglycerides, mean (SD), mg/dL HDL, mean (SD), mg/dL LDL, mean (SD), mg/dL Prolactin, mean (SD), ng/mL SF-36 PCS, mean (SD) SF-36 MCS, mean (SD)

90

46

44

90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 89 89 90 89 89

40 (44.4) 50 (55.6) 39.2 (8.0) 24.4 (8.0) 5.7 (1.0) 96.3 (16.8) 26.9 (5.7) 21.3 (6.0) 48.2 (7.9) 2.0 (3.5) 31.1 (8.8) 0.2 (1.0) 1.1 (2.0) 0.7 (1.2) 82.2 (13.2) 112.5 (19.3) 76.2 (13.3) 407.6 (21.7) 65.2 (13.9) 24.5 (4.7) 85.7 (11.9) 81.7 (11.4) 21.2 (14.3) 21.4 (9.0) 9.6 (3.0) 0.8 (0.1) 168.5 (40.3) 113.9 (64.3) 54.5 (24.2) 96.6 (29.9) 29.1 (29.5) 51.6 (7.1) 37.4 (11.2)

46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 45 45

22 (47.8) 24 (52.2) 39.4 (7.8) 23.7 (7.2) 5.6 (0.9) 97.7 (18.5) 26.7 (6.4) 22.2 (6.1) 48.8 (8.8) 2.0 (4.1) 29.8 (8.7) 0.3 (1.0) 1.5 (2.6) 0.8 (1.0) 82.2 (13.4) 115.4 (20.5) 78.4 (15.0) 410.0 (22.2) 63.9 (13.1) 24.4 (4.7) 84.6 (11.1) 80.7 (10.8) 19.1 (12.1) 21.1 (9.3) 9.2 (2.8) 0.8 (0.1) 174.8 (39.2) 105.1 (56.4) 54.6 (24.2) 102.3 (34.7) 30.2 (32.1) 52.5 (7.9) 39.0 (11.2)

44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 43 43 44 44 44

p 0.51a 18 (40.9) 26 (59.1) 39.1 (8.2) 25.1 (8.8) 5.7 (1.0) 94.9 (14.8) 27.0 (4.8) 20.3 (5.8) 47.5 (6.9) 2.1 (2.8) 32.6 (8.9) 0.2 (0.9) 0.7 (1.2) 0.6 (1.3) 82.3 (13.1) 109.5 (17.7) 74.0 (10.9) 405.1 (21.2) 66.7 (14.6) 24.7 (4.7) 86.8 (12.7) 82.8 (12.0) 23.5 (16.2) 21.6 (8.7) 10.1 (3.3) 0.8 (0.1) 161.9 (40.7) 123.1 (71.2) 54.3 (24.6) 90.6 (22.6) 27.9 (26.7) 50.6 (7.2) 35.7 (11.0)

0.86b 0.41b 0.49b 0.42b 0.81b 0.15b 0.44b 0.93b 0.14b 0.55b 0.10b 0.67b 0.97b 0.15b 0.11b 0.29b 0.34b 0.76b 0.38b 0.38b 0.15b 0.80b 0.19b 0.78b 0.13b 0.19b 0.95b 0.07b 0.71b 0.20b 0.18b

O + T = Olanzapine 5 mg/day + trifluoperazine 5 mg/day. O = Olanzapine 10 mg/day. CGI-S = Clinical Global Impression-Severity of Illness. PANSS = Positive and Negative Syndrome Scale. CDSS = Calgary Depression Scale for Schizophrenia. GAF = Global Assessment of Functioning. AIMS = Abnormal Involuntary Movement Scale. BAS = Barnes Akathisia Scale. SAS = Simpson-Angus Rating Scale. BMI = body mass index. BP = blood pressure. QTc interval = Bazett's correction of QT interval. ALT (GPT) = alanine aminotransferase. AST (GOT) = aspartate aminotransferase. BUN = blood urea nitrogen. HDL = high density lipoprotein. LDL = low density lipoprotein. SF-36 = Medical Outcomes Study Short-Form 36. PCS = physical component summary. MCS = mental component summary. a Independent t-test. b Pearson χ2 test.

3.2. Premature discontinuations Twenty-three of the 90 patients dropped out early from the study. Study completion rates were similar in the two groups: 37 (80.4%) of 46 patients in the polypharmacy group, and 30 (68.2%) of 44 patients in the monotherapy group (χ2 = 1.78, df = 1, p = 0.18). The three most common reasons for discontinuation were lack of efficacy (N = 6 for polypharmacy group; N = 8 for monotherapy group), intolerance of the medication (N = 1 for polypharmacy; N = 4 for monotherapy), and nonadherence to clinical trial (N = 2 for polypharmacy).

The mean time to discontinuation did not significantly differ between the groups (36.4 ± 1.8 days for polypharmacy; 34.1 ± 1.9 days for monotherapy, log rank = 1.52, df = 1, p = 0.22). 3.3. Efficacy The PANSS total score decreased markedly in both groups: from 97.7 ± 18.5 at baseline to 76.4 ± 21.8 at the end point in the polypharmacy group, and from 94.9 ± 14.8 to 74.7 ± 17.0 in the monotherapy group (Fig. 2). There were no significant between-group

Please cite this article as: Lin, C.-H., et al., A randomized, double-blind, comparison of the efficacy and safety of low-dose olanzapine plus low-dose trifluoperazine versus full..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.01.004

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test), week 4 (19.6% vs. 22.7%, p = 0.71), and week 6 (39.1% vs. 31.8%, p = 0.47). The mean time to response was not significantly different between the antipsychotic polypharmacy group (38.3 ± 1.2 days) and antipsychotic monotherapy group (36.8 ± 1.6 days) during the trial period (log rank = 0.44, df = 1, p = 0.51).

3.5. Safety and quality of life No significantly different changes in body weight, BMI, and waist circumference at weeks 1, 2, 3, 4, and 6 occurred between two groups after treatment (Table 2). The two treatment modalities had similar effects on EPS (AIMS, BAS and SAS), pulse, blood pressure, QTc interval, fasting glucose levels, liver function, renal function, fasting lipid profiles, prolactin levels and QOL (PCS & MCS) (Table 3). No QTc interval longer than 480 ms was found. The number of patients reporting at least one side effect determined by the individual item of the UKU Scale was similar in both groups (71.7% vs. 79.5%, p = 0.39). There were also no significant between-group differences in any individual side effect. Side effects occurring at an incidence of 10% or higher in each treatment group are shown in Table 4.

Fig. 2. No significantly different score changes in PANSS total scores between two groups at each visit (LOCF).

differences in score changes for the CGI-S scale, PANSS total and subscale scores (positive scale, negative scale, and general psychopathology scale), the CDSS scale, and the GAF scale at each visit (Table 2). Fig. 2 shows the PANSS total score changes of the two groups over the duration of the study period.

3.6. Co-medications A higher observed portion of patients in the polypharmacy group (N = 7, 15.2%) received biperiden than in the monotherapy group (N = 1, 2.3%), but this difference was not significant (p = 0.059, Fisher's exact test). There was no significant difference in the rate of patients taking benzodiazepine between the polypharmacy group (N = 35, 76.1%) and the monotherapy group (N = 33, 75.0%) (p = 0.91).

3.4. Response rates and time to clinical response Response rates did not differ significantly between the antipsychotic polypharmacy group and the antipsychotic monotherapy group at week 1 (0.0% vs.4.5%, p = 0.24, Fisher's exact test), week 2 (4.3% vs. 9.1%, p = 0.43, Fisher's exact test), week 3 (8.7% vs. 15.9%, p = 0.35, Fisher's exact

Table 2 Changes in efficacy in clinical measures, body weight, BMI, and waist circumference for patients with schizophrenia in a 6-week comparison of olanzapine 5 mg/day plus trifluoperazine 5 mg/day (N = 46) and olanzapine 10 mg/day alone (N = 44). Week 1 Scale CGI-S O+T O PANSS-Total O+T O PANSS-Positive O+T O PANSS-Negative O+T O PANSS-General psychopathology O+T O CDSS O+T O GAF O+T O Body weight (kg) O+T O BMI (kg/m2) O+T O Waist circumference (cm) O+T O a

Score change Mean ± SD

Week 2 a

p

Score change Mean ± SD

0.54 −0.4 ± 0.6 −0.5 ± 0.9

p

0.22

0.17 −3.0 ± 3.6 −4.0 ± 4.9 0.84 −0.9 ± 2.5 −1.0 ± 1.8 0.09 2.8 ± 3.8 4.4 ± 4.6 0.41 0.2 ± 1.4 0.2 ± 1.0 0.44 −0.003 ± 0.5 0.1 ± 0.4 0.13

0.88

0.81

0.69 1.5 ± 2.9 1.2 ± 2.1

0.81 0.4 ± 1.0 0.4 ± 0.7

0.50 1.4 ± 3.2 0.8 ± 3.0

0.66 15.1 ± 10.8 15.5 ± 12.0

1.1 ± 2.7 0.9 ± 1.9

0.3 ± 0.9 0.2 ± 0.6 0.12

1.5 ± 3.7 0.4 ± 2.4

0.45

0.90

0.67

0.93 −1.3 ± 3.8 −1.3 ± 2.0

12.2 ± 9.7 13.2 ± 9.9

0.8 ± 2.3 0.7 ± 1.7

0.2 ± 0.8 0.2 ± 0.6

0.84

0.22

0.59

0.86 −10.6 ± 8.6 −9.8 ± 7.5

−1.2 ± 3.8 −1.1 ± 2.1

8.9 ± 7.4 10.7 ± 8.9

0.5 ± 2.1 0.6 ± 1.6

0.84

0.53

0.051

0.82 −3.7 ± 4.3 −2.9 ± 3.6

−9.0 ± 7.9 −8.9 ± 6.9

−1.2 ± 3.6 −1.1 ± 1.9

5.9 ± 5.7 8.6 ± 7.2

0.74

0.61

0.99

0.73 −7.0 ± 5.3 −7.5 ± 5.7

−3.4 ± 3.9 2.5 ± 3.4

−7.1 ± 6.5 −7.4 ± 6.4

−0.9 ± 3.2 −1.0 ± 1.8

0.44

0.87

0.52 −5.7 ± 5.7 −6.1 ± 5.9

0.91 −21.4 ± 16.5 −20.2 ± 15.4

−5.9 ± 4.7 −6.7 ± 5.4

−2.8 ± 3.7 −2.3 ± 3.2

0.61 0.6 ± 1.1 0.5 ± 0.8

0.51 2.0 ± 3.6 1.4 ± 3.3

pa 0.90

0.83

0.43

0.45

Score change Mean ± SD −1.6 ± 1.2 −1.6 ± 1.3

−18.3 ± 14.9 −18.1 ± 14.3

−4.8 ± 3.8 −5.6 ± 5.1

−2.0 ± 3.1 −2.1 ± 2.6

p

0.72

0.63

0.30

0.32

Score change Mean ± SD

Week 6 a

−1.4 ± 1.1 −1.4 ± 1.3

−14.7 ± 12.6 −15.3 ± 13.5

−3.9 ± 3.4 −4.8 ± 4.5

−0.9 ± 1.9 −1.1 ± 2.0

p

0.81

0.43

0.36

Week 4 a

−1.1 ± 1.0 −1.2 ± 1.2

−11.7 ± 11.0 −13.0 ± 12.2

−2.0 ± 2.3 −2.7 ± 3.7

Score change Mean ± SD

0.77 −0.9 ± 0.9 −1.1 ± 1.1

−6.0 ± 6.9 −7.8 ± 9.7

0.8 ± 2.3 −0.03 ± 2.7

Week 3 a

0.64 2.8 ± 4.1 2.5 ± 4.8

p values were determined by analysis of covariance (ANCOVA), with baseline value as covariate.

Please cite this article as: Lin, C.-H., et al., A randomized, double-blind, comparison of the efficacy and safety of low-dose olanzapine plus low-dose trifluoperazine versus full..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.01.004

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Table 3 Changes of side effects and safety in each measure between week 0 and week 6 for patients taking olanzapine 5 mg/day plus trifluoperazine 5 mg/day and olanzapine 10 mg/day alone. Olanzapine 5 mg/day + trifluoperazine 5 mg/day

Olanzapine 10 mg/day

Variables

N

Mean ± SD

N

Mean ± SD

pa

AIMS SAS BAS Pulse rate (beat/min) Systolic BP (mm Hg) Diastolic BP (mm Hg) QTc interval (ms) Fasting glucose level (mg/dL) ALT (GPT) (U/L) AST (GOT) (U/L) BUN (mg/dL) Creatinine (mg/dL) Cholesterol (mg/dL) Triglycerides (mg/dL) HDL (mg/dL) LDL (mg/dL) Prolactin (ng/mL) SF-36 PCS MCS

37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37

−0.1 ± 0.4 −0.4 ± 2.5 −0.3 ± 1.2 −0.7 ± 16.5 1.2 ± 17.1 −1.5 ± 13.1 0.6 ± 21.3 5.3 ± 15.4 9.7 ± 33.0 4.2 ± 21.6 0.01 ± 3.5 −0.01 ± 0.10 18.3 ± 27.8 39.7 ± 78.8 1.3 ± 7.8 10.2 ± 28.2 −2.8 ± 25.4

30 30 30 30 30 30 30 30 30 30 30 30 30 30 29 29 30

−0.2 ± 0.7 0.2 ± 0.9 0.1 ± 0.8 −5.7 ± 1.3 −1.1 ± 17.8 2.7 ± 12.2 3.4 ± 18.4 0.6 ± 14.3 2.8 ± 13.6 1.4 ± 9.7 −1.2 ± 3.9 −0.04 ± 1.3 16.7 ± 37.4 32.2 ± 91.7 −0.7 ± 10.8 11.3 ± 32.3 −1.3 ± 19.7

0.32 0.71 0.34 0.22 0.12 0.44 0.66 0.71 0.42 0.55 0.33 0.34 0.60 0.95 0.39 0.93 0.89

37 37

0.2 ± 4.2 2.0 ± 10.6

30 30

0.1 ± 6.1 1.5 ± 9.0

0.86 0.49

a p values were determined by analysis of covariance (ANCOVA), with baseline value as covariate.

4. Discussion The major finding of this study was that a combination of 5 mg/day of olanzapine plus 5 mg/day of trifluoperazine had a comparable efficacy and safety to 10 mg/day of olanzapine monotherapy in the acute treatment of schizophrenia. Compared to the monotherapy group, the polypharmacy group was unable to achieve significantly less weight gain and decreased lipid levels. One possible reason is that weight gain is not dose-related for olanzapine in a dose range of 5–20 mg/day (Kinon et al., 2001).

Table 4 Side effects (determined by individual item of UKU Scale) occurring in at least 10% of the patients in either group, N (%). Olanzapine 5 mg/day + trifluoperazine 5 mg/day (N = 46)

Olanzapine 10 mg/day (N = 44)

Adverse event

N

%

N

%

p

At least one adverse event Asthenia/increased fatiguability Sleepiness/sedation Failing memory Depression Tension/inner unrest Reduced duration of sleep Tremor Akathisia Accommodation disturbances Increased salivation Reduced salivation Constipation Polyuria/polydipsia Weight gain Headache

33 3 5 7 6 8 9 6 6 7 6 10 1 7 13 2

71.7 6.5 10.9 15.2 13.0 17.4 19.6 13.0 13.0 15.2 13.0 21.7 2.2 15.2 28.3 4.3

35 7 5 8 6 9 11 6 2 1 1 12 6 8 12 6

79.5 15.9 11.4 18.2 13.6 20.5 25.0 13.6 4.5 2.3 2.3 27.3 13.3 18.2 27.3 13.6

0.39a 0.19b 0.94a 0.71a 0.93a 0.71a 0.54a 0.93a 0.27b 0.06b 0.11b 0.54a 0.06b 0.71a 0.92a 0.12b

a b

Fisher's exact test. Pearson χ2 test.

Brain imaging study indicates that D2 receptor occupancy of 60%– 70% is required to reach satisfactory antipsychotic response (Kapur and Seeman, 2001). Schizophrenia patients receiving 12 mg daily of olanzapine reveal a striatal D2 receptor occupancy of 65% (Bishara et al., 2013). According to dose-response curve, does N 10 mg daily of olanzapine offer only marginal benefit (Bishara et al., 2013). On the other hand, the effective dose of trifluoperazine has been reported to be between 15 and 80 mg/day in a meta-analysis study (Koch et al., 2014). The effective dose of olanzapine or trifluoperazine may be highly individualized (Bishara et al., 2013; Koch et al., 2014). Although SGAs with multiple receptor blockages can be regarded as a type of intrinsic antipsychotic polypharmacy rather than pure monotherapy (Correll and Gallego, 2012), antipsychotic polypharmacy is still criticized for being associated with increased antipsychotic doses, increased dose-related side effects, unexpected drug-drug interactions, and complicated dosing regimens that may result in poor adherence (Fleischhacker and Uchida, 2014; Galling et al., 2016). As we know, FGAs are much less expensive than SGAs. Combined with our previous studies on low-dose risperidone plus low-dose haloperidol vs. fulldose risperidone (Lin et al., 2010) or low-dose amisulpride plus lowdose sulpiride vs. full-dose amisulpride (Lin et al., 2013), the current study suggests that combination of low-dose antipsychotics is as efficacious and safe as, but cheaper than, full-dose antipsychotic monotherapy in the treatment of schizophrenia. For patients in low or middle income countries, or those without insurance coverage, the cost of drugs is a major barrier to treatment access (Razzouk et al., 2015). Therefore, if polypharmacy, combination of an appropriate ratio of one FGA dosage to another SGA dosage, can achieve favorable clinical responses and side effect profiles, it may lead to cost savings and improve treatment adherence (Farooq and Singh, 2015). Such an advantage of antipsychotic combination should not be neglected. Results from the current study should be interpreted within its limitations. First, the sample size was small due to difficulties in enrolling enough participants and limited financial support. According to the trial (Copolov et al., 2000) designed to evaluate the equivalence of the two treatments, a minimum clinically meaningful difference was defined as a 30% decrease from baseline in PANSS total score. A difference of half this amount (i.e., 15%) was defined as the maximum difference between treatments that would allow them to be considered to be equivalent. By Blackwelder's theory (Blackwelder, 1982) for clinical equivalence trials, the power of the current study was 0.60. Lower power may increase the chance of type II error. However, based on statistical theory for comparison groups, 30–50 patients in either group are sufficient for the initial trial (Forthofer et al., 2007). Therefore, the study should be considered as exploratory and the results as preliminary. Although random assignment and double blinding are important strengths of our study, definitive conclusions about the efficacy and safety of low-dose olanzapine plus low-dose trifluoperazine rely on future studies with a larger number of subjects. Second, the wash-out period of our study was relatively short due to ethical considerations, as it is inhumane to leave acutely psychotic patients untreated for too long. However, a wash out of at least 3 days is a common duration in clinical trials of antipsychotics (Davidson et al., 2007; Meltzer et al., 2011). Third, this was a short-term study; therefore, long-term efficacy and delayed side effects such as tardive dyskinesia and lipid profile changes warrants further studies. Fourth, there is still no head-to-head trial comparing trifluoperazine to olanzapine for efficacy and safety. Also, whether or not the dose equivalent of trifluoperazine to olanzapine is 1 to 1 should be confirmed. Fifth, without standardized and sensitive neuropsychological tests performed before and after treatment, we did not know whether two groups had comparable changes in cognitive function after treatment. Sixth, we did not monitor the blood levels of low-dose olanzapine and low-dose trifluoperazine for possible drugdrug interaction, although no pharmacokinetic interactions between olanzapine and trifluoperazine have been reported. Finally, all data came from a single psychiatric center, which limits the generalizability

Please cite this article as: Lin, C.-H., et al., A randomized, double-blind, comparison of the efficacy and safety of low-dose olanzapine plus low-dose trifluoperazine versus full..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.01.004

C.-H. Lin et al. / Schizophrenia Research xxx (2017) xxx–xxx

of our findings. However, the study generally requires fewer subjects to test differences because of lower variance. Further studies, preferably including multiple sites, larger sample sizes, standardized and sensitive neuropsychological tests to measure cognitive function, and long-term study durations should be conducted to confirm the efficacy and safety of antipsychotic polypharmacy with a combination of an appropriate ratio of one FGA dosage to another SGA dosage. Contributors Dr. Lin (1st author) enrolled the participants, rated the symptom severity, analyzed the data and wrote draft of the manuscript. Dr. Chen (corresponding author) directed the study and revised the manuscript. Dr. Wong (2nd author), Dr. Lin (3rd author), and Dr. Huang (4th author) managed the literature searches and rated the symptom severity. All authors contributed to and have approved the final manuscript. Conflict of interest The authors declare that they have no conflicts of interest. Role of funding source This study was funded by the Kai-Syuan Psychiatric Hospital (KSPH-2011-22) and the Ministry of Science and Technology, Taiwan (MOST-103-2314-B-280-001-MY3). Acknowledgments We would like to thank all the participants for this study.

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