The purpose of this study was to investigate the efficacy and tolerability of atypical antipsychotics (AAPs) with augmentation by blonanserin in schizophrenic patients.
aA total of 100 patients with schizophrenia who were partially or completely unresponsive to treatment with an AAP were recruited in this 12-week, open-label, non-comparative, multicenter study. Blonanserin was added to their existing AAP regimen, which was maintained during the study period. Efficacy was primarily evaluated using the Positive and Negative Syndrome Scale (PANSS) at baseline and at weeks 2, 4, 8, and 12. Predictors for PANSS response (≥20% reduction) were investigated.
The PANSS total score was significantly decreased at 12 weeks of blonanserin augmentation (-21.0±18.1, F=105.849, p<0.001). Moreover, 51.0% of participants experienced a response at week 12. Premature discontinuation of blonanserin occurred in 17 patients (17.0%); 4 of these patients dropped out due to adverse events. The patients who benefited the most from blonanserin were those with severe symptoms despite a treatment with a higher dose of AAP.
Blonanserin augmentation could be an effective strategy for patients with schizophrenia who were partially or completely unresponsive to treatment with an AAP.
Schizophrenia is a chronic and disabling mental disorder characterized by severe behavioral symptoms that commonly require life-long therapeutic intervention. While antipsychotic medications are the cornerstone of schizophrenia treatment, the effect of treatment is limited by unfavorable side effects, nonresponse to medication, and modest efficacy on negative symptoms.
In order to overcome the limited effectiveness of antipsychotic drugs, polypharmacy is very common in the treatment of schizophrenia. In fact, it has been reported that 4.1–48.0% of patients use two or more medications, with most studies report a prevalence of between 10% and 30%.
However, antipsychotic polypharmacy could be effective for patients with schizophrenia when a single agent does not adequately relieve symptoms. Pharmacologically, antipsychotic combinations seek to achieve greater therapeutic potential by optimizing dopamine D2 receptor occupancy or increasing activity across a wider range of receptors related to the pathogenesis of schizophrenia.
Blonanserin is a well-known second-generation antipsychotic commonly used in Japan and Korea with a unique pharmacological receptor profile; it has a higher dopamine D2 receptor occupancy (Ki=0.142 nM) and lower serotonin 2A receptor-blocking activity (Ki=0.812 nM) than other second generation antipsychotics.
The goals of this study were to test the hypothesis that blonanserin augmentation would improve psychotic symptoms and be well tolerated in patients who failed to respond to another AAP and to identify factors that can be used to predict a patients' response to blonanserin augmentation therapy.
This was an open-label, prospective, multicenter, 12-week study that included 100 patients. The patients were diagnosed with schizophrenia according to DSM-IV-TR criteria and did not respond or only partially responded to an AAP treatment. This study was conducted at 7 centers in Korea, including 5 university hospitals and two psychiatric hospitals.
After at least 6 weeks of treatment with recommended dose of AAPs, patients completed the 18-item Korean version of the brief psychiatric rating scale (BPRS, items scored on a 1–7 scale). Patients scoring 43 or more were classified as non-responders or partial responders.
The blonanserin was recommended to be dosed flexibly within the range of 8–24 mg/day. During the study period, it was recommended that the AAP dose to be kept constant. Concomitant treatment with ongoing mood stabilizers/anticonvulsants or antidepressants was permitted if the patient had been on a stable dose for at least 2 weeks prior to enrollment, but it was requested that the dose not be changed during the study period. Patients were not given any other antipsychotics, mood stabilizers/anticonvulsants, or antidepressants during the study. Benzodiazepines, anti-Parkinsonian agents, and hypnotics were permitted at the discretion of the investigator.
Psychiatric symptoms were evaluated with the Korean version of BPRS, the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impressions-Severity Scale (CGI-S) at baseline and at weeks 2, 4, 8, and 12. The primary efficacy assessment was defined as mean change from baseline to week 12 on the PANSS total score. Additional efficacy measures included response rates with PANSS and BPRS, mean change in PANSS-positive, negative, and general subscale, BPRS, and CGI-S scores. Response was defined as a decrease in the PANSS and BPRS total scores ≥20%.
Safety assessments included monitoring of vital signs and weight at baseline and week 12, a physical examination, and reported adverse events at each visit. At each visit, extrapyramidal symptoms were assessed using the Simpson-Angus Scale (SAS) and the Barnes Akathisia Rating Scale (BARS). The Abnormal Involuntary Movements Scale (AIMS) was applied to assess abnormal involuntary movement.
Data were analyzed on an intent-to-treat (ITT) group, and the last-observation-carried forward (LOCF) method was applied for endpoint analysis. The data included all patients who provided a baseline and at least one post-baseline data measurement. All subjects who received at least one dose of the study medication were included in the safety analysis.
Categorical variables are presented as absolute number and relative frequencies (%), and nominal variables are described as mean±standard deviation. Data for each psychometric scale and scale for adverse event scores were analyzed by repeated measure analysis of variance (RM-ANOVA). A Greenhouse-Geisser correction was used to test for non-sphericity. The chi-square test or Fisher's exact test was used to analyze categorical variables, and a paired t-test was performed for variables measured at baseline and endpoint.
We also investigated the predictors of response to blonanserin augmentation by comparing responders and non-responders with an independent t-test, chi-square test, or Fisher's exact test. A binary logistic regression analysis was conducted with age, sex, and variables with significance (p<0.05) or trend toward significance (p<0.10) on univariate analyses with response as an independent variable (i.e., responders and non-responders). All statistical tests were two-tailed with a significance level of 0.05.
The study was conducted according to the Declaration of Helsinki and Good Clinical Practices. Written informed consent was obtained from all subjects after the subjects were given an extensive explanation of the nature and procedures of the study. The study protocol was approved by the Institutional Review or Ethics Committees at each study site.
The number of participants who completed the 12-week treatment was 83 (83.0%). The demographic and clinical characteristics of the subjects at baseline are presented in
The mean total scores on the PANSS and BPRS significantly decreased from baseline to week 12 (-21.0±18.1, p<0.001 and -14.0±11.6, p<0.001, respectively;
Seventeen participants (17.0%) withdrew from the study prematurely. Six patients (6.0%) were lost to follow-up, 4 patients (4.0%) discontinued due to adverse events (two cases of akathisia, one case of weight gain, and one case of epidural hemorrhage from a fall), two patients (2.0%) due to insufficient response, non-compliance, and/or protocol violation, and one patient (1.0%) discontinued the study by withdrawal of consent. The adverse events frequently reported (≥3%) during the 12 weeks of the study are listed in
Blood pressure, body weight, and body mass index (BMI) were compared between baseline and endpoint. Systolic (p>0.999) and diastolic blood pressure (p=0.254) were not significantly different between the two time points (data not shown). Weight significantly increased from 66.7±14.8 kg at baseline to 68.0±15.6 kg at week 12 (p=0.001). Consequently, BMI also significantly increased from 24.6±4.1 kg/m2 to 25.1±4.4 kg/m2. For each concomitant antipsychotics groups, patients treated with blonanserin as an augmentation to olanzapine showed significant increase in weight from 66.3±13.0 kg at baseline to 68.0±14.2 kg at week 12 (p=0.002). There was no significant change in weight during study period in patients treated with other concomitant antipsychotics and blonanserin (data not shown). Ten patients (10.0%) experienced significant (≥7%) weight change during the study period. Among them, 9 patients (8 patients treated with olanzapine and blonanserin, and 1 patient treated with risperidone and blonanserin) gained weight and one patient lost weight.
Based on logistic regression analysis with covariates as age, sex, hospitalization, PANSS severity, PANSS-positive score, general subscale score, use of clozapine, dosing for both blonanserin and concomitant AAP (divided at the median value to achieve high and low dose groups), and the presence of baseline adverse events, there were two significant predictors of response (
As far as we can tell, this is the first prospective study to investigate the effectiveness and tolerability of blonanserin augmentation in schizophrenic patients. In the present study, blonanserin augmentation improved symptoms in schizophrenic patients who failed to respond sufficiently to treatment with an AAP, especially in patients with severe symptoms and treated with relatively higher dose of the AAP.
There have been only limited studies on the efficacy of augmentation strategies using antipsychotics for schizophrenia. Furthermore, several previous studies suggested only a limited benefit from the augmentation with antipsychotics.
However, in the present study, although the responders (who responded to blonanserin augmentation) were taking 565.7±125.1 mg/day of chlorpromazine equivalent, a dose that nearly corresponds to the upper recommended target range (600 mg/day),
We found two significant independent predictors of response to blonanserin augmentation: use of high dose concomitant AAPs and severe baseline psychiatric symptoms. Thus, blonanserin augmentation could be profitable for patients who retain severe symptoms despite compliance with a therapeutic regimen of an AAP. This result is in accordance with meta-analyses by Taylor et al.
However, the results from the present study require interpretation with caution. Because we did not collect data before the start of the intervention, we do not know the characteristics of the patients who were not eligible for the study; for example, several patients discontinued treatment with an AAP before the six-week minimum requirement for enrollment. Our eligibility criteria could have caused selection bias in favor of cases more tolerable to AAP treatment. Moreover, there is a possibility that a low-dose titration regimen could be effective in non-responders. To expound, non-responders could be less tolerable to AAP treatment than responders, and their relative intolerability could cause premature discontinuation of blonanserin, before they had enough time to respond to the blonanserin augmentation. In this situation, non-response may just mean 'intolerability' rather than true 'non-response'. However, two cases of premature discontinuation due to adverse events were reported in both responders and non-responders.
Although there has been a lot of concern regarding the tolerability of antipsychotic combinations,
There are several limitations that should be considered. First, we did not evaluate biochemical metrics such as metabolic parameters (fasting glucose and lipid profiles) and serum prolactin level, nor did we evaluate cognitive functioning, which could have been associated with antipsychotic polypharmacy.
In summary, the results from the present study suggest that blonanserin augmentation might show additional beneficial effect in patients with schizophrenia who showed an insufficient treatment response to AAP monotherapy. However, the results from the present study are insufficient to derive conclusive clinical recommendations. The treatment response was associated with severe baseline psychiatric symptoms and a relatively high baseline AAP dose. Despite the frequent use of antipsychotic polypharmacy in schizophrenia, there is still only limited evidence for its efficacy. Adequately designed, large, double-blind, placebo-controlled, randomized clinical trials and head-to-head comparisons of different AAPs are needed to address the usefulness of antipsychotic polypharmacy in difficult-to-treat schizophrenic patients. These studies need to include a long-term investigation of safety and drug-interactions when combining different AAPs. Furthermore, a further investigation for predictors of response to antipsychotic polypharmacy is needed so that individual cases that will benefit from AAP combinations can be quickly identified.
This study was supported by the Bukwang Pharmaceutical Company, Ltd, Korea. The Bukwang Pharmaceutical Company had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
SD: standard deviation, BPRS: Brief Psychiatric Rating Scale, PANSS: Positive and Negative Syndrome Scale, CGI-S: Clinical Global Impression Scale-Severity, GAF: Global Assessment of Functioning
PANSS: Positive and Negative Syndrome Scale, BPRS: Brief Psychiatric Rating Scale, CGI-S: Clinical Global Impression Scale-Severity, SD: standard deviation
*p<0.05. SD: standard deviation, BPRS: Brief Psychiatric Rating Scale, PANSS: Positive and Negative Syndrome Scale, CGI-S: Clinical Global Impression Scale-Severity, GAF: Global Assessment of Functioning
*p<0.05. PANSS: Positive and Negative Syndrome Scale, OR: odds ratio, CI: confidence interval