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.³¹ At the study entry, participants were ≥20 and ≤70 years of age and were being treated with one AAP: aripiprazole, clozapine, olanzapine, paliperidone, or risperidone. These AAPs were selected because of their pharmacokinetic properties. Blonanserin is known to be metabolized predominantly via the cytochrome P450 (CYP) enzyme CYP3A4 and does not inhibit any key CYP enzymes.³² Therefore, blonanserin is considered unlikely to have any significant clinical pharmacokinetic interactions with antipsychotics that are mainly metabolized by CYP1A2 (clozapine, olanzapine) or CYP2D6 (aripiprazole, risperidone);³³ paliperidone does not undergo significant hepatic metabolism.³²³⁴ Among the exclusion criteria were pregnancy or lactation, a medical condition that could interfere with everyday life activities, and a diagnosis of any Axis I disorder other than schizophrenia. Patients were excluded from participation if they had been prescribed blonanserin before the study, had been prescribed a depot of antipsychotics within 30 days of the study; were currently being treated with two or more antipsychotics; or were known to be treatment resistant. All patients gave informed consent before participation in the study.

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%.²⁸

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 Table 1. The mean chlorpromazine equivalent dose³⁵ of concomitant AAPs at baseline was 516.4±153.6 mg/day. The blonanserin dose at each visit is shown in Figure 1. The mean dose of blonanserin during the study period was 11.7±5.8 mg/day. There were 19 (19.0%) subjects who were treated with concomitant mood stabilizer/anticonvulsants and 8 (8.0%) who were treated with concomitant antidepressants at baseline.

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; Table 2). All three subscales of PANSS (positive, negative, and general psychopathology) also decreased significantly from baseline to endpoint (all p<0.001, Table 2). The CGI-S score decreased from 4.7±1.1, which means 'moderate to markedly ill,' to 3.8±1.1, which means 'mildly to moderately ill.' The number of responders who showed a reduction in PANSS and BPRS scores of 20% or greater at week 12 were 51 (51.0%) and 57 (57.0%), respectively (Figure 2).

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 Table 3. A total of 50 patients (50.0%) reported 225 adverse events. Among them, 41 adverse events in 19 patients were newly developed adverse events or worsening of existing adverse events after blonanserin augmentation was initiated. The severity of every reported adverse event was mild (79.1%, n=178) or moderate (20.4%, n=46), except for one severe case of epidural hemorrhage. The results by RM-ANOVA showed that the scores on SAS (F=1.476, p=0.232), BARS (F=0.400, p=0.672), and AIMS (F=1.204, p=0.305) (Figure 3) were not significantly changed during study period.

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.

Table 4 shows a comparison of baseline characteristics between people who responded to blonanserin augmentation vs. those who did not. Responders who showed a decrease in their total PANSS score of 20% or more exhibited a higher baseline BPRS total score (p=0.043) and a higher baseline PANSS total score (p=0.038). In addition, responders' scores on the PANSS-positive section (p=0.025) and the general psychopathology (p=0.016) section at baseline were significantly greater than non-responders' scores. Among the responders, 60.8% (n=31) were inpatients, while only 34.7% (n=17) of the non-responders were inpatients (p=0.009). Baseline symptom severity was categorized into mild to moderate symptoms (PANSS total score ≤85) and severe symptoms (PANSS total score >85). Only 9.8% (n=5) of responders exhibited mild to moderate severity, while the majority of responders exhibited severe baseline symptoms. In contrast, 38.8% (n=19) of non-responders had mild to moderate baseline symptoms and only 61.2% of nonresponders had severe baseline symptoms (p=0.001). Reflecting this difference in severity, the mean dose of blonanserin during the study period was 13.9±6.3 mg/day for responders and 9.4±4.3 mg/day for non-responders (p<0.001). Mean chlorpromazine equivalent dose of concomitant AAPs was also significantly different between the two groups (p<0.001); responders were administered 562.2±133.1 mg/day while non-responders took 437.6±193.9 mg/day. However, the starting dose of blonanserin in responders (5.0±1.9 mg/day) was not significantly different from that of non-responders (5.3±2.8 mg/day, p=0.476). Use of other concomitant medication was not significantly different between the groups (Table 4). At baseline, 39.2% (n=20) of responders reported one or more adverse event from their AAP and 22.4% (n=11) of non-responders reported an adverse event from their AAP (p=0.070).

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 (Table 5): severe (PANSS>85) baseline symptoms (OR=10.3, 95% CI=1.9-56.0, p=0.007) and high chlorpromazine equivalent dose (>600 mg/day) of the concomitant AAP (OR=4.6, 95% CI=1.4-15.5, p=0.014).