Post‐marketing surveillance of quetiapine fumarate extended‐release tablets in patients with bipolar depression

Abstract Aim This study aimed to verify the real‐world efficacy and safety of quetiapine fumarate extended‐release tablets (Bipresso® 50 mg and 150 mg; marketing authorization holder is KYOWA Pharmaceutical Industry Co., Ltd., Osaka, Japan) in patients with bipolar depression. Methods We performed a post‐marketing surveillance with an observation period of 12 weeks. Results In the safety analysis group (n = 345), adverse drug reactions (ADRs) occurred in 111 patients (32.17%). The most common ADRs (>1%) were somnolence in 55 patients (15.94%), akathisia in 11 (3.19%), dizziness in 10 (2.90%), weight increase in 6 (1.74%), thirst in 5 (1.45%), and hypersomnia, constipation, and nausea in 4 patients each (1.16%). The only severe ADR was one patient of suicidal ideation, and “longer time since the onset of the first episode” (p = 0.011) and “presence of complications” (p < 0.001) were identified as significant risk factors for the occurrence of ADRs. In the efficacy analysis group (n = 265), the average changes from baseline in the total Montgomery–Åsberg Depression Rating Scale (MADRS) score were −7.3 ± 8.8, −12.2 ± 10.7, −16.8 ± 12.7, and −13.2 ± 12.7 points after 4, 8, and 12 weeks, and at the last evaluation, respectively. The mean MADRS total score decrease had no significant association with maximum daily dose, diagnosis, and presence or absence of prior or concomitant treatment for bipolar disorder with mood stabilizers/antipsychotics/antidepressants. Conclusion The efficacy of quetiapine fumarate extended‐release tablets was confirmed in clinical practice, and no new safety concerns or risks were identified.


| INTRODUC TI ON
Bipolar disorder (BD) is an episodic mood alteration defined by episodes of mania/hypomania and depression.The prevalence of this disorder is approximately 0.1-0.4%, and its onset tend to occur late in the second or in the third decade of life. 1 Moreover, it is likely to relapse, thus the patients must be controlled with appropriate treatment.The diagnosis of a manic or hypomanic episode requires both elevated mood and increased activity.It is essential to confirm the presence of unusually increased activity and energy.Manic episodes are accompanied by marked impairment in social or occupational functioning, possibly requiring hospitalization to avoid harming self or others.In contrast, hypomanic episodes have less prominent impairments.Mania and hypomania are the criteria used to diagnose bipolar I and II disorders, respectively.On the other hand, the accompanying depressive episodes require particular attention, as they may be underdiagnosed or treatment-resistant and are prone to the risks of the transition to a manic episode or suicide.Even in remission, the patients may exhibit persisting problems of impulsivity and various other alterations of the cognitive function. 1etiapine fumarate (hereafter, quetiapine) is a dibenzodiazepine-derivative, synthesized and developed in the United Stated by Zeneca.Quetiapine has an affinity for serotonin 5-HT 2A receptors, dopamine D 2 receptors, and several other serotonin, dopamine, histamine, and adrenaline receptor subtypes; however, it is characterized by its higher affinity for serotonin 5-HT 2A receptors than for the dopamine D 2 ones. 2 In addition, its metabolite, norquetiapine, is a partial 5-HT 1A agonist and a norepinephrine reuptake inhibitor. 3Quetiapine is defined as a multi-acting receptor-targeted antipsychotic due to its diverse receptor interactions and is a second-generation antipsychotic.
A recent network meta-analysis demonstrated that quetiapine is effective for the treatment of bipolar mania 4 and bipolar depression (BDep), 5,6 and can also be used in the maintenance phase. 7 March 2023, the Japanese Society of Mood Disorders (JSMD) released its 2023 Diagnosis and Treatment Guidelines for Bipolar Disorder.This version revised the previous guidelines based on recent domestic and international studies evaluating the efficacy of various drugs for the depressive episodes of bipolar disorder with a high level of evidence and recommend quetiapine as one of the standard drugs. 8Moreover, the treatment guidelines published jointly by the Canadian Network for Mood and Anxiety (CANMAT) and the International Society for Bipolar Disorders (ISBD) recommend quetiapine as a first-line drug for acute bipolar I depression, acute bipolar II depression, and for maintenance in both types. 9ditionally, based on the results of our network meta-analyses, 4,7 quetiapine has been listed as one of the Essential Medicine by the WHO in 2023. 10though quetiapine was recommended by the domestic and international guidelines as a treatment of depression in patients with bipolar disorder, this indication had not been approved in Japan.Furthermore, a development request was issued by the Ministry of Health, Labour and Welfare (MHLW) in 2010.At that time, quetiapine tablets were approved for the treatment of schizophrenia.However, quetiapine tablets needed to be administered twice or three times a day.Therefore, once-daily quetiapine extended-release tablets were selected for development for this indication, as they were expected to result in good medication adherence.
This post-marketing surveillance was conducted over an observation period of 12 weeks to confirm the real-world safety and efficacy of the quetiapine extended-release (Bipresso® extendedrelease) tablets, a once-a-day sustained-release matrix formulation to improve patient adherence in individuals with bipolar depression in Japan.

| Participants
The study included patients diagnosed, by an enrolling physician, with depressive symptoms of bipolar disorder, with no history of quetiapine use (immediate-release tablets or the study drug).
The enrollment period was from January 2018 to December 2019.The trial period spanned the 2 years and 9 months from January 2018 to September 2020.The study was conducted in accordance with the Good Post-marketing Study Practice in Japan, using the central registration method and an electronic data collection system.
The target sample size was 300 patients, and the observation period 12 weeks.Previous domestic clinical trials of the study drug (Phase II/III trial CL-0021, trial of older adults CL-0022, trial of pharmaceutical formulation switching CL-0023) 11 reported various adverse events associated with severe and specific risks (such as "hyperglycemia, diabetic ketoacidosis, or diabetic coma," "agranulocytosis or leukopenia," or "hepatic impairment or jaundice"), and a causal relationship to the study drug could not be excluded.These events occurred at a markedly high frequency of approximately 1.0%.Therefore, the sample size was calculated to detect adverse drug reactions occurring at a frequency of 1.0% (with ≥95% reliability) and for which re-examinations could be collected for a 4-year period.Moreover, it was assumed that the 300 patients would include at least 100 who were not using the study drug in combination with mood stabilizers.

| Efficacy
The score of the MADRS was calculated at baseline, and changes from the baseline were evaluated at 4, 8, and 12 weeks, and at last evaluation.The response proportion was defined as the ratio of patients with a ≥50% reduction from baseline in the MADRS total score, and the remission proportion as the ratio of patients with a MADRS total score ≤12 points.

| Statistical analysis
The MADRS score summary statistics are presented as mean ± standard deviation (SD).

| Patients
In total, 369 patients were enrolled by December 31, 2019, and among them, survey forms were obtained for 353 patients from 60 facilities; for 16 patients, the survey forms could not be collected because the attending physician declined to participate.
Among these 353 patients, eight were excluded: five were lost to follow-up after the initial examination, two did not meet the The study involved patients diagnosed by enrolling physicians with depressive symptoms of bipolar disorder and no prior history of quetiapine use.This chart provides numbers regarding enrollment, survey forms collected, and analysis of safety analysis set and efficacy analysis set.
inclusion criteria, and one had unclear presence or absence of adverse events; therefore, the safety analysis was conducted on a group of 345 patients.Furthermore, 80 patients were excluded for unclear efficacy, leaving an efficacy analysis sample of 265 patients (Figure 1).Notably, ADRs were observed in two of the eight patients excluded from the safety analysis (one patient of malaise and one of somnolence, both mild).

| Status of study drug administration and concomitant drugs or therapies
The status of the study drug administration among the 345 patients in the safety analysis group is shown in Table 1.
The initial dosing frequency was once daily for all patients; 89.6% had a dosage of 50 mg and 10.4% had 100-300 mg.However, 47.5% of patients had their dose increased to 150 mg/day.The maximum

| Occurrence of adverse drug reactions
The ADRs occurring in each period and for each event are shown in

| Factors influencing the occurrence of adverse drug reactions
The analysis of the patient characteristics increasing the risk of ADR occurrence revealed that "longer time since the onset of the first episode" (p = 0.011) and "presence of complications" (p < 0.001) were statistically significant risk factors (Table 3).Furthermore, the mean change from baseline was negative for each MADRS item, and the score for all MADRS items was lower than at baseline both after 12 weeks and at the last evaluation (Figure 3).Metabolism and nutrition disorders 0 (0.00) 0 (0.00) 3 (100.00)0 (0.00) 0 (0.00) 0 (0.00) (0.87) Hyperglycemia 0 (0.00) 0 (0.00)

Concomitant drugs (antipsychotics or mood stabilizers)
The baseline MADRS total score was 24.0 ± 9.1 and 29.9 ± 11.2 points in patients taking concomitant antipsychotics or not, and the change from baseline at the last evaluation was −9.8 ± 10. Figure S3 shows the differences in mean change from baseline MADRS total score based on the use or not of concomitant drugs (antipsychotics or mood stabilizers).

Other influential factors
The number of older patients, patients with renal dysfunction, and those with liver dysfunction was very small.The change from baseline at the last evaluation by the MADRS total score in older patients, patients with renal dysfunction, and those with hepatic dysfunction were − 17.5 ± 17.3 (n = 17), −14.5 ± 11.9 (n = 4), and − 14.7 ± 17.9 (n = 6), respectively.

Period of occurrence
Total (%)

TA B L E 2 (Continued)
TA B L E 3 Proportion of adverse drug reactions related to patient background factors.

| Response and remission proportions
The proportions of patients demonstrating a positive response at   Safety specifications that should be specifically evaluated at the time of approval include "hyperglycemia, diabetic ketoacidosis, or diabetic coma," "hypoglycemia," "neuroleptic malignant syndrome," "rhabdomyolysis," "seizure," "agranulocytosis or leukopenia," "hepatic impairment or jaundice," "paralytic ileus," "tardive dyskinesia," "pulmonary embolism or deep vein thrombosis," "withdrawal syndrome," "lipid metabolism disorder," "suicidal ideation or suicidal behavior," "hostility or aggression," "urinary retention," "long QT syndrome," and "pancreatitis."In our study, a severe ADR of "suicidal ideation or suicidal behavior" occurred in one patient; a milder "hepatic impairment or jaundice" was noted The analysis of risk factors for ADR occurrence showed that "longer time since the onset of the first episode" and "presence of complications" were significant factors, whereas "diagnosis," "presence or absence of prior pharmacotherapy," and "presence or absence of concomitant drugs or therapies" showed no statistically significant difference.These results suggest that the proportion of occurrence of ADRs is higher after a longer time since the onset of the patient's first episode and in the presence of complications.
However, patients with complications are more likely to be in poor conditions than otherwise healthy patients, and this underlying situation may be a more relevant factor in the higher proportion of ADR occurrence in the former group.
Our study found that mood switches were not observed.A recent network meta-analysis demonstrated that quetiapine was associated with a lower incidence of manic switching compared to a placebo. 6This result is crucial to manage the individuals with bipolar disorder in the clinical practice.
The typical dosage of quetiapine in adults starts at 50 mg and is increased to 150 mg after an interval of at least 2 days.Then, after an additional interval of at least 2 days, the dosage can be further increased to the recommended 300 mg.In all patients, the drug is administered orally once daily before bedtime and at least 2 h after eating.This dosing schedule was determined based on a previous study that examined the plasma drug concentration in 24 healthy non-elderly men receiving a single 50 mg dose of the study drug, either fasting or after eating a low-or high-fat meal; the concentration was generally higher after eating than after fasting. 12e gradual increase to a recommended dose of 300 mg/day was also established based on a phase-III non-Japanese trial reporting no clear advantage from increasing the dose beyond 300 mg/ day. 13In addition, a network meta-analysis found no significant difference in efficacy between a maximum dose of 600 mg/day (quetiapine immediate release group) and 300 mg/day (extended release); in addition, the 600 mg/day dose was poorly tolerated. 14 the present study, more than 90% of patients started the treatment at a dose of 50 mg/day; approximately half of them increased to 150 mg/day, and a quarter to 300 mg/day.None of the patients received a dose exceeding the recommended 300 mg/ day.Furthermore, the Japanese guidelines regarding concomitant therapies only weakly recommend the combination of secondgeneration antipsychotics and mood stabilizers or the combination of multiple mood stabilizers for patients with bipolar depressive episodes (overall evidence level: 2C); 8 less than 60% of patients were using these drug combinations.In total, 177 patients were using concomitant mood stabilizers and 60 concomitant antipsychotics, and the analysis of the study drug's efficacy in relation to concomitant use or not of each drug type revealed similar decreasing changes in the MADRS total score from baseline, regardless of the use of concomitant drugs, and no differences in the occurrence of ADRs.
These results demonstrate that the mean MADRS total score decreased from baseline in the efficacy analysis group, irrespective of maximum daily dose, diagnosis, and whether prior or concomitant pharmacotherapy was used.
The MADRS total score in the present study showed a mean change of −13.2 ± 12.7 between baseline (28.8 ± 11.1) and last evaluation.This improvement is comparable to the decrease seen in the Japanese phase-II/III clinical trials (CL-0021), 11 where the MADRS total score for the 300 mg/day group decreased by 12.6 ± 11.4 points between baseline (30.9 ± 6.9) and the last evaluation of the treatment phase I (week 8 6 ± 15.0 years (range: 16-85 years), and 31 (9.0%) were ≥ 65 years old.One-hundred patients (29.0%) had bipolar I disorder, and 245 patients (71.0%) had bipolar II disorder.The mean number of episodes within the previous 12 months was 1.5 ± 1.1 (range: 0-8), and the mean time since the onset of the first episode was 128.6 ± 109.7 months (range: 2-624 months).Prior pharmacotherapy for the treatment of bipolar disorder was administered to 197 patients (57.1%).The most common prior pharmacotherapies were lithium carbonate (n = 74, 21.4%), sodium valproate (n = 71, 20.6%), and aripiprazole (n = 39, 11.3%).

Figure 4 Figure 5
Figure4shows the differences in mean MADRAS total score changes from the baseline according to the maximum daily dose.The baseline MADRS total score was 28.6 ± 11.5 in the group of patients with the maximum daily dose of the study drug <300 mg, and 29.0 ± 10.2 in those with 300 mg; the change in score from baseline at the last evaluation for these groups was −12.4 ± 13.6 and −14.7 ± 11.0 points, respectively.
2 in patients who received prior pharmacotherapy with antipsychotics or not, respectively; the change in score from baseline at the last evaluation for these groups was −10.1 ± 9.8 and −14.1 ± 13.3 points, accordingly.The baseline MADRS total score was 26.7 ± 9.2 and 31.0 ± 12.4 in patients with and without prior pharmacotherapy with mood stabilizers, and the change from baseline at the last evaluation was −11.7 ± 11.2 and −14.8 ± 14.1 points, respectively.

Figure
Figure S2 shows the differences in mean MADRS total score change from baseline based on the use of pharmacotherapy (antipsychotics or mood stabilizers) or not prior to use of the study drug.
8 and −14.1 ± 13.0 points for these groups, respectively.The total score at baseline was 27.3 ± 9.5 and 30.5 ± 12.4 points in patients taking concomitant mood stabilizers or not, respectively, and the corresponding change in score at the last evaluation was −12.4 ± 11.5 and −14.3 ± 14.1 points.

2
Differences in MADRS total score changes from baseline to last evaluation.The score on the Montgomery-Åsberg Depression Rating Scale (MADRS) was assessed at baseline, and changes from the baseline were evaluated at Week 4, 8, 12, and last evaluation.The values are expressed as mean ± standard deviation.patient of suicidal ideation.Somnolence, the most frequent ADR, occurred in the first 7 days for half of the patients who experienced it, and mostly recovered within 28 days.

F I G U R E 3 F I G U R E 4
Changes in score from baseline for each item of the MADRS (mean).Due to large SD values, means are presented in the graph, while SD values are displayed in the table.The Montgomery-Åsberg Depression Rating Scale (MADRS) comprises 10 items.This figure illustrates the average change from baseline at Week 12-the last evaluation for each of the 10 items.Differences in score change from the baseline MADRS total score in relation to the maximum daily dose of the study drug.The maximum daily dose approved in Japan for quetiapine extended-release tablets is 300 mg.The score on the Montgomery-Åsberg Depression Rating Scale (MADRS) was calculated at baseline, and changes from the baseline were evaluated at Week 4, 8, 12, and at last evaluation.The values are expressed as mean ± standard deviation.in three patients, and "hyperglycemia, diabetic ketoacidosis, or diabetic coma," and "lipid metabolism disorder" were experienced by one patient each.

F I G U R E 5
Differences in score change from the baseline MADRS total score in relation to the diagnosis.The score on the Montgomery-Åsberg Depression Rating Scale (MADRS) was calculated at baseline, and changes from the baseline were evaluated at Week 4, 8, 12, and at last evaluation.The values are expressed as mean ± standard deviation.however, these findings seem to suggest that the improvements in MADRS total score from baseline are similar in clinical trials and real-world settings.This study was observational, and some limitations must be considered.The study was non-interventional and with no control group, based on reports provided by physicians, thus inconsistencies in the judgments by each doctor are possible.It was based on a 12-week follow-up period and did not investigate the long-term use.Also, the inclusion and exclusion criteria were not rigorous, and as a result the patient characteristics were diverse.Concomitant drugs were not restricted, and the impact of such drugs could not be completely eliminated.Last, the reports were recorded under real clinical conditions; therefore, clinical test results were not available for all patients.In conclusion, this post-marketing surveillance of the real-world safety and efficacy of Bipresso® extended-release tablets suggests that this drug is effective in patients experiencing depressive symptoms of bipolar disorder, and no new safety concerns or risks concerning ADRs emerged in the period considered.AUTH O R CO NTR I B UTI O N SAstellas Pharma Inc. (Tokyo, Japan) designed the original study, developed the protocol, and performed the data analysis of Bipresso® extended-release tablets.Mr. Irie, Mr. Aikawa, and Dr. Kishi wrote the manuscript.Dr. Iwata supervised the review.All authors were involved in the decision to submit this article for publication, contributed to the interpretation, reviewed the manuscript, and approved the final version.

2.3 | Efficacy and safety evaluation
The variables considered were sex, age, body mass index (BMI), diagnosis, and number of episodes in the previous 12 months, time since onset of the first episode, time since onset of the current depressive episode, presence or absence of complications (if present, the diagnosis), presence or absence of other diseases in the medical history (if present, the diagnosis), presence and extent of hepatic or renal impairment, administration status of the study drug (daily dose and frequency, date of first/last dose, changes in the administration route and their reason, termination, or discontinuation), prior pharmacotherapy for bipolar disorder, concomitant drugs, and concomitant therapies.For prior pharmacotherapy of bipolar disorder and concomitant drugs, the total was calculated for the antipsychotic drugs (olanzapine, aripiprazole, and risperidone) and mood

Factor Number of patients (%) Number of patients who experienced adverse drug reaction (%) Hypothesis testing
11| DISCUSS IONThe overall proportion of occurrence of ADRs in the present study was 111/345 patients (32.17%), lower than the proportion of 287/341 patients (84.16%) reported in a clinical trial11at the time of drug approval.The most common ADRs were somnolence, akathisia, dizziness, weight increase, thirst, hypersomnia, constipation, and nausea; these ADRs were also observed in the clinical trial mentioned above, and all were mild.The only serious ADR was one Note: (χ) chi-squared test, (F) Fisher's exact test, (C) Cochran-Armitage trend test.