ARIQUELI Study I: Should quetiapine monotherapy be considered for any acute presentation of bipolar disorder?

doi:10.21203/rs.3.rs-2484630/v1

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ARIQUELI Study I: Should quetiapine monotherapy be considered for any acute presentation of bipolar disorder?

https://doi.org/10.21203/rs.3.rs-2484630/v1

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Background: Bipolar disorder type I is a chronic disorder with a polymorphic and plastic presentation. Most clinical trials limit the evaluation of treatment to one of the poles of the acute phase. The ARIQUELI study aimed to evaluate the efficacy and tolerability of quetiapine monotherapy as a treatment for bipolar disorder overall, regardless of clinical presentation in the acute phase and in the maintenance phase.

Method: The ARIQUELI study was divided into two phases: Phase I, to investigate the treatment of bipolar disorder with quetiapine monotherapy, and Phase II, to compare two augmentation strategies in the treatment of quetiapine-refractory patients. Patients aged 18 to 40 years with type I bipolar disorder received quetiapine monotherapy between 300 to 800 mg for eight weeks regardless of clinical presentation. Responders were included in a maintenance phase of up to 22 months. The primary outcome was achievement and maintenance of response scores. Outcomes for Phase I were compared between the three clinical presentation groups in the acute phase (depression/mania/mixed).

Results: 105 patients were included, and although some differences in tolerability and depressive symptoms scores were observed, no difference between the groups was observed regarding primary outcome.

Conclusions: Quetiapine is equally effective in treating all forms of bipolar disorder I, with smaller differences in side effects and depressed patients showing a greater reduction in depressive symptoms.

Limitations: High prevalence of rapid cycling in the sample limits the comparison with other studies. Sample size was determined based on the results of the augmentation phase.

Bipolar Disorder

Quetiapine

Psychopharmacology

Rapid Cycling

Monotherapy

Treatment.

Bipolar Disorder is a chronic and recurrent disorder affecting 2.1% of the population in its typical and another 2.4% in subclinical forms, regardless of nationality, ethnicity, sociodemographic characteristics or gender [1].

The clinical presentation is usually polymorphic and unpredictable in course. It may manifest in depressive, manic or mixed episodes, often associated with comorbidities and of unpredictable duration [2].

It often shows a progressive evolution that, correlates with shorter intervals between episodes, poorer response to treatment, greater number of comorbidities, cognitive and functional impairment, and increased risk of suicide and hospitalization [3,4].

Although some treatments are well established and their indications are well-supported by guidelines, the choice of treatment depends largely on the stage of clinical presentation of the disease at the present time. Often, effective treatment in the acute phase of a disease is not sufficient to prevent the recurrence of further episodes in the same patient [5,6].

The need to readjust treatments for each phase makes it difficult to implement treatments in practice according to evidence-based guidelines, which ultimately reduces the overall effectiveness of treatment for the disease "as a whole" [7].

The ideal treatment for the disease would therefore be one that is effective as a monotherapy not only for all acute manifestations of the disease, but also for the prevention of each type of disease flare [8].

According to the main current guidelines, the atypical antipsychotic quetiapine is the only drug with a Level I evidence score in monotherapy for all phases of the disorder: Depression, Mania, and Maintenance [9,10].

The aim of the present study was to evaluate the efficacy and tolerability of quetiapine monotherapy as treatment for Bipolar Disorder overall, in each presentation of the acute phase and in the maintenance phase.

Design and Setting

ARIQUELI study was a randomized, blinded, parallel-group clinical trial to evaluate treatment strategies and potentiation of bipolar disorder [11]. Following the same rationale used previously by our group in other studies, ARIQUELI proposes to reevaluate a proven treatment strategy without considering the patient's clinical situation at baseline. In this way, the treatment strategy is evaluated by understanding bipolar disorder as a chronic, complex and multifaceted disease over time [12,13,14]

The study was also registered at ClinicalTrials.gov under identifier: NCT01710163 on 19/10/2012. Methodological details of all phases were presented in accordance with the Consolidated Standard from Reporting Trials 2010 Statement [15] and were previously published in research protocol article [11].

Eligibility

Patients with Bipolar Disorder type I according to DSM-IV-TR criteria [10], in any episode of illness with a minimum score of eight points Hamilton Depression Rating Scale (HAMD)[16] or ten points on the Young Mania Rating Scale (YMRS)[17] were included in the trial.

Patients with schizoaffective disorder, schizophrenia, intellectual disability, and unstable clinical illnesses were excluded.

Interventions

Patients started monotherapy with quetiapine, increasing from 100 to 300 mg within three days and adjusted between 300 and 800 mg according to clinical criteria, and were followed for eight weeks. Patients who responded to treatment entered into a maintenance phase where they were assessed monthly until two years. Patients who did not respond were enrolled in the phase II (potentiation) of the study, the results of which will be published in further article.

Outcomes

The primary endpoint was the number of patients who achieved response at week eight. The response criterion followed Hirschfeld's definition: response (reduction in severity by ≥ 50% with no worsening in the opposite pole); no response (reduction in symptom severity less then 50% or worsening the opposite pole)[18]; remission was defined as a score below eight points on the HAMD and also below ten points on the YMRS.

Secondary endpoint included a) sustained response in the maintenance phase, which was considered loss to target response score at least one visit; b) safety and tolerability, which were determined by the adverse rated using the UKU Scale [19].

Sample size and randomization

The sample size was calculated to reach the number of patients for the ARIQUELI Phase II (potentiation) comparing the mean difference in Clinical Global Impression Scale (CGI-BP-M) between baseline and endpoint for two treatment potentiation groups: Lithium and Aripiprazol [20]. Comparison with Student's t-test showed that a sample of 50 patients (25 in each group) reached a power of 80% (at a significance level of five percent) to detect a difference of 0.8 standard deviations, which is considered a large effect size [21]. Due to the naturalistic characteristic of the study, the calculation of the sample size did not considered the type of acute presentation of the disease. The randomization method used was the sealed envelope method for the selection of the type of treatment in the potentiation phase of the study. Phase I patient recruitment ceased when the phase II sample was reached.

ARIQUELI was a study with strong naturalistic study and all patients received the same treatment. The acute phase results are a post-hoc analysis of the augmentation study, therefore there was no randomization for Phase I.

Blinding was maintained so that the reviewer had no contact with the patient's medical record.

Statistical analysis

For Phase I, subjects were divided into three groups at the end of the study according to the type of episodes present at admission: depressive, manic/hypomanic or mixed.

The primary analysis involves the evaluation of the mean values of the CGI-BP-M between baseline and endpoint in three groups of episodes: Depressed, Manic/Hypomanic, and Mixed.

For some analyzes of categorical variables such as response and remission, the method of imputation of Last Observation Carried Forward data was used.

Exploratory data analysis included descriptive statistics, mean, median, standard deviation, minimum and maximum values for numeric variables and number and proportion for categorical variables. Descriptive statistics, the specific test for theoretical normality assumption Kolmogorov-Smirnov were used to analyze the behavior of continuous variables [22].

Comparison between two groups was performed using Pearson's chi-square test for categorical variables. To compare numerical variables between three groups, the ANOVA, Bonferroni's or Kruskall Wallis tests were used. For maintenance treatment relapse analysis Log Rank Test was used [22].

Statistical analysis was performed using IBM-SPSS Statistics version 27. P values of 0.05 were considered significant.

Recruitment

The ARIQUELI study was conducted between July 2012 and June 2020 at the mood disorders outpatient clinic of the Hospital das Clínicas of the University of São Paulo. Patients were enrolled until December 2019, when the planned sample size was reached, and followed up until June 2020. 130 screening candidates were evaluated, of which 105 were actually included. [Figure 1]

Characteristics of the sample

Patients were divided according to the stage of the illness, with the mania/hypomania group comprising 19 (18.3%) participants, the depressive episodes group comprising 59 participants (56.7%), and the mixed states group comprising 26 (25%). No differences were observed between episode types [Table1].

Table 1: Characteristics of the sample

	General	Mania	Depression	Mixed	p
Age, years, (IQR)	31 (18 - 39)	31 (20 – 39)	30 (20 – 39)	31 (18 – 39)	.411 ^a
Womens, n (%)	73 (69.5)	12 (63.2)	39 (66.1)	12 (81.5)	.285 ^b
Age of onset BD I, years	16 (4 – 33)	14.5 (5 – 24)	16 (4 – 33)	15 (6 – 33)	.253 ^a
Illness duration, years (SD)	13.79 ± 7.64	16.14 (5.82)	13.42 (8.12)	12.57 (7.66)	.417 ^a
CGI-BP-M-Mania (IQR)	4 (1 – 5)	4 (1 – 5)	2 (1 – 5)	4 (1 – 5)	<.001 a
CGI-BP-M-Depression (IQR)	3 (1 – 6)	2 (1 – 5)	4 (1 – 6)	4 (1 – 5)	.008 a
CGI-BP-M-Overall (IQR)	4 (1.13)	4 (1 – 6)	4 (2 – 6)	4 (1 – 5)	.449 ^a

Depressed patients had lower scores for mania than manic or mixed patients (p < .001), and manic patients had lower scores for depression than depressed and mixed patients (p=.008).

76 patients (78.4%) had at least one psychiatric comorbidity, with alcohol abuse or dependence (33%), specific phobia (32%), obsessive-compulsive disorder (32%), social phobia (29.9%), and panic disorder (27.8%) being the most common. Specific phobia (p=0.026), Post-traumatic stress disorder (p=.045) and Body dysmorphic disorder (p=0.039), were more common in the mixed episode group.

Efficacy

With respect to the primary endpoint, we found a response rate of 38.5%, and a remission rate of 33.3%. There was no difference between groups with different episodes (Table 2).

Table 2: Response and Remission rates

	General	Mania	Depression	Mixed	p
Response, n (%)	40 (38.5)	5 (27.8)	27 (45.8)	8 (19.2)	.214
Remission, n (%)	35 (33.3)	7 (36.8)	23 (39.0)	8 (21.0)	.164

We examined whether rapid cycle was associated with response or remission. We found no significance but we observed a trend (p=.062) in depressed patients with rapid cycling to not respond and a trend in depressed patients with rapid cycling to discontinue therapy (p=.074).

Study participants experienced a significant decrease in CGI-BP-M scores between the baseline and week eight, with the median score decreasing to two points for the mania and depression scores and to three points for the total illness CGI-BP-M scores. There was also a significant decrease in scores between the first visit and the last observed visit (LOCF), with a decrease of 7.49 (9.2 SD) for the HAMD (p < 0.001) and a decrease of 4.60 (8.5 SD) for the YMRS (< 0.001).

The reduction in scores between groups from baseline to week eight was evaluated. No differences were found in the YMRS scale (p=.102), but there was a difference between groups in HAMD (p=.010). Patients with depression showed a mean decrease of 9.76 (5.79 SD), while patients with mania showed a decrease of 3.70 (5.76 SD) and in the mixed state of 4.65 (9.24). Bonferroni's analysis showed a greater decrease in the group of patients with depression compared to patients with mania (p=.044) and patients in the mixed state (p=.046). Something similar was also observed in the CGI score.

No differences were observed between the groups in the CGI-BP-M total or CGI-BP-M mania assessment, but differences were observed between the groups in the CGI-BP-M assessment depression: the group of patients in depression showed a greater decrease than the group of patients in mania (p=.007) and although not significant, it showed a tendency to decrease compared to the group in mixed state (p=.075).

Dosage

The median quetiapine dosage was 300 mg at weeks one and two, 400 mg at week three, and 500 mg at weeks four, six, and eight.

No differences were noted between episode groups with regard to quetiapine dose at the last visit in the acute phase. However, a difference (p=0.29) was observed between groups at the second week, where the depressed group had a greater number of patients on doses below the median than the mania or mixed state groups.

Safety and Tolerability

During this follow-up period, the sample “as a whole” evolved with no significant differences (p=.090) in weight between baseline weight (median 72 kg) and end of the acute phase (median 74 kg). No differences were observed between the episode groups either.

Regarding dropout rates, a total of 26 participants (24.8%) left the study during the acute phase, with no statistical differences between episode groups. In terms of reasons, 40% of the sample discontinued treatment due to adverse effects, 28% due to worsening condition or failure to respond, 24% due to treatment abandonment or failure to follow up, and 8% due to withdrawal of consent. No differences were observed between reasons or between groups of episodes.

Differences between group effects of episode type were observed for the adverse effect asthenia, fatigue or tiredness (p=.042) and for the adverse effect memory difficulties (p=.041), which were observed more frequently in patients in a mixed state compared to depressed or manic patients and less frequently in patients with a manic episode compared to depressed and mixed patients; a difference was also observed for the adverse effects migraine (p=.002), tension headache (p=.047) and weight gain (p=.006), which occurred less frequently in the manic patients than in the mixed and depressed patients; and finally in the effects menorrhagia (p=.014) and urticarial erythema (p=.012), which occurred more frequently in the mixed group than in the depressed and manic patients.

Maintenance of monotherapy

The median sustained response was five months, with only three patients completing 22 months of maintenance therapy without loss of response or dropout and no difference was seen between groups (p=.616).

The dropout rate in the maintenance phase was 58.3% in a total of 14 patients. Loss of response requiring treatment improvement was observed in seven patients (29.2%) of the sample.

Although no change in weight was observed in the acute phase, a significant increase was observed between baseline study weight (median 72 kg) and the last observation in the maintenance phase (median 80 kg) (p=.014).

Efficacy

The groups were well separeted, as observed by the mean score on the CGI-BP-M: depressed patients had lower scores for mania than manic or mixed patients (p <.001), and manic patients had lower scores for depression than depressed and mixed patients (p=.008).

Analysis of the general characteristics confirms the high prevalence of psychiatric comorbidities in bipolar patients [1,23,24]. The group of patients with a mixed episode showed an increase with statistical significance regarding the identification of specific phobia (p=0.026), post-traumatic stress disorder (p=.045) and body dysmorphic disorder (p=0.039). The greater presence of comorbidities or anxiety symptoms in patients with mixed episodes has been previously observed by other authors and may be associated with greater refractorines and greater complexity of the disease [23,25].

The response and remission rates found in the ARIQUELI study of 38 and 35, respectively, were far below the rates observed in the literature. In the EMBOLDEN I study, a response rate of 68.6% was observed in type I bipolar patients with depression treated with 300 mg quetiapine [26].

Cookson et al., (2007), found a 58% response and 52% remission with quetiapine between 300 and 600 mg, for bipolar depression [27]. Li et al. (2007) found a 77.8% and McElroy et al. (2010) found 93% of response rate for mania using quetiapine [28,29].

Our response rates were closest to the results of studies in which quetiapine was used to treat bipolar disorder in children and adolescents. Such studies have demonstrated the ineffectiveness of quetiapine compared to placebo in treating this population [30].

Our response and remission rates may have been influenced by the severity of the sample. One fact that reinforces this perception is that 49% of the sample had rapid cycling. This is much higher than the 12 to 30% found in the general population of patients with Bipolar Disorder and also higher than in other studies that have examined quetiapine [31]. EMBOLDEN I study included only six percent of patients underwent rapid cycling [26]. It is known that these patients are more refractory and often require combinations with anticonvulsants to better control the condition [5,26,32].

Another factor that may have contributed to the low remission rate is methodological: because the ARIQUELI study proposed to treat bipolar disorder "as a whole, response and remission were defined as a 50% decrease in one of the scales without an increase in the scale of the opposite pole. This fact is not reflected in other clinical trials that sought to assess only the decrease in scores of one of the polarities [33,29].

Randomized trials show weight gain ranging from 0.92 kg (2.35%) to 1.02 kg (3.99%) [34] until a weight gain of 6.4% in patients taking 300 mg/day quetiapine and 9.4% in patients taking 600 mg/day [35], which is statistically significant compared to placebo, according to Young and colleagues [36]. In contrast to data found in the literature, no significant weight difference (p=.090) was observed between baseline (median of 72 kg) and week 8 (median of 74 kg). However, was observed difference between baseline and at the last visit of the maintenance phase (p=.040). No differences were observed between episode type groups.

In the present study, quetiapine adverse event rates were higher than in EMBOLDEN I [26], and closer to those of Kanba and colleagues [35], but the side effects with higher incidence, show similarities between the mentioned studies: drowsiness, fatigue, dry mouth.

Some adverse effects occurred less frequently in patients with mania than in patients with depression or mixed states, such as asthenia, weight gain, memory loss, and migraine. Other effects occurred more frequently in mixed than in depressed or manic patients, such as tension headache, menorrhagia, and erythema.

As an adverse effect, headache was among the most common quetiapine adverse effects in the studies EMBOLDEN I and II. The finding of a lower frequency of headache as adverse effect in mania is consistent with previous observations by Saunders (2014) who found a lower prevalence in patients with mania and a higher prevalence in mixed patients [37].

The lower prevalence of asthenia and weight loss observed in patients with mania can be explained by the increase in energy and activity, respectively, in manic patients.

We found no rationale in the literature for the observed differences in adverse effects in patients in the mixed state.

The median duration of response observed in the ARIQUELI study was five months. It confirms CHOICE study results, which showed an improvement in bipolar depression scores in patients taking quetiapine over the six months of the study, with a better response in the first eight weeks [38].

Weight gain and metabolic changes with long-term use of quetiapine have been demonstrated in several studies [39]. Young et al. (2013) showed a significant increase (> 7%) in body weight of 6.4%, 9.4%, and 4.0% in patients receiving 300, 600 mg, and placebo, respectively, with a median increase of 0.8 kg for the group receiving 600 mg and decreases of 0.1 and 0.6 kg for quetiapine 300 mg and placebo, respectively [36]. In our sample, although we did not observe weight gain in the acute phase, there was a significant weight gain at the last visit of the maintenance phase compared to the baseline of the study.

The data obtained from ARIQUELI suggest equivalent efficacy of quetiapine in achieving response and remission in any acute episode of bipolar disorder. Although there were no differences in the assessment of the primary outcome, depressed patients were more sensitive to the antidepressant therapeutic effect of quetiapine compared with manic or mixed states.

We also concluded that quetiapine was tolerated with little difference between presentations of the illness, with some adverse effects occurring less frequently in manic patients and some occurring more frequently in mixed patients.

We consider ARIQUELI study to be a pioneer in presenting response and adverse effects by episode of illness, as there are no studies comparing quetiapine in patients in the depressive, manic and mixed state.

Limitations
ARIQUELI study has methodological limitations. First, the sample was determined based on the results of the augmentation phase, which limits the analysis of the acute phase data, especially since the sample was divided into three different groups. The study was also designed with a naturalistic bias to more closely resemble the real patient sample. Thus, patients with psychiatric comorbidities and rapid cycling were included. Due to these characteristics, the sample was more severe and limits the comparison with other studies.

Ethics approval and consent to participate

Ethical approval for this study was obtained from the Hospital das Clínicas Ethical Committee, (CAPPESQ #26436) and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants prior to enrollment in the study.

Consent for publication

Not Applicable

Availability of data and material

The data that support the conclusions of this study are available upon request from the corresponding author. The data are not publicly available due to restrictions as they contain information that could compromise the privacy or consent of the research participants.

Competing interests

The authors have no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author’s contributions

Giovani Missio, and Ricardo Moreno conceived the idea and methodology of the study. Giovani Missio, Doris Moreno, Frederico Demetrio, Fernando Fernandes and Carla Garcia worked on data acquisition and data curation. Giovani Missio, Carla Garcia and Ana Castagna worked on the formal statistical analysis. Giovani Missio, Carla Garcia, Ana Castagna, Francine Melo Matos, Marco Moreira and Fernando Pimentel worked on writing, reviewing and editing the manuscript. Ricardo Moreno was responsible for project management and supervision.

Acknowledgements

The authors would like to thank, Diego Tavares, Adriana Carneiro, Daniele Bio and Ana Moreira for their contributions to the methodology and interpretation of the data results. This research was supported by the Institute of Psychiatry of the Clinical Hospital of the University of São Paulo, which provided the structure and drugs to conduct the study.

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No competing interests reported.

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