A head-to-head randomised controlled trial of aripiprazole versus quetiapine as augmenting agents in treatment-resistant depression :Alok V Kulkarni, Advances in Human Biology

ORIGINAL ARTICLE
Year : 2022 | Volume : 12 | Issue : 3 | Page : 307--311

A head-to-head randomised controlled trial of aripiprazole versus quetiapine as augmenting agents in treatment-resistant depression

Alok V Kulkarni
Department of Psychiatry, S S Institute of Medical Sciences, Davangere, Karnataka, India

Correspondence Address:
Dr. Alok V Kulkarni
Department of Psychiatry, S S Institute of Medical Sciences, Davangere, Karnataka
India

Abstract

Introduction: Almost 30%–50% of the patients with major depressive disorder can be categorised as treatment-resistant depression (TRD). The use of augmenting agents such as aripiprazole (ARI) and quetiapine (QP) to the existing antidepressant (AD) therapy could be a suitable alternative for treating TRD. The superiority of anyone over others is not established in short-term studies. Hence, the present study was performed to compare the safety and efficacy of ARI and QP for the treatment of TRD. Materials and Methods: In the present study, a total of 50 patients with TRD who showed insufficient response to at least two ADs for 12 weeks were enrolled. The participants were assigned randomly in a double-blind trial to receive ARI (10 mg/day; n = 25) or QP (300 mg/day; n = 25) in addition to their standard AD therapy for 12 weeks. Montgomery–Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions (CGI) scale were used to measure treatment efficacy. The safety was evaluated by recording treatment-caused adverse effects (AEF). Results: A significant decrease in MADRS score was observed with ARI groups than in the QP group (‒7.5; ‒4.6, P < 0.001). The CGI scores in the ARI group also exhibit significant improvement compared with the QP group. There was a non-significant change in CGI score recorded in both groups. The AEF was observed in 11% of patients with more incidences in the QP groups. The incidences of AEFs resulting in discontinuation of therapy were found low in both groups (ARI: 1.6%; QP: 3.2%). Conclusion: The findings of this study conclude that TRD patients can be more benefitted by ARI augmentation therapy than QP.

How to cite this article:
Kulkarni AV. A head-to-head randomised controlled trial of aripiprazole versus quetiapine as augmenting agents in treatment-resistant depression.Adv Hum Biol 2022;12:307-311

How to cite this URL:
Kulkarni AV. A head-to-head randomised controlled trial of aripiprazole versus quetiapine as augmenting agents in treatment-resistant depression. Adv Hum Biol [serial online] 2022 [cited 2023 Mar 31 ];12:307-311
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Full Text

Introduction

Major depressive disorder (MDD) is seriously damaging and demands efficient treatment to decrease symptoms and enhance the quality of life.[1] However, primary MDD treatment does not always attain a suitable response and is usually associated with a delay in the set of therapeutic efficacy.[2] Treatment-resistant depression (TRD) is usually defined as a failure to respond to two or more adequate trials of antidepressants (ADs) in the current episode and may appear in almost 50% of patients in medical practice.[3]

The alternative treatment strategy for TRD includes changing the drug regimen within or out of the present AD class, a combination of AD drugs, augmentation of the current AD drug with another agent and a combination of primary AD drug with psychotherapy.[4] In recent times, different augmentation combination therapies have been studied for the effective treatment of TRD. In particular antipsychotic drugs have frequently been used as an augmenting agent in clinical practice.[4],[5]

Aripiprazole (ARI) and quetiapine (QP) (extended-release QP) are approved by the United States Food and Drug Administration as an adjuvant to AD treatment in persons with MDD.[6] In a study by Bauer et al., 2009, in patients with MDD and an insufficient response to ≥1 AD, QP augmenting combination to AD treatment significantly improved the Montgomery–Åsberg Depression Rating Scale (MADRS) score compared to placebo within 1 week.[7] In addition, QP reported reduced MDD symptoms in patients with MDD and an insufficient response to AD treatment.[8] Various open-label studies earlier have been reported regarding the effectiveness of ARI augmentation combination therapy for treating TRD.[9]

Although several studies have reported the effectiveness of augmentation therapy ARI and QP for the treatment of TRD, their comparative effectiveness for the treatment of TRD is not reported until now. Hence, the present study was performed to find better-augmenting agents in TRD treatment out of the two antipsychotic drugs (ARI and QP). The study further aimed to determine the safety of the two drugs (ARI and QP) when used as augmenting agents in the treatment of TRD.

Materials and Methods

Study design

The present study was a multisite, 12-week, double-blind, parallel-group study for random assignment to an adjunctive ARI and QP added to their regular prescription for patients affected by MDD events that have failed to respond to a minimum of two AD therapies. The present study was performed in New Delhi, India. Participants were enrolled in the outpatient psychiatric department of the Institute of Human behaviour and Applied Sciences, Lady Hardinge Hospital, and Ram Manohar Lohia Hospital from October 2019 to March 2021. The study was carried out as per norms of good clinical practice and relevant regulatory requirements. The written informed consent was taken from all participating patients. The ongoing medications of all participants include escitalopram, fluoxetine, paroxetine, amitriptyline, nortriptyline, isocarboxazid, rasagiline, aptazapine, duloxetine, carbamazepine, olanzapine and psychotherapy.

Sample size

In the present study, a total of 50 participants were enrolled for the study and randomly assigned into two groups ARI (n = 25) and QP (n = 25).

Ethical aspect

The institutional ethical committee approval was taken from all respective centres before the commencement of the study (IHB/ETH/2021/23).

Inclusion criteria

Participants aged between 18 and 65 yearsCurrent Diagnostic and Statistical Manual-5 (DSM-5) diagnoses of MDDUndergoing AD therapy for at least 4 weeks before baselineThe present episode of depression has failed to respond with at least 2 AD therapies (one of which is present AD medication)The patient should be able to take oral medicationIn females, the patient should be willing to take sufficient contraceptive precautions and have monthly pregnancy testsPatients who were willing to give written consent for participation.

Exclusion criteria

Serious medical illness relating to renal, hepatic, cardiac and pulmonaryPrevious history of intolerance with ARI and QPAccompanying anticoagulant and penicillin therapyIncidence of seizures disorderChange in AD medication within previous 4 weeksThe presence of any substance use disorder except caffeine and nicotine within the past 3 months as per DSM-5 criteria.Patients with pregnancy and breastfeedingIncidences of primary psychotic disorder

The conditions of leaving the study were:

Participant requestAs per the discretion of the responsible medical officer or investigatorAny incidence of pregnancy.

Study procedure

The selected participants were randomly assigned to anyone treatment ARI (n = 25) or QP (n = 25) (in 1:1 ratio) on the 1st-day by utilising a computer-generated randomisation record and an interactive web response system. The treatment was performed through a double-blind 12-week trial, and the patient, staff and person performing the assessment were unaware of prescribed drugs that were encapsulated in an identical pack. The ARI was initiated at a dose of 5–10 mg/day and then increased by an increment of 5 mg weekly to a maximum of 25 mg by the 4th week, and this dose was kept constant until the end of the study. QP was titrated at 50 mg on the 1st day, 150 mg on the 3rd to 4th day and 300 mg from the 5th day until the end of the study. The dose titration of QP could be extended to 3 additional days provided a dose of 300 mg/day reached on the 8th day. If any participant faced a tolerability problem after this period, the dose could be decreased to 200 mg/day. No other antipsychotic drug or intervention was given during trials.

Efficacy assessment

The first efficacy assessment was the change in the MADRS score from randomisation to week 12.[10] Other assessment includes MADRS response and MADRS remission rate at week 12, patients with clinical global impression improvement (CGI-I) score[11] of 'much'/'very much' improved at week 12 and change in CGI-severity (CGI-S) total score at 12 weeks. MADRS total score from randomisation on day 4, day 8 and MADRS item 4 (quality of sleep) at week 12.

Safety assessment

Throughout the study, adverse events were tracked for frequency, severity and causality. Laboratory assessment comprises haematology and liver enzymes, creatinine, bilirubin, glucose and lipids were carried out during enrolment of patients and at the end of 12 weeks of the study. The vital sign and body weight were also noted during enrolment, randomisation, and at the end of 12 weeks of the study. A significant weight change (≥7%) was recorded. Clinically significant change in glucose and lipids were defined as glucose ≥126 mg/dl, cholesterol (total) ≥240 mg/dl, triglycerides ≥200 mg/dl, high-density lipoprotein (HDL) ≤40 mg/dl and low-density lipoprotein (LDL) ≥160 mg/dl.

Statistical analysis

The evaluation of MADRS total scores change from randomisation to week 12 was analysed by utilising the analysis of covariance (ANCOVA) model that comprises centre as a random effect, treatment group as a fixed effect and MADRS total score as a covariate. ANCOVA model also analysed other parameters such as CGI-I and CGI-S as primary variable without adjusting for multiplicity. The descriptive statistics were used to analyse the MDRAS remission rates at 12 weeks. MADRS response, remission rates and CGI-I scores at 12 weeks were analysed using logistic regression. All the statistical analyses of different efficacy variables were two-sided, with a significance value of ≤0.05%. Descriptive statistics carried out the analysis of safety variables.

Results

At the start of the study, a total of 68 suitable patients were screened. However, 10 participants did not fit the inclusion criteria, and eight patients decided not to participate. Therefore 50 remaining patients were randomised, with 25 in the ARI group and 25 in the QP group. There was no significant difference in baseline demographic characteristics between the two group participants, including age and sex [Table 1]. All the enrolled participants completed the study. In the present study, during the 12-week trial, no change in AD therapy was made in both groups (ARI and QP groups).{Table 1}

The clinical results of both groups of patients at baseline and after the 12-week study are given in [Table 2]. The MADRS response rates (≥50% decrease in MADRS total score from randomisation to week 12) were statistically significant (P < 0.05) between the two groups, 56.8% for ARI and 51.7% for QP groups. The MADRS remission rates (MADRS total score of ≤10 at week 12) were 30.7% for ARI and 24.8% for the QP group showing statistically significant differences between the two groups (P < 0.05).{Table 2}

At the end of the study (12 weeks), the mean change in CGI-I score from randomisation was reported.

1.85 for the ARI group and‒1.43 for the QP group. The portion of patients reported to be 'much'/'very much' improved by the investigator was 67.5% for ARI augmentation therapy, whereas it was reported to be 60.4% for QP augmentation therapy. In addition, with respect to CGI-S, an insignificant change was observed by ARI (3.61–3.12) and QP (3.19–3.08), although ARI indicated a better response.

The quality of sleep evaluated by Montgomery–Åsberg Depression Rating Scale (MDRS) item 4 (less sleep) was found to be improved in both augmentation groups ‒2.15 for the ARI group and ‒1.09 for the QP group (P < 0.05).

The total AEF observed during the 12-week trial study was 68% and 60% in the augmentation therapy of ARI and QP, respectively. Most of the AFE reported were mild to moderate in severity. The common AEF reported (occurrence >5% in any group) during the study is given in [Table 3]. In the present study, two patients reported serious AEF in the ARI augmentation group, whereas four patients were observed with serious AEF in the QP augmentation group. Patients who discontinued treatment due to AEF were 3 (12%) (two due to somnolence and one dizziness) in the ARI group and 5 (20%) (one due to somnolence, two due to sedation and two by diarrhoea) in the QP group.{Table 3}

At the end of 12 weeks of the study, a number of patients observed with ≥7% increase in weight from randomisation were 7.3% and 8.5% in the augmentation therapy of ARI and QP, respectively. The number of patients with potentially significant changes to higher fasting glucose levels (≥126 mg/dl) was less in the ARI group (1.6%) than in the QP group (3.2%). In addition, other important laboratory assessments were high triglycerides (≥200 mg/dl) reported at 8.2% in the ARI group and 8.8% in the QP group, total cholesterol (≥240 mg/dl) reported at 9.8% in the ARI group and 10.7% in QP group, HDL (≤40 mg/dl) was recorded 7.2% in ARI group and 10.2% in QP group and LDL (≥160 mg/dl) was recorded 10.8% in ARI group and 6.8% in QP group. No clinically significant changes in regular haematology evaluation were reported.

Discussion

The present study investigated comparative evaluation augmentation therapy of ARI and QP in TRD patients. The findings in this study suggest that ARI augmentation would provide better treatment than QP augmentation for patients suffering from TRD. The augmentation therapy ARI was statistically significantly better than QP augmentation based on MADRS total scores at 12 weeks and various other important secondary parameters. The response rate of ARI (56.8%) was significantly >QP (51.7%). The early symptoms improvement (from day 5) with ARI was consistently reported throughout the study in a patient with TRD. This finding in our study is similar to various earlier reported studies.[12],[13] Berman et al. 2009 reported that ARI augmentation therapy to conventional AD treatment in patients who exhibited an inadequate response to at least two AD treatments was superior to adjunctive placebo for change in MADRS from baseline in three consecutive trials.[14]

The augmentation therapy of ARI was observed with significantly higher remission rates than QP augmentation from week 3 onwards. At the end of the study, there was a 1.23 fold more possibility of remission with ARI augmentation than with QP augmentation. The finding of this study is consistent with various earlier small-scale studies on ARI augmentation.[15]

There was a non-significant difference in CGI-I and CGI-S scores between the two groups of ARI and QP. These results in our study are comparable to the study reported by Safati et al., 2015.[16]

The poor quality of sleep is the main symptom of MDD, and relief from sleep disturbance might be an important parameter for total remission of MDD. In the present study, ARI augmentation therapy showed a more beneficial effect on sleep than QP augmentation therapy at the end of 12 weeks.

The ARI was usually well tolerated in TRD patients, and these findings were in accordance with the known safety profile of ARI. The observation of treatment discontinuation due to AEF was reported more with QP than ARI. This observation is similar to earlier reported studies.[17]

The augmentation therapy of both ARI and QP is associated with an increase in weight ≥7%, but it was more observed with QP augmentation therapy (12%) than ARI therapy (8%). Furthermore, potentially relevant changes to elevated values of total cholesterol, triglycerides and HDL-cholesterol were observed more with QP adjuvant therapy than ARI therapy. However, more patients showed higher values of LDL-cholesterol in ARI adjuvant therapy than in QP add-on therapy. The present study was a 12-week study, but MDD is a chronic ailment; hence it has become more important to consider long-term tolerability data, especially metabolic and haematologic data. ARI tolerability has previously been studied in a 6-week trial which reported a tolerability profile similar to our study.[5],[18] In addition, ARI significantly reduces the risk of depression in a patient with MDD as compared to placebo.[18] When choosing the treatment of MDD patients, it is advisable to maintain a balance between tolerability and efficacy.

The important strength of the present study is a relatively long period of trial of 12 weeks. Most of the reported studies are from 3 weeks to 6 weeks which have the inherent drawback of improper evaluation of treatment because MDD is a chronic disease hence a long-term treatment could be given a better picture of treatment.

Conclusion

The present multicentred, randomised, double-blind results concluded that augmentation therapy of ARI is superior to augmentation therapy of QP in the treatment of TRD. The results suggested that ARI is an essential augmentation option for the treatment of TRD. The early improvement of depression symptoms was observed with ARI and efficacy; safety was similar to the reported safety profile of both drugs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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