Introduction

Major depressive disorder (MDD) is one of the the most common psychiatric illnesses and a leading cause of disease burden worldwide. The United States National Institutes of Mental Health Epidemiologic Catchment Area study and the National Psychiatric Morbidity Surveys of Great Britain suggested the current rate of major depression affecting 2–5% of the population and the lifetime rate of as high as 10 to 20 per 100 people in developed countries.1 2 As a result, depression is now the third most common disorder, which contribute to the global disease burden as depression causes functional deterioration, and a large number of patients may end up committing suicide.3 It was estimated that by 2030, depression will become the the most common disorder contributing to global disease burden.4

There are several factors related to the occurrence and severity of depression. Other than depression, anxiety disorders are also prevalent among the global population. It is also common for depression to be presented comorbidly with anxiety disorders. The most common comorbid anxiety disorder, which occurred with depression, is generalised anxiety disorder, while the least common comorbid anxiety disorder is specific anxiety disorder.5–7 Comorbid depression and anxiety disorders may lead to several negative outcomes, such as increased psychosocial disability, decreased psychosocial functioning, reduced quality of life (QoL) and even increased suicide rate, compared with the occurrence of depression or anxiety disorder alone.8 9

QoL is the perception of one’s position in life in the context of the culture and values of the community one lives in and in relation to standards, goals, concerns and expectations.10 The QoL may have a bidirectional relationship with depression. Patients with depressive disorders have been reported to exhibit reduced QoL in all domains (physical health, psychological, social relationship and environmental-related QoL), while longer duration of depression was associated with lowering of three domains of QoL (physical health, social relationship and environmental-related QoL).11 On the other hand, a higher degree of QoL in all domains also predicted lower odds of depression.12

Although depression is mainly diagnosed and monitored clinically, there are several biomarkers, which have been identified as a significant mechanism for monitoring the treatment progress. Brain-derived neurotrophic factor (BDNF) modulates the synaptic plasticity of the neuronal pathway, which is involved in regulating the depressive behaviour.13 14 Studies have reported that the BDNF level in the brain decreases in the presence of MDD and the BDNF level may be restored with antidepressant treatment.15 In addition, vascular endothelial growth factor (VEGF) may have a role as a biomarker of depressive disorders.16 The serum VEGF level was found to be increased in depressed patients compared with that of control subjects in 16 studies. Finally, C-reactive protein (CRP) may also be a potential biomarker for depression. Studies have shown that elevated serum CRP indicates poor response to psychological treatment (such as cognitive behavioural therapy (CBT) or interpersonal therapy) but good response to antidepressant, such as fluoxetine or nortriptyline.17–20

Experiential avoidance (EA) is any attempts made to avoid thoughts, feelings, physical sensations, memories and other internal experiences. EA may maintain the negative reinforcement of a behaviour, wherein avoidance of any internal experiences reduces the discomfort that one’s felt; hence, it enhances the likelihood that the avoidance behaviour is prolonged. However, it is now believed that depressive disorders occurred due to habitual and unwillingness to experience uncomfortable thoughts and feelings as well as the avoidance and inhibition of these experiences, rather than caused by negative thoughts, feelings and sensations.21 Studies have shown that EA could be an important factor contributing to depression in patients with mental disorders.22 Similarly, EA appears to be an important predictor of MDD and generalised anxiety disorder symptomology, potentially serving as a treatment target for psychosocial intervention. There is a possible trait-like nature for EA, perhaps increasing the risk for the emergence and persistence of MDD and/or GAD.23

Acceptance and commitment therapy (ACT) is a third-generation cognitive behavioural approach, which attempts to enhance the psychological flexibility of the client by using acceptance and mindfulness techniques as well as commitment and behavioural change processes. ACT emphasises coaching of clients to focus on behaviours or actions that align towards the achievement of personal values, which the client care about most in their life.24 25 ACT targets self-defeating thoughts and emotions (internal barriers) by focusing onto working towards personal values, which foster development and maintenance of self-management of positive health behaviours.26 ACT has been reported to reduce depression by decreasing cognitive defusion and increasing personal value-based action.27 28

In addition to psychotherapy, another non-pharmacological intervention with reported efficacy to ameliorate the severity of depression is exercise, which include physical exercise and exergame. Exergame differs from physical exercise as it exhibited various motivational features, such as visual and audio performance feedback, which makes it more enjoyable and interesting to play. It not only improves motivation, physical fitness and cognitive function, but it also induces antidepressant effects similar to physical exercise.29 30 Bourbeau et al (2020) conducted a systematic review and meta-analysis on eight studies evaluating the effect of combined physical exercise and behavioural therapy on patients with depression and anxiety and reported that moderate-intensity exercise combined with behavioural therapy had significant effect size to reduce depressive symptoms, while increasing age moderated the above association.31

Depression has not been effectively treated with antidepressants and psychotherapy as studies documented that patients with depression exhibited substantial reduction in severity of symptoms while on antidepressant, only if additional psychosocial interventions are prescribed. It has been estimated that 10% to 30% of depression patients do not respond to antidepressant medication,32 while a larger study, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, revealed that 50% to 66% of depression patients did not recover fully on antidepressant medications.33 Hence, novel treatment strategies are needed to enhance the efficacy of treatment for depression. A recent study on prescribing moderate-intensity exercise immediately before CBT sessions (ActiveCBT) suggested plausible efficacy of ActiveCBT to decrease the severity of depressive symptoms among patients with depression. Hence, exercise priming of psychotherapy may enhance the effect of the psychotherapy programme in the treatment of depression.34 It would be interesting to compare how the combined Wii exergame-ACT (e-ACT) programme fare against its active comparator (such as ACT alone) in the treatment of MDD. Therefore, we have proposed a three-armed RCT to evaluate these effects over time compared with a control group receiving treatment-as-usual (TAU). The conceptual framework of the study is illustrated in figure 1.

Figure 1

Conceptual framework of the study.

Methods and analysisStudy design and setting

This RCT is multicenter, three-armed, parallel-group, double-blinded. This RCT is expected to run for a duration of 3 years to be conducted in the Psychiatric Outpatient Clinic in Advanced Medical and Dental Institute, Universiti Sains Malaysia (AMDI, USM) and Psychiatric Outpatient clinic and Inpatient wards in the Department of Psychiatry, Hospital Universiti Sains Malaysia (HUSM). AMDI, USM is a tertiary referral centre in which its psychiatry outpatient clinic has approximately 200 registered psychiatric patients in the northern region of Peninsular Malaysia. HUSM is a tertiary referral centre in the northeast region of Peninsular Malaysia, with the Department of Psychiatry comprising approximately 500 to 700 registered psychiatric patients.

Sample size

The sample size was determined based on G-Power 3.1.9.2 sample size calculator for repeated measures, between-within interaction analysis of variance (ANOVA). The sample size was calculated based on a previous three-group parallel RCT, which compared the efficacy of aerobic exercise plus antidepressants, placebo exercise plus antidepressants and antidepressants alone conducted by Legrand and Neff (2016), where the effect size was 0.18,35 with alpha error of 0.05 and two-tailed. The results indicated that a total sample size of 99 participants for three equal-sized groups is needed to achieve a power of 0.95, with three groups and three measurements. In anticipation of a drop-out rate of 30%, the final sample size estimated was at 126 participants. Therefore, 42 participants were needed for each group.

Recruitment of subjects

This study’s participants will be recruited from the source population. The source population includes all patients diagnosed with MDD and registered in AMDI, USM and Department of Psychiatry, HUSM. These patients will be approached by the research team and explained on the study objectives and procedures. Advertisement to participate in the study will be posted in the two recruitment centres and honorarium to compensate for participants travel expenses to the research sites will be provided. Those who are interested to participate in the study will be screened for inclusion and exclusion criteria.

The inclusion criteria include:

Patient diagnosed with MDD (confirmed by Diagnostic and Statistical Manual for Mental Disorder fifth Edition [DSM-V]).

Those with score of more than eight based on Hamilton Depression Rating Scale (HAM-D).

Age 18 to 60 years old.

Those on a stable medication regimen for at least the past 8 weeks and willing to maintain current treatments throughout the study.

The exclusion criteria are:

Pregnant women.

Those who have current and lifetime history of engaging in any psychotherapy.

Those who consumed alcohol and illicit drugs (heavy or mild).

Those who has current and lifetime history of other psychiatric illnesses, such as other depressive disorders (persistent depressive disorder, premenstrual dysphoric disorder), anxiety disorder affecting major functioning (generalised anxiety disorder), psychotic disorders (schizophrenia, schizophreniform disorder, schizoaffective disorders, brief psychotic disorder and delusional disorder), bipolar mood disorder, obsessive compulsive disorder, posttraumatic stress disorder, attention deficit hyperactive disorder and autism spectrum disorder.

Those who are on medications that can induce psychiatric symptoms, such as cardiovascular agents (clonidine, guanethidine, methyldopa, reserpine and beta-blockers), dermatologic agents (isotretinoin), anticonvulsants (levetiracetam), antimigraine medications (triptans), hormonal agents (corticosteroids, oral contraceptives, gonadotropin-releasing hormone agonists and tamoxifen), varenicline, immunological agents (interferons) and levodopa.

Patients with suicidal tendency.

All eligible patients (those with all inclusion criteria without any exclusion criteria) will be invited to participate in this study. The study’s purposes and procedures will be thoroughly explained (verbal explanation by the research assistant and a copy of the participant information will also be distributed) to prospective participants before they are invited to participate in this study, their anonymity will be assured and they will be informed of their right to withdraw from the study at any time and the data collected will be discarded. Eligible patients will be given 48 hours to decide on their participation in the study. Then, participants will sign written informed consent to participate in the study before they enrol in the study.

Randomisation

This study will use stratified permuted block randomisation, stratifying trial participants according to their age (18 to 40, 41 to 60 and over 60 years old) and gender (male and female). Participants will be randomised into three groups: an e-ACT programme group, an ACT-only group and a control group of patients on TAU. Using a 1:1:1 allocation ratio and block randomisation, the participants will be randomly assigned to the three groups. An allocation sequence will be generated via computer-generated random numbers, which will be obtained by a research assistant who is not otherwise involved in this study. The allocation sequence will be concealed in an opaque, sequentially numbered envelope.

Intervention

An 8 week psychosocial intervention will be administered to participants in each intervention group (e-ACT and ACT), while participants in the control group will receive TAU. The study’s outcomes will be assessed at three time points: pre-intervention (t0), immediately after the 8 week intervention (t1) and 24 weeks after the intervention (t2). Both the e-ACT and ACT interventions will comprise eight sessions delivered at a rate of one session per week.

(e-ACT) training program

In the e-ACT training programme, participants will perform a 30 min per session Nintendo-programme on TV for 3 days per week and a 50 min ACT session per week for 8 weeks, which will take place in the psychology labs of AMDI, USM. The ACT session will be held after 30 min break following the completion of the final exergame session of the week. Hence, the total duration of each weekly e-ACT training session will be approximately 2 hours. In addition, each weekly e-ACT training session will be held at the same time (± 2 hours) and at the same venue. Home assignments for participants in the form of behavioural practices and experiments for ACT will be distributed at the end of each session, wherein participants are provided with workbook on ACT based on a book entitled ‘Get out of your mind and into your life’ by Hayes et al (2005) and ‘ACT made simple’ by Harris (2009).36 37 The module for e-ACT is summarised in online supplemental data 1.

ACT

As for the ACT intervention, each ACT session will run for 50 min, one session per week for 8 weeks. Each weekly ACT session will be held at the same time (± 2 hours) and at the same venue (in the psychology lab). Home assignments for participants in the form of behavioural practices and experiments for ACT will be distributed at the end of each session, wherein participants are provided with the workbook on ACT based on a book entitled ‘Get out of your mind and into your life’ by Hayes et al. (2005) and ‘ACT made simple’ by Harris (2009).36 37 The module for e-ACT is summarised in online supplemental data 2.

TAU control group

The participants in the control group will receive TAU in which non-specific contents of the psychotherapeutic approach will be administered, such as psychological understanding to the management of an individual patient, identifying current problems and providing opportunities for disclosure, reassurance and deep breathing exercise. They will be given equal amount of time and attention from the professional figure compared with the intervention groups, whereby they will be attached to an eight-session programme (with one session per week for 8 weeks). Each weekly TAU session will be held at the same time (± 2 hours) and at the same venue (in the psychology lab).

Treatment fidelity

The ACT will be conducted for the e-ACT and ACT intervention groups by four therapists trained in ACT, whereby two therapists in charge of one intervention group. These four therapists are selected from postgraduate students in psychology who are not otherwise involved in the study. All the therapists have at least 2-year experience of conducting psychotherapy. They will also receive training manual detailing the psychotherapy sessions for e-ACT and ACT, and they will also undergo 2 full days of brief training workshop for ACT conducted by the principal investigator. As for monitoring the treatment integrity, a psychiatrist and a clinical psychologist, both trained in ACT will measure the delivery of the interventions by all the therapists independently. 15% of audio-recording of the psychotherapy sessions will be randomly selected and stratified according to therapists and the phase of intervention (early, middle or end) and then, treatment integrity assessments will be performed by using: (1) the Drexel University CT/ACT Therapist Adherence and (2) Competence Rating Scale for the selected ACT session recording.38 Each treatment integrity assessor will assess half of the selected sessions, and then the inter-rater reliability between the two treatment integrity assessors is computed to assess the treatment integrity of all therapists in delivering the interventions.39 Any therapist who is inconsistent in delivering the ACT sessions will discuss this issue with the principal investigator to solve any shortcomings during interventions.

Blinding

Participants will be kept unaware of the study’s randomisation into the designated groups, conducted by a research assistant who is not otherwise involved in the study and concealed in an opaque, sequentially numbered envelope. Therefore, participants will not know which group they are allocated to. In addition, the intervention groups (e-ACT or ACT) as well as the TAU control group will receive an eight-session programme (with one session per week for 8 weeks) and participants in the TAU group will also receive equal amount of attention and time from the professional figure who administer the programme.

The researchers will also be ‘blinded’ for the study since the participants’ randomised assignment into the designated groups will be conducted by a research assistant who is not otherwise involved in the study or data analysis. This project’s data collection will also be conducted by that research assistant who is not otherwise involved in the study or data analysis and who is unaware of the study’s hypotheses. Moreover, the project’s data analysis will be conducted by statisticians who are not otherwise involved in the study. A statistical analysis plan is established before the final unblinding of the data lock. Unblinding of researchers will occurred if there is any serious adverse effects related to the interventions prescribe in the study.

Measures

Figure 2 is a flowchart summarising this study’s procedures and outcome measures. The scheduled assessment of the study’s outcome measures is illustrated in table 1. Data collection will be conducted every weekday during working hours, and flyers announcing the study and the benefits of participating in this study will be disseminated to all patients at the study’s focal institutions to ensure adequate subject enrolment to achieve the calculated sample size. This clinical trial protocol was written according to the ‘Standard Protocol Items: Recommendations for Intervention Trials 2013’. Before the interventions began (t0), the participants will be administered the sociodemographic and clinical characteristics questionnaire, Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Acceptance and Action Questionnaire-II (AAQ-II) and WHO QoL Questionnaire-BREF (WHOQOL-BREF). Blood samples will also be collected from all participants to evaluate for the serum levels of BDNF, VEGF and CRP (biomarkers for depression). Then, immediately after the end of the interventions at 8 weeks (t1), assessments with HAM-D, HAM-A, AAQ-II and WHOQOL-BREF are repeated for all participants, and blood samples are collected for biomarker analysis. Finally, 24 weeks after the completion of the interventions (t2), the questionnaire assessment is repeated for all participants, and blood samples are collected for biomarker analysis.

Figure 2

The flow diagram of the study procedures and outcome measures. e-ACT, Wii-exergames-acceptance and commitment therapy training programme; ACT, acceptance and commitment therapy; HAMD, Hamilton Depression Rating Scale; AAQ-II, Acceptance and Action Questionnaire-II; HAMA, Hamilton Anxiety Rating Scale; DSM-V, Diagnostic and Statistical Manual for Mental Disorders fifth edition; WHOQoL BREF, WHO Health Organisation Quality of Life-BREF questionnaire; T0, pre-intervention assessment; T1, immediately post-intervention at 8 weeks; T2, 24 weeks post-intervention.

Table 1

Scheduled assessment of the randomised control trial’s outcome measures

To ensure participants’ attendance of the follow-up assessments and intervention sessions, an appointment card is provided to each participant. Emails and phone messages reminding participants regarding their follow-up appointment will be sent 3 days before the appointment date, and a phone call to the participant a day before appointment if they did not reply to emails or messages.

Sociodemographic and clinical characteristics

The sociodemographic characteristics, which will be recorded from each participant, include age, gender, ethnicity, marital status, education and employment status, while the clinical characteristics, which will be gathered from the participants, are duration of MDD, symptoms of depression, history of comorbid anxiety disorders, medication history, family history of depression and other psychiatric disorders.

Primary outcome (severity of depressive symptoms)

Hamilton Rating Scale for Depression (HAM-D)

The HAM-D measures depression in individuals before, during and after treatment. The HAM-D is an observer administered instrument. The scale contains 21 items but is scored based on the first 17 items, which are measured either on 5-point or 3-point scales. Scores of 0–7 are considered being normal, 8–16 suggest mild depression, 17–23 moderate depression and >24 are indicative of severe depression with a maximum score of 52. Studies on the psychometric properties of the HAMD indicated that it has adequate internal consistency where in most studies, its Cronbach’s α was >0.7. It also exhibited good convergent and discriminant validities.40

Secondary outcomesQoL

World Health Organization Quality of Life Questionnaire BREF (WHOQOL-BREF)

The WHOQOL-BREF is a self-administered tool which is use in this study to assess quality of life of the subjects. The tool consists of 26 items, whereby the first two items measure general quality of life (QOL), while the rest of the items are designated into four quality of life domains, such as physical health related-QOL, psychological related-QOL, social relationship related-QOL, and environmental related-QOL. Each domain of the WHOQOL-BREF is scored separately and as a 100-point score. The WHOQOL-BREF exhibits good psychometric properties and it is a reliable replacement for the WHOQOL-100 instrument for measuring QOL.41 The WHOQOL-BREF was translated into Malay and validated with good internal consistency with a Cronbach’s α of 0.89.42

Severity of anxiety symptoms

Hamilton Rating Scale for Anxiety (HAM-A)

The HAM-A measures anxiety in individuals before, during and after treatment. The HAM-A is an observer administered instrument. HAM-A consists of 14 items which assess psychological distress, mental agitation and anxiety-related physical symptoms. Each item is scored in a Likert scale, which ranges from 0 = ‘symptoms not present’ to 4 = ‘very severe symptoms’. Hence, the total score of the HAM-A ranges from 0 to 56. A total score of <17 denotes mild anxiety, 18 to 24 indicates mild to moderate anxiety, 25 to 30 demonstrates moderate to severe anxiety and>30 denotes severe anxiety.43 HAM-A exhibited good psychometric properties and widely use for assessment of severity of anxiety symptoms in clinical and research settings.43 44

EA

Acceptance and Action Questionnaire-II (AAQ-II)

The Malay version of the ‘Acceptance and Action Questionnaire’ (AAQ-II) will be used to measure the degree of EA or psychological inflexibility among participants. The AAQ-II is the questionnaire’s second version, revised from the original version and is shorter (seven items) while offering better psychometric consistency. Participants’ AAQ-II score will be calculated by summing up the questionnaire’s seven items. A higher score indicates a higher level of psychological inflexibility.45 Validation of the Malay version of the AAQ-II indicated that the tool has excellent internal consistency with a Cronbach’s alpha of 0.91, and it has been found to be a unidimensional scale that measures psychological inflexibility or EA.46

Other measures

All the participants are requested to fill in online dairies regarding their performance of home assignments and behavioural practices at home to record their compliance to the interventions. Any reasons for the absence from therapy sessions and dropouts to follow-up will be documented such as a lack of interest to engage in intervention, disruption due to the symptoms and signs of depression, suicidal tendency or death.

Blood analyses

Serum samples will be analysed for the concentration of proteins such as BDNF, VEGF and CRP by commercial enzyme-linked immunoabsorbent assay kit following manufacturer’s instructions. Samples may need to be diluted with appropriate amounts of buffer provided in the kit to give constant dilutions before analyses. A standard curve will be constructed, and the concentration of samples will be read against the standard curve and expressed as concentration per unit of the samples. The modulation of these immunological parameters will also be determined using gene expression analyses using real-time PCR.

Data analysis

All of this study’s data analysis will be conducted using the Statistical Package for Social Sciences, version 26 (SPSS 26; SPSS Inc., Chicago, Illinois, USA). Initially, the baseline sociodemographic and clinical characteristics will be presented according to the randomised groups (e-ACT, ACT and control groups).

The mean difference in the primary outcome (HAM-D score) for the three randomised groups (ACT, MBSR and control groups) at each specific time point (pre-intervention [t0], post-treatment at 8 weeks [t1] and 24 weeks after intervention [t2]) will be assessed using one-way ANOVA followed by false discovery rate adjustment.

For the main pool analysis, a 3×3 mixed factorial ANOVA is used to determine the interaction between the groups (e-ACT, ACT and control groups) and time points (t0, t1, and t2) on the primary outcome (HAM-D score; interaction=intervention × time, where time points are a within-subject factor and intervention groups are a between-subject factor). The main effects of interaction between the intervention groups and time points will be presented as estimated marginal mean and SE of mean. The study’s primary analysis will follow the intention-to-treat principle. The data analysis for the study’s secondary outcomes (QoL, severity of anxiety symptoms, EA and biological markers) will be conducted similarly to the primary outcome analysis. Statistical significance will be two-tailed and set at p<0.05.

As for the management of missing data, if the missing data represents less than 5% of the study’s total data collected, it will be ignored. If the missing data represents more than 5% but less than 40% of the total data collected and is assumed to be randomly missing, then multiple imputation (restricted maximum likelihood estimation) will be performed using Stata 15. However, if the missing data represents more than 40% of the total data collected or is assumed to be missing either not randomly or completely randomly, then only the collected data will be used for the study’s analysis, and the missing data will be explained as a research limitation in any publications of the study’s findings.47

Data availability

Anonymised individual data will be made available after publication of the study’s findings (data such as sociodemographic and clinical characteristics, HAM-D, HAM-A, AAQ-II and WHOQOL-BREF scores and biological markers serum levels (BDNF, VEGF and CRP). The data will be uploaded in Figshare data repository after completion of the study.

Patient and public involvement

There will be no patients and public involvement in the design, conduct and reporting of the study. However, the study findings will be disseminated to the study participants on request after completion of the study.

ETHICS AND DISSEMINATION

Approval of this study was obtained from the Human Research Ethics Committee of Universiti Sains Malaysia and will be conducted in compliance with the Declaration of Helsinki 1964 and its subsequent amendments, and the Malaysian Good Clinical Practice guideline. If there is further modification of the content of this research protocol, such as its inclusion and exclusion criteria, study procedures, interventions, outcome measures and data analysis, changes will be informed to the institutional review board in writing. In addition, a trial monitoring committee will be formed, which is led by the principal investigator and given the responsibility to monitor the day-to-day conduct of the study and will meet once a week, involved in an audit of the trial and prepare reports to be submitted to the institutional human research ethics committee. The trial’s data will be monitored and the trial audit will be conducted by the clinical trial coordination unit of AMDI, USM, which is independent of the trial funder.

All participants will be informed that the data collected will be used for research purposes and will not be recorded in the medical or personal file of the participants. All the personal identifiable information of the participants will not be used, as only the group data will be presented and their anonymity will be assured. All participants will be assigned research number for identification purposes, such as RT0001, RT0002, etc. All documents use in the study to assess the participants which contain personal information, such as sociodemographic and clinical characteristics, symptomatology, substance or alcohol history, and any responses to rating scale or measuring instruments will be stored in document files and/or thumb drive. These data will be locked in a secured cabinet or laptop in which only the principal investigator and co-investigators have access to. Duplicated data will be checked and omitted. The data collected will be stored for 2 years after completion of the study before it will be completely discarded. The findings of the study will be published in academic peer-reviewed journals and presented in conference and/or symposia. The principal investigator will be listed as the corresponding author and the eligibility of the co-investigator for authorship will be determined according to the International Committee of Medical Journal Editors’ recommendations.

All the participants will be issued a study card containing contact numbers and address of the researchers, and participants are encouraged to contact the researchers and report any adverse effects (AE). AE should be reported to the principal investigator (PI) within 3 days and to the funder 7 days after reporting to the PI. If a serious AE is reported in a participant or more, an interim analysis will be conducted to investigate the AEs. Interim analysis will be carried out by the Clinical Trial Coordination unit of Advanced Medical and Dental Institute, Universiti Sains Malaysia. If the AE is found to have safety concern related to the study intervention, then the Trial Monitoring Committee will take action to terminate the study prematurely. The indication for premature termination of AE include life-threatening self-harm, suicidal tendency and hospitalisation due to the psychological AE related to the study intervention. Post-trial referral to the nearest treatment facility will be arranged for the treatment of participants who presented with serious AE and compensation will be considered.