Evaluation of Comparative Efficacy of Brahmi vs. Haritaki Extract in the Management of Academic Stress in Adolescent Students- A Prakriti based Double-blind Randomized Controlled Trial

Introduction: Prevalence of mental illnesses among adolescents was found 7.3% (N=1191) by NMHS survey 2015-16 whereas the national crime record bureau in 2014 stated 1.8% of students committed suicide due to failure in their exams. The root cause, that is academic stress is often ignored which occurred due to various stressors like physical, mental, family, school, relationship, and social factors of which School factor (56.7%) and academic tests (45.6%) hold maximum association. Proper management can be provided with Ayurveda by Prakriti wise (exploring one physical, physiological and psychological factors) analysis of stress and their coping up strength and effect, when assisted with oral intakes of Ayurveda drugs like Brahmi and Haritaki along with Sattvavajaya Chikitsa having Achar Rasayana, Surya Namaskar, Dharna, and Dhyana practices. Aim and Objectives: The aim is to evaluate the comparative efficacy of Brahmi extract with Study Protocol Pandey et al.; JPRI, 33(48A): 159-169, 2021; Article no.JPRI.76197 160 Sattvavajaya Chikitsa over the effect of Haritaki extract with Sattvavajaya Chikitsa in the management of Academic Stress among adolescent students of different Prakriti. Material and Methods: A double-blind reference standard controlled stratified randomized superiority clinical trial is planned. The sample size of 198 participants with 13% dropout consideration will be enrolled after analysis of their Prakriti and stress level between 5-25 according to the SAAS scale. Total 6 subgroups (3 each for trial drug group and 3 for standard control) will have Vata, Pitta, and Kapha Doshic (V, P & K) dominant Prakriti participants of 10 to 17years of age. Total 33 participants in each subgroup will have the interventions for 90 days. Observation and Results: Participants will be assessed for changes in salivary cortisol, level of academic stress, IQ, and memory before and after the trial. The standard descriptive and inferential statistical measures will be used to assess the effect of interventions. Conclusion: Prakriti analysis will help stressed adolescents to know their strengths and interventions provided will be expected to help a stressed one to minimize stress level and also assist in developing their stress-coping mechanism.


INTRODUCTION
The adolescent stage is the stage of various mental and physical transformations in a developing body and a derangement can lead to developing a variety of related disorders. In an Indian study, adolescents feeling Academic Stress (AS) were 2.4 times more at risk for depression than those without it. [1] Furthermore, according to the National Mental Health Survey (NMHS) in India 2015-16, the prevalence of mental morbidity among adolescents was found as 7.3% (n=1191). [2] Among which anxiety disorder (3.6%), mood disorder (2.3%), and suicidal tendency (1.4%) are the commonest ones. Suicide is the third leading cause among reasons of death in adolescents and the national crime record bureau in 2014 stated that 1.8% of students committed suicide to failure in their exams. [3][4] That's why an early understanding of stressors and their proper coping mechanism should be developed in adolescents [3]. According to a survey of various factors like physical, mental, family, school, relationship, and social factors work as the source of a stressor for an adolescent of which school factors (56.7%), and academic tests (45.6%) are responsible for maximum. [3] Excess of homework, poor Academic Performance (AP), exam preparation, less concentration in some subjects, and teachers' punishments are the possible reasons for AS [3][4].
Ayurveda, with safe and effective anti-stress medicines along with Sattvavajaya Chikitsa (SC), holds an upper hand in the treatment of mental disorders [5]. Ayurveda believes that mental disorders occur due to the malfunctioning of Sattva (Manas or Chitta) and vitiation of Raja and Tama Mansika Doshas and advocates SC for their management [6]. ManoNighrah (~control of mental wishes) is the basic concept of SC [6][7][8]. Proper counseling, Achar Rasayana (AR~Ayurved code of conduct), Surya Namaskar (SN~sun salutation), Dharana(~concentration), and Dhyana(~meditation) are ways to control various mental wishes [9][10][11]. Further, Prakriti is a unique concept of Ayurveda that shows the Doshik predominance of Vata, Pitta, and Kapha (V, P& K) Dosha prevailing among seven physical constituents. The concept of Prakriti provides a person with his self-identity, understanding of his abilities, his susceptibility to various disorders, and his response to their treatment [12]. These features will help an adolescent to construct a strong mental, physical immunity towards multi-factorial stressors and provide a way to build up their coping up mechanism. This study plans to evaluate the effect of Ayurveda medicines with SC among students suffering from AS with various Prakriti and their Prakriti wise susceptibility toward AS and its management response.
AS is defined as "the body's response to academic-related demands that exceed capabilities of students." [13]. AS presents with psychological symptoms first and later converts them into psychosomatic if not properly managed. In Ayurveda, Chittodvega deals with the psychological part of stress, whereas Ojah Kshaya is a somatic part and joins this if Chittodvega is not treated properly. Chitta is also known as Manas or Satva. [7,[14][15][16] Chittodvega is a condition related to vitiation of Sharirika Doshas (~V, P &K) along with Mansika Dosha (Rajas and Tama) due to Prajnaparadha (~unwholesome activities) and Asatmendriya Samyoga (~primarily abnormal perception of senses). [7] Ojah Kshaya occurs due to untreated Chittodvega symptoms like Shoka (~grief), Dhyana (~wory), and Kopa (~anger) present somatic symptoms like Sandhi Vishlesh (~looseness of joint), Gatrasadana (~weakness of body), Stabhdh Gurugatrata (~stiffness and feeling of heaviness in the body), Glani, Tandra, Nidra (~exhaustion, stupor, and more sleep), Vibheti (~fearful) symptoms, and Abhikshan (~always worried) are the symptoms which are very close to the presentation of stress [14][15]. Stress symptoms like feeling of uncontrollability, weakness, and loss of weight are near to Vyathitendr eeya (~discomfort in the sense organs), Durbal (~debility), Ruksha (~dryness), and Durmana (~mental disturbance) symptoms of Ojah Kshaya [14][15].. property which helps in managing above symptoms and combating AS [16][17]. Ayurveda believes in the principle of Purusham Purusham Veekshya (~every person is different from others in its physical constitution and mental temperament) [18]. Prakriti's concept follows this principle. The Sanskrit prefix "Pra" means original and "Kriti" means "creation" [19]. Thus the meaning of Prakriti comes out as the time of "original creation" hence; both the drugs will be quantified for their effect in various Prakriti.

Recent Researches and Evidence on Research Drugs
Control drug Brahmi (Bacopa monnieri Linn.) has an established adaptogenic and anti-depressant effect. [20] It is effective in improving mood, attention, and memory in children [20]. Similarly, it is studied for changes in cognitive functions in Indian school children and found to have positive results [21][22]. Brahmi has alkaloid Brahmine, nicotine, and herpestine as their chemical constituent.
[24] So, this drug will be studied as a reference standard control for the research drug Haritaki.
Haritkaki extract will be evaluated for its action in the management of AS. Acharya Charaka has kept Haritaki among Vyasthapana drugs, which signifies the drug establishes longevity and helps in rejuvenation. [25] Furthermore, study drug Haritaki holds a finer position,being helpful in V, P &K vitiated conditions. [26] In Ojah Kshaya various conditions like Glani (~guilt) are related to a Vata nanatmaj Vikara (~Vata vitiated symptom). [27] Gurugatrata, Tandra, Nidra related to Kapha nanatmaj Vikara (~Kapha vitiated symptom). [27] Bhaya(~Fear), Krodha(~Anger), and Moha (~bewilderment) are the conditions related to vitiated Pitta dosha which make a favorable situation for Haritaki to act properly as it is a Tridosh Shamak drug. [26,28] Aqueous extract of Haritaki is found to have a good anxiolytic and antidepressant activity when evaluated against standard drug diazepam and imipramine respectively [29][30]. Tanin rich extract of Haritaki resulted in downregulation of serum cortisol level and maintained the level of 5HT and dopamine in the blood presenting anxiolytic activity [31]. Phytoconstituents found in Haritaki have a good therapeutic effect with no toxicity [32]. It constitutes Chebulic acid, chebulinic acid, and Corilagin as the main constituent [33].

Research Gap Analysis
Observational and cross-sectional studies present various stress factors which are responsible as stressors source for adolescents of which school factors having AP, and selfexpectation are major contributors of AS among adolescents [1,3]. This increases the risk 2.4 times to develop depression [1]. Our Indian education system lacks cope up strategies for different stressors among students. The present study will let a stressed student to identify his anatomical, physiological and psychological capacity by Prakriti analysis and which help him to recognize his stressors and develop a coping up mechanism with help of SC and antistress Ayurveda Drug [34][35][36][37][38]. Participants will be assessed before and after intervention by the SAAS scale covering cognitive, affective, physical, social, and interpersonal factors related to stress [13]. Previous Ayurveda studies on stress present the close association of Prakriti in developing stress. Mentioned works are either observational and if interventional, then with less sample size, single-blind, without objective assessment, or performed on adult and elderly populations [12,[39][40]. Present work involves the most vulnerable age group of adolescents, with an objective assessment of salivary cortisol, with optimum sample size, double blind-study, and with new research drug Haritaki for as and standard control drug Brahmi. One of the previous Ayurveda works shows the beneficial effect of Panchkarma on AS [41]. Panchkarma is an effective therapy but requires multiple hospital visits to show its effect, which is not possible for a student. Antianxiolytic allopathic medicines like Diazepam and Imipramine have the side effects of addiction, drowsiness, dizziness, and tiredness which are not associated with Ayurveda drugs like Brahmi and Haritaki [17][18].
Haritaki was evaluated for the anxiolytic and antidepressant property, but some researchers mention it as anxiolytic-like and antidepressantlike properties. This gap will be evaluated in the present study [29][30]42]. Most of the antistress research for Haritaki was performed in experimental animal models; the present study will evaluate the antistress potential of the drug in humans [27][28][29]38]. Ayurveda texts say Haritaki has Vayasthapni and Smriti Prada property according to Charka while Rasayan, Brihan, Medhya, and Buddhi Prada by Madanpal Nighantu. Having best-suited properties to relieve AS, this drug is still not researched in this field and so will be studied as a trial drug [16].

Study Design
A randomized reference standard control doubleblind superiority clinical trial. 2 groups will be made, for control and research drug separately, each group is subdivided into three different groups (total six subgroups, 3 for each standard control and research drug) with different Doshic Prakriti dominance (V, P & K).

Participant
Adolescent students of 10-17 years (covering early and middle stages of adolescence, according to WHO) with either Prakriti studying in C.B.S.E. Board schools suffering from AS.

Sources of Data and Place
C.B.S.E. Board schools nearby Mahatma Gandhi Ayurved College, Hospital and research center, Salod, Wardha.

Duration of Study
The duration of the study will be 24 months, of which 8 months for drug preparation, 10 months for survey and recruitment of sample, and drug administration, and 6 months for manuscript writing.

Inclusion Criteria
 Students whose parents are willing to participate and sign written informed consent for the research trial.  Adolescent students of 10 to 17 years age comprise an equal number of girls and boys of the CBSE board.  Students whose score ranges 5-25 for stress on the SAAS scale.  Students with Vata Pitta and Kapha dominant Dwandaj Prakriti suffering from AS to be enrolled in stratified sampling.

Exclusion Criteria
 Students suffering from chronic diseases and taking medicines for the disease.  Students suffering from diagnosed serious mental diseases and taking medicines.  Students with physical disabilities and with congenital anomalies.  Students with an IQ below 70 will be excluded from the study.  Students who are taking corticosteroids for any illness or any other reason.

Sample Size
168 participants-84 in each group. The sample size is calculated according to the effect size from the previous study [43]. Total 6 six subgroups will have 28 patients each, a 12% dropout rate increases 33 participants and will be recruited for each subgroup, which makes the total sample size of 198.

Setting
The study will be conducted on adolescent students of either sex with age group 10 to 17 years studying in C.B.S.E. Board schools nearby Mahatma Gandhi Ayurved College, Hospital and research center, Salod, Wardha [44]. After identification of students suffering from AS, they will be assessed for their Prakriti and will be randomly allocated by stratified sampling method to the 2 different groups having their total 6 subgroups.
Each subgroup will have a minimum of 33 participants, 3 groups with V, P & K Doshic dominant Prakriti will receive standard control Brahmi and the other three will receive research drug Haritaki for 90 days continuously by oral route. Both the groups will practice Sattvavajaya Chikitsa as adjuvant therapy. Initially, a general counseling session will be performed to teach AR, SN, Dharana, and Dhyana. Later they will be instructed to practice these procedures at home daily for 15 minutes just after a bath with being empty stomach. They will also be instructed to follow general instructions, counseling, and AR, as explained in the initial session. Like this total of 198 students will be assessed for drug effects in the management of AS. Detailed explanation in a schematic timeline is explained in the consort diagram in Fig. 1.

Primary outcome
Change in the salivary cortisol level and scoring of the SAAS scale.

Secondary outcome
Change in IQ and memory scoring and variability of all scores in different Prakriti pre and post-intervention.

Randomization
Stratified randomization will be done to have an equal number of subjects in each group. Total 6 strata will be made each 3 of standard control and research group will represent V, P & K Doshic dominant Prakriti. Randomization will be done by using the table of random numbering by computer-based randomization software.

Allotment concealment
Double blinding will be done with a regular change of code by using an opaque envelope.

Source of procurement of interventions and authentication
 Crude drug and research material will be procured from approved sources.  The Physical identity of the raw drugs to be used in the research trial will be verified by the Dravyaguna dept of MGACH & RC.  Analytical lab under Dattatraya Rasashala will verify the constituents of prepared drugs and raw drugs.  The standard control group with 3 subgroups of dominant Prakriti (Subgroup A, B, C having Vata, Pitta, and Kapha Prakriti dominant participants, respectively).  Subgroup A, B, and C will be given Brahmi extract (dose of 250 mg), twice a day having aqueous (water) extract solidified and filled in capsules followed by drinking plain water.  Trial drug group with 3 subgroups of dominant Prakriti (Subgroup D, E, F having Vata, Pitta, and Kapha Prakriti dominant participants respectively).  Group D, E, and F will be given Haritaki extract (dose of 250 mg), twice a day having aqueous (water) extract solidified and filled in capsules, followed by drinking plain water.  SC will be performed by the practice of SN, Dharana, and Dhyana 15 minutes per day. AR, will be told in general counseling and asked to follow regularly and will be enquired on every follow-up.  The whole management plan will be administered regularly for 90 days.  Achar Rasayana (~AR)-It is the general code of conduct as explained in Charak Chikitsa Sthana and will be used as a method to redevelop conduct. This will be explained to students during general counseling and asked to follow the same till the end of the trial [45][46].  Surya Namaskar (~SN)-This is also known as sun salutation has 12 Asanas in it. Students will be asked to practice 12 sets of SN daily. This has to be performed in 8 minutes [10].  Dharana-After SN the participant will be asked to relax and concentrate on one thing which he wished to do. This has to be performed for 2 minutes after SN [11].  Dhyana-In Continuation of Dharana, Dhyana will be practiced for 5 minutes.
Here all the thoughts get away and participants meditate freely [11].

Monitoring
It will be done by making daily attendance, video calls, and organizing group meetings on online meeting platforms like zoom and google meet.

Survey
A survey of adolescent students of 10-17 years studying in C.B.S.E. Board schools will be performed to identify students suffering from AS.

Survey questionnaire
 The scale of SAAS to identify sufferers of AS before treatment. It is a 30 item selfreporting tool with a total score of 30 showing maximum stress and 0 lowest or no stress [13,48]. It covers cognitive, affective, physical, social, and interpersonal factors related to stress [13,48].  Those who are positive with SAAS inclusion criteria will be analyzed for Prakriti. Prakriti assessment will be performed by the "Prakriti Vichaya" module of AyuSoft software of the center for the development of advanced computing (C-DAC). It covers the anatomical, physiological, and psychological prospects of a person. [34][35]  IQ, memory will be analyzed after Prakriti analysis by Draw a Man test and PGI memory scale, respectively [49][50].

Data Management
Data will be managed in tables of excel sheets properly titled for record and variables.

Adverse drug events
 All the adverse events will be recorded and their relation to the study drug will be seen.  All the recorded information and other severity will be immediately notified to the study monitor.  Periodical reporting of the study will be furnished to the ethical committee.

Discontinuation criteria
• Parents of the student not willing to complete the study • Development of any acute or chronic illness during treatment. • Development of any untoward effect by the use of drug administered for the study.

Anticipated translatory component of research
 This Prakriti-based study is anticipated to show a pathway of self-recognition to an adolescent.  This research will produce an extended opinion about the management of vulnerable Prakriti towards academic stress and their safe and effective management.
 Self-recognition will help adolescents to develop a self-management plan to cope with various stressors according to their capacity.  The study will provide a physical and mental management pathway with the help of Sattvavajaya Chikitsa and antistress Ayurveda drugs to combat various psychosomatic symptoms of stress.  This study will help in designing a holistic program having Sattvavajaya Chikitsa and other interventions for preventing mental illnesses among adolescents.

Limitations
The study will evaluate the combined effect of control and study drug along with adjuvant Sattvavajaya Chikitsa in various Prakriti but not the sole effect of both the drugs, in the future sole effect of the drug should be evaluated and compared with the effect of Sattvavajaya Chikitsa.
The study highlights the efficacy of ancient Ayurveda concept in the light of modern medical science and can be publicize if found efficacious.

CONCLUSION
AS occurs due to various stressors and Prakriti analysis will assess a stressed adolescent with different aspects to know their strength.
Interventions provided will be expected to help a stressed one to minimize their stress levels and that will be assessed on standard objective and subjective criteria. Interventions provided will also be expected to assist stressed adolescents to develop their stress coping mechanisms at the end of the trial.

CONSENT
As per international standard or university standard, patients' written consent has been collected and preserved by the author(s).