Research on treatment-related aspects of depression from India in the preceding decade (2014–2023): An updated systematic review

Abstract

Background:

The National Mental Health Survey reports a prevalence of 2.7% for depressive disorders in India. The services for depression patients may be organized differently in India as compared to Western countries. It is important to consider studies conducted in India to determine effective interventions for depression catered specifically to the needs of the Indian population. We intended to systematically review the articles studying the usefulness of various treatment modalities in the management of depression in the Indian context.

Materials and Methods:

We searched PubMed, Google Scholar, and ScienceDirect to identify studies published in peer-reviewed English language journals. All articles from India evaluating the clinical efficacy of anti-depressants, electro-convulsive therapy, repetitive transcranial magnetic stimulation, and psychological interventions for the management of depression were evaluated. Data were extracted using standard procedures.

Results:

A total of 36 studies were included in the review. Out of those, 15 were studies on drug efficacy, five on neuro-modulation, nine on psycho-social interventions, four on adverse effects, and three on miscellaneous studies. Innovations were seen in the field of neuro-modulation and psycho-social intervention. Trials on drug efficacy and adverse drug reactions require larger sample sizes, more studies on newer agents, and more robust study designs.

Conclusion:

More research is needed to understand the effectiveness and potential negative effects of depression treatments in India. Studies on ketamine have been inconclusive, and existing research on pharmacological agents is limited. Neuro-modulation studies show promise, but larger-scale studies are needed. Innovative psychological interventions tailored to the Indian population include community-based and digital technology-driven care.

INTRODUCTION

It has been predicted by the World Health Organization that by 2030, depression will become the primary cause of the global burden of diseases, surpassing all other health conditions.[1] With over 350 million people affected, depression is becoming an increasingly prevalent global epidemic.[2] The National Mental Health Survey reports a prevalence of 2.7% for depressive disorders in India.[3] Suicide is also a significant concern when it comes to depression and is currently the leading cause of death among youths in India.[4]

Despite multiple available therapeutic modalities for depression, pharmacotherapy remains the most effective. Treatment-resistant depression (TRD) poses a significant clinical, personal, and economic burden. About a third of patients with major depressive disorder, however, do not respond to pharmacotherapy or psychotherapy.[5] For patients with treatment-resistant depression, non-invasive brain stimulation techniques are an emerging option.[6]

Depression can present itself differently based on a person's ethnicity and region.[7] It stands to reason that these distinctions should lead to varying choices in treatment that prove both successful and suitable.[8] When treating Major Depressive Disorder (MDD), the American Psychiatry Association recommends a treatment plan that may involve medication, therapy, and somatic therapies like electro-convulsive therapy (ECT), trans-magnetic stimulation, or light therapy. Among these options, anti-depressant medication is the most commonly used and widely accepted form of treatment.[9]

Around 50 years ago, tricyclic anti-depressants (TCAs) and monoamine oxidase inhibitors (MAO-I) were developed. However, the discovery of selective serotonin reuptake inhibitors (SSRI) was a groundbreaking advancement in treating depression and remains the greatest achievement to date. The implementation of SSRIs significantly reduced suicide rates among adults and adolescents, though they were not without negative side effects, such as initial gastric discomfort, increased sleep, and sexual complications. The primary drawback of SSRIs is their delayed time to take effect.

It is common for there to be a delay of around 2 weeks between the start of treatment with anti-depressant drugs and the onset of their clinical anti-depressant effects, particularly with SSRIs. This delay is a major drawback of these drugs. It is believed to be caused by the time it takes for somatodendritic 5HT1A receptors to down-regulate. Although SSRIs are thought to work by increasing 5-HT concentration in the synapse, their initial effect is to turn off 5-HT neuronal firing due to increased concentration of 5-HT at presynaptic 5-HT1A auto-receptors.[10,11]

This is somewhat compounded by the fact that faster-acting modalities such as ECT are limited by negative attitudes toward the treatment, cognitive adverse effects, and geographical variations in its availability, among other factors. There is a need for alternate treatments that are as effective as ECT and with better adverse effect profiles. In this context, ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, is gaining credibility as a relatively safe, effective, and rapidly acting anti-depressant. During the past 10 years, several randomized clinical trials (RCTs) have compared the efficacy of ketamine and ECT in patients with MDD.[12]

For patients with treatment-resistant depression, non-invasive brain stimulation via techniques such as repetitive transcranial magnetic stimulation (rTMS) is an emerging option.[6] rTMS uses powerful, focused magnetic field pulses to induce durable changes in the activity of brain regions that are affected by major depressive disorder.[13,14] Large-scale multi-center trials and meta-analyses over the past 20 years have confirmed the efficacy and safety of rTMS of the left dorsolateral prefrontal cortex in treatment-resistant depression (TRD).[15,16,17] However, adoption of this treatment has been slow, partly due to high cost and low capacity. The conventional, FDA-approved protocol requires 37·5 min of 10 Hz stimulation per session.[16] Long session lengths restrict treatment capacity and increase the cost per session. Reduced session lengths could therefore improve the accessibility and cost-effectiveness of rTMS.

A newer form of rTMS called theta burst stimulation (TBS) has been developed.[17,18] Unlike 10 Hz stimulation, TBS mimics endogenous theta rhythms, which can improve induction of synaptic long-term potentiation.[18] One form of TBS, intermittent TBS (iTBS), delivers 600 pulses in just 3 min yet shows similar or more potent excitatory effects than conventional 10 Hz stimulation.[19] The THREE-D trial has demonstrated that in patients with TRD, iTBS is non-inferior to rTMS.[20]

Pharmacogenomic data also dictate that the genetic makeup of different racial groups varies, which can affect the pharmacokinetics and pharmacodynamics of medications.[21] As pharmacogenetics advances, it is important to understand how medications work in the Indian context. Recent studies on major depressive disorder (MDD) have focused on specific candidate genes and the mechanisms of action of anti-depressant drugs.[22] Drug response variations are complex and may involve fundamental aspects of human biology as drug response directly impacts well-being and survival.[23,24] Patients' perspectives on treatment may also differ based on cultural and regional differences.

It should be noted that most research on depression treatment has been conducted in Western countries. However, the services for depression patients may be organized differently in India, making the results of Western studies not entirely applicable. It has even been pointed out that not a single skill in psychiatry is a mandatory part of licensing to become a doctor under the undergraduate competency-based medical curriculum.[25] In India, doctors at primary health centers, which are essential for providing healthcare services, face limitations in managing common mental health issues like depression. This hinders their ability to provide effective treatment. Therefore, to tackle this situation, we need to explore all possible solutions to fight against depression. Patients' perspectives on the necessary type of treatment may also vary. Therefore, it is important to consider studies conducted in India to determine effective interventions for depression. This updated systematic review was conducted to assess the articles studying the usefulness of various treatment modalities in the management of depression in the Indian context.

METHODOLOGY

Search strategy

Electronic searches for published trials were carried out using PubMed, ScienceDirect, and Google Scholar search engines. Additionally, the website of the Indian Journal of Psychiatry (IJP) was used to search for studies published in IJP. The keywords “treatment”, “therapy”, “antidepressant” (names of individual antidepressants), “neuromodulation”, “rTMS”, “ECT”, and “depression” were used in various combinations. The multiple searches carried out in September 2023 yielded 11,232 titles. The studies were manually selected to be in the Indian context based on journal names or authors' affiliations on PubMed. On Google Scholar, the advanced search feature was used to specify the source as India. On ScienceDirect, author affiliation was specified as India to filter down studies carried out in India or on the Indian population. The databases included in the study were MEDLINE, PubMed Central, and the Elsevier database. Studies that are part of other databases but accessible via Google Scholar were also included. Unpublished work was not sought as a part of this review as till recently, there was no registry for recording all the drug trials in India. Hence, it is not possible to assess all the unpublished data.

Study selection

Studies published in peer-reviewed English language journals were included. The selection criteria for inclusion of various studies into this review were original articles, clinical research, and controlled trials conducted in India on the treatment of depression since 2010 and the diagnosis of depression made in accordance with any nosological system, including through the clinician's interview. Studies evaluating the anti-depressants in animal models and those evaluating the efficacy/effectiveness of anti-depressants in other conditions like enuresis, anxiety disorders, and sexual dysfunction were excluded. Recently, India has been a hub for evaluating the efficacy and tolerability of various newer anti-depressants. However, multi-national trials were excluded from the analysis if the Indian data were not analyzed separately. All studies were screened and selected by the three reviewers independently, with a high degree of concordance.

Data extraction

All the abstracts were reviewed by three investigators independently. After initial evaluation, 46 abstracts were selected for further evaluation. Full texts of all these articles were searched. There was a high degree of concordance between the evaluators of the studies. A total of 36 articles were identified after the review of the data. Any lack of concurrence was resolved by mutual consensus.

RESULTS

The research on depression treatment in India was found to encompass a wide variety of subjects ranging from drug efficacy to biomarkers and prescription patterns. A total of 11,892 studies were initially identified, out of which 2211 records were screened. A further 2165 studies were excluded after screening for being animal model studies or studies not on depression, among other reasons as shown in Figure 1. A total of 36 studies were included in the review. Of these, 15 were studies on the efficacy of drugs. The drugs assessed along with the study design and outcomes are elaborated in Table 1. Most of the studies were open-label studies. The most commonly assessed drug was Escitalopram. Among the newer drugs, Vilazodone was studied by three different researchers in varying study designs.[26,27,28,29] Two studies were carried out on the effects of ketamine on depression as well.[30,31] The drug trials conducted in India all had considerable sample sizes. The studies comparing different classes of anti-depressants failed to find significant improvements in efficacy with SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) over TCAs.[26,27,28,32,33,34,35,36]

Figure 1.

PRISMA flowchart

Table 1.

Studies on anti-depressant/drug efficacy in India

Authors	Drugs	Study Design	Outcome
Sandanapitchai V, et al.[32]	Amitriptyline vs Fluoxetine	Open label (n=80)	Both were found to be equally efficacious in the treatment of depression.
Bagewadi HG and Huded CB[33]	SSRI, SNRI, and TCA	Observational, cross-sectional study (n=200)	Similar efficacy of all three drug classes at 3 months and 6 months of treatment
Tafseer S, et al.[37]	Bupropion	Open label (n=30)	Significant reduction in HAM-D scores on bupropion monotherapy, with a significant increase in BDNF levels and a decrease in TNF-α levels at 12 weeks of treatment.
Bhat MDA and Ahmad H[38]	Nardostachys jatamansi (D.Don)	Randomized, double-blind, placebo-controlled trial (n=40)	Statistically significant reduction in HAM-D scores in patients of post-stroke depression in the active group. No significant reduction in the control group.
Ghosh R., et al.[34]	Fluoxetine and Desvenlafaxine	Randomized, open label (n=60)	Significant reduction in HAM-D scores and a significant increase in BDNF levels in both groups.
Kumar PNS, et al.[39]	Glucosamine	Pilot, open-label study (n=20)	HAM-D response in only 20% of patients and remission in only 10%.
Chittaranjan A, et al.[26]	Mainly desvenlafaxine, vilazodone, and escitalopram, among others	Naturalistic, investigator-initiated, open-label study (n=900)	MADRS response was seen in 66.1% of patients at 6 weeks of treatment. MADRS remission was recorded in 36.7% of patients at 6 weeks of treatment.
Iyer SS, et al.[40]	Flupentixol 0.5mg + Melitracen 10mg and Escitalopram + clonazepam	Randomized, double-blind, double-dummy, parallel-group, clinical phase IV trial (n=440)	Yet to be reported
Chilukuri H, et al.[30]	Ketamine IV infusion (0.5mg/kg) vs. IM administration (0.5mg/kg and 0.25mg/kg)	Randomized, open-label, parallel-group study (n=27)	Two hours after the injection, HAM-D fell by 58.86% (IV group), 60.29% (0.5mg/kg IM group), and 57.36% (0.25mg/kg IM group) in each group. The improvement was sustained for the next 3 days. Adverse effects noticed were rare and of mild nature and transient, lasting less than an hour.
Thakurta RG, et al.[31]	Ketamine infusion IV (0.5 mg/kg)	Prospective, open-label, single-arm pilot study (n=27)	The ketamine infusion was effective in reducing the SSI and HAM-D scores; the change remained significant from minutes 40 to 230 but was relatively ill-sustained, with score change not being statistically significant from day 1 onward compared with baseline scores.
Kapoor A, et al.[35]	Sertraline, Imipramine, and Desvenlafaxine	Open-label, randomized, longitudinal follow-up study (n=132)	The earliest improvement was seen in early insomnia (on day 3), followed by suicidal ideas and psychological anxiety (by day 7). Middle insomnia, late insomnia, and agitation improved by the 14th day. Depressed mood improved significantly on day 14 in the sertraline and imipramine groups and on day 21 in the desvenlafaxine group. The last symptoms to improve were general somatic symptoms, genital symptoms, and guilt feelings.
Bhatele P, et al.[36]	Venlafaxine vs Escitalopram	Double-blind, randomized controlled trial (n=90)	No significant difference in the efficacy of Venlafaxine vs Escitalopram at 8 weeks in mild to moderate depression in epilepsy patients
Sinha S, et al.[27]	Vilazodone vs Escitalopram	Multi-center, randomized, comparative study (n=375)	Vilazodone demonstrated comparable efficacy to escitalopram and superior efficacy over the placebo in the treatment of MDD
Kumar PNS, et al.[28]	Vilazodone vs Escitalopram	Open label, rater-blinded, randomized trial (n=52)	Flexibly dosed vilazodone (20–40 mg/day) was not superior to escitalopram (10–20 mg/day) for the primary outcome of endpoint depression scores at the end of 4 weeks of treatment. Diarrhea was more commonly reported in the vilazodone group.
Ankushe RD, et al.[29]	Vilazodone vs Escitalopram	Randomized, active-controlled, parallel-group, open-label study (n=92)	There was a significant decrease in HAM-D, HAM-A, MADRS, CGI-I, and CGI-S scores in the control and experimental groups. The experimental group receiving Vilazodone showed a significant decrease in the scores as compared to the control group (P<0.001) at the end of the 2nd and 4th week

SSRI: Selective Serotonin Reuptake Inhibitor; SNRI: Serotonergic Noradrenergic Reuptake Inhibitor; TCA: Tricyclic Antidepressant; HAM-D: Hamilton Depression Rating Scale; BDNF: Brain-Derived Neurotrophic Factor; TNF-α: Tumour Necrosis Factor-α; MADRS: Montgomery Asberg Depression Rating Scale; HAM-A: Hamilton Anxiety Rating Scale; MDD: Major Depressive Disorder; CGI-I Clinical Global Impression-Improvement; CGI-S: Clinical Global Impression-Severity; SSI: Scale for Suicidal Ideation

Considerable interest has been demonstrated by Indian researchers in the field of neuro-modulation. The greatest number of trials has been conducted using high-frequency rTMS.[41,42,43] Other modalities include transcranial direct current stimulation (tDCS)[44] and ECT.[45] A study was also conducted in Delhi using Single Photon Emission Computerized Tomography (SPECT)-guided rTMS.[41] Another less frequently used protocol was bifrontal tDCS, utilized for augmentation therapy in patients with MDD.[44] Bifrontal tDCS, SPECT-guided rTMS, and adjuvant rTMS were reported to be efficacious in the management of depression. Details are provided in Table 2.

Table 2.

Studies on neuromodulation in India

Authors	Neuromodulation Technique	Study Design	Outcome
Kumari B, et al.[44]	Bifrontal tDCS (10 sessions anodal to Left DLPFC, 10 sessions cathodal to Right DLPFC over two weeks)	Single-blind, randomized controlled trial (n=50)	A significant reduction in HAM-D, BDI, and HAM-A scores was observed in both groups from baseline to week 4. At week 2, the active group had a significantly greater reduction in HAM-D and BDI scores than the sham group. However, at the end of therapy, both groups were comparable.
Jha S., et al.[41]	Brain SPECT-guided rTMS vs hf-rTMS over left DLPFC (50 trains of 40 stimuli each over 2s, with an inter-train interval of 60s for 20 sessions)	Open-label, non-randomized (n=20)	Patients receiving hf-rTMS over the area of prefrontal hypoperfusion, as identified by SPECT, showed significantly better response compared to hf-rTMS over Left DLPFC (46% responders on MADRS vs 0).
Narayanaswamy JC, et al.[45]	ECT	Cross-sectional, observational study (n=150)	No significant difference in the efficacy of ECT in unipolar vs bipolar depression in real-life settings.
Chail A., et al.[42]	hf-rTMS (3000 pulses for 20 sessions) vs pharmacological augmentation	Randomized, controlled trial (n=40)	No statistically significant difference between the two groups after 4 weeks.
Gupta AK, et al.[43]	Adjuvant rTMS for 4 weeks	Prospective, open-label, randomized trial (n=40)	Statistically significant reduction in MADRS scores in the test group and the treatment as usual group, at both 2 weeks and 4 weeks. No statistically significant difference between the two

tDCS: Transcranial Direct Current Stimulation; HAM-D: Hamilton Depression Rating Scale; BDI: Beck's Depression Inventory; HAM-A: Hamilton Anxiety Rating Scale; DLPFC: Dorsolateral Prefrontal Cortex; SPECT: Single Photon Emission Computerized Tomography; rTMS; Repetitive Transcranial Magnetic Stimulation; hf-rTMS: High frequency-repetitive Transcranial Magnetic Stimulation; MADRS: Montgomery Asberg Depression Rating Scale; ECT: Electroconvulsive Therapy

Significant interest can be seen in the field of psychological management of depression in India, as demonstrated by a total of nine articles that were found eligible for inclusion in the review. As many as six studies were on the efficacy of novel intervention techniques provided by counsellors who were not professional psychologists, psychotherapists, or psychiatrists.[46,47,48,49,50,51] Two of the studies focused on the use of the Internet and technology as a means of providing psychological intervention for depression.[52,53] One of the studies utilized the services of nurses to provide counseling services in a sample population of mothers with perinatal depression.[48] All the studies utilizing novel community-led interventions or technological innovations showed benefits in depression management.[47,49,50,51,52,53,54] Details can be found in Table 3.

Table 3.

Studies on psychological management of depression in India

Authors	Intervention	Study Design	Outcome
Kapanee ARM, et al.[46]	Training video on depression for ASHA	Focus Group Discussion, systematic approach to training video development	The training video titled “Light of Hope: A Training Video on Depression” was developed along with two training booklets, which are complementary resource materials, for ASHAs and the training facilitators. The brief psychological intervention for depression elucidated in the training video incorporates the evidence-based strategies of psycho-education, activity scheduling, problem-solving skills training, and diaphragmatic/abdominal breathing skills training.
Pathare S, et al.[47]	Volunteer community-led intervention. Atmiyata community volunteers are trained to (i) identify persons with CMD and provide 4–6 counseling sessions, (ii) raise community awareness on social issues impacting mental health, (iii) refer cases of SMD to mental health services in the public health system, and (iv) facilitate access to social benefits.	Stepped-wedge cluster, randomized controlled trial (n=1191)	In an adjusted analysis, participants in the intervention condition showed significant recovery from symptoms of depression or anxiety at the end of 3 months, with effects sustained at an 8-month follow-up. Intervention participants had improved scores on the PHQ-9 at 3 months and PHQ-9, GAD-7, SRQ-20, EQ-5D, and WHO-DAS at 8 months follow-up.
Raghuveer P, et al.[48]	Brief psychological intervention delivered by a nurse in perinatal depression.	Prospective, open-label, parallel-group, multi-centric trial (n=816)	Yet to be reported
Patel V, etal.[49]	Trained lay health counsellor-led psycho-social intervention.	Cluster randomized controlled trial (n=2796)	Patients with ICD-10-confirmed common mental disorders (depressive and anxiety disorders) in the intervention group were more likely to have recovered at 6 months than were those in the control group. The intervention had strong evidence of an effect on public facility attendees but no evidence of an effect on private facility attendees.
Indu PS, et al.[50]	Community-based Depression Intervention Programme (ComDIP) in women with depression.	Randomized controlled trial (n=60)	At 8 weeks, women receiving ComDIP showed significant improvement in HAM-D scores compared to women receiving TAU.
Sureka P, et al.[34]	Sudarshan kriya and related practices in male prisoners with non-psychotic psychiatric disorders.	Randomized controlled trial (n=230)	Practicing SK&P for 6 weeks led to a statistically significant improvement in the mean±SD score of study participants in GAF, anxiety, depressed mood, positive well-being, general health, and total positive general well-being.
Patel V, et al.[51]	Lay counsellor-delivered brief psychological treatment (HAP) for severe depression	Randomized controlled trial (n=495)	Participants in the EUC plus HAP group had significantly lower symptom severity and higher remission than those in the EUC alone group. EUC plus HAP showed significantly better results than did EUC alone for the secondary outcomes of disability, intimate partner physical violence in women, and suicidal thoughts or attempts.
Maulik PK, et al.[52]	An intervention using the principles of task sharing supported by a technology-enabled mental health services delivery model for screening, diagnosing, and managing common mental disorders (CMDs)—defined here as stress, depression, and increased suicide risk	Before and after study (n=900)	At follow-up, 731 out of 900 (81.2%) reported visiting the doctor for their mental health symptoms, compared with 3.3% (30/900) at baseline. Mean depression and anxiety scores were significantly lower post intervention compared with baseline.
Roy A, et al.[53]	Video-assisted structured aerobic exercise module.	Pre-test post-test control group design (n=40)	A significant reduction in the mean mood score in HAM-D in the experimental group as compared to the control group. No statistically significant reduction in mean somatic symptom score between the groups.

ASHA: Accredited Social Health Activist; CMD: Common Mental Diseases; SMD: Severe Mental Diseases; PHQ-9: Patient Health Questionnaire-9; GAD-7: Generalized Anxiety Disorder scale; SRQ-20: Self-report Questionnaire; EQ-5D: Euro quality of life-5D; WHO-DAS: World Health Organization–Depression, Anxiety, Stress; ICD-10: International Classification of Diseases- 10th ed..ition; HAM-D: Hamilton Depression Rating Scale; TAU: Treatment As Usual; SK&P; Sudarshan Kriya and related practices; SD; Standard Deviation; GAF: Global Assessment of Functioning; HAP: Healthy Activity Program; EUC: Enhanced Usual Care

Studies on the adverse effects of depression treatment were fewer, only amounting to 4 in number, and are detailed in Table 4. Two of the studies evaluated the cardiac side effects of anti-depressant medication. Both studies found TCAs to have higher effects on cardiac function than SSRIs.[55,56] One study evaluated the effect of ECT on cognitive function using a tactual performance test (TPT), block design, and logical memory and digit span test and concluded that ECT and anti-depressants did not differ significantly in any of the tests.[57]

Table 4.

Studies on side effects of drugs in India

Authors	Adverse Drug Event	Study Design	Outcome
Mishra S., et al.[58]	Anti-depressant-associated adverse drug reactions (ADRs)	Longitudinal, observational study (n=160)	Of those prescribed anti-depressants, 26.9% reported ADRs with at least one possible causality. None were labeled as certain as a rechallenge was not performed. ADRs were mostly observed in polytherapy (14.37%) and with anti-depressants like TCAs (58.84%). Agitation, anxiety, and insomnia were the common ADRs observed.
Mishra DK, et al.[55]	Anti-depressant treatment-associated ECG changes	Open-label, controlled study (n=386)	Out of all the study subjects, 19% presented with ECG changes (especially tachycardia). Out of all patients with ECG changes, 55% were taking tricyclic anti-depressants. Only 10% of patients on SSRIs were found to have ECG changes. Other significant ECG changes seen were 1st degree heart block, abnormal QTc interval, left bundle branch block, T wave changes, and ST segment changes.
Udupa K, et al.[56]	Anti-depressant treatment actions on cardiac autonomic alterations	Before and after study (n=94)	Depression improved to a comparable extent across patients treated with the three treatments. Overall, there was no change in cardiac autonomic functions. HRV measures showed an increase with rTMS and a decrease with TCAs; they remained virtually unchanged with SSRIs.
Devaraj A., et al.[57]	Spatial cognitive functioning in depressed patients treated with bilateral ECT	Open-label, controlled trial (n=70)	The ECT and anti-depressant cohorts did not differ on any cognitive test or subtest at endpoint; the only exception was that ECT patients performed more poorly on the TPT shapes subtest at both baseline and endpoint but were more improved (at endpoint) than control patients on this outcome.

TCA: Tricyclic Antidepressant; ECG: electrocardiography; HRV: Heart Rate Variability; SSRI: Selective Serotonin Reuptake Inhibitor; HAM-D: Hamilton Depression Rating Scale; rTMS; repetitive Transcranial Magnetic Stimulation; ECT: Electroconvulsive Therapy; TPT: Tactual Performance Test

Table 5 lists three other studies evaluating other aspects of depression treatment such as prescription patterns, biomarkers, and factor structures of MADRS predicting anti-depressant response.[59,60,61]

Table 5.

Other studies on the treatment of depression in India

Authors	Objectives	Study Design	Outcome
Pillai A, et al.[59]	To examine the relationship between actual and recommended prescribing practices for depression in India	Retrospective cohort study (n=1320)	Anti-depressants were widely prescribed following screening in primary care, but prescription patterns were in poor accord with WHO recommendations. The data suggest under-prescription for people with moderate/severe depression; over-prescription for people with mild depression or non-depression diagnoses; and over-prescription for people with no disorders. About 47% of patients adhered to anti-depressant treatment for 1 month or more, and adherence was significantly better among older adults and those who received anti-depressants as part of the CSC treatment model compared with those attending the usual care clinic.
Khonglah D., et al.[60]	To determine the relationship between the level of CRP and remission rates after anti-depressant therapy.	Prospective, hospital-based study (n=50)	A significantly higher proportion of patients with low CRP levels attained remission than patients with higher CRP levels. The age, compliance to pharmacotherapy, and disability did not significantly affect the remission rates of the patients.
Basu A, et al.[61]	To find the factor structures of MDD as per MADRS and whether they predict escitalopram response.	Before and after study (n=116)	Non-psychotic unipolar major depression having moderate severity in north Indian patients as per MADRS resolved into four-factor structures (“detachment”, “psychic anxiety”, “mood-pessimism”, and “vegetative”) all significantly improved with adequate escitalopram treatment.

WHO: World Health Organization; CSC: Collaborative Stepped Care; CRP: C-Reactive Protein; MADRS: Montgomery Asberg Depression Rating Scale

DISCUSSION

A casual browsing at the tables listing the studies selected for this review shows that the researchers in India have covered a vast range of topics ranging from newly introduced molecules to novel, tele-enabled mental health intervention delivery models. A majority of time and resources seem to have been devoted to the study of pharmacological agents and community-based psychological interventions.

Among the pharmacological agents, a notable addition is the role of ketamine infusion in the rapid amelioration of depressive symptoms.[30,31] Irrespective of the mode of administration, the studies are in agreement over ketamine's usefulness in helping reduce the symptoms of depression rapidly, from just the 40^th minute onward.[31] The poor sustainability of the benefits after stopping the infusion remains a downside that has been replicated in studies elsewhere.[62] A major drawback of the studies conducted in India remains that they have not provided any solutions regarding the major concerns that exist regarding the use of ketamine in depression treatment, namely, how to maintain response, concerns regarding short- and long-term side effects, and the potential for abuse.[62]

Other new pharmacological agents that have been studied in a significant number of Indian patients are Vilazodone and Flupentixol+Melitracen.[27,28,29,40] The multi-center trials and RCT on vilazodone failed to report any significant improvements in efficacy over existing drugs, though it was found to be non-inferior to Escitalopram in the treatment of depression.[27] One open-label trial even reported higher instances of diarrhea as compared to Escitalopram.[28] Despite the theoretical benefits of 5HT1A partial agonism on efficacy and tolerability, no significant benefits were found in the Indian population which is similar to the international assessment of the drug's utility.[63] The results of the phase IV clinical trial on the Flupentixol + Melitracen combination are yet to be reported as of the time of submission of this review.

The wide availability of neuro-modulation machinery across medical colleges in India has led to a burgeoning interest in the effects and cost-effectiveness of this modality of treatment in depression. Despite this, there is still a dearth of good-quality research in neuro-modulation in India, as evidenced by the few novel studies that could be found for the review. The current literature supports the view of tDCS and rTMS as effective in adjuvant therapy or augmentation strategies in depression.[41,44] However, not all studies have reported positive outcomes when compared to pharmacological augmentation or treatment as usual.[42,43] Considering the high setup and training costs involved, the evidence is not sufficient to recommend neuro-modulation as a routine practice for the treatment of depression in a resource-sensitive country like India. The global outlook on neuro-modulation as a treatment method for depression has been largely positive,[64,65] but the Indian scenario still needs significant exploration.

Research on psycho-social aspects of the management of depression has also seen considerable innovation. Research has highlighted the importance of culturally sensitive approaches to depression treatment in India. Given the country's diverse cultural and social contexts, tailoring treatment approaches to the local cultural norms and beliefs has been recognized as crucial.[46,47] Various studies have identified barriers that prevent individuals in India from seeking and accessing mental health treatment. The stigma surrounding mental health issues, lack of awareness, and limited availability of mental health services, especially in rural areas, are some of the key barriers.[66,67] Researchers have tried to combat these hurdles by coming up with various innovative techniques such as the creation of new training videos for ASHA workers[46] and use of telemedicine and technology to deliver mental health interventions.[52,53] This is particularly important in a country as vast as India, where access to mental health services can be a challenge in remote areas. A lot of the research has focused on community-based interventions for depression. This involves training community health workers, counsellors, and nursing staff to identify and support individuals with depression.[46,47,48] The unique challenges posed by the Indian diaspora require unique solutions in the management of depression. This has led to a vibrant diversity in the studies and methodologies reported in psycho-social management in Indian settings, not seen in many countries around the world.[68,69]

Other studies on the treatment of depression have reported the findings on adverse effect profiles of biological treatments,[55,56,57] prescription patterns,[59] CRP as a potential biomarker,[60] and factor structures of MADRS and their use as predictors of response to treatment.[61] The studies are too few to comment conclusively on their findings with any level of confidence. However, a controlled trial by Mishra et al. on electro-cardiographic changes caused by anti-depressant medications has a large enough sample size to conclusively report that TCAs do seem to cause more ECG changes than SSRIs. This supports the widely reported international findings on the cardiotoxicity of TCAs and the comparatively safer profile of SSRIs in this regard.[70,71] The unique pharmacogenomic profile of the Indian population requires more robust studies and reviews on the safety profile of anti-depressants in other aspects as well.[72,73,74] This remains a field that is rife with opportunities for further research.

CONCLUSIONS

The importance of drug trials conducted in the Indian population cannot be overstated enough in providing insights to a clinician regarding the efficacy and adverse effect profiles of specific drugs. Though there is growing interest in new treatment modalities for depression in India, there is a lot of scope for further research. The trials conducted on the use of ketamine fail to answer the questions of sustained improvement and adverse effects, raised by Western studies. Further investigations are required regarding the adverse effects of drugs, with the existing literature failing to provide conclusive answers regarding any side effects other than electro-cardiographic changes. There is also a lack of data when it comes to the use of pharmacological agents in special populations. Studies on neuro-modulation show some innovations such as the use of bifrontal tDCS and SPECT-guided rTMS, but larger sample sizes and more rigorous study designs are needed before conclusions can be drawn. The field of research in psychological management shows a variety of interesting innovations and adaptations tailor-made for the unique needs of the Indian population, ranging from community-based and lay counsellor-driven interventions to the use of digital technology to provide care to poorly served regions of the sub-continent. The present study is limited by a lack of inclusion of unpublished data, inclusion of studies in only the English language, and no statistical tests being conducted to assess the quality of included studies. Future studies may focus on

1. Using newer molecules such as vortioxetine in larger, multi-centric trials.

2. Researching a wider array of adverse effects.

3. Studies on drug efficacy and adverse effects in special populations.

4. More innovative study protocols to help reduce the duration of treatment and improve the targeting of neuro-modulatory methods, such as priming.[75,76]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.