A systematic scoping review of Indian literature on ketamine use for treating psychiatric disorders

Abstract

This scoping review aims to systematically explore the use of ketamine for treating psychiatric disorders in India, mapping the landscape of research, and identifying gaps in the existing literature. The electronic literature search was conducted using PubMed, Scopus, and Clinical Trials Registry of India databases to identify both published and ongoing studies exploring ketamine’s efficacy and safety in treating psychiatric disorders in India. Twenty published studies and 29 trial protocols were included. Published studies comprised case reports (n = 8), case series (n = 2), prospective uncontrolled investigations (n = 5), retrospective reviews (n = 2), and randomized controlled trials (RCTs, n = 3). Most of them focused on ketamine infusion treatment for resistant depression and suicidality. An analysis of trial protocols revealed a significant number of RCTs (n = 26/29), with two non-randomized and one single-arm trial. The majority of trials focused on unipolar depression or suicidality, with other psychiatric conditions such as obsessive–compulsive disorder (OCD) and bipolar depression being explored in some trials. The review of the literature indicated a growing interest in exploring alternative routes of ketamine administration such as oral and subcutaneous, which contrasts with the predominantly intravenous administration reported in published studies. However, careful consideration of dosing, administration routes, and medical supervision is essential to maximize the benefits and minimize the risks. The review highlights the need for more methodologically rigorous research to optimize treatment protocols and expand ketamine’s therapeutic applications in psychiatric practice.

Ketamine, originally discovered in the 1960s as an anesthetic, has a long history of use in clinical settings primarily for inducing and maintaining anesthesia. Its unique cardio-respiratory effects (lack of respiratory or cardiac depression with other commonly used anesthetic agents) and rapid onset of action made it a popular drug in emergency and surgical departments.[1] However, its role expanded significantly in the early 21^st century when researchers identified its potential as a fast-acting antidepressant. This rediscovery of ketamine sparked considerable interest in the psychiatric community, particularly concerning its effectiveness at sub-anesthetic doses for rapid relief of suicidality and mood symptoms in treatment-resistant depression (TRD). Notably, its congener, esketamine (S-enantiomer of ketamine), has also received the Foods and Drug Administration (FDA) approval for adjunctive treatment of TRD, further fuelling the interest among the research community and general public alike in the exploration of ketamine’s broader therapeutic potential.[2] Emerging evidence suggests that ketamine may exert its antidepressant effects through several postulated mechanisms, including the N-methyl-D-aspartate (NMDA) receptor antagonism, modulation of glutamate release, and downstream effects on synaptic plasticity.[3] These mechanisms are believed to contribute to ketamine’s rapid and profound effects on conditions such as depression, obsessive–compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

In recent years, there has been a growing interest among healthcare professionals worldwide including those from India regarding the use of sub-anesthetic doses of ketamine beyond its traditional role in anesthesia. Though systematic reviews and meta-analyses assessing the safety and efficacy of ketamine for depression and suicidality have been published, they predominantly include studies from Western countries.[4,5] Contributions from studies conducted in India are minimal, if present at all in the currently available reviews on this important topic. The existing literature on widely used pharmacological agents, such as clozapine or tetrabenazine, has shown significant differences in pharmacokinetics, leading to varying dosing strategies and differing propensities for side effects among people of different ethnicities. For instance, individuals of East Asian descent and Indigenous American ethnicity have been recognized as slow metabolizers of clozapine, prompting recommendations to prescribe lower clozapine maintenance doses compared to doses typically recommended for individuals of European or West Asian descent.[6] This assumes critical importance when decisions regarding the optimal dosage and safety profile of a treatment are often made based on the findings from these systematic reviews and meta-analyses.

The aim of this scoping review was to map the scientific literature exploring the safety and efficacy of sub-anesthetic doses of ketamine for the management of patients with different psychiatric disorders from India. The focus was on examining the available literature from Indian settings on the use of sub-anesthetic doses of ketamine. This shall help summarize the knowledge regarding the safety and effectiveness of ketamine for different psychiatric indications, apart from its use as an anesthetic or analgesic agent among the Indian population. Finally, we also attempted to assess the methodological rigor of research studies and identified the key research gaps to guide future research in India. A summary of 29 clinical trial protocols analyzed in this review have also been described in supplementary file.

MATERIALS AND METHODS

A scoping review was conducted to explore the extent, range, and nature of research studies on the use of ketamine for various psychiatric indications in India. This review followed the methodological framework for scoping reviews proposed by Arksey and O’Malley, with further refinement as recommended by Levac et al.[7] The protocol for this scoping review was not registered online because it is not required as per the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) checklist.[8]

Search strategy

The research question framed for this scoping review was: What is the current state of the scientific literature from India on the safety and efficacy of ketamine for the management of patients with different psychiatric disorders?

A systematic literature search to identify all relevant studies assessing the use of ketamine for treating any psychiatric disorder was conducted in the following electronic databases: PubMed/MEDLINE and Scopus (see Supplementary File for details). All studies published since the inception of the database till March 2024 were considered for inclusion.

Study selection

All English language articles (case report, case series, cross-sectional, case–control, or longitudinal; retrospective or prospective study design) that reported empirical data related to ketamine use in patients with psychiatric disorders from India were considered for inclusion. Two reviewers (SS and BSR) independently screened all study titles and abstracts for eligibility based on pre-decided eligibility criteria. The full text of relevant studies was further evaluated in the next stage. Studies were excluded if they had no ketamine alone group or used ketamine in patients with no psychiatric disorder, or were review/opinion-based articles with no new patient-generated data. At each stage, selections made by the two reviewers were compared, and any disagreements were addressed through mutual discussion and consensus. If necessary, a third author was consulted to resolve disagreements. Additionally, references of selected articles were manually reviewed to identify any other relevant studies. Figure 1 depicts study selection process followed for this scoping review as per the PRISMA-ScR checklist.

Figure 1.

PRISMA flow diagram depicting the selection of studies for scoping review through different sources of evidence

Data extraction and synthesis

Two reviewers (SS and BSR) independently evaluated the full text of all selected studies and extracted data using a customized Excel spreadsheet. This spreadsheet was developed by authors specifically for this scoping review through an iterative process, which involved reviewing relevant literature, drawing on the authors’ experience, and consulting with experts in the field. It included information such as the name of the first author or trial ID, year of publication or registration date, type of study design, ketamine administration details, comparator used, sample size, study participants’ characteristics (e.g. age, gender, diagnosis, etc.), and findings related to the safety and efficacy of ketamine.

The details of included studies and trial protocols were presented in a tabular format. A narrative synthesis of salient findings describing the nature and extent of available literature from India was carried out.

RESULTS

A total of 20 published studies from India reporting on the use of ketamine or its congener (one case report on intra-nasal esketamine) in patients with psychiatric disorders were included in this review. There was a single case report of ketamine dependence in an anesthesiologist with a history of multiple substance use disorders before starting ketamine abuse for non-clinical purposes[9]; however, this was not included in the narrative synthesis of studies assessing the safety and efficacy of ketamine treatment in patients with different psychiatry disorders. Table 1 describes methodology-related aspects, the main findings related to ketamine’s effect on the psychiatric disorder being treated, and the reported side effects in the included studies. Most studies followed a similar protocol of diluting ketamine hydrochloride in normal saline, and administering it as an intravenous (IV) infusion at a dose of 0.5 mg/kg over 40 min. The most commonly reported side effects of ketamine treatment in Indian studies are elevated blood pressure, euphoria, headache, dizziness (more commonly observed at higher doses of parenterally administered ketamine), and increased thirst; all of them were generally mild, occurred either during or immediately after ketamine infusion or injection, and resolved spontaneously with supportive care within 40 min. Mild nausea was also reported in a few cases, typically resolving either spontaneously within 30 min to 1 h or with oral domperidone. Transient dissociative symptoms were noted in some patients but were invariably mild and resolved spontaneously post-infusion without any medical intervention. Out of them, the majority were case reports (n = 8/20; 40%) or case series (n = 2/20; 10%), followed by prospective, uncontrolled, open-label investigations (n = 5/20; 25%) and retrospective medical records reviews (n = 2/20; 10%). There were only three randomized controlled trials (3/20; 15%) assessing the safety and efficacy of ketamine treatment in the published literature from India. Further, only two of these RCTs were single-blinded with only one of them providing details about how the outcome assessor was masked to the treatment status of study participants; and only one RCT described about allocation concealment of the randomization sequence. Across the studies, there was a cumulative total of 300 participants. Of these, 237 participants received ketamine treatment. The age and gender distribution of participants varied significantly between various studies, with most of them having a mix of male and female patients, and sample sizes ranging from 1 to 30 individuals. The mean age of participants typically fell between their late 20s and early 50s (range: 19– 65 years). Most studies explored the clinical effects of IV ketamine infusion for the treatment of suicidality associated with unipolar, non-psychotic, depression. A few of them have also explored ketamine treatment in other psychiatric disorders such as bipolar depression, OCD, complicated grief, and borderline personality disorder (see Table 1 for details).

Table 1.

Summary of published articles exploring the use of ketamine for treatment of psychiatric disorders from India

DISCUSSION

We present findings from a scoping review of both published and planned or ongoing studies exploring ketamine use in psychiatry from India. This shall help us gain insights into the different types of research studies conducted on ketamine use for non-anesthetic purposes in psychiatry by the Indian research community. Further, by mapping the available scientific literature on this emerging topic of interest among psychiatrists, we identified key research gaps to guide future research in the right direction. To the best of our knowledge, there has been no systematic review of Indian peer-reviewed scientific literature synthesizing the empirical evidence available for sub-anesthetic doses of ketamine in treating patients with psychiatric disorders.

The exploration of sub-anesthetic doses of ketamine as a treatment option in Indian psychiatry practice has largely focused on its role in addressing suicidality, particularly in patients with non-psychotic depression. The majority of published studies focused on unipolar depression, with a few including patients with bipolar depression. One notable case involved a geriatric patient with treatment-resistant depression who responded positively to ketamine infusion, highlighting its potential in managing refractory depression even in the elderly.[14] However, none of the studies included special patient groups such as children or adolescents below 18 years of age or pregnant females suffering from psychiatric disorders. In most studies, ketamine was administered as intravenous (IV) infusions, typically 2 to 3 times per week over 1 to 2 weeks. However, there were no published studies comparing IV infusion of ketamine with other safer and more convenient routes of administration such as oral or subcutaneous ketamine. Additionally, a retrospective review of case records reported that a subset of patients (about one-fifth) with treatment-resistant OCD showed at least partial response in symptoms with ketamine augmentation. This underlines the need to conduct future studies aimed at exploring the predictors of response to ketamine treatment and identify those who are most likely to benefit from early initiation of ketamine treatment following the onset of psychiatric disorder symptoms. Despite these findings, there remains a significant gap in the research concerning the use of ketamine in other psychiatric disorders such as PTSD or nicotine dependence, with no studies exploring ketamine’s potential in these areas within the Indian population. Thus, our review of Indian studies on the use of ketamine for treating psychiatric disorders found that the most commonly reported route of administration was IV infusion at a dose of 0.5 mg/kg over 40 min, which aligns with the dosing protocol commonly reported in Western studies. Other modes of administration, including intra-muscular injection and oral ketamine, were also reported in a few studies, though less frequently as compared to the global literature.

The use of sub-anesthetic doses of ketamine in clinical settings appears to be a safe option for various psychiatric conditions, based on the available data from India. Adverse effects were generally transient and of mild intensity, with many studies reporting no side effects with ketamine treatment. Commonly reported side effects included nausea and vomiting, with very few patients reporting either dissociative experiences or excessive sedation or giddiness during ketamine administration. The frequency and pattern of side effects observed in Indian studies were comparable with those reported from studies conducted on Western patient populations,[30] suggesting that the adverse effects and efficacy of ketamine were similar across these populations. This consistency in both the dosing protocols and side effect profiles reinforces the generalizability of ketamine treatment effects across different ethnic populations, including Indian patients.

However, concerns about ketamine’s potential abuse have been expressed by a group of researchers, especially given its known dissociative and psychoactive effects.[31] Interestingly, none of the studies reviewed reported patients developing dependence on ketamine after a clinically guided course of treatment. This absence of reported dependence may be explained partly due to the lack of systematic side-effect assessment in these studies.[32] Future research should address this by employing standardized tools, such as the Ketamine Side Effect Tool (KSET), to monitor and evaluate side effects both during and after ketamine treatment sessions.[33] Another critical consideration is the limited duration of follow-up in most studies, with only a few case reports from India documenting long-term ketamine use, such as oral ketamine and intranasal esketamine for treating depression and suicidality for more than a year.[24,28] This points to the necessity of being vigilant about potential long-term side effects, including urinary bladder toxicity and neurological issues, which may arise with chronic ketamine use as a maintenance treatment.[34]

A total of 29 trial protocols exploring the use of ketamine for treating psychiatric disorders were identified by the Clinical Trials Registry of India (CTRI) in the last 5 years, as compared to only 19 published studies until March 2024, reflecting a growing interest regarding ketamine use in psychiatry among Indian researchers. The analysis of CTRI registered trial protocols underscores a significant shift in the research landscape on ketamine use in psychiatry in India, particularly reflected in the increased number of randomized controlled trials (RCTs) being planned or conducted. The current registry data reveal that 26 out of the 29 ongoing studies are RCTs, unlike only 3 out of 19 published studies identified in this scoping review being RCTs. Further, a few studies in the CTRI database are multi-centered trials with only two of them having a relatively larger target sample size of 120 or above. Importantly, one regulatory multi-centered randomized placebo-controlled trial sponsored by a pharmaceutical company investigating the safety and efficacy of subcutaneous ketamine in a pre-filled syringe for self-administration among patients with unipolar depression is currently ongoing in India. This suggests a growing commitment among researchers to generate high-quality, rigorous evidence on ketamine’s efficacy and safety across various psychiatric conditions. Additionally, a few ongoing and planned trials aim to explore ketamine use for treatment in several other psychiatric conditions apart from unipolar or bipolar depression and OCD. This included alcohol dependence, opioid dependence, and agitation in patients with various psychiatric disorders. Interestingly, one study reported combining ketamine with motivation-enhancement therapy for treating patients with alcohol dependence, though the protocol did not specify the dose or route of administration.

Moreover, there is a notable diversification in the routes of ketamine administration being explored. Although earlier research predominantly focused on intravenous (IV) ketamine, with only one or two studies examining oral or intramuscular routes, the CTRI-registered trials reflect a broader interest. Intravenous infusion is still the most common route of administering ketamine, with about three-fourths of ongoing or planned trial protocols reporting IV infusion of 0.5 mg/kg dose over 40 min using an intravenous pump. Other routes of ketamine are also being increasingly explored, with oral ketamine use in doses ranging from 150 mg to 2.5 mg/kg per treatment session being explored in about half of them. Other routes of ketamine administration included intramuscular and subcutaneous injections of ketamine either as a slow injection over 1 to 2 min or as a single shot. This shift shall not only broaden the potential applicability of ketamine in clinical settings but also facilitate a deeper exploration into optimizing the delivery methods to enhance patient outcomes and manage side effects with ketamine treatment more efficiently.[35] These trends suggest a more comprehensive and innovative approach to ketamine research in India being promoted by researchers and psychiatrists, with the potential to significantly impact future clinical practice.

The major limitations of the published studies reviewed here, include relatively small sample sizes, with patient recruitment often restricted to a single study site, limiting the validity and generalizability of study findings. Further, the excessive reliance on open-label or single-blinded study designs could lead to an overestimation of ketamine treatment effects due to participant expectancy bias.[36] These methodological constraints limit the strength of evidence base generated from Indian studies exploring the safety and efficacy of ketamine use for the treatment of psychiatric disorders and underscore the need for having more rigorously designed and adequately powered clinical trials to establish stronger evidence. Looking ahead, there is a pressing need to conduct studies that explore the efficacy of ketamine-assisted psychotherapy for conditions such as depression, OCD, and PTSD.[37] Additionally, research should investigate the effects of ketamine therapy on other often co-morbid conditions, such as tobacco use disorder, or associated symptoms such as body pain and cognitive deficits in patients with depression.[38,39,40] Finally, more methodologically robust studies are essential to identify the optimal ketamine treatment protocols for various psychiatric indications. These efforts will be crucial in further establishing ketamine’s role in psychiatric treatment, ensuring its safe and effective use, and expanding its application to a broader range of disorders.

CONCLUSION

This scoping review highlights the growing interest and evolving research on the use of sub-anesthetic doses of ketamine in Indian psychiatry and supports ketamine use, particularly for its rapid antidepressant and anti-suicidal effects. Although published studies from India demonstrate ketamine’s significant potential in managing specific psychiatric disorders, it is crucial to carefully consider dosing, administration routes, and the necessity of medical supervision to detect serious adverse events, ensuring that the benefits are maximized while minimizing risks. The research landscape is marked by certain gaps, such as limited exploration of ketamine use in other psychiatric conditions apart from depression or OCD, special populations such as children or elderly, and non-intravenous routes of administration. A preponderance of small-scale, open-label studies with short follow-up periods underscores the need for conducting more high-quality, multi-centered, and methodologically rigorous trials to bridge gaps in the available literature. Future research should focus on optimizing ketamine treatment protocols, investigating long-term safety, determining predictors of response to treatment, and expanding its potential therapeutic applications along with exploration of ketamine’s underlying mechanism of action responsible for causing rapid improvement in psychiatric disorder symptoms. Addressing these gaps will be crucial for establishing ketamine as a safe and effective treatment option across a broader spectrum of psychiatric disorders.

Authors’ contributions

Conceptualization, design, intellectual content, literature search, data acquisition, data analysis, statistical analysis, manuscript preparation, editing, and review: SS, BSR, PV, SK.

Data availability statement

This is a review article and does not involve any new patient-generated data. Review related data shall be shared by corresponding author upon receiving reasonable request.

Ethical statement

This article reviews already published data, and does not involve any new participant generated data. Thus, no ethical clearance was required.

Conflicts of interest

There are no conflicts of interest.

Supplementary File

SEARCH QUERRY

The search query used for the PubMed search was as follows:("ketamine"[All Fields] OR "ketamine"[MeSH Terms] OR "ketamin"[All Fields] OR "ketamine s"[All Fields] OR "ketamines"[All Fields] OR "esketamine"[Supplementary Concept] OR "esketamine"[All Fields]) AND ("india"[MeSH Terms] OR "india"[All Fields] OR "india s"[All Fields] OR "indias"[All Fields]). The search query was adapted as per the available search options for the Scopus database.

RESULTS OF CLINICAL TRIAL PROTOCOL ANALYSIS

A total of 29 trial protocols exploring ketamine use for treatment of patients with psychiatric disorders retrieved from the CTRI records in last five years were identified and analysed. Supplementary Table 1 described the salient characteristics of these clinical trials. The clinical utility of ketamine treatment is being explored across various psychiatric disorders in India. The cumulative number of participants planned to be enrolled in these trials is 1,632 patients. The individual target study sample sizes ranged from 20 to 128 participants. The large majority of registered trial designs were randomized controlled trials (26/29), with two trials being non-randomized, active controlled study design (2/29), and another one having a single arm (1/29). One phase 3 trial protocol was registered as a pharmaceutical company sponsored regulatory trial exploring utility of sub-cutaneous ketamine treatment in a pre-filed syringe intended for self-administered injection among patients with unipolar depression. The protocol of ketamine administration varied significantly across studies, with ketamine IV infusion being the most commonly reported route of administration (22 studies, 75.9%). This method usually involved administering ketamine, typically at a dose of 0.5 mg/kg over 40 to 45 minutes with the help of intravenous pump. Oral ketamine was the next most frequent route of administration (14 studies, 48.3), with fixed dosing across sessions in most of the studies ranging from 150 mg (irrespective of body weight) to 2.5 mg/kg (as per body weight), depending on the protocol. Intramuscular (IM) ketamine was being used in four studies (13.8%), involving IM injections at doses ranging between 0.5 mg/kg to 5 mg/kg, depending on the protocol. Sub-cutaneous ketamine was being used in three studies (10.3%). Finally, one study (3.45%) reported using ketamine in combination with motivation enhancement therapy for treatment of patients with alcohol dependence; but the route and dose of ketamine administration was not specified in the trial protocol.

Supplementary Table 1.

Details of planned or ongoing studies exploring use of ketamine for treatment of psychiatric disorders from the Clinical Trials Registry of India (CTRI) database in last five years

Funding Statement

Nil.