Intravenous Ketamine Treatment for Depression: One-year Retrospective Study from a Tertiary Care Psychiatry Center from India

Abstract

Background:

Major depressive disorder (MDD) is a debilitating mental health condition characterized by significant morbidity and mortality. The emergence of ketamine infusion therapy has provided a promising, rapidly acting treatment option. We aimed to assess the effectiveness of ketamine infusion therapy as an adjunct treatment in patients with depression and to study the patient’s profile undergoing ketamine therapy in a real-world clinical setting.

Methods:

This was a retrospective chart review. A total of 28 patients with depression who received ketamine infusion therapy at a tertiary care hospital were included in this retrospective analysis. The Hamilton Depression Rating Scale (HAMD) was utilized to assess depressive symptomatology.

Results:

A statistically significant reduction in HAMD scores was observed post-treatment (P < .0001). Notably, 53.6% of patients achieved a therapeutic response (≥50% decrease in HAMD score), while 39.3% attained remission (HAMD score < 7) after an average of 4.6 ketamine infusions. Furthermore, a substantial decrease in suicidal ideation was observed in 71.4% of patients.

Conclusion:

The finding of this study indicates that ketamine infusion therapy is safe and effective as a rapidly acting adjunct treatment for depression.

Key Messages:

• This retrospective study demonstrates the effectiveness of intravenous ketamine therapy in treating depression.

• Ketamine infusion shows potential as an adjunct antidepressant therapy with anti-suicidal effects in the short term.

• The long-term effects of ketamine infusion therapy require further evaluation to determine its sustained efficacy and safety.

Depression impacts not only the individual life of the patient but also the health of society. ¹ The lifetime prevalence of depressive disorder among Indians is 5.25%, as per the National Mental Health Survey 2015–2016. ² According to the National Crime Record Bureau (NCRB), the suicide rate has increased from 9.9 per lakh population in 2017 to 12.4 per lakh population in 2022.^3,4 Depression is one of the important causes of suicide. Hence, timely treatment for depression is of utmost importance. The most consequential study ever conducted for the treatment of depression is the Sequenced Treatment Alternatives to Relieve Depression STAR*D trial. According to it, only 33% of patients diagnosed with major depressive disorder (MDD) showed remission after the first antidepressant trial, and the cumulative remission rate was 67% after four acute treatment steps. ⁵ This underscores the need for innovative treatment options. Current treatments for depression, including antidepressants and psychotherapy, often have delayed therapeutic effects. ⁶ Electroconvulsive therapy (ECT) has a robust antidepressant and anti-suicidal effect, but its use is limited due to availability, social stigma, and concerns regarding cognitive impairment. ⁷

The emergence of ketamine has revolutionized the treatment landscape for depression. As an N-methyl-D-aspartate receptor antagonist, ketamine has demonstrated rapid antidepressant effects and anti-suicidal benefits, even after a single dose.^8–11 Despite its promising efficacy, there is a knowledge gap regarding the real-world utility of ketamine therapy, optimal treatment protocols as well as its comparative effectiveness to other treatments for depression.

Our study aims to address the knowledge gap regarding the real-world utility of ketamine therapy by undertaking a retrospective chart review. The objective is to assess the effectiveness of intravenous ketamine as an adjunct treatment for depression and describe the profile of patients undergoing ketamine therapy. Our study adds to the existing literature on ketamine therapy by providing a real-world perspective on its effectiveness and utility.

Methods

This retrospective chart review study included inpatients diagnosed with depressive disorder as per the International Classification of Diseases-10 (ICD-10), ¹² who received ketamine infusion therapy at our tertiary care hospital from March 2023 until September 2024. This retrospective study utilized existing electronic medical records (EMRs) and did not involve prospective data collection. A waiver of informed consent was granted by the Institutional Ethics Committee, acknowledging the study’s retrospective nature and ensuring minimal risk to patient privacy.

Eligibility Criteria

Inclusion criteria comprised patients with depression who either had suicidal ideation or treatment-resistant depression (TRD) (i.e., a failure to respond to at least two different classes of antidepressants for a period longer than six weeks at the maximum recommended dose), ¹³ or both and patients whose data is available. Patients receiving oral ketamine were excluded. Patients received ketamine infusion therapy in conjunction with antidepressants and mood stabilizers (e.g., lithium) as necessary.

Treatment Protocol

At our in-patient department (IPD) facility, after a detailed clinical assessment, ketamine infusion therapy is offered to patients across all adult age groups who are eligible for it. Prior to initiating ketamine therapy, informed consent is obtained from patients (or their authorized representatives), and medical fitness is taken. The Clinician-rated Hamilton Depression Rating Scale-17 (HAMD-17) is applied to all patients undergoing ketamine therapy to assess depression severity. ¹⁴ HAMD scale contains 17 items about symptoms of depression experienced over the past week. The following are the severity ranges for the HAMD: no depression (0–7), mild depression (8–16), moderate depression (17–24), and severe depression (≥24). ¹⁵

Recommended Treatment Regimen

Ketamine hydrochloride (50 mg/mL) is administered via continuous intravenous infusion at 0.5 mg/kg body weight in 100 mL normal saline over 40 minutes. All patients received the same dose of ketamine, but the number of sessions varied between individuals. At least three sessions are given as induction; the treatment is discontinued if the patient does not respond.

Premedication with intravenous antiemetic and glycopyrrolate (0.4–1 mg) is standard.

Vital signs and patient orientation are monitored every 10 minutes. Glycopyrrolate (0.4–1 mg) and promethazine HCl (25 mg) are available as needed. Ketamine infusion therapy is administered three times a week until a significant reduction in HAMD scores is achieved. HAMD scores are assessed at baseline and 24 hours post-infusion for each session. Following the initial response, maintenance ketamine therapy is recommended every two weeks to sustain therapeutic benefits. No limit is placed on the number of maintenance infusions. For this chart review, baseline and final ketamine session HAMD scores were analysed, and we did not include maintenance infusions. Also, Suicidal risk is comprehensively assessed during the mental status examination (MSE), enabling clinicians to evaluate and document participants’ suicidal ideation and risk.

Data Collection

The principal investigator conducted a retrospective review of the ketamine register maintained in the psychiatry ward since March 2023. This register contained patients’ diagnoses and in-patient numbers. Patients with depression who received ketamine therapy were identified from the register, and additional data were extracted from EMR after seeking permission from the concerned authorities. Subsequently, a standardized data collection form was filled out based on the patient’s EMR. Statistical analysis was then performed to evaluate treatment outcomes.

Statistical Analysis

The data collected were analysed using Microsoft Excel 2021. Descriptive statistics were employed to summarize socio-demographic variables. Continuous variables were analysed using means and standard deviations, while categorical variables were analysed using frequencies and percentages. Socio-demographic data was incomplete for some participants, and as a result, these variables were excluded from the analysis to maintain data integrity and avoid potential biases. The effectiveness of ketamine therapy was evaluated by comparing pre-treatment and post-treatment outcomes using paired t-tests. Effect sizes were calculated using Cohen’s d formula (mean difference ÷ standard deviation). Statistical significance was set at P < .05.

Results

Socio-demographic and Clinical Characteristics

Between March 2023 and September 2024, 42 patients received ketamine. Nine patients who received oral ketamine and five patients whose records could not be retrieved were excluded. Following these exclusions, 28 patients were included in the analysis. Socio-demographic data for five patients, specifically regarding occupation and education, were unavailable and consequently excluded from the analysis. Table 1 presents the socio-demographic characteristics of the study participants. The mean age of the participants was 37 years (13.5). The majority of participants (60.7%) were males. Table 2 depicts that the majority of patients, that is, 42.8%, had recurrent depressive disorder (RDD), while 28.6% of patients experienced a single depressive episode, 25% had dysthymia, and 3.6% had bipolar depression. Notably, half of the sample (50%) presented with at least one psychiatric comorbidity, with generalized anxiety disorder (GAD;17.9%), substance use disorder (SUD; 14.2%), and panic disorder (10.7%) being the most prevalent. The baseline HAMD scores revealed that the majority of patients, 85.7%, fell into the severe depression category. Furthermore, a subset of patients, 14.3%, were identified as having TRD, and a significant number of patients, 71.4%, reported thoughts of suicide. All patients were on concurrent antidepressants. The mean duration of the depression is 19.3 months. The total sessions ranged from three to ten, with a mean of 4.6 (±1.7) sessions per patient. Treatment was discontinued in patients who failed to show improvement after three sessions.

Table 1.

Social-demographic Characteristics of the Study Participants.

Sociodemographic Variable		Mean (SD)	Frequency n = 28)	Percentage (%)
Age		37 (13.5)	NA	NA
Gender	Male		17	60.7
	Female		11	39.2
Marital status	Married		16	57.1
	Unmarried		12	42.8
Religion	Hindu		24	85.7
	Islam		3	10.7
	Christian		1	3.6

SD = standard deviation, N = frequency.

Table 2.

Clinical Characteristics of the Study Participants.

Clinical Characteristics		Frequency (N = 28)	Percentage (%)
Diagnosis	RDD	12	42.8
	SDE	8	28.6
	Dysthymia	7	25
	Bipolar depression	1	3.6
Psychiatric co-morbidities	GAD	5	17.9
	SUD	4	14.2
	Panic disorder	3	10.7
	OCD	2	7.2
	None	14	50
Severity of depression	Moderate (HAMD =17–24)	4	14.3
	Severe (HAMD = >24)	24	85.7
Treatment-resistant depression	Yes	10	14.3
	No	18	85.7
Suicidal ideation	Present	20	71.4
	Absent	8	28.6
Psychiatric medications	Antidepressants	28	100
	Mood stabilizers (lithium)	13	46.4
	Antipsychotics	6	21.4
Duration of depression	Mean (SD)	19.3 months (57.5)
No. of ketamine infusions	Mean (SD)	(1.7)

RDD = recurrent depressive disorder, SDE = single depressive disorder, GAD = generalized anxiety disorder, SUD = substance use disorder, OCD = obsessive compulsive disorder, HAMD = Hamilton Depressive Rating Scale, SD = standard deviation.

Clinical Response and Safety Profile

The clinical efficacy of ketamine infusion therapy was noteworthy, as evidenced by a statistically significant reduction in mean (HAMD) scores post-treatment (8.3 ± 3.3, P < .0001), as depicted in Table 3. Cohen’s d formula calculated the study’s effect size to be 1.6. Table 4 shows that post-ketamine infusion, a remarkable 53.5% (n = 15) of the 28 participants achieved a response, that is, reduction in >50% in HAMD score, with 39.2% (n = 11) attaining remission, that is, HAMD score < 7. Notably, 80% of participants exhibited a substantial decrease in suicidal ideation, as evaluated through MSE assessments conducted after the ketamine infusion treatment cycle, highlighting the therapy’s effectiveness in alleviating severe depressive symptoms. The safety profile of ketamine infusion therapy was favorable, characterized by a low incidence of adverse events (7.1% of participants), primarily of headache and nausea, as shown in Table 5. These findings suggest that ketamine infusion therapy is generally well-tolerated in this patient population.

Table 3.

Clinical Response of the Study Participants.

Variables	Average	SD	Paired t-test
Pre-treatment HAMD score	18.8	5.55	<0.0001
Post-treatment HAMD score	8.3	3.37

Table 4.

Proportion of Participants Achieving Response and Remission with Ketamine Therapy.

Response to Ketamine	N (Out of Total Sample)	% (Out of Total Sample)
No response	13	46.4
Responsea (includes remission)	15	53.5
Remissionb	11	39.2

^aResponse: >50% reduction in HAMD score.

^bRemission: HAMD score < 7.

Table 5.

Ketamine Therapy Outcomes: Suicidal Ideation and Adverse Effects.

Clinical Variables	Frequency	Percentage (%)
Reduction in suicidal ideation	16 (n = 20)	80
Adverse effecta	2 (n = 28)	7.1

^aHeadache and nausea were the primary adverse events reported.

Discussion

This chart review assessed the effectiveness and safety of intravenous ketamine infusion therapy as an adjunct treatment for patients with depression at a tertiary care psychiatry unit in India. Notably, the treatment demonstrated rapid antidepressant effects, and the key findings were that following a single treatment cycle, which consisted of an average of four ketamine sessions, the response rate was 53.5%, indicating that more than half of the participants experienced a significant reduction in depressive symptoms and 39.2% participants reported remission of depressive symptoms. Our study’s response rate is consistent with previous research by McInnes et al. (53.6%), ¹⁶ Aust et al. (55%), ¹⁷ and Singh et al. (53.8%). ¹⁸ However, our findings diverge from other naturalistic studies, such as Sakurai et al. (18.3%), ¹⁹ and Wilkinson et al. (45.5%), ²⁰ which reported lower response rates. Conversely, studies employing similar ketamine infusion regimens as ours, with sessions conducted thrice a week, reported higher response rates. For instance, one study observed response rates of 62.5% after the first dose and 70.8% after the sixth dose. ²¹ Another study with a comparable treatment regimen reported a gradual increase in response rates, from 25% after the first dose to 92% after the sixth. ²² Furthermore, studies conducted by Juby et al. ²³ Rasool et al. ²⁴ reported a response rate of 70.6% and 70.27%, respectively. Remission rates in previous studies have ranged from 28.9% to 32.4%, which is lower than our study’s remission rate.^16,23 Notably, our findings align with those of Singh et al., who reported a remission rate of 39.2%. ¹⁸ Our study observed a large effect size (Cohen’s d = 1.67), which is consistent with the study done by D’Andrea G et al. ²⁵ and McInnes LA et al. ¹⁶ showing large effect sizes of 1.66 and 1.5, respectively. Systematic reviews and meta-analyses consistently demonstrate significant reductions in depressive symptoms with moderate to large effect sizes (Hedges’ g = 0.74, and SMD = –0.56).^26,27 A comprehensive international pooled patient-level meta-analysis also found a significant reduction in depressive symptoms with a large effect size (Hedges’ g = 1.13). ²⁸ Our study’s results are consistent with these reviews. However, it is essential to note that our findings might be influenced by the relatively small sample size, potentially limiting the generalizability of the results. Future studies with larger sample sizes are necessary to confirm these findings. Our study also highlights the effectiveness of ketamine infusion therapy in reducing suicidal ideation, with 71% of patients reporting a reduction in suicidal thoughts post-treatment. This outcome aligns with prior research indicating ketamine’s response rates for suicidal ideation as 73% and 63.16%.^16,24 However, our results surpass those of other studies, which reported lower response rates, including one study showing 17.9% of patients achieved resolution and other studies indicating 50% of patients reported resolution in suicidal ideations.^15,19,29

The safety profile of ketamine infusion therapy in our study was favorable, with only 7.1% of patients experiencing adverse events, primarily nausea and headache. This finding aligns with previous research reporting mild and transient side effects in 6.2% of patients, primarily nausea. ²³ Notably, our results are significantly lower than those reported in other studies, which found rates of 44.8% and 29.6% for nausea-related adverse events.^19,20 Other studies have identified common adverse events associated with ketamine infusion therapy, such as headache, anxiety, dissociation, nausea, and dizziness. ¹⁸ Our findings suggest that ketamine is well-tolerated with limited side effects in our population.

The demographic characteristics of our study population were notable; most patients were male, married, and Hindu, with a mean age of 37 years. Furthermore, the high prevalence of psychiatric comorbidities (50%) highlights the complexity of this patient population. Specifically, generalized anxiety disorder (17.9%) and substance use disorder (14.2%) were commonly observed, emphasizing the need for comprehensive diagnostic evaluations and tailored treatment planning.

The long-term maintenance of ketamine infusion therapy remains a topic of ongoing research. However, studies suggest that repeated infusions can sustain antidepressant effects.^21,30 Further research is needed to establish the optimal dosing regimen, duration of treatment, and long-term efficacy of ketamine infusion therapy.

Limitations

This analysis is subject to several significant limitations that may impact its findings. Key constraints include a retrospective chart review design that relies on existing data. Lack of demographic information like socio-economic status, medication history, medical comorbidity, details of adequate drug doses, compliance, or non-responders were missing. Furthermore, the limited sample size restricts the generalizability of the findings, potentially overlooking significant relationships or differences. The study could have provided a more comprehensive understanding of the long-term effects by including maintenance sessions. Limited assessment of treatment response, using HAMD scores only before and 24 hours after infusion, indicates short-term effects. We did not employ a standardized scale to assess suicidal ideation. These constraints highlight the need for more comprehensive research.

Conclusion

This retrospective analysis offers invaluable insights from real-world clinical experience, demonstrating the potential benefit of ketamine infusion therapy as a rapidly acting adjunct treatment for depression, with a notable response rate observed in nearly half of the patients. The findings of this study provide preliminary support for the antidepressant and anti-suicidal effects of ketamine infusion therapy when used in conjunction with existing treatments in a clinical setting. Favorable safety profile and tolerability are a plus points. Most patients were males, married, and Hindu, with a mean age of 37. However, further investigation with larger sample sizes and long-term follow-up is necessary to determine the specific patient populations most likely to benefit from this treatment approach and whether its therapeutic effects endure over time.