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Retrospective data analysis to determine the effectiveness of intravenous ketamine therapy on patients suffering from depression with suicidal ideation
Pradhyuman Chaudhary, Prathmesh Shah, Prakash Mehta
Department of Psychiatry, GMERS Medical College and Hospital, Sola, Ahmedabad, Gujarat, India
|Date of Submission||06-Nov-2021|
|Date of Acceptance||09-Jun-2022|
|Date of Web Publication||10-Nov-2022|
GMERS Medical College, Sola, Ahmedabad, Gujarat
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Depression is often a debilitating and recurrent psychiatric disorder. Depression with suicidal ideation, being a psychiatric emergency, often needs intensive intervention such as Electro-Convulsive Therapy (ECT). ECT may be refused because of stigma and perceived risk. Intravenous ketamine therapy, being an alternative to ECT for quick response compared to routine pharmaco-therapy, is analyzed to determine its effectiveness. Methods: Among patients suffering from depression with suicidal ideation, intravenous ketamine therapy is routinely offered as an alternative to ECT to the needy in the Department of Psychiatry affiliated with a teaching institute. There is a standard operative procedure laid down for ketamine therapy. Baseline and periodical assessment of depression by Hamilton Depression Rating Scale and suicidality by Columbia Suicide Severity Rating Scale is a part of it. Taking advantage of it, retrospective data analysis was done to determine the effectiveness of the therapy. Result: Significant improvement of depression and suicidality found at all the evaluation points after intravenous ketamine therapy. Conclusion: Intravenous ketamine therapy is an effective alternative to ECT among patients suffering from depression with suicidal ideation.
Keywords: Depression, ketamine, suicidal ideation
|How to cite this URL:|
Chaudhary P, Shah P, Mehta P. Retrospective data analysis to determine the effectiveness of intravenous ketamine therapy on patients suffering from depression with suicidal ideation. Ind Psychiatry J [Epub ahead of print] [cited 2022 Nov 30]. Available from: https://www.industrialpsychiatry.org/preprintarticle.asp?id=360858
The first clinical trial reporting antidepressant actions of ketamine was published in 2000, where ketamine was administered intravenously (40-min infusion) at the sub-anesthetic dose of 0.5 mg/kg. This contrasts with the typical dose of ketamine used in anaesthesia of up to 2 mg/kg. Ketamine was shown to elicit a rapid (within hours) and sustained (up to 7 days) antidepressant effect of a single dose in sub-anaesthetic repeated doses,,,,, which was shown to remain in effect (48 h) beyond its half-life,,, and 18–19 days following repeated infusions., The actions of ketamine to induce rapid antidepressant effects are in sharp contrast with the delayed effect onset of currently approved antidepressant treatments, which is particularly important in cases of patients with suicidal ideation (SI), where a lag in the onset of antidepressant action has been associated with increased risk for suicidal behavior. Ketamine has been also shown to induce a rapid amelioration of SI in major depressed patients, and to rapidly reduce anhedonia.,,
The evidence suggesting specific anti-suicidal effects of ketamine independent of its anti-depressive effect is consistent with the growing body of research implicating the glutamate system in the neurobiology of suicide. In study on initial single- and repeated-dose, the impact of ketamine on SI in treatment-resistant depression (TRD) found that IV ketamine (0.5 mg/kg over 40 min) was associated with rapid reductions in explicit and implicit suicidal cognitions within the first 24 h after infusion, which persisted for patients who received additional infusions. Ketamine is a new and effective option in future with rapid onset of action, but studies are limited with multiple doses of ketamine that have assessed depressive symptoms and SI comprehensively. Hence, index study aimed to assess the efficacy of multiple doses of intravenous (IV) ketamine in patients with severe depression with SI.
| Subjects and Methods|| |
Data extraction from records
Records of all indoor patients during the period of June 2019–June 2020 were extracted. There were 10 cases of depression with SI treated with ketamine therapy. These records were anonymised and demographic information, diagnosis, treatment, and outcome data were extracted.
There is a standard operative procedure (SOP) for ketamine therapy in the Department of Psychiatry, which is affiliated with a teaching institute. As per SOP, IV ketamine infusion was given in the dose range of 0.4–0.7 mg/kg over the period of 50 min. Usually, six such sessions, daily during the first week for four sessions and two sessions on alternate days on the second week were given. All patients were assessed by Hamilton Depression Rating Scale (HAM-D) and Columbia Suicidal Severity Rating Scale (C-SSRS) at baseline, at periodic interval, and post ketamine therapy. Assessment schedule is pre-treatment, 2 h after each session, and 7 days and 1 month after last session.
Because of the small sample size, outcome data are presented descriptively for subjects receiving infusions of ketamine. Study results used a last observation carried forward approach for those in the intent-to-treat population, defined as any subject who received all six infusions. Continuous parametric data were analyzed using the Student's t test for independent groups and the χ2 test or Fisher exact test, as appropriate, for categorical data. The HAM-D and C-SSRS were compared before and after ketamine injection by Friedman's test and Wilcoxon Signed-Rank Test paired t-test. The Friedman's test can also be used in place of the F test for repeated measures with interval- or ratio-level data that do not meet the assumptions of normality and homogeneity of variance and covariance. All statistical analyses were performed using SPSS 20, with P < 0.05 set for statistical significance and graphs drawn by Excel 2013.
| Result|| |
Patient demographics details: (n = 10)
The data were collected on a sample of 10 patients having depression with SI who were treated between June 2019 and July 2020. Out of 10 patients, three patients' records revealed lost follow up at month but received all six doses of IV ketamine and had follow-up at a week after the last infusion. The participants' age ranged from 22 to 49 years, with a mean of 33.1 (SD = 9.01). The majority of the patients were Hindu (80%) and educated up to secondary education (75%). Most of them were unemployed (55%) and married (70%). All patients were living with their joint family (100%) and most of them belonged to urban backgrounds (70%).
Clinical characteristics of the sample population: Patients (n = 10)
The mean age of onset of depression was 27.80 ± 10.72 years. Mean duration of the depression was 6.95 ± 4.31 months. All the patients had a diagnosis of a moderate depressive episode with SI. Two of them have a history of diabetes mellitus. None of them has a family history of medical illness or mental illness. Half of the patients were drug naïve.
Effect of ketamine treatment over time: Changes in the HAM-D scores
This study has shown that IV ketamine injection in sub-anesthetic doses results in a significant reduction of depressive symptoms in patients with major depression at 2 h, which was sustained until the 30 day after the last injection [Table 1].
|Table 1: Effect of ketamine treatment over time: Changes in the Hamilton Rating Scale for depression scores (n=10)a|
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Mean and standard deviation of HAM-D scores before and 2 h after each IV ketamine, one week after last dose, and one month after last dose show significant improvement in score serially and compared to baseline. There was a statistically significant difference in HAM-D score on Friedman's score after each doses, χ2 = 36.688, P = 0.000 (Serial means: 22.400 ± 1.7127; 9.400 ± 5.5817; 8.700 ± 5.8509; 8.300 ± 5.8699; 8.400 ± 6.1500; 7.500 ± 6.4679; 7.500 ± 6.4679; and 9.100 ± 7.5638). Post hoc analysis with Wilcoxon signed-rank tests was conducted, resulting in a significance level set at P < 0.01. There were statistically significant differences between the baseline score and score after each dose. Z and P values are shown in [Table 2].
|Table 2: Effect of ketamine treatment over time: Changes in the Hamilton Rating Scale for depression scores (n=10)a|
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One patient had not shown improvement of HAM-D scoring after six infusions and needed administration of ECT. Mean score of HAM-D was increased on the first week and one month follow-up but on sub analysis, it was not found statistically significant (P > 0.05) [[Table 1], sub analysis 1]. In addition, the baseline mean score of HAM-D was significantly reduced after the first dosage of IV ketamine infusion (P = 0.002) [[Table 1], sub analysis 2]. Serial HAM-D score before and after each dose of ketamine showed in [Figure 1].
C-SSRS SI and behaviour
IV ketamine significantly reduced C-SSRS score following the first dose and remained improved throughout all assessments [Table 3]. Nine patients reported no SI after the first dose that was sustained for 30 days. Serial C-SSRS score before and after each dose of ketamine showed in [Figure 2].
|Figure 2: C-SSRC score before and after ketamine dose – suicidal ideation category shifting|
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|Table 3: Effect of ketamine treatment over time: Shifting of suicidal ideation category in the C-SSRC (n=10)|
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Suicide-related adverse events: No completed suicides, suicide ideation, or suicidal behaviour occurred during study. Other adverse effects such as nausea and vomiting were reported by two subjects but they subsided within an hour of the injection.
| Discussion|| |
In this study, parenteral ketamine has resulted in a rapid and significant improvement in the depressive symptoms and SI. In addition, this study presents data indicating that repetitive ketamine infusions may be safe and feasible and, thus, may be an acceptable adjunct to standard antidepressant therapies for rapid relief of SI in inpatients with major depressive disorder (MDD). Two hours after the first injection of ketamine showed a significant reduction in the HAM-D and C-SSRS mean score of 58.04% and 88.46%, respectively. This improvement was sustained 1 month after the last dose (58.48% and 88.46%). Adverse effects noticed were of mild nature and transient lasting less than an hour. In this study, rapid decrease in HAM-D scores suggests overall improvement in depressive symptoms supporting rapid antidepressant effect of IV ketamine as similar results were found in a randomized placebo-controlled trials by Berman, Zarate, Murrough, and Sos.
In this study, rapid reduction in C-SSRC scores suggests overall improvement in SI supporting rapid anti-suicidal effect of IV ketamine as similar results were found in previous studies.,,,, This rapid antidepressant and anti-suicidal effects are in contrast to traditional monoamine-based antidepressants that take weeks to months to exert their full antidepressant effect. Studies focusing on of IV ketamine on depression and SI across the world showed in [Table 4].
|Table 4: Studies focusing on effect of intravenous ketamine on depression and suicidal ideation|
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Previous studies suggested repeated-dose ketamine as a potential antidepressant continuation strategy for patients who show initial response to ketamine infusion. For instance, a group of researchers used repeated-dose open-label ketamine (6 infusions over 12 days) in 10 medication-free TRD patients. In another study, a treatment-refractory MDD patient was treated with six doses of ketamine (0.5 mg/kg, IV, days 1, 3, 5, 8, 11, and 13) and his depressive symptoms were significantly improved within 13 days and persisted for 3 months. These data together with our data suggest that repeated doses of ketamine could also be effective in improving depressive symptoms in depressed patients.
No cognitive or psychotic symptoms were observed post infusion as similar finding was observed in previous studies with sub anaesthetic dose., However, ketamine ranks highly on the list of commonly abused substances.,,,, Ketamine abusers also have high rates of depression and experience significant brain dysfunction. Whereas these risks have not been demonstrated in serial infusions for depressed patients. Cognitive performance of poly-drug users and healthy controls were compared with the following three groups: ketamine ex-users, infrequent users, and frequent users. Cognitive impairments were significant among frequent users who self-administered greater than 1 g of ketamine at a minimum frequency of four times per week. Frequent users also showed impairments in recognition and working memory. No significant differences in performance were observed between controls, poly-drug users, and infrequent or ex-users of ketamine. This report also suggested that cognitive impairment associated with chronic and frequent ketamine use are reversible with abstinence.
There are some limitations to this study. First, like other published studies, this study suffers from its retrospective design. It is not randomized, controlled, blinded, or prospective in nature. Second, small sample size from a single site limits the interpretations that can be drawn and the generalizability of the sample to the broader population of patients. Third, treatment was open label and adjunct to any existing antidepressant treatments, with the absence of a control.
Although the sample size was limited, most of the patients with depression who were treated with low-dose IV ketamine experienced rapid (within hours), robust, and persistent improvement of depressive symptoms and SI with limited adverse effects. Ketamine in sub anaesthetic doses has demonstrated efficacy for anxious or non-anxious depression, unipolar depression, bipolar depression, TRD, and SI associated with depression. However, low doses (less than 0.5 mg/kg) of IV ketamine cannot ensure an antidepressant effect. In terms of treatment frequency, two to three repeated ketamine administrations per week may be required to maintain antidepressant efficacy. Furthermore, weekly maintenance doses could be used for maintaining remission or a significant response. Our findings support the need for large adequately powered randomized controlled trials to determine both the efficacy and safety of serial ketamine infusions as an adjunct to usual treatment in patients with depression with SI in real world settings.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]