Antisuicidal efficacy of ketamine infusion in suicidal patients of depressive disorder.

BACKGROUND: The efficacy of ketamine in the rapid alleviation of depressive and suicidal symptoms has been observed over the past few years around the globe. Exploration of rapid antisuicidal efficacy of ketamine in Indian subpopulation can be a good preventive pharmacological option for unprecedented rise in suicides in India. AIM: To assess efficacy of ketamine infusions on suicidal patients of depressive disorder. Severity of depression and suicidality were quantified daily over 1 week.
MATERIALS AND METHODS: This was a randomized control study, comprised sixty patients of age group 18-60 years, with a diagnosis of depressive episode, having the Modified Scale for Suicidal Ideations (MSSI) score >20 with exclusion of severe medical or surgical illness, pregnancy, and breast-feeding females. Patient were assigned to ketamine and normal saline group. Three infusions were given over 1 week on day 0, day 2, and day 4. Assessments were made at baseline using the 17-item Hamilton Depression Rating Scale (HAM-D17) and MSSI, for depression and suicidality, respectively. Assessments were repeated at 6 h after first infusion and then every day for 1 week.
RESULTS: There were significant reductions in HAM-D17 score and MSSI score within 6 h of the first dose in the ketamine group as compared to the normal saline group. Significant sustained improvement was seen on further days till 1 week in the ketamine group as compared to the normal saline group.
CONCLUSION: Ketamine might be a reasonable choice to fulfil the efficacy gap created by the delayed antisuicidal onset of standard treatments. Copyright:

INTRODUCTION

The unprecedented rise in suicidal cases in India is a serious public health problem. Psychiatric disorders are estimated to contribute a large proportion of suicides and suicide attempts. The most common psychiatric disorder in suicidal patients is depressive disorder. Suicidal thoughts in depressive patients are difficult to manage and is a crucial public health hazard. It is a devastating clinical emergency needing urgent intervention. Currently, very few treatment modalities are available to be effective for curbing suicidal thoughts. Treatments such as clozapine and lithium have demonstrated effects on suicidal behavior over weeks to months; these effects may be limited to specific diagnoses.[1] None of the currently available antidepressants such as tricyclics, selective serotonin reuptake inhibitors, and serotonin and norepinephrine reuptake inhibitors are capable of inducing immediate antisuicidal effect, leaving a considerable number of patients struggling with suicidal thoughts. Considering the delayed onset of action of antidepressants, electroconvulsive therapy (ECT) is still considered an acute indication to abort the suicidal thoughts due to its rapid response,[23] but it is a partly invasive procedure and besides procedural and anesthesia-related complications, poses consent-related issues. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, is currently being used for induction and maintenance of general anesthesia, chronic neuropathic pain, and sedation.[45678] Ketamine has been used earlier also in the field of psychiatry as an anesthetic agent in ECT, for catharsis and as psychedelics,[91011] but considering the occasional rise in intracranial pressure limited its usage. Researches on the use of ketamine for treating depression have shown rapid-acting antidepressant effects on patients with treatment-resistant depression (TRD).[121314] Multiple meta-analyses have confirmed ketamine's acute antidepressant effects in patients with major depressive episodes associated with major depressive disorder (MDD) or bipolar disorder.[15161718] Recent observations around the globe reveal that ketamine brings about rapid and marked alleviation of suicidal ideas in depressed patients.[192021] There is limited current knowledge regarding antisuicidal efficacy and safety of ketamine in the Indian population. The Indian population differs from the rest of the world due various sociodemographic, transcultural, and genetic differences. Therefore, this study was conducted to explore the antisuicidal effect of ketamine in depressed suicidal patients of Indian origin.

MATERIALS AND METHODS

Participants

This was a hospital-based single-blinded randomized controlled prospective study, conducted from February 2019 to August 2020 at the psychiatry department of a tertiary care center. During these 18 months, all suicidal patients presenting to our facility were assessed for eligibility and the patients who met the study criteria were enrolled for the study. Even enrollment numbers were allocated as Group A (Ketamine Group) and odd enrollment numbers as Group B (normal saline group). The participants were hospitalized for at least 1 week [Flowchart 1].

Flowchart 1

Flowchart of the study

Patients of 18–60 years age group, fulfilling the International Classification of Diseases-10 Diagnostic Criteria for Research (ICD-10 DCR) diagnostic criteria for the “depressive episode” with severe suicidal ideations (Modified Scale for Suicidal Ideations [MSSI] score >20), were included in the study and those having suicidal ideations other than depressive disorder were excluded. All compulsory investigations were done, wherever is applicable. Patients with severe medical/surgical illnesses, electrocardiogram abnormality, or abnormality on fundoscopy were also excluded from the study. Pregnant and breastfeeding females were excluded.

Ethical clearance was taken from the institutional ethical committee vide letter no. 9469/SS/PG/MC/2019. Because this study was conducted as a part of thesis by a postgraduate candidate, it was done under the supervision and directions of the ethical committee which did not direct us to get it registered in trial registry. We can take it as a limitation of the study if desired.

Procedure

A clinical and neuropsychiatric assessment was conducted by an experienced psychiatrist to confirm the diagnosis of depressive episode as per ICD-10 DCR. Data were collected in the semistructured data entry pro forma, and 17-item Hamilton Depression Rating Scale (HAM-D17) and MSSI scales were applied to quantify the baseline severity of depression and suicidality. Group A received subanesthetic dose of ketamine (0.5 mg/kg) in 100 ml normal saline slow intravenous (IV) infusion (in a microdrip set at the rate of 60 drops per minute) on day 0 and on day 2 and day 4 in patients of sustained or resurging suicidal ideations. Group B received 100 ml normal saline infusion similarly. Ketamine was infused under the surveillance of an expert anesthesiologist and proper monitoring of vitals and saturation in a well-equipped chamber comprising emergency drugs and instruments, Boyle's apparatus, oxygen delivery system, cardiac monitor, and defibrillator. Group B patients also received the normal saline infusions in similar (sham) conditions. Patients were reviewed 6 h postinfusion on day 0 and then every day till day 6 for the assessment of severity of depression and suicidal ideations using the 17-item HAM-D17 and Modified Scale for Suicidal Ideations (MSSI), respectively. Patients were allowed to continue antidepressant medication throughout the study. Psychotropics available in our government hospital were prescribed tablet fluoxetine 20 mg BD for unipolar depressive episode and tablet fluoxetine 20 mg BD with tablet olanzapine 5 mg BD for bipolar depressive episode.

Statistics

Data analysis was performed with statistical software (IBM SPSS Statistics for Windows, Version 26.0, IBM Corp., Armonk, NY, USA). The study was powered assuming a two-sided test of group effect at α =0.05 significance level and at the 95% confidence level. Group comparisons on baseline characteristics were made using Chi-square tests or Fisher's exact test, as appropriate, for categorical variables. The quantitative variables were compared with independent t-test. Comparisons of severity scores (mean HAM-D17 and mean MSSI) between the groups at baseline and at various points of time after infusion were performed using independent t-test. Changes in severity scores (HAM D17 and MSSI) over the time from baseline were analyzed using repeated measures ANOVA with Greenhouse–Geiser corrections for sphericity violation, examining effect of time, effect of group on severity scores, and time–group interaction. The “group” (ketamine vs. normal saline) was included as a between subject factor and “time” (baseline and post-infusion observations) represented within subjects factor.

RESULTS

All 60 participants received 3 infusions and completed the 1-week study.

Baseline sociodemographic and clinical characteristics

The two groups did not differ significantly in sociodemographic and clinical characteristics [Table 1].

Table 1

Sociodemographic and clinical variables (n=30)

Variable	Ketamine group, n (%)	Normal saline group, n (%)	χ 2	P
Sex: Female	16 (53.3)	18 (60)	0.271	0.602
Marital status: Single	15 (50.0)	15 (50.0)	0.000	1.000
Residence: Rural	16 (53.3)	18 (60)	0.271	0.602
Occupation: Unemployed	15 (50.0)	13 (43.3)	7.976	0.240
Family type: Nuclear	26 (86.7)	22 (73.3)	1.667	0.197
Nature of depressive episode
Unipolar	17 (56.7)	18 (60.0)	0.069	0.793
Bipolar	13 (43.3)	12 (40.0)
H/o suicidal behaviour in previous episode
Present	7 (23.3)	7 (23.3)	0.000	1.000
Absent	23 (76.7)	23 (76.7)
Family h/o psychiatric illness
Present	20 (66.7)	16 (53.3)	1.111	0.292
Absent	10 (33.3)	14 (46.7)
Age (years), mean±SD	31.43±11.17	31.93±13.72	t=−0.155	0.878
Education (years), mean±SD	11.30±4.9	12.10±3.9.	t=0.704	0.484
Age of onset (years), mean±SD	27.37±10.14	28.20±13.52	t=−0.270	0.788
Duration of current episode (weeks), mean±SD	12.23±6.678	11.77±7.578	t=0.253	0.801
Baseline HAM-D 17 score, mean±SD	29.30±3.43	29.70±3.78	t=0.429	0.670
Baseline MSSI score, mean±SD	33.93±5.407	32.70±3.99	t=1.005	0.319

SD – Standard deviation; HAM-D 17 – 17-item Hamilton Depression Rating Scale; MSSI – Modified Scale for Suicidal Ideation

Treatment outcomes

Change in severity of depression

In between ketamine and normal saline groups, the mean HAM-D17 score at baseline showed no significant difference (P = 0.670), but there were significant differences in the mean HAM-D17 score at each point of time (P < 0.05 at each time point). The mean HAM-D17 score dropped more significantly within 6 h after first infusion of IV ketamine in the ketamine group (from 29.30 ± 3.436 to 20.10 ± 3.133) as compared to the normal saline group (from 29.70 ± 3.780 to 27.50 ± 2.991) who received normal saline infusion. Further, the reductions in the mean HAM-D17 scores at day 1, day 2, day 3, day 4, day 5, and day 6 were more rapid in the ketamine group as compared to the normal saline group. Statistical analysis with repeated measures ANOVA and Greenhouse–Geiser corrections showed that there was a significant linear effect of ‘time’ (P < 0.05) and the ‘time × group interaction’ was significant (P < 0.05) within the subjects. There was a significant effect of ‘group’ between subjects (P < 0.05) Table 2a and Graph 1].

Table 2a

Change in the mean Hamilton Depression Rating Scale 17 scores with time in both groups

Time point	Ketamine group		Normal saline group		t	P
	n	Mean±SD	n	Mean±SD
Day 0 (baseline)	30	29.30±3.436	30	29.70±3.780	−0.429	0.670
Day 0 (6 h postinfusion)	30	20.10±3.133	30	27.50±2.991	−9.356	<0.05
Day 1	30	18.03±1.650	30	26.90±1.668	−20.697	<0.05
Day 2	30	16.20±1.215	30	26.50±1.889	−25.117	<0.05
Day 3	30	15.13±0.730	30	25.40±1.380	−36.023	<0.05
Day 4	30	11.27±1.015	30	24.40±1.453	−40.593	<0.05
Day 5	30	10.47±1.167	30	24.60±1.522	−40.364	<0.05
Day 6	30	10.10±1.125	30	23.70±1.579	−38.422	<0.05

SD – Standard deviation

Graph 1

Change in the mean 17-item Hamilton Depression Rating Scale scores with time in both groups

Change in severity of suicidal ideations

In between ketamine and normal saline groups, the mean MSSI score at baseline showed no significant difference (P = 0.319), but there were significant differences in the mean MSSI score at each point of time (P < 0.05 at each time point). The mean MSSI score dropped more significantly within 6 h after first infusion of IV ketamine in the ketamine group (from 33.93 ± 5.407 to 14.60 ± 1.632) as compared to the normal saline group (from 32.70 ± 3.993 to 32.20 ± 4.213) who received normal saline infusion. Further, the reductions in the mean MSSI scores at day 2, day 3, day 4, day 5, and day 6 are more rapid in the ketamine group as compared to the normal saline group. However, there was a slight increase in the mean MSSI on day 1 from 6 h after first infusion, which further decreased after subsequent infusions. Statistical analysis with repeated measures ANOVA and Greenhouse–Geiser corrections showed that there was a significant linear effect of ‘time’ (P < 0.05) and the ‘time × group interaction’ was significant (P < 0.05) within the subjects. There was a significant effect of ‘group’ between subjects (P < 0.05) [Table 2b and Graph 2].

Table 2b

Change in the mean Modified Scale for Suicidal Ideation scores with time in both groups

Time point	Ketamine group		Normal saline group		t	P
	n	Mean±SD	n	Mean±SD
Day 0 (baseline)	30	33.93±5.407	30	32.70±3.993	1.005	0.319
Day 0 (6 h postinfusion)	30	14.60±1.632	30	32.20±4.213	−21.336	<0.05
Day 1	30	16.60±1.673	30	30.60±3.410	−20.188	<0.05
Day 2	30	10.30±1.622	30	29.10±3.418	−27.220	<0.05
Day 3	30	10.57±2.269	30	27.30±2.842	−25.198	<0.05
Day 4	30	7.00±1.339	30	27.00±2.841	−34.882	<0.05
Day 5	30	6.53±0.973	30	24.10±2.155	−40.688	<0.05
Day 6	30	5.47±1.676	30	22.90±2.631	−30.612	<0.05

SD – Standard deviation

Graph 2

Change in the mean MSSI scores with time in both groups

DISCUSSION

Suicide is one of the leading causes of death worldwide and particularly among those with psychiatric disorders. The upsurge in the magnitude of suicide in India also is getting so alarming that its preventive strategies have become one of the national priorities. Suicidal ideation itself is a medical emergency requiring urgent intervention. Unfortunately, very few therapeutic options are currently available to combat suicidal ideation immediately. Ketamine's effectiveness in the relief of acute suicidal ideation in depressed patients is a highly valuable finding around the globe, but there are limited data on the Indian population. Considering the unprecedented rise of suicides and the limited data about immediate pharmacological treatment options in an emergency, the present study was conducted in a tertiary care center, comprising 60 depressed suicidal patients with the aims of evaluating the antisuicidal efficacy and safety of repeated subanesthetic dose IV ketamine in the Indian population. To our knowledge, this is the first randomized drug-placebo study to assess the antisuicidal efficacy of repeated ketamine infusions in depressed suicidal patients of the Indian subpopulation, especially the severe suicidal ideation group. The main findings are that (1) slow IV infusion of subanesthetic dose ketamine was associated with rapid reduction of suicidal ideations in patients with depressive episode; (2) repeated three infusions were associated with sustained effect for one week; and (3) the antisuicidal effect of ketamine might have a different mechanism that of antidepressant mechanism.

The mean HMAD17 score and mean MSSI scores of 60 depressed suicidal patients were analyzed at baseline and at 6 h after the first infusion. Among the 60 patients, the 30 patients, who were infused ketamine, showed a decline in the mean HAM-D17 score from 29.30 ± 3.436 to 20.10 ± 3.133 (31% reduction) and a decline in the mean MSSI score from 33.93 ± 5.407 to 14.60 ± 1.632 (57% reduction) within the 6 h of the first infusion. These changes were significantly higher than the decline in the mean scores of the rest 30 patients who were infused normal saline as placebo. These findings suggest that ketamine induces a rapid and dramatic response in ameliorating suicidal ideation in patients of depressive disorder as early as within the 6 h.

The improvement in scores (mean HAM-D17 and mean MSSI) on further assessments was numerically greater in the ketamine group compared to the normal saline group at all time points over the 1 week, with significant between-group differences observed at day 1, day 2, day 3, day 4, day 5, and day 6 with two more repeated infusions and ongoing conventional antidepressant treatments.

A previous study by Thakurta et al.[22] on Indian subjects also demonstrated rapid effect of ketamine on suicidal ideation in depressed patients with single IV infusion of ketamine hydrochloride (0.5 mg/kg) after a 2-week medication-free period. The ketamine infusion significantly reduced the Scale for Suicide Ideation (SSI) and HAM-D17 scores, within 40 minutes which remained persistent to 230 min at each time point. The mean HAM-D17 scores declined by 6 points from baseline (22.96 ± 1.2) to 80 min postinfusion (17.5 ± 5.34) (P < 0.01). The change remained significant from minute 80 to day 2 postinfusion at each time point. The mean SSI scores declined by four points from baseline (4.85 ± 5.37) to 40 min postinfusion (0.78 ± 1.48) (P = 0.001). The change remained significant from min 40 to min 230 postinfusion at each time point. However, it was a single-arm study with lack of comparator group and follow-up period was of 2 days only.

The preliminary findings of a recent study by Price et al.[19] support this study that subanesthetic dose of IV ketamine has rapid effects on suicidality in TRD, and that acute improvements in suicidality can be sustained through repeated ketamine infusions. Reductions in suicidality item of the Montgomery–Asberg Depression Rating Scale (MADRS) were sustained for 12 days by repeated infusions.

Adjunctive ketamine in RCT by Grunebaum et al.[23] also demonstrated a greater reduction of clinically significant suicidal ideation in depressed patients within 24 h compared to midazolam. Eighty patients with current MDD and score ≥4 on the SSI were randomized to ketamine or midazolam infusion. The primary outcome was day 1 SSI score (24 h postinfusion). The reduction of SSI score was 4.96 points greater after ketamine compared to midazolam at day 1.

The antidepressant and antisuicidal effectiveness of ketamine has also been supported by DiazGranados et al.[20] Subjects with MDD received a single infusion of ketamine (0.5 mg/kg) and rated at baseline, 40, 80, 120, and 230 min postinfusion with SSI, MADRS, and HAM-D17. Suicidal ideation scores decreased significantly on the SSI as well as on the suicide items of other rating scales within 40 min; these decreases remained significant through the first 4 h postinfusion. Depression, anxiety, and hopelessness were significantly improved at all time points. This was an open-label study with no comparator group.

Murrough et al.[24] supported rapid and sustained antidepressant effect of ketamine. Participants with TRD were administered a series of up to six IV ketamine infusions, three times weekly over a period of 12 days. There was a large mean decrease in MADRS score at 2 h following the first ketamine infusion. Suicidal ideation rapidly decreased across the total study sample, and this decrease was largely sustained for the duration of the infusion period.

Zarate et al.[14] also supported rapid and sustained antidepressant and antisuicidal effects of ketamine in a double-blind, randomized, crossover, placebo-controlled study. Fifteen subjects with bipolar depression received a single IV infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on two test days 2 weeks apart. Within 40 min, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared to placebo; this improvement remained significant through day 3.

The decline in HAM-D17 score was slightly slower than the decline in the MSSI scores in the ketamine group. Furthermore, there was an increase in the MSSI scores on day 1, while the HAM-D17 score was still declined [Graphs 1 and 2]. These findings suggest that the antisuicidal effect may be partly independent of the antidepressant effect and ketamine might have a different mechanism for the antisuicidal effect. Many studies have also found conflicting results as to whether the reductions in suicidality specific or rather related to overall reductions in depression.[1920212526] However, such an increase in the MSSI score was not seen on further days probably because of the repeated infusions on day 2 and day 4. It has been established in many studies that repeated infusions achieve superior outcomes compared with a single infusion.[24252728]

Multiple pathways may be involved in the mechanism of ketamine which have been postulated in recent years such as activation of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, activation of the mammalian target of rapamycin pathway, inhibition of glycogen synthase kinase-3, and involvement of kynurenine pathway. NMDA receptor antagonists may act as an antisuicidal through kynurenine pathway.

Limitations

The sample size was very small. This was a single-blinded study where only the patients were blinded to the allocation but not the investigator. Outcomes may vary due to subjective biases as the measurement scales used in the study were based on subjective experience and report. The duration of the longitudinal follow-up in this study was short. Long-duration longitudinal follow-up is needed to assess the long-term efficacy and safety of ketamine.

CONCLUSION

The beneficial effects of ketamine plus conventional antidepressant treatment on suicidal ideations and other depressive symptoms, as measured by MSSI and HAM-D17 scales, respectively, were distinguished from normal saline at 6 h after the first infusion and on further days with repeated infusions till 1 week, which suggests that ketamine has a strong antisuicidal as well as augmenting antidepressant property. The findings of this study are consistent with other studies that subanesthetic dosage of ketamine is an effective treatment for rapid reduction of suicidal ideations in patients of depressive disorder who are at impending risk for suicide. The early and speedy improvement in suicidal ideations by repeated slow IV infusions of ketamine with prompt safety monitoring may be the turning point in the management of suicidal symptoms associated with depression. Thus, ketamine might be a reasonable choice to fulfil the efficacy gap created by the delayed antisuicidal onset of standard treatments. However, considering the dependence and abuse potential of ketamine, it should be used with caution.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.