Rapid Antidepressant and Antisuicidal Effects of Low-Dose Ketamine Infusion in Patients With Treatment-Resistant Depression With or Without Low-Grade Inflammation

Abstract

Background

Low-grade inflammation (LGI) contributes to resistance against traditional antidepressants. However, whether the antidepressant and antisuicidal effects of ketamine on patients with treatment-resistant depression (TRD) differ between those with LGI and those without LGI remains unknown.

Methods

This study included 167 patients with TRD, among whom 46 had LGI and 121 did not have LGI. The patients received a single infusion of either low-dose ketamine or a placebo. A C-reactive protein level of≥3 mg/L indicated LGI. Depressive symptoms were measured from baseline to day 3 by using the 17-item Hamilton Depression Rating Scale (HDRS) and the Montgomery-Asberg Depression Rating Scale (MADRS).

Results

Generalized estimating equation models revealed antidepressant effect of ketamine in patients with no LGI (HDRS scores: p<0.001; MADRS scores: p<0.001) but not in patients with LGI (all p>0.05). The antisuicidal effect of ketamine (indicated by the score on item 10 of the MADRS) was observed in both groups of patients with (p=0.046) and without LGI (p<0.001). However, ketamine was effective for TRD regardless of whether inflammation levels were high or low, while the placebo response was notably greater only in patients with LGI.

Discussion

This study suggests that among patients with TRD, only those without LGI respond to low-dose ketamine infusion. Whether the negative findings of the antidepressant effect of ketamine among patients with LGI may be because of the effect of the placebo infusion needs further investigation. Further randomized, placebo-controlled studies are needed to validate these findings.

Keywords

low-grade inflammation - ketamine - antidepressant effect - antisuicidal effect

Introduction

Low-grade inflammation (LGI) is a systemic condition characterized by the chronic subclinical production of inflammatory factors, including C-reactive protein (CRP). LGI has been implicated in the pathogenesis of various noncommunicable diseases, such as metabolic diseases, cardiovascular diseases, degenerative disorders, and severe mental disorders [1] [2] [3]. In a meta-analysis involving 13,541 patients with depression and 155,728 control individuals, 27% of the patient cohort had LGI (i. e., CRP level≥3 mg/L) [1]. In patients with major depressive disorder, LGI has been associated with adverse clinical profiles, such as an elevated rate of relapse, worse cognitive deficits, and a poor response to antidepressants [4] [5] [6]. We previously reported an association between LGI and an elevated risk of treatment-resistant depression (TRD), defined as the lack of response to at least two distinct antidepressants administered at adequate dosages for appropriate durations [4].

Low-dose ketamine exerts rapid antidepressant and antisuicidal effects in patients with TRD and major depressive disorder with suicidal ideation [7] [8] [9]. Low-dose ketamine also increases the level of brain-derived neurotrophic factor and promotes synaptogenesis by modulating the mammalian target of the rapamycin pathway through the blockade of the N-methyl-D-aspartate receptor; evidence also suggests that the anti-inflammatory effect of low-dose ketamine mediates its antidepressant and antisuicidal effects [10] [11] [12]. We previously demonstrated a reduction in the tumor necrosis factor-α level 40 min after a single infusion of 0.5 mg/kg ketamine; this reduction was associated with reduced total scores on the Montgomery-Asberg Depression Rating Scale (MADRS) [12]. In a preclinical murine model of postoperative depression, esketamine attenuated the nuclear factor κB pathway – a prototypical proinflammatory signaling pathway – in the prefrontal cortex [13]. Yang et al. reported that proinflammatory cytokines, such as interleukin (IL)-6 and CRP, may serve as biomarkers of treatment response to low-dose ketamine in patients with TRD [14]. However, whether the antidepressant and antisuicidal effects of low-dose ketamine among patients with TRD differ between those with and without LGI remains unclear.

In this study, we reanalyzed data from three of our clinical trials, wherein 167 patients with TRD received low-dose ketamine infusions. Our goal was to clarify how LGI influences the antidepressant and antisuicidal effects of ketamine in patients with TRD. Considering the anti-inflammatory effect of ketamine, we hypothesized that low-dose ketamine exerts both antidepressant and antisuicidal effects in patients with TRD, regardless of the presence of LGI.

Methods

Participants and study protocols

In the present study, we reanalyzed the data from our three low-dose ketamine infusion clinical trials [8] [9] [15]. Details of the clinical trial protocols have been published in our previous papers and were illustrated in [Fig. 1] [8] [9] [15]. Briefly speaking, in clinical trials 1 and 3, 71 patients with TRD and 48 patients with TRD and strong suicidal ideation were randomized to a single low-dose ketamine (0.5 mg/kg or 0.2 mg/kg in clinical trial 1 and 0.5 mg/kg in clinical trial 3) or placebo (normal saline in clinical trial 1 and 0.045 mg/kg midazolam in clinical trial 3) group, respectively. All participants in clinical trials 1 and 3 were followed up to 28 days postinfusion [8] [9]. In clinical trial 2 phase 1, 49 patients with TRD (n=33) or treatment-resistant bipolar depression (n=16) received two infusions of 0.5 mg/kg ketamine on day 1 and day 4, respectively. Those who responded to 0.5 mg/kg ketamine in clinical trial 2 phase 1 were subsequently randomized to a 7-week treatment of D-cycloserine or placebo in phase 2 [15]. TRD was defined as the failure of treatment response for at least two different antidepressants with adequate dosage and treatment duration [8] [9]. Treatment-resistant bipolar depression was defined as a lack of response to at least two trials with antidepressants or mood stabilizers with documented efficacy in bipolar depression (lithium, lamotrigine, quetiapine, or olanzapine) in adequate doses and treatment duration [15] [16]. Depressive symptoms were rated using the 17-item Hamilton Depression Rating Scale (HDRS) and MADRS in three clinical trials [8] [9] [15]. The Maudsley staging method for the level of treatment refractoriness was also assessed [17]. In the current study, exclusion criteria included major medical (i. e., diabetes, autoimmune diseases, cardiovascular diseases, current infectious diseases), neurological (i. e., stroke, epilepsy) diseases or a history of alcohol or substance use disorders. Furthermore, those who used antibiotics or immune modulators, such as non-steroidal anti-inflammatory drugs and steroids, were excluded from our clinical trials. Regarding our research aim to examine the role of LGI on the antidepressant effect of a single low-dose ketamine infusion, we only analyzed the clinical data from day 1 to day 3 of three clinical trials ([Fig. 1]). The treatment response was defined as a≥50% reduction in overall depressive symptoms at Day 2 postinfusion. Three clinical trials were registered in the UMIN Clinical Trials Registry (UMIN000016985, R000027142-UMIN000023581, and UMIN000033916). This study was performed in accordance with the Declaration of Helsinki and was approved by the Taipei Veterans General Hospital Institutional Review Board. Witten informed consents were provided by all participants.

Fig. 1 Study illustration. TRD: treatment-resistant major depression; TRBD: treatment-resistant bipolar depression.

Measurement of C-reactive protein levels and definition of low-grade inflammation

Fasting serum samples were collected between 8:00 AM and 10:00 AM in serum separator tubes, clotted for 30 min, and stored at −80°C until use. Enzyme-linked immunosorbent assay (ELISA) kits (R&D systems, Minneapolis, MN, USA) were used to measure CRP levels for all participants. The vendor’s instructions were followed for all assays. An ELISA plate reader with Bio-Tek Power Wave Xs and Bio-Tek KC junior software (Winooski, VT, USA) was used to measure the final absorbance of each sample of the mixture and analyze the same at 450 nm. We considered the range specified in the vendor’s instructions as standard. A linear regression R² value of at least 0.95 was considered a reliable standard curve. LGI was defined based on CRP levels≥3 mg/L in the present study, which was compliant with the proposed cut-off point for CRP levels on LGI in previous studies [1].

Statistical analysis

Continuous and nominal variables were analyzed through one-way analysis of variance and Fisher’s chi-square tests, respectively, to assess the differences in the demographic and clinical data between groups. After adjusting for age, sex, body mass index (BMI), diagnosis, and psychiatric comorbidities, CRP level (<3 or≥3 mg/L)-stratified generalized estimating equation (GEE) models with the autoregressive method for correlations of repeated measures for the same individual over time was used to examine the effect of ketamine on overall depressive symptoms (total HDRS and MADRS scores) and specific suicidal symptoms (HDRS item 3 and MADRS item 10 scores) during the study period (baseline to day 3) with the group (ketamine or placebo) as a between-patient factor, time as a within-patient factor, and baseline depressive and suicidal symptoms as between-patient predictors as well as all possible interactions, respectively. Two-tailed p<0.05 was considered statistically significant. All data processing and statistical analyses were performed using SPSS, version 17 (SPSS Inc.).

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to Taiwan’s clinical trial ethical regulation but are available from the corresponding author upon reasonable request.

Results

In all, 167 patients with TRD were administered a single infusion of low-dose ketamine or placebo, including 46 in the LGI group and 121 in the non-LGI group ([Table 1]). Patients in the LGI group were younger (p=0.004) and more obese (p<0.001) compared with those in the non-LGI group ([Table 1]). In addition, patients with TRD and LGI had higher rates of comorbid posttraumatic stress disorder (p=0.010) and generalized anxiety disorder (p=0.037) than those with TRD without LGI ([Table 1]). Other demographic and clinical characteristics, such as diagnosis, duration of illness, levels of treatment refractoriness, and baseline overall depressive (total HDRS and MADRS scores) and suicidal (HDRS item 3 and MADRS item 10 scores) symptoms, did not differ between groups (all p>0.05) ([Table 1]). In the non-LGI group, patients in the low-dose ketamine group had a higher treatment response (HDRS: 41.9% vs. 8.6%, p<0.001; MADRS: 39.5% vs. 5.7%, p<0.001) than did those in the placebo group ([Table 2]). However, the treatment response rates did not differ between treatment groups (all p>0.05) among patients with LGI ([Table 2]).

Table 1 Demographic and clinical characteristics between groups.

	Non-LGI group (n=121)	LGI group (n=46)	All sample (n=167)	p-value
Age (years, SD)	44.89 (12.92)	38.63 (10.78)	43.17 (12.65)	0.004
Sex (n, %)				0.438
Male	31 (25.6)	15 (32.6)	46 (27.5)
Female	90 (74.4)	31 (67.4)	121 (72.5)
BMI (SD)	22.31 (4.11)	27.52 (4.09)	23.75 (4.71)	<0.001
Diagnosis (n, %)				0.863
Major depressive disorder	105 (86.8)	41 (89.1)	146 (87.4)
Bipolar depression	16 (13.2)	5 (10.9)	21 (12.6)
Duration of illness (years, SD)	12.03 (8.38)	10.28 (7.98)	11.55 (8.29)	0.225
Infusion group (n, %)				0.454
0.5 mg/kg ketamine	70 (57.9)	27 (58.7)	97 (58.1)
0.2 mg/kg ketamine	16 (13.2)	6 (13.0)	22 (13.2)
0.045 mg/kg midazolam	15 (12.4)	9 (19.6)	15 (14.4)
Normal saline	20 (16.5)	4 (8.7)	20 (14.4)
MSM scores (SD)	8.88 (1.75)	9.37 (1.83)	9.02 (1.78)	0.116
Baseline CRP levels (mg/L)	0.70 (0.69)	6.60 (3.49)	2.32 (3.26)	<0.001
Clinical symptoms at baseline (SD)
Total HDRS scores	22.71 (4.38)	22.26 (3.53)	22.59 (4.16)	0.534
Total MADRS scores	35.51 (5.66)	35.52 (5.15)	35.51 (5.51)	0.992
HDRS item 3 scores	1.86 (0.81)	2.09 (0.81)	1.92 (0.81)	0.107
MADRS item 10 scores	3.13 (1.23)	3.50 (1.05)	3.23 (1.19)	0.075
Psychiatric comorbidities (n, %)
Panic disorder	49 (40.5)	23 (50.0)	72 (43.1)	0.297
PTSD	11 (9.1)	12 (26.1)	23 (13.8)	0.010
GAD	65 (53.7)	33 (71.7)	98 (58.7)	0.037
History of attempted suicide (n, %)	69 (57.0)	27 (58.7)	96 (57.5)	0.863

LGI: low-grade inflammation; SD: standard deviation; BMI: body mass index; MSM: Maudsley Staging Method; CRP: C-reactive protein; HDRS: 17-item Hamilton Rating Scale for Depression; MADRS: Montgomery-Åsberg Depression Rating Scale; PTSD: post-traumatic stress disorder; GAD: generalized anxiety disorder.

Table 2 Response rates between groups, as stratified by LGI groups.

	Non-LGI group (n=121)		LGI group (n=46)
	Ketamine (n=86)	Placebo (n=35)	Ketamine (n=33)	Placebo (n=13)
Response rate at day 2 (n, %)
Based on HRDS	36 (41.9)	3 (8.6)	15 (45.5)	4 (30.8)
p-value	<0.001		0.510
Based on MADRS	34 (39.5)	2 (5.7)	14 (42.4)	2 (15.4)
p-value	<0.001		0.101

LGI: low-grade inflammation; HDRS: 17-item Hamilton Rating Scale for Depression; MADRS: Montgomery-Åsberg Depression Rating Scale.

CRP level (<3 or≥3 mg/L)-stratified GEE models showed an antidepressant effect of low-dose ketamine infusion only among patients with TRD without LGI (total HDRS scores: group effect: p<0.001; total MADRS scores: group effect: p<0.001) but not among those with TRD and LGI (p=0.535; p=0.587) ([Fig. 2]). An antisuicidal effect of low-dose ketamine was noted among patients with TRD without LGI, measuring HDRS item 3 (group effect: p<0.001) and MADRS item 10 (p<0.001) ([Fig. 3]). However, an antisuicidal effect of low-dose ketamine was only noted among patients with TRD and LGI based on the measure of MADRS item 10 (group effect: p=0.046) but not on that of HDRS item 3 (p=0.106) ([Fig. 3]).

Fig. 2 Trajectories of total HDRS and MADRS scores between groups, stratified by CRP levels. CRP: C-reactive protein; HDRS: 17-item Hamilton Rating Scale for Depression; MADRS: Montgomery-Åsberg Depression Rating Scale.

Fig. 3 Trajectories of HDRS item 3 and MADRS item 10 scores between groups, stratified by CRP levels. CRP: C-reactive protein; HDRS: 17-item Hamilton Rating Scale for Depression; MADRS: Montgomery-Åsberg Depression Rating Scale.

Discussion

Our findings revealed that among patients with TRD, only those without LGI responded to a single infusion of low-dose ketamine. The antidepressant and antisuicidal effects of low-dose ketamine were not observed in patients with LGI, potentially due to the much stronger placebo effect in this group.

Immunometabolic depression is a subtype of depression characterized by the convergence of LGI, metabolic dysregulation, and atypical depressive symptoms [18]. Findings from both our study and the meta-analysis by Osimo et al. demonstrated that the prevalence of LGI (CRP≥3 mg/L) in depression was approximately 27% [1]. However, our findings do not corroborate those of Park et al., who observed that ketamine effectively mitigated both typical/melancholic and atypical symptoms of depression [19]. However, 2 days after the infusion of ketamine, its antidepressant effect was more pronounced against typical/melancholic symptoms than against atypical symptoms [19]. The researchers further reported that the immunometabolic and inflammatory mechanisms underlying atypical symptoms of depression may be resistant to the rapid antidepressant effect of ketamine [19]. These findings are supported by those of our study. We observed the antidepressant effects of low-dose ketamine infusion only in patients without LGI. Therefore, inflammation-related depressive symptoms may be resistant to the antidepressant effects of ketamine.

Our finding pertaining to the absence of the antidepressant effect in patients with LGI may partially echo a clinical debate on whether anti-inflammatory drugs, including nonsteroidal anti-inflammatory drugs, proinflammatory cytokine inhibitors, and minocycline exert an adequately strong antidepressant effect against depression, particularly TRD and bipolar depression [20] [21] [22]. A meta-analysis involving 6,262 individuals – of whom 4,258 were participants of nonsteroidal anti-inflammatory drug trials and 2,004 were participants of cytokine inhibitor trials – demonstrated that anti-inflammatory agents ameliorated depressive symptoms (pooled standard mean difference: −0.34) compared with the effects of placebos [21]. However, the studies by Hellmann-Regen et al. [20] [22] and Husain et al. [20] [22] demonstrated that 200 mg/day minocycline had no antidepressant effect in patients with TRD or bipolar depression. By contrast, Nettis et al. demonstrated that minocycline had antidepressant effects in patients with TRD with CRP levels of≥3 mg/L [23]. Further studies are needed to explore the effects of anti-inflammatory agents against depression, particularly TRD, and to clarify whether ketamine’s inflammatory effect mediates its antidepressant effect.

In this study, the antisuicidal effect of ketamine – measured in terms of the score on item 10 of the MADRS – was observed in patients regardless of LGI status. However, the effect was more prominent in patients without LGI than in those with LGI. The antisuicidal effect of ketamine is partially independent of its antidepressant effect, which potentially highlights the shared yet distinct pathomechanisms underlying depression and suicide [24] [25]. Inflammation leads to the production of quinolinic acid and kynurenic acid, which are an agonist and an antagonist, respectively, of the N-methyl-D-aspartate receptor [26] [27]. Erhardt et al. [26] examined cerebrospinal fluid (CSF) samples from 64 medication-free individuals who had attempted suicide and 36 control individuals; the researchers found that the level of quinolinic acid but not kynurenic acid was substantially elevated in the CSF of those who had attempted suicide. Furthermore, levels of quinolinic acid and IL-6 in CSF were positively correlated with total scores on the Suicide Intent Scale. This finding is consistent with our finding that suggests that ketamine exerts antisuicidal effects in patients with TRD regardless of LGI status.

In this study, the rate of response (on day 2) to the antidepressant effect of ketamine was similar between the non-LGI group (HDRS: 41.9%; MADRS: 39.5%) and LGI group (HDRS: 45.5%; MADRS: 42.4%); however, the rate of response (on day 2) to placebo infusion was higher in the LGI group (HDRS: 30.8%; MADRS: 15.4%) than in the non-LGI group (HDRS: 8.6%; MADRS: 5.7%). This difference explains why the antidepressant effect of ketamine was noted only in the non-LGI group. To the best of our knowledge, our study is the first to report this finding. The association between inflammation and the placebo effect remains a mystery in neuroscience [28] [29] [30]. Kokkotou et al. demonstrated a stronger placebo effect (symptom relief) in patients with irritable bowel syndrome who had high levels of osteoprotegerin and TWEAK – two cytokines belonging to the tumor necrosis factor superfamily – than in those who had low levels of these cytokines [29]. Evans et al. and Kokkotou et al. [29] [30] proposed a counterintuitive hypothesis suggesting that patients exhibiting a stronger immune response were more likely to benefit from placebo treatment. In fact, despite the non-significance in the distribution of infusion drugs (ketamine, midazolam, and normal saline) in our study, more percentage of patients were allocated to midazolam than normal saline (genuine placebo) in the LGI vs. non-LGI group, and more positive effects in the LGI group may reflect this point since midazolam may have some antidepressant effects [9]. Further randomized, placebo-controlled trials investigating the effects of low-dose ketamine in patients with TRD and LGI are needed to validate our findings.

Our study has several limitations. First, the study was a post hoc analysis of three of our randomized placebo (normal saline or midazolam)-controlled and open-label clinical trials. Combining data from clinical trials with different study designs might have introduced a bias in our findings, necessitating further randomized, large-scale, placebo-control trials to clarify the complex association of LGI with the antidepressant and antisuicidal effects of ketamine. Second, our clinical trials involved add-on ketamine therapy because the medications used by patients with TRD were not discontinued during the trials. This is because an add-on design is ethically appropriate for patients with TRD and offers real-life data. Third, CRP levels may not be stable within the same individual. Further studies with repeated CRP assessments may be required to define an LGI state in patients. Fourth, as previously mentioned, the LGI prevalence was approximately 27% based on the CRP level≥3 mg/L threshold [1]. Osimo et al. further reported that the sample source (inpatient, outpatient, or population-based), participant age, BMI, ethnicity, or antidepressant treatment did not correlate with this LGI prevalence [1]. The definition of LGI based on CRP level≥3 mg/L may be arbitrary, but it was reliable between our study and the meta-analysis study. Finally, despite the exclusion of patients with current infectious diseases and other immunological conditions from our clinical trials, we discovered that six patients had CRP levels exceeding 10 mg/L. They did not exhibit any infectious symptoms or signs during the clinical trials. After excluding those six patients, the analyses revealed consistent findings.

In conclusion, among patients with TRD, only those without LGI respond to low-dose ketamine infusion. However, further investigation is necessary to determine if patients with TRD and LGI truly did not respond to low-dose ketamine, as our analysis revealed a significant placebo effect in this group. In addition, ketamine appears to exert antisuicidal effects in patients with TRD regardless of LGI status. Further studies should be conducted to clarify the association between ketamine’s anti-inflammatory effect and its antidepressant and antisuicidal effects.

Contributions

MHC and TPS designed the study. MHC, TPS, WCL, CTL, and HJW performed the clinical trials; MHC analyzed the data and drafted the manuscript; TPS, CTL, WCL, YMB, SJT, WCM, and PCT enrolled the candidate patients and performed the literature reviews. All authors reviewed the final manuscript and agreed to its publication.

Conflicts of interest

The authors in this study had no conflict of interest to declare.

Acknowledgements

Thank all research assistants, physicians, pharmacist and nursing staffs at D020 Unit of Department of Psychiatry, Taipei Veterans General Hospital and at Department of Psychiatry, Cheng Hsin General Hospital for their assistance during the study process, without whom this work could not have been possible. We thank Mr I-Fan Hu for his support and friendship.

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Publication History

Received: 09 October 2024

Accepted: 01 December 2024

Article published online:
20 December 2024