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Abstract

Background:

Ketamine is a rapid-acting antidepressant with robust evidence, but unclear predictors of therapeutic response.

Objectives:

Based on previous knowledge, hemodynamic parameters and acute altered state of consciousness have been hypothesized as potential correlates of subsequent antidepressant outcome.

Design:

A post hoc analysis was performed using the data from an open-label study, in which 39 patients with depression received a single intravenous infusion of ketamine (0.54 mg/kg). Antidepressant response was defined as ⩾50% reduction in the Montgomery–Åsberg Depression Rating Scale (MADRS) at day 7.

Methods:

Systolic and diastolic blood pressure (SBP and DBP), heart rate, Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS) were assessed during the infusion, alongside plasma levels of ketamine and norketamine. Data were analyzed using mixed-effects models and correlation and regression techniques.

Results:

Responders exhibited significantly higher SBP and DBP during ketamine infusion compared with nonresponders. The degree of dissociation or psychotomimetic symptoms during the infusion did not differ significantly between responders and nonresponders. Antipsychotic (AP) augmentation was associated with worse antidepressant outcome as well as with lower infusion-related blood pressure values. CADSS and BPRS did not differ between AP users and nonusers. None of the parameters correlated with plasma levels of ketamine or norketamine.

Conclusion:

Higher blood pressure during ketamine administration was associated with better antidepressant outcome, supporting the hypothesis concerning sympathetic activation in treatment responders. Psychological parameters (as measured by CADSS and BPRS) were not linked to subsequent outcomes and did not resolve inconsistencies in previous studies. Concomitant antipsychotic medication attenuated ketamine’s antidepressant effects.

Trial registration:

EudraCT 2018-001539-39.

Keywords

antidepressant antipsychotics blood pressure dissociation ketamine

Introduction

Major depressive disorder (MDD) is a disabling illness imposing a substantial socioeconomic burden.¹ Despite advances in treatment, up to 20% of patients fail to achieve remission even after 2 years of conventional therapy.^2,3 Recent research has thus shifted the focus to ketamine, a rapid-acting glutamatergic antidepressant, demonstrating a robust effect within hours in treatment-resistant patients^4,5 and confirmed across multiple meta-analyses.^6
–9

Despite evident therapeutic potential, ketamine has several limitations. First, the short-term effect of a single administration rarely exceeds a few weeks.¹⁰ Nevertheless, this can be addressed by repeated dosing, prolonging remission, and increasing the cumulative response rate.^11
–13 Second, ketamine is effective in an average of 45 ± 10% of patients with treatment-resistant depression,⁷ and existing research has not yet identified clear factors explaining better response in specific patient groups. Previously studied baseline predictors were mostly neurobiological, for example, the Val/Val brain-derived neurotrophic factor (BDNF) polymorphism,¹⁴ anterior cingulate cortical activity,^15,16 plasma D-serine¹⁷ or interleukin-6¹⁸ levels. However, accessible and feasible clinical predictors remain scarce. Broader studies in depressed patients suggest that greater symptom severity, suicidality, comorbid anxiety, and frequent depressive episodes predict a higher risk of treatment resistance.¹⁹ Few ketamine studies have addressed similar predictors, with sporadic findings indicating greater efficacy in patients with lower suicidality,²⁰ higher anhedonia,²¹ or anxiety.²² Recent systematic research has demonstrated better outcomes in patients with lower degrees of treatment resistance.²³ The predictive potential of other clinical parameters has not yet been systematically established.

As depression is associated with autonomic imbalance,^24,25 cardiovascular parameters can serve as accessible and noninvasive correlates to antidepressant effect. For example, a higher heart rate (HR) predicted better response to Selective serotonin reuptake inhibitors (SSRIs) or mirtazapine in drug-naïve patients.²⁶ An analysis of iSPOT trial data demonstrated an association between higher baseline HR and response to Serotonin and norepinephrine reuptake inhibitors (SNRIs) compared to SSRIs.²⁷ Our previous analysis has shown that responders to ketamine are characterized by a higher HR during the whole course of ketamine infusion.²⁸ A recent study, examining blood pressure and HR values in patients receiving repeated intravenous ketamine administration, revealed a greater change in systolic blood pressure from baseline during the first infusion in patients with a greater sustained antidepressant effect.²⁹ However, the depressive symptoms were only assessed by the Patient Health Questionnaire-9 (PHQ-9) self-report questionnaire, and it lacked the data on the phenomenology of intoxication, which may have modified autonomic nervous system activity. A more detailed relationship between cardiovascular parameters and the antidepressant effect of ketamine has not yet been documented elsewhere.

The next proclaimed impediment is the ketamine-induced transient altered state of consciousness. Nevertheless, N-methyl-D-aspartate receptor (NMDAR) antagonists lacking an acute psychotropic effect have failed in clinical studies in depression.^30,31 Given the phenomenological similarity between ketamine intoxication and classical psychedelics,^32,33 alongside shared synaptoplastic mechanisms and the effect on neuronal networks,^34,35 the altered state of consciousness may instead be perceived as an accompanying component of the resulting antidepressant action.^36
–39 An association between psychedelic-induced sense of ego dissolution and sustained antidepressant effect was shown in serotonergic psychedelics.^40,41 Similarly, several studies have examined the association between ketamine-induced acute alteration of consciousness and its antidepressant action. Independent studies assessing the correlation between dissociation, measured by the Clinician-Administered Dissociative States Scale (CADSS) during administration, and the subsequent antidepressant effect, have yielded inconsistent results with few studies supporting^13,42,43 or rejecting such association.^44
–47 A randomized, placebo-controlled trial in 27 patients at our site has demonstrated a negative correlation between the Brief Psychotic Rating Scale (BPRS) scores during administration and the Montgomery-Åsberg Depression Rating Scale (MADRS) 1 week after,³⁹ but three other studies did not confirm such correlation.^42,45,48 A better understanding could be gained by enriching the existing assessment of the altered state of consciousness (derived from observations of behavioral correlates) with objective parameters of the course of the infusion, such as plasma ketamine levels or aforementioned hemodynamic changes.

In this post hoc analysis, we aimed to elucidate the role of physiological and psychological parameters during ketamine infusion on sustained antidepressant effect. We hypothesized that a better response to ketamine will be linked to (a) higher sympathetic tone, as expressed by blood pressure and HR, and (b) a higher degree of altered state of consciousness, expressed in dissociative (CADSS) and psychotomimetic (BPRS) symptoms. In addition, we analyzed the influence of plasma levels of ketamine and norketamine during administration, as well as baseline concomitant medication, as both factors may potentially influence the course of ketamine administration.

Methods

Subjects and study design

The primary study was designed as an open-label trial focused on clinical and neurobiological predictors of antidepressant response to single-dose ketamine. It was conducted at the National Institute of Mental Health, Czech Republic (NIMH, CR), from 2019 to 2022, and included 40 patients with a depressive episode or recurrent depressive disorder according to ICD-10 and confirmed by the M.I.N.I. questionnaire.⁴⁹ Patients were referred to the study by their treating psychiatrists from outpatient and inpatient services. The inclusion criteria were: MADRS⁵⁰ score ⩾20, ⩾1 failed response to antidepressant treatment in the current episode and stable dose of antidepressants for ⩾4 weeks prior to ketamine administration. The exclusion criteria were: acute suicidal risk, current major psychiatric comorbidity, unstable somatic illness, treatment with monoamine oxidase inhibitors, typical antipsychotics, antiepileptics, or lithium, and lifetime history of psychosis. Atypical antipsychotics were allowed at stable doses during the study. Patients with arterial hypertension were only included if compensated (normal blood pressure on antihypertensive medication). Prior to inclusion, all participants underwent physical examination, vital signs assessment, and basic biochemical, hematological, and urine testing. One patient developed a panic attack with hypertension after enrollment in the study and was excluded before ketamine administration. The present work is a post hoc analysis derived from this primary study and focuses on the clinical parameters described below; the primary outcomes have not been published to date. The reporting of this study conforms to the STROBE statement.⁵¹

Treatment and assessment

Each subject received an intravenous infusion of racemic ketamine hydrochloride in a subanesthetic dose (0.54 mg/kg), via an infusion pump, with a loading dose of 0.27 mg/kg for the first 10 min, followed by a maintenance infusion of 0.27 mg/kg over 20 min. This dosing was calculated with respect to the pharmacokinetics of ketamine,^16,52 and the total dose applied was comparable to the majority of clinical trials with intravenous ketamine.⁵³ Throughout the administration and for at least 30 min after the infusion, all patients were in a relaxed semi-reclining position in a room with reduced noise and dimmed lighting, accompanied by quiet non-lyrical relaxing music and under continuous medical supervision.

The severity of depression was assessed by MADRS at baseline and at 24 hours, 3 days, and 7 days after the treatment. Response was defined as at least 50% reduction in MADRS on day 7 compared to baseline. Subjective measures of depression were assessed using the Beck Depression Inventory (BDI)⁵⁴ and the Quick Inventory of Depressive Symptomatology (QIDS).⁵⁵ Anxiety was measured by subjective Beck Anxiety Inventory (BAI)⁵⁶ and by the Hamilton Anxiety Rating Scale (HAM-A).⁵⁷ Melancholic features of depression were extracted from items of the M.I.N.I. 5.0.0 questionnaire⁴⁹ from the initial visit. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR were recorded in all patients at four time points: before the start of the infusion (baseline), 10 and 30 min into the infusion, and 30 min after the end of the infusion (60 min into the session). An OMRON automatic tonometer with calibrated accuracy of BP ± 3 mmHg and HR ± 5% was used. The altered state of consciousness was assessed using the CADSS⁵⁸ and BPRS⁵⁹ at four time points during the session: before ketamine administration and 10, 30, and 60 min after its onset. All patients underwent blood sampling at the same time points. Serum levels of ketamine and norketamine were measured by liquid chromatography-mass spectrometry (LC-MS/MS). Because ketamine was an add-on treatment, the patients remained on an unchanged dose of antidepressants (AD) and antipsychotics (AP) for the duration of the clinical trial. For reference purposes, the total dose of AD was assessed using fluoxetine equivalents (FL equi).⁶⁰ In the case of augmentation with atypical AP, the dose equivalents of olanzapine (OLA equi) were applied.^61,62

Statistical methods

Demographic, clinical, and treatment characteristics between responders (⩾50% MADRS score reduction at day 7 against baseline) and nonresponders were compared using unpaired t-test, Mann–Whitney U test, and Fisher’s exact test as appropriate. For quantitative data, the distribution was assessed by the Shapiro-Wilk test. Differences between responders and nonresponders across repeated measurements (change in depression and anxiety scores, blood pressure, and intoxication phenomenology) were analyzed using mixed-effects models for repeated measures with fixed effects for time, response, and time-response interactions, and a random effect for subjects. Covariates varied according to the dependent variable, including baseline values, age, BMI, baseline anxiety levels, or ketamine and norketamine levels. For ketamine and norketamine levels, data were log-transformed to normalize the distribution. Between-group differences in least-squares means (LS-means) at each time point, their confidence intervals, and p values were adjusted by the Bonferroni method. Relationships between variables were tested by Pearson’s or Spearman’s correlation coefficients with correction for multiple comparisons. Finally, multiple regression models were utilized to identify and investigate the independent and interactive effects of predictors (BP measures and medication status) on MADRS change. Statistical analysis was performed using NCSS 2023 Statistical Software (NCSS, LLC, Kaysville, Utah, USA) and Jamovi version 2.3.21.0 (The Jamovi Project, 2024).

Results

The data obtained from 39 patients were included in the analysis. Sixteen patients (41%) were on monotherapy with one AD, and the remaining 23 (59%) had a combination of two or more ADs. The most common ADs were venlafaxine in 12 patients (31%), SSRIs (n = 8), and mirtazapine (n = 8), followed by bupropion (n = 7), vortioxetine (n = 7), and tricyclic antidepressants (n = 4). Nineteen patients (49%) were on AP augmentation at subantipsychotic doses with a mean of 4.4 ± 2.6 mg OLA equi. Only 5 patients (12%) were medicated with benzodiazepine anxiolytics (BZD), with a mean dose of 6.6 ± 3.9 mg diazepam equivalent. Eight patients (20.5%) were regularly treated with antihypertensives (perindopril, indapamide, amlodipine, nebivolol, telmisartan, spironolactone, or their combinations).

Seventeen patients (43%) responded to a single dose of ketamine (⩾50% reduction in MADRS). Responders did not differ from nonresponders in demographic parameters, apart from more years of education in responders (t = −2.174, df = 37, p = 0.03). In clinical parameters, there was a higher proportion of AP users among nonresponders (Fisher’s exact test, p = 0.001). The groups were comparable in other baseline parameters, including depression severity and resistance rates (assessed by length of illness, number of hospitalizations, and number of previous failed treatment attempts). Responders did not differ from nonresponders in antidepressant doses. Due to minimal benzodiazepine use in this cohort, BZD doses were not further analyzed (Table 1). Both systolic and diastolic blood pressure values increased at 10 and 30 min into ketamine infusion. Ketamine responders significantly differed from nonresponders in the values obtained (Table 2).

Table 1.

Baseline characteristics in the study group and comparison of responders versus nonresponders.

Parameter	All(n = 39)	Responders (n = 17)	Nonresponders (n = 22)	p Value
Basic demographic parameters
Age (yrs)	43.1 ± 11	40.4 ± 11.7	45.7 ± 10.3	0.15^a
Female (%)	19 (49)	9 (53)	10 (46)	0.64^b
Education (yrs)	15.8 ± 2.4	16.6 ± 2.6	15.1 ± 2.1	0.03 ^c
Body weight (kg)	81.7 ± 21	79.0 ± 20.4	84.0 ± 21.8	0.48^a
BMI (kg/m²)	26.2 ± 6.1	25.6 ± 5.9	26.8 ± 6.5	0.58^a
Depression severity and treatment resistance
Years since MDD diagnosis	12.5 ± 8.3	11.7 ± 7.5	13.1 ± 9.2	0.60^a
Length of index episode (months)	12.8 ± 7.4	13.4 ± 7.5	12.3 ± 7.5	0.62^a
N hospital admissions	3 ± 3	2.2 ± 1.7	3.6 ± 3.7	0.11^c
N treatments for index episode	4.2 ± 2.5	3.8 ± 2.1	4.6 ± 2.8	0.3^c
Pharmacotherapeutic characteristics
AD dose FLX equi (mg)	55.3 ± 28.8	48.1 ± 28.4	60.8 ± 28.6	0.18^a
AP augmentation (%)	19 (49)	3 (18)	16 (73)	0.001 ^b
OLA equi (mg) in AP users	4.4 ± 2.6 mg	4.67 ± 4.73	4.42 ± 2.35	0.93^a
BZD (%)	5 (13)	3 (18)	2 (9)	0.64^b
Baseline clinical parameters
MADRS	28 ± 4.2	28.3 ± 4.6	27.0 ± 3.8	0.7^a
QIDS	19.4 ± 5.5	19.9 ± 5.4	19.0 ± 5.8	0.59^a
HAM-A	18.3 ± 4.8	19.2 ± 5.4	17.5 ± 4.3	0.28^a
BDI	25.7 ± 9.7	28.1 ± 9.7	23.8 ± 9.5	0.18^a
BAI	15.2 ± 8.8	16.5 ± 10.7	14.1 ± 7.0	0.41^a
Melancholic features (%)*	25 (64)	11 (65)	14 (64)	0.99^b

Values represent mean ± SD or counts (%).

Unpaired t-test.

Fisher’s exact test.

Mann–Whitney U test.

Extracted from items of the M.I.N.I. 5.0.0 questionnaire.

AD, antidepressant; AP, antipsychotic; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; BMI, body mass index; BZD, benzodiazepine; FLX equi, fluoxetine equivalent; HAM-A, Hamilton Anxiety Symptomatology Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, major depressive disorder; QIDS, Quick Inventory of Depressive Symptomatology.

Values in bold indicate statistically significant differences between responders and nonresponders (p < 0.05).

Table 2.

Comparison of responders and nonresponders according to SBP, DBP, and HR values.

Hemodynamic parameters	Responders (n = 17)	Nonresponders (n = 22)	p_corr Value
SBP, mmHg
SBP, before application	118 (113–124)	117 (112–122)	1.00
SBP, 10 min	149 (144–154)	133 (128–137)	<0.001
SBP, 30 min	150 (144–155)	137 (132–142)	0.03
SBP, 60 min	133 (128–138)	129 (123–133)	1.00
DBP, mmHg
DBP, before application	81 (77–84)	80 (76–83)	1.00
DBP, 10 min	99 (95–102)	87 (83–90)	<0.001
DBP, 30 min	97 (93–101)	86 (82–89)	<0.001
DBP, 60 min	90 (86–93)	83 (80–86)	0.3
HR/min
HR, before application	73 (66–80)	75 (68–81)	1.00
HR, 10 min	83 (77–89)	78 (73–83)	1.00
HR, 30 min	75 (67–82)	79 (73–86)	1.00
HR, 60 min	70 (64–76)	73 (67–78)	1.00

Values represent least square means and (their 95% confidence interval). p_corr = p value after Bonferroni correction.

DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure.

Values in bold indicate statistically significant differences between responders and nonresponders (p < 0.05).

Comparison of SBP measures between ketamine responders and nonresponders revealed distinct SBP dynamics over time (time effect: F = 52.1, df = 3.98, p < 0.001; group effect: F = 13.3, df = 1.30, p = 0.001; group × time: F = 5.03, df = 3.89, p = 0.003), with comparable values at baseline and session end, but significantly higher SBP at 10 min (mean difference 16.2, 95% CI 8.9–23.6 mmHg, t = 4.39, p_corr < 0.001, Hedges’ g = 1.39, 95% CI 0.70–2.08) and 30 min (mean difference 12.5, 95% CI 5.1–19.9 mmHg, t = 3.35, p_corr = 0.03, g = 1.06, 95% CI 0.4–1.72). DBP dynamics also differed between groups (time effect: F = 25.1, df = 3.98, p < 0.001; group effect: F = 24.5, df = 1.30, p < 0.001; group × time: F = 4.9, df = 3.98, p = 0.003), with comparable baseline DBP but significantly higher values in responders at 10 min (mean difference 12.1, 95% CI 7.1–17.2 mmHg, t = 4.79, p_corr < 0.001, g = 1.52, 95% CI 0.81–2.22), 30 min (mean difference 11.1, 95% CI 6.1–16.3 mmHg, t = 4.35, p_corr < 0.001, g = 1.38, 95% CI 0.68–2.07; Figure 1). In addition, SBP and DBP changes after 10 and 30 min significantly correlated with MADRS change at day 7, with r values ranging from 0.43 to 0.51 (all p < 0.05). No differences were found in HR (time effect: F = 7.9, df = 3.98, p < 0.001; group effect: F = 0.1, df = 1.30, p = 0.7; group × time: F = 2.5, df = 3.98, p = 0.06).

Figure 1.

Values of systolic and diastolic blood pressure at baseline and 10, 30 and 60 min after application in responders and nonresponders (error bars represent 95% CI).

The dissociation, as assessed by the CADSS, was negligible at baseline (0.35 ± 0.77) and increased at 10 min (24.05 ± 11.6) and 30 min (28.15 ± 10.9). At 60 min, the values returned to imperceptible (2.15 ± 3.82). Although responders had a slightly higher dissociation rate, no significant difference was found between the groups (time × group interaction: F = 2.48, df = 3.88, p = 0.10). Psychotic-like symptoms, as assessed by the BPRS, increased from 15.74 ± 5.85 to 23.74 ± 7.8 at 10 min and 23.57 ± 6.22 at 30 min into administration and decreased to 9.61 ± 5.91 at 60 min. Responders and nonresponders did not differ in any of the BPRS assessments, nor was there any group × time interaction (F = 0.96, df = 3.88, p = 0.40) (Supplemental Material 1). To investigate the link between altered consciousness and sympathetic activity, we additionally analyzed correlations between SBP/DBP and CADSS/BPRS at 10 and 30 min during the infusion; however, no relevant correlation was found between these parameters.

The plasma levels of ketamine and norketamine were only available from 29 patients. No significant group × time interaction was found for ketamine (F = 1.44, df = 2.58, p = 0.25) or norketamine levels (F = 0.68, df = 2.58, p = 0.51) between responders and nonresponders (Supplemental Material 2). There was no relevant correlation between plasma levels and SBP, DBP, or CADSS during intoxication (Supplemental Material 3).

Concerning concurrent medication, there was no correlation between AD doses and SBP or DBP before or during ketamine administration. Because nearly half of the patients were treated with atypical APs, an additional comparative analysis between AP users and nonusers was conducted to evaluate potential interference with the above findings. AP users (AP+, n = 19) differed significantly from nonusers (AP−, n = 20) in higher BMI (t = 2.13, df = 34, p = 0.03) and higher total FLX equi (t = 2.12, df = 37, p = 0.03), but not in other baseline demographic or clinical parameters (Supplemental Material 4). Only three responders to ketamine were AP+ in contrast to 16 AP+ among nonresponders. Comparison of MADRS between the AP+ and AP− groups revealed significantly different response trajectories (group × time interaction: F = 4.08, df = 3.114, p = 0.008). AP+ exhibited a worse outcome on day 3 (p_corr = 0.002) and on day 7 compared to AP− (p_corr < 0.001; Figure 2). However, no correlation between AP dose and MADRS change at day 7 was found (AP+, r = 0.18, p = 0.5).

Figure 2.

Difference in time of MADRS during the follow-up period (pretreatment, day 1, 3, 7) in AP users and nonusers (error bars represent 95% CI).

Using AP as the group variable (AP+/AP−), BP dynamics mirrored those between responders and nonresponders, with significantly lower SBP and DBP in AP+ at 10 min (Figure 3). No significant group differences were detected in CADSS or BPRS trajectories between AP+ and AP−.

Figure 3.

Difference of SBP and DBP values before ketamine administration and at 10, 30, and 60 min into administration in AP users and nonusers (error bars represent 95% CI).

Integrating previous findings, a final robust multiple regression model incorporating AP status, DBP change after 30 min (DBP30), and their interaction, revealed that both DBP30 (β = −0.26, p = 0.04) and AP status (β = 9.40, p = 0.003) significantly predicted MADRS change at day 7, with a nonsignificant interaction (β = −0.15, p = 0.5) indicating additive effects on MADRS change. Specifically, AP+ status and a lesser increase in BP were both associated with less improvement in MADRS.

Discussion

This post hoc analysis reveals significant differences in blood pressure during ketamine administration between responders and nonresponders, with higher SBP and DBP associated with superior antidepressant outcomes at 1 week. Ketamine administration is generally associated with increased BP and HR⁶³ through sympathomimetic properties and blockade of muscarinic M2 receptors.⁶⁴ When viewed alongside the recent systematic review²⁵ indicating reduced parasympathetic tone in MDD, our findings may be interpreted within a framework of autonomic dysregulation, suggesting that ketamine responders represent a subgroup characterized by relatively greater sympathetic predominance. This notion is consistent with prior observation of higher sympathetic and lower parasympathetic activity in responders to conventional antidepressants²⁴ and with the only previous work assessing the difference in hemodynamic parameters in patients undergoing ketamine treatment.²⁹ However, it remains possible that elevated BP could represent an epiphenomenon, potentially reflecting other confounding factors, such as variability in the intensity of intoxication (including arousal or anxiety, which modify autonomic response), concomitant medication or plasma ketamine concentration.

Psychological parameters during ketamine administration, measured by CADSS or BPRS, followed a similar trajectory in responders and nonresponders and, contrary to expectations, did not predict the antidepressant effect. The present analysis thus failed to replicate our previous findings concerning BPRS³⁹ or to resolve inconsistencies in previous studies.^42
–48 It is reasonable to acknowledge the limitations of the assessment tools and the fact that ketamine-induced states, while phenomenologically resembling psychosis or dissociation, are not identical.⁶⁵ A striking recent study linked the enduring antidepressant effect of ketamine to acute experiences measured by the Awe Experience Scale (AWE-S), suggesting awe-inspiring properties of ketamine’s psychoplastogenic effect.⁶⁶

Concerning concomitant medication, patients receiving AP were less likely to achieve an antidepressant effect after ketamine treatment. This was unrelated to plasma levels of ketamine or norketamine during the infusion. Attenuated response in AP+ resembles the detection of dampened ketamine effect in patients with higher doses of BZD from our earlier post hoc analysis.⁶⁷ Notably, both BZD and AP interfered with the delayed response (3–7 days after ketamine administration), raising speculations about their potential disruption of secondary synaptoplastic cascades essential for the antidepressant effect.^68,69 Such a premise could be consistent with the reported interaction of clozapine and ketamine on the intracellular phosphorylation cascade in laboratory animals.⁷⁰ It is interesting to view these results in light of preclinical evidence of chronic (but not acute) antipsychotic administration attenuating ketamine-induced gamma oscillations,⁷¹ as this electrophysiological finding can be considered a correlate of synaptic potentiation.^72
–75 Nevertheless, human research (e.g., studying temporal dynamics of neurotrophic proteins in patients with concomitant medication) is lacking to confirm these hypotheses. Given how easily AP medication status can be determined, it may represent a practical stratification variable for future ketamine trials. On the other hand, although in clinical practice APs are frequently used for treatment augmentation, current evidence indicates their limited efficacy in treatment-resistant patients. A recent meta-analysis reported that overall antipsychotic treatments (except aripiprazole) were less effective and less tolerated opposed to treatments such as ECT, TBS, rTMS, or ketamine.⁷⁶ Similarly, in a randomized study, esketamine demonstrated greater antidepressant efficacy compared to quetiapine in treatment-resistant depression.⁷⁷ These findings raise the question of whether current pharmacological strategies in treatment-resistant depression, including antipsychotic augmentation, should be more carefully re-evaluated.

We also observed significant differences in BP values between AP+ and AP−, with AP users achieving lower SBP and DBP during the administration, in line with a lower likelihood of antidepressant response to ketamine. Several pathophysiological factors should be considered here. First, the cardiovascular effect of AP per se—most antipsychotics induce orthostatic hypotension due to anticholinergic effects and/or alpha-1 blockade,^78,79 which can be particularly prominent in multiacting receptor-targeted agents (10 of 19 AP+ (52%) were prescribed quetiapine or olanzapine). However, as all subjects were on long-term antipsychotic therapy, an elevated metabolic risk and tendency toward hypertension⁸⁰ may be expected rather than orthostasis. Notably, AP+ and AP− did not differ in baseline BP values, with differences emerging only during the administration. Second, we can speculate about prior indication of antipsychotic augmentation being a reflection of greater depression severity. Responders did not differ from nonresponders in AD doses; however, AP+ had higher AD doses in comparison to patients without AP, thus we may suppose greater initial severity of the psychopathology (not statistically significant in the targeted assessment already after AP prescription). Taken together, lower BP (as a correlate of weaker sympathetic tone in AP+ and ketamine nonresponders), higher AD doses and higher BMI in AP+, rather than being independent predictive factors, they may represent accompaniments of a broader treatment-resistant clinical phenotype.

Additional evaluation showed no effect of concomitant medication on the altered state of consciousness, which contradicts earlier assumptions, derived from animal and anesthetic studies, about the ability of antipsychotics to block acute manifestations of ketamine intoxication, but supports later human studies.^81,82 Yet it is important to consider distinct mechanisms of anesthetic and subanesthetic doses of ketamine^71,74,83 as well as obviously lower sub-antipsychotic/augmentation doses of APs administered in depression.⁸⁴

Plasma levels of ketamine and norketamine did not differ between responders and nonresponders, nor was there any correlation between plasma levels and dissociation or changes in SBP and DBP during the administration. This may either imply that plasma concentration does not reflect the pharmacodynamic action of ketamine in the CNS, or indicate the weakness of a small sample size. Also, focusing only on ketamine and norketamine can be insufficient in light of the possible independent AMPA-related effect of hydroxynorketamine.⁸⁵

Limitations

Several limitations must be acknowledged. First, the study was conducted as an open-label trial without a control group. Second, the small sample size weakens the statistical power when assessing subgroup differences. Third, as discussed above, clinician-administered scales (CADSS, BPRS) can be limited because of impaired cooperation during intoxication, and finally, the post hoc nature of the analysis inherently limits the strength of causal inferences.

Conclusion

Higher blood pressure during ketamine administration was associated with better subsequent antidepressant outcome, supporting the hypothesis of sympathetic predominance in treatment responders. Dissociative and psychotomimetic experiences or plasma levels of ketamine and norketamine were not related to subsequent outcomes. Concomitant antipsychotic augmentation was associated with a lower likelihood of antidepressant response and with lower blood pressure during ketamine administration.

Our results support the advantage of objective and easy-to-register hemodynamic parameters, which appear to be more accurate than altered state of consciousness characteristics. Parameters obtained during ketamine infusion may potentially serve as continuous predictors (mediators), allowing clinical decisions about early treatment change,⁸⁶ for example, about repeated ketamine infusions, considering the growing evidence supporting this practice.^{11
–13,85
–89} Diminished antidepressant effect in AP+ has implications for the broader discussion about pharmacotherapy of treatment-resistant depression, as ketamine is typically prescribed following unsuccessful prior treatments and is therefore seldom administered in drug-naïve patients.

Future research should consider (a) comprehensive assessment of hemodynamic parameters in larger samples and/or meta-analyses, (b) utilization of advanced measures of cardiac autonomic tone, such as spectral or nonlinear HR variability indices,^25,28 to disentangle the relative contributions of sympathetic and parasympathetic modulation to ketamine’s antidepressant effect, (c) inclusion of concomitant medication as an independent variable in meta-analyses, and (d) linking clinical characteristics with biological markers of synaptoplasticity (e.g., temporal dynamics of neurotrophic proteins or electrophysiological correlates) following ketamine administration.

Supplemental Material

sj-docx-1-tpp-10.1177_20451253261419636 – Supplemental material for Sympathetic activation but not dissociation linked to ketamine’s sustained antidepressant effect

Supplemental material, sj-docx-1-tpp-10.1177_20451253261419636 for Sympathetic activation but not dissociation linked to ketamine’s sustained antidepressant effect by Veronika Andrashko, Tomas Novak, Miloslav Kopecek, Anna Sulakova, Vit Knop and Jiri Horacek in Therapeutic Advances in Psychopharmacology

Supplemental Material

sj-docx-2-tpp-10.1177_20451253261419636 – Supplemental material for Sympathetic activation but not dissociation linked to ketamine’s sustained antidepressant effect

Supplemental material, sj-docx-2-tpp-10.1177_20451253261419636 for Sympathetic activation but not dissociation linked to ketamine’s sustained antidepressant effect by Veronika Andrashko, Tomas Novak, Miloslav Kopecek, Anna Sulakova, Vit Knop and Jiri Horacek in Therapeutic Advances in Psychopharmacology

Footnotes

Acknowledgements

We acknowledge Julie Jindrova for assistance with laboratory assessments and the late Alice Heuschneiderova for dedicated nursing assistance during ketamine administration.

Declarations

ORCID iDs

Veronika Andrashko

Tomas Novak

Miloslav Kopecek

Anna Sulakova

Jiri Horacek

Supplemental material

Supplemental material for this article is available online.

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