This open-label study (n=51) found that a large increase in heart rate (HR) and -variability (HRV) predicted better outcomes for those suffering from depression (MDD) after administration of ketamine.
Papers cited by this study that are also in Blossom
Han, Y., Chen, J., Zou, D. et al. · Neuropsychiatric Disease And Treatment (2016)
Objective
Ketamine has been shown to be effective in treatment of episodes of major depressive disorder (MDD). This controlled study aimed to analyse the predictive and discriminative power of heart rate (HR) and heart rate variability (HRV) for ketamine treatment in MDD.
Methods
In 51 patients, HR and HRV were assessed at baseline before and during ketamine infusion and 24 hours post ketamine infusion. Montgomery-Åsberg Depression Rating Scale (MADRS) was used to assess changes of depressive symptoms. A 30% or 50% reduction of symptoms after 24 hours or within 7 days was defined as response. A linear mixed model was used for analysis.
Results
Ketamine infusion increased HR and HRV power during and after infusion. Responders to ketamine showed a higher HR during the whole course of investigation, including at baseline with medium effect sizes (Cohen’s d = 0.47-0.67). Furthermore, HR and HRV power discriminated between responders and non-responders, while normalized low and high frequencies did not.
Conclusion
The findings show a predictive value of HR and HRV power for ketamine treatment. This further underlines the importance of the autonomous nervous system (ANS) and its possible malfunctions in MDD.
Significance
The predictive power of HR and HRV markers should be studied in prospective studies. Neurophysiological markers could improve treatment for MDD via optimizing the choice of treatments.
Meyer and colleagues frame the study against a background in which ketamine has shown rapid antidepressant effects, but objective predictors of which patients will benefit remain scarce. Previous work has explored genetic markers (for example BDNF polymorphisms), functional neuroimaging correlates, MRS glutamate metrics and sleep-architecture features as candidate predictors, yet clinical implementation has been limited. The authors note that ketamine exerts marked effects on the autonomic nervous system (ANS), typically increasing heart rate (HR) via sympathetic activation, and highlight prior literature linking reduced heart rate variability (HRV) to depression severity and to differential antidepressant response, suggesting that ANS measures could carry predictive information. This study set out to evaluate whether HR and HRV-derived parameters, measured before, during and after a single intravenous ketamine infusion, discriminate responders from non-responders in major depressive disorder (MDD). The principal aim was to test the predictive and discriminative power of simple ECG-derived markers for ketamine treatment outcome, with the hypothesis that higher baseline sympathetic tone (higher HR, greater HRV power and increased low-frequency power) would be associated with larger symptomatic improvement after ketamine.
Two consecutive controlled trials conducted between 2010 and 2015 were pooled for this secondary analysis. Fifty-one patients with MDD aged 18–65 were enrolled; diagnoses were confirmed with the M.I.N.I. and baseline severity required a MADRS score of at least 20. Most participants remained on stable antidepressant medication (no dose changes four weeks prior to study); augmentation with lamotrigine, lithium, antipsychotics and MAO inhibitors was not permitted. Exclusion criteria included suicidality, major psychiatric comorbidity, significant unstable medical or neurological illness and any cardiac condition or cardiac medication (for example beta-blockers). The first trial was double-blind and randomized (placebo versus ketamine), while the second was a single-blind, fixed-sequence design (placebo first, then ketamine for all). For the present analysis only data from the ketamine (verum) cohorts were used. Ketamine was administered intravenously as racemic ketamine hydrochloride with a loading dose of 0.27 mg/kg over 10 minutes, followed by 0.27 mg/kg over 20 minutes, yielding a total of 0.54 mg/kg over 30 minutes. Placebo infusions used matched saline infusion times. Ketamine and norketamine blood levels were sampled 10 and 30 minutes after infusion start. Depressive symptoms were measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline and at 24 h, 72 h and 7 days post infusion. Response definitions included the conventional 50% symptom reduction and a modified 30% reduction at 24 h; analyses also considered response at any time up to 7 days. ECG was recorded in a semi-recumbent, eyes-closed resting state using a BrainScope amplifier, with a baseline window limited to 5 minutes before infusion and 10-minute segments available at the start and end of the ketamine bolus; 36 subjects had an additional 10-minute ECG 24 hours later. Sampling rates were 250 Hz (Study 1, N = 27) and 1000 Hz (Study 2, N = 24), the latter downsampled to 250 Hz for analysis. RR intervals were processed in Kubios to derive HR, total HRV power (0.04–0.4 Hz) and normalized low-frequency power (nLF; 0.04–0.15 Hz); normalized high-frequency power was not reported separately to avoid redundancy. Statistical analysis pooled the two trials and excluded placebo arms. Baseline comparisons used t-tests or Fisher's exact test. The primary inferential approach was linear mixed modelling with fixed effects for group (responders versus non-responders), time (repeated measures), and group-by-time interaction, plus random intercepts and a random effect for participant; age and sex were included as covariates. Schwarz's Bayesian criterion selected the covariance structure. Post hoc tests were Bonferroni corrected. Cohen's d was calculated from raw ECG parameters for effect-size estimation. Sensitivity analyses restricted models to the first three ECG timepoints when 24-hour recordings were missing. Logistic regression and receiver operating characteristic (ROC) analyses assessed discriminative/predictive performance of HR and HRV measures, using either baseline parameters alone or all available ECG-derived parameters.
Patients: Fifty-one patients were recruited into two consecutive controlled trialsbetween 2010 and 2015. The first trial was double-blind (blinded for both participants and care providers) and randomized, using sealed envelopes and random permuted blocks (size of six) for a balanced group design and allocation of subjects for placebo/ketamine. The second trial had a controlled single-blind, one-arm, fixed sequence design without randomization, i.e. the sequence was the same for all participants: first infusion was placebo, second was ketamine. All participants were enrolled by the principal study investigator and subsequently assigned by the study assistant. Therefore, both, care providers and those assessing outcomes, were informed about the sequence. These studies aimed to identify clinical, electrophysiological, and biological predictors of response to a single intravenous dose of ketamine as treatment for depression (monotherapy or combination) in patients with MDD. More details have been published elsewhere. In both studies identical inclusion and exclusion criteria were applied. All patients were between 18 and 65 years old with MDD (recurrent or single episode) diagnosed according to DSM-IV criteria (APA 2006), confirmed using the Mini-International Neuropsychiatric Interview-M.I.N.I., Czech version 5.0.0. Further main inclusion criteria were: Score ! 20 on the Montgomery-Åsberg Depression Rating Scale (MADRS), !1 prior non-response to adequate antidepressant treatment in current major depressive episode (while in total 21 of the participants could be classified as TRD with ! antidepressant trials during the current episode, see Supplement Table), and being on a stable dose of drugs for depressions for a minimum of four weeks prior to admission. Treatment augmentation by lamotrigine, lithium, antipsychotics and monoamine oxidase inhibitors was not allowed. Exclusion criteria were any suicidal risk assessed by clinical examination, current psychiatric comorbidity on Axis I and II, serious unstable medical illness or neurological disorder (e.g. epilepsy, head trauma with loss of consciousness) as well as lifetime history of psychotic symptoms and psychotic disorders in first-or second-degree relatives. Further, during the screening period, all patients underwent physical examination, routine blood tests, electrocardiogram, urinalysis, and urine toxicology before inclusion in the study, excluding patients with somatic diseases with a need of treatment, especially any cardiac condition including hypertension and medication for cardiac condition (e.g. beta-blockers). Patients continued their psychopharmacological treatment in unchanged dose over duration of the study. The study details were explained to all patients; a complete description was handed out before written informed consent was subsequently obtained. No changes to trial methods had been implied after trial commencement. The studies were approved by the Ethical committee of Prague Psychiatric Centre/National Institute of Mental Health, Czech Republic and were performed in accordance with the ethical standards laid down in the Declaration ofKetamine Treatment/Infusion: A unilateral intravenous catheter was inserted into the subjects' forearm for ketamine infusion. Racemic ketamine hydrochloride (Calypsol, Gedeon Richter Plc., Czech Republic) was administered using an infusion pump (ID 20/50, Polymed medical CZ Ltd). Ketamine was dispensed in a loading dose of 0.27 mg/kg for the first 10 min, followed by an infu-sion of 0.27 mg/kg within 20 min. Thus, total dose was 0.54 mg/kg within 30 min. These infusion rates were calculated with respect to the pharmacokinetics of ketamine. For placebo infusions, equal amount of saline (sodium chloride 0.9%) solution was administered via the infusion pump within an equal time period. All infusions were applied in clinical premises of Prague Psychiatric Centre, Czech Republic. Ketamine and norketamine blood levels were assessed via blood samples respectively 10 minutes and 30 minutes after starting the infusion. Depression Rating: Severity of depressive symptoms was assessed using the MADRS. Ratings were obtained at baseline (before the infusion), and 24 h, 72 h and 7 days post infusion. Response to treatment often is defined as a reduction of at least 50% from baseline. In case of a fast-acting response to ketamine, we considered this criterion too stringent with a chance to omit a substantial number of patients who benefited from the treatment fast within 24 h but did not meet the 50% criterion. Further, the 50% response criterion yielded a too low number of responders for trustworthy statistical results. Thus, besides the 50% response criterion after 24 hours, a modified response criterion was used, defined as a decrease of depressive symptoms by means of MADRS > 30% at 24 h after infusion. Further analysis was done using > 30% and > 50% symptom decrease at any further assessment until day 7 after infusion. Electrocardiogram Measurements, Heart Rate (HR) and Heart Rate Variability (HRV) Parameters: The HR is a measure of the autonomous nervous system (ANS) and reflects the interaction of the two involved branches, i.e. the sympathetic part (responsible for positive chronotropy) and the parasympathetic part (negative chronotropy). Parameters of the HRV yield more detailed information on the activity of the ANS: The HRV-power is derived from the spectral analysis of changes of consecutive ECG R-peaks in milliseconds. The involved frequency spectra include the Low Frequency spectrum from 0.04 to 0.15 Hz and are mainly driven by sympathetic activity while the high frequency range from 0.15 to 0.4 Hz is more influenced by the parasympathetic branch. Higher HRV power values are supposed to reflect increased parasympathetic tone and decreased sympathetic activity. The normalized units of the different spectra show the contribution of the two ANS branches to the total power. To calculate these parameters, electrocardiogram (ECG) recordings were acquired by a BrainScope digital amplifier (M&I, Prague, Czech Republic) with the subjects sitting in a semi-recumbent position, eyes closed in a maximal alert state in a sound attenuated room with subdued lighting. ECG was recorded from electrode placed at the lowest left rib. The data sampling rate was 250 Hz (Study 1, N = 27) or 1000 Hz (Study 2, N = 24). The data of the second trial was downsampled to 250 Hz before analysis of the data. Recording took place before, during and in some cases 24 hours after infusion. Heart rate (HR) and heart rate variability (HRV) measures were assessed using Kubios software (Kubios HRV software Version 2.0,) while RR-peaks were detected using an automatic RR detection algorithm with visual inspection of the time series and consecutive correction, when necessary. To include similar length of intervals for all subjects, the baseline duration was limited to 5 minutes just before infusion onset. For all subjects 10 minutes of resting state were available at the beginning of the ketamine bolus infusion as well as 10 minutes at the end of infusion. 36 subjects underwent another 10 minutes ECG 24 hours later. Analysis: From R-peak to R-peak (RR)-intervals, heart rate (HR, measured as R-peak intervals) was computed as an overall estimator of the activity of the autonomous nervous system (ANS). The following parameters were extracted for assessment of parasympathetic and sympathetic activity (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996): Heart rate variability(0.04-0.4 Hz), normalized spectral power in the high frequency band (nHF; 0.15-0.4 Hz) as parameters for parasympathetic activityand normalized spectral power in the low frequency band (nLF; 0.04-0.15 Hz) as parameters for sympathetic activity; Task Force of the European Society of Cardiology and the North American Society of. The normalized units of HRV frequency band power yield information about the sympathovagal balance and are reported in [%] of the total power. Thus, low and high normalized power values add up to 100%, so only low frequency values are reported to avoid redundancy. Statistics: Data from the two controlled trials were pooled. Only data from the verum-cohorts were analysed since the main question here was whether HRV measures might predict antidepressant response. The sample size for both studies initially was calculated to detect the standardized mean difference of 0.8 or larger between ketamine and placebo in the primary endpoint (change in MADRS after 24 hours), given the alpha (type I error) was set at 0.05, 1-beta (power) at 0.90, and two-tailed paired t-test was used. The baseline clinical data of the groups of responders and non-responders were compared with an unpaired t-test or Fisher's exact test as appropriate. Linear mixed models were used to examine differences between responders and non-responders by means of HR and HRV measures before, at beginning of infusion, at the end of infusion, and up to 24 hours after ketamine infusion as secondary outcome measures. The model included fixed effects for group (responders and non-responders), a repeated measures time factor, as well as a group by time interaction. Fixed and random intercepts were included in the model along with a random effect for participant. Schwarz's Bayesian criterion was used to determine the best fitting covariance structure, which was diagonal. Additionally, gender and age served as covariates. Bonferroni corrected post hoc tests were used following significant effects and interactions. Cohen's d was calculated using raw ECG parameters since no established method exists for calculating effect sizes for linear mixed models. SPSS software (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.) was used for calculations of all models. Since not all patients had an ECG recording after 24 hours, we performed a sensitivity analysis using only the first three ECG recording intervals (before, at the beginning and at the end of infusion). Further analysis included a logistic regression to calculate receiver operating curves (ROC) for significant parameters, including either only baseline HR parameter to obtain the predictive power or all available HR parameters.
Create a free account to open full-text PDFs.
Sanacora, G., Frye, M. A., McDonald, W. et al. · JAMA Psychiatry (2017)
ECG data suitable for analysis were available from 47 of 51 participants (92%); four recordings were discarded for artefact or insufficient length. The analysed sample had mean age 43.0 (SD 12.3) and 20 males (43%). Mean baseline MADRS was 24.0 (SD 6.3). Antidepressant treatments in the sample most commonly included sertraline/escitalopram (36% combined), venlafaxine (28%) and mirtazapine (17%). After ketamine infusion, 9 patients (19%) met the conventional 50% MADRS reduction criterion at 24 h, 9 were in remission (MADRS < 10), and 21 (45%) met the modified 30% reduction criterion at 24 h. Across the cohort, HR increased significantly from baseline to during infusion and further post infusion, then returned to baseline by 24 hours (all p < 0.001). Total HRV power showed a significant increase during infusion compared to 24 hours post infusion (p < 0.009). Normalized low-frequency power (nLF) rose significantly immediately post infusion versus baseline (p < 0.035) and versus 24 hours (p < 0.026). There were no significant differences in ECG measures between the two original studies. Mixed-model analyses differed by response definition. Using the 50% reduction at 24 h (n = 9 responders) there was no significant group effect on HR. Applying the 30% criterion at 24 h (n = 21 responders) produced a significant group effect for HR (F = 10.86, df = 147.65, p = 0.001) with additional significant covariate effects for sex and age; Cohen's d for all HR measures was 0.47, and 0.61 when considering baseline HR alone. No significant time or time-by-group interactions were found. Analyses restricted to the first three ECG intervals produced similar results, as did analyses using the 30%/50% response window up to 7 days (30% criterion: F = 11.32, p = 0.001). For HRV power the mixed models showed a significant group effect for the 30% at 24 h criterion (F = 6.65, p = 0.011) and time effects; nLF analysis yielded only a significant time effect. ROC analyses indicated that baseline-only HR and HRV parameters produced an area under the curve (AUC) of 0.68 with sensitivity 72% and specificity 64%, with pre-infusion HR contributing most strongly. When logistic regression included HR and HRV measures from all available recordings (up to four timepoints), the reported AUC rose to 0.96 (sensitivity 94%, specificity 93%), with total HRV power during infusion and post-infusion nLF contributing most. The extracted text, however, also states that including parameters after the first infusion "has no predictive value," and that point is not fully clear from the available extraction. Correlation analyses showed that ketamine and norketamine blood levels correlated positively with HR and negatively with total HRV power; only the negative correlation between ketamine at 30 minutes and total HRV power at 24 hours survived Bonferroni correction. No serious adverse events were reported.
The investigators interpret their findings to mean that ANS activity profiles, particularly higher HR and greater HRV power, differ between ketamine responders and non-responders and that baseline HR carries medium-sized predictive information for clinical improvement. A simple elevated HR before infusion was associated with better symptomatic outcome using the 30% MADRS reduction threshold. The observed increase in HR with ketamine is consistent with known sympathomimetic effects and with ketamine's pharmacology; the authors discuss a possible dissociation in which central nervous system arousal decreases while ANS activity remains high or increases. Meyer and colleagues situate their results alongside prior work showing reduced HRV in depression and earlier studies linking HR/HRV changes to antidepressant response to other agents; they acknowledge that elevated ANS activity in responders might not be specific to ketamine but could mark a broader susceptibility to treatment. The correlation between drug blood levels and HR could suggest a pharmacokinetic contribution, but the authors note that baseline HR was already higher in responders before ketamine exposure, arguing against a purely dose-dependent explanation. Whether higher HR represents a stable trait or a situational state (for example anticipatory arousal) remains unresolved and is highlighted as an area for future work. Key limitations recognised by the authors include the low number of strict (50%) responders at 24 h, which limited statistical power for that outcome; the pooling of two trials with different blinding designs and the fact that HRV analyses were not the primary endpoints of those trials; exclusion of placebo-arm data from the present analysis, which limits inferences about specificity to ketamine; and the exclusion of suicidal patients, which constrains generalisability. Concurrent antidepressant medication in participants is also acknowledged as a potential confounder though the authors argue the setting reflects real-world practice. They recommend prospective studies that pre-specify ANS markers, compare different treatment modalities, and combine multiple biomarkers rather than relying on a single parameter. The authors conclude that further work should assess whether ANS-derived electrophysiological profiles can be used to individualise fast-acting treatment or augmentation strategies in MDD.
The authors conclude that ECG-derived measures of autonomic nervous system regulation, notably heart rate and HRV power, show promise as markers for identifying subgroups of patients more likely to respond to ketamine. They recommend prospective studies to test whether such electrophysiological profiles can guide rapid treatment or augmentation strategies and thereby help personalise therapy for major depressive disorder.
ECG data from 47 out of 51 (92%) subjects was used. No unintended effects or important harms occurred in neither of the trials. Both trials ended on schedule. Included subjects were aged 19-62 years (Mean 43.0, SD 12.3) with 20 (43%) males. Severity of depressive symptoms at baseline measured by MADRS was 24.0 ± 6.3. For further sociodemographic and clinical data see Supplement Table. Four ECGs had to be discarded due to missing or too short recording periods or artefacts so that the ECG data could not be processed (mean age 53.0, SD 7.3; 3 males; MADRS at baseline 2.0,SD 7.7, MADRS after 24 h 18.0, SD 9.0). For study 1, mean MDRS baseline scores was 20.4 (SD = 5.8) and MDRS score after 24 h was 13.9 (SD = 8.8); for study 2 mean MDRS baseline scores was 27.3 (SD = 4,8) and MDRS score after 24 h was 21,3 (SD = 7,1). The mean % change of MDRS scores showed no significant differences between the two studies (two-tailed T-test, T = 1.4, p = 0.18). Baseline demographic and clinical characteristics are shown in Table. Sertraline and escitalopram (together 36%), venlafaxine (28%), and mirtazapine (17%) were the most frequently used drugs for depression in the study. After ketamine infusion, nine (19%) patients were rated as full responders (!50% reduction in MADRS 24 h after infusion), nine were rated as remitted (MADRS score < 10 after 24 h) and 21 (45%) as responders when modified criterion (!30% after 24 h) was applied. Responders and nonresponders were comparable in age, sex, baseline MADRS score and antidepressant treatment regimen together with drugs for depression dosage equivalent to fluoxetine according to(Table). Heart rate and ketamine infusion: In all patients we found a significant increase of HR from baseline recording to infusion, a further significant increase to post infusion and a normalization without a difference to baseline recording after 24 hours (all values p < 0.001, ANOVA with post hoc testing, Bonferroni corrected, see Fig., left panel). For HRV power, there was only a significant increase during infusion compared to 24 hours post infusion (p < 0.009, Fig., middle panel) while nLF power showed a significant increase directly post infusion compared to baseline (p < 0.035) and 24 hours post infusion conditions (p < 0.026, Fig., right panel). The comparison between the two separate studies for all RR, HRV power and nLF power values at all time points did not show significant differences (two tailed T-tests, all p values < 0.16). Mixed Linear Regression Model: When the traditional criterion of 50% decrease of symptoms after 24 h was applied with only 9 subjects classified as responders, the linear mixed model for HR showed no significant group effect (responders vs. nonresponders; F = 0.05, df = 150.28, p = 0.83), a significant effect for covariate sex (F = 5.73, df = 162.30, p = 0.02, Table). For the 30% criterion after 24 h with 21 patient classified as responders, the linear mixed model for HR showed a significant group effect (responders vs. non-responders; F = 10.86, df = 147.65, p = 0.001) and significant effects for covariates sex (F = 5.83, df = 162.67, p = 0.017) and age (F = 4.24, df = 161.93, p = 0.041, Table). Cohen's d was 0.47 for all HR measures and 0.61 when only the baseline HR measures before infusion were considered. No significance was found for the effect of time (F = 2.58, df = 68.88, p = 0.061) or for the time  group interaction (F = 0.16, df = 67.33, p = 0.924). To figure out whether sex had a pivotal influence on the results, we performed the analysis separately for females and males with similar results concerning the group effects (e.g. F = 8.22, df = 34.20, p = 0.007 for males and F = 10.00, df = 89.79, p = 0.002 for the 30% criterion after 24 h). The additional analysis with the response criterion (decrease of MADRS > 30% or 50% any time within up to 7 days) for the 30% criterion revealed a similar group effect for HR (F = 11.32, df = 149.05, p = 0.001) and significant effects for covariate sex (F = 7.59, df = 163.63, p = 0.007) but not for age (F = 2.80, df = 162.63, p = 0.10). For the 50% criterion, there was a group effect (responders vs. non-responders) for HR (F = 4.55, df = 144.63, p = 0.035) and a significant effect for covariate sex (F = 6,68, df = 162.56, p = 0.011). Further analysis on specific HRV power revealed significant effects for group (responders vs. non-responders, 30%-24 h criterion; F = 6.65, df = 133.30, p = 0.011) and covariate age (F = 8.08, df = 81.52, p = 0.006) and time (F = 5.41, df = 93.10, p = 0.002), and no effect for sex (F = 3.00, df = 89.24, p = 0.087) and for time  group interaction (F = 0.75, df = 89.08, p = 0.97). The nLF analysis showed only a significant effect of time (F = 3.50, df = 63.20, p = 0.02) with no other significant effect or interaction (Fig.). A sensitivity analysis was carried out since not all subjects had a fourth ECG recording after 24 hours. Therefore, only the first three measurements (before infusion, during infusion and directly after infusion) were considered for the linear mixed model. Results for the HR were a significant group-(F = 9.67, df = 131.65, p = 0.002) and time-effect (F = 3.71, df = 89.18, p = 0.028) and significant effects for covariates sex (F = 4.32, df = 131.59, p = 0.04) and age (F = 6.32, df = 131.59, p = 0.13). No significance was found for the time  group interaction (F = 0.24, df = 89.18, p = 0.79). Similar results were found for HRV parameters. Hence these results resampled the findings from the model with inclusion of all measurements. Receiver Operating Curves: To demonstrate the discriminative power of the HR and HRV measures for the outcome of ketamine infusions in major depression, we performed a logistic regression analysis. When considering only HR and HRV measures from the baseline condition for predictive reasons, i.e. parameters obtained before infusion, the area under the curve was 0.68 with a sensitivity of 72% and a specificity of 64% (Fig.). Here, mainly pre infusion Heart Rate (Wald = 4.42) and to a smaller degree also pre infusion Total HRV Power (Wald = 2.25) contributed to the results. When logistic regression was performed on all available HR and HRV measures (thus including HR, HRV power and nLF power from all four recordings) and response groups, the area under the curve increased to 0.96 with a sensitivity of 94% and a specificity of 93%. The highest contribution to this result was made by total HRV power during ketamine infusion (Wald = 1.94) and normalized Low Frequency after infusion (Wald = 2.26). However, including all available measures, i.e. also parameters after the first infusion, has no predictive value. The area under the curve for the 50% decrease criterion after 24 h was 0.53 for both conditions, the baseline parameters and for all available parameters over time. Correlation of heart rate measures and ketamine/norketamine blood levels: To clarify the relationship between heart rate measures and ketamine/norketamine levels, the correlation analysis revealed several significant associations. In general, ketamine and norketamine levels were positively correlated with heart rate and negatively correlated with total HRV power. No clear trend was seen with correlations with normalized low frequency power. Only the negative correlations between ketamine levels after 30 min post infusion and total HRV power after 24 h survived Bonferroni correction (see Table).
This study shows that the profile of the autonomous nervous system activity, namely the heart rate and its associated measures, differ for responders and non-responders to ketamine infusion treatment in major depressive disorder. This held true with a response criterion of 30% MADRS decrease after 24 h or a 30%/ 50% decrease within 7 days. The baseline HR parameters obtained before infusion yielded significant medium effect size differences between responders and non-responders, suggesting a predictive value. The simple measure of a high heart rate was associated with a positive treatment effect. These findings show that HR and HRV are potentially useful clinical biomarkers for treatment outcome. The increase of HR after infusion of ketamine is in line with the literature and with the expected effect of ketamine and its increase of sympathetic activity. Ketamine induces sympathomimetic cardiovascular and respiratory effects such as increased heart rate and blood pressure as well as bronchodilation with evidence for direct interaction of ketamine with alpha-1 and beta-2-adrenoceptors of the autonomous nervous system. The dissociative syndrome at higher ketamine dosage refers to a functional and electrophysiological separation of contradictory nervous system activityand is defined by a decrease of central nervous system (CNS) arousal, whereas the activity of the autonomous nervous system (ANS) is kept at high levels or even increases. When trying to figure out the mode of function of ketamine in MDD, one has to bear in mind that MDD has been associated with a hyperarousal by means of EEG wakefulness regulationor sleep latency. Thus, the antidepressant effect of keta-Fig.. Time series of heart rate (HR, left panel) showed a significant increase during infusion and post infusion with a return to baseline 24 hours after infusion while heart rate variability power (HRV, middle panel) showed a significant alteration only when comparing start infusion condition and 24 hours post infusion condition. HRV normalized low frequency power (right panel) was increased post infusion when compared to baseline and 24 hours post infusion condition.