Spectral changes of EEG following a 6-week low-dose oral ketamine treatment in adults with major depressive disorder and chronic suicidality

Major depressive disorder (MDD) is highly prevalent and a leading contributor to suicide risk, yet clinical diagnosis and prognosis still rely largely on symptom reports and clinical screening. To improve objective characterisation of MDD and suicidality, prior research has explored neurophysiological biomarkers. Electroencephalography (EEG) — especially spectral (frequency-band) analysis of resting-state signals — has shown promise for distinguishing depressed or suicidal individuals from healthy controls and for tracking effects of antidepressant interventions, including ketamine. This study aimed to characterise changes in EEG spectral power following a 6-week course of low-dose oral ketamine in adults with MDD and chronic suicidality, and to test whether EEG changes associate with clinical outcomes. Based on earlier ketamine-EEG work, the investigators hypothesised that at the end of treatment (Post) versus baseline (Pre) there would be: i) decreased theta power across regions, ii) decreased alpha power in the centro-parietal region, and iii) decreased low- and/or high-beta power in the centro-parietal region; they further predicted that at 4-week follow-up (FUP) EEG power would trend back towards pre-treatment values alongside clinical measures.

This report used data from the open-label Oral Ketamine Trial on Suicidality (OKTOS). Participants received six weekly oral, sub-anaesthetic ketamine doses over six weeks with flexible titration from 0.5 up to 3.0 mg/kg. Assessments occurred at three principal timepoints: Pre (up to 14 days before the first dose), Post (4–7 days after the final dose) and FUP (28–32 days after the final dose). Of 32 trial completers, 25 participants were included in the EEG analyses because of withdrawals or missing EEG sessions. The analysed cohort comprised 11 males and 14 females aged 22–71 years (mean 46.41, SD 14.12). All participants had DSM‑5 MDD and chronic suicidality; most (92%) were taking psychotropic medications and 76% had additional psychiatric comorbidities. Resting-state EEG comprised 4 minutes of eyes-closed recording using a 32-channel BioSemi ActiveTwo system sampled at 1024 Hz. Channels were grouped into four regions for analysis: frontal, temporal, centro-parietal and occipital (channel lists provided in the paper). Pre-processing used an in‑house pipeline (EEG‑pyline) and standard steps: 0.5–30 Hz band-pass filtering, removal of ocular artefacts via signal-space projection using recorded EOG channels, segmentation into consecutive 5-second epochs, automated epoch/channel rejection with Autoreject, and visual screening of global field power. Delta band (1–3.9 Hz) was excluded because it failed a reliability check across epochs. Spectral analysis estimated power spectral density (PSD) with Welch’s method (2-second Hamming window, 50% overlap). PSD values (µV2/Hz) were averaged for theta (4–7.9 Hz), alpha (8–12 Hz), low-beta (12.1–18 Hz) and high-beta (18.1–30 Hz) bands for each region. The primary clinical outcome was change in suicidality measured by the Beck Scale for Suicide Ideation (BSS); secondary measures were the DASS‑21 subscales (depression, anxiety, stress). Paired comparisons across timepoints used the Wilcoxon signed‑rank test due to non-normal distributions. Associations between change scores on EEG bands and clinical measures were tested with Spearman rank correlations (two‑tailed; significance p < 0.05).

Alpha band: The principal, pre-specified finding was a decrease in centro‑parietal alpha power from Pre to Post. Between Post and FUP, centro‑parietal alpha power increased again toward baseline. Temporal alpha also increased between Post and FUP; however, the Pre-to-Post decrease at the temporal region was not statistically significant. Overall, no significant difference in alpha was observed when comparing Pre to FUP, consistent with a transient modulation during the treatment period. Theta band: No significant theta power changes emerged immediately after treatment (Pre vs Post). Significant changes appeared between Post and FUP: occipital theta power decreased, while temporal and centro‑parietal theta power increased. The paper notes these delayed theta changes differ from some prior ketamine studies that measured EEG shortly after infusion, reflecting the longer post-treatment interval used here. Beta bands: High‑beta showed no statistically significant differences across any of the timepoint comparisons. Low‑beta exhibited region‑specific Post-to‑FUP changes: a decrease at the temporal region and an increase at the occipital region. The abstract and discussion also report an increase in occipital low‑beta between Post and FUP. Clinical correlations: Changes in EEG power did not correlate with the primary clinical outcome (BSS) for any timepoint pair. Several significant correlations were found between EEG changes and the DASS‑21 subscales. Notable examples (timepoint pair, region, band, Spearman r, p): DASS‑Depression (Post–FUP) with occipital theta r = 0.431, p = 0.032; frontal low‑beta r = -0.464, p = 0.019; frontal high‑beta r = -0.571, p = 0.003. DASS‑Anxiety showed correlations such as Pre–Post occipital theta r = -0.522, p = 0.007 and Pre–FUP temporal alpha r = -0.455, p = 0.022. DASS‑Stress yielded several correlations including Pre–Post occipital theta r = -0.659, p = 0.0003, Pre–Post temporal theta r = -0.585, p = 0.002, and Post–FUP occipital theta r = 0.526, p = 0.007. The extracted text lists multiple other region‑ and band‑specific correlations with DASS subscales (many in the moderate range, p < 0.05). Additional results and sample characterisation: From the larger trial, responders (defined by BSS change) numbered 17 (68%) and non‑responders 8 (32%); prolonged responders were 11 (44%) and prolonged non‑responders 14 (56%), but subgroup EEG analyses were not reported. The study did not identify delta‑band results due to reliability concerns. High‑beta produced no significant timepoint effects.

Anijärv and colleagues interpret the principal finding as support for a transient modulation of alpha power by low‑dose oral ketamine: centro‑parietal alpha decreased during the active treatment phase and reverted toward baseline by the 4‑week follow‑up. The authors note this pattern is consistent with prior ketamine EEG work that observed short‑lived alpha effects, and they therefore characterise the alpha changes here as transient. Theta-band results were more complex. Changes in theta power did not appear immediately after the treatment but emerged between Post and FUP, with occipital theta decreasing and temporal/centro‑parietal theta increasing. The investigators propose two tentative interpretations: the occipital theta decrease could reflect delayed positive neuroplastic effects of ketamine, whereas increases in other regions might indicate remission of treatment effects and return of depressive neurophysiology. Because these patterns are mixed and differ from studies that measured EEG soon after infusion, the authors describe theta findings as inconclusive and in need of replication. Regarding beta activity, high‑beta showed no reliable changes, while low‑beta exhibited regional Post‑to‑FUP shifts. The discussion links beta‑band activity to cognitive constructs such as sense of agency and to anxiety, suggesting possible pathways by which ketamine's clinical effects might be mediated, but the authors emphasise that these mechanistic inferences are preliminary. On clinical associations, none of the EEG changes correlated with the primary suicidality measure (BSS), but multiple correlations were found with DASS‑21 subscales, notably several moderate correlations involving occipital theta and various beta measures. The authors caution that the absence of BSS correlations and the pattern of DASS associations leave the utility of resting EEG as a biomarker for ketamine’s long‑term antidepressant or anti‑suicidal effects unresolved. The investigators acknowledge several limitations that temper inference: the relatively small sample (N=25 for EEG analyses), the open‑label design without healthy controls or placebo/active comparator, heterogeneity introduced by concurrent psychotropic medications, variable daytime timing of EEG recordings, and the focus on chronic suicidality which may not generalise to other populations. They conclude that the results show significant EEG spectral changes after long‑term low‑dose oral ketamine in this cohort but argue that randomised controlled trials with larger samples and comparator groups are required to establish whether EEG can serve as a robust biomarker of sustained clinical response.