Treatment-emergent psychiatric adverse events in patient-reported outcomes during ketamine use for major depressive disorder: a retrospective analysis

Abstract

Background

Treatment-resistant depression (TRD) poses a significant therapeutic challenge, with remission often unattainable. Recognition and detection of treatment-emergent adverse events (TEAEs) are essential, as these events may significantly influence the quality of treatment response. This knowledge aids in personalizing care and selecting the best treatment strategy.

Methods

In a retrospective analysis of an observational study of inpatients (n = 28) with TRD, who were administered 8 ketamine infusions as an add-on therapy, psychiatric TEAEs were assessed using the Inventory of Depressive Symptomatology Self-Report 30 (IDS SR-30) and defined as symptoms that were not present at baseline but emerged during ketamine administration. The protocol was registered at ClinicalTrials.gov on Jan 2, 2020 (NCT04226963).

Results

Sleep disturbances were the most consistently reported psychiatric TEAEs, with nighttime sleep problems increasing by the 7th infusion and persisting at follow-up (n = 5), and early waking reported across timepoints (n = 3–4). Appetite and weight changes were also observed, with both increased and decreased appetite peaking early in treatment (n = 7 and n = 6 at the 3rd infusion) and persisting at lower levels at follow-up. In contrast, mood, cognitive, and most somatic symptoms were rare (≤ 2–4 participants), and suicidal ideation was minimal (n = 1 at the 3rd infusion and follow-up).

Conclusions

This study identified sleep disturbances, appetite changes, and weight fluctuations as common patient-reported TEAEs during ketamine use for TRD inpatients. These preliminary results highlight the need for larger, controlled trials to gain a comprehensive understanding of ketamine’s psychiatric safety profile.

Supplementary Information

The online version contains supplementary material available at 10.1007/s43440-026-00867-1.

Introduction

Treatment-resistant depression (TRD) is a complex and chronic disorder that is defined by regulators as a failure of at least two antidepressants at an adequate dose and for an adequate time [1]. Various augmentation strategies have been utilized to improve patient outcomes; however, lithium and atypical antipsychotics appear to be among the most consistently recommended options [2]. TRD still poses a major challenge for the psychopharmacology of mood disorders [1].

In recent years, ketamine use has been repurposed due to its observed rapid-acting antidepressant properties [3]. Primarily used solely as an anaesthetic, it has gained wide recognition in mental disorders. In contrast to conventional monoaminergic antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), ketamine primarily exerts its therapeutic effects through modulation of glutamatergic neurotransmission. Alongside its S-enantiomer, esketamine, ketamine has demonstrated rapid-acting antidepressant properties, with clinical effects often observed within hours of administration. This distinct mechanism of action has generated considerable interest, particularly in the context of TRD, where traditional agents may require weeks to achieve therapeutic benefit [4]. Apart from its antidepressant profile, ketamine has demonstrated antisuicidal [5] and antianhedonic [6]. While the results are encouraging, the racemic ketamine is an off-patent substance and consequently is not tightly regulated by a Risk Evaluation and Mitigation Strategy (REMS), which is in stark contrast to esketamine [7]. Therefore, the regulatory monitoring of ketamine use in mental disorders is not as strict and requires further attention. Classic antidepressants produce certain treatment-emergent adverse events (TEAEs) such as sleep disturbances, changes in appetite and weight or decreased energy [8, 9], or emotional blunting [10]. It might be assumed that ketamine possesses its distinct psychiatric safety profile.

Hence, the aim of this paper is to retrospectively assess the frequency and clinical characteristics of psychiatric TEAEs in hospitalized patients with TRD within major depressive disorder (TRD-MDD) receiving short-term ketamine administration.

Materials and methods

Participants

The study population comprised subjects enrolled in a naturalistic observational registry protocol of intravenous ketamine infusions for TRD. The registry included inpatients experiencing a depressive episode in the course of either major depressive disorder (MDD) or bipolar disorder (BD). Only participants with MDD were included in this paper. Diagnoses were established by a clinician psychiatrist in accordance with the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria and confirmed using the Mini International Neuropsychiatric Interview (MINI). All participants met criteria for treatment resistance in the current depressive episode. TRD was defined as the absence of a clinical response after at least two trials of first-line, evidence-based treatments, each administered over an 8-week period, which is in line with the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) guidelines [11]. Where clinically indicated, patients continued their ongoing pharmacotherapy during ketamine treatment. Exclusion criteria included pregnancy, breastfeeding, the presence of uncontrolled medical conditions, or a history of adverse reactions to ketamine. For the present analysis, only patients with MDD were included. Details are provided in our previous paper [12]. The protocol was registered at ClinicalTrials.gov on Jan 2, 2020 (NCT04226963) and approved by the Independent Bioethics Committee for Scientific Research at the Medical University of Gdańsk, Poland (NKBBN/172–674/2019). Participants provided written informed consent for participation and data utilization. The study was conducted in accordance with the Declaration of Helsinki.

Study design

The study used an observational design. All participants continued their baseline psychotropic medications, as well as any necessary treatment for chronic somatic conditions, throughout the course of ketamine infusions. The therapeutic intervention consisted of eight intravenous ketamine infusions administered over 4 weeks. Ketamine was delivered at a dose of 0.5 mg/kg based on actual body weight, administered as a 40-minute intravenous infusion. Psychometric assessments were conducted before the first, third, fifth, and seventh infusions, as well as one week following the final infusion.

Psychometric measures

Depressive symptoms were scored using the Inventory of Depressive Symptomatology Self-Report 30 (IDS SR-30). This inventory is a self-report questionnaire that comprehensively evaluates various depressive symptoms. Participants rate each item based on the severity of the symptom experienced from 0 to 3 with higher scores indicating more severe symptoms [13]. Data were collected at baseline, following the 3rd, 5th, and 7th infusions, and seven days after the final infusion.

Treatment response was defined as a ≥ 50% reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) score from baseline. Participants were classified as responders or non-responders based on scores at the seventh infusion.

Operational definition of treatment-emergent psychiatric adverse events (TEAEs)

According to the International Council for Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) E6(R3), a TEAE is defined as an adverse event that arises during treatment after being absent before treatment, or that represents a worsening in severity or frequency relative to the pre-treatment condition, and the adverse event does not necessarily have a causal relationship with the treatment [14]. In this context, IDS SR-30 items were analyzed as indicators of symptom change in patient-reported outcomes (PROs), reflecting TEAEs over the course of ketamine use. For pragmatic purposes, in this paper we consider TEAEs as psychiatric symptoms that were absent at baseline (score = 0) and appeared during the course of drug administration at any time point (score > 0). Symptoms were categorized as mild when assigned a severity score of 1, and as moderate to severe when assigned a score of 2 or 3.

Infusion-related phenomena (e.g., dissociation and psychotomimetic effects) were collected within the registry and reported elsewhere [15]; the present study focuses on IDS-SR–based patient-reported symptom changes.

Data analysis

Given the exploratory nature of the study and the constrained sample size, formal statistical procedures were not applied. Rather, the results are presented descriptively to illustrate observed patterns within the data.

Results and discussion

The characteristics and clinical outcomes of the complete sample (n = 28) of TRD-MDD patients enrolled to receive adjunctive ketamine therapy to baseline psychotropic medication are reported below (see Table 1). The study cohort was predominantly female (57%), with a mean age of 48.6 ± 14.3 years and a mean IDS SR-30 score of 47.5 ± 11.8 at baseline. Baseline data stratified by responder versus non-responder status are reported separately in a prior publication [16].

Table 1.

Summary of baseline demographic, clinical, and treatment-related characteristics in patients with TRD-MDD (n = 28)

Variables	Value
Age
Mean, years (SD)	48.6 (14.3)
BMI
Mean, kg/m² (SD)	27.4 (5.2)
Sex, n (%)
Female	16 (57%)
Male	12 (43%)
Education, n (%)
Elementary	2 (7%)
Vocational	3 (11%)
Secondary	10 (36%)
Higher	13 (46%)
Employment status, n (%)
Unemployed	6 (21%)
Pensioner	1 (4%)
Retirement	6 (21%)
Employed	10 (36%)
Study	5 (18%)
Marital status, n (%)
Single	6 (21%)
Informal relationship	2 (7%)
Married	14 (50%)
Divorced	4 (14%)
Widowed	2 (7%)
Concomitant meds, n (%)*
TCA	4 (14.3%)
SSRI	16 (57.1%)
SNRI	5 (33.3%)
Other**	12 (50%)
Antipsychotics	7 (25%)
Mood stabilizers	10 (33.3%)
Benzodiazepines	12 (43%)
IDS-SR 30
Mean (SD)	47.5 (11.8)

* - Percentages for concomitant medications may exceed 100% because participants could receive more than one medication class; ** - mirtazapine, mianserin, trazodone, bupropion, vortioxetine; BMI – body mass index; IDS-SR 30 – Inventory of Depressive Symptomatology Self-Report 30 item; SD – standard deviation; SSRI - selective serotonin reuptake inhibitors; SNRI – serotonin and noradrenaline reuptake inhibitors; TCA - tricyclic antidepressants; TRD-MDD – treatment-resistant depression within major depressive disorder

Patient-reported TEAEs assessed with the IDS SR-30 were generally uncommon across repeated IV ketamine infusions (see Fig. 1), particularly nighttime sleep difficulties, which increased by the 7th infusion and remained elevated at follow-up (n = 5), and early waking (n = 3–4 across timepoints). Changes in appetite and weight were also notable, with both increased and decreased appetite peaking early in treatment (n = 7 and n = 6 at the 3rd infusion) and pe(n = 3–4 across timepoints). Changes in appetite and weight were also notable, with both increased and decreased appetite peaking early in treatment (n = 7 and n = 6 at the 3rd infusion) and persisting, albeit at lower levels, through follow-up. In contrast, mood, cognitive, and most somatic symptoms were infrequent, typically reported by only a small number of participants (≤ 2–4), and suicidal ideation was rare (n = 1 at 3rd infusion and at follow-up). Additional analyses stratified by response status are presented in the Supplementary Materials (Figure S1).

Fig. 1.

Temporal profile of psychiatric TEAEs during repeated ketamine infusions. This study was conducted at the Department of Psychiatry of the Medical University of Gdańsk, Poland, and enrolled adult participants diagnosed with TRD within the context of MDD. All participants were deemed eligible for short-term IV ketamine use. The study employed an observational design (NCT04226963) and was conducted between 2019 and 2022. A total of 28 participants received eight ketamine infusions at a dose of 0.5 mg/kg. Depressive symptoms were assessed using the 30-item IDS SR-30 at baseline, as well as after the 3rd, 5th, and 7th infusions, and at a 7-day follow-up. For pragmatic purposes, TEAEs were defined in this study as psychiatric symptoms that were absent at baseline (score = 0) and emerged during the infusions at any subsequent time point (score > 0). Values represent the number of participants endorsing each symptom, with color intensity reflecting the frequency of endorsement. Symptoms are categorized into domains (sleep, mood, appetite/weight, cognitive, and somatic), which are delineated by horizontal lines. Abbreviations: IDS SR-30 - Inventory of Depressive Symptomatology Self-Report, IV – intravenous, MDD – major depressive disorder, NCT - The National Clinical Trial, TEAEs – treatment-emergent adverse events, TRD – treatment-resistant depression

Further analyses show that when symptoms did emerge, they were predominantly mild in severity (see Fig. 2). Moderate-to-severe symptoms were limited and occurred most often in sleep-related domains, especially nighttime sleep disturbance, which peaked at 7th infusion (n = 4) and follow-up (n = 5). A smaller number of moderate-to-severe cases were observed for appetite/weight changes and bodily symptoms. Mood and cognitive symptoms, when present, were almost exclusively mild. There was no clear increase in symptom severity over time, and more severe symptoms were confined to a minority of patients. Overall, patient-reported TEAEs during ketamine administrations were infrequent and typically mild, with more pronounced effects observed primarily in sleep and somatic domains.

Fig. 2.

Severity profile of psychiatric TEAEs across repeated ketamine infusions. This study was conducted at the Department of Psychiatry of the Medical University of Gdańsk, Poland, and enrolled adult participants diagnosed with TRD within the context of MDD. All participants were deemed eligible for short-term IV ketamine use. The study employed an observational design (NCT04226963) and was conducted between 2019 and 2022. A total of 28 participants received eight ketamine infusions at a dose of 0.5 mg/kg. Depressive symptoms were assessed using the 30-item IDS SR-30 at baseline, as well as after the 3rd, 5th, and 7th infusions, and at a 7-day follow-up. Severity was classified as mild (score = 1; left panel) or moderate-to-severe (scores = 2–3; right panel). For pragmatic purposes, TEAEs were defined in this study as psychiatric symptoms that were absent at baseline (score = 0) and emerged during the infusions at any subsequent time point (score > 0). Values represent the number of participants endorsing each symptom, with color intensity reflecting the frequency of endorsement. Symptoms are categorized into domains (sleep, mood, appetite/weight, cognitive, and somatic), which are delineated by horizontal lines. Abbreviations: IDS SR-30 - Inventory of Depressive Symptomatology Self-Report, IV – intravenous, MDD – major depressive disorder, NCT - The National Clinical Trial, TEAEs – treatment-emergent adverse events, TRD – treatment-resistant depression

This paper illustrates psychiatric TEAEs, based on PROs, associated with short-term IV ketamine administration in inpatients with TRD-MDD. Sleep disturbances were the most consistently reported symptoms, with nighttime sleep problems increasing by the 7th infusion and persisting at follow-up (n = 5), while early waking was reported across timepoints (n = 3–4). Appetite and weight changes were also observed, with both increased and decreased appetite peaking early in treatment (n = 7 and n = 6, respectively, at the 3rd infusion) and persisting at lower levels at follow-up. In contrast, mood, cognitive, and most somatic symptoms were infrequent, generally affecting no more than 2–4 participants. Importantly, suicidal ideation was minimal, being reported by only one participant at the 3rd infusion and at follow-up.

Although ketamine has been linked to beneficial changes in sleep parameters, these effects are not uniform. Duncan and Zarate noted that ketamine may improve slow wave activity and sleep continuity in some patients, but the relationship between ketamine, sleep, and mood remains incompletely understood. Our finding of treatment-emergent sleep worsening supports the view that ketamine’s effects on sleep may be heterogeneous and sometimes adverse [17]. Similarly, changes in appetite and body weight were among the most frequently reported TEAEs. However, these findings should be interpreted with caution, as ketamine’s impact on appetite-related depressive symptoms appears to be less pronounced than its effects on other symptom domains [18]. In a pooled analysis of treatment-resistant unipolar and bipolar depression, ketamine was associated with overall improvement in atypical symptoms; nevertheless, its effects on appetite-related symptoms were relatively limited at the level of individual items [19]. In a clinical sample of bipolar patients from naturalistic inpatient registry, the most frequently observed TEAEs were diminished appetite, increased body weight, hypersomnia, and diurnal variation in mood. In contrast, affective symptoms such as low mood, negative expectations regarding the future, reduced sexual interest, and physical discomfort were uniformly absent across all participants. Of note, 13.6% of patients endorsed thoughts of death or suicidal ideation [20]. In a five-year naturalistic study of 71 outpatients with MDD-TRD, Gutierrez et al. found that IV low-dose ketamine was generally well tolerated, with 78.26% of patients reporting mostly mild and transient adverse effects and 11.27% discontinuing treatment, mainly for personal reasons or lack of efficacy rather than adverse events [21]. In contrast, with respect to tolerability, a relevant benchmark can be drawn from adjacent treatment-resistant mood disorder populations. An exploratory meta-analysis of acute treatment-resistant bipolar depression trials reported that ketamine studies were associated with a pooled dropout rate of 21.2% [22]. In literature, the most reported psychotomimetic effects of ketamine in TRD include dissociation, perceptual changes, unusual sensory experiences, derealization, and depersonalization. While the induction of psychotic symptoms in TRD is disputable, ketamine may provoke psychotic symptoms in individuals with schizophrenia [23]. Nevertheless, in their report, Brody et al. (2024) described several clinically significant adverse events associated with ketamine treatment in TRD inpatients [26]. Ketamine use was discontinued in four non-responders due to emerging safety concerns. Two patients developed dysphoric dissociation during infusions, including one who also reported suicidal ideation, while another patient exhibited self-injurious behavior raising concern for ketamine-related disinhibition. Importantly, one patient developed treatment-emergent paranoid delusions. Also, a patient who had achieved remission during the ketamine course died by suicide several weeks following the final infusion and subsequent hospital discharge [24]. Furthermore, case reports have documented affective switching in individuals with bipolar disorder [25]. On the other hand, Niciu and colleagues observed delayed-onset dysphoria, exacerbation of anxiety and suicidal ideations in two out of three subjects with obsessive-compulsive disorder [26]. Although clinical trials of ketamine have shown limited evidence of procognitive effects, most studies indicate that subanesthetic doses do not produce measurable cognitive impairment. This contrasts with findings from research on chronic recreational ketamine use, which consistently reveal detrimental effects on cognitive functioning [27].

In terms of medical serious adverse events (MSAEs), across analyzed randomized and open-label clinical trials with ketamine and its enantiomers, four participants experienced MSAEs, representing an incidence of roughly 0.1%, all of which resolved without lasting effects. Above 80% of studies screened for medical comorbidities and excluded high-risk individuals, but in analyzed sample, no serious cardiac events or deaths were reported [28].

This study possesses a number of limitations that need to be taken into account when interpreting results. Firstly, this study represents a retrospective analysis, as the original study design was not specifically intended to assess the outcomes examined here but rather to investigate other aspects of ketamine use; therefore, the findings should be interpreted as exploratory and subject to inherent limitations of retrospective designs. Accordingly, the findings should be regarded as exploratory and interpreted with caution, particularly with respect to mechanistic inferences and clinical generalizability, as emphasized in the literature [4]. Secondly, the results are descriptive and statistical tests were not performed. Next, neither the placebo nor the control group was included, and thus we did not perform randomization. Similarly, patients were provided with information about the study drug utilized. The sample size was limited to 28 participants, limiting the generalizability of the findings. The follow-up period was limited to a period of merely seven days precluding the determination of whether the observed symptoms persisted beyond this timeframe or resolved shortly thereafter, and psychometric evaluations were rated using PROs. As most of the sample consisted of non-responders, it might be considered that the emergence of new symptoms reflects the natural disease trajectory and could not definitely be attributed to ketamine. Last, but not least, participants maintained their baseline psychotropic medications, which are known to have unique safety profiles and might have affected the outcome.

Future studies should aim to address these limitations by incorporating a randomized, double-blind, placebo-controlled design to enhance internal and external validity. Longer follow-up periods are recommended to capture both short- and long-term effects of treatment and to better understand the trajectory of treatment-emergent changes over time. Additionally, future research should include objective clinical assessments alongside self-report measures to reduce bias and improve the reliability of findings.

In conclusion, this study identifies sleep disturbances, changes in appetite, and weight fluctuations as commonly observed psychiatric TEAEs during ketamine use in inpatients with TRD, while suicidality appeared to remain largely unaffected. As the results are preliminary, they emphasize the importance of conducting larger, well-controlled clinical trials to enable a more comprehensive and robust understanding of the psychiatric symptom-specific adverse events of ketamine.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Abbreviations

BD

Bipolar disorder

DSM

5–Diagnostic and Statistical Manual of Mental Disorders

EMA

European Medicines Agency

FDA

Food and Drug Administration

GCP

Good Clinical Pracitce

ICH

International Council for Harmonisation

IDS SR-30

Inventory of Depressive Symptomatology Self-Report 30

IV

Intravenous

MADRS

Montgomery–Åsberg Depression Rating Scale

MDD

Major depressive disorder

MINI

Mini International Neuropsychiatric Interview

MSAE

Medical serious adverse event

PRO

Patient–reported outcome

REMS

Risk Evaluation and Mitigation Strategy

SSRI

Selective serotonin reuptake inhibitor

TEAE

Treatment–emergent adverse event

TRD

Treatment–resistant depression

TRD-MDD

Treatment resistant depression within major depressive disorder

Author contributions

Aleksander Kwaśny: conceptualization, data curation, formal analysis, methodology, project administration, writing - original draft; Alina Wilkowska: formal analysis, supervision, writing - review & editing; Michał Pastuszak: data curation; formal analysis, writing – review & editing; Krzysztof Pastuszak: statistical analysis, software, visualization, writing – review & editing; Wiesław Jerzy Cubała: conceptualization, methodology, formal analysis, methodology, supervision, writing - review & editing;

Funding

Funding for this study was provided by Medical University of Gdańsk grant number ST: 01-10026 / 0010396/ 01/ 221 / 221/ 0 / 2026; the funder had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author upon reasonable request.

Declarations

Competing interests

Krzysztof Pastuszak has no conflict of interestMichał Pastuszak received research support from Beckley Psytech, Compass Pathways, Definium Therapeutics, GH Research, MSD. Aleksander Kwaśny received research support from Beckley Psytech, Compass Pathways, Definium Therapeutics, GH Research, MSD. Alina Wilkowska has received research support from Angelini, Biogen, Eli Lilly and Company, Janssen- Cilag, Lundbeck, Polpharma, Sanofi, Termedia, Valeant, Bristol Myers Squibb.Wiesław Jerzy Cubała has received grants: Acadia, Alkermes, Allergan, Angelini, Auspex Pharmaceuticals, Beckley Psytech, BMS, Celon, Cephalon, Compass Pathways, Cortexyme, Ferrier, Forest Laboratories, GedeonRichter, GH Research, GWPharmaceuticals, HMNC Brain Health, IntraCellular Therapies, Janssen, KCR, Lilly, Lundbeck, MindMed (Definium), Minerva, MSD, NIH, Neumora, Novartis, Orion, Otsuka, Recognify Life Sciences, Sanofi, Seaport, Servier; Honoraria: Adamed, Angelini, AstraZeneca, BMS, Celon, GH Research, GSK, Janssen, KRKA, Lekam, Lundbeck, Minerva, NeuroCog, Novartis, Orion, Pfizer, Polfa Tarchomin, Sanofi, Servier, Zentiva; Advisory boards: Angelini, Celon (ended 2021), Douglas Pharmaceuticals, GH Research, Janssen, MSD, Novartis, Polpharma, Sanofi, Tasman Therapeutics.