Ketamine or Esketamine in Special Populations of Patients With Treatment-Resistant Depression

Introduction

Treatment-resistant depression (TRD), as defined by the United States Food and Drug Administration (FDA) and the European Medicines Agency, constitutes failure to respond to at least 2 antidepressant trials of adequate dose and duration [1–3]. For affected patients, therapeutic options include electroconvulsive therapy and transcranial magnetic stimulation; however, only about 50% achieve remission with these approaches [4]. Conventional antidepressants typically exert their effects via modulation of the serotonergic and/or dopaminergic systems. In contrast, the glutamatergic system – regulated by N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and targeted by ketamine – offers a promising alternative therapeutic pathway. A key advantage of ketamine lies in its exceptionally rapid onset of action: after a single infusion, nearly three-quarters of patients report symptomatic improvement within 24 h, with effects lasting 7 to 14 days [1]. This rapid response is particularly relevant because many conventional antidepressants require weeks to months to produce clinically meaningful symptom relief. In the general population, the efficacy and safety of ketamine and its S-enantiomer, esketamine, have been well documented across numerous meta-analyses and systematic reviews [eg, 5–10]. This review examines the use of ketamine in patients with TRD who belong to populations of particular interest due to age or comorbid conditions. Additionally, it explores the neurobiological mechanisms underlying ketamine’s antidepressant effects in greater detail, given their relevance to comorbidity profiles.

Pharmacology and Mechanism of Action

PHARMACOKINETICS AND METABOLISM:

Ketamine is a cyclohexanone derivative of phenylcyclohexylamine, structurally related to phencyclidine. Due to its rapid absorption and distribution, ketamine exhibits a rapid onset of action [11]. After intramuscular or subcutaneous administration, sedation or anesthesia develops within 10 to 15 min and typically lasts 30 to 120 min [12]. When administered intravenously, onset occurs within 1 to 2 min, and anesthesia persists for approximately 20 to 60 min [12]. After oral administration, onset usually occurs within 20 to 30 min, with effects lasting 60 to 90 min [12]. Bioavailability varies according to the route of administration (Table 1). Ketamine undergoes extensive hepatic metabolism. The main metabolic pathway involves N-demethylation by the CYP3A4 and CYP2B6 isoenzymes to form the active metabolite norketamine, which is approximately threefold less potent than ketamine; norketamine is subsequently converted to hydroxynorketamine (HNK) and dehydronorketamine (DHNK) [13]. Demethylation proceeds in a stereoselective manner: CYP3A4 demethylates esketamine more rapidly than arketamine, whereas CYP2B6 demethylates both enantiomers with similar efficiency [14]. These metabolites undergo further conjugation and degradation; they are primarily excreted via the kidneys as glucuronides in urine (approximately 80%); 2% is excreted unchanged, 2% as norketamine, and 16% as DHNK [15]. A small fraction is eliminated in bile [16]. Ketamine and its metabolites remain detectable in urine for several days after administration, and DHNK persists for up to 10 days [17]. The estimated elimination half-life of racemic ketamine ranges from 2 to 4 h; it is 5 h for esketamine [9,18–20]. Ketamine shows relatively low plasma protein binding (about 20%–50%) and a large volume of distribution (3–5 L/kg) [21]. Impaired renal function exerts only a modest effect on excretion [12]. Ketamine is both metabolized by and inhibits hepatic cytochrome P450 enzymes, explaining several drug interactions [12]. In particular, ketamine metabolism is influenced by concomitant use of CYP450 inducers or inhibitors [12], and enzyme inducers exert a pronounced effect on norketamine metabolism [16].

PHARMACODYNAMICS:

Ketamine primarily acts as a non-competitive NMDA receptor antagonist via binding to the allosteric phencyclidine site within the receptor channel pore in the central nervous system. This inhibition blocks calcium influx, thereby disrupting cortical–cortical and cortical–subcortical signaling [16,18]. NMDA receptor blockade reduces activation of eukaryotic elongation factor 2 kinase, enhancing translation of brain-derived neurotrophic factor (BDNF) and decreasing acetylcholine release. Additionally, ketamine interacts with AMPA receptors and induces a rapid increase in glutamate release, leading to acute AMPA receptor activation. This mechanism is thought to substantially contribute to the antidepressant effects of ketamine [22]. Along with its primary action on NMDA receptors, ketamine exerts antagonistic effects on anticholinergic and serotonergic receptors, as well as sodium channels. Furthermore, it binds to opioid receptors, acting as an antagonist at the μ-opioid receptor and as a partial agonist at the δ-opioid and κ-opioid receptors [22,23]. Preclinical studies indicate that HNK, rather than ketamine itself, may serve as a key mediator of antidepressant effects [24]. The (2R,6R)-HNK enantiomer activates postsynaptic AMPA receptors and triggers the mechanistic target of rapamycin (mTOR) signaling pathway, which promotes synthesis of synaptic proteins, including BDNF; it also modulates metabotropic glutamate receptor 2 activity [25]. HNK exhibits lower addictive potential and weaker dissociative effects; because dissociation is not required for therapeutic efficacy, HNK is considered a promising next-generation antidepressant [26]. These mechanisms converge on 2 interrelated theories that explain ketamine’s rapid and sustained antidepressant effects: the glutamate surge hypothesis and the neurotrophic theory of depression. The glutamate surge hypothesis emphasizes immediate consequences of NMDA receptor blockade. By inhibiting this receptor, ketamine suppresses inhibitory glutamatergic interneurons, producing a rapid but transient increase in glutamate release and subsequent activation of AMPA receptors, key mediators of synaptic plasticity. This process aligns with the neurotrophic theory of depression, which links depressive states to synaptic connection loss and reduced neurotrophic support in brain regions such as the prefrontal cortex and hippocampus [27]. Ketamine counteracts these changes: AMPA receptor activation initiates intracellular signaling pathways, including mTOR complex 1, that promote synaptogenesis [28]. BDNF is central to this process: patients with depression often show reduced BDNF levels, which contribute to synaptic loss. Ketamine administration rapidly increases BDNF expression through glutamate-driven AMPA receptor signaling. The resulting rise in BDNF facilitates synapse formation, strengthens neural circuits, and supports repair of stress- and depression-related neural damage. The rapid induction of BDNF and synaptogenesis is considered a major reason ketamine can produce antidepressant effects within hours, rather than the weeks required for conventional monoaminergic antidepressants [29].

Ketamine is a racemic mixture of 2 enantiomers; esketamine is approximately twice as potent as the racemate and 3 times as potent as arketamine [30]. In analgesic and anesthetic applications, the potency of esketamine is presumably due to its higher affinity for the phencyclidine binding site compared with arketamine [31]. Although ketamine has been used for decades as an anesthetic and analgesic agent, it has also been utilized off-label for psychiatric indications, including major depressive disorder and conditions associated with suicidal ideation, anxiety, and post-traumatic stress disorder (PTSD). In contrast, a nasal spray formulation containing esketamine has received FDA approval specifically for TRD, which has facilitated its increasing use in clinical settings.

MECHANISTIC PATHWAYS IN DEPRESSION AND COMORBIDITIES:

Depression often co-occurs with other psychiatric and somatic disorders, such as neurodegenerative diseases, chronic pain, addiction, and cardiovascular conditions. A growing body of evidence indicates that depression and many somatic illnesses share common biological mechanisms. A central element is glutamatergic dysfunction. Similar dysregulation of glutamatergic signaling contributes to the pathogenesis of depression, addiction, and Alzheimer disease (AD), in which glutamate-mediated excitotoxicity may promote neuronal injury. Modulation of AMPA and metabotropic glutamate receptors, as observed with ketamine and its metabolites, represents a potential strategy to restore neurochemical balance in these conditions.

Inflammation represents another important shared factor, both at the systemic level and within the central nervous system. Elevated concentrations of proinflammatory cytokines, including interleukin (IL)-1β, interleukin-6, and tumor necrosis factor (TNF)-α, are observed in patients with depression and in various comorbid conditions, such as autoimmune disorders, chronic pain syndromes, and obesity. These inflammatory processes influence neurotransmitter metabolism, neuroplasticity, and hypothalamic–pituitary–adrenal axis function, which is disrupted in depression and in chronic stress associated with other diseases. Therefore, the anti-inflammatory properties of ketamine may substantially contribute to its broad therapeutic profile.

Impairments in neuroplasticity and neurogenesis, often associated with reduced BDNF levels, are widely recognized features of depression. Comparable deficits in neuroplasticity are evident in neurodegenerative disorders (eg, AD, which is characterized by synaptic loss) and in the aftermath of PTSD. By rapidly increasing BDNF expression and activating signaling pathways that support synaptogenesis, ketamine may target shared biological substrates across these disorders.

Special Populations

Neurological Disorders

ALZHEIMER DISEASE: Depression in AD is particularly difficult to treat because it may arise from distinct pathophysiological mechanisms, including progressive neurodegeneration and imbalance of neurotransmitter systems, which can reduce the effectiveness of conventional antidepressant therapies [32,33]. The potential efficacy of (es)ketamine in AD has been hypothesized for many years [34,35]; however, it was not until 2024 that 2 systematic reviews compiled evidence regarding its effectiveness in this population.

In the first review, Altamura et al extensively discussed ketamine’s mechanisms of action in patients with AD based on preclinical studies and summarized available clinical data, including case reports and small cohort studies involving patients with cognitive impairment and TRD linked to end-of-life conditions [36]. A second systematic review indicated that ketamine exerted either beneficial or neutral effects on cognitive function in patients with TRD. Due to the limited number of studies involving individuals with AD, this analysis primarily focused on the general TRD population [37].

One published case report describes a 76-year-old woman with a confirmed diagnosis of AD and a 10-year history of depressive symptoms that preceded the onset of dementia by 2 years. The patient received 7 subcutaneous doses of ketamine. After the first dose (0.5 mg/kg), clinical improvement was minimal; after the second dose (0.75 mg/kg), administered 2 days later, substantial improvement was observed [38]. No serious adverse events were reported.

TRAUMATIC BRAIN INJURY: Among survivors of traumatic brain injury (TBI), the risk of developing depression is increased by approximately 33% compared with matched controls, and the risk of suicide is approximately twofold higher [39–41]. Nevertheless, reports of (es)ketamine efficacy in patients with TRD and comorbid TBI remain extremely limited.

Hentig et al described a case of a disabled veteran with TRD, chronic PTSD, and TBI who had not responded to a wide range of prior treatments. These included antimanic agents, antipsychotics, anxiolytics, benzodiazepines, mood stabilizers, norepinephrine–dopamine reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, tetracyclic antidepressants, and tricyclic antidepressants. Pharmacologic therapy was combined with multiple psychotherapeutic approaches, including group and individual psychotherapy, prolonged exposure therapy, and eye movement desensitization and reprocessing [42].

During the first and second weeks of (es)ketamine treatment, substantial reductions were observed in Patient Health Questionnaire-9, Beck Depression Inventory, and Neurobehavioral Symptoms Inventory total and subscale scores. By week 3, however, scores had returned to approximately 75% of pretreatment levels and exceeded baseline values by week 4. Notably, shortly after the first infusion, the patient abandoned an active suicide plan. During the fifth infusion, a complete dissociative episode accompanied by an extreme panic attack occurred; the patient became distressed, combative, and disoriented, which required interruption of the infusion and administration of 1 mg midazolam. Despite this adverse event and fluctuating scale scores, the patient reported subjective relief of depressive symptoms and suicidal ideation after ketamine treatment.

A multivariate regression analysis of 119 patients with PTSD and/or TBI who received 8 (es)ketamine infusions for TRD showed significant reductions in depressive and PTSD symptoms; however, this effect was observed only in patients without comorbid TBI [43].

CHRONIC NEUROPATHIC PAIN: Chronic neuropathic pain results from injury or disease affecting the somatosensory system and includes conditions such as postherpetic neuralgia, painful peripheral nerve injury, trigeminal neuralgia, and post-amputation pain. Although etiological links between pain and depression remain incompletely understood, recent studies indicated that this comorbidity involves multiple shared pathophysiological mechanisms: dysregulation of monoaminergic neurotransmission (serotonin, dopamine, norepinephrine), reduced BDNF expression, activation of inflammatory pathways that cross the blood–brain barrier, and enhanced glutamatergic signaling through NMDA and AMPA receptors. All of these processes contribute to impaired neuroplasticity and central sensitization [44].

Ketamine alleviates neuropathic pain by inhibiting inflammatory signaling within neuroglial cells [45]. In a preclinical model, mice subjected to spared nerve injury and exhibiting depression-like behavior received a single subanesthetic dose of ketamine (10 mg/kg). This intervention improved affective symptoms but failed to attenuate nociceptive sensitization, consistent with the limited analgesic efficacy of low doses typically used in psychiatric practice [46].

In contrast, a clinical study of 66 patients showed that individuals with comorbid neuropathic pain and TRD responded more favorably to ketamine than those without pain. Specifically, the pain group demonstrated a shorter time to antidepressant response (8.2±7.2 vs 12.4±8.6 days), faster remission (12.0±7.6 vs 15.8±7.5 days), a higher response rate after 6 infusions (72.7% vs 48.5%), and a greater remission rate (51.5% vs 27.3%) [47]. Furthermore, repeated intravenous ketamine infusions (0.5 mg/kg) substantially reduced a broad panel of proinflammatory cytokines in the pain group – namely TNF-α, IL-6, granulocyte-macrophage colony-stimulating factor, fractalkine, interferon-γ, IL-10, macrophage inflammatory protein (MIP)-3α, IL-12p70, IL-17α, IL-1β, IL-2, IL-4, IL-23, IL-5, IL-7, and MIP-1β – after 13 days of treatment. In contrast, only TNF-α levels declined in the non-pain group. These findings suggest that repeated ketamine infusions in patients with TRD and comorbid pain exert both analgesic and antidepressant effects, likely mediated in part by anti-inflammatory mechanisms.

PSYCHIATRIC COMORBIDITIES:

Electroencephalographic studies indicate that ketamine’s non-competitive antagonism of NMDA receptors results in suppression of alpha rhythms and predominance of theta activity [48]. Consequently, dissociative phenomena may arise – including “out-of-body” experiences and the so-called reemergence phenomenon during recovery – manifesting as visual and auditory disturbances along with disorganization of mood, body image, and time perception. These effects, which can occur even at low concentrations, resemble the psychotomimetic symptoms observed in patients with schizophrenia [49]. The most frequently reported acute psychiatric adverse effect of ketamine is anxiety, followed by agitation or irritability, euphoria or elevated mood, delusions or unusual thoughts, panic or apathy, emotional blunting, psychosis, emotional lability, attention-seeking behavior, and formal thought disorder. These symptoms are generally manageable through appropriate dose selection, route of administration, choice of enantiomer, and use of concomitant medications [49].

Ketamine has demonstrated efficacy in patients with TRD and co-occurring psychiatric disorders. Beneficial effects have been identified in TRD episodes within bipolar disorder [50] and in anxiety symptoms within TRD and comorbid generalized anxiety disorder [51–54]. Efficacy has also been observed in TRD with comorbid PTSD [55–57], treatment-resistant obsessive-compulsive disorder [57,58], histories of childhood trauma [59], antisocial personality disorder [60], social anxiety disorder [61], eating disorders [62–65], borderline personality disorder [66–68], and psychogenic non-epileptic seizures [69]. In autism spectrum disorder, findings remain inconclusive. Intravenous ketamine, but not esketamine, has been associated with improvement in social withdrawal; 5 case reports have also described reductions in depressive symptoms and increased social interaction [70].

A recently published systematic review examined the use of ketamine in patients with mood disorders accompanied by psychotic features [71]. The authors analyzed 9 case reports or case series and 3 observational studies, comprising a total of 64 patients with depression and psychotic features and 19 adults with bipolar disorder and psychotic features who received 0.5 mg/kg of (es)ketamine via intravenous, subcutaneous, or oral administration. Of the 6 articles that reported dissociative symptoms, only 2 used a validated assessment scale. Although transient increases in dissociation (lasting up to 2 h post-infusion) were described in 6 articles, no subacute or chronic worsening was observed, with the exception of a substantial increase in Clinician-Administered Dissociative States Scale over 4 weeks. Among the 12 articles that reported psychotic symptoms, only 3 employed a validated scale (Brief Psychiatric Rating Scale); none documented symptom exacerbation. One article described deterioration over 4 weeks, whereas 8 reported resolution of psychotic features. The risk of ketamine-induced psychotic symptoms during TRD treatment appears to be higher in male patients [72] and individuals with epilepsy [73].

SUBSTANCE USE DISORDERS:

In the United States, the number of individuals receiving a ketamine prescription increased more than fivefold, from 0.55 per 100 000 in 2017 to 3.01 per 100 000 people in 2022. During the same period, the proportion of patients receiving ketamine specifically for depression rose from 5.3% to 28.3% [74]. Although ketamine is a valuable rapid-acting antidepressant, its potential for non-medical use warrants careful consideration.

A systematic review of 16 studies including 2174 patients concluded that ketamine is relatively safe for the treatment of depression in adults when administered under supervision with appropriate monitoring and judicious dosing [75]. Another review [76] indicated that intranasal esketamine remains safe among patients with TRD, including those with a history of substance use.

Non-medical ketamine use is associated with several risk factors, including young age (75% of users are younger than 25 years), socioeconomic disadvantage, affiliation with nightlife subcultures, polysubstance use, and self-medication resulting from limited access to professional mental health care [77]. Ketamine dependence may lead to cortical overactivation, dysregulation of reward pathways, redirection of synaptic plasticity toward addiction-related circuits, structural brain alterations, and impairment of memory and impulse control [77].

Paradoxically, ketamine is also under investigation as a potential treatment for substance use disorders, including dependence on alcohol, cocaine, opioids, and cannabis. In this context, ketamine has been reported to reduce withdrawal symptoms and cravings and to support abstinence, particularly when combined with psychotherapy. However, conclusions regarding its efficacy remain limited due to the scarcity of randomized controlled trials and the small size of available study populations [78,79].

CANCER:

Several case reports have described beneficial effects of ketamine on both pain and depression in patients with malignancies, and the mechanisms underlying its actions in cancer have been extensively characterized [80]. However, a systematic review of 5 Chinese studies evaluating intravenous (es)ketamine in patients with cancer did not provide conclusive evidence of antidepressant efficacy in this population [81].

The impact of ketamine on underlying oncologic disease also remains uncertain. Specifically, ketamine exhibits multifaceted antitumor activity. First, through NMDA receptor antagonism, it induces Ca2+ influx and activates the calcium/calmodulin-dependent protein kinase II (CaMKII) signaling pathway, which can influence tumor cell survival [82]. Second, ketamine enhances lipid peroxidation and induces ferroptosis in cancer cells, impairing their capacity to counteract oxidative stress [83]. Third, ketamine has been shown to reduce intracellular calcium concentrations, thus inhibiting tumor cell survival, proliferation, angiogenesis, and metastatic potential [84]. Conversely, at anesthetic doses, ketamine exerts immunosuppressive effects that may increase susceptibility to tumor progression and metastasis [80]. Consequently, patients with cancer represent another subgroup in which further investigation is required to define the efficacy and safety profile of ketamine.

CARDIOVASCULAR DISEASES:

Ketamine exerts sympathomimetic effects on the cardiovascular system by increasing catecholamine release, enhancing cardiac output, and inducing systemic vasoconstriction. These properties may contribute to hemodynamic stabilization; however, clinically significant adverse effects include hypertension, tachycardia, and tachyarrhythmias [16,85]. Therefore, cardiovascular diseases are relative contraindications to ketamine administration, although individualized risk–benefit assessment in end-of-life settings may support its use [86].

The risk of cardiologic complications is particularly high in patients with a history of hypertension, as well as older adults. In a study of 138 patients who received a total of 2342 ketamine infusions, systolic and diastolic blood pressure increased by a mean of 16.0 mmHg (standard deviation, 11.2) and 11.0 mmHg (standard deviation, 8.45), respectively, 40 min after infusion onset. Severe hypertension occurred in 12.5% of patients, and its incidence was highest during the first 3 infusions (43.4%) [85]. Additional risk factors for post-infusion blood pressure elevation included diabetes, hyperlipidemia, prior stroke, and epilepsy; however, odds ratios were not reported, limiting secondary analysis [87]. Notably, blood pressure elevation during ketamine infusion in patients with TRD is reportedly amenable to non-pharmacologic management through music therapy administered during treatment [88].

An analysis of data from the FDA’s Adverse Event Reporting System identified sex-related differences in cardiovascular complications: men exhibited a higher risk of blood pressure increases during ketamine therapy, whereas women showed higher absolute blood pressure values [72,89]. Women also were more likely to experience bradycardia [89].

METABOLIC CONDITIONS:

Individuals with depression display an increased risk of obesity, and coexistence of these conditions may exacerbate clinical severity. Analyses of the association between body mass index and the antidepressant effects of ketamine have yielded inconsistent findings. In studies by Niciu et al [90] and Tan et al [91], patients with TRD and higher body mass index demonstrated better responses to subanesthetic intravenous ketamine (0.5 mg/kg). In contrast, Machado-Vieira et al [92] reported an inverse association; Lipsitz et al [93] observed no relationship between body mass index and treatment response. These discrepancies may reflect differences in study design or indicate that therapeutic response is more closely related to metabolic syndrome than to obesity alone [94].

Among patients with insulin resistance, ketamine disrupts glucose metabolism, mitochondrial function, and oxidative balance; this disruption represents 1 mechanism underlying its adverse cardiovascular effects [95]. A case report has also described ketamine-induced hypoglycemia (<70 mg/dL; 4 episodes during 11 infusions) in a patient with type 1 diabetes mellitus receiving treatment for TRD [96]. Current understanding of ketamine–insulin interactions remains limited, especially regarding its potential to induce hypoglycemia in individuals with diabetes. Close monitoring of blood glucose concentrations is recommended for patients with type 1 diabetes who receive ketamine infusions to treat depression.

RENAL AND HEPATIC DISEASES:

Ketamine metabolites, primarily excreted via the kidneys, can contribute to bladder injury. Among individuals who use ketamine recreationally, ulcerative cystitis – which may involve both the lower and upper urinary tracts – has been reported in more than 25% of cases. In contrast, only a single case of ketamine-induced cystitis has been described in a patient receiving low-dose ketamine for TRD [97]. Typically, ketamine-induced cystitis manifests as dysuria, urgency, nocturia, and urinary frequency; symptoms may later progress to incontinence, hematuria, bladder wall fibrosis, ulcerative cystitis, hydronephrosis, and ultimately chronic kidney failure [98]. Proposed mechanisms include urothelial barrier disruption, bladder inflammation, direct ketamine toxicity, nerve hyperplasia and hypersensitivity, cellular apoptosis, microvascular injury, and overexpression of carcinogenic genes [99]. Views concerning the reversibility of ketamine-induced cystitis remain inconsistent; prevention primarily relies on monitoring for signs of ketamine dependence [100]. Sex-related differences in adverse events have also been observed. Urinary retention and cystitis occur more frequently in men; sterile pyuria, elevated transaminase levels, and sclerosing cholangitis are more common in women [72,89].

RESPIRATORY DISEASES:

Ketamine exerts stimulatory effects on the respiratory system and acts as a potent bronchodilator. This bronchodilatory action is thought to occur through β2-adrenergic agonism and antagonism of histamine and acetylcholine receptors, which may make it suitable for selected patients with asthma or bronchoconstriction [3]. However, findings from systematic reviews remain inconsistent; therefore, ketamine is not recommended for treatment-resistant asthma exacerbations [101,102]. Adverse effects of (es)ketamine include respiratory depression; nevertheless, analyses of the Janssen Global Medical Safety database indicate that such events are generally manageable [103]. The risk of respiratory complications was not increased in subgroups with preexisting respiratory disease. Among 50 patients receiving esketamine for major depressive disorder, 1 had chronic obstructive pulmonary disease, 2 had asthma, 4 had cardiovascular disease, 8 had obesity, 23 had PTSD or anxiety disorders, and 22 had either no reported comorbidities or no comorbidity data available [103]. The most frequently reported comorbidities potentially contributing to (or predisposing individuals to) respiratory depression included anxiety, panic disorder, or PTSD (n=23), obesity (n=8), cardiovascular disease (n=4), and respiratory disorders (n=3). Additionally, an unhealthy lifestyle was noted in 4 cases.

GERIATRIC PATIENTS:

Ketamine (in nasal spray or subcutaneous form) is reportedly better tolerated among older adults with TRD linked to end-of-life conditions than bupropion, lithium, or nortriptyline [104]. However, evidence regarding efficacy in geriatric populations is derived from individual studies and remains inconclusive. In a study by George et al, subcutaneous ketamine at doses of at least 0.2 mg/kg was significantly more effective than midazolam in alleviating depressive symptoms [105]. In contrast, another trial showed no superiority of adding ketamine to a previously unused antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine XR) compared with placebo augmentation [106]. In a study of 10 patients (aged 61–77 years) treated with intravenous ketamine, all showed clinical improvement and 2 achieved remission; no serious adverse events were reported [107]. In a cohort of 33 veterans (mean age, 62 years; range, 55–72 years), there was an 89% estimated probability that intravenous ketamine was superior to midazolam after 7 days of treatment. The response rate in the ketamine group was 70% compared with 46% in the control group on day 7 and 82% versus 32% on day 28 [108]. The authors of a systematic review evaluating intravenous ketamine concluded that its efficacy in the geriatric population (>60 years) with TRD appears comparable to that in the general TRD population [19]. Importantly, participants in these studies were typically at the lower end of the geriatric age range. Evidence regarding ketamine’s effectiveness in older geriatric patients remains limited. We identified a single case report of a 79-year-old woman with a long history of major depressive disorder and a current episode of TRD accompanied by pseudodementia, in whom a 6-month course of intranasal esketamine led to substantial reductions in both depressive symptoms and cognitive impairment [20]. In the context of population aging, further investigation of ketamine use is warranted among individuals with TRD linked to late-life depression.

CHILDREN AND ADOLESCENTS:

Due to ketamine’s addictive potential and the higher risk of drug-seeking behavior among individuals younger than 25 years, its use in adolescents remains controversial. Nevertheless, numerous reports describe safe and effective use of ketamine in pediatric populations. Bruton et al identified 16 articles, including 7 case studies, 6 observational studies, 3 randomized trials, and 6 secondary analyses [109]. These studies showed rapid improvement in depression, anxiety, and suicidality, with effects sustained for weeks to months after treatment. Reported adverse events included dizziness, nausea, mild dissociation, and transient hemodynamic changes. A meta-analysis based on another systematic review demonstrated standardized mean differences in depression scores favoring ketamine over electroconvulsive therapy or transcranial magnetic stimulation [110].

Ketamine, and particularly esketamine, also exhibits anti-suicidal effects, which have been documented in adolescents [111]. One case report described the effectiveness of ketamine in an exceptionally severe case involving an adolescent with TRD and comorbid generalized anxiety disorder, eating disorder, PTSD, and borderline personality disorder. Over a 10-year period, this patient had received antidepressant monotherapy, adjunctive treatment with antipsychotics, lithium, or lamotrigine, and several series of electroconvulsive therapy; had been hospitalized 22 times; and had participated in 3 intensive outpatient programs, 2 partial hospitalization programs, and 3 residential treatment programs. Despite these interventions, 7 suicide attempts occurred [112].

The authors of a prior review, Kim et al [113], reported that in a study by Cullen et al involving adolescents aged 12 to 18 years [114], no drug-seeking behavior was observed; however, no such information was provided in other studies. Preclinical investigations in rats have demonstrated the dose-dependent nature of drug-seeking behavior, suggesting that the risk is lower at doses used for depression treatment [115]. Furthermore, ketamine addiction is more common in adolescents with concurrent dependence on other substances, which may constitute an independent risk factor [116].

PREGNANCY AND BREASTFEEDING:

During pregnancy, ketamine is not approved by the FDA because it crosses the placenta, resulting in similar concentrations in the fetus and the mother. The summary of product characteristics indicates that no studies have evaluated ketamine transfer into breast milk; its use during lactation is not recommended by the FDA. However, a recent study indicated that transfer into breast milk occurs at levels below 1% [117].

GENERAL SAFETY REMARKS:

Absolute contraindications include conditions in which increases in blood pressure would pose a high risk of complications, such as aortic dissection, uncontrolled hypertension, myocardial infarction, or aneurysms, as well as documented hypersensitivity due to the risk of anaphylaxis and angioedema [12]. Adverse effects rarely occur at low doses; ketamine is considered relatively safe when used appropriately. No new safety signals have been identified for esketamine relative to ketamine among patients with depression during an observation period encompassing 3777 cumulative patient-years [118]. Nevertheless, careful monitoring remains essential, and treatment should be discontinued if safety concerns arise.

An important safety consideration in this context is polypharmacy, given that esketamine was originally approved for use in combination with an oral antidepressant. This issue was recently examined by other investigators [119], who evaluated esketamine administered with selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs) among more than 50 000 patients treated in real-world settings. Compared with the esketamine plus SSRI cohort, patients receiving esketamine plus SNRI treatment showed significantly lower all-cause mortality (5.3% vs 9.1%; P<0.001), reduced hospitalization rates (0.1% vs 0.2%; P<0.001), and fewer relapses of depressive episodes (14.8% vs 21.2%; P<0.001). In contrast, the esketamine plus SSRI group exhibited a lower incidence of suicide attempts (0.3% vs 0.5%; P=0.04). These results indicate that selection of the concomitant antidepressant in combination with esketamine plays a critical role in determining clinical outcomes in TRD.

Quality of Life in Patients With TRD Receiving Esketamine

The rapid onset of antidepressant effects in TRD has a substantial impact on patient quality of life. A recent systematic review identified 5 relevant studies, 3 involving major depressive disorder and 2 involving TRD [120]. All demonstrated significant improvements in quality of life, assessed with the World Health Organization Quality of Life–Brief Version, the Assessment of Quality of Life 8D instrument, and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) scale. In a study of patients with TRD who received intranasal esketamine or placebo in addition to an oral antidepressant, improvement was observed across all 5 EQ-5D-5L dimensions: mobility (10.6% vs 25.0%), self-care (13.5% vs 32.0%), usual activities (51.9% vs 72.0%), pain/discomfort (35.6% vs 54.0%), and anxiety/depression (69.2% vs 78.0%) [121].

The presumed reason for improvement in quality of life is the alleviation of depressive symptoms; however, mechanistic pathways through which ketamine and esketamine enhance quality-of-life outcomes remain unclear.

Arketamine: A Future Direction?

Despite the well-documented efficacy of ketamine and esketamine, the role of arketamine remains insufficiently defined because it has not yet received approval for use in humans. Although isolation of esketamine from the racemic mixture enhanced therapeutic efficacy, multiple studies suggest that arketamine also possesses antidepressant properties and may offer advantages over both the racemate and esketamine in selected clinical contexts.

Arketamine exhibits a fourfold lower affinity for NMDA receptors than esketamine in laboratory studies; however, in rodent models, its antidepressant effects are stronger and more sustained, with lower abuse potential and fewer psychomotor adverse effects [30]. Compared with the racemic mixture, arketamine produces a longer-lasting antidepressant response while inducing less dopamine release in the medial prefrontal cortex, although this does not entirely eliminate addiction risk [30,122]. The antidepressant effects of arketamine do not depend on NMDA receptor inhibition, lateral habenula activity, or dopamine receptor activation. Instead, alternative mechanisms are involved; AMPA receptor activation, transforming growth factor–β1, colony-stimulating factor 1 receptor signaling, and γ-aminobutyric acid A receptor inhibition play key roles in sustained efficacy. Arketamine enhances expression of BDNF and cyclic AMP response element–binding protein (CREB) in the medial prefrontal cortex; it restores BDNF levels in the prefrontal cortex, cornu ammonis 3, and dentate gyrus [30]. Moreover, it activates BDNF–TrkB signaling, suppresses NFATc4 gene expression, and increases serotonin release in the medial prefrontal cortex [30]. In some experimental models, activation of mTOR and extracellular signal–regulated kinase pathways has been observed, depending on the stress protocol used to induce depression. Arketamine also modulates microRNAs, particularly miR-132-5p, and genes such as BDNF and methyl-CpG-binding protein 2 (MeCP2) [30]. It has modest regulatory effects on endoplasmic reticulum stress–related genes and may influence the unfolded protein response/OASIS pathway [30]. Additionally, partial restoration of gut microbiota composition has been observed, suggesting involvement of the microbiota–gut–brain axis [123].

Although arketamine has demonstrated efficacy in animal models of depression, its clinical effectiveness remains uncertain. Leal et al [124] administered a single intravenous infusion of arketamine (0.5 mg/kg) to 7 patients with TRD and observed rapid, clinically meaningful antidepressant effects. Improvement began 60 min after infusion onset, peaked at 4 h, and persisted for up to 7 days in 43% of participants. No dissociation or hypertension was reported; adverse effects were limited to blurred vision and dizziness. In a subsequent randomized, double-blind crossover trial involving 10 patients, the same investigators found no difference between arketamine and placebo. Notably, participants in the latter study had longer illness duration and more comorbid conditions. Furthermore, therapeutic response in some patients appears to require achievement of a cumulative dose threshold, warranting multiple infusions [125].

Arketamine has also shown efficacy and safety in depressive episodes associated with bipolar disorder [126–128]. A randomized controlled trial comparing arketamine with esketamine and the racemic mixture in the treatment of TRD has been underway since 2018 [129]. Further studies are needed to determine the efficacy of arketamine and clarify its roles relative to esketamine and the racemate in the general population with depression, patients with TRD, and TRD subgroups within special populations.

Evidence Gaps and Limitations

Future research should assess not only the efficacy of arketamine but also address common limitations observed across patient subgroups. Studies should incorporate larger sample sizes and longer follow-up periods, with mandatory, standardized safety monitoring that includes cardiovascular function, neurocognitive outcomes, and misuse risk. Issues related to patient selection, dose optimization, and treatment monitoring in vulnerable populations require further clarification. Equally important is the development of safe administration procedures (eg, staff training) and integration of treatment into existing psychiatric and somatic care pathways.

The encouraging findings of this review should be interpreted in light of some important limitations. First, this was not a systematic review; therefore, all relevant articles identified were included regardless of methodological quality, given that evidence for some conditions remains limited to case reports or small series. Second, selection of conditions for discussion was based on expert judgment because a comprehensive review of all possible comorbidities would exceed the scope of this article.

Despite strong theoretical rationale and early data, ketamine and esketamine remain difficult to implement in most clinical settings. Availability is limited in many settings, therapeutic effects may be transient, and prolonged use may increase addiction risk. These factors contribute to a gap between evidence from the literature and real-world clinical practice.

Conclusions

Esketamine and ketamine demonstrate efficacy and relative safety in selected sensitive subgroups of patients with TRD when appropriate monitoring is ensured. Preliminary results in patients with multiple comorbidities are particularly encouraging; however, these findings were derived from very small samples, underscoring the need for larger, well-designed clinical trials.