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Cite as: Archiv EuroMedica. 2024. 14; 6. DOI 10.35630/2024/14/6.611
,
Szczepan
Pośpiech , ,
Piotr Serwicki , Aims: This review aims to explore the efficacy, mechanisms, administration routes, and safety profiles of ketamine and esketamine in the treatment of treatment-resistant depression (TRD).
Methods: A comprehensive review of recent studies on ketamine and esketamine’s therapeutic applications in TRD was conducted. Sources included randomized controlled trials, systematic reviews, and meta-analyses from PubMed and Google Scholar.
Results: Ketamine demonstrated rapid antidepressant effects within hours of administration, with symptom relief lasting several days to weeks. Esketamine, developed as an intranasal spray, provided an alternative route, improving accessibility while delivering therapeutic benefits. Additionally, ketamine has shown rapid effects on suicidal ideation, making it a viable option for crisis management in TRD patients. Both ketamine and esketamine enhance neuroplasticityby antagonizing NMDA receptors, leading to increased glutamate release, which activates AMPA receptors and promotes synaptogenesis. Clinical studies have shown that ketamine induces an immediate surge in brain-derived neurotrophic factor (BDNF) and upregulates the mTOR pathway, essential for the formation and strengthening of synaptic connections in mood-regulating brain regions. Although treatment is effective in the short-term, the data on long-term safety is scarce.
Conclusions: Ketamine and esketamine represent significant advancements in the treatment of TRD, offering rapid symptom relief and neuroplastic benefits not achieved with traditional antidepressants. Future studies are required to establish long-term safety profiles and optimize dosing regimens. Overall, ketamine-based therapies provide a promising alternative for patients unresponsive to conventional treatments.
Keywords: ketamine, esketamine, treatment-resistant depression, major depressive disorder, suicidal ideation, neuroplasticity
Major depressive disorder (MDD) is a prevalent and debilitating condition, significantly impacting individuals’ well-being. Treatment-resistant depression (TRD), which affects up to one-third of individuals with MDD, poses a significant challenge in management of patients. The high number of non-responders, as well as the overall delayed therapeutic effect of standard first-line medications, motivated researchers to find alternative treatment options. Ketamine and its S-enantiomer, esketamine, have gained substantial attention due to their novel mechanisms of action.
A comprehensive review of recent studies on ketamine and esketamine’s therapeutic applications in TRD was conducted from PubMed and Google Scholar. Sources included randomized controlled trials, systematic reviews, and meta-analyses examining clinical outcomes, pharmacodynamics, neuroplasticity effects, and safety concerns.
The selection process for this review included a search of relevant studies on ketamine and esketamine’s use in treatment-resistant depression (TRD). Sources encompassed randomized controlled trials, systematic reviews, meta-analyses, and key clinical trials. The final selection prioritized studies that evaluated the antidepressant efficacy, mechanisms of action, insights into pharmacodynamics, and safety profiles of ketamine and esketamine in TRD. The search combined keywords and phrases, such as: “ketamine,” “esketamine,” “treatment-resistant depression,” “TRD,” “NMDA antagonist,” “suicidal ideation,” and “neuroplasticity.” Focused on the use of ketamine or esketamine in treating TRD.
Studies were included if they:
Unipolar major depressive disorder (MDD) is one of the most common mental-health disorders and affects approximately 350 million people worldwide, making it the leading cause of disability. It’s associated with harmful consequences to the functioning of affected individuals and society.23,31 Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly prescribed first-line therapies. However, while these drugs can be effective, they often have delayed onset times, requiring anywhere from 6 to 12 weeks to produce full therapeutic effects.36 This delay can lead to extended periods of suffering for patients who remain symptomatic and may experience increased feelings of hopelessness, frustration, and potential risk for suicide during the waiting period. A critical challenge in treating MDD is the high prevalence of treatment resistance. Up to one-third of patients with MDD do not achieve adequate relief from standard antidepressant therapies, a condition defined as treatment-resistant depression (TRD).7 TRD is typically diagnosed when a patient fails to respond to at least two different classes of antidepressant medications at adequate doses and treatment durations.9 The persistence of depressive symptoms in TRD can severely impact a patient’s quality of life. Individuals with TRD are at higher risk for both physical and mental comorbidities, including cardiovascular disease, obesity, chronic pain, and increased risk for suicide.40 22 The lack of adequate response in TRD patients has driven a search for alternative treatment methods capable of delivering faster and more effective relief than conventional therapies.37
Among the alternative treatments that modulate other neurotransmitter systems. ketamine and its S-enantiomer, esketamine, have gained considerable interest. Ketamine is a glutamatergic N-methyl-d-aspartate (NDMA) receptor antagonist, on the WHO Essential Medicine List for use as an anaesthetic and prescribed off-label to treat chronic pain.20 24 Racemic ketamine was first introduced into clinical practice in the 1960s, however, its use in the management of TRD is a much more recent addition to therapy of depression.20 Early ketamine studies demonstrated rapid, potent reductions in depressive symptoms following the administration of a single sub-anesthetic dose of intravenous racemic ketamine.30 41 These early findings were groundbreaking, suggesting that ketamine could provide almost immediate relief for individuals unresponsive to conventional treatments. Following ketamine’s promising results in treating depression, researchers sought ways to refine its application, aiming to retain its efficacy while minimizing side effects. Studies indicated that the S-enantiomer, esketamine, was more potent at the NMDA receptor than the R-enantiomer, allowing for therapeutic effects at lower doses.39 This made esketamine an attractive candidate for development as a more targeted treatment for depression, particularly in patients with TRD. Esketamine was eventually formulated as an intranasal spray, offering a more practical administration route compared to intravenous ketamine, which requires clinical settings for safe administration. The intranasal form also allowed for easier dose control and more accessible outpatient use, reducing the logistical challenges associated with IV infusions.17
The administration of ketamine and esketamine for treatment-resistant depression (TRD) is an area of active exploration, with multiple delivery routes being studied to maximize efficacy and accessibility. Tested routes for clinical use include intravenous (IV)27, intranasal5, oral1, subcutaneous12, and intramuscular21, each with its own benefits and limitations. However, IV and intranasal administration have the most compelling evidence for efficacy and bioavailability in treatment of TRD.26 IV administration of racemic ketamine is the most studied and widely used route for TRD, delivering the drug directly into the bloodstream to achieve quick therapeutic effects. The standard dosing regimen involves a subanesthetic dose of 0.5 mg/kg, which typically produces antidepressant effects from 40 minutes to 2 hours, with symptom relief peaking within 24 hours and lasting usually 3-7 days for many patients.18, 23, 34, 46 However, the IV route requires a controlled clinical environment with medical monitoring to manage potential side effects like dissociation, blood pressure elevation, and nausea. Because of these monitoring requirements, IV ketamine is usually limited to specialized clinics, which can restrict access for some patients. Intranasal esketamine is a significant advancement for TRD treatment, providing a more accessible option for patients who may not have easy access to IV infusions. Esketamine’s intranasal formulation was specifically developed to allow for outpatient administration in certified treatment centers, where patients self-administer the spray under medical supervision. The recommended dosing protocol for esketamine begins with twice-weekly doses during the induction phase (typically 4 weeks), followed by weekly or biweekly maintenance doses depending on patient response.29 Intranasal administration offers a practical alternative to IV, as it avoids the need for venous access and allows for self-administration, though it still requires in-clinic monitoring due to possible dissociative effects and cardiovascular side effects. Esketamine’s intranasal route has somewhat lower bioavailability (about 45%) compared to IV administration, leading to a slower onset of effects.15 43
Both ketamine and esketamine primarily act as antagonists at the NMDA receptor. By inhibiting NMDA receptors, ketamine disrupts normal excitatory signaling, leading to a temporary increase in extracellular glutamate,13 which, in turn, activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (also known as AMPA receptors) and initiates intracellular signaling pathways that promote synaptogenesis and neuroplasticity. By activating the brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR), ketamine and esketamine help to restore synaptic connections in mood-relevant brain regions, addressing the neurobiological underpinnings of depression.16 45 BDNF is a crucial mediator of neural plasticity, which involves changes in the structure and function of synapses to enhance resilience against stress-related damage. Traditional antidepressants, by contrast, gradually increase BDNF levels over several weeks, while ketamine activates BDNF release much more rapidly. This rapid activation of BDNF is crucial for its fast-acting antidepressant effects, contributing to the rapid formation of new synaptic connections in mood-regulating brain regions.2 Signaling of mTOR, when upregulated by ketamine’s action, increases protein synthesis and contributes to neural growth, neurogenesis, and the stabilization of synaptic connections.16 Ketamine’s antidepressant effects are further supported by its impact on intracellular pathways and glycogen synthase kinase-3 (GSK-3) inhibition. By inhibiting GSK-3, ketamine enhances neuroplasticity and synaptic resilience, which helps stabilize mood in depressive states. GSK-3 inhibition supports the maintenance of newly formed synapses, adding another layer to ketamine’s rapid neurogenic effects.3 Esketamine binds more strongly to NMDA receptors than racemic ketamine, allowing for lower doses to achieve therapeutic effects. Racemic ketamine, which contains equal parts S- and R-enantiomers, is associated with both antidepressant effects and side effects like dissociation due to its broader receptor activity profile.39 The elimination half-lives are approximately 5 hours for esketamine and 2–4 hours for racemic ketamine.47
Clinical trials have consistently demonstrated ketamine’s effectiveness in alleviating depressive symptoms in patients with TRD, with most studies focusing on intravenous (IV) racemic ketamine and intranasal esketamine. In comparative studies, ketamine has consistently demonstrated superior response and remission rates in TRD patients over the short term compared to placebo and traditional antidepressants.19 25 35 Research indicates that ketamine’s rapid effects are partly due to its impact on neuroplasticity, which is particularly valuable for patients with TRD, as it helps repair and strengthen mood-regulating neural circuits that are often compromised in chronic depression. The changes induced by ketamine can, therefore, contribute to a broader, more robust improvement in depressive symptoms, allowing patients to experience relief even in cases where previous treatments have been ineffective.28 Additionally, racemic ketamine has shown potential as an augmentation strategy, effectively complementing existing antidepressants and cognitive-behavioral therapy to improve outcomes in patients with partial responses to conventional therapies.14 42 One of ketamine’s most compelling treatment effects is its ability to rapidly reduce suicidal ideation, even within a single day of administration. This effect, which can persist for up to a week, is partly independent of ketamine’s general antidepressant properties. Studies also indicate that reduction in suicidal ideation can last for up to 6 weeks in people receiving repeat-dose intravenous racemic infusion (0.5 mg/kg). This rapid mechanism can be crucial in managing psychiatric emergencies. 10, 33
One of the limitations is the overall duration of the effects. They tend to be short-lived, often lasting between several days to one week, necessitating repeated dosing or maintenance therapy to sustain improvement. Some patients report sustained benefits even with once-weekly or biweekly dosing, though this varies significantly across individuals. Another significant limitation of ketamine and esketamine is the relative lack of long-term safety and efficacy data. While short-term studies have demonstrated ketamine’s rapid antidepressant effects, the potential impacts of long-term ketamine use remain unclear. The primary side effects associated with ketamine and esketamine include dissociation, characterized by symptoms such as depersonalization and perceptual disturbances, which typically peak within the first hour post-administration and subside within a few hours. Additionally, psychotomimetic effects, like mild hallucinations, can occur, though they are less common. While some patients tolerate these effects, others may find them distressing, especially in outpatient settings where immediate support may not be available.38 Although these cognitive effects are generally transient, the potential for long-term impact with repeated or prolonged use remains under investigation. Cardiovascular effects, such as transient increases in blood pressure and heart rate, are another safety concern, particularly for patients with pre-existing hypertension or cardiovascular disease.41 These effects tend to resolve within hours but warrant careful monitoring during treatment. While controlled medical use at therapeutic doses has not shown a significant increase in substance use disorder risk, the potential for misuse and dependence persists. Recreational ketamine use has been associated with tolerance and dependency, leading to psychological and physical addiction.8 Although the risk is lower in clinical settings due to strict dosing and monitoring, caution and patient education remain essential to mitigate misuse. The development of esketamine with an intranasal formulation and a more controlled administration route reduces misuse risk, but vigilance is still necessary, especially among individuals with a history of substance use disorders.
Comparison of ketamine, esketamine and traditional treatment options 6 7 11 26 32 36 44
| Parameter | Ketamine (IV) | Esketamine (Intranasal) | Standard Antidepressants (SSRIs/SNRIs) | Augmentation Strategies (e.g., Lithium, Atypical Antipsychotics) |
| Onset of Antidepressant Effect | 40 mins to 2 hrs | 1-2 hrs | 4-8 weeks | Varies depending on combination, typically weeks |
| Peak Efficacy Time | Within 24 hours, effect lasts 3-7 days | Within 24 hours, effect lasts 3-5 days | Weeks to months with continuous treatment | Weeks; may enhance efficacy in partial responders |
| Response Rate in TRD | 70-80% within 24 hrs | 40-60% within 24 hrs | 40-50% after several weeks | Improves response in partial responders |
| Remission Rate | 50-60% | 30-40% | 25-40% | Enhances remission rates when added to antidepressants |
| Reduction in Suicidal Ideation | 50-60% reduction within hours | 30-40% reduction within hours | Minimal, usually delayed | Supportive effect when combined with antidepressants |
| Discontinuation Due to Side Effects | ~5% for single low dose | 10-15% | 5-20% depending on drug tolerance | 15-25%, based on tolerability of adjunct medications |
| Long-Term Efficacy | Limited data, efficacy decreases with time | Variable, some efficacy up to 6 months | High with consistent use | Effective when continued alongside antidepressant therapy |
| Administration Frequency | 1x weekly or biweekly (maintenance) | Twice-weekly (induction), weekly maintenance | Daily | Dependent on therapy, often daily or as per need |
| Bioavailability | 100% (IV route) | ~45% (intranasal route) | Varies (50-90% for SSRIs, 40-80% for SNRIs) | Dependent on individual drug and route of administration |
| Neuroplasticity Effects | Strong activation of BDNF and mTOR pathways | Moderate neuroplasticity via AMPA | Delayed, usually requires weeks | Augments neuroplastic effects of primary antidepressant |
Ketamine and esketamine present promising alternatives for treating treatment-resistant depression (TRD) which affects a substantial number of individuals who do not respond to conventional antidepressants. The rapid response to treatment is especially beneficial for patients in crisis, including those with acute suicidal ideation. The primary administration methods—intravenous (IV) ketamine and intranasal esketamine—expand options for TRD treatment, providing flexibility for patients and clinicians. However, more data is needed and continued research is necessary to assess the long-term safety and efficacy of ketamine-based therapies. Overall, ketamine and esketamine represent significant advancements in the treatment of TRD, providing a faster-acting alternative to traditional antidepressants and offering hope for patients unresponsive to existing therapies.
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