Ketamine and Esketamine for Treatment-Resistant Depression

Approximately 30% of patients with major depressive disorder do not find relief with traditional antidepressant treatments, leading to a condition known as treatment-resistant depression (TRD). Ketamine and esketamine have shown promise as rapid treatment modalities for TRD. This project aims to examine ketamine and esketamine's efficacy for TRD along with the mechanisms of action, safety/side effects, clinical application for TRD, legal considerations, research on ketamine and esketamine in relation to TRD, and research gaps.

1 Ketamine and Esketamine for Treatment-Resistant Depression Olivia Akerley, Haleigh Downing, Andrea Tillotson, and Elizabeth Hanna College of Nursing: Westminster University MSN 610: Masters Project Elizabeth Hanna, DNP, APRN, AGACNP-C November 26, 2024 2 Abstract Background: Approximately 30% of patients with major depressive disorder do not find relief with traditional antidepressant treatments, leading to a condition known as treatment-resistant depression (TRD). Ketamine and esketamine have shown promise as rapid treatment modalities for TRD. Purpose: This project aims to examine ketamine and esketamine’s efficacy for TRD along with the mechanisms of action, safety/side effects, clinical application for TRD, legal considerations, research on ketamine and esketamine in relation to TRD, and research gaps. Search Terms: A literature search was conducted using EBSCOhost, CINAHL, PubMed, and Google Scholar, including papers in English published within the past ten years. Search topics included “ketamine,” “esketamine,” “intranasal ketamine,” “treatment-related depression,” “treatment-resistant depression,” “ketamine and depression treatment,” “esketamine or ketamine and TRD,” “ketamine and esketamine,” ‘long-term side effects of esketamine,’ “esketamine or ketamine and mental health,” “esketamine or ketamine and adolescent treatment,” “esketamine as monotherapy,” “ECT compared to ketamine,” “ECT and treatment-resistant depression,” esketamine and ECT,” “IV ketamine vs. intranasal ketamine,” “intravenous ketamine and TRD” “ketamine regulations,” and “REMS protocol for esketamine.” “ketamine or esketamine and regulations.” Research/ Findings: Although there is limited research, much of the research has proven ketamine and esketamine to be efficacious in providing rapid antidepressant effects in patients with TRD. Research comparing the efficacy of ketamine to other treatment modalities such as electroconvulsive therapy (ECT), esketamine, and differing administrations are discussed. 3 Research limitations: Research limitations are as follows: limited studies, long-term studies, direct comparisons on modalities and molecular forms, inclusion/exclusion bias, publication bias, and conflicts of interest. Continued research is essential in the use of ketamine and esketamine in the treatment of TRD. Practical implications/discussion: It is under a primary care providers’ scope of practice to treat TRD; however, ketamine and esketamine are specialized treatments, and providers should have extensive education on the therapy. Given the regulations, FNPs should refer patients to trained mental health providers for evaluation of ketamine or esketamine treatment. 4 Introduction Depression is the leading cause of disability worldwide, affecting over 300 million people (World Health Organization, 2017). In the United States, the lifetime risk of a major depressive episode is approximately 30% (Park & Zarate, 2019). When depression is untreated it can have devastating consequences, including suicide; more than 50% of the time, the diagnosis of depression is associated with suicide (Park & Zarate, 2019). These alarming statistics underscore the urgent need for global action to address depression. Over 700,000 individuals die by suicide each year (World Health Organization, 2023), and this has since increased to the 10th leading cause of death in the United States (Park & Zarate, 2019). Since the 1970s, monoaminergic antidepressants such as selective-serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) have been the gold standard for treating major depressive disorder; however, they do not work for everyone. Individuals with depression, 3 million people in the United States, approximately 30%, do not find relief with traditional antidepressant treatments, leading to a condition known as treatment-resistant depression (TRD). TRD is commonly defined as “a non-response to at least two different courses of antidepressants, with verified adherence to treatment, adequate dosage, and adequate duration of treatment” (Baldinger-Melich et al., 2024, p.1). Ketamine has been proven to have rapid antidepressant effects and has been found to be beneficial in patients’ treatment of TRD (Boudieu et al., 2023). Primary care providers and family nurse practitioners (FNPs) are at the forefront of mental health. It is estimated that 60% of mental health conditions are treated in primary care, and 79% of antidepressant prescriptions are not written by mental health providers (Park & Zarate, 2019). 5 Aims and Objectives This paper provides a comprehensive review of major depressive disorder depression, treatment-resistant depression (TRD), ketamine, and esketamine, along with the efficacy of research, safety regulations, and ethical concerns, while focusing on relevance and application to primary care settings. It aims to equip family nurse practitioners (FNPs) with the knowledge to make informed decisions and referrals regarding ketamine and esketamine therapy inquiries for the management of TRD. Methods On-Site Interview ​ ​ Our group conducted an on-site visit and interview with the Spravato (branded intranasal esketamine) drug representative and the owner and clinical team at Mountain Mental Health in Salt Lake City, Utah. This facility is certified as a risk evaluation and mitigation strategy (REMS), offering intranasal Spravato and compounded intranasal ketamine treatments. During the visit, the team provided detailed insights into patient outcomes, treatment benefits/drawbacks, potential side effects, REMS protocol, and a comparison between branded Spravato product and compounded ketamine. Additionally, the discussion covered the use of off-label ketamine versus Spravato. The visit offered an opportunity to engage in dialogue with qualified professionals actively utilizing these therapies. A tour of the facility allowed for observation of treatment protocols and brief interaction with a patient receiving treatment. A particularly impactful aspect of the visit was hearing firsthand from the clinic owner, who provided personal testimony of the clinical benefits observed in his patients. 6 Engaging with professionals and practitioners applying the research in real-world clinical settings offers a level of depth and practical understanding beyond what can be gained from a literature review alone. This interactive experience allowed us to ask questions, clarify complex topics, and participate in a dynamic, real-time discussion, enhancing our comprehension knowledge on ketamine and esketamine in TRD. Literature Review The literature review was conducted using a systematic approach to identify relevant studies, articles, and publications related to ketamine and esketamine as a treatment for TRD. Search topics included “ketamine,” “esketamine,” “intranasal ketamine,” “treatment-related depression,” “treatment-resistant depression,” “ketamine and depression treatment,” “esketamine or ketamine and TRD,” “ketamine and esketamine,” ‘long-term side effects of esketamine,’ “esketamine or ketamine and mental health,” “esketamine or ketamine and adolescent treatment,” “esketamine as monotherapy,” “ECT compared to ketamine,” “ECT and treatment-resistant depression,” esketamine and ECT,” “IV ketamine vs. intranasal ketamine,” “intravenous ketamine and TRD” “ketamine regulations,” and “REMS protocol for esketamine” “ketamine or esketamine and regulations.” The inclusion criteria for the review consisted of studies that focused on clinical outcomes, safety profiles, and comparative analyses between esketamine and other forms of ketamine therapy. Articles discussing regulatory requirements, such as REMS certification, and patient experiences, were also included. Studies were excluded if they lacked clinical data, were focused on populations outside the scope, or were opinion pieces without empirical evidence. Each article was reviewed for methodological rigor, sample size, and relevance to the research question. The data from the selected studies were synthesized to identify common themes, 7 discrepancies, and gaps in the literature. This review aimed to provide a comprehensive overview of the current evidence base surrounding esketamine and its use in clinical practice. Background ​ Major depression disorder (MDD) is the leading cause of disability, it affects 300 million people globally and approximately 19.8 million in the United States (Greenberg et al., 2023). Nearly two-thirds of individuals diagnosed with MDD consider suicide, with 10-15% completing suicide (Bains & Abdijadid, 2024). In 2019, MDD was related to one-third of all suicides (Greenberg et al., 2023). The DSM-5 diagnostic criteria for MDD requires symptoms of depression lasting at least two weeks. Patients must present with anhedonia or a depressed mood, along with four other symptoms, which may include: guilt, sleep disturbance, low energy, appetite changes, suicidal thoughts, agitation, and concentration issues (Bains & Abdijadid, 2024). One previous major depressive episode must be documented, and a history of mania or hypomania ruled out (Rush, 2024). Increased risk factors for MDD include early childhood stress, genetic predisposition, female gender, alcohol use, and divorce (Bains & Abdijadid, 2024). MDD itself raises the risk for several diseases, including obesity, diabetes, and cardiovascular disease (McIntyre et al., 2023). ​ MDD accounts for an enormous financial and economic burden on the United States. In 2019, it was estimated to be 333.7 billion dollars, equating to 382.4 billion dollars in 2023 (Greenberg et al., 2023). Greenberg et al. (2023) found the main economic burden of MDD to be related to healthcare costs, decreased productivity at work, increased sick calls, and household-related costs. Healthcare costs equated to 127.3 billion dollars, with 30 billion dollars related to unemployment. MDD is associated with increased sick time off work, costing around 38.4 billion dollars annually. People suffering from MDD also have decreased work productivity, 8 approximated to be 43.3 billion dollars a year. It is estimated that finding an effective treatment option could decrease the costs associated with MDD by 7.7% (Greenberg et al., 2023). The FDA has approved several medications for treating MDD, including SSRIs, SNRIs, atypical antidepressants, TCAs, MAOIs, mood stabilizers, and antipsychotics (Bains & Abdijadid, 2024). Many patients discontinue these medications due to the side effects; side effects include sedation, insomnia, sexual dysfunction, constipation, nausea, vomiting, diarrhea, hypertension, seizures, QT prolongation, weight gain, and serotonin syndrome (Rush, 2024). Only 50% of patients on a first-line antidepressant respond, and 30% of these fully recover (Ouazana-Vedrines et al., 2022). Nine percent switch antidepressants when starting treatment (Hirsch & Birnbaum, 2023). Regular monitoring is required, with follow-ups for titration and efficacy assessment at two to four weeks. Most medications require tapering when discontinuing (Rush, 2024). For severe cases, such as psychosis, acute suicidality, or severe depression during pregnancy, electroconvulsive therapy (ECT) may be used. A non-pharmacological option is psychotherapy (Bains & Abdijadid, 2024). “An estimated 60% of mental health care delivery occurs in the primary care setting, and 79% of antidepressant prescriptions are written by providers who are not mental health care providers” (Park & Zarate, 2019, p. 560). ​ The FDA and the European Medicines Agency criteria for TRD is “inadequate response to two or more antidepressants despite adequate treatment intensity and duration” (McIntyre et al., 2023, p. 398). However, with no single definition, exact numbers are challenging. It is estimated that 100 million people suffer from TRD worldwide and 2.8 million in the US (McIntyre et al., 2023; O’Connor et al., 2023). With this definition, 55% of people suffering from MDD have TRD (McIntyre et al., 2023). Research has shown that certain people are at increased risk for developing TRD. They have higher depression scores, longer duration of 9 depression, and suffer from cardiovascular disease, insomnia, suicidality, younger age of onset, autoimmune disorders, cerebrovascular disease, anxiety disorder, female gender, substance disorder, thyroid problems, and increased complaints of pain more often than patients with MDD (Kverno & Mangano, 2021; O’Connor et al., 2023). ​ TRD has a higher mortality rate than MDD, and patients are at increased risk for suicide. TRD’s mortality rate is 35% higher when compared to MDD, and 30% will attempt suicide (Boudieu et al., 2023; Lähteenvuo et al., 2022). Sufferers often experience more unemployment, difficulty performing daily tasks, decreased productivity with work, and increased hospitalizations for their condition (Kverno & Mangano, 2021; O’Connor et al., 2023). Only five medications are approved by the FDA to treat TRD, four of which are atypical antipsychotics: aripiprazole (Abilify), Brexiprazole (Rexulti), Quetiapine (Seroquel XR), Olanzapine (Zyprexa) combined with Fluoxetine (Prozac) (Kverno & Mangano, 2021). The side effect profile of atypical antipsychotics is lengthy and includes seizures, weight gain, metabolic disturbances, rhinitis, constipation, sleeping problems, orthostatic hypotension, dizziness, increased prolactin levels, sedation, and tachycardia. More rarely, they can cause agranulocytosis, extrapyramidal symptoms, tardive dyskinesia, and neuroleptic malignant syndrome (Woo & Robinson, 2020). The newest agent is the only non-antipsychotic, intranasal esketamine (Spravato), an anesthetic drug, which was approved in 2019. Esketamine must be paired with an oral antidepressant as an add-on therapy. Esketamine is one of the enantiomers found in ketamine and can be referred to as (S)-ketamine. It is four times more potent on the NMDA receptors. Ketamine or racemic ketamine is used off-label for TRD and comprises both (S)-ketamine and (R)- ketamine (Boudieu et al., 2023). Side effects of esketamine include 10 dizziness, vomiting, hypertension, dissociation, headache, vision changes, and drowsiness, which tend to resolve quickly (Boudieu et al., 2023). ​ Other approved treatments for TRD are electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and vagus nerve stimulation (VNS) (Bains & Abdijadid, 2024). ECT is used for patients with TRD or suicidal ideation. The patient receives a general anesthetic along with a muscle relaxant, electors are then placed on the head, and electrical currents produce a seizure. Treatment and assessment occur three times a week. Maintenance ECT is often required for symptom management, and add-on therapy is common, which consists of antidepressants and/or mood stabilizers. TMS uses a transcranial magnetic device sending low-intensity pulses that stimulate nerve cells in the brain. Treatment does not require sedation and is usually five days a week for four to six weeks. VNS consists of a surgical procedure where a device is placed under the skin that connects to the vagus nerve; it sends electrical pulses via the vagus nerve to the brain. A provider determines how often the device will trigger the vagus nerve. The side effects of ECT, TMS, and VNS can be dysphagia, voice changes, memory loss, dizziness, head tingling, confusion, headache, neck pain, myalgia, and vision changes (National Institute of Mental Health, n.d.). Treating patients with TRD can be complex, with no set standard of treatment. Although current medications and treatment options have shown to be effective in treating TRD, they have major side effects that often result in discontinuation of treatment. Additionally, the likelihood of relapse tends to rise with each additional treatment failure (Boudieu et al., 2023). More research into treatment options for TRD is needed. Ketamine and esketamine have shown to be an effective option for TRD, with intranasal ketamine already approved. Emerging Hope for TRD- Ketamine/Esketamine 11 History of Ketamine ​ Ketamine is a common drug used in anesthesia for its ability to provide pain relief, sedation, and disassociation while also maintaining stable respiratory function during painful procedures or conditions. “It has been found to be highly effective for brief medical procedures that do not necessitate skeletal muscle relaxation and can be utilized as a pre-anesthetic for the induction general anesthesia when combined with other general anesthetic agents” (Rosenbaum et al., 2024, p. 1). In 1962, ketamine was discovered while researchers were attempting to find a shorter-acting analog for phencyclidine (PCP), an intravenous anesthetic that had an undesirable side effect profile, including prolonged delirium and agitation (Li & Vlisides, 2016). Ketamine, at one-tenth the potency of PCP, was proven to have a wide safety margin and proven effective as an anesthetic agent. Ketamine was approved by the FDA in 1970 and used during the Vietnam War for its anesthetic properties and added dissociative benefit. There were increased concerns with the dissociative and delirium effects associated with ketamine, which led to a decline in usage as a human anesthetic. By the 1980s, ketamine increased in popularity as a recreational drug due to its psychedelic and dissociative effects in subanesthetic doses. In the '90s, additional research on ketamine’s mechanism of action and efficacy led to an increase in use for its anesthetic properties (Rueda Carrillo et al., n.d.). Today, ketamine continues to be widely used in human and veterinary medicine for its fast-acting and reliable anesthetic effects (Yavi et al., 2022). Although ketamine is FDA approved only for its anesthetic properties, it is often used off-label by medical professionals for pain management and other conditions (Rosenbaum et al., 12 2024). Over the past several decades, research on ketamine’s effects on neurological and psychiatric conditions has gained in popularity, leading to promising results. In 2019, the FDA approved esketamine (branded name, Spravato), one of the enantiomers in ketamine, along with an antidepressant for the treatment of TRD. Additionally, in 2020, esketamine was approved for the treatment of patients with major depressive disorder (MDD) accompanied by acute suicidal ideation or behavior (Mischel & Balon, 2021). Pharmacology Structure Ketamine, or cyclohexanone hydrochloride, is an arylcyclohexylamine derivative, composed of a cyclohexanone ring attached to a chlorophenyl group and an amino group, as shown in Figure 1 (Matveychuk et al., 2020). The asterisk specifies the chiral center. Figure 1 Structure of Ketamine (Matveychuk et al., 2020, p. 2) 13 Ketamine is lipophilic, facilitating its rapid penetration into the central nervous system by crossing the blood-brain barrier (Zorumski et al., 2016). Because of its chiral center, ketamine is a racemic mixture composed of two mirror image enantiomers: (R)-ketamine (arketamine) and (S)-ketamine (esketamine). Esketamine is only available under the branded-label, Spravato. As stated above, esketamine is the only enantiomer FDA-approved for the treatment of TRD. One study suggests that esketamine produces three to four times more anesthetic potency than (R)-ketamine with less cardiac stimulation, less spontaneous motor activity, better analgesic effects, rapid recovery, fewer psychotomimetic effects, and therefore, less delirium (White et al., 1985). However, some research suggests that (R)-ketamine may be more potent with fewer side effects (Zhang et, al. 2014). Mechanism of Action Ketamine is classified as a nonbarbiturate dissociative anesthetic, creating a rapid anesthesia and analgesic effect without affecting spontaneous respiration. (Rosenbaum et al., 2024). Though the mechanism of action is not fully understood, recent research has shed light on its benefits on depression. Structurally, ketamine acts as an N-methyl-D-aspartate (NMDA) receptor antagonist; binding to the receptor’s phencyclidine (PCP) site and blocking the effects of glutamate, glutamate, the chief excitatory neurotransmitter in the central nervous system. Glutamate acts on NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and metabotropic glutamate receptors (Matveychuk et al., 2020). Matveychuket et al. (2020) noted that: The release of glutamate into the synaptic cleft initially activates AMPA receptors, which allow entry of sodium ions into the postsynaptic membrane. Subsequent depolarization of 14 the postsynaptic membrane results in removal of the NMDA receptor channel voltage-dependent magnesium ion block and facilitates NMDA receptor activation, allowing entry of sodium and calcium ions. (p. 4) Research has shown plasma glutamate levels are elevated in patients with depression, therefore supporting the hypothesis that glutamatergic neurotransmission is dysregulated in such patients (Matveychuk et al., 2020). Beyond NMDA receptor antagonism, research has found that ketamine affects multiple neurotransmitter systems including the opioidergic, monoaminergic, muscarinic, substance P, and sigma receptors, which may influence depression (Yavi et al., 2022). As these mechanism of actions are complicated, it is better described below by Mani Yavi (3033) and depicted in Figure 2. Ketamine’s actions at the glutamate receptor that may mediate antidepressant effects include: (1) blocking the N-methyl-D-aspartate (NMDA) receptor at the gamma aminobutyric acid (GABA)-ergic inhibitory interneuron, leading to disinhibition of presynaptic neurons and resulting in increased glutamate release into the synapse (disinhibition hypothesis). Other downstream molecular and cellular pathways have also been investigated to better understand ketamine’s rapid acting antidepressant properties and its effects on promoting neuroplasticity. These include: (2) inhibition of synaptic and (3) extra-synaptic NMDA receptors leading to intracellular pathways promoting neuroplasticity; (4) inhibitory effects of the NMDA receptor in the lateral habenula (LHb) neurons; (5) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation from increased synaptic glutamate release and/or ketamine metabolites (e.g., (2R, 6R)-hydroxynorketamine (HNK)); and (6) presynaptic metabotropic glutamate receptor (mGluR) (group II) antagonism leading to enhanced glutamate release and 15 subsequent AMPA receptor activation, leading to downstream molecular and cellular pathways promoting neuroplasticity. (p. 2) Figure 2 Mechanism of Action of Ketamine (Yavi et al., 2022, p.3) Studies demonstrate that AMPA activation triggers several intracellular processes, including an increase in brain-derived neurotrophic factor (BDNF) and activation of the mammalian target of rapamycin (mTOR). Both BDNF and mTOR pathways play integral roles in the increase of synaptogenesis, the process involving synthesis of synaptic proteins and the formation of new synaptic connections. Increased synaptogenesis is hypothesized to reduce depression, as low levels of BDNF have been linked to depressive symptoms (Duman et al., 2016). As shown in Figure 3, ketamine rapidly promotes synaptogenesis by increasing BDNF 16 levels through AMPA receptor activation and mTOR signaling, contributing to improved mood (Duman et al., 2016). Figure 3 Increase in Synaptogenesis (Duman et al., 2016) ​ Another emerging hypothesis centers around ketamine’s impact on inflammation and its potential correlation to depression. Research indicates that inflammation may play a role in depressive disorders, a study reported that roughly one-third of patients with TRD had elevated inflammatory markers (Matveychuk et al., 2020). Ketamine has been associated with anti-inflammatory effects and may decrease cytokines in the brain. Studies have supported that racemic ketamine may be beneficial; however, most studies conducted had small sample sizes and more research is needed (Matveychuk et al., 2020). Lastly, recent studies suggest that ketamine’s effects on depression may be associated with the subgenual anterior cingulate cortex (sgACC). Overactivity in the sgACC has been correlated with MDD, while decreased activity has been correlated with a positive response to traditional antidepressants. Research on nonhuman primates showed that overactivity of the sgACC led to anhedonia, which was then alleviated by an injection of ketamine directly into the sgACC (McIntyre et al., 2021). 17 Pharmacokinetics ​ Ketamine is available in several formulations for different therapeutic uses, common options include intravenous (IV), intranasal (IN), intramuscular (IM), sublingual, and oral. Racemic ketamine has a plasma protein binding of 10-15% and a half-life of two to four hours, while esketamine has a half-life of five hours (McIntyre et al., 2021). The bioavailability of ketamine differs with each route. IV ketamine administration has a rapid onset and 100% bioavailability. IM provides the second highest at 93% bioavailability. Intranasal’s bioavailability is 45%, sublingual’s 30%, and oral’s 20% (Matveychuk et al., 2020). Due to the liver's first pass effect, higher doses of oral ketamine are needed to achieve the desired effect, which may increase risks of adverse side effects (Sobule & Ithman, 2023). Ketamine’s lipophilic structure is metabolized mainly through CYP3A4 and CYP2B6 to produce its principal metabolite, norketamine. It was noted that esketamine is demethylated faster though CYP3A4 than R-ketamine, but CYP2B6 demethylates both enantiomers at equal rates. The slight difference in demethylation might explain the varying effects seen in research on esketamine, arketamine, and racemic ketamine (McIntyre et al., 2021). Ketamine and Esketamine- Innovating Research in TRD The pathophysiology of depression is complex and not completely understood, nor clearly defined (Chand & Arif, 2024). Research indicates there are many factors and hypotheses that work together to explain the pathophysiology of depression including neurotransmitters, genetics, environmental factors, among others. Clinical studies have found correlations between depression and a decrease in neural synapses and a decrease in size specifically to regions of the brain in charge of cognition and mood regulation. The synaptogenic hypothesis of depression 18 suggests that ketamine [and esketamine] rapidly induce synaptogenesis and reverses the synaptic deficits, quickly decreasing depressive symptoms (Duman & Aghajanian, 2012). Duman and Aghajanian (2012) explain that antidepressants can block or decrease these deficits, however, they can take weeks to months to have a response. Additionally, traditional antidepressants may have limited efficacy or may not be useful at all, as seen in TRD. A meta-analysis indicates that treatments that affect the glutamatergic system, such as ketamine and esketamine, could be more beneficial than antipsychotic medications in patients with TRD (McIntyre et al., 2023). Intravenous (IV) Ketamine In 2000, Berman et al. conducted the first study on ketamine and its antidepressant potential, with a small study group of only seven patients. Results showed improved mood, as measured by the Hamilton Depression Rating Scale, within four hours of the IV ketamine administration (0.5 mg/kg of ketamine over 40 minutes). This study has since been replicated on patients with TRD, and results have shown rapid antidepressant effects seen within two hours of administration (Shin & Kim, 2020). Research supports the use of IV racemic ketamine to quickly decrease depressive symptoms in addition to decreasing suicidal ideation in real-world sample of patients with TRD (Matveychuk et al., 2020). Randomized controlled trials found IV ketamine to have a response rate of 60-70% with IV ketamine treatment (Matveychuk et al., 2020). Both single-dose and multiple doses of IV ketamine have been found to be beneficial; however, research supports that repeated dosing leads to improved response rates along with continued decrease in depressive symptoms (Shin & Kim, 2020). It was reported that a single dose of IV ketamine provides antidepressant effects for up to seven days. In an open-label study, where both the researchers and participants were aware of the treatment, six IV ketamine infusions were given over two weeks. In this study, 70-80% of patients with TRD had a response 19 and the median relapse occurred at 18 days (Shin & Kim, 2020). Additionally, research on multiple doses concluded that there was no significant difference between twice-weekly and three-times-weekly dosing of IV ketamine; both were found to be similarly beneficial comparied to the placebo (Singh et al., 2016). Since ketamine is known to cause dissociative effects, some studies testing IV ketamine used intravenous midazolam, a short-acting benzodiazepine, to recreate a dissociative effect for the placebo/control group (Shin & Kim, 2020). It should be noted that benzodiazepines may have mild antidepressant effects. In these studies, ketamine was found to be more effective than midazolam for TRD. The efficacy of ketamine was slightly decreased when the placebo group was given normal saline rather than midazolam; suggesting the dissociative effects may have affected results (Shin & Kim, 2020). Research also supports the benefits of IV ketamine treatment along with an antidepressant in patients with MDD. In a randomized control trial, one group of patients started escitalopram, while another group of patients received a single dose of IV ketamine and escitalopram. The IV ketamine and escitalopram group showed significant improvements in their depressive symptoms and remission at the four-week completion mark (Shin & Kim, 2020). Electroconvulsive Therapy (ECT) compared to Ketamine/Esketamine Electroconvulsive therapy (ECT) is considered the gold-standard for the treatment of TRD; it has been proven to be highly effective for acute and maintenance treatment (McIntyre et al., 2020). Although research supports its efficacy, ECT continues to be underused due to social stigma, limited availability, and concerns with cognitive impairment (Anand et al., 2023). A meta-analysis by Rhee, which included six trials and 340 patients, concluded that ECT may be superior to ketamine. However, treatment decisions should be individualized and 20 patient-centered, as each treatment has its own set of adverse effects (Rhee et al., 2022). This meta-analysis included research that included hospitalized and/or psychotic depressive patients, populations proven to respond to ECT (Rhee et al., 2022). Conversely, a literature review focusing on ECT and esketamine, concluded that both ECT and esketamine are highly effective in TRD, with no treatment being superior (Baldinger-Melich et al., 2024). Recent research by Amit Anand, a professor of psychiatry at Harvard Medical School, suggests that ketamine is non-inferior compared to ECT. Anand conducted an open-label randomized trial with over 400 TRD non-psychotic patients comparing ECT (three sessions a week) to IV ketamine (twice a week) over a period of three weeks. The study resulted in 55.4% of patients treated with IV ketamine and 41.2% of patients treated with ECT showed a response, as noted by at least a 50% decrease in their Quick Inventory of Depressive Symptomatology (QIDS-SR-16) score. The study showed ECT patients to have increased memory loss and musculoskeletal events compared to the ketamine group which reported more dissociative effects. As the study was a non-inferiority comparison, it could only determine that IV ketamine was non-inferior to ECT for the treatment of TRD and thus, further studies are required to conclude if ketamine may be superior to ECT in TRD (Anand et al., 2023). With ECT and ketamine both showing efficacy, ketamine may be seen as the favorable option due to its lack of memory loss and lack of requirement for general anesthesia (Anand et al., 2023). Intranasal Ketamine and Intranasal Esketamine ​ Both intravenous (IV) ketamine and esketamine have proven to be effective in treating TRD; however the intranasal (IN) route may offer advantages, such as FDA- approval, better 21 tolerability, greater accessibility, and being less invasive compared to IV administration (Shin & Kim, 2020). In short-term randomized controlled trials, IN ketamine demonstrated improvement on depressive symptoms as seen by a decrease in Montgomery-Asberg Depression Rating Scale (MADRS) scores (Boudieu et al., 2023). Additionally, IN esketamine (Spravato), approved by the FDA as an add-on therapy to an antidepressant, has shown effectiveness in TRD (Boudieu et al., 2023). Most IN esketamine research compares the outcomes of a monotherapy antidepressant (serving as the placebo group) and an antidepressant combined with IN esketamine (experimental group) (McIntyre et al., 2023). Additional studies support the usage of IN esketamine as an add-on specifically with an SSRI/SNRI in comparison to a second-generation antipsychotic, such as quetiapine (Boudieu et al., 2023). However, IN esketamine’s efficacy in patients over 65 years old remains uncertain; as studies showed no significant difference in outcomes between the monotherapy antidepressant groups and the IN esketamine add-on therapy group (McIntyre et al., 2023). Double-blind randomized control trials of IN ketamine and IN esketamine indicate that both treatments decrease MADRS scores in comparison to the antidepressant or placebo group (Boudieu et al., 2023). While neither treatment was found to be statistically superior, IN ketamine showed significant improvements on day seven, whereas the IN esketamine group showed improvements on day eight (Boudieu et al., 2023). Long-term studies also support IN esketamine’s role as an add-on in sustaining depressive symptoms in TRD. Research by Daly et al., reports promising outcomes for IN esketamine with one-year response and remission rates of 76.5% and 58.2%. Additionally, it reduced relapse by 51% for patients in remission and by 70% for those with stable response (Daly et al., 2019; Boudieu et al., 2023). Lastly, long-term research (specifically over three years) indicates that IN esketamine is safe and tolerable for patients with TRD (McIntyre et al., 22 2023). These findings support using IN esketamine as a long-term option for the management of TRD, though additional research would be beneficial. Intravenous Ketamine compared to Intranasal Esketamine Research directly comparing IV ketamine and IN esketamine remains limited. A 2023 meta-analysis, by Boudieu et al., identified one head-to-head study directly comparing both treatments with a sample size of 62 TRD patients. It was an observational study, conducted by Singh et al. in 2023, which concluded that both IV ketamine and IN esketamine produced similar rates of response and remission. However, IV ketamine required fewer treatments to achieve remission than the IN esketamine group. Singh et al. notes the need for further investigation including randomized control trials to compare both treatments directly (Singh et al., 2023). There have been several meta-analyses comparing the efficacy of IV ketamine and IN esketamine, however, the research lacks head-to-head comparisons, rather the meta-analyses analyze studies of the treatments individually. Bahji et al. (2021) found that IV ketamine demonstrated better overall response and remission rates and fewer treatment dropouts that IN esketamine, while d’Andrea et al. (2024) reported that both treatments effectively manage TRD. The latter study highlighted that IV ketamine tends to reduce symptoms more, though remission rates were comparable. Both meta-analyses called for more direct comparison studies to clarify the benefits of each treatment modality (Bahji et al., 2021; d’Andrea et al., 2024). Limitations in Research ​ Evidence-based research is crucial to support the efficacy and safety of ketamine and esketamine as emerging therapies for TRD. Over the last 30 years, research has shown positive 23 results, however gaps remain, including a lack of comprehensive research and various ethical challenges. Additional research is needed, particularly to replicate findings, evaluate long-term outcomes, and conducting direct comparisons between racemic ketamine and its enantiomers. Comparisons between outpatient electroconvulsive therapy (ECT) and ketamine-based treatments are also limited. Additionally with the rise of compounding pharmacies, comprehensive safety and efficacy data across all administration routes is necessary; more studies comparing administration routes, such as IV, IN, IM, oral, and sublingual would be beneficial (Sobule & Ithman, 2023). Ethical challenges further complicate research efforts. Publication bias and conflicts of interest can lead to exaggerated results. For instance, Boudieu et al. (2023) suggests that negative findings on IN ketamine and IN esketamine may not have been published. Similarly, meta-analyses may suffer from inclusion/exclusion bias, which can skew data (Boudieu et al., 2023). Funding and conflict of interest also limit the reliability of research. It was noted that many studies are associated with Janssen Pharmaceuticals (the patent holder for IN esketamine, Spravato) which raises concerns of financial motives behind the focus on IN esketamine over alternatives like racemic ketamine or arketamine. Study design limitations are another concern with research reliability. Boudieu et al. (2023) highlights that randomized control trials may not be representative of the broader population of TRD patients due to their strict inclusion/exclusion criteria. Research could be improved if observational studies and open-label studies were reconducted as randomized control trials. Additionally, conflicting results across similar studies emphasize the need for replication of studies. Finally, ketamine’s potential for abuse may influence research samples and results. To advance the treatment of TRD, ongoing research is essential. Future research should 24 prioritize unbiased and reliable data, direct treatment comparisons, and evaluation of long-term safety and efficacy of ketamine and its formulations. Safety and Contraindications of Ketamine/Esketamine While ketamine and esketamine offer significant benefits for TRD, it also has side effects and contraindications. Prescribing ketamine or esketamine for TRD requires awareness of potential side effects and strategies for management, as well as familiarity with contraindications. Ketamine and esketamine’s side effects can be categorized by body systems, starting with the nervous system. Dissociation or altered consciousness is the most common affecting 50% and 80% of patients; it typically occurs during treatment but resolves within two hours. Other neurological effects include agitation, anxiety, and irritability, which can be distressing for patients and require supportive management (Ceban et al., 2021). When managing neurological effects involves creating a calming environment with dimmed lighting, soothing music, and breathing exercises, while closely monitoring patients during and two hours after treatment. If symptoms persist, stopping treatment may be necessary. Thorough mental health evaluations and pre-treatment screenings also help mitigate these effects (Ceban et al., 2021). Ketamine and esketamine treatment can impact the cardiovascular system; it is known to cause hypertension and tachycardia. Proper monitoring of vital signs pre-treatment, during, and after treatment is essential for the patient's health. Hypertension is more common in intravenous ketamine than intranasal esketamine. Using intranasal esketamine in people with cardiovascular issues can minimize complications. A prior diagnosis of hypertension does not automatically rule out the use of ketamine for the patient; deciding if the benefits outweigh the risks is necessary. Also, ensuring patients comply with their blood pressure medication will help prevent 25 hypertension crises. Additional recommendations to help prevent or reduce hypertension and tachycardia are the same as listed above to produce a calming environment and decrease blood pressure. Providers must obtain a comprehensive medical history, as other medications may contribute to cardiovascular side effects. For example, stimulants should not be taken in conjunction with ketamine treatment. Usually, hypertension can be managed with antihypertensives; however, in some cases, hypertension can be so severe causing a hypertensive crisis. When that is the case, ketamine and esketmine may be contraindicated. (Ceban et al., 2021). ​ Ketamine and esketamine can impact the gastrointestinal (GI) system, potentially causing nausea and/or vomiting, which affects 15% to 40% of people (Ceban et al., 2021). Even though GI distress can be daunting, it is easily manageable. It is recommended that patients avoid consuming food for at least two hours prior to administration. Patients at higher risk for nausea and/or vomiting are recommended to fast for at least eight hours and may be prescribed antiemetics. Patients have also reported an unpleasant taste with ketamine and esketamine treatment, which can be managed with mints or candies. Liver damage can also be a rare side effect of ketamine, however is often reversible. Monitoring liver enzymes is essential to identify potential liver damage. If laboratory results indicate liver impairment, adjusting the dosage may be required; in cases of significant liver damage, discontinuing may be necessary (Ceban et al., 2021). The Role of Primary Care Provider As mentioned earlier, over 60% of patients seek depression treatment from their primary care provider (PCP), which includes family nurse practitioners (FNPs) (Pincus et al., 2020). A PCP's responsibilities in treating depression include proper prescribing, continual assessment, 26 recognizing treatment-resistant depression (TRD), understanding associated risk factors, and managing TRD when appropriate. While it is within the scope of practice for PCPs to treat TRD, those without experience in ketamine or esketamine therapy should refer patients to mental health clinics experienced in these treatments. Referrals to clinics with established regulatory standards may enhance patient safety and improve treatment outcomes. FNPs may also establish ketamine clinics, provided they adhere to regulatory standards, obtain specialized training, and implement ethical guidelines to ensure safe and effective practice (Bloomfield et al., 2023). Patient-centered care must be prioritized when administering ketamine or esketamine. A comprehensive history and physical examination are critical to identifying contraindications and determining if ketamine is a suitable treatment option. Careful evaluation helps mitigate risks, especially for patients predisposed to adverse effects. Providers should adopt safe protocols for administering all forms of ketamine, including oral, nasal, or intravenous (IV) routes (Bloomfield et al., 2023). For example, IV ketamine is recommended to be administered over 40 minutes to decrease adverse reactions (Parikh et al., 2021). Properly trained staff under the provider's supervision are essential for safe ketamine administration. Managing potential adverse events is crucial. Severe reactions, such as hypertensive crises, typically occur within two hours post-administration, necessitating close monitoring during this period. Providers should have rescue medications, such as antihypertensives and antiemetics, readily available and ensure at least one staff member is trained in advanced airway management to maintain a safe environment (Mo et al., 2020). Comprehensive patient education is important for improving treatment adherence and minimizing adverse effects. Providers should educate patients on what to expect during treatment, including potential side effects, to reduce anxiety and foster preparation. For example, 27 advising patients to avoid eating at least two hours before treatment can reduce the risk of gastrointestinal side effects, which could contribute to a more positive treatment experience. A thorough review of the patient’s medications is essential, particularly when prescribing oral ketamine. Ketamine can interact with other drugs, affecting their metabolism through CYP3A enzymes, either increasing or decreasing the potency of ketamine or the other medications. For instance, clarithromycin, a strong CYP3A4 inhibitor, can elevate ketamine levels, causing it to remain in the body longer than usual (Langmia et al., 2022). Similarly, interactions can occur with certain herbs, such as St. John’s wort, which can reduce ketamine levels by approximately 58%, potentially decreasing its effectiveness (Langmia et al., 2022). Dietary interactions should also be considered. For example, grapefruit juice inhibits CYP3A4, delaying ketamine metabolism and prolonging its presence in the body (Langmia et al., 2022). Providers must carefully review patients' diets, medications, and herbal supplement use to avoid subtherapeutic dosing or overdose. Educating patients on the risks of interactions and emphasizing the importance of informing their provider about any changes in medication or supplements is critical. If significant interactions are identified, alternative administration routes, such as IV or intranasal, may be more suitable. Providers must also monitor for potential ketamine or esketamine abuse. Signs of abuse include behavioral changes, mood swings, and neglect of responsibilities. Patients suspected of abusing ketamine may require referral to an addiction specialist. If treatment continues, increased monitoring, such as regular urine toxicology screenings, should be implemented. Abuse potential remains low when ketamine is administered strictly in a clinical setting, but providers should emphasize the importance of adhering to prescribed use. A consent form can further support this, 28 requiring patients to agree not to seek ketamine treatment at unauthorized facilities or use it recreationally (Le et al., 2022). Regulatory and Legal Considerations Ketamine was first approved by the FDA in 1970 as an anesthetic and has since been found to be effective in TRD (Yavi et al., 2022). Recently ketamine clinics have been proliferating across the country. Currently, ketamine is used "off-label" for TRD, as it cannot be patented, making FDA approval financially unviable (Wilkinson & Sanacora, 2017). This brings up safety concerns for the patient regarding long-term side effects and the risk of using a medication off-label. The FDA does not regulate medications used off-label or how a provider practices, however, they can regulate the promotion of off-label use (Pai et al., 2022). The FDA emphasizes that if a healthcare provider prescribes a medication “off-label”, they must be well-informed about the research and evidence supporting its “off-label” use. Providers should also document any side effects and provide a clear rationale for the “off-label” prescription (Pai et al., 2022). ​ Ketamine is a Schedule III controlled substance, and a provider must have a DEA (Drug Enforcement Administration) license to prescribe, which is federal regulated. Consumers should be aware that anyone with a DEA license can prescribe ketamine. As ketamine clinics continue to increase, it has brought about the need for state regulation (Pai et al., 2022). Utah recently passed ketamine regulations. This law was signed into action on March 15, 2023, and will be enforced on May 3, 2023 (Utah State Legislature, 2023). According to Harris (2023) the law now requires: If the anesthesia or sedation provider is administering ketamine for a non-anesthetic purpose, having at least one individual on-site and available who has advanced airway 29 training and the knowledge and skills to recognize and treat airway complications and rescue a patient who entered a deeper than intended level of sedation. (para. 4) This legislation could inspire similar measures in other states, promoting patient safety and standardizing clinic practices. In contrast, esketamine (Spravato), FDA-approved for TRD and suicidal ideation, is subject to strict safety regulations (McIntyre et al., 2021). The FDA requires the implementation of a risk evaluation and mitigation strategy (REMS) for esketamine. Facilities that want to administer esketamine must follow strict guidelines. The facility must apply for enrollment into the program and have patients complete enrollment forms. Esketamine can only be obtained through a certified pharmacy. The medication must be administered under the supervision of a healthcare provider, and a prescriber must be on site (Janssen Pharmaceuticals, 2020). A patient monitoring form is required for each esketamine treatment session. It should document the patient’s current medications, the esketamine dose given, and the total duration of treatment. Monitoring must include vital signs, a minimum observation period of two hours, and a record of any side effects, noting their onset, duration, and resolution. Additionally, the form should record any serious adverse events and how they were managed. The form must be done with every dose administration and submitted within seven days to Spravto REMS (Janssen Pharmaceuticals, 2020; Janssen Pharmaceuticals, 2021). Primary care providers will encounter patients inquiring about ketamine as an option for treating their depression or TRD. PCPs must be educated in both therapeutic options and associated regulatory frameworks to ensure patient safety and legal compliance. As there are few regulations surrounding ketamine administration, it falls to the providers to protect their patients. The American Association of Nurse Anesthesiology (AANA) and The American Psychiatric 30 Nurse Association (APNA) recognize some patients will benefit from ketamine therapy. They have made a joint statement on who should be providing ketamine infusion therapy, and they recommend that a CRNA and a psychiatric-mental health advanced registered nurse be involved (American Association of Nurse Anesthesiology, 2023). Providers need to have documented informed consent with off-label use of ketamine. They should document treatments tried and failed by the patient, and all discussions held with the patient, including the need for repeated treatments of ketamine, the off-label use, and alternative FDA-approved treatments for TRD (Kritzer et al., 2022). If providing subanesthetic ketamine, the provider should educate the patient on the evidence of ketamine for treating depression, be able to manage cardiovascular side effects, have advanced life support certification, and complete a behavior risk assessment (Pai et al., 2022; Wilkinson & Sanacora, 2017). Ethical Considerations in the use of Ketamine and Esketamine ​ Ethical dilemmas arise when considering ketamine or esketamine for TRD. While IN esketamine is the only FDA-approved formulation for this indication, the cost of IN esketamine may be exceptionally high compared to non-FDA approved ketamine (Mo et al., 2022). With FDA-approval, insurance is more likely to cover IN esketamine, decreasing patients’ costs. However, pre-authorizations, and obstacles for insurance approval may be timely and delay treatment. Uninsured patients and those unable to obtain insurance coverage for esketamine, may not be able to receive treatment due to the cost. ​ Off-label ketamine may offer a more affordable alternative, this raises an ethical question: Should patients unable to afford esketamine be denied treatment or is it justifiable to offer a less-regulated or ‘off-label” alternative? As mentioned above, TRD increases the risk of 31 suicide, ketamine or esketamine treatment may be life-saving. Healthcare provider's job is to do what is the most ethically right for their patients. Financial barriers must be carefully considered when determining treatment plans. In cases where esketamine is not a viable option, IV ketamine clinics may present a more affordable solution, provided they adhere to rigorous safety protocols. Ultimately, providers must tailor decisions to provide patient-centered care, while balancing ethical, clinical, and financial considerations. The Promising Future of Ketamine and Esketamine Evidence-based research has shown that ketamine and esketamine are effective options for patients suffering from TRD (McIntyre et al., 2021). Ketamine's and esketamine's exact mechanism of action on depression are unknown, however, research is currently being conducted, with many new pathways being discovered (McIntyre et al., 2021; Yavi et al., 2022). This research could introduce new theories behind depression. If new theories are developed, this could result in new medication for treating depression. Esketamine (Spravato), although approved to treat TRD, must be with an oral antidepressant. As previously discussed, antidepressants are not without their side effects, causing many to discontinue use. A new esketamine monotherapy study, Phase 4 TRD4005, resulted in decreased MADRS scores at both the two day and one month mark. The most reported side effects were nausea, dissociation, headache, and dizziness (Janssen Scientific Affairs, 2024). Janssen Pharmaceuticals have now applied for a new supplemental drug application through the FDA. “Rates of depression in adolescents are climbing, and suicide is now the leading cause of death in individuals aged 15-19 years old” (Ryan & Hosanager, 2023, p. 339). FDA-approved treatment options for depression in adolescents include psychotherapy (Ryan & Hosanagar, 2023). The only FDA-approved medications for depression in adolescents are fluoxetine 32 (Prozac) and escitalopram (Lexapro) (Wagner, 2022). SSRIs have a black box warning of suicidal ideation in this patient demographic, making careful monitoring essential. There are no medications that are FDA-approved for suicidality in adolescents (Lee & Tiefenthaler, 2024). Ketamine studies in suicidality are limited; two adolescents who were treated with ketamine both responded with reduction scores using the Scale for Suicidal Ideation (Ryan & Hosanagar, 2023). Additionally, a small study done using esketamine via subcutaneous or intravenous routes showed a decrease in depression and suicidality (Wagner, 2022). Esketamine is only approved for eighteen and older; however, it is currently being studied in adolescents (Janssen Pharmaceuticals, n.d.; Ryan & Hosanagar, 2023). Of the limited studies using ketamine, all had a decrease in depression scores (Ryan & Hosanagar, 2023). Ketamine and esketamine could be a future treatment option, but more research is needed into efficacy, safety, side effect, and long-term effects and outcomes. Research is showing promise for ketamine use in anxiety, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, and substance use disorder (Walsh et al., 2021; Yavi et al., 2022). According to Walsh et al., research has shown a 50% decrease in anxiety, but symptoms return quickly if the treatment is stopped. PTSD patients had remission up to 80%, and at two months post-treatment, half were still in remission. When used in patients who have alcohol use disorder, 70% remained abstinent for one year. Opioid disorder reported a decrease in cravings and were able to sustain abstinence, but the results were dose-dependent (2021). Limited studies have compared IV ketamine to intranasal (IN) esketamine. To address this, a recent open-label observational study concluded that ketamine and IN esketamine were beneficial in treating suicidality and TRD. A faster response to IV ketamine for depression and a faster suicidality response to IN esketamine was seen. They speculated that the result could be 33 due to the bioavailability and molecular structures. They reported that baseline depression, age, and sex did not play a role in the response. The side effects of IN esketamine were depersonalization and nausea, while the ketamine group had an increased risk of sedation and blurred vision. Other studies have also shown that the IV group had more side effects than the intranasal group. Research indicates that both IV ketamine and IN esketamine are beneficial, resulting in “treatment response for depressive symptoms around 30% or higher, and a remission rate around 20% or higher” (Gutierrez et al., 2024, p. 340). Some studies found that IV ketamine administration response and remission rates were superior to intranasal esketamine (Gutierrez et al., 2024). With those findings, one must ask what role arketamine plays in treating TRD. More research is needed into the arketamine enantiomer regarding its effects on depression, along with randomized control trials comparing IV ketamine and IN esketamine rather than observational studies. The long-term use and long-term side effects of ketamine use are not well documented due to its use off-label and lack of regulations by the FDA. There are concerns regarding the long-term safety of ketamine, proper dosing, frequency, efficacy, and side effects (McIntyre et al., 2021; Wilkinson & Sanacora, 2017). Long-term safety concerns exist for the neurological and urinary systems (Price & Price, 2024). Neurological concerns include cognitive impairment and memory changes, while urinary concerns consist of hydronephrosis, interstitial cystitis, ureter thickening, and vesicoureteral reflux (McIntyre et al., 2021; Price & Price, 2024). More research is needed on the long-term use and effects of ketamine. Research on long-term treatment with IN esketamine showed that the improved MADRS scores were sustained, and there was a decrease in relapse risk by 51% (Boudieu et al., 2023). Dosing, frequency, and safety have been established in IN esketamine (McIntyre et al., 2021; 34 Price & Price, 2024). “Four years of weekly or every other week esketamine showed no new safety signals in an open-labeled study that enrolled 1006 patients” (Price & Price, 2024, p. 11). It also does not cause increased weight gain or sexual dysfunction like oral antidepressants can (Price & Price, 2024). While concerns exist about potential abuse, with limited studies, there are reported no links to an increase in substance abuse, and patients did not have cravings for ketamine after discontinuation (Boudieu et al., 2023; McIntyre et al., 2021). Ketamine and esketamine offer hope for TRD patients who have exhausted other options. Providing the potential to reinvent the treatment for depression and other mental health disorders. Emerging research suggests ketamine and esketamine are beneficial as a monotherapy. As these therapies reshape mental health care, continued research is essential to maximize their potential and ensure safe, effective treatment. Conclusion ​ Treatment-resistant depression (TRD) is a serious health concern that is increasing in prevalence. Treatment of TRD is challenging as treatment options are limited, and traditional medications often result in unfavorable side effects, leading many patients to discontinue use. While research on ketamine and esketamine is still ongoing, these medications are emerging as effective and fast-acting treatments for TRD, offering relief with short-lived and manageable side effects. Continued research is pivotal to further support the efficacy, safety, and long-term effects of ketamine and esketamine in treating TRD. Regulations regarding the usage of ketamine are minimal, with many providers administering and prescribing ketamine for off-label purposes. Advocating for state-level comprehensive regulations for ketamine is critical to ensure standardization and patient safety. 35 Such guidelines would assist providers in making well-informed treatment decisions. Close to 80% of antidepressants are prescribed by primary care providers (PCPs) rather than mental health providers. PCPs must have a basic understanding of TRD and its treatment options, including knowledge of ketamine and esketamine’s benefits, potential drawbacks, and when to refer patients to mental health specialists. PCPs play a crucial role in identifying TRD, addressing patients' questions, and collaborating with mental health professionals to optimize patient outcomes. 36 References American Association of Nurse Anesthesiology. (2023, November 3). AANA and APNA Issue Joint Statement on Ketamine Infusion Therapy for Psychiatric Disorders. Retrieved September 27, 2024, from https://www.aana.com/news/aana-and-apna-issue-joint-statement-on-ketamine-infusion-the rapy-for-psychiatric-disorders/ Anand, A., Mathew, S. J., Sanacora, G., Murrough, J. W., Goes, F. S., Altinay, M., Aloysi, A. S., Asghar-Ali, A. A., Barnett, B. S., Chang, L. C., Collins, K. A., Costi, S., Iqbal, S., Jha, M. K., Krishnan, K., Malone, D. A., Nikayin, S., Nissen, S. E., Ostroff, R. B., … Hu, B. (2023). Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. New England Journal of Medicine, 388(25), 2315–2325. https://doi.org/10.1056/NEJMoa2302399 Bahji, A., Vazquez, G. H., & Zarate, C. A. (2021). Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of Affective Disorders, 278, 542–555. https://doi.org/10.1016/j.jad.2020.09.071 Bains, N., & Abdijadid, S. (2024). Major Depressive Disorder. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK559078/ Baldinger-Melich, P., Spies, M., Bozic, I., Kasper, S., Rujescu, D., & Frey, R. (2024). Perspectives in treatment-resistant depression: Esketamine and electroconvulsive therapy. Wiener Klinische Wochenschrift. https://doi.org/10.1007/s00508-024-02358-w 37 Bloomfield, A., Chan, N., Fryml, L., Horace, R., & Pyati, S. (2023). Ketamine for chronic pain and mental health: Regulations, legalities, and the growth of infusion clinics. Current Pain and Headache Reports, 27(8), Article 11. https://doi.org/10.1007/s11916-023-01150-1 Boudieu, L., Mennetrier, M., Llorca, P.-M., & Samalin, L. (2023). The Efficacy and Safety of Intranasal Formulations of Ketamine and Esketamine for the Treatment of Major Depressive Disorder: A Systematic Review. Pharmaceutics, 15(12), 2773. https://doi.org/10.3390/pharmaceutics15122773 Ceban, F., Rosenblat, J. D., Kratiuk, K., Lee, Y., Rodrigues, N. B., Gill, H., Subramaniapillai, M., Nasri, F., Lui, L. M. W., Lipsitz, O., Kumar, A., Lee, J. G., Chau, E. H., Cao, B., Lin, K., Ho, R. C., Mansur, R. B., Swainson, J., & McIntyre, R. S. (2021a, August 7). Prevention and management of common adverse effects of ketamine and ketamine in patients with mood disorders - CNS drugs. SpringerLink. https://link.springer.com/article/10.1007/s40263-021-00846-5 Chand, S. P., & Arif, H. (2024). Depression. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK430847/ d’Andrea, G., Pettorruso, M., Di Lorenzo, G., Rhee, T. G., Chiappini, S., Carullo, R., Barlati, S., Zanardi, R., Rosso, G., Di Nicola, M., Andriola, I., Marcatili, M., Clerici, M., Dell’Osso, B. M., Sensi, S. L., Mansur, R. B., Rosenblat, J. D., Martinotti, G., & McIntyre, R. S. (2024). The rapid antidepressant effectiveness of repeated dose of intravenous ketamine and intranasal esketamine: A post-hoc analysis of pooled real-world data. Journal of Affective Disorders, 348, 314–322. https://doi.org/10.1016/j.jad.2023.12.038 38 Domino, E. F. (1980). History and Pharmacology of PCP and PCP-Related Analogs. Journal of Psychedelic Drugs. https://www.tandfonline.com/doi/abs/10.1080/02791072.1980.10471430 Duman, R. S., & Aghajanian, G. K. (2012). Synaptic Dysfunction in Depression: Potential Therapeutic Targets. Science (New York, N.Y.), 338(6103), 68–72. https://doi.org/10.1126/science.1222939 Gaynes, B. N., Lux, L., Gartlehner, G., Asher, G., Green, J., Boland, E., & Weber, R. (2019). I am defining treatment-resistant depression. Depression and anxiety. https://pubmed.ncbi.nlm.nih.gov/31638723/ Greenberg, P., Chitnis, A., Louie, D., Suthoff, E., Chen, S.-Y., Maitland, J., Gagnon-Sanschagrin, P., Fournier, A.-A., & Kessler, R. C. (2023). The Economic Burden of Adults with Major Depressive Disorder in the United States (2019). Advances in Therapy, 40(10), 4460–4479. https://doi.org/10.1007/s12325-023-02622-x Gutierrez, G., Kang, M. J. Y., & Vazquez, G. (2024). IV low dose ketamine infusions for treatment resistant depression: Results from a five-year study at a free public clinic in an academic hospital. Psychiatry Research, 335, 115865. https://doi.org/10.1016/j.psychres.2024.115865 Gutierrez, G., Swainson, J., Ravindran, N., Lam, R. W., Giacobbe, P., Karthikeyan, G., Kowara, A., Do, A., Baskaran, A., Nestor, S. M., Kang, M. J. Y., Biorac, A., & Vazquez, G. (2024). IN Esketamine and IV Ketamine: Results of a multi-site observational study assessing the 39 effectiveness and tolerability of two novel therapies for treatment-resistant depression. Psychiatry Research, 340, 116125. https://doi.org/10.1016/j.psychres.2024.116125 Harris Sliwoski LLP. (2023, February 27). Utah ketamine clinic update. Retrieved September 27, 2024, from https://harris-sliwoski.com/psychlawblog/utah-ketamine-clinic-update/ Hirsch, M., & Birnbaum, R. J. (2023, December 4). UpToDate. Evidence-based Clinical Solutions for Healthcare | UpToDate | Wolters Kluwer. Retrieved September 26, 2024, from https://www.uptodate.com/contents/switching-antidepressant-medications-in-adults Iqbal, S., Patel, R., Barlas, Z., Safavi, R., McDeavitt, K., & Shah, A. (2024). Ketamine in Treatment-Resistant Depression. Psychiatric Annals, 54(6), E170–E170. https://doi.org/10.3928/00485713-20240613-01 Janssen Pharmaceuticals. (2020, August). SPRAVATO® REMS Program Overview. Retrieved September 27, 2024, from https://www.spravatorems.com/pdfs/REMSProgramOverview Janssen Pharmaceuticals. (2021, December). SPRAVATO REMS Patient Monitoring Form – Outpatient Use Only. Retrieved September 27, 2024, from https://www.spravatorems.com/pdfs/SPRAVATO_REMS_Patient_Monitoring_Form Janssen Pharmaceuticals. (n.d.). Spravato® (esketamine) | Healthcare professional website. SPRAVATO® (esketamine): A Prescription Nasal Spray | SPRAVATO® HCP. Retrieved November 7, 2024, from https://www.spravatohcp.com/spravato-indications/?&utm_source=google&utm_medium= cpc&utm_campaign=GO-USA-ENG-PS-Spravato-BP-PH-RN-HCP_Generic&utm_conten 40 t=Esketamine+-+Info&utm_term=about+esketamine&gclid=Cj0KCQiA57G5BhDUARIs ACgCYnyYWpJPuh0glGuLqSihqUJtsSmyk0xtORwjJFVorlANgbCd_5tB8SUaAj4GEAL w_wcB&gclsrc=aw.ds Janssen Scientific Affairs. (2024, September 30). Use of SPRAVATO as monotherapy. Retrieved October 26, 2024, from https://www.janssenscience.com/products/spravato/medical-content/use-of-spravato-as-mo notherapy Kritzer, M. D., Mischel, N. A., Young, J. R., Lai, C. S., Masand, P. S., Szabo, S. T., & Mathew, S. J. (2022). Ketamine for treatment of mood disorders and suicidality: A narrative review of recent progress. Annals of Clinical Psychiatry: Official Journal of the American Academy of Clinical Psychiatrists, 34(1), 33–43. https://doi.org/10.12788/acp.0048 Kverno, K. S., & Mangano, E. (2021). Treatment-Resistant Depression: Approaches to Treatment. Journal of Psychosocial Nursing & Mental Health Services, 59(9), 7–11. https://doi.org/10.3928/02793695-20210816-01 Lähteenvuo, M., Taipale, H., Tanskanen, A., Rannanpää, S., & Tiihonen, J. (2022). Courses of treatment and risk factors for treatment-resistant depression in Finnish primary and special healthcare: A nationwide cohort study. Journal of Affective Disorders, 308, 236–242. https://doi.org/10.1016/j.jad.2022.04.010 Langmia, I., Just, K., Yamoune, S., Muller, J., & Stingl, J. (2022, July 21). Pharmacogenetic and drug interaction aspects of ketamine. British Journal of Pharmacology, 41 doi:10.1111/bcp.15467. https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bcp.15467 LE, T. T., PAZOS CARDERO, I., Youshay Jawad, M., Swainson, J., Vincenzo, J., Jaberi, S., Phan, L., Lui, L., Ho, R., Rosenblat, J., & Mcintyre, R. (2022, May 10). The abuse liability of ketamine: A scoping review of Preclinical and Clinical Studies. Journal of Psychiatric Research. https://www.sciencedirect.com/science/article/pii/S0022395622002394?casa_token=RD_ zR1Owhy8AAAAA%3AiW3V2M7dftyMyieSBdEmHe18QXeDTxFx0D5F_4yMMQfC gSIgDbC8dtW-z9Bt5dCUzSrNX1u5xpE Lee, K. C., & Tiefenthaler, C. M. (2024). A narrative review of advances in pharmacotherapy for depression and suicidal behavior in youth within the era of heightened social media. Pediatric Medicine, 7(0), Article 0. https://doi.org/10.21037/pm-23-23 Li, L., & Vlisides, P. E. (2016). Ketamine: 50 Years of Modulating the Mind. Frontiers in Human Neuroscience, 10, 612. https://doi.org/10.3389/fnhum.2016.00612 Matveychuk, D., Thomas, R. K., Swainson, J., Khullar, A., MacKay, M.-A., Baker, G. B., & Dursun, S. M. (2020). Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers. Therapeutic Advances in Psychopharmacology, 10, 2045125320916657. https://doi.org/10.1177/2045125320916657 McIntyre, R. S., Alsuwaidan, M., Baune, B. T., Berk, M., Demyttenaere, K., Goldberg, J. F., Gorwood, P., Ho, R., Kasper, S., Kennedy, S. H., Ly‐Uson, J., Mansur, R. B., McAllister‐Williams, R. H., Murrough, J. W., Nemeroff, C. B., Nierenberg, A. A., 42 Rosenblat, J. D., Sanacora, G., Schatzberg, A. F., … Maj, M. (2023). Treatment‐resistant depression: Definition, prevalence, detection, management, and investigational interventions. World Psychiatry, 22(3), 394–412. https://doi.org/10.1002/wps.21120 McIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., Sanacora, G., Murrough, J. W., Berk, M., Brietzke, E., Dodd, S., Gorwood, P., Ho, R., Iosifescu, D. V., Jaramillo, C. L., Kasper, S., Kratiuk, K., Lee, J. G., Lee, Y., Lui, L. M., Mansur, R. B., Papakostas, G. I., … Stahl, S. (2021). Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. The American Journal of Psychiatry, 178(5), 383. https://doi.org/10.1176/appi.ajp.2020.20081251 Mo, H., Campbell, M. J., Fertel, B., Lam, S., Wells, E. J., Casserly, E., & Meldon, S. W. (2022, September 23). Cost-effectiveness of esketamine nasal spray compared to intravenous ketamine for patients with treatment-resistant depression in the US utilizing clinical trial efficacy and real-world effectiveness estimates. Journal of Affective Disorders. https://doi.org/10.1016/j.jad.2022.08.043 National Institute of Mental Health (NIMH). (n.d.). Brain stimulation therapies. Retrieved September 20, 2024, from https://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-ther apies O’Connor, S. J., Hewitt, N., Kuc, J., & Orsini, L. S. (2023). Predictors and Risk Factors of Treatment-Resistant Depression: A Systematic Review. The Journal of Clinical Psychiatry, 85(1), 50375. https://doi.org/10.4088/JCP.23r14885 43 Ouazana-Vedrines, C., Lesuffleur, T., Cuerq, A., Fagot-Campagna, A., Rachas, A., Gastaldi-Ménager, C., Hoertel, N., Limosin, F., Lemogne, C., & Tuppin, P. (2022). Outcomes associated with antidepressant treatment according to the number of prescriptions and treatment changes: 5-year follow-up of a nation-wide cohort study. Frontiers in Psychiatry, 13, 923916. https://doi.org/10.3389/fpsyt.2022.923916 Pai, S. M., Gries, J., & ACCP Public Policy Committee. (2022). Off‐Label Use of Ketamine: A Challenging Drug Treatment Delivery Model with an Inherently Unfavorable Risk‐Benefit Profile. The Journal of Clinical Pharmacology, 62(1), 10–13. https://doi.org/10.1002/jcph.1983 Parikh, S. V., Lopez, D., Vande Voort, J. L., Rico, J., Achtyes, E., Coryell, W., Goddard, A., Goes, F., Greden, J. F., Singh, B., Kaplin, A., Frye, M. A., Maixner, D., Watson, B., Drake, K. Tarnal, V., Riva-Posse, P., Bobo, W. V., & Bio-K Study Team. (2021). Developing an IV ketamine clinic for treatment-resistant depression: A primer. Psychopharmacology Bulletin, 51(2), 37-50. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374924/ Park, L. T., & Zarate, C. A. (2019). Depression in the Primary Care Setting. New England Journal of Medicine, 380(6), 559–568. https://doi.org/10.1056/NEJMcp1712493 Price, M. Z., & Price, R. L. (2024). Benefits and risks of esketamine nasal spray continuation in treatment-resistant depression. Biomarkers in Neuropsychiatry, 11, 100104. https://doi.org/10.1016/j.bionps.2024.100104 44 Pincus, H. A., Adler, D. A., Finley, P. R., Bull, S. A., Barkil-Oteo, A., & Caballero, J. (2020, July 12). Efficiencies and outcomes of depression treatment by a psychiatric pharmacist in a primary care clinic compared with treatment within a behavioral health clinic. Journal of the American Pharmacists Association. https://doi.org/10.1016/j.japh.2020.05.006 Rhee, T. G., Shim, S. R., Forester, B. P., Nierenberg, A. A., McIntyre, R. S., Papakostas, G. I., Krystal, J. H., Sanacora, G., & Wilkinson, S. T. (2022). Efficacy and Safety of Ketamine vs Electroconvulsive Therapy Among Patients with Major Depressive Episode: A Systematic Review and Meta-analysis. JAMA Psychiatry, 79(12), 1162. https://doi.org/10.1001/jamapsychiatry.2022.3352 Rosenbaum, S. B., Gupta, V., Patel, P., & Palacios, J. L. (2024). Ketamine. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK470357/ Rush, A. J. (2024, May 13). Major depressive disorder in adults: Initial treatment with antidepressants. UpToDate. Retrieved September 18, 2024, from https://www.uptodate.com/contents/major-depressive-disorder-in-adults-initial-treatment-w ithantidepressants?search=antidepressant%20side%20effect%20table&source=search_resu lt&selectedTitle=3%7E150&usage_type=default&display_rank=3 Ryan, K., & Hosanagar, A. (2023). Ketamine Use in Child and Adolescent Psychiatry: Emerging Data in Treatment-Resistant Depression, Insights from Adults, and Future Directions. Current Psychiatry Reports, 25(8), 337–344. https://doi.org/10.1007/s11920-023-01432-w 45 Serafini, G., Howland, R. H., Rovedi, F., Girardi, P., & Amore, M. (2014). The Role of Ketamine in Treatment-Resistant Depression: A Systematic Review. Current Neuropharmacology, 12(5), 444–461. https://doi.org/10.2174/1570159X12666140619204251 Shin, C., & Kim, Y.-K. (2020). Ketamine in Major Depressive Disorder: Mechanisms and Future Perspectives. Psychiatry Investigation, 17(3), 181. https://doi.org/10.30773/pi.2019.0236 Singh, J. B., Fedgchin, M., Daly, E. J., De Boer, P., Cooper, K., Lim, P., ... & Van Nueten, L. (2016). A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. American Journal of Psychiatry, 173(8), 816-826. Singh, B., Kung, S., Pazdernik, V., Schak, K. M., Geske, J., Schulte, P. J., Frye, M. A., & Vande Voort, J. L. (2023). Comparative Effectiveness of Intravenous Ketamine and Intranasal Esketamine in Clinical Practice Among Patients with Treatment-Refractory Depression: An Observational Study. The Journal of Clinical Psychiatry, 84(2), 22m14548. https://doi.org/10.4088/JCP.22m14548 Sobule, R., & Ithman, M. (2023). Ketamine: Studies Show Benefit. Missouri Medicine, 120(1), 29. Utah State Legislature. (2023, March 15). S.B. 197 Anesthesia Amendments. Retrieved September 27, 2024, from https://le.utah.gov/~2023/bills/static/SB0197.html 46 Wagner, K. D. (2022, August 11). Update on depression treatments for youth. Psychiatric Times. Retrieved October 26, 2024, from https://www.psychiatrictimes.com/view/update-on-depression-treatments-for-youth Walsh, Z., Mollaahmetoglu, O. M., Rootman, J., Golsof, S., Keeler, J., Marsh, B., Nutt, D. J., & Morgan, C. J. A. (2021). Ketamine for the treatment of mental health and substance use disorders: Comprehensive systematic review. BJPsych Open, 8(1), e19. https://doi.org/10.1192/bjo.2021.1061 White, P. F., Schüttler, J., Shafer, A., Stanski, D. R., Horai, Y., & Trevor, A. J. (1985). COMPARATIVE PHARMACOLOGY OF THE KETAMINE ISOMERS. British Journal of Anaesthesia, 57(2), 197–203. https://doi.org/10.1093/bja/57.2.197 Wilkinson, S. T., & Sanacora, G. (2017). Considerations on the Off-label Use of Ketamine as a Treatment for Mood Disorders. JAMA, 318(9), 793–794. https://doi.org/10.1001/jama.2017.10697 Woo, T. M., & Robinson, M. V. (2020). Pharmacotherapeutics for advanced practice nurse prescribers (5th ed.). F.A. Davis. Yavi, M., Lee, H., Henter, I. D., Park, L. T., & Zarate, C. A. (2022). Ketamine treatment for depression: A review. Discover Mental Health, 2(1), 9. https://doi.org/10.1007/s44192-022-00012-3 Yip, R., Swainson, J., Khullar, A., McIntyre, R. S., & Skoblenick, K. (2022, September 29). Intravenous ketamine for depression: A clinical discussion reconsidering best practices in 47 acute hypertension management. Frontiers in Psychiatry. https://doi.org/10.3389/fpsyt.2022.847288 Zorumski, C. F., Izumi, Y., & Mennerick, S. (2016). Ketamine: NMDA Receptors and Beyond. The Journal of Neuroscience, 36(44), 11158. https://doi.org/10.1523/JNEUROSCI.1547-16.2016 Zhang, J., Li, S., & Hashimoto, K. (2014). R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacology Biochemistry and Behavior, 116, 137–141. https://doi.org/10.1016/j.pbb.2013.11.033 Tillotson_Andrea_approval.pdf APPROVAL of a thesis/project submitted by Author(s): Andrea Tillotson | Advisor: Elizabeth Hanna Haleigh Samayoa Olivia Akerley School Department: School of Nursing and Health Sciences Title of Thesis: Ketamine and Esketamine for Treatment- Resistant Depression Chairperson, Supervisory Committee: Elizabeth Hanna Approved on 03-06-2025 Dean of School of Nursing and Health Sciences: Sheryl Steadman Approved on 03-06-2025 Tillotson_Andrea_permission.pdf STATEMENT OF PERMISSION TO DEPOSIT & DISPLAY THESIS IN THE INSTITUTIONAL REPOSITORY Name of Author: Andrea Tillotson | Advisor: Elizabeth Hanna Additional Authors: Haleigh Samayoa | Olivia Akerley | | School Department: School of Nursing and Health Sciences Title of Thesis: Ketamine and Esketamine for Treatment- Resistant Depression With permission from the author(s), the staff of the Giovale Library of Westminster University has the right to deposit and display an electronic copy of the above named thesis in its Institutional Repository for educational purposes only. I hereby give my permission to the staff of the Giovale Library of Westminster University to deposit and display as described the above named thesis. I retain ownership rights to my work, including the right to use it in future works such as articles or a book. Submitted by the Author(s) on 3/4/2025 1:58pm The above duplication and deposit rights may be terminated by the author(s) at any time by notifying the Director of the Giovale Library in writing that permission is withdrawn.