Ketamine Infusion Therapy

Major depressive disorder (MDD) is a leading cause of suicide in the world (Kim et al., 2024) and ranks third in terms of its global disease burden, placing tremendous strain on societal costs due to disability (Abdallah et al., 2016; Harding et. al., 2025; Kawczak et al., 2024). There are multiple drug classes utilized as monotherapy or as combination therapy to treat depression, but they can be of limited efficacy. Many patients never experience adequate response or reach sustained remission of symptoms, leaving a critical gap in treatments that offer a rapid onset of action and sustained efficacy. Although ketamine was originally used in surgery for anesthesia, it has transitioned to a groundbreaking treatment for depression and chronic pain, highlighting its versatility and potential while raising ethical and medical questions (Abdallah et al., 2016; Kawczak et al., 2024). Research over the last two decades increasingly supports ketamine and esketamine for the treatment of MDD in clients who have not responded well to conventional antidepressants and psychotherapy modalities (Kim et al., 2024). As of January 2025, esketamine (the S-enantiomer of ketamine) has been approved for monotherapy for treatment-resistant depression (Grossi, 2025). This course will discuss the use of ketamine, a drug classified by the Drug Enforcement Administration (DEA) as a Schedule III drug with moderate abuse potential, as a viable treatment option for treatment-resistant depression, as well as the legal and ethical challenges that come with using controlled substances.

Laura is a 34-year-old housewife with a 20-year history of severe, recurrent MDD. Her symptoms began post-delivery of her first child and progressively worsened despite multiple treatment interventions. She experienced persistent feelings of hopelessness, worthlessness, emptiness, anhedonia, poor concentration, crying spells, fatigue, and profound sadness. Her symptoms significantly impaired her daily functioning and prevented her from maintaining employment and social relationships.

Laura has attempted suicide three times in the last five years, with the most recent attempt six months ago. She was hospitalized following this last attempt and subsequently enrolled in an intensive outpatient treatment program. The program offered her a supportive environment, but her depressive symptoms remained largely unchanged.

Laura has been diagnosed with treatment-resistant depression due to her lack of response to at least four different antidepressants from various classes, including selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline and fluoxetine), serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine), norepinephrine-dopamine reuptake inhibitors (e.g., bupropion), and tricyclic antidepressants (TCAs) (e.g., amitriptyline). She also underwent augmentation strategies with atypical antipsychotics (e.g., aripiprazole) and mood stabilizers (e.g., lithium) without significant improvement. Additionally, she participated in cognitive behavioral therapy (CBT) and dialectical behavior therapy (DBT), which she found beneficial for coping strategies but insufficient to alleviate her core depressive symptoms.

Esketamine, a nasal spray formulation of ketamine approved as monotherapy by the Food and Drug Administration (FDA) for treatment-resistant depression, was recommended as a novel approach due to its rapid-acting mechanism and efficacy in addressing depressive symptoms and suicidal ideation. Laura met the eligibility criteria for Spravato therapy, including her history of treatment-resistant depression, lack of recent substance abuse, and ability to attend the required supervised administration sessions.

Laura underwent comprehensive education about Spravato, including its potential benefits, risks, and side effects. She was informed of common side effects, such as dizziness, dissociation, nausea, and sedation, as well as the need for monitoring during and after administration. She expressed hope that this therapy might provide relief where other treatments had failed.

The Diagnostic and Statistical Manual (DSM-5-TR) (American Psychiatric Association [APA], 2022) categorizes MDD as severe, having a depressed mood nearly every day (e.g., feeling sad, empty, or hopeless) for two weeks or more. MDD can be categorized as mild, moderate, or severe depending on the number and severity of the symptoms. To qualify as severe, the person must have at least five of the following symptoms: anhedonia, significant unintentional weight loss or gain, insomnia or hypersomnia nearly every day, fatigue or very little energy, poor concentration, feelings of worthlessness or excessive inappropriate guilt (which may be delusional) and recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a significant plan or a suicide attempt or a specific play for committing suicide. The symptoms must cause a significant impairment in the person’s ability to function in the community, at home, at work, and at school.

Research by the World Health Organization (2023) identified MDD as one of the most common mental health disorders worldwide, with an estimated 3.8% of the population impacted (approximately 280 million people), with more than 700,000 people committing suicide every year. Suicide is the fourth leading cause of death in 15-29-year-olds (World Health Organization, 2023).

Although there are effective treatment options, approximately one-third of adults will not respond to oral antidepressants (Greenberg et al., 2023), which greatly impacts quality of life and creates a high economic burden while increasing the risk of suicide. “The primary drivers include healthcare costs ($127.3 billion); household-related costs ($80.1 billion); presenteeism ($43.3 billion), and absenteeism ($38.4 billion)” (Greenberg et al., 2023, p 3). MDD is one of the leading causes of disability (Antos et al., 2024), as more than two-thirds of people diagnosed with this disorder will fail to respond to first-line treatment options, and an additional 30% of people will fail on two or more antidepressants, thus classifying them as treatment-resistant (Antos et al., 2024; APA, 2022).

In the past, treatment for MDD mainly focused on the monoamine serotonin (5-HT), norepinephrine (NE), and dopamine (DA) deficiency hypothesis. Available treatment options, such as TCAs, monoamine oxidase inhibitors (MAOIs), SSRIs, and SNRIs, act by regulating monoamines in the central nervous system, increasing serotonergic and noradrenergic neurotransmission (Antos et al., 2024; Edinoff et al., 2021). The problem with these drugs is that they have a delayed onset of action, requiring 4-6 weeks of consistent, daily use before any clinical improvement is realized. In contrast, ketamine has a unique rapid onset, alleviating suicidal thoughts within 1-2 hours of initiating infusion and obtaining remission of symptoms within four weeks, which offers a critical lifeline for people at high risk for suicide (Antos et al., 2024; Grossi, 2025).

Calvin Stevens, a chemist for Parke-Davis Pharmaceutical Company (Ann Arbor, Michigan), first synthesized ketamine in 1962 while investigating alternatives to phencyclidine (PCP) for general anesthesia (Dinis-Oliveira, 2017). Ketamine is very similar to the recreational drug PCP, causing analgesia and amnesia without the severe cardiovascular and respiratory depressive symptoms associated with common anesthetics (Orhurhu et al., 2023). However, ketamine was associated with vivid dreams and hallucinations during recovery (Kawczak et al., 2024). It was first labeled as C1-581 and has one-tenth the potency of PCP. Ketamine was approved by the FDA for human use in surgical patients in 1970 (Orhurhu et al., 2023). “Ketamine was the most common battlefield anesthetic used during the Vietnam War” (Orhurhu et al., 2023, p 2). Off-label, subanesthetic doses of ketamine are currently being used for acute and chronic pain management, sedation, and treatment of severe depression (Antos et al., 2024; Orhurhu et al., 2023).

Ketamine is a mixture of two enantiomers (S-ketamine (also known as esketamine) and R-ketamine (also known as arketamine) (Kawczak et al., 2024). These two compounds, enantiomers S-ketamine and R-ketamine, are mirror images of each other but not identical, much like one’s hands are mirrors of each other but not identical. According to Kawczak et al (2024), esketamine has a high affinity for sigma receptors, causing symptoms such as delusions, hallucinations, and disorganized thinking (also known as psychotomimetic effects). These overt changes manifested in the central nervous system both in the electroencephalogram (EEG) and in glucose metabolism (Lodge & Mercier, 2015). Sigma receptors are a newly discovered central nervous system receptor and are not yet fully understood. However, it is hypothesized that changes in sigma receptor function or expression play significant roles in central nervous system (CNS) disorders (Piechal et al., 2021).

(S)-ketamine (also known as esketamine or Spravato) was FDA-approved in 2019 in conjunction with an oral antidepressant for treatment-resistant depression in adults (Stewart, 2025). In January 2025, the FDA expanded the approval of esketamine nasal spray as a stand-alone monotherapy for patients with treatment-resistant depression (Grossi, 2025; U.S. FDA, 2025; Stewart, 2025).

The exact mechanism of action is not yet fully understood, but research suggests that ketamine works on several different key pathways in the brain to help treat depression. “Ketamine is a phencyclidine derivative and a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor for which glutamate is the full agonist. It produces a functional dissociation between the thalamocortical and limbic systems, a state that has been termed as “dissociative anesthesia” (Dinis-Oliveira, 2017, p. 1). By inhibiting these receptors, ketamine increases the release of glutamate, the brain’s primary excitatory neurotransmitter. This triggers the activation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, which promote the growth and strengthening of synapses (connections between neurons). Ketamine then stimulates the release of brain-derived neurotrophic factor, a protein critical for the growth and survival of neurons. Increased brain-derived neurotrophic factor and glutamate activity promote synaptogenesis, or the formation of new synaptic connections, particularly in areas of the brain like the prefrontal cortex, which is often impaired in depression. Ketamine also has an anti-inflammatory effect, which may contribute to its antidepressant properties. Chronic inflammation is associated with depression, and ketamine may help by reducing inflammatory markers in the brain (Abdallah et al., 2016). As an N-methyl-D-aspartate antagonist, ketamine has a rapid onset of antidepressant activity in treatment-resistant depression (Glue et al., 2024).

Esketamine is known to have a rapid onset of action that is linked to brain-derived neurotropic factor production. Esketamine is thought to work by enhancing synaptic plasticity signaling and increasing synapse formation in the prefrontal cortex (Kawczak et al., 2024). The synthesis of depression is believed to be a sequel to a disruption in the functional circuits connecting different regions of the brain (Rǎdulescu et al., 2021). The regions believed to be most impacted include the frontal lobe, hippocampus, temporal lobe, thalamus, striatum, and amygdala.

Michael Merzenich observed that the brain is highly plastic and can change in response to intrinsic and extrinsic factors, including learning a new skill, reading, and thinking (Shaffer, 2016). Marian Diamond, considered the “mother of neuroplasticity,” first proved that a brain will shrink with an impoverished milieu and grow in an enriched milieu at any age (Shaffer, 2016). The plasticity of the brain allows for adaptation and change throughout one’s life. When a new skill is learned, the brain forms new connections to adapt to the new information, enhancing resilience.

Both esketamine and some antidepressants have been shown to enhance neuroplasticity by repairing damage to neural circuits and strengthening synapses (Kawczak et al., 2024; Rǎdulescu et al., 2021). The downside to treatment with antidepressants is the weeks-long delays before clinical benefit and low remission rates (McIntyre & Jain, 2024). Where antidepressants typically only work on serotonin and dopamine, esketamine acts on glutamate, a neurotransmitter directly linked to brain plasticity. The effects of esketamine are more immediate, offering relief of depressive symptoms within hours or days of treatment. The higher the rate of neuroplasticity and recovery, the higher the potential for a client to have the ability to learn new coping skills and adapt to stress, as well as relief from depressive symptoms (Glue et al., 2024; Grosi, 2025; Harding et al., 2025; Kawczak et al., 2024).

The downside: ketamine carries medical risks that require a health care professional to monitor a patient who has been administered the drug (DEA, n.d.-b). In August 2024, five people, including two doctors, were charged in connection with actor Matthew Perry’s fatal overdose (DEA, 2024) that occurred in October 2023. The press release from the DEA (2024) indicates that ketamine was distributed outside the usual course of professional practice and without a legitimate medical purpose on numerous occasions. Matthew Perry, who had a drug addiction, was taught how to self-inject ketamine on his own without any supervision. These two physicians, understanding the risks of serious adverse events of ketamine, including sedation and dissociation after administration, as well as the risks for abuse and misuse of the drug, sold him ketamine and the syringes used to inject the drug.

Laura’s Spravato therapy was initiated in a controlled clinic setting. She received twice-weekly administration for four weeks under direct medical supervision. She then moved into a maintenance phase, receiving once-a-month dosing while she continued to take her duloxetine to maximize therapeutic synergy. Each session included a pre-treatment assessment, nasal spray administration, and a two-hour observation period to monitor side effects and ensure her safety. At the end of eight weeks of treatment, Laura’s symptoms had decreased by over 50% based on her Montgomery-Asberg Depression Rating Scale (MADRS) scores. She was cautiously optimistic and motivated to rebuild her life.

Esketamine clinics can be established in a hospital setting or an outpatient clinic setting. One provider at the site of the hospital or outpatient clinic must be certified in ACLS (advanced cardiac life support). Providers and clients must be on-site for administration, and vital signs must be monitored at regular intervals throughout the treatment cycle. Clients must meet with a medical provider to establish care and determine the appropriateness of treatment prior to initiating therapy. Exclusion criteria for treatment includes any of the following: hypersensitivity to esketamine or ketamine or any of the excipients, a history of seizures, recent (within 30 days) delirium, uncontrolled hypertension (systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg), history of intracerebral hemorrhage, aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels), arteriovenous malformations, Class IV heart failure or unstable angina, severe hepatic impairment (Child-Pugh class C), or current or previous interstitial or ulcerative cystitis. None of the following comorbid psychiatric conditions may be present, including schizophrenia, schizoaffective disorder, MDD with psychotic symptoms, bipolar disorder, obsessive-compulsive disorder, intellectual disability, autism, cluster B personality disorder, or a major neurocognitive disorder diagnosis. Clients may not have a history of drug abuse and must pass a urine drug screen and have a negative urine pregnancy test prior to induction of treatment. Clients cannot be pregnant or breastfeeding to receive this treatment. The clients cannot currently be taking any opioids, barbiturates, or cannabis products. A history of deep-brain stimulation is also an exclusion criterion (Janssen Pharmaceuticals, 2020b; Veterans Affairs, 2022).

All clients who receive esketamine treatment must be enrolled in the Spravato REMS program by their licensed healthcare provider. Without enrollment in the REMS program, a prescription for esketamine cannot be dispensed to start treatment. A licensed psychiatric mental health provider (e.g., psychiatrist, NP or PA) evaluates the client and determines if the client is eligible for treatment by meeting the DSM-5 criteria for unipolar MDD and they have not received remission from at least four adequate therapeutic trials (dose and duration) on antidepressants, either alone or in combination with evidence-based psychotherapy or the client has been hospitalized with MDD complicated by acute suicidal ideations or behaviors. The client must have a driver to take them home after the appointment, and the client must agree to stay and be monitored for at least two hours after esketamine administration. The client must understand that he or she cannot drive, operate machinery, or make major financial or legal decisions for the remainder of the day after drug administration (Jannsen Pharmaceuticals, 2020b; Veteran Affairs, 2022).

Ketamine is a Schedule III-controlled substance that is FDA-approved for induction and maintenance of general anesthesia only (FDA, 2024). A drug classified by the DEA as a Schedule III means the drug has abuse potential and is considered dangerous. Drugs classified as Schedule III include ketamine, esketamine, products containing less than 90 mg of codeine per dosage unit (e.g., Tylenol with codeine), anabolic steroids, and testosterone (DEA, n.d.-a). Some providers have utilized ketamine off-label for the treatment of chronic pain, but it is not yet approved by the FDA as an indication for this disorder.

Esketamine, considered a Schedule III-controlled substance, is only available through a restricted distribution program called Spravato REMS (Risk, Evaluation and Mitigation Strategy) because of the risks of serious adverse events, including sedation and dissociation after administration, as well as the risks for abuse and misuse of the drug. Only certified healthcare settings are approved to administer this drug. Esketamine must be dispensed from a pharmacy certified in Spravato REMS directly to the provider administering the drug. This drug is never dispensed directly to the patient for home use and must be administered with supervision. The patient must plan to be at the approved healthcare clinic for a full two hours for monitoring after administration (FDA, 2020) and must be clinically stable prior to discharge home. Esketamine is not intended for use in children (Jannsen Pharmaceuticals, 2020b).

John R. is a 35-year-old male who was a former teacher and is now on disability. He is divorced and the father of two girls (ages 10 and 11). He has a fifteen-year history of treatment-resistant depression that started following the death of his mother.

John reports persistent feelings of hopelessness, anhedonia, low energy, and suicidal ideation without intent. He has experienced no significant improvement in his symptoms despite years of treatment. His current symptoms are measured as “severe” based on the Hamilton Depression Rating Scale (HAM-D) with a score of 24. John has tried and failed a number of medications in various drug classes, including SSRIs, SNRIs, TCAs, and MAOIs, without any sustained benefits. He has also failed on adjunct treatment options, including lithium, antipsychotics (aripiprazole), and thyroid hormone. He has engaged in therapy (CBT, DBT, and psychodynamic therapy) for the last five years. Five treatments of electroconvulsive therapy (ECT) resulted in partial improvement, but symptoms returned within a few weeks. He completed two cycles of transcranial magnetic stimulation (TMS) treatment without meaningful progress.

John has become increasingly frustrated with traditional treatment options and is expressing hope after reading about ketamine’s rapid-acting effects for treatment-resistant depression. His pre-treatment assessment showed normal lab values and no contraindications for ketamine use. His baseline blood pressure and electrocardiogram (EKG) were within normal limits. His mental health is without acute psychosis, mania, or substance use disorder. His suicidal ideations remain passive without a plan or intent. Family support is minimal as he remains estranged from his children and siblings. John understands that ketamine is not a cure, but a potential intervention to reduce symptoms and allow engagement in other therapies.

The initial trial of ketamine included IV ketamine, 0.5mg/kg over 40 min, administered twice weekly for four weeks. John’s vital signs were monitored during the IV sessions, and he came in for a 24-hour follow-up assessment after each treatment. He continued in weekly psychotherapy sessions to process any insights or emotional shifts that occurred during or after treatment. He continued his use of escitalopram to assess synergistic effects. After four weeks of treatment, his HAM-D score was reduced to 15 (moderate depression), and he self-reported an increase in his quality of life (resuming hobbies and connecting with family again), a decrease in suicidal ideations, and improved functional impairments. The only side effect John experienced during treatment was mild dissociation during the infusions, which he found unsettling but tolerable.

The challenge for John was to maintain the expectation that ketamine was not a permanent fix. He would need to continue ongoing psychotherapy and continue maintenance infusions at a reduced frequency.

Ketamine therapy has demonstrated early promise in alleviating John’s treatment-resistant depression, enabling him to experience hope and functionality after years of ineffective treatments. While further research is needed to optimize protocols and determine long-term efficacy, ketamine represents a valuable tool for select patients like John.

As of January 2025, esketamine was approved as monotherapy for treatment-resistant depression (Grossi, 2025). MDD is a leading cause of suicide in the world (Kim et al., 2024) and ranks third in terms of its global disease burden, placing tremendous strain on societal costs due to disability (Abdallah et al., 2016; Harding et. al., 2025; Kawczak et al., 2024). However, the use of ketamine is not without its risks and ethical considerations.

Ketamine was originally used in surgery for anesthesia, transitioning into a groundbreaking treatment for depression and chronic pain, thus highlighting its versatility and potential while raising ethical and medical questions (Abdallah et al., 2016; Kawczak et al., 2024). Ketamine and esketamine have been used for the treatment of MDD in clients who have not responded well to conventional antidepressants and psychotherapy modalities (Kim et al., 2024). Use of ketamine has risks including sedation, dissociation, abuse and misuse, and increased suicidal thoughts and behaviors after use, including the risk for hallucinogen persisting perception disorder, where patients can experience prolonged visual disturbances several weeks after ketamine use (DEA, n.d.-b). Ethical considerations include the misuse of the drug as a tool for control, the high addictive qualities of ketamine, risking future abuse, and the risks for long-term brain changes, including lesions and decreased grey matter. The potential to help these clients who suffer from severe, debilitating depression is high, and the potential for ketamine to revolutionize psychiatry exists, but as with all things powerful, the benefits must be weighed against the risks. Consequently, continued research and ethical vigilance are paramount to the safety of society.

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