Ketamine’s use dates back to the early days of the 1960s, when it was used as an anesthetic agent. It was even used to treat injured soldiers during the Vietnam war. Today, we continue to use ketamine in the operating room, providing it as a sedative. However, in more recent years, ketamine has gained traction as a therapeutic agent for other settings and conditions. In 2019, the Food and Drug Administration (FDA) actually approved ketamine for the treatment of depression. Its robust efficacy profile within this condition has led researchers to study it in the context of other disease states. This article will discuss ketamine’s potential in post-traumatic stress disorder (PTSD), depression, pain, fatigue, and post-COVID syndrome.
PTSD is a condition characterized by repeated, unpleasant memories, flashbacks, and dreams. These episodes occur in response to internal or external stimuli that remind the individual of a specific traumatic event. These traumatic events can include things like sexual assault, death, injury, or more.
PTSD is prevalent in about 8.7 percent of individuals in the United States. Certain individuals may be more susceptible to PTSD, particularly military veterans, law enforcement, and emergency medical workers who are exposed to traumatic events. PTSD can cause disability, as it is linked with poor social relationships, low income, work absence, and low educational and occupational success. It is also associated with comorbidities such as anxiety, depression, and substance abuse.
Thankfully, several treatment options exist for PTSD, including serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs). Recently, research has indicated the potential of intravenous (IV) ketamine in PTSD (1).
The American Journal of Psychiatry published results from the first randomized, controlled study evaluating the effect of ketamine on chronic PTSD. The study included those with severe and chronic PTSD, with trauma from sexual assault, abuse, combat exposure, and more. Individuals received six infusions of ketamine over the course of two weeks.
The ketamine group had a statistically significant reduction in symptoms versus the midazolam (control) group. In fact, 67 percent of individuals taking ketamine had a least a 30 percent decrease in symptoms. Ketamine also improved PTSD symptoms such as mood, intrusions, and avoidance (2).
Major depressive disorder (MDD) is a serious mental illness affecting millions of individuals worldwide. Likewise, it is a leading cause of disability globally. In the U.S. alone, roughly 16 million adults experienced a major depressive episode within a year. Depression is closely associated with suicide, and suicide rates have risen over the past decade by greater than 30 percent in 25 states (3).
Pharmacologic options exist to treat depression; however, they typically take four to 12 weeks to start working. Ketamine has emerged as a potential new treatment option, given its effects on the N-methyl-D aspartate (NMDA) receptor. Ketamine blocks the NMDA receptor.
Current research indicates that ketamine acts rapidly in the context of depressive symptoms, alleviating symptoms as early as the first day. Treatment is associated with less suicidal ideation and decreased self-harm. One study evaluated its effects on depression and anxiety after receiving six ketamine doses over the course of two weeks. Individuals demonstrated improvements in anxiety, depression, and illness severity for up to one month. Participants experienced only mild and transient adverse effects that resolved within an hour of ketamine administration (4).
Anxiety is a very common condition affecting 18.1 percent of adults in the United States and 14 percent of adults in Europe. Though treatment options exist, there is still an unmet need in certain patient populations. For example, refractory anxiety is a condition in which anxiety symptoms persist despite active treatment. These patients have serious symptoms and are more likely to experience relapse. Evidence exists suggesting that ketamine can significantly decrease refractory anxiety symptoms via its modulation of the NMDA receptor (5).
Roughly 12 percent of adults experience social anxiety disorder (SAD), which is the phobia of social situations and consequent social impairment and distress. Because of ketamine’s effect on NMDA receptor, it may help with treatment of SAD. One study treated SAD patients with intravenous ketamine at a dose of 0.5 mg/kg over the course of 40 minutes or placebo. Individuals demonstrated improved outcomes with ketamine versus placebo. They performed better on the Liebowitz Social Anxiety Scale (LSAS) and visual analog scale (VAS-Anxiety). These results indicate ketamine’s potential in anxiety treatment (6).
In conclusion, ketamine induces temporary anxiolytic effects that typically return to baseline within two weeks. It offers an effective option for those seeking treatment for anxiety, specifically refractory anxiety or SAD.
Outside of its effects on mental illness, ketamine also has analgesic effects. Thus, the field of medicine uses it frequently in the setting of pain. For example, ketamine can help with opioid-resistant pain, perioperative pain, chronic noncancer pain, and more. Ketamine exerts its analgesic properties via the NMDA receptor. The NMDA receptor contributes to the development of pain signals, sensitization, and opioid tolerance. By antagonizing this receptor, ketamine relieves pain. It also demonstrates the ability to decrease or reverse opioid tolerance.
In the context of surgery, ketamine treatment induced lower post-op pain scores, decreased opioid requirements, and increased the time to first analgesic request. It also alleviated nausea and vomiting. In terms of cancer, ketamine can decrease pain intensity and morphine requirements. However, some studies suggest an increased incidence of adverse events with ketamine treatment, such as cardiac arrest or bradyarrhythmia. Less evidence exists for the use of ketamine in palliative care and noncancer pain settings.
Adverse effects associated with ketamine treatment for pain include high blood pressure, urotoxicity, hepatotoxicity, dependency, and loss of smell. Ketamine also has potential for addiction and substance abuse, which represents an additional risk (7).
Fatigue is a very common but debilitating condition associated with numerous medical conditions such as cancer, anemia, and thyroid dysfunction. Fatigue is defined as tiredness, muscular weakness, low cognitive functioning, and low energy levels. It is associated with feelings of hopelessness, depression, and suicidal ideation. Chronic fatigue is expected to cost between 17 to 24 billion dollars annually.
Because of ketamine’s action on the NMDA receptor and its efficacy in depression, researchers hypothesized that ketamine may benefit those suffering from fatigue. One study evaluated how low dose ketamine influenced fatigue in individuals with treatment-resistant depression. The study followed 36 subjects with treatment-resistant bipolar disorder while in a depressive episode. Participants were treated with 0.5 mg/kg of ketamine over the course of 40 minutes and followed through day 14 post-treatment.
Results indicated that ketamine decreased fatigue versus placebo immediately after treatment and through Day 14 of follow-up. Likewise, ketamine and its target, the NMDA receptor, offer potential treatment targets for alleviating feelings of fatigue (9).
Bipolar disorder represents a disabling yet persistent psychiatric disorder. It affects more than one percent of the population and is associated with the highest chance of suicide compared with other psychiatric conditions. Bipolar disorder treatment failure rates are even greater than those of depression. Likewise, there is a significant unmet need for safe and effective treatments for this condition.
Given ketamine’s anti-suicidal and antidepressant effects, experts postulate that it may benefit patients with bipolar disorder. In a randomized, placebo-controlled study, investigators treated subjects with bipolar depression with ketamine. Results indicated a robust antidepressant effect with just one ketamine infusion when used together with mood stabilizers. Several studies mimicked the results of the previous study, with a high response rate and antidepressant effect present after a single ketamine dose.
Evidence supporting multiple ketamine treatments in bipolar disorder is lacking. However, one study demonstrated that low dose ketamine received every two to three days or weekly improved cognition, mood, and sleep in bipolar subjects (10).
In conclusion, ketamine may be an effective adjunctive agent when treating bipolar disorder. It demonstrates robust anti-suicidal and antidepressant effects.
Most of us are familiar with the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 is characterized by a respiratory tract infection that is often accompanied by symptoms such as diarrhea, stomach pain, pericarditis, and muscle pain. What many do not know, however, is that COVID-19 can cause neuropsychiatric problems, including issues like anxiety, mood disorders, depression, and psychosis. One study found that in over 40,000 COVID-19 infected individuals, 22 percent of patients had some kind of neurological or psychiatric symptom associated with the infection.
Ketamine provides an anti-inflammatory effect, contributing to its potential in conditions such as depression. Likewise, some experts postulate that its anti-inflammatory properties and effect on mental disorders could make it a therapeutic candidate for COVID-associated psychiatric symptoms (11).
The scientific evidence makes it clear that ketamine is here to stay. It provides robust clinical results in the setting of several psychiatric disorders in addition to chronic fatigue and post-COVID syndrome. While more research is necessary to establish its full safety and efficacy profile in these conditions as well as its potential in other disease states, the current data looks extremely promising.
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