The medical care model today traditionally emphasizes the diagnosis and treatment of illnesses following the onset of diseases. However, the notion of preventative medicine, or as Dr. Peter Attia terms it, “Medicine 3.0”, presents a more favorable approach for the future. Instead of merely applying a bandage, a proactive strategy to prevent injuries from occurring in the first place should be the focal point of medical resource allocation.
The efficacy of a preventative approach is evident in the history of medicine and infectious diseases, exemplified by the development of routine vaccinations against tuberculosis, smallpox, and polio. Additional examples include maintaining a healthy and well-balanced diet, incorporating regular physical exercise, and abstaining from the use of tobacco and alcohol. These efforts aim to prevent the onset of chronic illnesses such as heart disease, diabetes mellitus, lung cancer, and others. Extending this concept to the field of psychiatry demands equal consideration. This is where ketamine and psychedelics come into play as tools with the potential to be utilized prophylactically, fostering resilience against future trauma and upcoming stressful situations.
Published last year in the ScienceDirect journal, the review by Brain K. Chen and Christine A. Denny, titled "Weapons of Stress Reduction: (R,S)-ketamine and its Metabolites as Prophylactics for the Prevention of Stress-Induced Psychiatric Disorders," highlights the potential use of ketamine in enhancing stress resilience. Groundbreaking research demonstrates that a single dose of ketamine could serve as a preventive measure against stress-induced psychiatric conditions, including major depressive disorder, post-traumatic stress disorder (PTSD), and anxiety disorders. Join me as we delve deeper into this review and explore how ketamine and psychedelic therapies may play a crucial role in psychiatry, reshaping the way we approach medicine with a more preventative mindset.
Experiencing stress stands as one of the primary factors contributing to the onset of psychiatric conditions, including major depressive disorder, bipolar disorder, premenstrual dysphoric disorder, PTSD, or anxiety disorders. Research suggests that approximately 80% of cases involving major depressive disorder can be linked to exposure to traumatic life events, such as the loss of a loved one, active combat, or a natural disaster.
Stress, in the context of mental health, refers to a state of emotional or psychological strain resulting from challenging or adverse situations. It can manifest as a response to various external pressures, demands, or changes that individuals perceive as threatening or overwhelming. Mental stress can impact cognitive functions, emotional well-being, and may lead to severe impairments in personal and work life. To provide context, it is worth noting that depression is the leading cause of disability in the United States for individuals ages fifteen to forty-four
Prolonged or excessive stress can manifest in symptoms like heightened anxiety, irritability, difficulty concentrating, mood changes, and sleep disturbances, significantly influencing both mental state and daily functioning. This chronic stress has been linked to various mental health conditions, including anxiety disorders and depression. From a medical perspective, stress can profoundly impact the body, contributing to the development or worsening of conditions such as heart disease, irritable bowel syndrome, metabolic disorders (e.g., type 2 diabetes, hypothyroidism), autoimmune diseases, and reproductive issues.
Resilience refers to the ability to bounce back from adversity, cope with stress, and adapt to challenges. It involves maintaining psychological well-being in the face of life's difficulties, setbacks, or traumatic experiences. Resilient individuals often demonstrate emotional strength, flexibility, and the capacity to recover and thrive despite facing adversity. Many individuals exhibit stress resilience, demonstrating the capacity to adapt to stressors without developing psychopathology. Building resilience can contribute to improved mental health and a more positive overall outlook on life.
Studies on mice, employing exercise and environmental enrichment to enhance resilience, have demonstrated that these measures are potent stimuli for inducing resilience. This occurs through mechanistic effects on the brain, similar to the actions of antidepressant drugs and ketamine, via a mechanism known as neurogenesis.
The authors of the review highlight that behavioral interventions, such as psychotherapy, and specific skills teaching, such as optimism, mental agility, and self-regulation, have been reported as methods for building psychological resilience, these approaches sometimes only result in a moderate decrease in rates of depressive disorders. Additionally, these methods require programs or professionals with extensive training, making them difficult to administer, given our current shortage of mental health providers and limited access for patients. Instead, the authors advocate for pharmacological or psychedelic methods to enhance stress resilience, akin to a vaccine-like approach. This is proposed as a more effective, rapid, and practical means to reduce stress-induced mental disorders.
Another key point to consider is highlighted in previous studies where prophylactic compounds such as ketamine are particularly noteworthy for their long-lasting biological effects, persisting long after the drug has been cleared from the body. Specifically, despite having an elimination half-life of two to three hours in humans, ketamine exerts prolonged protection against stress for up to an entire month after administration.
Studies on the prophylactic efficacy of ketamine using rodent subjects have revealed promising results. In chronic stress models, a single injection of ketamine in mice one week prior to stress exposure significantly reduced maladaptive behaviors, suggesting a means to enhance stress resilience. Moreover, these effects were found to be specific to ketamine and not observed with other compounds, such as serotonin reuptake inhibitors.
Interestingly, studies have demonstrated that administering ketamine one week before exposure to stressors yields a more protective response compared to administration one month or even one hour prior to the stress-inducing event. This suggests an ideal potential therapeutic window for the administration of ketamine in anticipation of a stressful event. From a practical, real-life perspective, this has intriguing implications. Consider, for instance, administering ketamine to a soldier scheduled to enter combat in a week as a means to prevent PTSD. Or, for a civilian undergoing major surgery, adopting a prophylactic approach through its use in the perioperative period could be a viable option and a game-changer for their mental health.
The prophylactic effects of ketamine appear to exhibit age differences. Studies have demonstrated that ketamine is effective in preventing stress-related behaviors in adolescent mice. Administered one week before exposure to stressors, ketamine attenuates learned fear (e.g., phobias, fear of heights, social anxiety, and PTSD), perseverative behavior (e.g., repetitive checking, counting, hoarding, routine fixation), and behavioral despair (e.g., feelings of hopelessness, social withdrawal, loss of appetite or overeating, self-harm, or suicidal behavior). Furthermore, the effects of prophylactic ketamine appear to be "extremely long-lasting" in adolescents. In contrast, ketamine does not exert such robust prophylactic effects in aged mice, aligning with clinical studies that also indicate reduced antidepressant effects in the geriatric population.
Ketamine demonstrates effectiveness in protecting against inflammatory stressors as well. In studies using rodent models, inflammatory stress was induced by the injection of pro-inflammatory agents, such as lipopolysaccharide (LPS), the major component of the outer membrane of gram-negative bacteria (e.g., E.coli and Salmonella). Normally, these pro-inflammatory agents trigger an immune response and sickness behavior. However, when ketamine was administered one week prior to LPS, results showed significantly attenuated fear behavior and behavioral despair. Overall, these findings suggest that ketamine not only protects against external stressors but also prevents behavioral consequences induced by an inflammatory response.
One application that comes to mind is the use of ketamine after a viral infection such as COVID. Far too often, we hear about the lingering, long-lasting effects of the virus, as it presents itself in Long COVID. Individuals suffering from inflammatory effects, such as cardiovascular issues (e.g., vasculitis and pericarditis), neurological symptoms (e.g., brain fog, difficulty concentrating, and headaches), and chronic fatigue and malaise, could potentially benefit from ketamine administration.
Other studies have shown that administering sub-anesthetic ketamine shortly after birth holds promise in preventing postpartum depression (PPD). Postpartum depression affects approximately 15% of mothers, making it the most prevalent complication of delivery, surpassing preterm delivery and gestational diabetes in frequency. Typically, postpartum depression arises within weeks after delivery, but about 50% of mothers may experience symptoms even before or during delivery. Furthermore, the duration of postpartum depression can extend up to a year after delivery, with symptoms sometimes lingering even longer, hence the appeal of adopting a prophylactic approach.
While it is essential to avoid using ketamine during pregnancy, it is considered a safe option postpartum, including for mothers who are breastfeeding, as long as they take appropriate protective measures. Given ketamine's short half-life, recommendations include pumping and discarding milk for at least one day prior to infant feeding after ketamine treatment.
Clinical studies on the prophylactic efficacy of ketamine indicate potential therapeutic benefits, as suggested by a lowered incidence of PTSD in burn victims treated with intraoperative ketamine. Ketamine is frequently employed in treating burn victims, for a unique reason. When individuals are exposed to fire, they may incur inhalation injuries, making them exceptionally susceptible to respiratory distress. Unlike other anesthetic agents, such as propofol, ketamine does not compromise the airway, nor necessitate the insertion of a breathing tube (intubation), making it an appealing choice when airway potency is tenuous. Furthermore, ketamine provides the added benefit of inducing pain relief (analgesia), making it an ideal option for situations requiring burn debridement. Coincidently, my first encounter with ketamine occurred during my surgical residency while performing a debridement procedure on a child burn victim.
Studies like these show great promise for the use of ketamine in a preventative medicine model, leveraging its potential protective prophylactic nature. The clinical applications of ketamine and antidepressants can extend beyond our current approach to psychiatric care, which primarily focuses on treating mental illness after symptoms have become severe enough to seek medical attention or, perhaps, in some cases, too late.
I refer again to Dr. Attia in his book titled "Outlive," where he vividly describes his reoccurring nightmare where he finds himself standing on a sidewalk, holding a basket, trying to catch eggs falling from above. Unable to catch them all, with eggs splattering on the ground, he has a realization – instead of trying better to catch all the fallen eggs, why not consider stopping the person from up above from throwing them in the first place? Indeed, we need to reevaluate how we approach mental health treatment in this day and age, where our current methods, by all standards, appear to be falling short of a long-term solution.
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