Exploring Ketamine's Impact on Depression: New Insights
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Chapter 1: Understanding Depression and Treatment Options
Ketamine has emerged as a significant player in redefining our comprehension of depression and its underlying neurological mechanisms. Experts believe that it may not only illuminate the biological roots of depression but could also pave the way for potential cures in the future.
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"Some individuals describe the sensation of ketamine as akin to feeling like a marshmallow," a therapist from the ketamine clinic conveyed to me during our initial online consultation. In my quest for understanding, I had queried various individuals about their experiences with ketamine, each offering slightly different perspectives. However, the general consensus pointed towards feelings of floatiness, possible hallucinations, and a mix of relaxation and unease. My primary concern was the prospect of experiencing a panic attack. "We can always provide you with something to ease that," the therapist reassured me.
My journey towards seeking ketamine treatment was a culmination of two decades of battling depression. I had lost touch with the feeling of wanting to live, often succumbing to the worst-case scenarios in my mind. The isolation brought on by the pandemic—such as bidding farewell to my grandmother through a screen, enduring my own COVID-19 battle despite precautions, and stepping back into the demanding role of caregiver—pressed heavily on me, igniting fears of leaving my children motherless. Thus, I resolved to seek a novel treatment.
Over the years, I had experimented with various antidepressants, including Celexa, Lexapro, Elavil, and Cymbalta, all of which failed to alleviate the turmoil in my mind. With age, my depression morphed into anxiety and panic attacks, and motherhood intensified these struggles. Yet, psychiatrists continued to prescribe the same medications. "These aren't effective," I would insist, to which they'd reply, "We must keep trying different options."
Most antidepressants operate based on the monoamine hypothesis of depression, a theory that emerged in the 1950s. This hypothesis posits that depression stems from low levels of monoamine neurotransmitters—such as serotonin, dopamine, and noradrenaline—in the brain. The premise is straightforward: enhance the levels of these neurotransmitters to combat depression.
The medications designed to achieve this fall into various categories, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and older classes like tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). They work by prolonging the presence of monoamines in the synaptic cleft, the gap between neurons, and their effectiveness is believed to relate to processes such as neurogenesis in the hippocampus—a brain region critical for learning, memory, and emotions—and the increased production of brain-derived neurotrophic factor (BDNF), which promotes neural connections. However, these effects take time, often resulting in a delayed response that can span weeks to months.
Sadly, these medications are only effective for about half of those who try them.
A 2019 review in the journal Neuron suggests that the narrow focus on neurotransmitters over the decades has limited the exploration of other neurobiological factors contributing to depression, thereby missing potential new treatment avenues. The authors noted, "There had long been clues" indicating that changes in the brain beyond monoamines were relevant to depression. For instance, BDNF levels can be influenced by signaling pathways outside monoamine pathways. While antidepressants may increase BDNF, the change is likely minimal compared to the substantial shifts needed to treat depression, shifts that other treatments, such as electroconvulsive therapy, can achieve.
It's no wonder, then, that traditional antidepressants often fall short for many. The STAR*D trial, a prominent study on antidepressant efficacy, revealed that over half of participants treated with various antidepressants continued to experience symptoms. "A significant proportion of them relapsed; it was clear these medications weren't performing as effectively as we believed," states Dr. Robert McClure, a psychiatrist and associate professor at the University of North Carolina School of Medicine.
When these medications were initially approved by the FDA, they were based on data demonstrating efficacy. "But when these studies were repeated in a more rigorous manner, divorced from the pharmaceutical industry's agenda to secure approvals, we found that the effectiveness of these treatments was overestimated," he explains.
Beyond the Monoamine Hypothesis
Recent treatments for depression, such as ketamine and psychedelics, diverge from conventional drugs targeting monoamine neurotransmitters. While not classified as a psychedelic, ketamine is an anesthetic that can induce hallucinatory and dissociative effects. According to Dr. Carlene MacMillan, a psychiatrist and co-founder of Brooklyn Minds, there may be overlaps in how these substances impact the brain.
Ketamine can rapidly induce neuroplasticity—the process of forming and strengthening connections between neurons—and it suppresses the brain's default mode network (DMN), areas linked to self-reflection and mind-wandering. "When this area quiets down, the more primitive and emotional parts of the brain can take the spotlight," MacMillan explains. "In this state, we observe new connections and shifts in perspective."
Michael Pollan's book, How to Change Your Mind, describes another perspective on psychedelics. He compares the brain to a snow-covered hill dotted with sled tracks, where the sleds represent thoughts. Over time, certain paths become worn, making alternate routes challenging. Psychedelics act like a fresh layer of snow, erasing old tracks, allowing thoughts to wander in new directions, thereby creating fresh neural pathways.
The therapist at my clinic also used the snow metaphor, suggesting that ketamine allows for new neural connections and innovative thinking. "Approach it with curiosity rather than fear," she advised.
A Game-Changer in Treatment
Ketamine is not a novel drug; it was developed in the 1960s and gained popularity during the Vietnam War as an anesthetic. "You could administer ketamine during surgery, and patients would remain completely unaware of their surroundings by essentially shutting down the cerebral cortex," explains Dr. McClure.
It wasn't until years later that researchers began to explore its potential as an antidepressant. Unlike traditional medications that focus on monoamines, ketamine operates via a different neurotransmitter: glutamate. The N-Methyl-d-aspartate (NMDA) receptor is a specific protein that responds to glutamate. Agents like ketamine, which inhibit NMDA receptor activity, have shown improvements in rodents' stress responses. Researchers at Yale subsequently discovered that ketamine alleviated major depression symptoms in humans. In 2006, it was found to be effective for individuals with treatment-resistant depression—those who had tried multiple antidepressants without success—and it also proved effective in reducing suicidal thoughts.
"This was a monumental breakthrough," says McClure. "We hadn't seen new pharmacological treatments for depression in years."
Ketamine's effects are also rapid. "Anyone who has taken an oral antidepressant knows it may take six weeks for it to take effect," McClure states. "In contrast, ketamine can yield improvements within 24–48 hours."
Due to its established nature, ketamine isn't easily patentable, prompting pharmaceutical companies to develop alternatives that mimic its NMDA receptor blockade. In 2019, the nasal spray esketamine, branded as Spravato, received FDA approval.
"Ketamine has given us a unique opportunity to observe the brain's quick transition from severe depression to improved mood within hours," MacMillan notes. "Response rates typically range between 50% and 80% for individuals receiving intravenous ketamine infusions." In comparison, Spravato also tends to outperform traditional antidepressants, with a response rate of approximately 53% to 69% after a month of treatment.
However, McClure highlights that no large-scale head-to-head trials have been conducted, making it challenging to determine which treatment is superior. Intravenous administration allows for more tailored dosing, although the nasal spray is often more likely to receive insurance coverage since intravenous ketamine is still classified as "experimental."
Not a Cure, But a Valuable Tool
Many experts consider ketamine a valuable tool for uncovering the biological underpinnings of depression and potentially paving the way for future cures. "Ketamine has granted us a rare glimpse into the brain's rapid transition from severe depression to improved mood within hours," says Dr. Chadi Abdallah, an associate professor of psychiatry at Baylor College of Medicine.
While the precise mechanisms by which ketamine affects the brain remain under investigation, researchers largely agree that it pertains to glutamate—the brain's most prevalent neurotransmitter—and the strengthening of neural connections in regions associated with depression. MacMillan likens ketamine's action to fertilizing a garden. "Ketamine swiftly enhances glutamate activity in the frontal lobe, which often underperforms in depressed individuals. This leads to the formation of new neural connections in that area and the regeneration of older ones."
Depression can cause synaptic loss, disrupting certain brain networks—networks that ketamine may temporarily restore.
At Vanderbilt University, Dr. Lisa Monteggia and her research team are diligently mapping the effects of ketamine on the NMDA receptor and its activity. These receptors play a crucial role in signaling between neurons, given their positioning at the synapse where communication occurs. "The antidepressant effects arise from being situated precisely at the junction of rapid neurotransmission changes," Monteggia explains.
Her lab has discovered that when ketamine reduces NMDA receptor activity, a cascade of events unfolds, leading to a new form of synaptic signaling—termed potentiation—via a different glutamate receptor known as AMPA. "This potentiation constitutes the antidepressant effect."
Nevertheless, ketamine does not offer a permanent solution. Instead, it provides a window of opportunity. "We're revealing the mechanisms, not fixing the underlying problems," Monteggia clarifies. Unfortunately, the benefits of ketamine are fleeting, with effects typically diminishing within 10 to 14 days.
"We utilize ketamine as a sort of Rosetta Stone to comprehend the rapid antidepressant effects," Monteggia notes, emphasizing the multifaceted nature of depression, which involves numerous genes, environmental influences, and disrupted brain circuits. "It's hard to imagine that ketamine can address all these different circuits, but it might mask the symptoms by triggering potentiation."
The challenge lies in determining how to sustain these newly formed synaptic connections.
Potential clues may emerge from other areas of depression research. "It's believed that excessive inflammation in depression contributes to the initial loss of brain connections and subsequent loss of ketamine-induced connections," Abdallah explains. His recent study found that administering rapamycin, an anti-inflammatory medication, prior to intravenous ketamine extended the antidepressant effects; remission rates at the two-week mark were higher in the pre-treatment group.
Rapamycin may have preserved new connections by reducing inflammation, but it has additional functions that could also explain the results. For instance, it promotes autophagy—the process by which cells eliminate toxic materials and debris. "This process helps clear neurons of waste, potentially aiding in the preservation of new synapses," Abdallah adds.
It's premature to conclude whether this strategy or others will successfully prolong ketamine's effects. McClure believes that research into inflammation and the microbiome may provide valuable insights into depression and its treatment. At UNC, he notes that they are investigating biological markers—measurable features of patients, such as specific protein levels—to explore additional mechanisms by which ketamine may function. "Psychiatrists are eager to identify predictors, whether through clinical characteristics or biomarkers, that could guide us in determining who will benefit from particular treatments, like ketamine."
Most studies on ketamine focus on the effects following a single infusion, yet clinical protocols usually involve biweekly infusions for at least a month, followed by maintenance treatments spaced out based on patient responsiveness. McClure mentions that some studies indicate ongoing ketamine treatment is essential for sustained remission. "This is unsurprising, as we know that maintenance antidepressant therapy is crucial for individuals with recurrent major depressive disorder to prevent relapse," he states.
Ketamine has undeniably provided me with unique experiences. I have felt like I was in the womb, a singular point in space; I have witnessed swirling mandalas, experienced the collapse of time, and felt as if I had become the ocean, with my body’s boundaries dissolving.
However, neurobiology is just one aspect of the equation. Individuals with depression may find psychotherapy beneficial alongside or after ketamine treatment. Working with a knowledgeable therapist can help individuals process their experiences and integrate new insights into their lives—something that is also recommended post-psychedelic treatments. "Engaging in therapy shortly afterward can leverage this window of heightened neuroplasticity to inspire changes in perspective," MacMillan advises. While many hope for a reduction in depressive symptoms, McClure warns that even positive change can be stressful.
What's on the Horizon?
Like many medications, ketamine will yield remarkable results for some individuals while proving ineffective for others (approximately 30% may not respond). For those like me, the effects may fall somewhere in between. After eight sessions, I cannot claim that I am free from depression, though I suspect the treatments would have been more effective without the overwhelming stress and rigidity imposed by the pandemic. However, both my husband and therapist have noted improvements, even as I remain somewhat skeptical.
Ketamine has undeniably offered me new experiences. I have felt a connection to something greater than myself, an ecstasy that engulfed me, and a profound grief that terrified me. Throughout these experiences, there has been a lingering sense of standing on the brink of a revelation.
Yet, ketamine is not the ultimate solution. Scientists like Monteggia are diligently mapping the molecular pathways and synaptic impacts of various treatments, including psychedelics, transcranial magnetic stimulation therapy, and electroconvulsive therapy. Both MacMillan and McClure affirm that these treatments can be effective for many, but finding the right provider is essential.
For Monteggia, the key element is synaptic potentiation. The more treatments or drugs capable of inducing this effect are discovered, the broader the spectrum of treatment options available. When ketamine fails to work for individuals, Monteggia suggests, "Perhaps they have some form of synaptic abnormality along this pathway. They might respond to a different drug that triggers potentiation through an alternative route." "The reasons for a lack of response can be complex, and we need to appreciate that complexity. Identifying treatment advancements for these individuals would be immensely beneficial."
I remain uncertain whether my brain will rewire or if the new synapses will wither over time. Yet, I am confident that I will never forget my myriad ketamine experiences. As Andrew Solomon, PhD, professor of clinical psychology at Columbia University Medical Center, writes in The Noonday Demon, "In depression, you do not perceive that you have donned a gray veil and are viewing the world through the haze of a bad mood. Instead, you believe that the veil of happiness has been lifted, and you are now seeing the truth."
I would argue that if depression leads you to believe you see reality as it truly is, ketamine offers a glimpse—if only briefly—of all that could be.
Chapter 2: The Science Behind Ketamine's Efficacy
The exploration of ketamine as an antidepressant continues to evolve, shedding light on its mechanisms and implications for treatment.
The first video titled "Ketamine & Depression: How it Works - Yale Medicine Explains" provides an overview of the mechanisms by which ketamine affects depression and its treatment.
The second video, "Ketamine: Benefits and Risks for Depression, PTSD & Neuroplasticity | Huberman Lab Podcast," discusses the potential benefits and risks associated with ketamine treatment for depression and PTSD.