Understanding the Biology of Depression—and How Ketamine Can Help

April 8, 2024 by Steve Suntala

We hear the word “depression” often in our day-to-day lives, and it comes up in many contexts: clinically, casually, and culturally. But what does it mean?

Though it’s a complicated topic even on face value, depression is generally characterized by pervasive sadness, loss of interest, and a suite of cognitive and physical symptoms. This is a complex interplay of biological processes. 

Understanding those processes (in order to treat them) requires at least a basic understanding of the brain’s structure. This includes neurotransmitter dynamics, genetic factors, and the influence of external stressors.

This article will explore the biology of depression and the actual effects of depression experienced by individuals. Then we’ll get into the role that ketamine may play in counteracting that biology.

Want a quick summary? Here are three frequently asked questions about the biology of depression:

What is the traditional understanding of depression’s biological basis? For a long time, researchers believed that depression is linked to a deficit in certain brain chemicals that are essential for mood regulation, motivation, and handling stress. More recent research indicates that the issue might also involve a more complicated matter: the sensitivity and density of neurotransmitter receptors and the efficiency of their release.

How does the structure of the brain influence depression? The limbic system, particularly the hippocampus and amygdala, plays a significant role in depression. For instance, an overactive amygdala can lead to heightened emotional responses and negative perceptions, contributing to depressive states.

How does ketamine counteract the biological underpinnings of depression? Ketamine acts rapidly, primarily affecting glutamate, an essential neurotransmitter for neuroplasticity and brain connectivity. By enhancing glutamate activity, ketamine promotes the formation of new neural connections, potentially rewiring brain areas affected by depression. It may also normalize stress response systems and have anti-inflammatory effects, addressing several biological aspects of depression simultaneously.

Interested in a free consultation on ketamine treatments? If you’d like to pursue this journey, we have locations in Cleveland, Columbus, and Cincinnati.

The Biology of Depression 

Neurotransmitter Dynamics

For a long time, conventional wisdom held that depression stems from a shortage of certain brain chemicals. Those chemicals included neurotransmitters like serotonin, dopamine, and norepinephrine. Each of those chemicals is important because they help our brains send messages and control how we feel, what we want to do, and how we deal with stress. 

Think of serotonin as the “happy chemical” that makes us feel good and calm. Dopamine is like the brain’s reward system—it makes us feel pleasure when we enjoy something. Norepinephrine helps us focus and deal with stress, kind of like an internal alarm system that tells us to pay attention.

You need all of them in proper doses to be happy and productive!

Recent research suggests, however, that the matter of depression may not lie in the quantity of neurotransmitters alone but in the sensitivity and density of their receptors. If the brain does not efficiently release neurotransmitters, this can cause problems.

In short, when you’re depressed, the balance of those chemicals may be off

The Brain’s Emotional Centers

Deep inside your brain is an area called the limbic system: mission control for your emotions. 

Two parts of the brain, the hippocampus and amygdala, play influential roles in depression. 

The hippocampus, part of the limbic system, is involved in memory formation and mood regulation. Studies have examined the question of whether individuals suffering from depression have a smaller hippocampus, which would impair their ability to regulate emotions effectively. 

In those cases, the individual’s toolkit just may not have the right neural tools to manage those emotions. The chicken-and-egg debate over hippocampus size and depression has not entirely been resolved, however. Nonetheless, the role of the hippocampus is important to understand. 

Similarly, for those suffering depression, the amygdala can become hyperactive, leading to a heightened state of emotional arousal and a skewed perception towards negative experiences. The amygdala is like an alarm that goes off too much, making everything seem more scary or sad than it should. 

It’s in the Genes… Sort of

The heritability of depression, estimated at nearly 40% based on twin studies, cannot be overlooked.

But don’t rush to call your parents just yet: Studies have not identified a single “depression gene,” per se. Rather, it’s believed that multiple genes interact with environmental factors to increase susceptibility. These genes may influence neurotransmitter systems, stress response mechanisms, or neuronal plasticity.

Research is ongoing. Epigenetics, the study of how genes can be turned on or off by environmental factors without altering the DNA sequence, has emerged as a crucial area in depression research. Stressful life events, for example, can lead to epigenetic modifications that alter the expression of genes related to the stress response, potentially contributing to the onset of depressive episodes.

Inflammation and Feeling Down

An intriguing area of research links depression to increased levels of inflammation and abnormalities in the immune system. 

Our bodies fight illness with a process called inflammation, which is good in small doses. But when there’s too much for too long, it can affect the brain and contribute to depression. It’s like the body’s defense system is working a bit too hard and ends up attacking its mood control centers by mistake.

Gut Feeling

Recent studies suggest that the gut-brain axis, the two-way communication line between the gastrointestinal tract and the central nervous system, is a significant player in depression. Believe it or not, your gut talks to your brain. 

If the good bacteria in your stomach are out of balance, it can send signals that mess with your mood. Eating healthy might help keep these bacteria happy, which could make you feel better, too. 

Stress and Brain Flexibility

Then there’s the simple matter of stress. You can see that process playing out biologically, too, in those suffering depression. Life’s stress can change how your brain works. 

When stressed, our bodies make a hormone called cortisol. A little bit helps us deal with emergencies, but too much for too long can wear out parts of the brain that help us manage our mood and make it harder for the brain to adapt or heal.

The Experience of Depression

The National Institutes of Health (NIH) reports that major depression is relatively common in the U.S. But that doesn’t mean it’s any less detrimental. 

“Major depression can result in severe impairments that interfere with or limit one’s ability to carry out major life activities,” the NIH’s National Institute of Mental Health states

According to the NIH’s 2022 National Survey on Drug Use and Health, one in 11 U.S. adults had experienced a major depressive episode that year (8.8% of the adult population). 

The NIH explains the symptoms of major depression: “If you have been experiencing some of the following signs and symptoms, most of the day, nearly every day, for at least two weeks, you may be experiencing depression:”

  • Persistent sad, anxious, or “empty” mood
  • Feelings of hopelessness or pessimism
  • Feelings of irritability, frustration, or restlessness
  • Feelings of guilt, worthlessness, or helplessness
  • Loss of interest or pleasure in hobbies and activities
  • Decreased energy, fatigue, or feeling slowed down
  • Difficulty concentrating, remembering, or making decisions
  • Difficulty sleeping, waking early in the morning, or oversleeping
  • Changes in appetite or unplanned weight changes
  • Physical aches or pains, headaches, cramps, or digestive problems that do not have a clear physical cause and do not go away with treatment
  • Thoughts of death or suicide or suicide attempts

Those symptoms are all important to understand and monitor, but it’s perhaps the quality of “hopelessness” that drives the dynamics of depression. 

In a state of hopelessness, the individual sees no remedy, no alternative. This compounds the mental health problem and makes it that much more difficult for someone to reach out and attempt a solution.

This is where ketamine therapy offers something critical to the U.S. population suffering from major depression: hope.

How Ketamine Addresses the Biology of Depression

Ketamine, originally used as an anesthetic, has emerged as a novel treatment for depression, working through mechanisms quite distinct from those of traditional antidepressants. 

Its rapid action on depression is primarily attributed to its effect on glutamate, the most abundant excitatory neurotransmitter in the brain, unlike traditional treatments that target serotonin and norepinephrine over longer periods. Ketamine quickly enhances glutamate activity, facilitating the growth of new neural connections, essentially rewiring parts of the brain that are impaired by depression. 

This process promotes something called “neuroplasticity,” which allows the brain to form new, healthy neural connections. This is critical because depression often leads to a weakening of these connections.

Moreover, ketamine might help normalize the stress response system in the body. In depression, the biological forces in that stress response system can generate excessive cortisol and subsequent brain function impairment. 

Its potential anti-inflammatory effects also play a role in combating depression, as increased inflammation is linked to depressive symptoms. 

While research into ketamine’s effects on hormonal balance and the gut-brain axis is ongoing, its overall rapid and significant antidepressant effects make it a promising option for treatment-resistant depression, showcasing its ability to counteract various biological factors underlying depression.

This multifaceted action makes ketamine a powerful option for treating depression, especially in cases where traditional treatments have failed.

Interested in a free consultation? If you’d like to pursue this journey, we have locations in Cleveland, Columbus, and Cincinnati.

At New Pathways Clinic our heartfelt mission is to establish a holistic mental wellness campus that touches the lives of individuals in the greater Cleveland, Columbus, and Cincinnati regions. We are dedicated to combining state-of-the-art mental health treatments, like Ketamine therapy infusions and Spravato nasal spray, with the expertise of compassionate mental health professionals to treat depression, anxiety, PTSD, migraines, and bipolar disorder.

Our unwavering commitment drives us to continuously evolve and adapt as the scientific landscape of ketamine research expands and diversifies, leading to innovative mental health treatments. We are determined to pave the way for a healthier future for Cleveland, central Ohio, and southern Ohio.

New Pathways Clinic also offers Semaglutide & Tirzepatide weight-loss shots, ketamine-assisted psychotherapy, and  ketamine/Spravato support groups for patients.

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