Depression is one of the most common and most misunderstood medical conditions in the world. It is not simply sadness, weakness, or a failure of willpower. Depression is a whole-body syndrome that alters brain circuits, hormones, inflammation, metabolism, sleep, motivation, and the ability to feel pleasure and connection.

In Part 1 of this two-episode series, Dr. Ravi Kumar breaks down the biology of depression. Drawing from neuroscience, psychiatry, and personal experience, he explains what depression actually is, how it develops, and why the popular “low serotonin” explanation fails to capture the true complexity of the disease.

This episode is designed to give clarity. Understanding what is happening in your brain and body is often the first step toward hope and recovery. When depression stops feeling mysterious and personal, it becomes something that can be understood, measured, and treated.

Episode Highlights

• Why depression is not just sadness but a whole-body biological syndrome
• How depression is diagnosed using DSM criteria and the M SIGECAPS framework
• How the PHQ-9 provides an objective way to measure depression severity and track recovery
• Why depression is not a character flaw or lack of resilience
• Why the “low serotonin” theory is an oversimplification
• How reward circuits shut down in depression, leading to anhedonia and low motivation
• Why the brain’s salience network misfires, amplifying negative experiences
• How an overactive default mode network drives rumination and negative self-talk
• The role of reduced neuroplasticity and low BDNF in depressive states
• How chronic stress and HPA-axis dysregulation reshape mood circuits
• Why inflammation and metabolic dysfunction contribute to depression
• How circadian rhythm disruption worsens mood and energy
• Why loneliness creates real biological stress, not just emotional pain
• Why depression treatment often feels like it fails — and why that belief is misleading
• How understanding the biology of depression opens multiple paths to healing

Show Notes

What Depression Really Is

Depression affects mood, energy, sleep, appetite, cognition, motivation, movement, and social connection. It is diagnosed clinically using DSM criteria, not blood tests or imaging. The M SIGECAPS framework helps clinicians recognize symptom clusters that persist long enough to disrupt daily life.

Measuring Depression Objectively: The PHQ-9

One of the most useful tools discussed in this episode is the PHQ-9 questionnaire, a validated clinical scale that quantifies depressive symptoms and severity. It can serve as a baseline and a way to track improvement or worsening over time.

You can complete the PHQ-9 here: PHQ-9 Depression Questionnaire

For more details on the validation and clinical utility of the PHQ-9, see: PHQ-9 Validity: Brief Depression Severity Measure

Tracking symptoms objectively helps turn depression from something vague and overwhelming into something measurable and manageable.

Why the Serotonin Story Falls Short

While serotonin signaling changes in depression, it is only one part of a much larger network. Depression involves dysregulation across multiple neurotransmitters, brain circuits, hormones, immune pathways, and metabolic systems. Focusing only on serotonin ignores why so many different treatments can work through different entry points.

Key Brain Networks Involved in Depression

Depression quiets the brain’s reward circuitry, reducing pleasure and motivation. The salience network loses calibration, making negative experiences feel disproportionately intense. The default mode network becomes overactive, trapping people in cycles of rumination, self-criticism, and hopeless future projections.

Neuroplasticity, Stress, and Inflammation

Neuroplasticity drops in depression, making change feel harder. Chronic stress dysregulates the HPA axis and cortisol signaling, reshaping emotional control centers in the brain. In many people, inflammation and metabolic dysfunction further impair mood regulation and neurotransmitter function.

Circadian Rhythm and Social Disconnection

Sleep-wake cycles often drift out of alignment in depression, worsening energy and emotional stability. Loneliness compounds the illness by activating stress pathways and inflammatory signaling, even in people who appear socially connected.

Why Understanding Biology Creates Hope

Each disrupted system in depression also represents a point of intervention. Sleep, movement, nutrition, therapy, medication, neuromodulation, and social reconnection all act on different parts of the same network. Knowledge transforms confusion into direction.

What’s Coming in Part 2

This episode focused on the why behind depression. In Part 2, Dr. Kumar will translate this biology into a clear, evidence-based, step-by-step roadmap for recovery. That episode will outline how to prioritize treatments, layer interventions, and build a realistic plan even when motivation and energy are low.

Think of Part 2 as the ladder out of the hole.

Important Disclaimer

This podcast is for educational purposes only. Dr. Kumar is a physician, but he is not your physician. The information shared is intended to help you understand your body and mind more clearly so you can make informed decisions with your healthcare provider.

If you are experiencing depression, especially if you have thoughts of self-harm, seek professional medical care.

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Transcript

[00:00 –> 00:22] Speaker 1: On this episode of the Doctor. Kumar discovery. Because depression is not just sadness, it’s a whole body syndrome. Your mood, your energy, your sleep, your appetite, your motivation, your thinking, and your behavior are all affected. So you may have heard people say that depression is caused by low serotonin, which is a neurotransmitter in our brain and body.

[00:22 –> 00:57] Speaker 1: That idea has been repeated for decades, but the literature suggests it’s not accurate. Giving a patient a single pill and expecting it to fix an extraordinarily complex condition is simply not realistic. Depression affects multiple systems in the brain and body, and restoring balance usually requires pulling more than one lever at a time. Because I truly believe that the first part of any healing process is understanding the biology and understanding that there are real tools that can help you change your life. Knowledge creates hope, and hope creates the first spark of momentum that you need.

[00:57 –> 01:21] Speaker 1: I’m gonna help you understand the whole ecosystem of therapies so you can have an informed discussion with your doctor. My name is Doctor. Ravi Kumar. I’m a neurosurgeon in search of the causes of human illness and the solutions that help us heal and thrive. I want you to join me on a journey of discovery as I turn over every stone in search of the roots of disease and the mysteries of our resilience.

[01:21 –> 01:38] Speaker 1: The human body is mysterious and miraculous machine with an amazing ability to self heal. Let us question everything and discover our true potentials. Welcome to the Doctor. Kumar discovery. Welcome to the Doctor.

[01:38 –> 01:51] Speaker 1: Kumar discovery. My name is Doctor. Ravi Kumar. I’m a board certified neurosurgeon and assistant professor at UNC. Today, we’re talking about depression, one of the most common and misunderstood diseases on the planet.

[01:51 –> 02:10] Speaker 1: The nature of depression is hard to describe. It doesn’t always roar into your world. Sometimes it quietly sneaks up and begins to erode the very core of who you are. It can touch your personality, your drive, your sense of meaning. It feels like a force that slowly churns down the spark of life.

[02:10 –> 02:27] Speaker 1: Your inner light becomes dim, and you may not even notice you’re slipping until you’re already deep in the darkness. I like to explain depression with a simple metaphor. Imagine you’re walking down the street and everything seems fine. Then without warning, you fall into a hole. It’s deep and dark.

[02:27 –> 02:39] Speaker 1: The walls are narrow, so you can’t move your arms. You can’t see anything. You have no traction. You feel powerless and lost. After enough time in that hole, you begin to think escape is impossible.

[02:39 –> 02:49] Speaker 1: You feel isolated. You feel hopeless. You feel despair settling in. Everything that once felt good begins to fade. Food stops tasting good.

[02:49 –> 03:11] Speaker 1: Music doesn’t move you anymore. Time slows down to a crawl. Motivation evaporates, and your world shrinks. The excitement you once carried, the dreams you had for your life, the joy you expected to feel with both ordinary and extraordinary events, all begins to slip away. The world that once felt bright turns gray, and reaching out becomes too exhausting.

[03:11 –> 03:36] Speaker 1: So you pull back and life becomes smaller. Depression can be mild, like a faded version of your normal self, or it can reach the point where you no longer want to live. It’s a state where you’re alive but feel disconnected from life itself. You lose relationships, joy, and the ability to shine in ways that you were meant to in this world. And you start to believe there’s no way out because depression lies to you.

[03:36 –> 03:50] Speaker 1: It tells you that you’re stuck forever. But the truth is this, recovery is possible. People climb out every day. I was there too. I was stuck in that hole with my hands figuratively tied and my eyes closed.

[03:50 –> 04:05] Speaker 1: One moment I was walking normally through life, and the next I was trapped. But I found my way out, and you can too. This episode will be the first in a two part series. We’ll first start by learning the biology of depression. This is the why and the how.

[04:05 –> 04:38] Speaker 1: I’ve often found that the first and most important step to healing is understanding the disease itself. This gives you an objective way at observing what’s happening to you and why it’s happening to you. This perspective alone is therapeutic, and it has helped me immensely. Then we’ll discuss many of the different therapies that you can use to climb out of depression and understand the mechanisms of how they work. So by the end of this episode, you’ll understand the science of depression and the tools that can be deployed to claw your way out of the darkness.

[04:38 –> 05:12] Speaker 1: In the second part of this series, I’ll give you a detailed and evidence based road map for healing from depression and reclaiming your neurological balance. When you’re depressed, organizing, triaging, and executing plans can be near impossible and out of reach. But don’t worry, because in episode two, I’m gonna do that for you by giving you a protocolized and algorithmic map for deciding what to do and when. Think of this as a figurative ladder that I’m lowering into that hole. You’ll learn how to feel each rung beneath your feet and rise slowly back up into the world.

[05:12 –> 05:35] Speaker 1: So before we go any further, I wanna mention that this podcast is for informational purposes only. I am a doctor, but I’m not your doctor. Everything I share here is meant to give you knowledge. I want you to understand your body and your mind more clearly so you can have better conversations with your doctor and work together to solve problems. If you’re depressed, your doctor should absolutely be in the loop with any steps you take.

[05:35 –> 05:57] Speaker 1: The knowledge I share with you today is meant to give you the clarity, the understanding, and the sense of hope that will allow you to make thoughtful decisions about your health. And also, I wanna be clear that this podcast is separate from my role as assistant professor at UNC. So let’s start by defining what depression actually is. Because depression is not just sadness. It’s a whole body syndrome.

[05:57 –> 06:30] Speaker 1: Your mood, your energy, your sleep, your appetite, your motivation, your thinking, and your behavior are all affected. It’s something that has been studied intensively, and psychiatry has created a very specific criteria to help identify it. These criteria are laid out in the Diagnostic and Statistical Manual of Mental Disorders, which we call the DSM. Identification is always the first step in solving any problem, and the DSM gives us a clear way to recognize when depression is present. The DSM describes nine symptoms that define depression.

[06:31 –> 07:00] Speaker 1: To meet the diagnosis, a person needs at least five of the nine symptoms most of the day, nearly every day, for at least two weeks. One of those symptoms must be low mood, and another must be a loss of interest or pleasure, which we call anhedonia. A helpful way to remember the nine symptoms is with this mnemonic, m sig e c a p s. That’s spelled m s I g e c a p s. Let me walk you through each part of it so you can understand how broad depression truly is.

[07:00 –> 07:22] Speaker 1: The m in MCG E CAPS stands for mood. This is the low mood that most people think of, although some people experience significant mood volatility instead of just sadness or low mood. The s stands for sleep changes. This can be trouble falling asleep, trouble staying asleep, or sleeping far more than usual. The key is that it represents a shift from your normal pattern of sleep.

[07:22 –> 07:41] Speaker 1: The I stands for interest. This is the loss of interest, joy, motivation, and drive. Activities you once cared about now feel flat and unimportant. The g stands for guilt or worthlessness. This includes irrational shame, feeling like a burden to others, or blaming yourself for things you would not normally blame yourself for.

[07:42 –> 07:59] Speaker 1: The e stands for energy. People often feel drained or exhausted for no clear reason. Even simple tasks can feel completely overwhelming. The c stands for concentration problems. You may have brain fog, slower thinking, trouble focusing, difficulty making decisions, or memory problems.

[08:00 –> 08:14] Speaker 1: A stands for appetite or weight changes. You may eat far less or far more than usual. Weight can go up or down. The key is that the change has no clear explanation other than depression. The p stands for psychomotor changes.

[08:14 –> 08:37] Speaker 1: This means noticeable slowing of movement or thinking or the opposite, such as agitation and restlessness. You may not notice this symptom, but these changes are usually observable to others. The final s stands for suicidal thoughts. This can range from passive thoughts like I wish I wouldn’t wake up to active thoughts and plans to take your life. Any one of these symptoms by itself does not mean you have depression.

[08:37 –> 09:10] Speaker 1: We all experience moments of low mood, low energy, poor sleep, or stress. But when these symptoms cluster together, when they persist, and when they begin to dismantle your daily life, that’s when we diagnose depression. There’s another very simple tool that does an excellent job of helping identify depression, and that’s the PHQ nine questionnaire. It asks a series of questions based on the symptoms we just talked about and gives you a score that reflects the degree of depression, whether it’s mild, moderate, or severe. I’ll include a link to the p h q nine in the show notes for this episode.

[09:10 –> 09:27] Speaker 1: This is something we’ll come back to because the p h q nine can serve as your baseline. It gives you an objective quantitative sense of how depressed you are or how depressed someone you love might be. As you begin interventions, following that number becomes incredibly useful. You can see improvement. You can see worsening.

[09:27 –> 09:44] Speaker 1: You can see no change. Either way, you now have something measurable to guide your decisions. And unlike many other medical conditions, there’s no lab test for depression. It’s a clinical diagnosis. The PHQ nine helps us put a number on those symptoms so we can track progress in a clear and structured way.

[09:44 –> 10:06] Speaker 1: The most important thing to understand when reviewing the symptoms of depression is that these are not character flaws. They’re not signs of weakness. They’re not problems with your personality. Depression changes the way you interact with the world because something in the homeostatic balance of your brain and your body has shifted. That imbalance can happen for many reasons, and it can truly happen to anyone.

[10:06 –> 10:34] Speaker 1: It’s happened to me, and I’m generally a very resilient person. About one in five Americans will experience depression at some point in their life, and it’s prevalent around the world. Some people are naturally resistant to the changes that cause depression, but developing depression does not mean you lack resilience, and it doesn’t mean you lack grit. It simply means you’re facing a challenge that needs attention and care, and it’s a challenge you can absolutely overcome. So I hope you’re enjoying this episode so far.

[10:34 –> 10:50] Speaker 1: I have a quick favor to ask you. If you haven’t rated and reviewed this show, please head over to Apple Podcasts and let the world know what you think. This makes a huge difference in the reach of this show. The more people who leave positive reviews, the greater the reach of this podcast becomes. Okay.

[10:50 –> 11:16] Speaker 1: Let’s get back to it. So now that we know how to diagnose depression, we need to understand why it actually happens. This matters because knowing the why helps us understand ourselves, and it makes recovery feel more possible. When we understand the origin of something, it feels less mysterious and less overwhelming. So you may have heard people say that depression is caused by low serotonin, which is a neurotransmitter in our brain and body.

[11:16 –> 11:45] Speaker 1: That idea has been repeated for decades, but the literature suggests it’s not accurate. It’s an oversimplification that doesn’t hold up when you look closely at the science. Yes, serotonin is involved, and yes, there can be changes in serotonin signaling, but that’s only one small piece of a much larger picture. Serotonin is just one neurotransmitter among many. It exists in the brain, in the gut, and throughout the body, and shifts in its signaling do happen in depression.

[11:46 –> 12:20] Speaker 1: But focusing only on serotonin ignores the complexity of the entire network that becomes dysregulated in depression. Depression involves multiple body and brain systems that fall out of sync with one another. This complexity helps explain why so many different tools can be effective. Therapy, cognitive behavioral techniques, medication, exercise, and sleep all work through different entry points into the same network that has lost balance. The way I like to think about depression is as a breakdown in circuits of communication within the body and brain.

[12:20 –> 12:47] Speaker 1: These involve neurotransmitters, hormones, codependent body systems that normally keep you stable, motivated, and emotionally regulated. When these circuits lose their balance, the neurological signals that define your character and your mind don’t work properly. A good example is how your reward system goes quiet in depression. Under normal circumstances, when you do something that benefits you, you experience pleasure. That pleasure reinforces the behavior.

[12:47 –> 13:06] Speaker 1: You wanna do it again. That’s how human motivation works. But in depression, that reward system dims. Activities that once felt great, like a touch, a kiss, watching a game, hearing a song you love, or accomplishing something meaningful, no longer produce the same response. The pleasure signal drops out.

[13:06 –> 13:32] Speaker 1: The motivation drops out. The drive to reengage with the world weakens, and the things that once nourished you, inspired you, and kept you emotionally afloat start to feel distant and flat. Another thing that happens in depression is that the salience network begins to misfire. Salience simply means importance. It helps you decide what deserves your attention, what matters in the moment, and what should trigger an emotional response.

[13:32 –> 13:51] Speaker 1: When this system is working, it keeps your emotional reactions proportional and helps you move through life with a sense of stability. Think about daily life. Say something unpleasant happens. A normal reaction is, well, that wasn’t great, but I’m gonna shake it off and keep going. Your brain gives the event the right amount of weight, and then you move on.

[13:51 –> 14:04] Speaker 1: Animals are an even clearer example of how this system should work. Take a zebra. When it’s being chased by a lion, its entire world is in crisis in that moment. It could die. The threat is immense.

[14:04 –> 14:26] Speaker 1: But as soon as that lion gives up and walks off to rest, the zebra immediately goes back to eating grass. The danger was important when it was happening, but the moment has passed. The danger’s gone, and the zebra returns to baseline and doesn’t dwell on the harrowing event. Its salience network is functioning perfectly. In depression, that system loses its calibration.

[14:26 –> 14:51] Speaker 1: Positive things fail to feel positive. Negative things become far more negative than they need to be, and they stick with you preventing you from shaking it off. The emotional volume knob is metaphorically cranked up, and small things feel enormous. This is what it means for the salience network to misfire in depression. The brain is assigning the wrong level of importance to things, and that shift affects every part of how you interpret your life.

[14:51 –> 15:17] Speaker 1: Finally, there’s one more neural circuit that breaks down in depression, and that’s the default mode network. The default mode network is where your brain goes when you’re not actively focused on a task. It’s the space of inward thinking, daydreaming, remembering the past, and imagining the future. If you’ve ever seen the movie, The Secret Life of Walter Mitty, he spends most of his time in that space. I relate to that because I constantly drift into the default mode network myself.

[15:17 –> 15:38] Speaker 1: This state of mind is where we process our memories, reflect on our experiences, and think about who we are in this world. The default mode network is essential for self reflection and emotional balance. But in depression, the default mode network becomes hyperactive. It runs too hot. Instead of healthy reflection, it pulls you into rumination.

[15:38 –> 15:56] Speaker 1: You get stuck in loops of self criticism and regret and anger. You hear questions like, what’s wrong with me? Or why did I do that? Or how could they do this to me? You imagine the worst possible future, and the network doesn’t disengage, allowing you to step out of this negative swirl of ruminating thoughts.

[15:56 –> 16:13] Speaker 1: Normally, when you shift your attention to a task, the default mode network should quiet down so you can focus outward. In depression, it doesn’t wanna turn off. That internal monologue keeps running while you try to participate in the world. It becomes hard to concentrate. You feel detached or less present.

[16:13 –> 16:37] Speaker 1: You feel like you’re watching life happen from a distance. This leads to low self worth, hopelessness, mental fatigue, and social withdrawal. All of this is connected to an overactive default mode network that will not quiet when it should and spins viciously when activated. I am no longer depressed, and I still spend much of my day in the default mode network. But it’s in this world of fantastical daydreams and exciting or victorious storylines.

[16:37 –> 17:03] Speaker 1: They may take away from my productivity, but they don’t sap my happiness. And overall, it’s a very enjoyable state for me to be in. But when I was depressed, I would become trapped in a world of negative thoughts that would torment me day and night. Through trial and error and constant thought experimentation, I learned a simple trick where I could just step out of a negative swirl on command. It took me years to learn, and it’s hard to describe with words how I do it.

[17:03 –> 17:21] Speaker 1: But it’s something that you can learn with constant intention. And once you learn how to do it, stepping out of those ruminating negative thought patterns becomes very doable on command. We’ll also learn about many therapies that help quiet the default mode network. Okay. So let’s also talk about the chemical changes that we know happen in depression.

[17:21 –> 17:45] Speaker 1: One hallmark finding is that neuroplasticity in the brain drops. Neuroplasticity is the brain’s ability to adapt. It is how we form new connections, learn new patterns, adjust to new situations, and stay mentally flexible. A key driver of this process is a chemical called brain derived neurotrophic factor or BDNF. BDNF helps neurons grow, strengthen, and form new synapses.

[17:45 –> 18:10] Speaker 1: When neuroplasticity fails, as it does in depression, it becomes harder to learn, to shift gears, and to create new emotional or behavioral patterns. Life starts to feel rigid instead of adaptable. Another major factor at play is the stress system, known as the HPA axis. This stands for hypothalamic pituitary adrenal axis. This is the network that regulates your stress hormones.

[18:10 –> 18:32] Speaker 1: In many people with depression, this system is running in overdrive. Chronic stress causes cortisol to be released at the wrong times and in the wrong amounts. Sometimes cortisol stays high when it should fall. Other times, it doesn’t rise when you actually need it to. Over months or years, this chronic stress reshapes parts of the brain like the hippocampus and the prefrontal cortex.

[18:32 –> 19:04] Speaker 1: These regions are involved in memory, emotional regulation, and decision making, and they begin to adapt to a world that feels constantly threatening. We also see increased inflammation and depression. Studies show that approximately a third of people with depression have higher levels of inflammatory cytokines in their blood and sometimes in their brain. There’s also a strong association between depression and metabolic issues, such as insulin resistance and obesity. When metabolism becomes dysregulated, inflammation rises, and inflammation affects mood circuits in the brain.

[19:04 –> 19:24] Speaker 1: This is one of the reasons why lifestyle interventions that improve metabolic health often improve mood as well. Better metabolism leads to less inflammation. Less inflammation supports better emotional regulation. Circadian rhythm disruption is another common phenomenon in depression. Your circadian rhythm is your internal clock.

[19:24 –> 19:54] Speaker 1: It tells your body when it’s day, when it’s night, when you should feel alert, and when you should feel sleepy. In depression, this clock can drift out of alignment. People may find themselves awake late at night when they should be asleep and tired or sleeping during the day when they should be awake. The internal clock no longer matches the natural light cues that regulate hormones and neurotransmitters. When people with depression are able to realign their sleep wake cycles with consistent light exposure and routine, many symptoms begin to improve.

[19:54 –> 20:21] Speaker 1: The last pattern that is very common in depression is social disconnection, especially the link between depression and loneliness. Many people who are depressed feel profoundly lonely, even when they are surrounded by people who care about them. They may be married, have supportive family members, or have close friends, yet still feel completely alone. This is not a failure of their relationships. It’s a misfiring of the brain’s ability to connect socially during depression.

[20:21 –> 20:46] Speaker 1: Loneliness in this context is not just an emotional experience. It creates a real biological stress. The body responds to loneliness in much the same way that it responds to a difficult or threatening situation. Hormones shift, stress pathways activate, and the physiology of loneliness becomes part of the depressive cycle. This kind of loneliness is incredibly common in depression, and it can show up even if your life is full of people.

[20:46 –> 21:05] Speaker 1: The brain simply loses its ability to feel connected, and that loss of connection becomes another layer of the illness. So when we step back and look at why depression happens and understand the biology behind it, something important becomes clear. You realize you’re not a bad person. You’re not weak. You’re not failing.

[21:05 –> 21:39] Speaker 1: You’re just experiencing a condition that disrupts your chemistry, your rhythms, and your ability to connect with the world. And when you understand that, you can also begin to see how change is possible. If your circadian rhythm is disrupted, you can improve it with consistent sleep habits. If inflammation is contributing to your symptoms, changes in nutrition and weight can reduce that inflammation and ease the load on your brain. If your reward circuits have gone quiet, therapy and certain treatments can help rewire them and reframe the way you interpret pleasure in life.

[21:39 –> 22:00] Speaker 1: Each piece of biology that becomes unbalanced in depression also offers an entry point for healing. That’s why learning the underlying mechanisms of depression is so empowering. Once you understand what is happening, you can see that there are many ways to intervene. There are practical steps you can take, there are tools that work, and there’s a clear path forward. Okay.

[22:00 –> 22:25] Speaker 1: So now that we understand what depression is and why it happens, we need to address a very common misconception. Many people believe that depression treatment frequently fails or is not useful. This belief usually comes from personal or anecdotal experiences. A person feels suppressed, goes to their doctor, is given an antidepressant pill, and when that medication doesn’t help, they assume nothing will. But the issue is not that treatments don’t work.

[22:26 –> 22:48] Speaker 1: The issue is that taking a medication is not the most effective approach to treating depression. It may play a role, but it should never be the entire strategy. Depression is complex. It affects multiple systems in your brain and body, and effective treatments need to reflect that complexity. The real reason people feel that depression treatment fails is that our medical system is not designed properly to manage it.

[22:48 –> 23:08] Speaker 1: Primary care visits are often short, rushed, and packed with multiple concerns. Depression, on the other hand, requires time. It requires assessment, education, follow-up, and adjustments over weeks and months. It requires a plan, not a single prescription. Right now, the system pushes doctors into making one shot decisions.

[23:08 –> 23:38] Speaker 1: And then if it doesn’t work, the patient feels discouraged and hopeless. No follow-up, no adjustments, no deeper evaluation. Giving a patient a single pill and expecting it to fix an extraordinarily complex condition is simply not realistic. Depression affects multiple systems in the brain and body, and restoring balance usually requires pulling more than one lever at a time. So my message to you is that the treatments we have are effective when used in the right order and combination and with a little experimentation.

[23:38 –> 24:00] Speaker 1: I’m gonna help you understand the whole ecosystem of therapies so you can have an informed discussion with your doctor. Okay. So let’s start talking about the treatments. In depression, the first and most important place to start is with your diet and lifestyle, and that’s very hard for many people to do because they feel so helpless when they’re depressed. In that state, taking a pill just feels like the easiest solution.

[24:00 –> 24:21] Speaker 1: We live in a world where the default solution from almost any problem is medication. You swallow something, there’s a chemical reaction, and the issue improves. But depression is far more complex than that. Medication can help, and in many cases, you may eventually need it, but you wanna use it in the right setting. That’s why starting with diet and lifestyle is so important.

[24:21 –> 24:42] Speaker 1: When you optimize your diet and lifestyle, you’re leveling the terrain. Here’s a metaphor I like to use to understand this better. Imagine I ask you to push a heavy boulder to a target in the distance. In front of you is a rugged, uneven landscape, full of bumps, rocks, and hills. You have to push that boulder uphill the entire way and fight constant resistance.

[24:42 –> 25:04] Speaker 1: Now imagine you take a bulldozer and you smooth the ground. You clear the rocks, level the hills, and create a clean, flat path. When you go back to push that same boulder, the effort is completely different. The force that you apply now actually moves you towards your goal instead of being lost in a struggle against rough terrain. That’s exactly what diet and lifestyle do for depression.

[25:04 –> 25:29] Speaker 1: They level the ground. They reduce the resistance, and they make every other treatment you use more effective. If medication and therapy is the force that pushes the boulder, lifestyle is the terrain beneath it. When the terrain is smooth, the push becomes easier, more powerful, and far more likely to get you where you wanna go. So what I’m telling you is don’t discount the power of these diet and lifestyle optimizations.

[25:29 –> 25:59] Speaker 1: The first and most powerful lifestyle intervention is exercise. Exercise is one of the most reliable antidepressants we have. A massive BMJ meta analysis of more than 200 studies in over 14,000 participants showed that exercise produces moderate to large reductions in depressive symptoms. The antidepressant effect of exercise is often as strong as cognitive behavioral therapy and stronger than the most common antidepressant drugs alone. Some types of exercise perform especially well.

[26:00 –> 26:21] Speaker 1: Walking or jogging, yoga, and strength training consistently show the strongest improvements, often providing 30 to 45% more symptom reduction compared with no exercise. And one clear pattern emerges. The more vigorous the activity, the stronger the antidepressant effect. Exercise works through multiple pathways. It boosts neuroplasticity.

[26:21 –> 26:37] Speaker 1: It lowers inflammation. It improves insulin sensitivity. It reengages reward circuits that have gone quiet in depression. And when it’s done regularly, it keeps those systems all online. The sweet spot found in many studies is about a hundred and fifty minutes per week of exercise.

[26:37 –> 26:59] Speaker 1: But what matters most is consistency. Break it into daily movement. You don’t need to train like an elite athlete, but you do want your heart rate up and your muscles working. Whatever form of movement you’re willing to start with is the right starting point. Walking, resistance training, yoga, tai chi, cycling, aerobic exercise, they all reduce depressive symptoms.

[26:59 –> 27:14] Speaker 1: Even a ten minute walk helps. Do it once or twice a day and build from there as your mind begins to heal. Movement is a signal to the brain that life is happening. When movement stops, decline begins. When movement returns, the brain wakes up.

[27:14 –> 27:41] Speaker 1: And exercise remains one of the most scalable, accessible, and biologically powerful tools we have to improve depression. Another powerful intervention is recalibrating your circadian rhythm. Your circadian rhythm is your internal clock. It governs wakefulness, sleep, hormone timing, body temperature, and even mood. When this rhythm is disrupted, achieving neurological balance becomes nearly impossible no matter how many medications you take.

[27:41 –> 28:05] Speaker 1: Optimizing your circadian rhythm should be a nonnegotiable part of recovery. One of the most effective steps you can take is waking up at the same time every single morning, weekends included. Set an alarm that does not change day to day. The time doesn’t matter as long as it’s in the morning, and it still allows for you to have a functional day. As soon as you wake up, go outside and get natural light in your eyes.

[28:05 –> 28:30] Speaker 1: It doesn’t matter if it’s rainy, snowy, cloudy, cold, or overcast. Outdoor light is far brighter even on a cloudy day than indoor light and more biologically active. When sunlight hits the retinal ganglion cells in your eyes, it sends a signal to your hypothalamus. That signal triggers a healthy morning cortisol rise. It sets your melatonin clock for the evening and aligns your body with the natural world.

[28:30 –> 29:00] Speaker 1: And there’s strong clinical evidence to support the importance of this habit. A systematic review and meta analysis of 31 studies with more than 1,000 younger patients found that thirty to fifty minutes of bright morning light for five to seven weeks significantly reduced depressive symptoms. The biology is simple. Your brain needs a consistent morning light cue, just as human eyes and brains have received for thousands of years. And when it gets that cue, mood regulation becomes far more stable.

[29:00 –> 29:27] Speaker 1: At night, reduced blue light from LEDs and screens create a predictable wind down routine and cool your sleeping environment. A warm shower followed by a cool bedroom helps lower your core body temperature, which triggers sleepiness. For people with insomnia contributing to depression, cognitive behavioral therapy for insomnia is remarkably effective. I also have a full podcast on sleep where I walk you through a complete road map for improving it. I highly suggest you take a listen to it.

[29:27 –> 29:45] Speaker 1: Without good sleep, being happy is almost impossible. Nutrition is another major factor. Your diet influences brain function, inflammation, metabolism, and mood, and the principle is simple. Garbage in, garbage out. If you put garbage in your body, you’re gonna feel like garbage.

[29:45 –> 30:04] Speaker 1: That’s not just a metaphor. It’s biology, and it’s supported by thousands of studies. Ultra processed foods and refined carbohydrates drive metabolic dysfunction. When you eat these foods, your blood sugar spikes rapidly and repeatedly. Over time, this leads to insulin resistance, which increases systemic inflammation.

[30:04 –> 30:33] Speaker 1: Seed oils such as corn oil and soybean oil contribute to oxidative stress and inflammatory signaling throughout your body. And when inflammation rises, the brain follows suit. Inflammation disrupts neurotransmitter production, impairs neuroplasticity, worsens mood regulation. These metabolic shifts make depression harder to treat, and for some people, they are part of the root cause of the disease itself. Healthy nutrient dense foods do the opposite.

[30:33 –> 30:54] Speaker 1: They reduce inflammation. They stabilize blood sugar. They support mitochondrial energy production and provide vitamins, minerals, and fats your brain needs to produce neurotransmitters. In other words, healthy food produces healthy brain output. Among all the dietary patterns studied, the Mediterranean diet has the strongest evidence for improving depression.

[30:54 –> 31:23] Speaker 1: It centers around vegetables, fruits, legumes, fish, nuts, whole grains, and olive oil with minimal or no ultra processed foods. The landmark smiles trial put this to the test. In this randomized controlled study, people with major depression were assigned either to a Mediterranean style diet or to a social support group. The results were remarkable. The dietary group experienced about 2.8 times more improvement in depressive symptoms compared to the control group.

[31:23 –> 31:53] Speaker 1: They had a forty two percent reduction in depression scores versus fifteen in the control group. And thirty two percent of participants in the diet group achieved full remission from depression compared to eight percent in the control group. That means one in three no longer met criteria for depression after twelve weeks. This study essentially confirmed that food is medicine for the brain. What you eat directly shapes how you feel, and improving your nutrition is one of the most powerful ways to support any treatment you choose.

[31:53 –> 32:32] Speaker 1: Omega three fatty acids are also another key component of diet that needs to be paid attention to. Meta analyses consistently show modest but real antidepressant effects, especially when the omega three supplement is EPA dominant. The reason is simple. EPA lowers inflammation, supports metabolic health, and integrates into the brain cell membranes to improve neurotransmitter signaling and neuroplasticity. A large meta analysis, 26 randomized controlled trials with more than 2,100 participants found that omega three supplementation led to twenty to twenty five percent more improvement in depressive symptoms compared to placebo.

[32:32 –> 32:59] Speaker 1: EPA dominant formulations were far more effective than DHA alone. And pure EPA at around one gram per day produced thirty to fifty percent improvement in depressive symptoms. Omega threes work best as an add on treatment, not a replacement for therapy or medication. But their safety profile is excellent. And based on the data, there are very few people who wouldn’t benefit from taking a high quality EPA dominant omega three supplement.

[32:59 –> 33:23] Speaker 1: Omega threes work best as an add on treatment, not as a replacement for therapy or medication. But their safety profile is excellent. And based on the data, there are very few people who wouldn’t benefit from taking a high quality EPA dominant omega three supplement. I did a complete podcast episode just on omega three fatty acids. Please do yourself a favor and go back and listen to that episode.

[33:23 –> 33:43] Speaker 1: We should also talk about the gut brain axis here. The gut and your brain are in constant conversation through the vagal nerve. The gut actually contains more neurons than the spinal cord does. And when the gut becomes inflamed or dysregulated, the brain often follows. This is one of the reasons why depression so often travels with digestive symptoms.

[33:43 –> 34:17] Speaker 1: These systems are essentially wired together. Psychobiotics, which are specific probiotic strains that influence mood pathways, have shown small but meaningful benefits in clinical trials. In one randomized controlled study, when probiotics were added to standard antidepressant therapy, eighty percent of patients improved compared to forty eight percent in the placebo group. These probiotics increased beneficial lactobacillus levels in the gut and even change brain activity on imaging. If you’re looking for specific strains, lactobacillus halviticus and bifidobacterium longum have the best data so far.

[34:17 –> 35:03] Speaker 1: But I generally say the most powerful way to support your microbiome is with food, not capsules. Diets high in ultra processed foods, seed oils, and refined carbohydrates tend to feed inflammatory bacteria and increase gut permeability. This triggers immune activation, systemic inflammation, and cytokine release that can worsen mood and blunt neurotransmitter function. In contrast, whole foods, especially whole plant foods, unprocessed animal foods, and naturally fermented foods like yogurt, kimchi, and sauerkraut, reduce gut inflammation and promote microbial diversity. A healthier gut ecosystem produces more neurotransmitter precursors, more short chain fatty acids that feed the gut lining, and fewer inflammatory signals, all of which support better brain function.

[35:03 –> 35:25] Speaker 1: So the gut brain axis is not just a trendy idea. It’s a real biological pathway with measurable effects on both the microbiome and the brain, and nurturing it is a powerful part of recovering from depression. The last lifestyle factor to address is loneliness. Loneliness is not just an uncomfortable feeling. It’s a biological stress state with real physiological consequences.

[35:25 –> 35:59] Speaker 1: It predicts both the onset of depression and the persistence of depression, even after controlling for every other factor. We know that loneliness increases inflammation, disrupts immune function, and chronically activates the stress response system. In fact, large population studies show that social isolation increases the risk of premature death by around thirty percent, and strong social connection can increase survival by up to fifty percent. That’s in the same range of risk that we talk about with smoking or physical inactivity. And the connection to mental health is just as strong.

[36:00 –> 36:23] Speaker 1: Adults who rarely receive social support are twice as likely to report depression. And loneliness itself is now considered a causal factor for major depressive disorder. When you look at the healthiest and longest lived populations of the world, they all share one common thing, strong, reliable social networks. Human connection is not optional. It’s essential to our physiology.

[36:23 –> 36:51] Speaker 1: So anyone trying to rebuild their foundation should intentionally find ways to reconnect. The steps don’t need to be dramatic. Send a text message, call a friend, join a club or a walking group, sit in a coffee shop, and simply be around other humans. Even small social interactions begin to soften the stress response and reduce inflammatory signaling. Social contact is medicine, and just like any medicine, the dose you can tolerate today is the right place to start.

[36:51 –> 37:24] Speaker 1: Over time, those tiny actions accumulate and help pull you out of the isolation that fuels depression. The next category of treatment I wanna talk about is psychotherapy. When most people hear that word, they picture a psychiatrist or a psychologist sitting in a leather chair while a patient lies on a couch being analyzed in a very Freudian way. In reality, modern psychotherapy looks nothing like that. Psychotherapy is simply a structured way of reframing your thoughts, feelings, and behaviors so you can approach your life differently, and it’s remarkably effective.

[37:25 –> 37:48] Speaker 1: Many people assume that if they’re depressed, the solution must be a pill. But cognitive therapies can be as effective as medication, if not more effective than medication. And when they’re combined with medication, they often create powerful improvements that go far beyond what either approach alone can do. We know this partly through imaging studies. When people are depressed, certain areas of their brain become underactive.

[37:48 –> 38:18] Speaker 1: When they go through good psychotherapy, those same regions begin to light up and become more active. These changes correlate with improvements in mood. In other words, psychotherapy can create measurable changes in the brain. The first and most well known psychotherapy for depression is cognitive behavioral therapy or CBT. CBT is a structured therapy that helps you notice unhelpful thoughts, test them against reality, and then change the behaviors that keep depression going.

[38:18 –> 38:37] Speaker 1: It’s simple and practical. While traditionally done with a therapist, there are now digital CBT programs and apps that have shown effectiveness in clinical studies. At its core, CBT works by retraining the brain to see the world differently. When you’re depressed, you predict the worst. You think efforts won’t pay off.

[38:37 –> 38:53] Speaker 1: You assume people won’t care. You assume the future will not improve. These predictions bias you. And because you expect the worst, you start noticing only the negative events, and those negative events confirm your beliefs. This creates a self fulfilling loop.

[38:53 –> 39:11] Speaker 1: CBT breaks that loop through cognitive restructuring. You catch an automatic negative thought like, no one likes me or no one will help. Then you ask yourself, what is the actual evidence for that? Is there another way to interpret this? You imagine, what would you tell a friend in the same situation?

[39:11 –> 39:37] Speaker 1: Then you perform small behavioral experiments. For example, if you think nobody likes you, you might text one person and see what happens. When that person texts you back, it becomes a piece of real world evidence that contradicts the depression driven prediction. You then record how your mood shifts when the actual outcome does not match your feared outcome. Over time, this retrains your brain’s forecasting system.

[39:37 –> 40:06] Speaker 1: As those forecasts become more accurate, your emotional system begins to calm down. Many studies show that CBT reduces depressive symptoms as effectively as medication for mild to moderate depression. When combined with medication, it improves outcomes and lowers relapse rates. Another form of psychotherapy is behavioral activation. Behavioral activation is a structured way to shut down depression by reintroducing small, meaningful actions before motivation returns.

[40:06 –> 40:25] Speaker 1: When you’re depressed, you stop doing things because they no longer feel rewarding. Behavioral activation reverses that sequence. You act first and then allow your brain to notice the reward afterwards. You don’t wait for motivation. Instead, you actually create the conditions that bring motivation back.

[40:25 –> 41:04] Speaker 1: Even small actions can slowly wake up the reward circuits that have gone quiet. Clinical trials show that behavioral activation works as well as antidepressant medications for many people and can work as well as CBT. It is simple, durable, and can be done at home without a therapist, which is why I often recommend it as a go to strategy. In addition to CBT and behavioral activation, other evidence based therapies include interpersonal psychotherapy, acceptance and commitment therapy, and mindfulness based cognitive therapy. These can reduce depressive symptoms and help prevent relapse, and they’re typically done with a licensed therapist.

[41:04 –> 41:27] Speaker 1: So those are the psychotherapies, and they are remarkably effective. Many of them work as well as medication, and they deserve to be treated as main tools, not side tools. It’s easy to underestimate the power of talking and thinking as therapeutic interventions. But keep this fact in mind. The placebo effect alone can reduce depression by thirty percent simply because your mind believes something might help.

[41:27 –> 41:54] Speaker 1: That alone shows how powerful the mind is. When you fully harness that power with structured psychotherapies, you can create significant and lasting improvements in your symptoms. Psychotherapy should be a central part of any depression treatment plan. Another set of tools that can help you climb out of the hole of depression are supplements and herbal medications. These are sold over the counter and are not prescription drugs, but they have real biological effects.

[41:55 –> 42:18] Speaker 1: Many have been studied in clinical trials and show measurable improvements in depression. They’re not magic cures, but they can be very effective as part of a multimodal plan. The first and most well known herbal option is St. John’s wort. It’s one of the few supplements that has been studied in large, high quality, randomized controlled trials, and the results are surprisingly strong for mild to moderate depression.

[42:18 –> 42:46] Speaker 1: Many studies show that it reduces symptoms as well or better than standard antidepressant medications. In a recent meta analysis of more than 2,200 patients found that taking St. John’s wort had two point four times greater odds of improvement compared to SSRIs. And one of its biggest advantages is tolerability. SSRIs, which are the common antidepressant medications, cause sexual dysfunction, weight gain, and sensory disturbances.

[42:46 –> 43:09] Speaker 1: St. John’s wort tends to avoid these issues, which is why many people find it easier to stay on. The typical dose is around nine hundred milligrams per day split into two or three doses, and some trials go as high as eighteen hundred milligrams per day. Mechanistically, St. John’s wort boosts serotonin, norepinephrine, and dopamine, and it also appears to lower inflammation and reduce stress signaling.

[43:09 –> 43:34] Speaker 1: So in many ways, it acts like a broad spectrum antidepressant, but it comes with one major drawback. St. John’s wort dramatically increases liver enzyme activity, which means your liver breaks down other medications much faster than normal. This can make some drugs far less effective. If you’re on birth control pills, blood thinners, HIV medications, transplant medications, chemotherapy, or anti seizure drugs, St.

[43:34 –> 43:53] Speaker 1: John’s wort can actually negate their therapeutic effects. It can also cause vivid dreams or nightmares in some people. So while St. John’s wort can be very effective and is supported by real clinical data, it truly is the king of drug interactions. It must be used with caution and always with medical supervision if you’re on other medications.

[43:53 –> 44:21] Speaker 1: Personally, I’ve used St. John’s wort, and it worked amazingly for me. Another well studied botanical is saffron, the same spice used in Indian and Mediterranean cooking. It comes from the crocus flower, and several randomized controlled trials show that saffron works better than placebo and performs similarly to SSRIs from mild to moderate depression. A meta analysis of eight trials found no difference in effectiveness between saffron and standard antidepressants.

[44:21 –> 44:52] Speaker 1: And saffron caused about six percent fewer side effects. The typical dose is twenty eight to thirty milligrams per day, usually split into two doses. Its active compounds, crocin and safranol, support serotonin signaling and have antioxidant and anti inflammatory effects. Most people tolerate saffron very well, though it should be avoided in pregnancy. Saffron is one of those few herbal compounds with head to head data against SSRIs, which makes it a legitimate option for people for a natural treatment and who cannot tolerate SSRIs.

[44:53 –> 45:20] Speaker 1: L theanine is another option. This is a naturally occurring amino acid in green tea. One randomized controlled trial showed that L theanine can provide benefit when added to sertraline, which is an SSRI used to treat depression, especially if anxiety, stress, or sleep difficulty is part of the picture. It has calming and mild sedative effects. It’s not usually a primary antidepressant, but can be a useful add on when anxiety is a dominant symptom.

[45:20 –> 45:54] Speaker 1: SAM e, which stands for s adenosylmethionine, is another well studied option with consistent clinical evidence behind it. Across multiple randomized controlled trials, SAM e produces moderate but meaningful reductions in depressive symptoms, outperforming placebo and matching the effectiveness of standard antidepressants in head to head comparisons. Typical dosing is eight hundred to sixteen hundred milligrams per day. SAM e’s mechanism of action is unique. It acts as a primary methyl donor supporting methylation, which is essential for neurotransmitter production and recycling.

[45:54 –> 46:20] Speaker 1: When methylation is sluggish, mood pathways suffer. SAM e helps restore that chemical efficiency. The major caution is for people with bipolar disorder, where SAMe can rarely trigger mania. Outside of that group, it’s generally well tolerated and offers a strong evidence based alternative for people who want either a natural option or who haven’t done well on traditional antidepressants. Magnesium is another supplement that can help.

[46:20 –> 46:52] Speaker 1: Research shows modest but meaningful improvements in depressive symptoms, especially in people who are magnesium deficient to begin with. It also reliably improves sleep quality, which is often a common problem in depression. In fact, magnesium is one of my top recommended supplements for sleep. A meta analysis of seven randomized trials found that magnesium led to about a forty to forty five percent greater reduction in depression scores compared to placebo. Interestingly, lower doses, two hundred and fifty milligrams per day or less, actually performed better than higher doses.

[46:52 –> 47:24] Speaker 1: And across all studies, there was no significant side effects reported, which makes magnesium one of the safest options in this category. Magnesium supports the brain by calming the nervous system, blocking NMDA receptors, which can drive depressive symptoms, and supporting brain derived neurotrophic factor. So while it’s not a standalone antidepressant for severe cases, it’s a smart foundational supplement for anyone dealing with stress, poor sleep, anxiety, or nutritional deficiency. Vitamin d is another important nutrient. Close to half the world is vitamin d deficient.

[47:24 –> 47:53] Speaker 1: When vitamin d is low, the entire body and mind operate in a depressed physiological state. Restoring normal levels can lead to significant improvements. Some studies suggest that maintaining higher optimal levels of vitamin D may improve depressive symptoms more effectively than staying on the low end of the normal range. If you’re vitamin d deficient, correcting that deficiency is a foundational step for your overall health. I’ve done a complete episode on vitamin d alone, and it’s definitely worth taking a listen to.

[47:53 –> 48:06] Speaker 1: Okay. So those are the supplements. Let’s finally talk about the pharmaceuticals. This is my personal take based on the evidence. Antidepressants are powerful tools, but for most people, they should not be the very first step.

[48:06 –> 48:34] Speaker 1: The first step should be leveling your life’s terrain like we talked about. That means sleep, nutrition, routines, activity, connection, and basic stability of your life. If you’re in a dangerous place, suicidal or completely nonfunctional, then medication may need to come first. But if you have even a bit of room to work, leveling the ground first makes everything that follows easier. Again, think of it like trying to push that boulder up the mountain.

[48:34 –> 48:59] Speaker 1: When the ground is steep and uneven, you have to push with enormous force to get just a little bit of movement. But if you smooth the terrain first, the same boulder moves with far less effort. Depression works the same way. When your life’s terrain is stabilized, medications tend to work faster with fewer side effects and with much better results. The most common medications for depression are SSRIs and SNRIs.

[48:59 –> 49:27] Speaker 1: These stand for selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors. The original idea behind these drugs was based on the belief that depression came from low serotonin and low norepinephrine levels. We now know that the biology is far more complex, but these medications can still help by modulating those systems. To understand how they work, think about how neurons communicate. A neuron has a cell body and a long projection called an axon.

[49:27 –> 50:03] Speaker 1: At the end of the axon is the axon’s terminal, which connects to the next neuron across a microscopic gap called the synaptic cleft. Neurotransmitters like serotonin or norepinephrine are released into this cleft, cross the gap, and stimulate the next neuron. Once that signal is delivered, the neurotransmitters are usually taken back up into the original or the downstream neuron to clear the space for the next signal. SSRIs and SNRIs block that reuptake. They prevent the neurotransmitter from being pulled back into the cells so it remains in the synaptic cleft longer and stimulates the next neuron longer.

[50:04 –> 50:26] Speaker 1: Across many clinical trials, these medications outperform placebo. On average, antidepressants improve symptoms by forty percent. Placebo improves symptoms by thirty percent. So the difference between the two numbers, roughly ten percent, is the true drug effect of these antidepressants. That may sound small, but the value of these medications is not only in their symptom reduction.

[50:26 –> 50:54] Speaker 1: They also recalibrate stress circuits, reengage reward pathways, and increase neuroplasticity in the brain. These changes have been directly measured in scientific studies. And over time, these shifts help the brain move from a depressive state towards a more stable and resilient one. The medications you’ll most likely hear of are sertraline, fluoxetine, citalopram, escitalopram, and paroxetine. Even though they’re all grouped together, they’re not identical.

[50:54 –> 51:26] Speaker 1: Escitalopram, citalopram, and sertraline tend to balance effectiveness with tolerability and are often used as first line options. Fluoxetine is the most gentle in terms of side effects, but may be a little less potent for some people. Paroxetine is effective but can cause more side effects. Across the board though, all SSRIs have one core idea. They gradually increase serotonin availability, and over several weeks, this helps reset stress circuits, strengthen emotional regulation, and increase neuroplasticity.

[51:26 –> 51:52] Speaker 1: So while the timeline for improvement is similar across medications, their feel and side effect profiles can differ greatly. When you start these medications, some changes begin within the first two to four weeks, but the early changes are fairly small. The moderate improvements usually show up between weeks four and six, and the biggest improvements tend to appear between weeks six and eight. That’s when these medications reach their maximal effect. The dosing strategy is straightforward.

[51:52 –> 52:16] Speaker 1: You start with the lowest appropriate dose. If you get no response, you increase the dose. If you get a partial response, you increase the dose. If you increase the dose and still get no benefit or you experience side effects that you can’t tolerate, you switch to a different medication. There are many SSRIs and SNRIs, and the goal is to find the one that offers the best balance of benefit and tolerability.

[52:16 –> 52:44] Speaker 1: An important piece of guidance comes from the STARD trial, which was the largest antidepressant trial ever conducted. It used citalopram and found that remission rates with the first medication were about thirty percent. But the most significant insight came from the next steps. When treatment was adjusted, switched, or augmented, the cumulative remission rate rose to about two thirds of patients. This taught us that when the first medication fails, you must keep adjusting the strategy.

[52:44 –> 53:00] Speaker 1: Switching or adding treatments is not a failure. It’s the actual evidence based path to remission. Another thing to keep in mind is that these drugs do have side effects. They create real biological effects in the body. Sexual side effects are very common.

[53:00 –> 53:22] Speaker 1: People may lose their libido, and men may experience erectile dysfunction. That alone can be devastating. Weight gain is another major issue, especially with long term use. Other side effects can include gastrointestinal upset, sleep changes, emotional blunting, or a flat affect that makes people feel like zombies. Also, if their medications are stopped abruptly, withdrawal symptoms can occur.

[53:22 –> 53:50] Speaker 1: And if SSRIs or SNRIs don’t give you the benefit you hoped for despite trying multiple or if the side effects are not tolerable, there are many other antidepressant classes that can be used. The first and most well known non SSRI option is bupropion, also called Wellbutrin. This medication works very different from SSRIs and SNRIs. It’s a norepinephrine and dopamine reuptake inhibitor. Because of this, it can improve energy, motivation, and concentration.

[53:50 –> 54:09] Speaker 1: It also has fewer sexual side effects than SSRIs or SNRIs, which makes it appealing to many people. On the other hand, it can worsen anxiety or insomnia, and that’s one of its main drawbacks. It’s also one of the medications that doesn’t cause weight gain. Another option is mirtazapine. This medication helps with sleep and appetite.

[54:09 –> 54:35] Speaker 1: It increases norepinephrine release, boosts serotonin signaling, blocks certain serotonin receptors, and blocks histamine receptors. All of this produces a strong antidepressant effect and improves sleep and appetite. The trade off is that it commonly causes sedation and weight gain, which are two of the side effects that patients notice the most. There’s also vortioxetine. Vortioxetine is a serotonin receptor modulator that can both block and stimulate different serotonin receptors.

[54:35 –> 54:55] Speaker 1: It’s well known for its cognitive benefits. Many patients feel more mentally clear on it with improved awareness and reduced brain fog. It tends to be more weight neutral, which means you don’t gain a bunch of weight, and it has a lower chance of causing sexual side effects. And it’s often preferred when cognitive symptoms are the biggest issue. Tricyclic antidepressants are another category.

[54:55 –> 55:20] Speaker 1: They can be very effective for some people, especially in treatment resistant cases. But they come with more side effects and require more careful monitoring. MAOIs, which stands for monoamine oxidase inhibitors, are another option. They’re usually reserved for severe cases because they require significant dietary restrictions. People taking MAOIs must limit tyramine, which is an amino acid found in aged cheese and fermented foods.

[55:20 –> 55:46] Speaker 1: If tyramine builds up, it can trigger a hypertensive crisis. Despite this, MAOIs are remarkably effective when used correctly. In addition to these traditional medications, we now have newer treatments that show striking levels of efficacy. One of these is ketamine. Ketamine is a dissociative medication that at low doses increases BDNF, opening up a brief neuroplasticity window where mood circuits can rapidly reset.

[55:46 –> 56:12] Speaker 1: In clinical studies, IV ketamine leads to responses in about forty percent of patients within the first week. The benefit of ketamine is that it works far faster than traditional antidepressants. I’m talking within hours or days. But because ketamine causes transient dissociation or perceptual changes, it must be administered under supervision, and care must be taken to prevent misuse. Psychedelics have also shown striking results in clinical trials.

[56:12 –> 56:48] Speaker 1: A single therapeutic dose of psilocybin can produce improvements that last weeks to months, even in people with treatment resistant depression. These compounds, psilocybin, LSD, mescaline, and ayahuasca, all activate five h two a serotonin receptors, which loosen rigid neural patterns and cause BDNF levels to rise, opening a window of intense neuroplasticity. This allows the brain to update old pathways and form new ones. One of the most important effects of psychedelics is on the default mode network. That’s the same system we talked about that drives self focus and rumination.

[56:48 –> 57:18] Speaker 1: Psychedelics temporarily quiet this network while increasing communication across the brain. In clinical trials, this shift correlates with therapeutic benefit. In one study of treatment resistant depression, forty seven percent of patients responded after a single dose of psilocybin, that’s the compound in magic mushrooms, and many maintained improvements for six weeks to six months. The greater the reduction in default mode network activity, the greater the symptom relief was. There are also situations where depression arises from hormonal shifts.

[57:19 –> 57:40] Speaker 1: Postpartum depression is a clear example. During pregnancy, progesterone levels rise dramatically. Progesterone converts into a substance called allopregnenolum, which stimulates calming GABA receptors in our brains. After birth, progesterone drops rapidly, and the calming signal disappears. Without that inhibition, the brain becomes more excitable and emotional.

[57:41 –> 58:07] Speaker 1: And some women develop severe depression. This is why postpartum depression responds extremely well to neurosteroid treatments like bruxanolone and zuranolone. These medications mimic the calming effects of allopregnenolone on GABA receptors. A related condition is premenstrual dysphoric disorder, or PMDD. During the luteal phase of the menstrual cycle, progesterone rises and converts into allopregnolum, which affects the GABA system.

[58:07 –> 58:35] Speaker 1: When progesterone drops, that sudden loss of inhibition can again trigger severe emotional symptoms, including agitation, sadness, and anxiety. PMDD often responds very well to birth control regimens and SSRIs. So those are the medications and how they fit into depression treatment. They’re important tools, but they should be implemented as part of a broader strategy. And when used correctly and adjusted when needed, they can help most people find real relief.

[58:35 –> 59:02] Speaker 1: Now there’s another category of tools that can help you climb out of the hole of depression, and these are biohacks. Biohacks are simple interventions that create controlled stressors or stimulus on the body, which then nudges your brain in the right direction. In my experience, they can shift your neurochemistry very quickly and often give you a sense of forward momentum. One of the most effective biohacks I found personally is cold water immersion. This can be a cold shower or a cold plunge.

[59:02 –> 59:28] Speaker 1: When cold water hits your skin, your body releases norepinephrine, which is essentially adrenaline. This increases alertness, drive, and focus. Cold exposure also boosts dopamine and beta endorphins, which will lift your mood, and it triggers something called neurohormesis. Hormesis is a beneficial stress. So basically, cold exposure creates a small controlled stress on the brain and body, and the brain responds by restoring balance.

[59:28 –> 59:58] Speaker 1: That shift often snaps people out of a depressive mindset almost immediately. Even a simple ice cold shower can do this. You feel the adrenaline rush through your body, the endorphins release, and when you step out, you often feel a noticeable lift. You can do this several times a day with very little risk. Small studies using the Wim Hof method, which combines cold exposure with specific breathing techniques, have shown reductions in stress, anxiety, and depressive symptoms compared with active control groups.

[59:58 –> 60:26] Speaker 1: Heat therapy or sauna therapy is another intervention with surprisingly strong data. One sham controlled trial showed that a single sauna session improved mood within a week, and the effect lasted several weeks. Growing evidence suggests that sauna therapy can be a helpful add on to standard depression treatment. Heat exposure activates heat shock proteins, which improves cellular stress resistance. It reduces inflammatory cytokines, improves autonomic balance, and deepens sleep.

[60:26 –> 61:03] Speaker 1: Practical protocols include one to four sessions per week, ten to twenty minutes per session, with proper hydration and a gradual cool down. As with exercise, consistency is more important than intensity. And then there’s breath work, and this is something that I love doing and has been super beneficial for me. There are several different types of breathing techniques that directly affect your nervous system and your immune system. Examples include Tummo breathing, which involves fast breathing followed by breath holds, Sudarsan Kriya, which uses cycles of slow, medium, and fast breathing, and slow diaphragmatic breathing, which emphasizes calm, steady breaths.

[61:03 –> 61:28] Speaker 1: Meta analyses show small to moderate reductions in depression and anxiety with breath work. Sudarsan Kriya has randomized controlled trials showing reductions in stress and depressive symptoms. And Tummo style breathing, which is similar to the Wim Hof method, has shown improvements in depression compared to active breathing controls. The idea behind breathwork is that it increases your vagal tone. This acts like a parasympathetic break on your system.

[61:29 –> 61:54] Speaker 1: It calms rumination, reduces emotional reactivity, and improves your awareness of how your body feels. Breathwork must always be done safely. Never do it while you’re standing, never in water, never while driving. You should be sitting or lying down in a very secure environment. You would need to avoid hyperventilation based techniques if you have seizure disorders or other conditions that make rapid breathing unsafe.

[61:54 –> 62:22] Speaker 1: In those cases, slow breathing methods are better. Your breath is essentially a dial for your nervous system. Slow breathing, breath holds, and controlled hyperventilation can churn that dial and help quiet the negative mental loops that drive depression. So those are some of the biohacks that can meaningfully support recovery. They don’t replace therapy or medication, but they can create immediate shifts in your physiology and help move your brain back towards a state of balance.

[62:22 –> 62:55] Speaker 1: And finally, there’s another group of treatments that are reserved for severe or treatment resistant depression, and these can be extraordinarily effective. If depression is long lasting, deeply impairing, or not responding to first line steps, these interventions can often help people reach remission. One of the most remarkable and fascinating treatments is repetitive transcranial magnetic stimulation, or TMS. Our last episode was all about TMS, and if you haven’t listened to it yet, you should definitely go back and give it a listen. TMS uses a magnetic coil placed over the scalp.

[62:56 –> 63:25] Speaker 1: There’s no surgery, no disruption of the skin or tissue. The coil creates focused pulses of magnetic energy that changes the electrical activity in your brain in mood regulating circuits without the need for anesthesia. TMS is FDA cleared for major depressive disorder when someone has not improved after at least one antidepressant trial. It’s widely used in treatment resistant depression. The target area is usually the left prefrontal cortex, which is a control hub for emotion and reward processing.

[63:26 –> 63:58] Speaker 1: In depression, this region often shows low activity on functional imaging. When the magnetic coil stimulates this area repeatedly, it increases neuron firing and connectivity and helps rebalance the reward networks in the underactive pathways that are linked to depression. Meta analyses show that TMS outperforms sham stimulation with meaningful responses and remission rates. And there’s a five day protocol based on a study out of Stanford called the SYNC protocol. And in this randomized controlled trial, remission from depression was seventy nine percent with this therapy.

[63:58 –> 64:26] Speaker 1: And at six months out, seventy five percent of patients maintained their benefit. These results far outperform medications and with almost no side effects. TMS has a very low complication rate and does not cause cognitive or memory side effects. It is a remarkably underutilized treatment that can make substantial difference in the right patients. The next treatment, can save lives, is called electroconvulsive therapy, or ECT.

[64:26 –> 64:53] Speaker 1: For patients with suicidal depression, ECT is lifesaving. When I was a medical student on my psychiatry rotation, I was assigned to ground on a woman who was profoundly depressed. She had attempted suicide multiple times in a single month and was utterly devastated by depression. She had failed many treatments, and the psychiatrist I was mentoring under recommended ECT. We brought the woman into a treatment room and placed her under general anesthesia.

[64:53 –> 65:18] Speaker 1: The psychiatrist took two handheld electrodes and squeezed them on the side of her temples and gave her an electric jolt. We monitored her brain waves on EEG as the electricity sent the brain into a generalized seizure. After about thirty to sixty seconds, the anesthesiologist administered a medication that terminated the seizure. She received the ECT twice each week. Gradually over the next several weeks, her depression lifted.

[65:18 –> 65:28] Speaker 1: The transformation was remarkable. She was smiling. She was engaged. She felt alive again. She was able to go home, and the improvement was not from medication.

[65:28 –> 65:44] Speaker 1: It was from carefully induced controlled seizures that reset her brain’s networks. During treatment, she was slower cognitively. But after the ECT course ended, her thinking returned to normal. She was no longer suicidal and no longer depressed. It literally saved her life.

[65:44 –> 66:11] Speaker 1: But ECT does carry risks. Memory impairment and short term cognitive effects can occur, especially during the treatment period. And because of these risks, ECT is usually reserved for severe life threatening or treatment resistant depression after all other options have been tried. Another modern approach is neurofeedback. Neurofeedback uses real time EEG or fMRI, which is functional MRI, to show the patient what their brain is actually doing.

[66:12 –> 66:46] Speaker 1: The patient then practices mental strategies such as reappraising negative thoughts, imagining calming scenes, emotional distancing, slow breathing, or recalling positive memories. When they see their brain activity change in response to these internal strategies, they learn how to influence their own neural patterns. Seeing your brain respond to your thoughts creates a powerful loop of self regulation. People can also visualize future goals, imagine social connection, or practice gratitude while watching their brain activity shift. The effects are modest but meaningful.

[66:46 –> 67:13] Speaker 1: Randomized controlled trials show reductions in depressive symptoms with neurofeedback, and it can be a helpful part of a multi part treatment plan. Okay. So that was a lot of information, and I don’t expect you to remember it all. But to sum it up, we talked about what depression is, how it happens, why it happens, and we walked through the wide range of therapies that can help you climb out of the hole. And believe it or not, I didn’t even cover all the treatments.

[67:13 –> 67:55] Speaker 1: What I really want you to get from this episode is a general understanding of the hows and the whys because I truly believe that the first part of any healing process is understanding the biology and understanding that there are real tools that can help you change your life. Knowledge creates hope, and hope creates the first spark of momentum that you need. In the next episode, I’m gonna take everything we discussed today, plus some more interesting and effective therapies, and turn it into a clear step by step road map for recovery. I know I just gave you a huge amount of information, and when you’re depressed, organizing that information and churning it into action is 10 times harder than it would be normally. I understand that.

[67:55 –> 68:15] Speaker 1: So in the next episode, I’m gonna do the heavy lifting for you. I’ll lay out the plan that you can follow. I’ll even have a printable version for you on my website so you can take it to your doctor, you can use it as a guide, and you can use it to climb out of the hole one step at a time. Think of it like the rungs of a ladder. You don’t have to leap out of your hole.

[68:15 –> 68:37] Speaker 1: You just put one foot above the other, one rung at a time, and you will rise. So before we end today, I do have some homework for you. These are small but powerful steps that start to shift your biology in the right direction. First, I want you to complete the p h q nine questionnaire. The link will be in the show notes and on my website, but you can also just Google it.

[68:37 –> 68:58] Speaker 1: This gives you a starting score. Without measuring your depression objectively, it’s hard to know whether you’re improving. This score will be your baseline. And as you begin your journey, you will see how it changes over time. Second, I want you to wake up at the same time every single morning, Monday, Tuesday, Wednesday, Thursday, Friday, Saturday, and Sunday.

[68:58 –> 69:10] Speaker 1: Pick a time that works for you. Five in the morning is fine. Nine in the morning is fine. What matters is consistency. When you wake up, I want you to go outside and get sunlight in your eyes immediately.

[69:11 –> 69:30] Speaker 1: Not through a window, not through a screen, not through a windshield. You need to go outside. Cloudy, sunny, hot, cold, it doesn’t matter. Give yourself ten to thirty minutes of natural light in your eyeballs first thing in the morning. This resets your circadian rhythm, improves your energy, and regulates your mood.

[69:30 –> 69:49] Speaker 1: Third, I want you to move your body every day. At least twenty minutes of dedicated physical activity every single day. Walking, yoga, biking, resistance training, tai chi, anything that keeps you moving. Physical activity is one of the most reliable antidepressants we have. Start with something you’re willing to do and build from there.

[69:49 –> 70:08] Speaker 1: Fourth, I want you to clean up your diet or at least start. Remove all processed foods. Take out refined carbohydrates and especially seed oils. If you haven’t listened to my episode on seed oils, you should go back and listen to it. The food industry wants you to think that these seed oils are okay, but basic chemistry and biology tell a much different story.

[70:08 –> 70:38] Speaker 1: Seed oils and refined carbohydrates are highly inflammatory and can worsen metabolic health, which directly affects your brain and your mood. Focus on whole unprocessed foods as much as possible. Finally, I want you to ask your doctor to check five labs if they haven’t recently been checked. Your vitamin d level, your b twelve and folate levels, a CBC, and your thyroid function. Deficiencies or imbalances of these can cause or worsen depressive symptoms, and they are simple and easy to treat once identified.

[70:38 –> 70:58] Speaker 1: So that’s your homework for the week. These steps may feel small, but they begin to shift your brain and your body towards healing. And when we meet again in part two, I’ll walk you through a complete road map for recovery, something you can print, follow, and share with your doctor. So until then, stay curious, stay skeptical, and stay healthy. Cheers.

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