Episode 156: Can't Get Off Antidepressants? Ask for These Tests First

"There's so much hope. Depression has treatable causes we can test for."

— Dr. James Greenblatt”

Why do so many people struggle with depression? And why do they struggle to stop their antidepressants? What if it all came down to missing nutrients the brain needs to be happy?

Dr. James Greenblatt has spent 30 years in inpatient psychiatry watching patients go from one medication to two, then three, then five. Suicide rates kept climbing. Side effects stacked up. And he started asking a different question: What if we looked at what the brain actually needs? His new book Finally Hopeful explores the biological causes of depression that most doctors never test for — including vitamin D deficiency, brain inflammation, and gut dysfunction.

This conversation aligns with the Biology of Trauma^® framework about the importance of addressing biology alongside somatic work and parts work. When the body is missing raw materials, nervous system regulation becomes harder. Dr. Greenblatt's research validates what we understand: all three levels — mind, body, and biology — must be supported together for lasting change.

In This Episode You'll Learn:

• [04:09] Why Dr. Greenblatt wrote Finally Hopeful after 30 years in psychiatry

• [12:50] Vitamin D as the foundation: Why nothing else works without it — not meds, not therapy

• [14:35] How vitamin D deficiency affects serotonin production in the brain

• [12:50] Dr. Aimie's personal story: vitamin D levels of 12, then only 20 with supplementation

• [17:06] Why vitamin D deficiency is one of the most common factors in people who can't stop antidepressants

• [18:48] The gut-serotonin connection: 90-95% of serotonin is made in the gut

• [21:00] The building blocks your brain needs: iron, B12, folate, zinc, magnesium

• [24:57] Brain inflammation and its connection to suicide risk

• [26:14] Why sleep deprivation creates inflammatory markers within hours

• [32:07] The simple labs to ask your doctor about — and why testing is the only path forward

Main Takeaways

• Vitamin D Is the Foundation for Brain Chemistry: Dr. Greenblatt calls vitamin D "the foundation." Without adequate levels, the brain cannot produce the serotonin it needs — and no medication will fully work. At one addiction treatment center, 99 out of 100 patients were deficient.

• Vitamin D Deficiency Blocks Antidepressant Withdrawal: One of the most common factors in people who struggle to stop antidepressants is low vitamin D. The brain needs this nutrient to make serotonin on its own. Without it, your body doesn't know what to do when you try to stop the medication.

• Brain Inflammation Predicts Suicide Risk: Inflammatory markers are highly predictive of suicide risk. Sleep deprivation for even an hour or two a night creates measurable inflammatory markers. Head trauma, chronic infections like Lyme, and other sources of inflammation all increase risk.

• The Gut-Brain Serotonin Connection: 90-95% of the body's serotonin is made in the gut, not the brain. When vitamin D is deficient, the body produces less serotonin in the brain while producing more in the gut — creating inflammation. Someone born vitamin D deficient may have gut inflammation from day one, with profound implications for mental and physical health.

• Testing Is the Only Path to Personalized Treatment: Everyone's biochemistry is different. Guessing with supplements rarely works. Simple blood tests — vitamin D, iron, B12, thyroid, MTHFR — can reveal what your body is actually missing.

• Biology Integrates with Somatic and Parts Work: We can do the somatic work. We can do the parts work. And we can address the biology. All three are important because they're all part of our experience, our body, our life. Integration means supporting all of these pieces together.

Notable Quotes

"Vitamin D has profound effects on brain function. It is a cofactor to make serotonin." — Dr. James Greenblatt

"Vitamin D stimulates serotonin in the brain and inhibits serotonin in the gut."  — Dr. James Greenblatt

"Inflammatory markers are very predictable of suicide risk." — Dr. James Greenblatt

"My mental health depends on my bedtime."  — Dr. Aimie Apigian

Episode Takeaway

What becomes clear in this conversation is how simple some of this is. Not easy — but simple. A blood test. A nutrient level. A deficiency that has a name and a solution. Dr. Greenblatt has spent 30 years watching people lose hope in our traditional model of depression treatment. More medications. More side effects. More confusion. And all along, some of those patients were missing basic building blocks their brains needed to function.

The insight that vitamin D deficiency is one of the most common factors in people who can't get off antidepressants is significant. Your brain needs vitamin D to make serotonin. Without it, your body doesn't know how to function without the medication. This isn't about willpower or readiness. It's about biology.

This aligns with what we teach in the Biology of Trauma^® framework. The body can't regulate without the raw materials it needs. We can do the somatic work to complete protective responses. We can do the parts work to address fragmented younger parts. But when we integrate the biology — when we give the body what it's been missing — all three levels support each other. Small shifts at each level create remarkable changes together.

If you've been on medication for years and wonder why you still don't feel like yourself, this episode offers a different lens. Not to replace what you're doing, but to ask: what else might your body need? The labs are simple. The answers might be waiting in your blood work.

Resources/Guides:

• Free Guide: Top 3 Biochemical Imbalances That Affect Mood - a starting point for understanding most common imbalances connected to depression 

• The Biology of Trauma book - Get your copy here 

• Foundational Journey - The 6-week program to lay the foundation of safety and skills for self-regulation to do the deeper work.

• Dr. James Greenblatt - Get a copy of the Finally Hopeful book and find more resources at https://www.jamesgreenblattmd.com/

Related Podcast Episodes:

• Episode 41: Solutions for Low Serotonin and GABA in Trauma with Trudy Scott

• Episode 101: Brain Inflammation: Addressing The Overlooked Gatekeeper To Trauma Release with Dr. Austin Perlmutter

About the Guest: Dr. James Greenblatt is a board-certified psychiatrist and pioneer in integrative psychiatry with over 30 years of experience in inpatient psychiatric care. He is the author of multiple books including Finally Hopeful and founder of Psychiatry Redefined. His work focuses on the role of nutrition, genetics, and biochemistry in mental health treatment.

Your host: Dr. Aimie Apigian, double board-certified physician (Preventive/Addiction Medicine) with master's degrees in biochemistry and public health, and author of the national bestselling book "The Biology of Trauma" (foreword by Gabor Maté) that transforms our understanding of how the body experiences and holds trauma. After foster-adopting a child during medical school sparked her journey, she desperately sought for answers that would only continue as she developed chronic health issues. Through her practitioner training, podcast, YouTube channel, and international speaking, she bridges functional medicine, attachment and trauma therapy, facilitating accelerated repair of trauma's impact on the mind, body and biology.

How Depression's Missing Link Might Be in Your Blood Work

We've been told depression is a chemical imbalance. Take the pill. Wait six weeks. If that doesn't work, try another. But what if your brain is missing the raw materials it needs? What if it can't make those chemicals in the first place?

Dr. James Greenblatt has spent 30 years in inpatient psychiatry. He watched patients go from one medication to two, then three, then five. Suicide rates kept climbing. Side effects stacked up. He started asking a different question: What if we looked at what the brain actually needs? His findings align with what we teach in the Biology of Trauma^® framework. We can do the somatic work. We can do the parts work. But when the body is missing basic building blocks, regulation becomes harder. Biology must be addressed alongside everything else.

The Foundation Most Doctors Never Test For

Dr. Greenblatt calls vitamin D "the foundation." Without adequate levels, the brain cannot produce serotonin. No medication will fully work. No therapy will fully land. At one addiction treatment center, 99 out of 100 patients were deficient. Vitamin D is a cofactor for making serotonin. It's rate-limiting. Without it, your brain doesn't have what it needs.

I experienced this myself. During my health crash, my vitamin D level was 12. With supplementation, it came up to 20. It’s still not enough. My body couldn't absorb what I was giving it. That was when I realized something deeper was happening.

Why Some People Can't Get Off Antidepressants

Vitamin D deficiency is common in people who struggle to stop their medications. The mechanism makes sense. These medications affect serotonin activity. When you stop them, your body needs to make serotonin on its own. Without adequate vitamin D, your brain lacks the cofactor it needs. Your body doesn't know what to do. This is biology, not willpower.

The Gut Connection

90-95% of the body's serotonin is made in the gut, not the brain. Dr. Greenblatt explained how vitamin D affects each location differently. When vitamin D is deficient, the brain makes less serotonin. But the gut makes more. This creates inflammation. Someone born vitamin D deficient may have gut inflammation from day one. The implications are profound.

This connects to what we teach about the Cell Danger Response. When the body is pushed beyond capacity — or not given what it needs — cells shift into protection mode. Inflammation is part of that response. The body is doing exactly what it's designed to do. It adapted to the conditions it was given.

Inflammation and What It Predicts

Inflammatory markers are highly predictive of suicide risk. Sleep deprivation for even an hour or two creates measurable markers. Head trauma and chronic infections like Lyme increase risk through the same pathway.

Dr. Greenblatt described lying in bed with the flu once. He went through a mental checklist of his symptoms. Fatigued. Lethargic. Sad. Unmotivated. He started laughing. He had just diagnosed himself with major depression. But it was inflammation. The symptoms are identical.

This is why sleep matters. Nothing makes me depressed faster than losing sleep. The body can't build capacity when it's depleted. We talk about this in the Foundational Journey — you can't expand capacity while running on empty. Safety and rest come first.

The Path Forward Is Testing

Everyone's biochemistry is different. Guessing with supplements rarely works. Dr. Greenblatt recommends simple blood tests. Start with vitamin D, iron, B12, and thyroid. Add the MTHFR genetic test if possible. Most physicians have access to these. For B12, the norms aren't quite right. Anything under 500 should be addressed.

What This Confirms

We can do the somatic work to complete protective responses. We can do the parts work to address younger parts. And we can address the biology. All three are important. They're all part of our experience, our body, our life. When we integrate biology — when we give the body what it's been missing — all three levels support each other.

Capacity increases when the body has what it needs. The critical line shifts. What felt overwhelming becomes manageable. Not because you're trying harder. Because your system has the resources to regulate.

Start small. Ask your doctor for a vitamin D test. See what your blood work reveals.

Helpful Research

1. Vitamin D and Serotonin Synthesis Patrick, R.P. & Ames, B.N. (2014). "Vitamin D hormone regulates serotonin synthesis." FASEB Journal, 28(6), 2398-2413. Vitamin D regulates serotonin synthesis by controlling tryptophan hydroxylase 2 (TPH2) — the rate-limiting enzyme Dr. Greenblatt describes. This research explains the biological mechanism behind his clinical observation that vitamin D is "the foundation" for brain chemistry. Without adequate vitamin D, the brain cannot produce sufficient serotonin regardless of other interventions.

2. Inflammatory Cytokines and Suicide Risk Yang, Y., Gu, K., & Li, J. (2024). "Relationship between serum inflammatory cytokines and suicide risk in patients with major depressive disorder." Frontiers in Psychiatry, 15, 1422511. This research supports Dr. Greenblatt's clinical observation that inflammatory markers predict suicide risk. The study found that higher levels of IL-6, CRP, and TNF-α were associated with increased suicide risk in patients with major depression. This validates the connection he draws between inflammation and depression symptoms.

3. Gut Microbiome and Serotonin Production Yano, J.M., et al. (2015). "Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis." Cell, 161(2), 264-276. Caltech research demonstrated that gut bacteria are essential for serotonin production — supporting the 90-95% figure Dr. Greenblatt cites. In mice lacking specific gut bacteria, serotonin levels dropped by more than 50%. This research validates why addressing gut health matters for mood and why vitamin D's differential effects on gut versus brain serotonin production have such significant implications.

Listen to Episode 156 →

Disclaimer: By listening to this podcast, you agree not to use this podcast as medical, psychological, or mental health advice to treat any medical or psychological condition in yourself or others. This podcast is for informational and educational purposes only and does not constitute professional advice, diagnosis, or treatment. Always consult your own physician, therapist, psychiatrist, or other qualified health provider regarding any physical or mental health issues you may be experiencing.

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