Treatment-resistant depression: Addressing the root causes

What is treatment-resistant depression?

Treatment-Resistant Depression (TRD) refers to major depressive disorder that doesn’t respond—or only partially responds—to traditional treatments such as antidepressant medications or talk therapy. For millions, this can feel like hitting a wall, again and again. But what if the problem isn’t you—but rather the approach?

Most conventional models treat depression as a chemical imbalance. But this view is increasingly antiquated. Depression is multifactorial: it’s influenced by inflammation, gut health, trauma, lifestyle, and even subtle nutrient deficiencies. By targeting root causes comprehensively, many people can find profound relief—even after years of unchanging progress. (1, 2)

1. Uncovering biological imbalances  

Inflammation and depression

Chronic low-grade inflammation is a major contributor to TRD. Studies show that people with high inflammatory markers (like C-reactive protein) are less likely to respond to SSRIs. This makes inflammation a key—and often overlooked—target. (2)

What helps:

• An anti-inflammatory diet (rich in leafy greens, fatty fish, or antioxidants like berries)

• Avoiding processed sugar and trans fats

• Prioritizing high quality sleep and good sleep hygiene

• Gentle, consistent movement (like walking or yoga)

Nutrient deficiencies

Even mild deficiencies in nutrients like magnesium, omega-3s, vitamin B12, or vitamin D can disrupt mood regulation.

Consider being tested for:

• Vitamin D3 (especially if spending considerable amount of time indoors)

• B12 and folate levels

• Magnesium RBC or ionized magnesium

• Ferritin (especially in women)

Tip: read more here in a previous Meru Health blog post. (3)

2. The Gut-Brain axis: Balancing from the inside out

Your gut is home to over 100 trillion microbes that influence neurotransmitters like serotonin, dopamine, and GABA. Dysbiosis (an imbalance in gut flora) or intestinal permeability (“leaky gut”) can trigger neuroinflammation and depressive symptoms. (4)

Healing the gut may include:

• A short-term elimination diet to identify triggers

• Probiotic-rich foods (like sauerkraut, kefir, or kimchi)

• Prebiotic fiber (onions, leeks, artichokes)

• Targeted probiotics (e.g., strains like Lactobacillus helveticus or Bifidobacterium longum)

Working with a licensed healthcare professional who has familiarity with microbiome testing and treatments can be beneficial for bringing the gut back into balance.

3. Addressing unresolved emotional trauma

Emotional trauma is one of the most profound—yet least pharmacologically treatable—drivers of depression. In TRD, trauma may be “stuck” in the nervous system, creating a persistent fight-flight-freeze pattern. (5)

What may help:

• Somatic therapies (like Somatic Experiencing or EMDR)

• Trauma-informed mindfulness

• Body-based practices: breathwork, yoga, biofeedback (HRV-biofeedback) 

• Deep relational healing: working with a trauma-aware therapist or group

Trauma isn’t “just in your head.” It’s stored in the body—and healing often starts there.

4. Restoring nervous system balance

People with TRD often live in chronic hyper- or hypo-arousal. The nervous system gets “stuck,” impairing one’s capacity for joy, motivation, or connection.

To rewire your nervous system:

• Practice slow, nasal breathing (especially 4-7-8 breathing)

• Get 10+ minutes of morning sunlight every day

• Spend time outdoors, especially in the nature and in the forests

• Use cold exposure (like cold showers) to improve vagal tone

Tools like HRV biofeedback and mindfulness-based digital interventions (such as Meru Health’s program) can also help the nervous system reset and learn resilience. (6, 7, 8, 9, 10)

5. Reconnecting with purpose and meaning

Sometimes, depression can be a signal of a misalignment with deeper values or unmet needs. Healing means tuning into a deeper purpose—not just “fixing” the symptoms.

Ask yourself:

• What parts of me have I abandoned to survive?

• What brings me a quiet sense of joy—even if it’s small?

• Where in my life do I feel most like me?

Sometimes the most profound healing comes not from adding more treatments—but from stripping away the noise and returning to what truly matters. (11)

Final thoughts: Healing is possible

If you’ve been told your depression is “resistant,” don’t lose hope. Many people who felt stuck for years find freedom when they begin to treat depression as a whole-body, whole-life issue—not a flaw in brain chemistry.

Healing TRD isn’t about trying harder—it’s about trying differently.

Want to learn more?

At Meru Health, we combine evidence-based mental health care with root-cause healing—addressing nutrition, lifestyle, emotional processing, and mindfulness in a single, comprehensive program. We’re here for the people who haven’t given up—even when others have.

➡️ Learn how Meru Health can help you

References 

1. Berlim, M.T. and Turecki, G. (2007a) ‘Definition, assessment, and staging of treatment—resistant refractory major depression: A review of current concepts and methods’, The Canadian Journal of Psychiatry, 52(1), pp. 46–54. doi:10.1177/070674370705200108

2. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Howren et al., 2009

3. Mader, I.M. (2023) ‘Recovery from (treatment-resistant) depression after lifestyle changes and micronutrient precision supplementation: A preliminary field study in patients’, BMC Psychology, 11(1). doi:10.1186/s40359-023-01263-7

4. Randeni, N. and Xu, B. (2025) ‘Critical review of the Cross-Links between dietary components, the gut microbiome, and Depression’, International Journal of Molecular Sciences, 26(2), p. 614. doi:10.3390/ijms26020614

5. Minelli, A. et al. (2019) ‘Clinical efficacy of trauma-focused psychotherapies in treatment-resistant depression (TRD) in-patients: A randomized, controlled pilot-study’, Psychiatry Research, 273, pp. 567–574. doi:10.1016/j.psychres.2019.01.070

6. Lehrer, P.M. and Gevirtz, R. (2014) ‘Heart rate variability biofeedback: How and why does it work?’, Frontiers in Psychology, 5. doi:10.3389/fpsyg.2014.00756

7. Petrowski, K. et al. (2023) ‘Effects of post-awakening light exposure on heart rate variability in healthy male individuals’, Applied Psychophysiology and Biofeedback, 48(3), pp. 311–321. doi:10.1007/s10484-023-09581-7

8. Liu, C.-R. et al. (2023) ‘Bright morning lighting enhancing parasympathetic activity at night: A pilot study on elderly female patients with dementia without a pacemaker’, Healthcare, 11(6), p. 793. doi:10.3390/healthcare11060793

9. Scott, E.E. et al. (2020) ‘The autonomic nervous system in its natural environment: Immersion in nature is associated with changes in heart rate and heart rate variability’, Psychophysiology, 58(4). doi:10.1111/psyp.13698

10. Chen, H., Meng, Z. and Luo, J. (2025) ‘Is forest bathing a panacea for mental health problems? A narrative review’, Frontiers in Public Health, 13. doi:10.3389/fpubh.2025.1454992

11. Boreham, I.D. and Schutte, N.S. (2023) ‘The relationship between purpose in life and depression and anxiety: A meta‐analysis’, Journal of Clinical Psychology, 79(12), pp. 2736–2767. doi:10.1002/jclp.23576