February 11, 2026
Metabolic dysfunction may drive treatment-resistant depression through inflammation, insulin resistance, and impaired brain energy.
Treatment-resistant depression (TRD) is commonly defined as major depressive disorder that does not adequately respond to at least two trials of antidepressant medication. While this definition is widely used, it often overlooks a critical reality: many cases of non-response are driven by underlying metabolic and systemic factors rather than purely psychiatric ones.
From an integrative psychiatry perspective, treatment-resistant depression is not simply a disorder of neurotransmitters but a condition involving energy metabolism, inflammation, hormonal signalling, and brain-body communication. Understanding these metabolic contributors can expand treatment options and restore hope for individuals who feel they have “tried everything.”
The concept of resistance in psychiatry differs from resistance in infectious disease or oncology. In depression, resistance does not imply that the brain is actively rejecting medication, but rather that the biological environment required for medications to work is impaired.
In clinical practice, apparent resistance may reflect:
These mechanisms help explain why individuals with depression, anxiety disorders, bipolar disorder, OCD, trauma-related conditions, or eating disorders may fail to respond to standard treatments despite adherence and appropriate dosing.
The brain is one of the most metabolically active organs in the body, consuming a disproportionate amount of glucose and oxygen. When metabolic processes are disrupted, the brain’s ability to regulate mood, cognition, and stress response is compromised.
Integrative psychiatry views depression as a whole-system condition, recognising that metabolic health directly influences:
This framework is especially relevant for individuals experiencing chronic depression or non-response despite high-quality psychiatric care.
Insulin plays a critical role in brain function, influencing glucose uptake, synaptic plasticity, and neurotransmitter balance. When insulin resistance develops, brain cells may struggle to access sufficient energy even when blood glucose levels appear normal.
Research suggests insulin resistance is associated with:
For patients receiving care for depression through integrative models such as those used in https://www.integrative-psych.org/nyc/depression, metabolic screening can uncover treatable contributors that standard psychiatric evaluations may miss.
Mitochondria generate ATP, the energy currency required for neuronal signalling and brain repair. In treatment-resistant depression, mitochondrial dysfunction can lead to persistent symptoms even when neurotransmitter levels are pharmacologically targeted.
Low mitochondrial efficiency may contribute to:
Addressing mitochondrial health through nutrition, lifestyle interventions, and targeted supplementation may enhance both medication response and engagement in therapies such as CBT, ACT, or EMDR.
Chronic low-grade inflammation is one of the most consistent biological findings in treatment-resistant depression. Elevated inflammatory markers can alter neurotransmitter metabolism, increase glutamate activity, and impair neuroplasticity.
Inflammation has also been linked to:
For individuals seeking care for anxiety, OCD, or trauma-related disorders, integrative treatment approaches such as those offered through https://www.integrative-psych.org/nyc/anxiety, https://www.integrative-psych.org/nyc/ocd, and https://www.integrative-psych.org/nyc/trauma-ptsd often incorporate attention to inflammatory and stress-related pathways.
The gut microbiome plays a central role in immune regulation, nutrient absorption, and neurotransmitter production. Disruptions in gut health can influence mood, cognition, and treatment response.
Gut-brain dysregulation has been associated with:
Patients with complex presentations, including ADHD or eating disorders, may benefit from coordinated care models such as those reflected in https://www.integrative-psych.org/nyc/adhd and https://www.integrative-psych.org/nyc/eating-disorder.
Hormones such as cortisol, thyroid hormones, estrogen, and testosterone have direct effects on mood regulation and metabolic function. Chronic stress, trauma exposure, or postpartum changes can disrupt these systems, contributing to depressive symptoms and non-response to medication.
Nutrient deficiencies, including B vitamins, iron, magnesium, zinc, and omega-3 fatty acids, can further impair neurotransmitter synthesis and mitochondrial function. These factors are especially relevant in populations experiencing trauma, postpartum mood disorders, or chronic stress.
Evidence-based psychotherapies remain essential in the treatment of depression and related conditions. However, their effectiveness can be limited when underlying metabolic barriers are unaddressed.
Modalities such as:
may be significantly more effective when combined with metabolic and biological optimisation. Integrative models of care, including https://www.integrative-psych.org/nyc/cbt, https://www.integrative-psych.org/nyc/dbt, https://www.integrative-psych.org/nyc/act, and https://www.integrative-psych.org/nyc/emdr, reflect this multidimensional approach.
Reframing treatment-resistant depression as a potentially metabolically mediated condition expands both assessment and treatment options. Rather than escalating medications alone, integrative psychiatry encourages clinicians to evaluate systemic contributors and tailor care accordingly.
This approach may be especially valuable for individuals with co-occurring conditions such as bipolar disorder, schizophrenia, borderline personality disorder, addiction, or trauma-related disorders, where symptom complexity often reflects overlapping biological and psychological processes.
Integrative Psych is a national integrative psychiatry practice serving individuals across the United States through both in-person and virtual care. The clinic combines psychiatric expertise with evidence-based psychotherapy and whole-person assessment to address the biological, psychological, and social factors influencing mental health. To learn more about its team of clinical experts and comprehensive treatment offerings, visit https://www.integrative-psych.org/ or explore https://www.integrative-psych.org/top-psychiatrists-therapists-integrative-psych-nyc.
We're now accepting new patients
