For many people living with long term depression, the most painful part is not only the symptoms but the sense that nothing seems to work. Months or even years of medication and therapy can pass with little improvement, leaving individuals struggling to function at work, at home, and in relationships. This growing group of patients is increasingly recognised as facing difficult to treat depression rather than simple treatment failure.
Reflecting on this problem, Walter Paganin, PhD, explains that the way treatment failure is commonly framed has long caused frustration in both clinical practice and research. He notes that “many patients are labeled as having treatment resistant depression simply because they do not respond to standard antidepressants”, adding that this definition is narrow and often overlooks persistent functional impairment, reduced quality of life, and cognitive difficulties.
New research suggests that biology may explain why standard approaches fall short for some people. Instead of a lack of effort or poor adherence, persistent symptoms may reflect an underlying inflammatory process that conventional antidepressants are not designed to address. This shift in thinking reframes stubborn depression as a mismatch between treatment and biology rather than a personal or clinical failure. The findings were published in Clinical Neuropsychiatry.
Difficult to treat depression is broader than the traditional idea of treatment resistant depression. It includes people who continue to experience significant symptoms, disability, and reduced quality of life despite careful optimisation of care. Importantly, it recognises that improvement is not only about mood but also about daily functioning, thinking ability, and emotional engagement with life.
Paganin situates this perspective within his broader research framework, stating that “my work is grounded in the concept of difficult to treat depression, which shifts the focus from how many drugs have failed to a more relevant question, why a person continues to suffer despite reasonable and sustained treatment efforts”.
The research highlights a subgroup of patients whose depression is associated with low grade inflammation. This is measured using a blood marker called high sensitivity C reactive protein, which is commonly used in cardiovascular medicine. When levels are elevated, patients are less likely to benefit from antidepressants that mainly target brain chemicals such as serotonin.
According to Paganin, the central contribution of the paper is the proposal that “within difficult to treat depression there may exist an inflamed endotype, characterized by low grade systemic inflammation”. He explains that this is operationalised pragmatically using high sensitivity C reactive protein, supported when feasible by a small panel of pro inflammatory cytokines. He is careful to clarify that “this is not presented as a diagnostic test or a definitive biomarker of depression, but as a stratification signal that can enrich clinical reasoning and research design”.
Inflammation is not a fringe theory in mental health research. A substantial minority of people with depression show signs of ongoing immune activation, often linked to chronic stress, metabolic problems, early life adversity, or physical illness. In these cases, the immune system can influence brain circuits involved in motivation, pleasure, energy, and concentration.
People with inflammation linked depression often report particular patterns of symptoms. These include profound fatigue, slowed thinking, reduced motivation, and difficulty experiencing pleasure rather than intense sadness alone. Such features are consistent with changes in brain reward systems affected by inflammatory signals.
The research proposes a practical way for clinicians to identify this subgroup. A simple blood test can be used as an initial screen, followed by more detailed immune markers where appropriate. Paganin describes this pattern as “a mechanistic mismatch rather than a nonspecific resistance”, emphasising that persistent inflammatory signalling may help explain why standard treatments fail for some individuals.
Crucially, this approach does not suggest abandoning existing treatments. Instead, it supports combining them with strategies that address inflammation. These may include lifestyle changes such as physical activity and diet, psychological therapies that reduce stress related immune activation, and in some cases carefully selected anti inflammatory or neuromodulatory interventions.
The research also emphasises that success should be measured differently. Rather than focusing only on symptom scores, clinicians are encouraged to prioritise outcomes that matter to patients, including daily functioning, quality of life, and cognitive clarity. Paganin notes that this broader framework “encourages a more integrated therapeutic horizon, prioritizing patient centered outcomes such as functioning, quality of life, and cognition”.
While the framework is promising, it is not yet a standard clinical algorithm. Paganin stresses that “future work should focus on biomarker enriched clinical trials that test these hypotheses rigorously rather than promoting premature clinical adoption”. He also highlights the importance of ensuring that any move toward precision psychiatry remains equitable, feasible within public health systems, and embedded within comprehensive care rather than replacing it.
What this work offers is a hopeful reframing. For people whose depression has not improved despite doing everything asked of them, inflammation may help explain why and open the door to more targeted and compassionate care.