Difficult-to-treat Depression in Public Mental Health Services: A Hypothesis for Integrating Inflammatory Stratification into Clinical Management

Abstract

Approximately a quarter of patients with major depressive disorder have low-grade systemic inflammation, with higher
rates in difficult-to-treat subgroups; service-level prevalence within European public mental health services for difficultto-
treat depression (DTD) remains undetermined. Emerging data suggest that inflammation does not operate as a simple
linear cause of major depressive disorder, but rather as a modulator of corticostriatal circuits, altering reward processing,
effort–cost estimation, feedback-based learning and decision-making. This can give rise to a depressive phenotype
characterized by motivational anergia, effort avoidance, attenuated responsiveness to conventional treatments, frequent
relapse, and a substantial burden for patients, clinicians and services. In this viewpoint we propose an operational model
for community mental health services based on: (1) a pragmatic and accessible inflammatory stratification pathway using
a focused biomarker panel (high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)
and interleukin-1β (IL-1β); (2) the integration of a circuit-based perspective into the functional formulation of DTD; and
(3) the reorganization of community and outpatient mental health provision around point-of-care biomarker testing,
standardized protocols, and explicit attention to equity of access. Unlike existing frameworks that require specialist
biomarker infrastructure, this model articulates a tiered pathway in which point-of-care hs-CRP is feasible at community
level, within routine publicly funded provision, while IL-6, TNF-α and IL-1β phenotyping is reserved for district specialist hubs.

Full Text

Introduction

Major depressive disorder affects approximately 5% of the global population and remains one of the leading causes of years lived with disability worldwide1. Lifetime prevalence estimates range from 8.1% to 11.2% in low- and middle-income countries and approach 13% in high-income countries, underscoring the substantial and pervasive burden of this condition across different healthcare contexts^1,2. Despite the availability of evidence-based interventions, including stepped-care models, structured psychotherapies and neurostimulation techniques, access to these treatments remains disproportionately concentrated in healthcare systems with greater economic and organizational resources2 [1]. Clinically, a substantial subgroup of patients, estimated at 20% to 35% of those receiving treatment, fails to achieve sustained remission despite adequate pharmacological trials, thereby meeting criteria for treatment-resistant depression (TRD) [2]. Compared with TRD, the introduction of the newer construct of difficult-to-treat depression (DTD) represents a conceptual advance that shifts clinical attention from mere pharmacological non-response towards the broader multidimensional complexity of the depressive clinical picture. This defines the condition on the basis of the overall clinical profile rather than solely on failure to respond to antidepressant pharmacotherapy [3–6].

DTD is a condition associated with substantial clinical and social impact, characterized by persistent symptoms, functional impairment and inadequate response despite appropriately delivered treatment [3].

Prevalence and global distribution of difficult-to-treat depression

Systematic prevalence figures for DTD as such have not yet been established, as the construct is operationally recent and documented primarily in research settings, with few real-world studies available to date. However, assessment of the burden of DTD is unlikely to be uniform across countries and the construct is likely underestimated in resource-constrained settings, including several European healthcare systems, such as Italy, where marked regional variability in access to specialized mental health services may influence recognition, treatment intensity, and continuity of care. The clinical impact of DTD includes [3, 4]:

• persistent depressive symptoms with low remission rates and protracted episode duration;

• residual symptoms, in particular anhedonia, motivational deficits, cognitive fatigue and insomnia, that persist between episodes and predict relapse;

• elevated suicide risk relative to treatment-responsive depression; 

• increased medical and psychiatric comorbidity, including metabolic and cardiovascular diseases.

The social impact includes [3, 4]:

• increased healthcare expenditure, since patients with difficult-to-treat depression require multidisciplinary and personalized interventions, with consequent demands on healthcare resources and personnel;

• high caregiver burden and strain on the family system;

• disability and lost productivity, as the persistent and refractory nature of DTD impairs occupational functioning, leading to absenteeism and unemployment.

Rationale for a public mental health services perspective

Three prerequisites justify locating the present model within publicly funded community psychiatry. First, in most European jurisdictions, the national health systems are the principal point of reference for the long-term care of patients with chronic and disabling depressive disorders [7]. Second, although only a small proportion of patients with major depression develop DTD, this subgroup accounts for a disproportionate share of long-term depression-related costs [8], making it a priority for service-level resource allocation. Third, immunopsychiatric stratification pathways currently remain confined to specialist or research settings [9], generating an implementation gap that risks widening rather than narrowing health inequities if not deliberately addressed. Translating biomarker-guided care into routine public-sector practice is therefore not an incidental application but a structural priority of the present proposal. The identification of DTD requires systematic assessment of the factors that characterise it and complicate its management [6]:

• psychiatric comorbidities and/or general medical conditions, such as anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, substance use disorders, chronic pain syndromes, metabolic syndrome, cardiovascular disease, hypothyroidism and chronic inflammatory conditions;

• variability in symptom profile, in particular the presence of anhedonia, anxiety and insomnia;

• history of significant emotional trauma in childhood;

• problems with treatment adherence;

• nature, number and sequencing of previous failed treatments;

• psychosocial dysfunction and disability.

Considering the possibility of low-grade inflammation in DTD may support biologically informed stratification proposals [10]. However, the implementation of immunopsychiatric models in European national healthsystems and particularly within Italian publicly funded community mental health services remains hindered by preanalytical variability, cost, limited standardization, and the risk of widening territorial inequities in access [11]. Although several etiopathogenetic models of depression have been proposed, the neuroinflammatory framework offers a more integrative perspective by linking immune dysregulation with early-life adversity, chronic stress, metabolic dysfunction and impaired neuroplasticity. This model is particularly relevant to DTD because it provides a biologically plausible explanation for persistent symptoms, cognitive dysfunction and poor response to conventional antidepressants, while also identifying measurable biomarkers which may support more precise patient stratification and the development of personalized therapeutic approaches.

Why a neuroinflammatory framework may add value in difficult-to-treat depression

Most contemporary models of depression have been grounded in monoaminergic hypotheses, stress-diathesis formulations, and neurotrophic or glutamatergic perspectives [12]. These models have been instrumental in guiding pharmacological innovation and remain foundational to clinical practice [13]. However, in patients with DTD, the explanatory and therapeutic scope appears incomplete [2]. The monoaminergic model conceptualizes depression as a disorder of serotonergic, noradrenergic and dopaminergic transmission [14]. Although this framework led to the development of effective first-line treatments, it does not fully explain the delayed onset of antidepressant efficacy, the marked clinical heterogeneity of depressive disorders, or the substantial proportion of patients who fail to achieve adequate response despite multiple evidence-based interventions. In moderate-to-severe and treatment resistant presentations, effect sizes are often modest, and residual symptoms, particularly anhedonia, motivational deficits and cognitive fatigue, remain common [15]. Similarly, stress-diathesis formulations elucidate vulnerability trajectories but do not directly account for the persistence of motivational impairment or partial pharmacological response [16]. Subsequent models, including the neurotrophic hypothesis centred on brain-derived neurotrophic factor, hypothalamic–pituitary– adrenal (HPA) axis dysregulation, glutamatergic dysfunction and large-scale neural network disconnection models, have substantially expanded the understanding of depression by highlighting the role of impaired neuroplasticity, chronic stress and circuit-level abnormalities [17]. However, their translation into scalable stratification strategies for routine clinical practice and publicly funded mental health services remains limited. Within this landscape, the neuroinflammatory framework does not replace existing models but introduces a biologically grounded modulatory dimension with specific relevance for DTD [8, 10]. By linking genetic vulnerability, psychosocial stress, early-life trauma (ELT), metabolic dysfunction and both peripheral and central immune activation, the neuroinflammatory hypothesis provides a more integrated conceptual model of depressive illness. This perspective is particularly relevant to DTD, in which chronic low-grade inflammation may contribute to symptom persistence, cognitive dysfunction, functional impairment and reduced responsiveness to conventional antidepressant treatments. Inflammatory processes may contribute to DTD by modulating reward — motivation circuitry and dopaminergic function, thereby helping to explain persistent anhedonia, effort aversion, and partial response to monoaminergic treatments in a subgroup of patients [8, 18]. Beyond circuit-level effects, the neuroinflammatory framework integrates early-life trauma, chronic stress, and metabolic vulnerability within a convergent immunometabolic axis [19, 20], consistent with the multidimensional nature of DTD [3]. Although peripheral biomarkers may not directly index central neuroinflammation [21], when interpreted contextually they can function as pragmatic indicators of immunometabolic risk, supporting biologically informed, tiered stratification approaches in publicly funded services [9, 22].

In this perspective, neuroinflammation is best understood not as an alternative theory of depression, but as an integrative, modulatory dimension that refines clinical stratification and helps explain heterogeneity in treatment response and functional burden in DTD [8, 23].

Inflammation as a circuit-level modulator: neurobiological mechanisms

Neuroinflammation refers to an inflammatory response within the central nervous system which, through microglial activation and the release of proinflammatory cytokines, durably modifies the physiology of corticostriatal circuits [22]. Clinically, this does not constitute a new discrete cause of depression, but rather a selective distortion of neural systems involved in reward processing, effort valuation, feedback-based learning and decision-making, with downstream consequences for motivation, treatment adherence and everyday functioning in depression [24]. A central element is the transition of microglia from a ramified surveillance state to an amoeboid effector state, accompanied by the release of IL-1β, IL-6 and TNF-α and the activation of transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Activator Protein-1 (AP-1) [24, 25]. This sustains a self-amplifying inflammatory cascade that disrupts synaptic homeostasis in fronto-striato-limbic circuits [26]. These alterations give rise to anhedonia, effort aversion, cognitive fatigue, and difficulty maintaining goal-directed behavior [18, 27]. A further key mechanism is activation of the kynurenine pathway: cytokine-induced (interferon-γ (IFN-γ), TNF-α) upregulation of indoleamine 2,3-dioxygenase 1 diverts tryptophan away from serotonin synthesis towards neuroactive kynurenine metabolites (e.g. quinolinic acid), producing N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic overactivity, oxidative stress and excitotoxicity in limbic regions and the basal ganglia [17, 28]. The resulting reduction in serotonergic tone and dopaminergic dysfunction contributes to a phenotype of reduced motivation [28, 29]. Neuroinflammation also interferes with mitochondrial function, increasing reactive oxygen species and reducing neuronal energetic capacity [23]. In parallel, dysregulation of the HPA axis, driven by chronic stress and pro-inflammatory cytokines, favors hypercortisolaemia and glucocorticoid resistance,
thereby stabilizing microglial priming and a sustained lowgrade inflammatory tone over time [22, 24]. Additional signals further promote microglial activation, including damage-associated molecular patterns released by stressed or injured cells [30]. Among these, the calciumbinding protein S100B can act as a danger signal for the innate immune system by engaging microglial patternrecognition receptors, thereby integrating and perpetuating the inflammatory response and contributing to progressive neuronal damage [25]. Taken together, these mechanisms indicate that inflammation contributes to depressive phenotypes characterized by anhedonia, effort aversion, low motivation and poor responsiveness to conventional treatments, providing a rationale for distinguishing subgroups of patients who may require differentiated care pathways [10].

Multiple origins of neuroinflammation

Neuroinflammation in depression represents the convergent outcome of multiple interacting pathogenic trajectories, each of which interfaces with individual vulnerability and can be conceptualized as a clinically relevant axis of stratification for mental health services [8, 10].
Psychological stress and ELT. ELT and chronic stress are robust determinants of long-term inflammatory vulnerability. ELT is associated with enduring programming of immune and neuroendocrine responses, with increased C reactive protein (CRP) and IL-6 levels in adulthood and heightened HPA axis reactivity [19]. Chronic stress in adult life maintains this configuration via the mechanisms of hypercortisolaemia and glucocorticoid resistance described above, favoring microglial priming and lowgrade inflammation [24]. For clinical services, ELT and chronic stress define a stable, trait-like “trauma–stress” dimension that should be systematically incorporated into the assessment of DTD [6].
Microbiota–gut-brain axis. Intestinal dysbiosis and increased gut permeability (“leaky gut”) allow translocation of lipopolysaccharide into the circulation, activating innate immunity and a persistent inflammatory response that modulates neuroinflammation via cytokine signalling and neural pathways [20, 31]. Microbial metabolites such as short-chain fatty acids and secondary bile acids regulate immune tone and glial function, contributing to more severe depressive phenotypes [31]. This “somatoinflammatory” dimension is often associated with gastrointestinal comorbidities, chronic pain and adverse lifestyle patterns [31, 32].
Metabolic inflammation and adipose tissue. In obesity and metabolic disorders, adipose tissue becomes an active source of cytokines and adipokines that amplify systemic inflammation [30, 32]. S100B, acting as a RAGEbinding adipokine, promotes M1 microglial polarisation and activates the NLRP3 inflammasome, sustaining an S100B–TNF-α feed-forward loop. Obesity is associated with increased circulating S100B [30]. This “metabolic– inflammatory” dimension can be recognized through body mass index (BMI), metabolic syndrome and glycaemic profile, and can be used to stratify patients for integrated psychiatric and internal medicine interventions [8, 32].

The blood–brain paradox: critical limitations of peripheral biomarkers

Having outlined the principal origins of neuroinflammation, it is essential to address the limitations of how these processes can be measured clinically. Distinguishing systemic inflammation from neuroinflammation is crucial for the clinical use of biomarkers [21, 33]. Meta-analytic data show that peripheral levels of IL-6, TNF-α and CRP do not systematically correlate with concentrations in the cerebrospinal fluid, indicating at least partially independent dynamics in the two compartments [21]. A blood-brain paradox thus emerges: peripheral biomarkers reliably detect systemic inflammation but do not represent direct proxies of neuroinflammation [33, 34]. CRP, by virtue of its accessibility and analytical standardization, remains the most pragmatic peripheral marker. The cascade linking immune activation to increased CRP is well characterized: microglial and monocyte–macrophage activation → IL-1β/NF-κB signalling → systemic IL-6 → hepatic STAT3 activation  → CRP synthesis [24, 35]. From a service perspective, three points are particularly important:

1. Elevated CRP may precede the onset of depression, indicating a general immunometabolic risk state [22, 35].

2. Clinically relevant neuroinflammation may be present even when CRP is within the reference range, especially in the context of ELT and chronic stress [19].

3. Raised CRP may derive from extra-cerebral sources (high BMI, metabolic syndrome, dysbiosis, subclinical infections) [32].

CRP should therefore be regarded as an imperfect yet clinically usable biomarker: it can identify patients with probable immunometabolic involvement and an unfavourable motivational-decisional profile, but it does not, on its own, permit conclusions about the degree of neuroinflammation [33]. In community-based mental health services, CRP may function as an operational marker of immunometabolic vulnerability if interpreted contextually (metabolic status, BMI, cognitive symptoms, history of early stress) and integrated with other indicators (IL-6, TNF-α, metabolic indices, comorbidities) [9, 22]. This is consistent with data linking elevated CRP to greater clinical severity and somatic burden in depression [15].

Chronic stress and early-life trauma: a trait risk axis

Early-life trauma and chronic stress together form a genuine trait risk axis [36], as previously described in the section on psychological stress and early-life trauma. ELT is associated with epigenetic modifications in regulatory regions of the IL-6 gene, with methylation patterns that favor increased cytokine expression and higher CRP production [19]. Chronic stress drives hyperactivity of the HPA axis, persistent hypercortisolaemia and glucocorticoid resistance, thereby reducing the capacity of cortisol to restrain immune responses and facilitating chronic elevations of IL-6, TNF-α and CRP [24]. For stratification in routine services, this implies that a history of ELT and chronic stress should be regarded as a stable modifier of biomarker interpretation, and that patients with ELT plus raised CRP and/or IL-6 constitute a high-risk subgroup with severe, persistently inflamed depressive presentations, who should be prioritized for dedicated DTD care pathways [6, 10, 19].

Metabolic confounders and multi-axial integration

The most important methodological limitation is that peripheral biomarkers do not reliably reflect central inflammation [21] and are influenced by multiple variables: timing of blood sampling, fasting status, sample handling and storage, BMI, metabolic syndrome, smoking, diet, physical activity and concomitant medication [37]. In patients with major depressive disorder who are overweight or obese, higher plasma levels of TNF-α, IL-8 and IL-1β are associated with poorer performance in processing speed and working memory [32]. BMI partially mediates the relationship between inflammation and depressive severity, and CRP shows a robust correlation with BMI [15, 32, 33]. Increased inflammatory activity may therefore constitute a mechanism linking adiposity, cognitive impairment and treatment refractoriness [38]. Analytically, only hs-CRP is currently amenable to validated point-of-care testing and should be regarded as the pragmatic communitylevel backbone of the pathway, whereas the cytokine panel, and IL-1β in particular, whose circulating levels often fall below assay quantification limits, remains a laboratory-based, not-yet-standardized, exploratory hub component contingent on future standardization. For community mental health services, these findings imply that peripheral biomarkers must be interpreted alongside clinical indicators (symptom phenotype, psychosocial functioning, cognition) and basic somatic data [10]. Stratification cannot be purely biological; it must be constructed across multiple axes (clinical, contextual, metabolic, inflammatory), with the inflammatory component functioning as one module within a broader framework rather than as the sole criterion [8]. These mechanistic and methodological considerations converge on a clinically recognizable pattern at the level of motivation and decision-making, which is particularly relevant for service-based stratification [18, 39].

The motivational-decisional phenotype: neurobiological mechanisms and clinical relevance

Low-grade inflammation exerts a selective impact on corticostriatal circuits through a set of convergent mechanisms [33, 40]. At a neurochemical level, activation of the kynurenine pathway depletes tetrahydrobiopterin (BH4), a critical cofactor for tyrosine hydroxylase, thereby reducing dopaminergic synthesis [28, 29]. Positron emission tomography studies have demonstrated reduced striatal dopamine availability and release in individuals with raised inflammatory markers, which correlate with anhedonia and psychomotor slowing [8]. Quinolinic acid, an NMDA-receptor agonist, further contributes to excitotoxicity within limbic regions and the basal ganglia. At the level of connectivity, higher CRP concentrations are associated with reduced functional connectivity between the ventral striatum and ventromedial prefrontal cortex, in turn linked to anhedonia; analogous associations have been reported for IL-6 in treatment-resistant depression, suggesting a degree of specificity for reward-motivation circuitry [18]. Functionally, effort-based decision-making is altered [41]. Experimentally induced inflammation increases the perceived subjective “cost” of effort. Treatment with infliximab can reduce TNF-α, normalize activity in the dorsomedial prefrontal cortex, ventral striatum, and putamen, and increase willingness to exert effort for reward [39, 42]. These mechanisms converge on a motivational-decisional phenotype characterized by:

• reduced reward responsiveness and effort aversion, with a preference for low-demand options;

• impairments in feedback-based learning, reduced decisional flexibility and perseveration of suboptimal choices;

• difficulty in capitalising on therapeutic opportunities and a high risk of disengagement or dropout due to lack of energy [18, 27].

This phenotype helps to explain why many patients with an inflammatory component appear refractory to monoaminergic treatments: if the core problem is inflammatory modulation of dopaminergic systems and corticostriatal connectivity, simply increasing serotonergic tone is unlikely to be sufficient [15, 35]. Data with levodopa indicate that enhancing dopaminergic availability can partially restore reward-circuit connectivity and reduce anhedonia in patients with elevated CRP [27, 43]. For community-based mental health services, this phenotype is highly relevant because:

• it is directly linked to everyday functioning, adherence and likelihood of dropout;

• it can be identified using clinically accessible tools (anhedonia scales, fatigue measures, assessment of effort avoidance);

• it constitutes a priority target for stratified pathways (neuromodulation, effort-based interventions, targeted engagement strategies);

• it should be explicitly incorporated into the criteria used to identify DTD.

The following sections outline how this neurobiological and  phenotypic framework can be translated into an operational stratification model that integrates peripheral  biomarkers, the motivational-decisional phenotype, and  the organizational constraints  of community mental health services.

A multi-axial stratification model for DTD in publicly funded mental health services

DTD, in its inflamed variant, can be conceptualized in routine services through stratification along four principal axes:

1. Axis A — Illness trajectory and treatment response:

• number, quality and sequencing of previous treatment attempts;

• persistence of disability despite optimization of usual care.

2. Axis B — Complicating clinical factors (trauma, comorbidity):

• history of ELT, personality disorder, anxiety disorders, substance use disorders;

• associated symptom patterns (severe anhedonia, chronic insomnia, marked anxiety).

3. Axis C — Contextual and service-related factors:

• rotation of clinicians, fragmentation of care between community mental health teams, acute psychiatric wards and private providers;

• limited access to psychotherapy, psychosocial programs and group-based interventions.

4. Axis D — Biological and somatic factors (including the inflammatory component):

• obesity, metabolic syndrome, chronic pain, proinflammatory medical conditions;

• low-grade inflammation (hs-CRP, IL-6), where measurable, interpreted in the context of BMI and comorbidities [26, 35].

The primary aim is not to demonstrate neuroinflammation in a strict sense, but to identify patients at highest risk of DTD, in whom immunometabolic vulnerability, a history of stress and/or ELT, and an unfavorable motivational– decisional phenotype converge [10]. This multi-axial stratification can be implemented in routine services using relatively simple tools, provided it is embedded within formal protocols rather than left to unaided clinical impression [11].

Minimal toolset for community-based services

Building on this multi-axial model, community-based services require a minimal but coherent toolset to operationalize stratification in everyday practice [3, 9]. Peripheral
biomarkers can function as pragmatic risk indicators when interpreted in the appropriate clinical context [33, 34]. For community-based and publicly funded mental health services, we propose an essential panel comprising:

• hs-CRP as a first-line marker, with operational cut-offs (≥3 mg/L; ≥5 mg/L for higher suspicion), always interpreted in relation to BMI, metabolic syndrome, smoking status, intercurrent infections and concomitant medications;

• IL-6 as a second-line marker, available in a limited number of district- or hospital-based specialist centers, for cases with persistently raised hs-CRP and a severe motivational-decisional phenotype [26, 33].

The increasing availability of point-of-care (POC) platforms for CRP (and, where feasible, IL-6) allows rapid, low-cost triage and reduces dependence on central laboratory services [22, 44]. POC testing should be embedded as a decision-support tool within the routine workflows of community mental health services and primary care, rather than used as an occasional optional investigation [11].

Integrated diagnostic framework

The assessment of a patient with DTD and a suspected inflammatory component should systematically include:

1. Targeted clinical history: detailed enquiry about ELT, recurrent stressful life events, pro-inflammatory medical conditions, metabolic disorders, and patterns of response and non-response to previous treatments (pharmacological, psychotherapeutic and neuromodulatory) [6].

2. Symptomatic and motivational phenotyping: quantification of anhedonia, fatigue and psychomotor slowing; indicators of effort-based decision-making (e.g. a tendency to disengage from therapeutic opportunities, dropout due to lack of energy); standardized measures of psychosocial functioning (e.g. Sheehan Disability Schedule 2.0, WHO Disability Assessment Scale) and cognition (e.g. THINC-it), where available [27, 39, 45].

3. Inflammatory and metabolic profile: core biomarkers (CRP ± IL-6), together with assessment of BMI, metabolic syndrome, lifestyle factors and concomitant medications. The focus is on overall immunometabolic vulnerability rather than on single markers in isolation [32].

4. Exclusion of secondary causes: appropriate screening for autoimmune diseases, chronic infections, malignancies and severe metabolic syndromes [3].

This framework does not depend on advanced technologies, but on an organizational decision to assess every DTD patient through this lens. Its therapeutic implications require an integrated model centred on motivational circuits and the somatic-psychological determinants of DTD, structured in tiers of increasing complexity (see Table S1 in the Supplementary). Within this framework, the most costly and complex interventions are explicitly reserved for stratified subgroups of patients with DTD (elevated CRP/IL-6, severe motivational-decisional phenotype, multiple treatment failures), while the majority of cases are managed at the first two steps through optimization of usual care, interventions targeting motivational circuits and lifestyle modification. In this way, the inflammatory component does not become an exclusion criterion or a “luxury” restricted to academic centers, but a variable that realistically guides the sequencing and intensity of treatments within community-based services.

Agenda for the reorganization of community-based services

Operationalizing the proposed framework requires a reorganization agenda that includes:

1. Standardization of first-line testing requires harmonized procedures for blood sampling, agreed interpretative thresholds for hs-CRP, and clear criteria for second-line investigations. Districtlevel specialist hubs should function as designated centers within secondary mental health services, acting as referral nodes for IL-6 testing, integrated metabolic panels, and more complex motivational phenotyping.

2. Collaboration with primary care: shared-care protocols with primary care based on DTD criteria; joint use of point-of-care CRP testing; and agreed pathways for patients at elevated risk.

3. Uniform multimodal protocols: service-wide guidance on combining pharmacotherapy, neuromodulation, psychotherapy, lifestyle interventions and specific measures targeting the motivational phenotype.

4. Integrated clinical dashboards: digital tools that collate symptoms, functioning, motivational phenotype, biomarkers and metabolic indicators to monitor DTD care pathways over time.

5. Workforce training: education on pre-analytical issues, contextual interpretation of biomarkers, recognition of the motivational–decisional phenotype and effective communication of these concepts to patients.

6. Regular evaluation of effectiveness and costeffectiveness: periodic assessment of clinical impact, economic sustainability and organizational consequences to support rational allocation of resources.

From this perspective, inflammation becomes an organizing principle for rethinking the management of DTD in publicly funded mental health systems, integrating biological, motivational and contextual dimensions within a single stratification framework.

Limitations

This work is based on narrative synthesis rather than systematic review, and the proposed model has not undergone empirical validation in routine community psychiatric practice. The prevalence of the inflamed endotype within the DTD construct remains unquantified, with existing data referring mainly to TRD. Peripheral inflammatory biomarkers do not directly index central neuroinflammation and require contextual interpretation alongside metabolic and behavioral confounders. Finally, the model is calibrated on European publicly funded mental health systems, and its transferability to settings with different structural and financing arrangements requires dedicated implementation studies.

Conclusion

Neuroinflammation in DTD should be understood primarily as a modulator of motivational and decisionmaking circuits, rather than as an additional variable within the monoaminergic model. It contributes to a depressive presentation characterized by refractoriness, marked anhedonia, effort aversion and functional impairment. Inflamed DTD is not a new nosological category, but the clinical expression of the interaction between immunometabolic vulnerability, stress and/or early-life trauma, and motivational–decisional distortion mediated by corticostriatal circuits. This profile corresponds to patients whom services tend to label as "resistant" after years of therapeutic attempts: pronounced anhedonia, effort avoidance, disengagement, and poor response to standard interventions.

If this framework is accepted, the key innovation is not another niche biomarker but the reorganization of care pathways in community-based mental health services. This entails systematic integration of trauma and stress history, motivational phenotyping, basic inflammatory and metabolic assessment, and tiered care selectively deploying neuromodulation, dopaminergic interventions, anti-inflammatory strategies and psychosocial programs. Only by embedding this logic within publicly funded community psychiatry does inflamed DTD become a realistic treatment target.

1 WHO overview “Depression and other common mental disorders”. Available from: https://www.who.int/publications/i/item/depression-global-health-estimates
2 Institute for Health Metrics and Evaluation. Global Burden of Disease 2023: Findings from the GBD 2023 study. Available from: https://www.healthdata.org/research-analysis/gbd