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From Monoamines to Systems Psychiatry: Rewiring Depression Science and Care (1960s–2025)

A peer-reviewed article of this preprint also exists.

Submitted:

01 December 2025

Posted:

03 December 2025

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Abstract
Major depressive disorder was, until recently, framed as a single entity arising from a linear stress–monoamine–hypothalamic–pituitary–adrenal (HPA) axis cascade, modeled by forced swim and learned helplessness tests and evaluated by brief Hamilton Depression Rating Scale (HAM-D)/Montgomery–Åsberg Depression Rating Scale (MADRS) symptom trials. This “unitary cascade” view has been dismantled by imaging, immune–metabolic and sleep profiling, and plasticity markers, which reveal divergent circuit, inflammatory, and chronobiological patterns across anxious, pain-laden, and cognitively weighted depression, with non-response and relapse common. Translationally, face-valid rodent assays that equated immobility with despair have yielded limited bedside benefit, whereas cross-species bridges—electroencephalography (EEG) motifs, rapid eye movement (REM) architecture, effort-based reward tasks, and inflammatory/metabolic panels—are beginning to provide mechanistically grounded, clinically actionable readouts. In current practice, depression care is shifting toward systems psychiatry: inflammation-high and metabolic-high archetypes, anhedonia- and circadian-dominant subgroups, formal treatment-resistant depression (TRD) staging, connectivity-guided neuromodulation, esketamine, selected pharmacogenomic panels, and early digital phenotyping, as endpoints broaden to functioning and durability. A central gap is that heterogeneity is acknowledged but rarely built into trial design or implementation. This perspective advances a plasticity-centered systems psychiatry in which a testable prediction is that manipulating defined prefrontal–striatal and prefrontal–limbic circuits in sex-balanced, chronic-stress models will reproduce human network-defined biotypes and treatment response, and proposes hybrid effectiveness–implementation platforms that embed immune–metabolic and sleep panels, circuit-sensitive tasks, and digital monitoring under a shared, preregistered data standard.
Keywords: 
major depressive disorder (MDD)
;  
neurocircuitry
;  
synaptic plasticity
;  
neuroimmune interactions
;  
metabolic syndrome
;  
treatment-resistant depression (TRD)
;  
neuromodulation
;  
biomarkers
;  
kynurenine
;  
precision medicine
Subject: 
Medicine and Pharmacology  -   Neuroscience and Neurology

1. Framing the Journey—Prompts

Major depressive disorder has long been framed through a monoamine-centric lens, a narrative that catalyzed pharmacotherapy yet left substantial non-response and relapse [1]. Historical reassessments of the monoamine hypothesis and contemporary work on clinical, neurobiological, and treatment advances now converge on a simple conclusion: incremental refinements of the same model are no longer sufficient [2,3]. In an era of high dimensional neuroimaging, immune profiling, and digital phenotyping, revisiting the trajectory from 1960s monoamine theories to emerging systems psychiatry is therefore a strategic necessity [4,5](Figure 1). (4 refs)
This perspective views major depressive disorder as a nexus condition with dense cross talk to anxiety, chronic pain, and dementia, where shared and distinct pathways blur categorical boundaries [6]. Large scale cohort and imaging studies reveal common yet dissociable alterations in prefrontal and limbic circuitry across depression, anxiety, post-traumatic stress disorder, and pain, while mechanistic work highlights bidirectional links with cardiometabolic and neurodegenerative disease [7,8,9]. Within this landscape, anxious, pain enriched, and cognitively loaded depression exemplify how comorbidity patterns reshape prognosis, treatment response, and trial outcomes [10,11]. (5 refs)
Our central thread traces the shift from neurotransmitter first thinking toward an integrated immune, metabolic, and circuit-based framework that can anchor precision care [12]. This perspective synthesizes evidence on central–peripheral immune interactions, network-level biotypes, and model-driven subtypes of brain organization, and outlines how these advances should inform next-generation therapeutics and trial design [13,14,15]. Rather than another unitary model of depression, this perspective advances frameworks that treat heterogeneity as signal, not noise, enabling stratified, personalized interventions across intertwined spectra of mood, anxiety, pain, and cognitive decline [16]. (4 refs)

Box A—Key Terms

A biomarker is an objective biological signal that indexes state, risk, or treatment response. An endophenotype reflects a heritable, mechanistic intermediate—closer to circuitry than symptoms. Anhedonia captures reduced reward sensitivity or effort, a core transdiagnostic deficit. Treatment-resistant denotes limited response after adequate therapeutic trials. Rapid-acting refers to interventions producing meaningful change within hours to days. A network target is a circuit-defined node guiding drug or device precision. A digital endpoint leverages passive or task-based sensors to quantify behavior in real time.

2. Early Paradigms & Assumptions (1960s–1990s)

Early paradigms of depression research crystallized around stress, monoamines, and the hypothalamic pituitary adrenal axis as the primary translators of adversity into “behavioral despair” [2,17] Forced swim and learned helplessness tests, later complemented by chronic stress paradigms in rodents and primates, operationalized immobility, withdrawal, and subdued exploration as proxies for hopelessness [18,19]. These models were highly sensitive to monoaminergic and hypothalamic–pituitary–adrenal axis (HPA) modulating drugs and, for a time, appeared to bridge synapse and symptom [20,21]. Parallel work on glucocorticoid feedback, neurosteroids, and early immune and gut brain signals refined this picture, yet still treated depression largely as a unitary endpoint of a relatively linear stress monoamine HPA cascade [22,23].
On the clinical side, the introduction of DSM III and DSM III R reconfigured nosology around symptom checklists, while Hamilton Depression Rating Scale (HAM-D) and later Montgomery–Åsberg Depression Rating Scale (MADRS) scores became the dominant trial endpoints [24,25]. Response and remission were quantified by cutoffs on these scales, and short, fixed duration trials with single primary mood outcomes became the gold standard for regulatory sensitive evidence [26,27]. Placebo run in phases, designed to screen out early improvers and sharpen drug signal, further shaped effect sizes and sample composition, often at the cost of ecological validity [26,28]. Translation across trials relied on scale equivalence rather than deeper phenotyping or mechanistic anchors [29,30].
Within this framework, crucial sources of heterogeneity were marginalized [31]. Sex and age dependent profiles of mood, anxiety, and somatic symptoms were rarely modeled explicitly in either preclinical or clinical research, despite emerging data on sex specific monoamine and HPA signatures [32,33,34,35]. Ancestry, social context, chronic pain, and subthreshold anxiety were treated as noise, not structure [36]. Endpoint myopia, focused on short term mood change in narrowly defined samples, left longer term trajectories, functional outcomes, and comorbidity patterns largely uncharted, planting many of the seeds for the replication, generalization, and treatment resistance challenges that later decades would confront [37,38,39].

3. Pivot Suite (10 Mini-Cards)

This Pivot Suite condenses ten mechanistic “mini-cards” that reorient depression from a monoamine-shortage model toward a multiscale systems disorder. Each card anchors a specific lever—plasticity and circuit dynamics, reward and stress alignment, immune–metabolic and genomic milieu, or multi-point intervention logic—and links it to concrete translational readouts. Together, these pivots outline how synapses, circuits, body-wide signals, and trial architectures can be jointly tuned to redesign treatment-resistant depression (TRD) as a tractable, stratified systems problem.

3.1. Plasticity & Circuit Control of Depressive States

Across these cards, depression science shifts from monoamine scarcity toward dynamic systems. Each mini-anchor foregrounds mechanisms, actionable readouts, and clinically tractable targets that scaffold next-generation translational trial designs.

3.1.1. Synaptic Plasticity & Intrinsic Excitability

  • Synaptic plasticity and intrinsic excitability reframe depression as a disorder of experience-dependent wiring rather than transmitter shortage [40,41].
  • Long-term potentiation and depression, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor throughput, and evoked excitatory postsynaptic potentials (eEPSPs) index rapid remodeling, while neurogenesis and extracellular signal-regulated kinase (ERK)-sensitive priming by ketamine extend effects [42,43,44,45].
  • Early electroencephalography (EEG), local field potential (LFP), resting-state functional magnetic resonance imaging (rsfMRI) plasticity markers and AMPA-forward assays become core translational readouts [46,47].

3.1.2. Glutamate/γ-Aminobutyric Acid (GABA) Microcircuit Control

  • Glutamate and γ-aminobutyric acid (GABA) microcircuits position excitation/inhibition balance, shaped by somatostatin and parvalbumin interneurons, as a tunable affective set point [48,49,50,51].
  • N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptor modulation, inhibitory postsynaptic potentials, and layer-specific oscillations provide mechanistic levers [52,53,54].
  • Oscillation-anchored endpoints, task-locked transcranial magnetic stimulation–electroencephalography (TMS-EEG), and interneuron-specific in silico or animal models link inhibition deficits to scalable EEG and behavioral signatures [55,56].

3.1.3. Circuit-Level Nodes (Drugs & Devices)

  • Circuit-level nodes highlight how drugs and devices now target networks connecting habenula, subcallosal cingulate, and ventromedial prefrontal cortex.
  • Deep brain, vagus nerve, and transcranial magnetic stimulation, including accelerated theta-burst protocols, are steered by connectivity-guided targeting and TMS-EEG physiology.
  • Proof of target engagement, intensified dosing schedules, and responder enrichment by baseline network topology redefine how device parameters map onto durable outcomes [57].

3.2. Reward, Motivation & Stress Systems

The pivot pair tracks how stress reshapes reward pursuit and timekeeping, linking mesolimbic opioid tone and HPA plus circadian drift to anhedonia and fatigue.

3.2.1. Reward, motivation, and stress–opioid tone

  • Anhedonia is reframed as a mesolimbic dialogue where dopamine driven reward signaling is gated by dynorphin and kappa (κ)-opioid stress tone [58,59].
  • Effort based choice behavior, ventral striatal activity, and inflammatory status jointly index motivational collapse [60,61,62,63].
  • Selective κ-opioid antagonists and κ-opioid-active antidepressants invite augmentation trials that separate hedonic liking, motivated effort, and stress challenge responses [64,65].

3.2.2. HPA–Circadian–Stress Axis

  • The HPA and circadian system form a coupled stress axis in which glucocorticoid receptor (GR) sensitivity, cortisol rhythms, and sleep architecture tune mood regulation [66,67,68,69].
  • Delayed dim light melatonin onset, altered actigraphy, and a dysregulated cortisol awakening response signal internal misalignment [70,71,72].
  • Chronotype aware protocols, sleep linked endpoints, and GR assays operationalize this chronobiological vulnerability in real patients [73,74].

3.3. Immune–Metabolic–Genomic Modifiers of Risk and Treatment Response

This pivot gathers immune, metabolic, and genomic modifiers that quietly bias risk, symptom expression, and durability of response, turning background milieu into explicit treatment design variables.

3.3.1. Tryptophan (Trp)–kynurenine (KYN) steering

Tryptophan (Trp)-kynurenine (KYN) steering links immune activation to serotonin scarcity and neurotoxic load [75]. indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) divert Trp into KYN, tuning kynurenic acid (KYNA) versus quinolinic acid (QA) and aryl hydrocarbon receptor (AhR) signaling [76]. Peripheral C-reactive protein (CRP), KYN/Trp ratios, and microglia astrocyte metabolism align with cognitive, affective, and somatic symptom clusters, inviting inflammation stratified, longitudinal KYN panels in back translation [77,78,79,80,81,82,83,84,85,86,87].

3.3.2. Neuroimmune and glia

  • Neuroimmune and glial modifiers position microglia, astrocytes, complement, and colony-stimulating factor 1 receptor (CSF1R) or purinergic P2X7 receptor signaling as active sculptors of synaptic strength and network tone [88,89,90].
  • Positron emission tomography (PET) ligands, cerebrospinal cytokine panels, and EEG complexity provide convergent signatures of immune engagement [91,92,93,94].
  • Trials should treat sex, inflammatory state, and electroconvulsive or stimulation induced immune shifts as designable dimensions for precision psychiatry [95].

3.3.3. Metabolic–endocrine crosstalk

  • Metabolic endocrine crosstalk highlights insulin resistance, adiposity, and glucagon-like peptide-1 (GLP-1) signaling as levers that couple energy allocation to mood, cognition, and treatment response.
  • Metabolic syndrome phenotypes and type 2 diabetes (T2D) comorbidity flag patients in whom antidepressant efficacy, tolerability, and neuromodulation outcomes hinge on brain insulin signaling.
  • Pragmatic trials should embed metabolic stratification and functional endpoints.

3.3.4. Epigenetic/transcriptional gating

  • Epigenetic and transcriptional gating captures how histone deacetylases (HDACs), bromodomain, lysine-specific demethylase 1 (LSD1), and DNA methyltransferases (DNMTs) stabilize or relax depressive states and treatment induced remissions [96,97].
  • Cell type resolved assay for transposase-accessible chromatin (ATAC) and ribonucleic acid (RNA) sequencing, combined with peripheral chromatin marks, chart medication and neuromodulation trajectories [98,99,100].
  • Future trials should incorporate durability endpoints and convergent multi omic panels that track chromatin state ladders clinically [97,99,100].

3.4. Multi-Point Precision Strategies & Emerging Targets

The pivot turns from single levers to integrated playbooks, treating TRD as a heterogeneous systems problem that demands multiscale, multi-point intervention logic frameworks.

3.4.1. Multi-point strategies and next-wave targets

  • Multi point strategies view TRD as overlapping biotypes that require coordinated pharmacology, psychedelics, neuromodulation, and psychotherapeutic or digital tools [101,102,103,104].
  • Biomarker informed sequencing, pharmacogenomics, and biotype specific combinations replace linear trials of single agents [101,105,106,107].
  • Adaptive platform and N-of-1 designs, coupled to digital phenotyping and recovery focused endpoints, orient care toward precision and durability [102,103,104,107].

4. Divergence → Reconnection

As monoamine and stress-based models began to fray, a new translational strategy sought bridges that could genuinely scale across species rather than rely on face validity alone [108]. Electrophysiological motifs, such as frontal alpha asymmetry and reward related event related potentials, emerged as candidate intermediate phenotypes that can be measured in rodents and humans using homologous paradigms [109,110,111]. Sleep architecture, particularly REM density and slow wave fragmentation, offered another shared metric, mirrored by alterations in stress exposed animals and patients with melancholic or TRD [112,113,114]. In parallel, probabilistic reward tasks and cognitive control batteries were adapted across rodents, non-human primates, and humans, while longitudinal inflammatory and endocrine panels were integrated into both preclinical and clinical protocols, enabling richer cross species modeling of reward inflammation coupling [115,116].
Yet the field also accumulated clear failures to learn from earlier missteps [117]. The assumption that immobility equals despair persisted long after it became evident that forced swim behavior reflects a narrow coping style, not the multidimensional construct of depression [118,119]. Short duration trials and brief stress paradigms continued to dominate despite growing evidence that synaptic, circuit, and immune remodeling unfold over weeks to months [120,121]. Single endpoint thinking, usually centered on global depression scores or single behavioral tests, repeatedly obscured domain specific gains and masked heterogeneity in trajectories [122,123].
The most promising advances have come from deliberate back translation [124,125]. Symptom clusters and rating scale factors are first decomposed into Research Domain Criteria (RdoC) like domains of negative valence, reward processing, arousal, and cognition, then re instantiated as tractable tasks and physiological readouts in animals [125,126]. Multimodal biomarker programs now use human defined phenotypes to guide the design of cross species EEG batteries, reward and cognitive paradigms, and peripheral immune signatures [127,128]. In doing so, they begin to reconnect bench and bedside around shared dimensions rather than diagnostic labels alone [129,130].
Table 1. Cross-species bridge map for depression-relevant constructs and translatable assays. Cross-species bridge map linking human constructs to preclinical assays, quantitative readouts, and clinical analogs that can be implemented in contemporary trials. “Status” summarizes translational maturity (routine, emerging, or exploratory), while “Design tip” highlights one concrete way to embed each bridge into mechanistically anchored, heterogeneity-aware study designs.
Table 1. Cross-species bridge map for depression-relevant constructs and translatable assays. Cross-species bridge map linking human constructs to preclinical assays, quantitative readouts, and clinical analogs that can be implemented in contemporary trials. “Status” summarizes translational maturity (routine, emerging, or exploratory), while “Design tip” highlights one concrete way to embed each bridge into mechanistically anchored, heterogeneity-aware study designs.
Human construct Preclinical assay Readout Clinical analog Status Design tip
Anhedonia/ motivational deficit Effort-based decision tasks (progressive ratio, T-maze barrier, operant sucrose) Breakpoint, lever presses, willingness to work under stress or inflammation Probabilistic reward tasks, EEfRT, ventral striatal BOLD, anhedonia scales Emerging trial biomarker Separate hedonic “liking” from motivational “wanting”; include stress/inflammation challenge blocks.
Negative affect/threat bias Fear conditioning and extinction; chronic social defeat Freezing/avoidance, extinction curves, startle, social withdrawal Fear-learning and extinction tasks, startle paradigms, threat-bias tasks in anxious/MDD subgroups Robust basic science; limited clinical use Use as domain-specific endpoint in anxious and trauma-loaded depression; pair behavior with EEG/fMRI.
Cognitive control/executive dysfunction Attentional set-shifting, 5-CSRTT, reversal learning Errors, omissions, reaction times, perseveration indexes Set-shifting (e.g., CANTAB), n-back, Stroop, Trail Making, DLPFC activation Secondary endpoint in several trials Pre-stratify “cognitively loaded” depression; link change to functioning and return-to-work outcomes.
Sleep and circadian disruption Rodent EEG/EMG with chronic stress or light-cycle shift; REM-deprivation models REM latency/density, NREM slow-wave power, activity rhythms, phase shifts Polysomnography, actigraphy, DLMO, sleep/circadian questionnaires Strong observational; emerging endpoints Align dosing and assessments with chronotype; treat sleep/circadian metrics as primary modifiable targets.
HPA axis and stress reactivity Chronic mild stress, restraint, social defeat; Dex/CRH challenges Corticosterone profiles, GR sensitivity, coping style, stress-induced behavioral shift Cortisol awakening response, DST, lab stress tests, hair cortisol Mixed but promising for subtyping Sample across diurnal cycle; co-model stress markers with symptom domains (anergy, anxiety, cognitive fog).
Inflammation–KYN steering LPS/IFN-α or stress-sensitized immune activation; Trp–KYN pathway assays KYN/Trp ratio, QA/KYNA balance, microglial activation, cytokine panels CRP, IL-6/TNF panels, plasma KYN/Trp, symptom clusters (anergia, anhedonia, psychomotor slowing) High translational interest Pre-specify “inflammation-high” strata; collect longitudinal KYN panels and align with treatment response.
Metabolic–endocrine load High-fat diet, genetic obesity, insulin-resistance models Glucose tolerance, insulin signaling, adiposity, spontaneous activity BMI, waist-to-hip ratio, HOMA-IR, HbA1c, metabolic-syndrome indices Growing but underused in trials Embed metabolic panels into TRD studies; design dedicated obesity/T2D depression trials with functional endpoints.
Synaptic plasticity / rapid-acting response Ketamine/psychedelic paradigms; LTP/LTD, in vivo spine imaging, AMPA-forward assays Spine density, AMPA/NMDA ratio, LTP/LTD magnitude, early oscillatory changes Early EEG/MEG plasticity markers, TMS-LTP readouts, 24–72 h symptom and cognition shifts Strong mechanistic, clinical for ketamine Build in early (24–72 h) windows and plasticity markers as key secondary endpoints in rapid-acting trials.
Network-level connectivity biotypes Chemogenetic/optogenetic PFC–striatal/limbic manipulation; rodent rsfMRI/EEG Resting-state connectivity, oscillatory coupling, causal node influence, behavior under circuit control rsfMRI biotypes, TMS-EEG connectivity, SCC/vmPFC network markers for neuromodulation targeting Emerging targeting tool Require “target engagement” thresholds for drugs/devices; enrich samples by baseline network topology.
Digital behavior and passive monitoring Home-cage automated monitoring of movement, sleep, and social interaction Continuous activity, sleep–wake structure, social proximity, exploration patterns Smartphone-based mobility, call/text patterns, speech and behavior passively captured by sensors Early exploratory Predefine digital endpoints (e.g., mobility, social withdrawal) and link them to functional and relapse outcomes.
5-CSRTT, five-choice serial reaction time task; BMI, body mass index; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BOLD, blood-oxygen-level–dependent; CANTAB, Cambridge Neuropsychological Test Automated Battery; Dex/CRH, dexamethasone/corticotropin-releasing hormone; DLPFC, dorsolateral prefrontal cortex; DLMO, dim light melatonin onset; DST, dexamethasone suppression test; EefRT, Effort Expenditure for Rewards Task, EEG, electroencephalograph; EMG, electromyography; fMRI, functional magnetic resonance imaging; GR, HbA1c, glycated hemoglobin; glucocorticoid receptor; HOMA-IR, homeostatic model assessment of insulin resistance; HPA, hypothalamic–pituitary–adrenal; IFN-α interferon-alpha; IL-6, interleukin-6; KYN, kynurenine; LTD, long-term depression; LPS, lipopolysaccharide; LTP, long-term potentiation; MEG, magnetoencephalography; MMD, major depressive disorder; NMDA, N-methyl-D-aspartate; NREM, non- rapid eye movement; PFC, prefrontal cortex; QA, quinolinic acid; REM, rapid eye movement; rsfMRI, resting-state functional magnetic resonance imaging; SCC, subcallosal cingulate; T2D, type 2 diabetes; TMS, transcranial magnetic stimulation; TNF, tumor necrosis factor; TRD, treatment-resistant depression; Trp, tryptophan; vmPFC, ventromedial prefrontal cortex.

5. Clinical Applications Today

Clinical applications of systems psychiatry are moving beyond one-size-fits-all algorithms toward stratified care grounded in biology and behavior [131]. Depression is increasingly parsed into inflammation high, metabolically burdened, anhedonia dominant, and sleep or circadian disrupted profiles, overlaid on formal staging of treatment resistance [132,133]. Elevated CRP altered neutrophil to lymphocyte ratios, and immune metabolic gene signatures delineate patients whose symptoms cluster around anergia and anhedonia, while sleep fragmentation and circadian misalignment identify another modifiable axis that cuts across stages of non-response [134]. Parallel work on pharmacogenomics, circuit-based biotypes, and age specific EEG signatures is entering specialist clinics and early phase trials [13,135,136].
A clear distinction now separates tools that are clinically ready from those that are almost ready [137]. Structured TRD staging, esketamine, neuromodulation devices, and several pharmacogenomic panels have achieved regulatory approval and are supported by comparative effectiveness data [106,138,139]. By contrast, multiplex inflammatory and metabolic panels, task based cognitive emotional biomarkers, and digital phenotyping batteries remain largely in the candidate domain, often validated in carefully selected cohorts but not yet embedded in stepped care pathways [128,140].
Translating these advances into everyday practice faces substantial hurdles [141]. Access to neuromodulation, ketamine-based interventions, and genomic testing is uneven, constrained by cost, infrastructure, and workforce training [142]. Regulatory frameworks still privilege drug over device and algorithm, and reimbursement rarely rewards stratified assessment [143]. Without deliberate attention to equity, biologically enriched care risks deepening disparities, as populations with higher inflammatory burden, multimorbidity, and limited digital access may be the least likely to receive precision guided interventions [144,145,146].
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Figure 2. Evolution of depression trial design across eligibility, endpoints, timing, stratification and durability. The schematic contrasts conventional antidepressant trials (Then, left) with emerging systems-psychiatry-informed designs (Now, right). Eligibility. Earlier trials typically enrolled narrowly defined adults with “pure” major depressive disorder, excluding common comorbidities, older age, suicidality and medical complexity; contemporary designs move toward staged, better-characterized and more inclusive samples, with comorbidities, treatment resistance and functional impairment captured as structured baseline variables rather than automatic exclusions. Endpoints. Traditional studies relied on a single clinician-rated symptom scale (for example, HAM-D or MADRS) at one acute time point; modern trials incorporate multi-domain outcome batteries, including anhedonia and cognition, functioning and quality of life, patient-reported outcomes, and mechanistic readouts (for example, inflammatory markers, circuit or plasticity measures, digital behavior). Timing. Classic trials emphasized 6–8-week acute response with relatively sparse visits; new designs layer dense early sampling windows (hours to days for rapid-acting agents) onto longer follow-up to 6–12 months, enabling characterization of onset, offset and relapse dynamics. Stratification. Earlier studies used minimal or post-hoc subgrouping (for example, melancholic versus atypical) and randomization only at the syndrome level; contemporary designs prespecify strata and enrichment rules based on clinical staging, comorbidity clusters, biomarkers (such as inflammation or KYN metrics), cognitive or circuit biotypes, and sometimes deploy adaptive or umbrella/basket architectures. Durability. Historically, continuation and maintenance phases were optional or handled in separate extension studies; current trials increasingly embed durability as a co-primary objective, tracking time to relapse, sustained response, taper/discontinuation effects and real-world effectiveness via registries or digital follow-up, thereby aligning trial design with the long-term course of depressive illness. HAM-D, Hamilton Depression Rating Scale; KYN, kynurenine; MADRS, Montgomery–Åsberg Depression Rating Scale; MDD, major depressive disorder.
Figure 2. Evolution of depression trial design across eligibility, endpoints, timing, stratification and durability. The schematic contrasts conventional antidepressant trials (Then, left) with emerging systems-psychiatry-informed designs (Now, right). Eligibility. Earlier trials typically enrolled narrowly defined adults with “pure” major depressive disorder, excluding common comorbidities, older age, suicidality and medical complexity; contemporary designs move toward staged, better-characterized and more inclusive samples, with comorbidities, treatment resistance and functional impairment captured as structured baseline variables rather than automatic exclusions. Endpoints. Traditional studies relied on a single clinician-rated symptom scale (for example, HAM-D or MADRS) at one acute time point; modern trials incorporate multi-domain outcome batteries, including anhedonia and cognition, functioning and quality of life, patient-reported outcomes, and mechanistic readouts (for example, inflammatory markers, circuit or plasticity measures, digital behavior). Timing. Classic trials emphasized 6–8-week acute response with relatively sparse visits; new designs layer dense early sampling windows (hours to days for rapid-acting agents) onto longer follow-up to 6–12 months, enabling characterization of onset, offset and relapse dynamics. Stratification. Earlier studies used minimal or post-hoc subgrouping (for example, melancholic versus atypical) and randomization only at the syndrome level; contemporary designs prespecify strata and enrichment rules based on clinical staging, comorbidity clusters, biomarkers (such as inflammation or KYN metrics), cognitive or circuit biotypes, and sometimes deploy adaptive or umbrella/basket architectures. Durability. Historically, continuation and maintenance phases were optional or handled in separate extension studies; current trials increasingly embed durability as a co-primary objective, tracking time to relapse, sustained response, taper/discontinuation effects and real-world effectiveness via registries or digital follow-up, thereby aligning trial design with the long-term course of depressive illness. HAM-D, Hamilton Depression Rating Scale; KYN, kynurenine; MADRS, Montgomery–Åsberg Depression Rating Scale; MDD, major depressive disorder.
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6. What We Got Wrong/Right

Many of the field’s “failures” now look like solvable design problems rather than fatal errors [147,148]. Trial and error prescribing, short term symptom focused trials, and inflated remission estimates exposed what happens when heterogeneity is ignored and protocols drift [147,149,150]. The corrective principles are clearer now: implement decision support and data driven personalization, redesign trials to prioritize long term functioning and real-world effectiveness and adhere strictly to pre specified protocols with transparent reporting [151,152,153]. The concept of difficult to treat depression and consensus definitions of TRD are direct products of these lessons [104,154,155].
A second cluster of mistakes involved what and whom we chose to measure [156,157]. Overbroad diagnostic criteria without biomarkers, unclear psychotherapy “active ingredients,” late recognition of comorbidity, and neglect of patient preference and digital engagement all narrowed impact [147,158,159,160]. The responses are already reshaping practice [161]. Biomarker informed and endophenotype based frameworks, component focused psychotherapy trials, integrated care models, shared decision tools, guided digital and blended interventions, and Delphi based TRD guidelines collectively represent durable gains and a more realistic architecture for precision psychiatry [104,155,159,162].

7. Outlook

The next decade will be judged by whether it can turn systems psychiatry from an attractive narrative into falsifiable science [163,164]. Two preclinical predictions are within reach. First, that manipulating specific prefrontal–striatal and prefrontal–limbic circuits in sex balanced, chronic stress models will yield biotypes that map onto human imaging defined network patterns and differential treatment response [165,166,167]. Second, that patient derived cellular systems combined with multi-omic profiling will prospectively predict which immune and metabolic perturbations in animals reproduce anhedonia dominant, inflammation high phenotypes observed in humans [134,168].
On the clinical side, trial design must shift in two concrete ways. Large, multivariate, cross trial prediction studies should be powered not only to detect average effects but to learn stable individual level treatment rules [169,170,171]. In parallel, factorial and adaptive designs need to dissect psychotherapy and combined treatment “active ingredients” rather than testing monolithic packages [172,173,174,175].
A viable implementation pathway is hybrid effectiveness implementation research embedded in integrated care, where stratification tools, targeted pharmacotherapy, and digital monitoring are co designed with health systems [176]. Underpinning all of this should be a shared data standard that harmonizes symptom networks, EEG and imaging markers, and trial metadata, with preregistered analytic pipelines and mandatory external validation [177,178].

8. Conclusions

In this perspectives review, I propose plasticity centered systems psychiatry as the key lens through which both model building and bedside decisions can be restructured. Synaptic remodeling, circuit dynamics, immune metabolic context, and sleep dependent homeostasis become explicit levers for intervention rather than diffuse background. A concrete practice change is to implement structured, plasticity informed care pathways that link symptom profiles to simple circuit sensitive indices such as reward tasks, sleep and circadian metrics, and low burden immune or metabolic panels. A parallel research change is to develop adaptive, multimodal platforms in which the ten subsequent papers systematically interrogate promising synaptic, microcircuit, network, immune, and chronobiological targets for depression treatment.

Author Contributions

Conceptualization, M.T.; methodology, M.T.; software, M.T.; validation, M.T.; formal analysis, M.T.; investigation, M.T.; resources, M.T.; data curation, M.T.; writing—original draft preparation, M.T.; writing—review and editing, M.T.; visualization, M.T.; supervision, M.T.; project administration, M.T.; funding acquisition, M.T. Author has read and agreed to the published version of the manuscript.

Funding

This work was supported by the HUN-REN Hungarian Research Network.

Acknowledgments

The graphical abstract and figures are created using biorender.com (accessed on 1 December 2025)

Conflicts of Interest

The author declares no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
5-CSRTT five-choice serial reaction time task
AhR aryl hydrocarbon receptor
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
ATAC assay for transposase-accessible chromatin
BMI body mass index
BOLD blood-oxygen-level–dependent
CANTAB Cambridge Neuropsychological Test Automated Battery
CRP C-reactive protein
CSF1R colony-stimulating factor 1 receptor
Dex/CRH dexamethasone/corticotropin-releasing hormone
DLMO dim light melatonin onset
DLPFC dorsolateral prefrontal cortex
DNMTs DNA methyltransferases
DSM Diagnostic and Statistical Manual of Mental Disorders
EEG electroencephalography
EefRT Effort Expenditure for Rewards Task
eEPSPs evoked excitatory postsynaptic potentials
ERK extracellular signal-regulated kinase
EMG electromyography
fMRI functional magnetic resonance imaging
GABA γ-aminobutyric acid
GLP-1 glucagon-like peptide-1
GR glucocorticoid receptor
HAM-D Hamilton Depression Rating Scale
HbA1c glycated hemoglobin
HDACs histone deacetylases
HOMA-IR homeostatic model assessment of insulin resistance
HPA hypothalamic–pituitary–adrenal axis
IDO indoleamine 2,3-dioxygenase
IFN-α interferon-alpha
IL-6 interleukin-6
IPSPs inhibitory postsynaptic potentials
κ kappa
KYN kynurenine
KYNA kynurenic acid
LFP local field potential
LPS lipopolysaccharide
LSD1 lysine-specific demethylase 1
LTD long-term depression
LTP long-term potentiation
MADRS Montgomery–Åsberg Depression Rating Scale
MDD major depressive disorder
MEG magnetoencephalography
NMDA N-methyl-D-aspartate
PET positron emission tomography
PFC prefrontal cortex
QA quinolinic acid
RDoC Research Domain Criteria
REM rapid eye movement
RNA ribonucleic acid
rsfMRI resting-state functional magnetic resonance imaging
SCC subcallosal cingulate cortex
T2D type 2 diabetes
TDO tryptophan 2,3-dioxygenase
TMS transcranial magnetic stimulation
TMS-EEG transcranial magnetic stimulation–electroencephalography
TNF tumor necrosis factor
TRD treatment-resistant depression
Trp tryptophan
vmPFC ventromedial prefrontal cortex
VNS vagus nerve stimulation

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Preprints 187628 g001
Figure 1. Translational timeline strip linking preclinical models, diagnostic milestones, and first-line depression treatments. Stylized timeline strip spanning the mid-20th century to the present, organized in three horizontal bands: (top) preclinical depression-relevant models, (middle) diagnostic milestones, and (bottom) first-line pharmacological and psychotherapeutic treatments. Each band highlights when core tools entered the field (e.g., forced-swim and learned helplessness assays, Diagnostic and Statistical Manual of Mental Disorders (DSM)-III formalization of major depressive disorder, the SSRI era, evidence-based psychotherapies, and rapid-acting agents such as ketamine/esketamine), emphasizing where innovation in models, nosology, and frontline care has been synchronized—or strikingly decoupled. Arrows and shaded zones indicate potential “bridgeable gaps” where contemporary preclinical assays could be explicitly linked to diagnostic refinements and treatment decisions in next-generation clinical trial designs.
Figure 1. Translational timeline strip linking preclinical models, diagnostic milestones, and first-line depression treatments. Stylized timeline strip spanning the mid-20th century to the present, organized in three horizontal bands: (top) preclinical depression-relevant models, (middle) diagnostic milestones, and (bottom) first-line pharmacological and psychotherapeutic treatments. Each band highlights when core tools entered the field (e.g., forced-swim and learned helplessness assays, Diagnostic and Statistical Manual of Mental Disorders (DSM)-III formalization of major depressive disorder, the SSRI era, evidence-based psychotherapies, and rapid-acting agents such as ketamine/esketamine), emphasizing where innovation in models, nosology, and frontline care has been synchronized—or strikingly decoupled. Arrows and shaded zones indicate potential “bridgeable gaps” where contemporary preclinical assays could be explicitly linked to diagnostic refinements and treatment decisions in next-generation clinical trial designs.
Preprints 187628 g001
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