Endocrine psychiatric comorbidity in metabolic disorders: Integrative mechanisms and traditional Chinese medicine

Table 2 Mechanism modules linking metabolic-endocrine disorders with psychiatric and behavioral phenotypes: Candidate readouts and actionable leverage points (Figure 1)

Mechanism module (Figure 1)	Candidate readouts (clinical-first; research in italics)	Phenotypes most linked	Actionable leverage points
Chronic stress and circadian disruption (HPA/SNS)	Sleep timing/regularity; ISI/PSQI; resting HR/HRV; diurnal cortisol pattern; actigraphy/light exposure metrics[73]	Depression/anxiety; insomnia; fatigue[97]	Sleep-circadian repair; stress regulation; autonomic balancing[98]
Metabolic inflammation (immunometabolic signaling)	CRP; IL-6/TNF-α; NLR; visceral adiposity proxies (waist)[40]	Low mood/anergia; anxiety; cognitive complaints[44]	Weight reduction; anti-inflammatory lifestyle pattern; address inflammatory drivers[99]
Insulin resistance and metabolic toxicity	Glycated hemoglobin; fasting glucose/insulin; HOMA-IR; triglycerides/high-density lipoprotein; waist circumference[100]	Anhedonia/fatigue; cognitive slowing; reduced motivation	Improve insulin sensitivity (diet + activity ± pharmacotherapy); structured exercise; reduce metabolic toxicity[41]
Gut barrier and microbiome dysbiosis (gut-brain-metabolic axis)	GI symptom profile; diet quality (fibre/ultra-processed food exposure); stool microbiome/metabolites (SCFAs, indoles, bile-acid pathways)[101]	Depression/anxiety; sleep disturbance; disordered eating	Diet-based gut modulation; evidence-dependent pre/probiotics; vagal-mediated strategies[102]
Neuroimmune activation (microglia/BBB-related)	Peripheral inflammation proxies (CRP/NLR); symptom-triggered cognitive screening; neuroimaging/CSF markers (research)[39]	Cognitive dysfunction; mood symptoms; stress sensitivity[103]	Reduce upstream inflammatory/metabolic drivers; neuroprotective lifestyle; multimodal modulation
Neural circuitry and neurotransmission (reward/mood/cognition)	PHQ-9/GAD-7; sleep score; eating-behavior screening; adherence indicators	Disordered eating; depression/anxiety; impaired self-management	Psychotherapy/behavioral coaching; motivational support; reinforce adherence loops
Treatment-emergent metabolic liability (psychotropics)	Weight/waist trajectory; BP; glycated hemoglobin/glucose; lipids; adverse-effect checklist[104]	Weight gain; reduced adherence; metabolic deterioration[37]	Psychotropic stewardship; proactive metabolic monitoring; shared decision-making with risk mitigation[105]

HPA: Hypothalamic-pituitary-adrenal; SNS: Sympathetic nervous system; ISI: Insomnia Severity Index; PSQI: Pittsburgh Sleep Quality Index; HR: Heart rate; HRV: Heart rate variability; CRP: C-reactive protein; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; NLR: Neutrophil-to-lymphocyte ratio; HOMA-IR: Homeostasis Model Assessment of Insulin Resistance; GI: Gastrointestinal; SCFAs: Short-chain fatty acids; BBB: Blood-brain barrier; CSF: Cerebrospinal fluid; PHQ-9: Patient Health Questionnaire 9; GAD-7: Generalized Anxiety Disorder 7; BP: Blood pressure.