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

Table 1 Endocrine-psychiatric and behavioral comorbidity patterns across major metabolic-endocrine disorders

Index condition	Psychiatric and behavioral phenotypes (typical)	Evidence framing (psychiatric phenotype ascertainment)	Predominant comorbidity pattern1	Salient clinical burden (why it matters)
Type 2 diabetes/prediabetes	Depression; anxiety; sleep disturbance; cognitive dysfunction	Mixed	Bidirectional; disease-driven + behavior-driven[91]	Suboptimal metabolic control; reduced adherence/self-management; higher cardiometabolic risk (Figure 3)
Obesity/metabolic syndrome	Depression; anxiety; sleep disturbance (incl OSA-related); disordered eating	Mixed	Bidirectional; behavior-driven; treatment-emergent[92,93]	Weight trajectory reinforcement; impaired lifestyle persistence; increased cardiometabolic risk (Figure 3)
MAFLD/MASLD spectrum	Depression; anxiety; sleep disturbance; cognitive complaints	Mixed	Bidirectional; disease-driven + behavior-driven	Reduced quality of life; fatigue-related functional impairment; poorer lifestyle maintenance (Figure 3)
PCOS	Depression; anxiety; disordered eating; sleep disturbance	Mixed	Bidirectional; endocrine-metabolic-driven + psychosocial/behavior-driven[94]	Quality-of-life impairment; barriers to weight and symptom management; treatment non-persistence (Figure 3)
Thyroid dysfunction	Anxiety; depression; sleep disturbance; cognitive symptoms	Mixed	Primarily disease-driven; potential bidirectional feedback[95,96]	Functional impairment; symptom-related healthcare use; diagnostic misattribution risk (Figure 3)

¹Pattern terminology aligns with the bidirectional framework in (Figure 3): Disease-driven, behavior-driven, and treatment-emergent.

Evidence framing indicates whether the cited literature primarily defined psychiatric/behavioural phenotypes using DSM/ICD-based categorical diagnoses (“Diagnosis”), validated scale-based symptom thresholds or continuous scores (“Dimensional”), or a combination of both approaches (“Mixed”). OSA: Obstructive sleep apnea; MAFLD: Metabolic dysfunction-associated fatty liver disease; MASLD: Metabolic dysfunction-associated steatotic liver disease; PCOS: Polycystic ovary syndrome.

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.

Table 3 Traditional Chinese medicine intervention evidence matrix for metabolic-psychiatric comorbidity, prioritising dual endpoints (Figures 1 and 2)

TCM modality	Target clinical context (metabolic-psychiatric focus)	Intervention use (typical delivery)	Outcomes commonly captured	Dual-endpoint capture1	Evidence maturity and key limitations
Chinese herbal medicine	Depressive symptoms in patients with cardiometabolic comorbidity; adjunctive care when tolerability/acceptability is a concern	Pattern-informed prescriptions; monotherapy or adjunct to antidepressants	Mental health: Depressive symptoms, anxiety, sleep-related complaints; metabolic: Often absent or secondary	Inconsistent (mental-health-dominant in many trials)	Evidence base includes syntheses and condition-specific reviews; limitations: Formulation heterogeneity, variable standardisation, limited integrated metabolic endpoints
Acupuncture/EA (PCOS-focused)	PCOS with negative emotions plus metabolic features (weight/insulin resistance concerns)	Protocol-based acupuncture/EA; often alongside lifestyle/usual care	Mental health: Depression/anxiety; metabolic/PCOS: Weight-related and PCOS clinical features commonly reported	More consistent (mood + metabolic/PCOS features often co-reported)	Recent synthesis suggests potential benefit for negative emotions; limitations: Trial quality and heterogeneity; psychiatric endpoints not always primary[106]
Acupuncture for insomnia (sleep as a mechanistic amplifier)	Insomnia (often coexisting with metabolic disorders), targeting the sleep-stress-metabolic loop	Manual acupuncture; protocol-driven courses; sometimes adjunct to CBT-I/usual care	Sleep: PSQI/ISI and daytime function; mental health: Mood may be secondary; metabolic: Seldom captured	Partial (sleep-centric; metabolic endpoints uncommon)	Systematic reviews support insomnia improvement; limitation: Integrated metabolic-psychiatric cohorts and dual-endpoint designs remain limited[107]
Mind-body therapies (Tai Chi/Qigong)	Adults at risk of MetS/obesity-related risk with psychological distress or reduced self-efficacy	Group-based, adherence-friendly programmes; combined physical + meditative components	Psychosocial: Depressive mood/anxiety, self-efficacy, quality of life; metabolic: Cardiometabolic risk indicators often assessed	Often yes (psychosocial + metabolic outcomes co-reported)	Systematic reviews in MetS-risk populations support multidomain benefits; limitations: Programme heterogeneity, comparator variability, adherence reporting[107]
EA for anxiety/depression (general psychiatric target with metabolic relevance via stress axis)	Anxiety/depressive symptoms where stress biology and autonomic dysregulation are prominent (metabolic impact often indirect)	EA protocols; adjunct to standard care	Mental health: Anxiety/depression; metabolic: Typically not collected	Rare (psychiatric endpoint-dominant)	Evidence from systematic reviews exists; limitation: Metabolic outcomes and psychotropic–metabolic stewardship endpoints are rarely incorporated
TCM-integrated lifestyle counselling (TCM-informed diet/exercise guidance)	Prediabetes/metabolic risk states where behavior change is central and psychological burden may affect adherence	Individualised counselling aligned with constitution/pattern concepts; pragmatic delivery	Metabolic: Lifestyle adherence and metabolic risk markers; mental health: Usually under-measured	Usually no	Evidence supports metabolic prevention approaches, but dual-endpoint capture and standardized mental-health assessment are uncommon (gap aligns with Figure 2)[108]

¹Dual-endpoint capture: Concurrent assessment of metabolic endpoints (e.g., glycaemic/adiposity/cardiometabolic risk measures) and mental health endpoints (e.g., validated mood/anxiety/sleep scales), consistent with the integrated pathway (Figure 2).

TCM: Traditional Chinese medicine; PCOS: Polycystic ovary syndrome; EA: Electroacupuncture; ISI: Insomnia Severity Index; PSQI: Pittsburgh Sleep Quality Index; ISI: Insomnia Severity Index; MetS: Metabolic syndrome.

Table 4 Pragmatic interpretation framework for the minimal screening package and stepped-care triggers

Measure	Score range	Risk tier (suggested)	Suggested stepped-care trigger in metabolic-endocrine clinics
PHQ-9	0-4	Low	Monitor; provide brief education on sleep regularity, activity planning, and stress hygiene; re-screen if symptoms persist or self-management becomes difficult
	5-9	Low-moderate	Consider brief, skills-based support and reassess; explore functional impact and adherence barriers
	10-14	Moderate	Consider structured, module-targeted intervention and closer follow-up; evaluate co-occurring anxiety/insomnia and treatment burden
	15-19	High	Prompt more comprehensive assessment (including function and safety) and consider referral/co-management with mental health services, while continuing metabolic care
	20-27	High	Urgent specialist evaluation should be considered when severe symptoms are present, particularly with marked functional impairment or safety concerns; coordinate integrated management and monitor metabolic effects of psychotropic treatment where applicable
GAD-7	0-4	Low	Monitor; provide brief stress-management and sleep regularity guidance
	5-9	Low-moderate	Consider short, skills-based interventions and reassess
	10-14	Moderate	Consider structured intervention and closer follow-up; assess hyperarousal and its interaction with sleep and glycaemic variability
	15-21	High	Prompt comprehensive assessment and consider referral/co-management; review medication effects and adherence barriers
ISI (preferred)	0-7	Low	Provide sleep regularity counselling; monitor
	8-14	Moderate	Consider brief behavioural insomnia management and reassess; evaluate common contributors (e.g., pain, nocturia)
	15-21	High	Prompt targeted insomnia intervention and closer follow-up; consider differentiating insomnia phenotype from sleep-disordered breathing when clinically indicated, and consider targeted screening for obstructive sleep apnea in higher-risk metabolic phenotypes1
	22-28	High	Consider specialist sleep/mental health referral when severe insomnia persists or functional impairment is substantial, and consider sleep evaluation when sleep-disordered breathing is suspected
PSQI (alternative)	≤ 5	Low	Generally indicates acceptable sleep quality; monitor and reinforce regularity
	> 5	Elevated	Suggests impaired sleep quality; consider further assessment (including insomnia severity and possible sleep-disordered breathing) and module-targeted sleep intervention

¹Cut-offs reflect commonly used screening conventions and should be interpreted in clinical context. Escalation may be warranted regardless of total score when functional impairment is substantial, symptoms deteriorate rapidly, or safety concerns (including suicidality) are identified. Where relevant, sleep complaints should be interpreted with attention to phenotype, as suspected sleep-disordered breathing may warrant targeted evaluation in parallel with insomnia-focused behavioural strategies.

PHQ-9: Patient Health Questionnaire 9; GAD-7: Generalized Anxiety Disorder 7; ISI: Insomnia Severity Index; PSQI: Pittsburgh Sleep Quality Index.