SCOPE AND PURPOSE
This protocol is designed for Psychiatric Mental Health Nurse Practitioners (PMHNPs), consultation-liaison psychiatrists, and psychiatric physicians (MD/DO) who encounter patients with treatment-resistant anxiety, depression, insomnia, cognitive dysfunction, or OCD-like symptoms in the context of multisystem somatic complaints — particularly when these patients have been referred to psychiatry with a diagnosis of "somatic symptom disorder," "conversion disorder," or "functional neurological disorder" without adequate medical workup for mast cell activation syndrome (MCAS), postural orthostatic tachycardia syndrome (POTS), or hypermobile Ehlers-Danlos syndrome (hEDS).

This protocol does not replace allergy-immunology evaluation. It provides a structured framework for psychiatric providers to (1) screen for these conditions, (2) initiate guideline-concordant empiric treatment that simultaneously addresses psychiatric and mast cell–mediated symptoms, (3) document therapeutic response as diagnostic evidence, and (4) generate a compelling referral package for specialty care.

SECTION 1: CLINICAL SCREENING
1.1 — When to Suspect MCAS in a Psychiatric Patient

Suspect MCAS when a patient presents with psychiatric symptoms PLUS episodic symptoms affecting ≥2 of the following organ systems (AAAAI/Consensus-1 requirement):
- Cardiovascular: Tachycardia, hypotension, presyncope, syncope
- Dermatologic: Flushing, urticaria, pruritus, angioedema, dermatographism
- Gastrointestinal: Crampy abdominal pain, diarrhea, nausea, bloating
- Respiratory: Wheezing, dyspnea, nasal congestion, throat tightness
- Neuropsychiatric: Brain fog, poor concentration, headache, anxiety, depression, insomnia

Red flags suggesting MCAS rather than primary psychiatric disorder:
- Psychiatric symptoms are episodic/fluctuating rather than constant
- Symptoms triggered by heat, stress, alcohol, certain foods, hormonal changes, or physical stimuli
- Psychiatric symptoms accompanied by flushing, GI distress, or tachycardia
- Symptoms worsen perimenstrually or with temperature changes
- Treatment-resistant to standard psychiatric medications
- Antihistamines (e.g., diphenhydramine, cetirizine) provide unexpected relief of anxiety or insomnia
- Family history of similar multisystem complaints, hypermobility, or "allergic" conditions
 

1.2 — Bedside Screening for POTS
Equipment needed: Blood pressure cuff with heart rate capability or pulse oximeter.

Procedure (Active Stand Test):
1. Patient rests supine for 5–10 minutes
2. Record baseline HR and BP
3. Patient stands quietly (no walking, no leaning)
4. Record HR and BP at 1, 3, 5, and 10 minutes

Diagnostic threshold: Heart rate increase ≥30 bpm (≥40 bpm ages 12–19) sustained during the standing period, without orthostatic hypotension (BP drop >20/10 mmHg). Symptoms of orthostatic intolerance (lightheadedness, palpitations, brain fog, visual changes) should be present.

Note: The active stand test has higher specificity (79%) than tilt table testing (23%) and is considered sufficient for diagnosis in most clinical settings.

1.3 — Bedside Screening for hEDS
Beighton Score (9-point scale):
- Passive dorsiflexion of 5th MCP >90° — 1 point each side (2 total)
- Passive thumb apposition to forearm — 1 point each side (2 total)
- Elbow hyperextension >10° — 1 point each side (2 total)
- Knee hyperextension >10° — 1 point each side (2 total)
- Palms flat on floor, knees extended — 1 point (1 total)

Generalized Joint Hypermobility (GJH) thresholds:
- ≥6 for prepubertal children and adolescents
- ≥5 for adults ≤50 years
- ≥4 for adults >50 years

If Beighton score is 1 point below cutoff, administer the Five-Point Questionnaire (5PQ):

1. Can you now (or could you ever) place your hands flat on the floor without bending your knees?

2. Can you now (or could you ever) bend your thumb to touch your forearm?

3. As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits?

4. As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?

5. Do you consider yourself "double-jointed"?

If 5PQ ≥2 positive items AND Beighton is 1 point below cutoff → GJH can be diagnosed.

If GJH is confirmed, apply the full 2017 International EDS Consortium criteria (Criteria 1–3) for hEDS diagnosis.

SECTION 2: LABORATORY WORKUP
2.1 — Baseline Labs (Order at Initial Visit)
 

Standard psychiatric labs:
- CBC with differential
- CMP (comprehensive metabolic panel)
- TSH
- Vitamin D, B12, folate
- hs-CRP (inflammatory marker)

MCAS-specific labs:  
- Serum tryptase (baseline) — available through all major reference labs
- If patient presents during or shortly after an acute episode: STAT serum tryptase within 1–4 hours of symptom onset
- Diagnostic rise formula: Acute tryptase ≥ (1.2 × baseline) + 2 ng/mL

2.2 — Extended Labs (If Baseline Tryptase Is Normal but Clinical Suspicion Remains High)
Order through reference laboratory:
- 24-hour urine N-methylhistamine (histamine metabolite)
- 24-hour urine 11β-prostaglandin F2α (PGD2 metabolite — most frequently elevated marker)
- 24-hour urine leukotriene E4

Note: These must be collected during a symptomatic period for maximum sensitivity. Instruct patients to begin collection when symptoms flare.

2.3 — POTS-Specific Labs (If Active Stand Test Is Positive)
- CBC (rule out anemia)
- TSH (rule out thyroid disease)
- AM cortisol (rule out adrenal insufficiency)
- Consider: Supine and standing plasma catecholamines (norepinephrine >600 pg/mL standing suggests hyperadrenergic subtype)
- Consider: Ganglionic AChR antibodies (if autoimmune POTS suspected)


SECTION 3: VALIDATED OUTCOME MEASURES
Administer at baseline and at each follow-up visit (minimum every 2–4 weeks during titration):
- PHQ-9 (depression severity)
- GAD-7 (anxiety severity)
- ISI — Insomnia Severity Index
- MoCA (if brain fog/cognitive complaints are prominent)
- Daily Symptom Diary: Patient rates severity (0–10) across domains:
- Anxiety
- Depression/mood
- Sleep quality
- Brain fog/concentration
- Flushing
- GI symptoms (nausea, cramping, diarrhea)
- Pruritus/urticaria
- Tachycardia/palpitations
- Headache

A ≥30% reduction in composite symptom score on antimediator therapy constitutes a clinically meaningful response and satisfies the Consensus-2 therapeutic response criterion.

SECTION 4: STEPWISE PRESCRIBING PROTOCOL
STEP 1 — FOUNDATION: H1 + H2 BLOCKADE (Weeks 1–4)
Initiate in ALL patients with suspected MCAS regardless of psychiatric symptom profile.
Cetirizine 10 mg PO daily (morning)
- May increase to 20 mg daily (or 10 mg BID) if tolerated
- Nonsedating; does not impair cognition
- Can increase up to 4× standard dose (40 mg/day) per AAAAI guidance

PLUS
Famotidine 20 mg PO BID (morning and evening)
- First-line H2 blocker for GI and cardiovascular mast cell symptoms
- May increase to 40 mg BID if needed

Assessment at Week 4: Document symptom response on all validated scales. If ≥30% improvement → continue and proceed to Step 2 for residual psychiatric symptoms. If no improvement → proceed to Step 2.

STEP 2 — ADD ANTIDEPRESSANT WITH ANTIHISTAMINE/MAST CELL PROPERTIES (Weeks 4–12)
Select based on predominant symptom profile:
PATHWAY A: Depression + Insomnia Predominant → DOXEPIN
Rationale: Dual H1 + H2 blockade, mast cell inhibitory properties, TCA antidepressant, 50–90% brain H1 receptor occupancy. The only psychiatric medication providing simultaneous H1 + H2 blockade. AAAAI-listed for MCAS/SM CNS manifestations.

Dosing:
- Start: 10–25 mg PO QHS
- Titrate: Increase by 25 mg every 5–7 days
- Target for mast cell/pruritus symptoms: 25–75 mg QHS
- Target for depression: 100–200 mg daily (may split doses; max 300 mg/day)
- Half-life: ~13 hours (once-daily dosing adequate)

 

Monitoring:
- ECG at baseline and when dose exceeds 100 mg/day (QTc prolongation risk)
- Metabolic panel at baseline and 3 months
- Weight monitoring
- Anticholinergic burden assessment (especially if on other anticholinergic agents)

Contraindications/Cautions:
- Avoid in patients >65 years (Beers Criteria — anticholinergic, sedating, orthostatic hypotension risk)
- Avoid in patients with POTS if orthostatic symptoms are prominent (alpha-blocking effects may worsen orthostasis)
- Black box warning: Suicidality risk in patients <25 years
- Avoid with MAOIs; caution with other QT-prolonging agents
- Numerous CYP2D6 and CYP2C19 drug interactions

PATHWAY B: Depression + Insomnia + Nausea/GI Symptoms + Weight Loss → MIRTAZAPINE
Rationale: 80–90% brain H1 receptor occupancy at 15 mg, potent 5-HT3 antagonism (antiemetic), appetite stimulation, anxiolytic properties. Particularly suited for MCAS patients with weight loss and prominent GI symptoms.

Dosing:
- Start: 7.5 mg PO QHS
- Titrate: Increase to 15 mg after 1 week, then by 15 mg every 1–2 weeks
- Target: 15–45 mg QHS
- Note: Lower doses (7.5–15 mg) are MORE sedating due to predominant H1 effects; higher doses (30–45 mg) activate noradrenergic pathways that counteract sedation

Monitoring:
- Weight and metabolic panel at baseline, 1 month, 3 months
- Lipid panel at baseline and 3 months (can cause dyslipidemia)
- CBC (rare risk of agranulocytosis — counsel patient to report fever/sore throat)
 

Contraindications/Cautions:
- Beers list: Use with caution in elderly; monitor sodium (SIADH risk)
- Hepatic impairment: Reduce starting and max dose by 50%
- Severe renal impairment: Start lower, titrate slower
- Weight gain is common and may be unacceptable for some patients

PATHWAY C: Depression Without Prominent Insomnia → FLUOXETINE
Rationale: Direct mast cell stabilization via FcεRI-ATP pathway disruption (independent of serotonin reuptake). Reduces mast cell degranulation, cytokine production, and inflammatory lipid secretion. Preferred SSRI when MCAS is suspected.

Dosing:
- Start: 10 mg PO daily (morning)
- Titrate: Increase to 20 mg after 1 week, then by 10–20 mg every 2–4 weeks
- Target: 20–60 mg daily
- Long half-life (1–3 days; active metabolite norfluoxetine 4–16 days)

Monitoring:
- Standard SSRI monitoring
- Sodium levels (SIADH risk, especially in elderly)

Contraindications/Cautions:
- QT prolongation risk — use caution with other QT-prolonging agents
- Potent CYP2D6 inhibitor — significant drug interaction potential
- Long washout period required before switching to MAOIs or other serotonergic agents
- Hepatic impairment/elderly: Lower or less frequent dosing

PATHWAY D: Acute/Severe Anxiety as Primary Complaint → HYDROXYZINE (Bridge)
Rationale: FDA-approved for anxiety, potent H1 blockade, rapid onset. Useful as a bridge while titrating long-term agents. Avoids benzodiazepine dependence risk.

Dosing:
- 25–50 mg PO Q4–6H PRN (max 100 mg QID)
- Daytime doses may need to be lower than nighttime doses due to sedation

Cautions:
- Beers list: Avoid in elderly
- Renal/hepatic impairment: Reduce dose by 25–50%
- No mast cell stabilizing properties — purely symptomatic H1 blockade
- Intended as short-term/PRN adjunct, not long-term monotherapy
 

STEP 3 — ADD MAST CELL STABILIZER (Weeks 8–16)
If residual symptoms persist after Steps 1–2, add one of the following:
OPTION A: Cromolyn Sodium 200 mg PO QID
- Take 30 minutes before meals and at bedtime
- Begin at 100 mg QID and titrate weekly to 200 mg QID
- Primarily stabilizes GI mast cells (<1% systemic absorption)
- AAAAI notes benefit "might extend to neuropsychiatric manifestations"
- Excellent safety profile; no significant drug interactions
- Best for patients with prominent GI symptoms

OPTION B: Compounded Ketotifen 1 mg PO BID
- H1 antihistamine + mast cell stabilizer with 72% brain H1 receptor occupancy
- Dose-dependent sleep promotion (non-REM enhancement)
- Must be compounded (not FDA-approved for oral use in US)
- Sedation is dose-limiting; start at 0.5 mg BID if concerned
- Best for patients with insomnia + brain fog + skin/GI symptoms
- NCCN Step 4 for neurologic symptoms

STEP 4 — ADD LEUKOTRIENE RECEPTOR ANTAGONIST (Weeks 12–20)
Montelukast 10 mg PO daily (evening)
- Blocks cysteinyl leukotriene receptor (CysLT1)
- AAAAI: "might reduce bronchospasm or gastrointestinal symptoms"
- NCCN: Step 2 for skin symptoms
- Monitor for neuropsychiatric adverse effects (FDA boxed warning): agitation, aggression, depression, suicidal ideation — though these are rare and the risk-benefit in MCAS patients with neuropsychiatric symptoms driven by mast cell activation may differ from the general population
- If neuropsychiatric worsening occurs on montelukast, discontinue and document

STEP 5 — REFRACTORY SYMPTOMS: SPECIALTY REFERRAL
If inadequate response after Steps 1–4 (typically 16–24 weeks), refer to allergy-immunology with the following documentation package:

Referral should include:
- Systematic symptom documentation across organ systems
- Beighton score and active stand test results
- Baseline and (if obtained) acute serum tryptase levels
- 24-hour urine mediator results (if obtained)
- Validated scale scores (PHQ-9, GAD-7, ISI) at baseline and serial follow-up
- Detailed medication trial log with quantified response at each step
- Working diagnosis: "Suspected MCAS per Consensus-2 criteria with documented therapeutic response to antimediator therapy; recommend Consensus-1 confirmatory testing"

Agents requiring specialist initiation:
- Omalizumab (anti-IgE monoclonal antibody): 75% of refractory MCAS patients show partial or complete response; most common dose 150 mg SC every 2 weeks
- Avapritinib (KIT inhibitor): FDA-approved for indolent systemic mastocytosis; requires hematology/oncology involvement


SECTION 5: MEDICATIONS TO USE WITH CAUTION OR AVOID
5.1 — Medications That May Worsen MCAS
- Opioids (codeine, morphine): Can trigger mast cell degranulation
- NSAIDs: May trigger mast cell activation in susceptible patients (though aspirin is used therapeutically in some MCAS patients — individualize)
- Vancomycin (Red Man Syndrome — direct mast cell degranulation)
- Radiocontrast dye: Premedicate if imaging is needed
- Alcohol: Common MCAS trigger

5.2 — Psychiatric Medications Requiring Caution in MCAS/POTS
- First-generation antipsychotics (chlorpromazine, haloperidol): Strong alpha-blocking effects may worsen POTS orthostasis; some may trigger mast cell activation
- Quetiapine: Significant alpha-blocking and antihistaminic effects; may worsen orthostasis in POTS but H1 blockade could theoretically benefit MCAS — use with caution and monitor orthostatic vitals
- Trazodone: Alpha-blocking effects may worsen POTS
- TCAs other than doxepin: Amitriptyline and nortriptyline have antihistaminic properties but less H2 activity; significant anticholinergic and alpha-blocking effects may worsen POTS
- Benzodiazepines: Not contraindicated but avoid long-term use; NCCN actually lists anxiolytics (including benzodiazepines) as part of pre-anesthetic treatment in mastocytosis patients
- SNRIs (venlafaxine, duloxetine): Generally safe; venlafaxine may actually benefit POTS through noradrenergic effects but monitor blood pressure

5.3 — Preferred Psychiatric Medications in MCAS/POTS Overlap
- Fluoxetine (mast cell stabilizing SSRI)
- Doxepin low-dose (if no POTS or mild POTS — monitor orthostatics)
- Mirtazapine (potent H1 blockade, antiemetic)
- Hydroxyzine PRN (anxiety + H1 blockade)
- Cetirizine/famotidine (foundation — not psychiatric medications but within prescribing scope)

SECTION 6: SPECIAL POPULATIONS
6.1 — Pediatric/Adolescent Patients (Age <18)
- POTS threshold: HR increase ≥40 bpm (not 30 bpm) on standing
- Beighton score threshold: ≥6 for GJH
- Doxepin: Black box warning for suicidality in patients <25 years; avoid if possible in this age group
- Fluoxetine: FDA-approved for pediatric depression (age ≥8) and OCD (age ≥7); preferred SSRI in this population given mast cell stabilizing properties
- Montelukast: FDA boxed warning for neuropsychiatric events — monitor closely

6.2 — Geriatric Patients (Age >65)
- Beighton score threshold: ≥4 for GJH
- Avoid doxepin (Beers Criteria — anticholinergic, sedating, orthostatic hypotension)
- Avoid hydroxyzine (Beers Criteria)
- Avoid first-generation antihistamines (NCCN explicitly states these are "not recommended in adult patients ≥65 years of age")
- Preferred agents: Cetirizine (nonsedating H1), famotidine (H2), mirtazapine at low dose with monitoring, fluoxetine with sodium monitoring

6.3 — Pregnant Patients
- Cetirizine: Generally considered safe (Category B)
- Famotidine: Generally considered safe (Category B)
- Cromolyn: Minimal systemic absorption; generally considered safe
- SSRIs: Individualize risk-benefit; fluoxetine has extensive pregnancy safety data
- Doxepin: Avoid in pregnancy
- Refer to maternal-fetal medicine and allergy-immunology for co-management

SECTION 7: DOCUMENTATION TEMPLATE
For each visit, document:
SUBJECTIVE:
- Psychiatric symptom severity (PHQ-9: , GAD-7: , ISI: )
- Mast cell symptom diary composite score: /100
- Triggers identified: [list]
- Medication adherence and tolerability
- New or worsening symptoms

OBJECTIVE:
- Vital signs including orthostatic set (supine → standing HR/BP)
- Beighton score (if not previously documented): /9
- Skin exam: Flushing, urticaria, dermatographism (present/absent)
- Weight

ASSESSMENT:
- Primary psychiatric diagnoses with severity
- Working diagnosis: Suspected MCAS per Consensus-2 criteria
- Major criterion: [document multisystem symptom pattern]
- Minor criterion: [document therapeutic response or lab findings]
- POTS status: Confirmed / Suspected / Ruled out
- hEDS status: GJH confirmed / Full criteria met / Not assessed

PLAN:
- Current medication regimen with doses
- Titration plan for next interval
- Labs ordered or pending
- Referral status
- Next follow-up interval
- Safety plan (if applicable)


SECTION 8: DIAGNOSTIC FRAMEWORK REFERENCE
This protocol uses the Consensus-2 diagnostic framework as a clinical screening tool, with the goal of generating Consensus-1 confirmatory data for specialty referral if needed.

Consensus-1 (AAAAI/Valent et al.) — All 4 required:
1. Episodic symptoms consistent with mast cell activation affecting ≥2 organ systems
2. Decrease in symptoms with antimediator therapy
3. Elevation of validated mast cell mediator (tryptase, N-methylhistamine, 11β-PGF2α, or LTE4)
4. Exclusion of other causes

Consensus-2 (Afrin et al.) — Major criterion + ≥1 minor:
- Major: Clinical complaints attributable to pathologically increased mast cell activity (multisystem, episodic)
- Minor criteria include: Elevated mast cell mediator levels OR symptomatic response to mast cell–directed therapy OR histopathologic findings
The therapeutic trial conducted in Steps 1–4 of this protocol, with quantified symptom response, satisfies the Consensus-2 therapeutic response minor criterion.

Important caveat: Consensus-2 is not endorsed by the AAAAI. Document which framework is being used and why. Frame as "working/preliminary diagnosis pending confirmatory testing" rather than definitive diagnosis.



SECTION 9: QUICK-REFERENCE PRESCRIBING TABLE
Agent       | Starting Dose | Target Dose    | Primary Indication             | Key Monitoring

Cetirizine | 10 mg daily    | 10–40 mg daily | Foundation H1 blockade | None required

Famotidine | 20 mg BID  | 20–40 mg BID | Foundation H2 blockade | None required

Doxepin | 10–25 mg QHS | 25–200 mg QHS | Depression + insomnia + full MCAS | ECG if >100 mg; weight; anticholinergic burden

Mirtazapine | 7.5 mg QHS | 15–45 mg QHS | Depression + insomnia + nausea + weight loss | Weight; lipids; CBC; sodium

Fluoxetine | 10 mg daily | 20–60 mg daily | Depression + mast cell stabilization | Sodium; drug interactions (CYP2D6)

Hydroxyzine | 25 mg PRN | 25–100 mg Q4–6H PRN | Acute anxiety + pruritus | Sedation; avoid in elderly

Cromolyn | 100 mg QID | 200 mg QID | GI-predominant MCAS | None required

Ketotifen | 0.5 mg BID | 1–2 mg BID | Insomnia + brain fog + skin/GI | Sedation; must compound

Montelukast | 10 mg daily | 10 mg daily | Adjunctive leukotriene blockade | Neuropsychiatric AEs (FDA boxed warning)

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VERSION HISTORY

Version 1.0 — July 2026

Developed for PMHNP/MD/DO psychiatric practice

Based on: AAAAI MCAS Work Group Report (2019), NCCN Systemic Mastocytosis Guidelines (v2.2026), Consensus-2 Diagnostic Criteria (Afrin et al., 2021/2026), AGA Clinical Practice Update on hEDS (2025), and supporting pharmacologic literature.

This protocol should be reviewed and updated annually as new evidence emerges.

This protocol integrates evidence from multiple authoritative sources. The stepwise treatment framework is adapted from the NCCN Systemic Mastocytosis Guidelines (v2.2026), which provide organ-specific stepwise approaches for mediator-related symptoms.[2] The medication recommendations and safety caveats for doxepin, ketotifen, cromolyn, and antihistamines are drawn directly from the AAAAI Mast Cell Disorders Committee Work Group Report.[1] Ketotifen and doxepin dosing follows the NEJM review by Theoharides et al.[3]

The Consensus-2 diagnostic framework referenced in Section 8 is based on Afrin et al. (2021/2026), who specifically note that MCAS patients "often present neuropsychiatric symptoms" and that psychiatrists have the opportunity to "short-circuit the often decades-long delay in establishing the correct diagnosis." The hEDS screening criteria (Beighton score and 2017 International Consortium criteria) are drawn from McGillis et al. and Ritelli et al.[4][5][7] The AGA Clinical Practice Update (2025) specifically recommends incorporating the Beighton score as a screening tool and applying the 2017 diagnostic criteria.[8]

The fluoxetine mast cell stabilization data comes from Haque et al. (2023) in Science Signaling.[9] Mirtazapine dosing and safety data are from the FDA label and JAMA Internal Medicine pharmacotherapy tables.[10][6] The omalizumab referral recommendation is supported by a systematic review showing 75% partial or complete response in refractory MCAS.[11]

Key caveats for implementation: (1) This protocol uses Consensus-2 as a screening framework, which is not endorsed by the AAAAI — this should be transparently documented. (2) Evidence for most MCAS treatments is based on expert opinion and case series rather than RCTs — the AAAAI explicitly notes this limitation. (3) The montelukast FDA boxed warning for neuropsychiatric events requires careful risk-benefit discussion in this population. (4) Doxepin's anticholinergic and alpha-blocking properties may worsen POTS — orthostatic vitals should be monitored when used in MCAS/POTS overlap patients.[1]

 

References

1. AAAAI Mast Cell Disorders Committee Work Group Report: Mast Cell Activation Syndrome (MCAS) Diagnosis and Management. Weiler CR, Austen KF, Akin C, et al. The Journal of Allergy and Clinical Immunology. 2019;144(4):883-896. doi:10.1016/j.jaci.2019.08.023.

2. Systemic Mastocytosis. National Comprehensive Cancer Network. Updated 2026-04-09.

3. Mast Cells, Mastocytosis, and Related Disorders. Theoharides TC, Valent P, Akin C. The New England Journal of Medicine. 2015;373(2):163-72. doi:10.1056/NEJMra1409760.

4. Progress in Mast Cell Activation Syndrome: The Global Consensus-2 Diagnostic Criteria at Six Years. Afrin LB, Blitshteyn S, Bluestein LS, et al. Diagnosis (Berlin, Germany). 2026;:dx-2026-0016. doi:10.1515/dx-2026-0016.

5. Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers–Danlos syndrome clinic: A retrospective review. McGillis L, Mittal N, Santa Mina D, et al. American Journal of Medical Genetics. Part A. 2020;182(3):484-492. doi:10.1002/ajmg.a.61459.

6. Treatment of Anxiety for Adults in Primary Care Settings. Shepardson RL, Khan JS, Buckheit KA, Funderburk JS. JAMA Internal Medicine. 2026;:2848049. doi:10.1001/jamainternmed.2026.0395.

7. Looking back and beyond the 2017 diagnostic criteria for hypermobile Ehlers‐Danlos syndrome: A retrospective cross‐sectional study from an Italian reference center. Ritelli M, Chiarelli N, Cinquina V, et al. American Journal of Medical Genetics. Part A. 2024;194(2):174-194. doi:10.1002/ajmg.a.63426.

8. AGA Clinical Practice Update on GI Manifestations and Autonomic or Immune Dysfunction in Hypermobile Ehlers-Danlos Syndrome: Expert Review. Aziz Q, Harris LA, Goodman BP, Simrén M, Shin A. Clinical Gastroenterology and Hepatology : The Official Clinical Practice Journal of the American Gastroenterological Association. 2025;23(8):1291-1302. doi:10.1016/j.cgh.2025.02.015.

9. Fluoxetine Restrains Allergic Inflammation by Targeting an FcɛRI-ATP Positive Feedback Loop in Mast Cells. Haque TT, Taruselli MT, Kee SA, et al. Science Signaling. 2023;16(802):eabc9089. doi:10.1126/scisignal.abc9089.

10. Mirtazapine. Food and Drug Administration. Updated date: 2026-05-20.

11. Systematic Review of Omalizumab for Refractory Clonal and Non-Clonal Mast Cell Activation Syndrome. Matheny MV, Craig T, Al-Shaikhly T. Allergy and Asthma Proceedings. 2025;46(1):11-18. doi:10.2500/aap.2025.46.240076.

12. Refining patterns of joint hypermobility, habitus , and orthopedic traits in joint hypermobility syndrome and Ehlers–Danlos syndrome, hypermobility type. Morlino S, Dordoni C, Sperduti I, et al. American Journal of Medical Genetics. Part A. 2017;173(4):914-929. doi:10.1002/ajmg.a.38106.

13. Bridging the Diagnostic Gap for Hypermobile Ehlers‐Danlos Syndrome and Hypermobility Spectrum Disorders: Evidence of a Common Extracellular Matrix Fragmentation Pattern in Patient Plasma as a Potential Biomarker. Ritelli M, Chiarelli N, Cinquina V, et al. American Journal of Medical Genetics. Part A. 2025;197(1):e63857. doi:10.1002/ajmg.a.63857.