How should I evaluate and manage orthostatic hypotension that began after starting or increasing quetiapine (Seroquel)?

Evaluation and Management of Quetiapine-Induced Orthostatic Hypotension

Discontinue or significantly reduce quetiapine immediately, as medication-induced orthostatic hypotension is the most frequent cause of this condition and elimination of the offending agent is the primary treatment strategy—not dose reduction alone. 1

Diagnostic Confirmation

• Measure blood pressure after 5 minutes of supine or seated rest, then repeat at 1 minute and 3 minutes after standing 1
• Document a drop of ≥20 mmHg systolic or ≥10 mmHg diastolic to confirm orthostatic hypotension 1
• Record accompanying symptoms (dizziness, lightheadedness, syncope, falls) that correlate with postural changes 1

Immediate Medication Review

Quetiapine causes orthostatic hypotension through α1-receptor antagonism, which blocks peripheral vasoconstriction needed to maintain blood pressure when standing. 2, 3 All antipsychotics are associated with significant orthostatic hypotension risk, with phenothiazines and atypical agents like quetiapine being particularly problematic. 2

• Review all concomitant medications that worsen orthostatic hypotension: diuretics, other vasodilators, α-blockers (doxazosin, prazosin, terazosin, tamsulosin), centrally-acting agents (clonidine, methyldopa), and other antihypertensives 1, 4
• Switch—do not simply reduce—any blood pressure medications that exacerbate orthostatic symptoms to long-acting dihydropyridine calcium channel blockers or RAS inhibitors, which have minimal orthostatic impact 1, 4
• Discontinue α-blockers completely, as they are the most problematic agents in older adults 1

Assessment of Contributing Factors

• Evaluate volume status for dehydration, acute blood loss, or hypovolemia as reversible contributors 1
• Obtain focused history of recent fluid intake, diuretic use, vomiting, diarrhea, or heat exposure 1
• In diabetic patients >50 years, assess for cardiovascular autonomic neuropathy using cardiac autonomic reflex tests, as orthostatic hypotension may represent advanced autonomic failure 1

Non-Pharmacological Management (First-Line)

These measures must be implemented before considering pharmacological treatment for orthostatic hypotension. 1, 3

• Increase fluid intake to 2–3 liters daily and dietary sodium to 6–9 grams daily, unless contraindicated by heart failure or uncontrolled hypertension 1
• Teach physical counter-pressure maneuvers: leg crossing, squatting, stooping, and muscle tensing during symptomatic episodes 1
• Advise gradual positional changes—sit on bedside for 2–3 minutes before standing, avoid prolonged standing 1
• Apply waist-high compression stockings (30–40 mmHg) and abdominal binders to reduce venous pooling 1
• Elevate head of bed by approximately 10 degrees to prevent nocturnal polyuria and improve fluid redistribution 1
• Recommend smaller, more frequent meals to reduce postprandial hypotension 1
• Encourage acute water ingestion of ≥480 mL for temporary relief, with peak effect at 30 minutes 1

Pharmacological Treatment (If Symptoms Persist Despite Non-Pharmacological Measures)

Pharmacological treatment is only recommended when symptomatic orthostatic hypotension persists despite proper non-pharmacological therapy and there is a compelling indication for continued antipsychotic treatment. 3

First-Line Agent: Midodrine

• Midodrine has the strongest evidence base among pressor agents, supported by three randomized placebo-controlled trials 1
• Start at 2.5–5 mg three times daily at roughly 4-hour intervals during waking hours 1
• Titrate up to 10 mg three times daily based on symptom response 1
• Administer the last dose at least 3–4 hours before bedtime (not after 6 PM) to prevent supine hypertension during sleep 1
• Increases standing systolic blood pressure by 15–30 mmHg for 2–3 hours via α1-adrenergic vasoconstriction 1

Second-Line or Combination Agent: Fludrocortisone

• Fludrocortisone is a reasonable first choice for symptomatic orthostatic hypotension and can be used alone or combined with midodrine 3
• Start at 0.05–0.1 mg once daily, titrate to 0.1–0.3 mg daily 1
• Acts through sodium retention and vessel wall effects, complementing midodrine's mechanism 1
• Monitor for supine hypertension, hypokalemia, congestive heart failure, and peripheral edema 1
• Avoid in patients with active heart failure or severe renal disease 1

Refractory Cases: Pyridostigmine

• Consider pyridostigmine 60 mg three times daily for patients refractory to midodrine and fludrocortisone, particularly when supine hypertension limits further pressor use 1
• Does not worsen supine blood pressure, making it advantageous in complex cases 1
• Common side effects include nausea, vomiting, abdominal cramping, sweating, salivation, and urinary incontinence 1

Monitoring and Treatment Goals

• The therapeutic goal is to minimize postural symptoms and improve functional capacity, NOT to restore normotension 1
• Measure both supine and standing blood pressure at each follow-up visit 1
• Reassess within 1–2 weeks after any medication changes 1
• Monitor for development of supine hypertension, which can cause end-organ damage 1
• Check electrolytes periodically when using fludrocortisone due to mineralocorticoid effects causing potassium wasting 1

Critical Pitfalls to Avoid

• Do not simply reduce the dose of quetiapine—switch to an alternative antipsychotic with lower orthostatic risk or discontinue entirely 1
• Do not administer midodrine after 6 PM 1
• Do not use fludrocortisone in patients with heart failure or supine hypertension 1
• Do not combine multiple vasodilating agents without careful monitoring 1
• Do not overlook volume depletion as a contributing factor 1
• Asymptomatic orthostatic hypotension during treatment should not trigger automatic down-titration of necessary cardiovascular medications, as intensive blood pressure control may actually reduce orthostatic hypotension risk by improving baroreflex function 5

Special Consideration: Acute Overdose Management

In cases of quetiapine overdose with severe hypotension unresponsive to fluids, noradrenaline is the preferred vasopressor—not adrenaline—because quetiapine's α1-receptor antagonism makes adrenaline's β2-agonism counterproductive, potentially worsening hypotension through vasodilation. 6 Noradrenaline maintains α1-receptor agonism with less affinity for α2- and β2-receptors. 6