Does Invega (paliperidone) cause hyponatremia?

Does Invega (Paliperidone) Cause Hyponatremia?

Yes, Invega (paliperidone) can cause hyponatremia, and this is a recognized adverse effect that requires clinical monitoring.

Evidence for Paliperidone-Induced Hyponatremia

A recent disproportionality analysis of the Spanish Pharmacovigilance System identified paliperidone as a statistically significant safety signal for hyponatremia, with a Reporting Odds Ratio of 2.7 (95% CI: 1.3-5.7), meeting EMA criteria for a new safety signal 1. This finding is particularly notable because hyponatremia is not currently listed in paliperidone's Summary of Product Characteristics, suggesting the risk may be underrecognized 1.

The mechanism appears to be nephrogenic syndrome of inappropriate antidiuresis (NSIAD) rather than classic SIADH 2. Antipsychotics, including paliperidone's parent compound risperidone, can upregulate aquaporin-2 (AQP2) in the renal collecting duct through intrarenal V2 receptor activation, leading to water retention even when plasma AVP levels are suppressed 2.

Clinical Context and Risk Profile

Incidence and Patient Characteristics

• The overall incidence of antipsychotic-induced hyponatremia may be much higher than currently recognized 3
• Both atypical antipsychotics (like paliperidone) and older typical agents have been associated with hyponatremia 3
• Most drug-induced hyponatremia cases are serious (93%) and predominantly affect women (63.7%) and elderly patients (71.9%) 1
• Time to onset is highly variable, ranging from 1 to 7030 days (median 79 days), with approximately 70% occurring within the first year of treatment 1

Mechanism of Action

Paliperidone, as the major active metabolite of risperidone, shares similar pharmacological properties 4. Antipsychotics induce hyponatremia through intrarenal AQP2 upregulation via V2R-cAMP-PKA signaling pathways, a mechanism distinct from classic vasopressin-mediated SIADH 2. This intrarenal activation can occur independently of circulating AVP levels 2.

Clinical Monitoring Recommendations

Who to Monitor

• Elderly patients (>65 years) on paliperidone require heightened surveillance 1
• Women appear at higher risk than men 1
• Patients on multiple medications (polypharmacy) face increased risk 1
• Those with pre-existing risk factors for hyponatremia (heart failure, cirrhosis, concurrent diuretic use) 5

Monitoring Protocol

• Check baseline serum sodium before initiating paliperidone 5
• Monitor serum sodium at 2-4 weeks after initiation, as hyponatremia can develop rapidly (within days) or gradually over months 1, 6
• Continue periodic monitoring throughout treatment, as onset can occur even after prolonged therapy 1
• If sodium drops below 135 mmol/L, investigate further with serum osmolality, urine sodium, and urine osmolality 5

Management if Hyponatremia Develops

Immediate Actions

• Discontinue paliperidone if hyponatremia is detected 1
• Most patients (82.9%) show complete recovery after withdrawal of the suspected medication 1
• Assess volume status (hypovolemic, euvolemic, or hypervolemic) to guide treatment 5

Treatment Based on Severity

For mild hyponatremia (130-135 mmol/L):

• Discontinue paliperidone and monitor closely 5
• Implement fluid restriction to 1 L/day if euvolemic 5

For moderate hyponatremia (120-125 mmol/L):

• Discontinue paliperidone immediately 5
• Fluid restriction to 1-1.5 L/day 5
• Monitor sodium every 24-48 hours 5

For severe symptomatic hyponatremia (<120 mmol/L with neurological symptoms):

• Discontinue paliperidone 5
• Administer 3% hypertonic saline with target correction of 6 mmol/L over 6 hours 5
• Never exceed 8 mmol/L correction in 24 hours to prevent osmotic demyelination syndrome 5

Common Pitfalls to Avoid

• Do not assume hyponatremia is unrelated to paliperidone simply because it is not prominently listed in current prescribing information 1
• Do not delay monitoring until symptoms appear, as hyponatremia can be asymptomatic initially 1
• Do not continue paliperidone without addressing hyponatremia, as the condition can progress 1
• Avoid rapid overcorrection if severe hyponatremia develops, as this risks osmotic demyelination syndrome 5

Alternative Considerations

If paliperidone-induced hyponatremia occurs, consider switching to an antipsychotic with lower hyponatremia risk after careful risk-benefit assessment, though all antipsychotics carry some risk 3. The choice should account for efficacy for the underlying psychiatric condition and individual patient risk factors 3.