What antipsychotics are less likely to cause hyponatremia?

Antipsychotics Less Likely to Cause Hyponatremia

Based on available evidence, atypical antipsychotics with higher serotonin 5-HT2A receptor occupancy and lower dopamine D3 receptor occupancy are less likely to cause hyponatremia, with aripiprazole being the preferred option due to its receptor profile. 1

Mechanism of Antipsychotic-Induced Hyponatremia

Hyponatremia associated with antipsychotics is a rare but potentially life-threatening adverse drug reaction. The pharmacological mechanism involves:

• Positive association between dopamine D3, D4 receptor occupancy and hyponatremia 1
• Negative association (protective effect) of serotonin 5-HT2A, 5-HT1A, and adrenergic α1 receptor occupancy against hyponatremia 1
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH) as a common mechanism 2
• Possible polydipsia in some cases, particularly in schizophrenia patients 3

Antipsychotics with Lower Risk of Hyponatremia

Preferred Options:

1. Aripiprazole - Has a favorable receptor profile with higher 5-HT2A occupancy relative to D3 occupancy 1
2. Brexpiprazole - Similar receptor profile to aripiprazole with better safety profile overall 4

Moderate Risk:

1. Risperidone - Better tolerated than traditional neuroleptics but may still cause hyponatremia 5, 3
2. Ziprasidone - Less commonly associated with hyponatremia in case reports 3

Higher Risk (Avoid if Possible):

1. Olanzapine - Most frequently reported antipsychotic associated with hyponatremia (27% of cases) 1, 6, 2
2. Quetiapine - Associated with significant risk of hyponatremia 3
3. Haloperidol and other typical antipsychotics - Higher risk profile for hyponatremia 3

Monitoring Recommendations

When prescribing antipsychotics, especially in high-risk patients:

• Check baseline sodium levels before initiating treatment
• Monitor sodium levels within 1-2 weeks after starting treatment or changing doses 4
• Continue periodic monitoring, especially in elderly patients or those on other medications that may cause hyponatremia
• Be vigilant for early signs of hyponatremia: confusion, headache, lethargy, muscle cramps, nausea

Risk Factors for Antipsychotic-Induced Hyponatremia

• Advanced age (elderly patients)
• Female gender
• Concomitant use of other medications known to cause hyponatremia (diuretics, SSRIs, etc.) 7
• History of hyponatremia
• Diagnosis of schizophrenia (70% of reported cases) 3
• History of polydipsia (67% of reported cases) 3

Clinical Implications

• The incidence of antipsychotic-induced hyponatremia may be higher than currently recognized 3
• Both typical and atypical antipsychotics can cause hyponatremia, though atypical antipsychotics generally have a more attenuated risk profile 1
• Hyponatremia can develop rapidly after initiation of antipsychotic treatment, even at low doses 2
• Medical conditions are often overlooked in psychiatric patients, so maintain high clinical suspicion 6

Pitfalls to Avoid

• Failing to monitor electrolytes when starting antipsychotics
• Overlooking early signs of hyponatremia due to attribution to psychiatric symptoms
• Not considering drug interactions that may increase hyponatremia risk
• Continuing the same antipsychotic after an episode of hyponatremia

When hyponatremia occurs, consider switching to an antipsychotic with higher 5-HT2A receptor occupancy and lower D3 receptor occupancy, such as aripiprazole or brexpiprazole, as these pharmacological properties appear to be protective against developing hyponatremia.