What is the relationship between antipsychotics, such as haloperidol (Haloperidol), risperidone (Risperidone), and olanzapine (Olanzapine), and the development of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in patients with a history of psychiatric disorders, particularly schizophrenia or bipolar disorder?

Antipsychotics and SIADH: Clinical Overview

Established Association

Antipsychotics, including haloperidol, risperidone, and olanzapine, are recognized causes of SIADH and should be considered in any psychiatric patient presenting with hyponatremia. 1, 2, 3, 4, 5

The syndrome of inappropriate antidiuretic hormone secretion occurs with both first-generation (typical) and second-generation (atypical) antipsychotics, though the exact incidence may be significantly underreported. 5

Mechanism of Action

• Antipsychotics induce SIADH primarily through serotonin 5-HT2A and dopamine D2 receptor antagonism, which disrupts normal hypothalamic regulation of ADH secretion. 2
• Risperidone's particularly high affinity for these receptors may explain its association with SIADH, especially at doses ≥6 mg/day. 2
• The mechanism differs from polydipsia-induced hyponatremia, which is a separate phenomenon seen in psychiatric patients. 5

Clinical Presentation and Risk Factors

SIADH from antipsychotics can present insidiously, with seizures sometimes being the first and only manifestation of severe hyponatremia. 2

High-Risk Patient Characteristics:

• Mean age of affected patients is 46 years, with 57% being male. 5
• Schizophrenia diagnosis present in 70% of reported cases. 5
• Increasing age, comorbid medical conditions, and polypharmacy substantially elevate risk. 4
• Concomitant use of other medications that prolong QT interval or affect electrolytes (diuretics, SSRIs, anticonvulsants) increases vulnerability. 1

Distinguishing Features:

• Patients are clinically euvolemic with inappropriately high urine osmolality (>100 mOsm/kg) and reduced serum osmolality. 1
• Urine sodium concentration typically >40 mmol/L despite hyponatremia. 2
• History of polydipsia was positive in 67% of cases but negative in 23%, indicating SIADH can occur independently of excessive water intake. 5

Specific Antipsychotic Agents

Haloperidol:

• Well-documented cause of SIADH with demonstrated inability to excrete water loads during treatment. 3
• SIADH can recur with rechallenge. 3, 4

Risperidone:

• SIADH risk increases significantly at doses ≥6 mg/day. 2
• Documented cases show serum sodium dropping to dangerously low levels (106 mmol/L) with seizure presentation. 2
• Also carries increased extrapyramidal symptom risk at higher doses. 6

Olanzapine:

• Associated with SIADH development, though may have a more favorable cardiac profile compared to other agents. 7, 8
• Can cause tardive dyskinesia requiring additional treatment that may further complicate electrolyte management. 8

Quetiapine:

• Documented to cause SIADH similar to haloperidol. 4
• Switching to clozapine resolved SIADH in at least one documented case. 4

Monitoring Protocol

Monitor serum sodium during the first 2-4 weeks of antipsychotic initiation or dose escalation, particularly in high-risk patients. 4

Baseline Assessment:

• Obtain serum sodium, serum osmolality, and renal function before starting treatment. 1
• Document baseline fluid intake patterns and any history of polydipsia. 5
• Check for concurrent medications that increase SIADH risk (SSRIs, carbamazepine, NSAIDs, opioids). 1

Ongoing Surveillance:

• Repeat serum sodium at 1-2 weeks and 3-4 weeks after initiation or dose changes. 4
• Monitor for neurological symptoms: confusion, headache, nausea, seizures, altered mental status. 2
• Assess urine osmolality and sodium if hyponatremia develops (serum Na <136 mmol/L). 5

Management of Antipsychotic-Induced SIADH

Immediate discontinuation of the offending antipsychotic is the primary intervention when SIADH is confirmed. 1, 2

Acute Treatment:

• Stop the causative antipsychotic immediately. 1, 2
• Implement fluid restriction (typically 800-1000 mL/day). 1
• Ensure adequate oral salt intake. 1
• For severe symptomatic hyponatremia (Na <120 mmol/L) with seizures, administer hypertonic saline (3%) cautiously to avoid osmotic demyelination syndrome. 2

Medication Adjustment:

• Consider switching to an alternative antipsychotic with lower SIADH risk (e.g., clozapine showed no SIADH recurrence in one case series). 4
• Avoid polypharmacy with multiple QT-prolonging or SIADH-inducing agents. 1
• Rule out adrenal insufficiency before confirming SIADH diagnosis. 1

Recovery Timeline:

• Serum sodium typically normalizes within days to weeks after drug discontinuation with appropriate fluid restriction. 2
• Seizures resolve once sodium levels are corrected. 2

Critical Pitfalls to Avoid

• Do not attribute hyponatremia solely to polydipsia without checking urine osmolality and sodium—SIADH can occur independently. 5
• Do not overlook SIADH in younger psychiatric patients—while risk increases with age, the mean age of affected patients is only 46 years. 5
• Do not continue the offending antipsychotic while attempting to manage hyponatremia with fluid restriction alone—drug discontinuation is essential. 1, 2
• Do not assume atypical antipsychotics are safer than typical agents regarding SIADH risk—both classes are implicated. 5
• Do not miss the diagnosis when seizures are the presenting symptom—SIADH can be clinically silent until severe. 2
• Do not forget to monitor potassium levels concurrently, as hypokalemia compounds arrhythmic risk with QT-prolonging antipsychotics. 1

Special Considerations for Polypharmacy

• Combining antipsychotics increases both metabolic side effects and SIADH risk—avoid unless clozapine has failed. 1, 9
• Concomitant benzodiazepines do not prevent SIADH but may be used for acute agitation management. 1, 7
• Monitor drug-drug interactions affecting CYP450 metabolism, which can alter antipsychotic plasma concentrations and side effect severity. 1