Aripiprazole-related hyponatremia and consequent valproic acid–related hyperammonemia in one patient

To the Editor

Aripiprazole-related hyponatremia and valproic acid (VPA)-related hyperammonemia have been reported (Vazquez et al., 2014; Yam et al., 2013), but a possible connection between the two has rarely been discussed. Herein, we report a case with both aripiprazole-related hyponatremia and VPA-related hyperammonemia.

A 35-year-old Taiwanese female patient with a 10-year history of bipolar I disorder was admitted to our psychiatric ward due to a manic episode after she had stopped taking her medication because of pregnancy (olanzapine 10 mg and lithium 900 mg daily) for 8 months. After a Caesarean section, pharmacological therapy then resumed in another hospital, and she was transferred to our ward because of persistent manic symptoms despite 1 month of treatment with aripiprazole 10 mg and VPA 1500 mg per day. Her serum sodium level decreased from 128 mmol/L to 119 mmol/L during aripiprazole therapy even under fluid restriction and then recovered to a normal range after she stopped taking aripiprazole. Her serum transaminases were in normal range; however, her serum ammonia level increased from 93 µg/dL to 226 µg/dL without response to lactulose solution. The serum ammonia level then returned to a normal range after VPA was switched to lithium. Her bipolar I disorder was eventually controlled with lithium 900 mg a day.

Hyperammonemia is a well-known adverse effect of VPA. The main metabolic pathway of VPA is beta-oxidation in the mitochondria. VPA can cross the membrane of liver mitochondria, facilitated by carnitine (Vazquez et al., 2014). A carnitine deficiency can increase omega-oxidation leading to a higher concentration of 4-en-VPA and insufficient ammonia elimination through the urea cycle, which can then lead to hyperammonemia (Vazquez et al., 2014).

Our patient had aripiprazole-related hyponatremia which was likely due to serotonin-mediated syndrome of inappropriate antidiuretic hormone (Yam et al., 2013). There might be a connection between these two metabolic abnormalities. Carnitine palmitoyltransferase I (CPT-1) catalyzes what is thought to be a rate-limiting step in fatty acid transportation to the mitochondrial matrix (Guzman and Geelen, 1988) that is also responsible for carnitine-assisted VPA transportation. Vasopressin, also known as antidiuretic hormone, has been reported to inhibit the activity of carnitine palmitoyltransferase (Guzman and Geelen, 1988) and is also responsible for carnitine-assisted VPA transportation.

In conclusion, we report a rare case of aripiprazole-related hyponatremia and VPA-related hyperammonemia in one patient. This case should remind clinicians of the importance of the possible interaction between these two commonly used medications to prevent the risk of severe adverse effects.