Hypophosphatemia and Neuroleptic Malignant Syndrome

To the Editors: The neuroleptic malignant syndrome (NMS) is a rare but potentially fatal adverse event associated with the use of conventional and atypical antipsychotic medications. In addition to the commonly observed symptoms of fever, muscular rigidity, autonomic dysregulation, and delirium, several abnormalities in laboratory indices are also associated with NMS. Laboratory abnormalities commonly associated with NMS include elevations of serum creatine phosphokinase, leukocytosis, decreased serum iron, and abnormalities in serum sodium. Less commonly reported in NMS are abnormalities in serum phosphate, although derangements of serum phosphate concentrations may be common and potentially associated with substantial morbidity and mortality. We briefly report on cases of hypophosphatemia associated with NMS and review some potential implications of this finding. Phosphate is widely distributed in the body and essential for many physiological processes. The highest concentrations of phosphate are present in the skeleton, skeletal muscle, and viscera. The reference range of serum phosphate in humans is between 0.80 and 1.45 mmol/L. Most complications associated with serum phosphate abnormalities occur in moderate (serum phosphate 0.32–0.65 mmol/L) or severe (<0.32 mmol/L) states of phosphate depletion. Hypophosphatemia is associated with cardiac arrhythmias, reduced cardiac performance, respiratory failure, seizures, and coma. Rhabdomyolysis is also a potential complication of both hypophosphatemia and NMS. Common causes of hypophosphatemia include internal redistribution from the serum into other body compartments, decreased intestinal absorption, and increased urinary losses. We previously described a case of NMS during treatment with risperidone and clozapine that was associated with moderate to severe hypophosphatemia (serum phosphate level 0.36 mmol/L), and a chart review of NMS diagnoses at our hospital revealed another case of NMS complicated by hypophosphatemia during treatment with haloperidol and quetiapine (serum phosphate level 0.52 mmol/L). Review of the literature revealed 10 additional cases of hypophosphatemia associated with NMS with phosphate levels reported in 3 cases. The average serum phosphate level in the 5 cases reporting serum phosphate was 0.38 mmol/L (range, 0.23–0.52 mmol/L). Unfortunately, baseline serum phosphate levels before the development of NMS were not reported. Another case described the development NMS in a patient with cancer who had severe hypophosphatemia (serum phosphate 0.06 mmol/L) before receiving antipsychotics or displaying symptoms of NMS. Hypophosphatemia is not reported as a risk factor or potential sequelae of NMS in major review papers and textbooks of this subject, and serum phosphate levels are infrequently reported in published case reports of NMS in the medical literature. There are many potential mechanisms by which NMS may be associated with hypophosphatemia. Phosphate deficiency is an uncommon cause of hypophosphatemia except in malabsorption syndromes and states of severe malnutrition. Increased renal excretion of phosphate is an unlikely cause of hypophosphatemia in NMS as NMS is associated with renal failure, a condition more often resulting in hyperphosphatemia. Redistribution of serum phosphate from the serum to body tissues is the most common cause of hypophosphatemia in clinical settings and likely explains the association between hypophosphatemia and NMS. Redistribution of phosphate may occur in several pathological conditions associated with nonspecific acute-phase responses including respiratory alkalosis from hyperventilation, systemic inflammation (eg, sepsis), and states associated with increased levels of circulating catecholamines. Tachypnea resulting in hyperventilation, markers of inflammation including leukocytosis, decreased serum iron, and elevated serum catecholamines are all associated features of NMS providing support for the redistribution of phosphate during NMS as the mechanism of hypophosphatemia with this disorder. Hyperphosphatemia has also been observed in NMS, although less frequently than hypophosphatemia. Calcium is also linked to phosphate homeostasis, and intracellular calcium has also been implicated in the pathophysiology of NMS. Chronic states of calcium depletion, hyperparathyroidism through the action of parathyroid hormone on phosphate reabsorption, and vitamin D deficiency may all contribute to hypophosphatemia. Calcium levels in cases of NMS associated with hypophosphatemia have been reported as decreased or within normal limits when calcium levels are reported. At present, it is uncertain whether hypophosphatemia is a risk factor or a consequence of NMS. Published case reports of NMS infrequently noted phosphate levels, making it difficult to determine if most NMS episodes are associated with abnormal levels of serum phosphate or whether phosphate levels were measured and not reported because they were within normal limits. Considering the potential complications associated with hypophosphatemia, clinicians are advised to be aware of this finding and to evaluate and monitor serum phosphate levels carefully in all individuals suspected of having NMS.