Paliperidone, an active metabolite of risperidone, is a new atypical antipsychotic agent. Syndrome of inappropriate antidiuretic hormone (SIADH), neuroleptic malignant syndrome (NMS), and rhabdomyolysis are the uncommon side effects of psychotropic drugs
Paliperidone, an active metabolite of risperidone, is a new second-generation neuroleptic recently introduced to market as an antagonist of brain dopamine D2 and serotonin 5-hydroxytryptamine (5-
We report a case of patient with schizoaffective disorder on paliperidone showing three concomitant different clinical adverse effects, “neuroleptic malignant syndrome (NMS), syndrome of inappropriate antidiuretic hormone (SIADH), and rhabdomyolysis.”
A 35-year-old male with a history of schizoaffective disorder for six years, treated with oral paliperidone, was brought by emergency medical services for irrational behavior, paranoia, and aggression in the setting of noncompliance with psychiatric treatment for three months. He was hospitalized for acute-on-chronic exacerbation of his psychotic disorder for which intramuscular paliperidone 234 mg injection was given. He denied any other concomitant drug ingestion or alcohol abuse; however, he had a history of previous hospitalization for exacerbation of his psychosis due to his nonadherence towards his treatment.
Two days after admission, he developed an episode of generalized tonic clonic seizures lasting for less than 5 minutes and resolved spontaneously. The patient was transferred to ICU for hyponatremic seizures; pertinent laboratory values included serum sodium 108 mg/dL (136–146), serum osmolality 242 mosm/L (275–295), urine osmolality 438 mosm/L (50–1200), and anion gap metabolic acidosis pH 7.32/PCO2 30/PO2 78/AG 16. Other labs including vitamin B12 (442; 223–1132 pg/mL); folate (8.3; 5.9–24.8 ng/mL); and rapid plasma regain (RPR) were negative. His electroencephalogram (EEG) showed very slow background consistent with diffuse cerebral dysfunction possibly secondary to medication effect. Brain imaging showed no acute intracranial hemorrhage, mass defect, or definite lobar infarction. A diagnosis of euvolemic hyponatremia and hypo osmolality secondary to SIADH was made and he was treated with 3% hypertonic saline 15 gm/500 mL at 50 cc/hr.
On the third hospital day, he developed high grade fever of 102.2 F and severe muscle rigidity. Physical exam revealed his upper limbs were severely contracted. His laboratory data revealed elevated creatine phosphokinase (CPK) 34,548 IU/L (26–189); raised liver enzymes; lactate 6.3 (0.5–2.2); serum cortisol 77.03
Timeline changes in creatine phosphokinase (CPK) and sodium levels.
Timeline | CPK (26–189 IU/L) |
Sodium (136–146 mg/dL) |
Temperature | Leucocytes count (4.5–11.0K/ |
AST (10–40 IU/L) |
---|---|---|---|---|---|
Day 1 | 999 | 113 | Afebrile | 15.7 | 38/31 |
Day 3 | 31173 | 108 |
102.2 F | 13.0 | 289/67 |
Day 4 | 34548 | 131 | 101.0 F | 13.0 | 226/86 |
Week 1 | 5218 | 137 | 100.5 F | 10.9 | 165/96 |
Week 2 | 288 | 135 | Afebrile | 8.1 | 63/93 |
Long acting injectable (LAI), paliperidone palmitate, is efficacious for the acute and maintenance treatment of schizoaffective disorder and is reasonably well tolerated as reported in the present case. It offers a guaranteed delivery system, does not require supplementation with oral antipsychotics, can be administered once monthly, does not require an additional precautionary observation period after the injection, and thus enhances adherence. However, the high acquisition cost of LAI will likely be an important obstacle to its routine use [
Many antipsychotic drugs have been reported to cause SIADH as reported in the current case. Various mechanisms though not yet clear have been suggested, including long-term D2 receptor supersensitivity resulting in ADH release [
NMS is described as an idiosyncratic drug reaction that results in dysregulation of multiple neurochemical and neuroendocrine systems potentially culminating in an end-stage hypermetabolic syndrome. Dehydration, rapid rate of neuroleptic loading, depot neuroleptics, age extremes, prolonged restraints use, use of other medications with neuroleptics (especially lithium), poorly controlled neuroleptic-induced extrapyramidal symptoms (EPS), treatment resistant EPS, withdrawal of antiparkinsonian medications, affective disorder, alcoholism, organic brain syndrome or previous brain injury, extrapyramidal disorder, iron deficiency, and catatonia are the most common risk factors for NMS [
The underlying pathophysiology of NMS is complex and is still debated among experts. Markedly sudden reduction in central dopaminergic activity resulting from D2 receptor blockade within the nigrostriatal, hypothalamic, and mesolimbic/cortical pathways might explain the rigidity, hyperthermia, and altered mental status, respectively. Secondly, sympathoadrenal hyperactivity resulting from the removal of tonic inhibition and defect in calcium regulatory proteins within the sympathetic nervous system may further play a key role in its pathogenesis. Thirdly, release of calcium from the sarcoplasmic reticulum of muscle cells with antipsychotic usage may possibly lead to increased muscle contractility and rigidity, muscle breakdown, and hyperthermia [
In psychiatric patients, rhabdomyolysis usually occurs in association with the intramuscular route of administration, mechanical restraints, and acute dystonia, or in the context of an episode of psychomotor agitation due to specific muscle dysfunction. Rhabdomyolysis induced by antipsychotics is usually associated with NMS, although it may occur alone. The period between the initiation of antipsychotic treatment and the onset of rhabdomyolysis may differ considerably from one case to another which can range between 2 and 5 days and one and a half and two years after starting antipsychotic treatment [
To the best of our knowledge, this is the first case which reports the occurrence of both NMS and SIADH in the same patient treated with paliperidone which further led to rhabdomyolysis. This states that second-generation antipsychotics have potential to cause SIADH, NMS, and rhabdomyolysis and thus highlights the need for health care providers to be aware of these rare, potentially life threatening but preventable conditions. Further studies to investigate the etiology of antipsychotics inducing SIADH and NMS are necessary as these drug induced conditions can be associated with significant morbidity and mortality. Patients treated with paliperidone warrant close clinical monitoring as well as monitoring of serum sodium and CPK.
There is no conflict of interests for the authors of this paper.