Case Reports in Critical Care

Case Reports in Critical Care / 2016 / Article

Case Report | Open Access

Volume 2016 |Article ID 2587963 |

Jaspinder Kaur, Dileep Kumar, Mostafa Alfishawy, Ricardo Lopez, Issac Sachmechi, "Paliperidone Inducing Concomitantly Syndrome of Inappropriate Antidiuretic Hormone, Neuroleptic Malignant Syndrome, and Rhabdomyolysis", Case Reports in Critical Care, vol. 2016, Article ID 2587963, 3 pages, 2016.

Paliperidone Inducing Concomitantly Syndrome of Inappropriate Antidiuretic Hormone, Neuroleptic Malignant Syndrome, and Rhabdomyolysis

Academic Editor: Kenneth S. Waxman
Received22 May 2016
Accepted28 Aug 2016
Published18 Sep 2016


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. We report a case of 35-year-old male with schizoaffective disorder who was admitted for acute-on-chronic exacerbation of his psychotic disorder for which intramuscular paliperidone 234 mg injection was given. Two days later, the patient developed hyponatremic seizures secondary to SIADH which was treated with hypertonic saline. On the third day, he developed high grade fever and severe muscle rigidity with raised creatine phosphokinase (CPK) and liver enzymes levels. He was treated with dantrolene 100 mg, bromocriptine 2.5 mg, and lorazepam 2 mg. Our patient required management of the three rare conditions following treatment with paliperidone. This case highlights the need for health care providers to be aware of the rare, potentially life threatening but preventable hyponatremia, NMS, and rhabdomyolysis as a possible adverse effect of paliperidone.

1. Introduction

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-) receptors. Food and Drug Administration (FDA) has approved it for the treatment of schizophrenia and schizoaffective disorders, whereas off-label uses include management of psychosis and bipolar disorder [1]. The safety of paliperidone was evaluated in six-week clinical trials performed prior to FDA approval. In these placebo-controlled double-blind trials, the most common adverse reactions were extrapyramidal symptoms (3–10%), tachycardia (9–22%), hyperkinesia (3–11%), hypertonia (1–6%), and drowsiness (4–13%). Other observed side effects were cardiac disorders (various cardiac rhythm disturbances, prolonged QTc interval, and orthostatic hypotension), gastrointestinal disorders, anxiety, sleep disorder, and headache [2].

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.”

2. Case Report

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 μg/dL (0.7–22.4); free T4 1.00 ng/dL (0.58–1.64); serum magnesium 2.08 mg/dL (1.7–2.7); and serum phosphorus 3.5 mg/dL (2.5–4.9). The patient was intubated for airway protection. Intravenous hydration with sodium chloride 0.9% and sodium bicarbonate 75 cc/hour was given to prevent acute kidney injury, and gradual improvement of his sodium level was noticed. A diagnosis of paliperidone induced SIADH, NMS, and rhabdomyolysis was made. He was treated with dantrolene 100 mg intravenously (IV) two times a day (BID) for two days; bromocriptine 2.5 mg orally (PO) via nasogastric tube three times a day (TID) for the first five days and then once daily (QD) for the next five days; and lorazepam 2 mg IV as needed (PRN). After two weeks of treatment with this regimen, all his labs normalized (Table 1) and he was transferred to psychiatric unit.

TimelineCPK (26–189 IU/L)Sodium (136–146 mg/dL)TemperatureLeucocytes count (4.5–11.0K/μL)AST (10–40 IU/L)/ALT (7–50 IU/L)

Day 1999113Afebrile15.738/31
Day 331173108
102.2 F13.0289/67
Day 434548131101.0 F13.0226/86
Week 15218137100.5 F10.9165/96
Week 2288135Afebrile8.163/93

Values in the brackets correspond to normal range.

3. Discussion

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 [3].

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 [4], antipsychotic induced hypotension leading to ADH release through baroreceptor reflex, and serotonin mediated effects on central 5-HT2 and 5-HT1c receptors stimulating ADH secretion [5].

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 [6]. In our case, history of schizoaffective disorder, use of depot neuroleptic, and catatonia might have predisposed the patient to 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 [7]. Moreover, it was recently hypothesized that long-term treatment with second-generation antipsychotics might cause imbalances in serotonergic neurotransmission, leading to sensitization towards them, and an excess of central serotonin could determine a “relative hypodopaminergic state” which might increase the risk of developing NMS [8]. However, Martino et al. reported that NMS induced by second-generation antipsychotics is characterized by lower incidence, lower clinical severity, and less frequent lethal outcome than NMS induced by first generation antipsychotics [8]; contrarily, our patient has a typical presentation with mental status alteration, rigidity, diaphoresis, hyperpyrexia, tremor, and other EPS but with a favorable evolution and complete recovery.

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 [9]. Moreover, both the hyponatremia and quick supplementation of sodium chloride can also cause rhabdomyolysis. The exact etiology of rhabdomyolysis secondary to hyponatremia is unclear, but several mechanisms have been proposed. First, lower osmolality of the extracellular fluid in acute hyponatremia causes cell swelling, and lowered transmembrane potential hours after the extrusion of intracellular potassium causes the release of CPK and myoglobin [10]. Secondly, the decreased extracellular sodium may disturb the Na-Ca exchange pumps which cause increased intracellular calcium and cell death by releasing proteases and lipase [11]. In our patient, rhabdomyolysis may be secondary to intramuscular antipsychotic use, NMS, and hyponatremia.

4. Conclusion

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.

Competing Interests

There is no conflict of interests for the authors of this paper.


  1. R. A. Schneider and M. H. Lizer, “Apparent seizure and atrial fibrillation associated with paliperidone,” American Journal of Health-System Pharmacy, vol. 65, no. 22, pp. 2122–2125, 2008. View at: Publisher Site | Google Scholar
  2. J. Kane, F. Canas, M. Kramer et al., “Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial,” Schizophrenia Research, vol. 90, no. 1–3, pp. 147–161, 2007. View at: Publisher Site | Google Scholar
  3. L. Citrome, “Paliperidone palmitate—review of the efficacy, safety and cost of a new second-generation depot antipsychotic medication,” International Journal of Clinical Practice, vol. 64, no. 2, pp. 216–239, 2010. View at: Publisher Site | Google Scholar
  4. W. V. R. Vieweg and R. A. Leadbetter, “Polydipsia-hyponatraemia syndrome: epidemiology, clinical features and treatment,” CNS Drugs, vol. 7, no. 2, pp. 121–138, 1997. View at: Publisher Site | Google Scholar
  5. I. Kohen, S. Voelker, and P. Manu, “Antipsychotic-induced hyponatremia: case report and literature review,” American Journal of Therapeutics, vol. 15, no. 5, pp. 492–494, 2008. View at: Publisher Site | Google Scholar
  6. A. L. Pelonero, J. L. Levenson, and A. K. Pandurangi, “Neuroleptic malignant syndrome: a review,” Psychiatric Services, vol. 49, no. 9, pp. 1163–1172, 1998. View at: Publisher Site | Google Scholar
  7. B. D. Berman, “Neuroleptic malignant syndrome: a review for neurohospitalists,” The Neurohospitalist, vol. 1, no. 1, pp. 41–47, 2011. View at: Publisher Site | Google Scholar
  8. B. M. Martino, G. Argentina, B. Michele et al., “Second-generation antipsychotics and neuroleptic malignant syndrome: systematic review and case report analysis,” Drugs in R&D, vol. 15, no. 1, pp. 45–62, 2015. View at: Publisher Site | Google Scholar
  9. K. Star, N. Iessa, N. B. Almandil et al., “Rhabdomyolysis reported for children and adolescents treated with antipsychotic medicines: a case series analysis,” Journal of Child and Adolescent Psychopharmacology, vol. 22, no. 6, pp. 440–451, 2012. View at: Publisher Site | Google Scholar
  10. H. Trimarchi, J. Gonzalez, and J. Olivero, “Hyponatremia-associated rhabdomyolysis,” Nephron, vol. 82, no. 3, pp. 274–277, 1999. View at: Publisher Site | Google Scholar
  11. J. Y. S. Ting, “Rhabdomyolysis and polydipsic hyponatraemia,” Emergency Medicine Journal, vol. 18, no. 6, article 520, 2001. View at: Publisher Site | Google Scholar

Copyright © 2016 Jaspinder Kaur et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.