Olanzapine induced hyponatremia and rhabdomyolysis

Abstract

Rapid‐onset hyponatremia and rhabdomyolysis are rare, but potential, complications of olanzapine treatment. Hyponatremia, secondary to atypical antipsychotic use, has been reported in many case reports and is thought to be associated with an inappropriate antidiuretic hormone secretion syndrome. We report a case of sudden‐onset hyponatremia associated with a severe rhabdomyolysis resulting in a coma‐necessitating intensive care unit admission. His evolution was favorable after correction of all his metabolic disorders and olanzapine suspension.

Short abstract

Disturbances of consciousness are very common in emergency departments, and metabolic causes are often at the root of them. In the case of dysnatremia, drug‐related causes should always be considered.

1. INTRODUCTION

The association between hyponatremia and antipsychotic drug use has been widely reported in the literature; however, it remains poorly understood and underestimated by practitioners, as does rhabdomyolysis.

We report a patient with both symptomatic profound hyponatremia and rhabdomyolysis following the use of olanzapine.

2. CASE REPORT

Mr M. R., 57 years old, was admitted to the intensive care unit of the emergency room for apyretic loss of consciousness. He had a history of schizophrenic disorders for which he was treated with olanzapine 10 mg/day. His family reported that the symptoms were poorly controlled pushing the patient to increase the daily dosage of his medication by himself. He had no history of drug use or any other medical condition.

On the day of admission, the patient was found unconscious by his family, prompting a visit to the emergency room.

On admission, his Glasgow Coma Scale score was 6, pupils were equal and reactive, with no neurological deficits or extrapyramidal syndrome and no signs of seizures.

He was polypneic at 34 cpm, his saturation was 80% on room air with paradoxical breathing and respiratory pauses. Pulmonary auscultation was unremarkable.

Hemodynamically, blood pressure was 115/70 mmHg, HR 110 bpm, and capillary refill time <3 s. Capillary glycemia was 2 g/L, and the temperature was 37.3°. His diuresis was preserved, and urine was slightly concentrated.

After conditioning, the patient was intubated and then sedated, with a cerebral CT scan that came back normal, and a biological workup that came back in favor of hyponatremia at 106 mEq/L and rhabdomyolysis with creatine phosphokinase (CPK) at 19,829 IU/L, lactate dehydrogenase (LDH) at 2254 IU/L, and concomitant hyperkaliemia at 6.9 mEq/L.

Management consisted of correction of the natremia and forced alkaline diuresis.

The rest of the workup showed a urinary osmolarity of 638 mOsm with a natriuresis of 190 mEq/L and a blood osmolarity of 219 mOsm and thus met all the major criteria for inappropriate secretion of antdiuretic hormone (ISADH). The etiological investigation came back negative, and the patient was diagnosed with ISADH with rhabdomyolysis secondary to olanzapine.

The patient was subsequently transferred to a medical intensive care unit for further management. The evolution was marked by a complete awakening of the patient, extubation on day 6 of his admission, after correction of the natremia (146 mEq/L), decrease in the markers of rhabdomyolysis from day 3 (CPK: 1681 UI/L, LDH: 503 UI/L) and normal kaliemia and was transferred to the psychiatric ward on day 10 of his admission.

3. DISCUSSION

Hyponatremia is the direct consequence of inappropriate ADH secretion. Depending on its depth, the clinical picture may range from asymptomatic patient to coma or cardiorespiratory arrest, via neurological disorders such as convulsions, stupor, agitation, and confusion if it is acute, or apathy, anorexia, muscle cramps and memory, and balance disorders when it is progressive. The clinical picture thus depends mainly on the speed of onset and depth of hyponatremia. ¹

Inappropriate secretion of antdiuretic hormone combines several symptoms first described by Schwartz and Bartter in 1967, resulting in normovolemic hyponatremia. ² However, it remains a diagnosis of elimination in the presence of hyponatremia. The diagnostic criteria are presented in Table 1. ¹

TABLE 1.

Diagnostic criteria for ISADH ¹

Major criteria	Minor criteria
Plasma osmolarity <280 mOsm/L Inappropriate urine osmolarity >150 mOsm/L Normal extracellular volume: no orthostatic hypotension, tachycardia, edema or ascites Natriuresis >30 mmol/L on a normosed diet Normal thyroid and adrenal function	No recent use of diuretics No correction of the natremia after infusion of 0.9% saline Correction of the natremia after water restriction

The most common causes of ISADH are pulmonary, neurological, or paraneoplastic. ¹ However, a drug‐related cause should always be sought. The drugs most frequently associated with ISADH are shown in Table 2. ¹

TABLE 2.

Drugs that increase risks of ISADH syndrome ¹

Drugs that increase the production of ADH by the hypothalamus	Antidepressants: tricyclics, serotonin reuptake inhibitors IMAOS Anti‐psychotics: phenotiazine, haloperidol Anti‐epileptics: carbamazepine, valproic acid Anti‐cancer drugs: alacaloids, platinum salts, alkylating agents, methotrexate, Interferon, monoclonal antibodies Opioid analgesics: tramadol, morphine Miscellaneous: proton pump inhibitors, nicotine, “ecstasy” (MDMA), clofibrate
Medication that potentiates the effect of ADH	Anti‐epileptics: carbamazepine, lamotrigine Anti‐diabetics: chlorpropamide, tolbutamide Anti‐cancer drugs: intravenous cyclophosphamide Non‐steroidal anti‐inflammatory drugs
Medicines with ADH activity	Desmopressin, oxytocin, vasopressin

Olanzapine is a new atypical antipsychotic drug with proven efficacy in several psychiatric conditions such as schizophrenia and autism. ³ , ⁴

Olanzapine is a thienobenzodiazepine derivative with affinity for a number of neurotransmitter receptors. It has a significant in vitro inhibitory activity at dopamine, serotonin, histamine, alpha‐adrenergic, and muscarinic receptors. The mixed receptor activity of olanzapine is similar to that of clozapine. ⁵

In a pharmacovigilance study of olanzapine in 8858 patients in the UK, the main adverse effects were somnolence with sedative effect, extrapyramidal signs, weight gain, lassitude, agitation, liver abnormalities and so on. ³

In a study based on cases reported to the WHO International Drug Monitoring Collaboration, Mannesse and all found that olanzapine was the second most common atypical antipsychotic associated with hyponatremia/ISADH, after risperidone. ⁶

In animal models, it has been shown that dopamine has an inhibitory effect on ADH secretion. This effect can be blocked by dopamine receptor antagonists. Olanzapine is a selective monoaminergic antagonist with a high affinity for dopamine receptors and causes ISADH through its antagonism to them. ⁷ , ⁸

The association between olanzapine use and rhabdomyolysis and CPK elevation has also been reported in the literature. ⁴ , ⁹ , ¹⁰ The exact mechanism associated with them remains to be elucidated; however, some authors suggest the existence of an important role for serotonin (5‐HT), as olanzapine would have a more potent activity than antagonists of the serotonin receptors of dopamine. 5‐HT is believed to be toxic to skeletal muscle, which contains high‐affinity receptors in the sarcolemma, and the cell membrane. ¹¹ , ¹²

In our patient, the diagnosis of rhabdomyolysis was retained based on the association of elevated CPK, LDH, and kaliemia levels on the blood test, and the search for myoglobinuria was not performed. The questioning and clinical examination did not reveal any signs of muscle lysis other than toxic, thus allowing olanzapine to be considered the direct cause.

The thorough investigation in order to eliminate all other ISADH main etiologies included dosage of other drugs responsible for SIADH cited in Table 2, thoraco‐abdomino‐pelvic CT scan in search of neoplasic localizations and cerebral CT scan which showed no brain tumors.

The chronology of the symptoms that appeared and worsened concomitantly with the untimely intake of olanzapine, as well as the improvement and correction of the hyponatremia and rhabdomyolysis following the cessation of the said drug and therapeutic measures, without recurrence, support our diagnostic hypothesis.

4. CONCLUSION

The association between the use of olanzapine and the occurrence of episodes of hyponatremia has been reported quite frequently in the literature, as has rhabdomyolysis. They do not seem to be correlated with any risk factor or toxic dose and their occurrence is sporadic. Similarly, the concomitant occurrence of these two complications in the same patient remains exceptional.

Their diagnosis remains of elimination, but this does not delay treatment, which is mostly symptomatic.

AUTHORS CONTRIBUTIONS

N'joumi Younes is the main author of the manuscript. Haimeur Yassine, El Harfaoui Yassine, and Benhlima Abdelkader drafted the manuscript. Elhamzaoui Hamza has revised the manuscript. Alilou Mustapha has given final approval of the version to be published.

CONFLICT OF INTEREST

The authors declare no competing interest.

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

Younes N, Yassine H, Yassine EH, Abdelkader B, Hamza E, Mustapha A. Olanzapine induced hyponatremia and rhabdomyolysis. Clin Case Rep. 2023;11:e05951. doi: 10.1002/ccr3.5951

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.