Does olanzapine cause rhabdomyolysis and increased muscle enzymes? A detailed look

October 10, 2025 •

3 min read

While considered a rare adverse effect, (<1%) olanzapine is documented in case reports and pharmacovigilance studies to cause rhabdomyolysis and significant increases in muscle enzymes. This serious condition can occur in some individuals and requires prompt medical attention.

Quick Summary

Yes, olanzapine can cause rhabdomyolysis and elevated muscle enzymes, though it is a rare complication. Case reports document instances occurring with both short-term and long-term use, in the absence of neuroleptic malignant syndrome (NMS).

Key Points

Rhabdomyolysis Risk: Olanzapine can cause rhabdomyolysis, a rare side effect in less than 1% of patients.
Associated with Elevated Enzymes: Rhabdomyolysis leads to increased serum creatine kinase (CK) and other muscle enzymes.
Not Always NMS-Related: Olanzapine-induced rhabdomyolysis can occur without neuroleptic malignant syndrome (NMS).
Diverse Timing: This adverse effect can appear soon after starting treatment, after overdose, or after years of use.
Recognize Key Symptoms: Watch for muscle pain, weakness, fatigue, and dark urine.
Importance of Monitoring: Monitoring is crucial, especially during dose changes or in patients with risk factors; check CK levels if symptoms arise.
Genetic Factors: Genetic differences, particularly in drug metabolism enzymes like CYP2D6, can increase risk due to higher drug levels.
Highest Signal in Databases: Pharmacovigilance studies, like a FAERS database analysis, show olanzapine having the highest reporting signal for rhabdomyolysis among some atypical antipsychotics.

The Connection Between Olanzapine and Rhabdomyolysis

Olanzapine, an atypical or second-generation antipsychotic used for conditions like schizophrenia and bipolar disorder, is generally well-tolerated. However, rhabdomyolysis and elevated muscle enzymes are a rare but serious potential side effect. Rhabdomyolysis involves the breakdown of skeletal muscle tissue, releasing components like creatine kinase (CK) and myoglobin into the bloodstream, which can lead to acute kidney injury. A CK level exceeding 1,000 U/L or five times the upper limit of normal typically confirms the diagnosis.

Olanzapine-induced rhabdomyolysis can occur independently of neuroleptic malignant syndrome (NMS), a condition also involving muscle rigidity and elevated CK, and without the full set of NMS symptoms. Reports indicate cases occurring both upon starting therapy and after years of stable use.

Proposed Mechanisms of Action

The precise way olanzapine causes muscle breakdown is not fully understood, but its pharmacological actions on various receptors are thought to be involved. Olanzapine interacts with dopamine D2 and serotonin 5-HT2A receptors. Potential mechanisms include:

Serotonergic Blockade: Antagonism of the 5-HT2A receptor may affect muscle glucose uptake and cell membrane permeability, leading to CK leakage and muscle damage.
Dopaminergic Blockade: While more linked to typical antipsychotics, this can cause muscle rigidity and involuntary movements that might elevate CK.
Electrolyte Changes: Some theories suggest antihistamine effects could alter sodium and calcium levels within cells, activating enzymes that damage muscle.
Genetic Factors: Genetic variations in drug metabolism, such as with the CYP2D6 enzyme, might increase olanzapine levels and raise risk.

Pharmacovigilance Data and Case Reports

Evidence linking olanzapine to rhabdomyolysis comes from case reports and analyses of adverse event databases. A study of the FDA Adverse Event Reporting System (FAERS) database found that olanzapine showed the strongest association signals for rhabdomyolysis among several atypical antipsychotics. For specific case examples and potential risk factors, including genetic factors, medication changes, drug overdose, and potential vulnerability in pediatric and adolescent patients, refer to {Link: Dr.Oracle https://www.droracle.ai/articles/278964/can-olanzapine-or-lorazepam-cause-rhabdomylysis-}.

Clinical Recognition and Management

Prompt identification of rhabdomyolysis is vital to prevent serious complications like acute kidney failure. Symptoms can be non-specific, requiring clinicians to consider the possibility in patients taking olanzapine who develop new muscle-related issues.

Warning Signs and Symptoms

Patients on olanzapine should be aware of these potential signs:

Muscle pain, aches, or tenderness
Muscle weakness or fatigue
Dark, reddish, or tea-colored urine
Abdominal pain

Monitoring and Management

If rhabdomyolysis is suspected, key steps include:

Immediate Discontinuation: Stop olanzapine right away.
Laboratory Tests: Check serum creatine kinase and kidney function promptly.
Supportive Care: Administer aggressive intravenous fluids to help prevent acute kidney injury.
Specialist Consultation: Consider consulting a pharmacologist or genetic counselor if pharmacogenetic factors are suspected.

Comparison of Antipsychotic Rhabdomyolysis Risk

A retrospective analysis of the FAERS database (2004-2023) examined the link between atypical antipsychotics and rhabdomyolysis. The study identified reporting associations for several drugs. The table below presents the reported odds ratios (RORs) from this analysis:


Antipsychotic	Reported Odds Ratio (ROR)	95% Confidence Interval	Clinical Context
Olanzapine	4.02	3.72–4.35	Highest positive signal value among atypical antipsychotics for rhabdomyolysis.
Quetiapine	3.81	0.53–27.6	Most reported drug in rhabdomyolysis cases, possibly due to higher prescription rates.
Ziprasidone	2.76	2.19–3.49	Associated with rhabdomyolysis, with risk decreasing over time.
Risperidone	2.12	1.91–2.35	Also linked to rhabdomyolysis, with early failure-type risk characteristics.
Aripiprazole	2.00	1.80–2.21	Has also been reported to cause rhabdomyolysis, even at low doses.
Clozapine	1.47	1.31–1.64	Association noted, but with a significantly longer median time to onset compared to others.

Note: RORs indicate reporting associations and are not definitive proof of cause, but they highlight potential safety concerns.

Conclusion

Olanzapine is associated with rhabdomyolysis and elevated muscle enzymes, though this is a rare event. It can occur independently of NMS at different times during treatment. The mechanism is complex, involving receptor effects and genetics. Clinicians should monitor for symptoms like muscle pain or dark urine, especially in those with risk factors. Discontinuation, CK monitoring, and supportive care are essential. For additional information on antipsychotic adverse effects, refer to the {Link: NAMI website https://www.nami.org/About-Mental-Illness/Treatments/Mental-Health-Medications/Types-of-Medication/Olanzapine-Zyprexa}.

Frequently Asked Questions

It is a rare adverse effect, reported in less than 1% of patients.

Yes, delayed-onset cases have been reported after several years of stable treatment.

Early signs include muscle pain, tenderness, weakness, fatigue, and possibly dark urine.

Olanzapine-induced rhabdomyolysis can occur without the full NMS syndrome, which includes fever, altered mental status, and autonomic dysfunction.

Treatment involves stopping olanzapine, aggressive intravenous hydration to prevent kidney injury, and monitoring CK and kidney function.

Yes, those with genetic variations affecting drug metabolism (like CYP2D6) and potentially pediatric/adolescent patients may be more vulnerable.

Although the risk is low, it is serious. Contact your doctor immediately if you experience new muscle pain, weakness, or urine changes for testing.

Yes, overdose is linked to acute muscle toxicity and elevated creatine kinase in a dose-dependent manner.