What is rhabdomyolysis?
Rhabdomyolysis is a medical condition in which damaged skeletal muscle breaks down rapidly. This breakdown releases muscle fiber contents, like myoglobin and creatine kinase (CK), into the bloodstream. These substances can harm the kidneys and lead to complications such as acute renal failure. While physical trauma, infections, and toxins are common causes, certain medications, including antipsychotics, can also trigger this dangerous condition.
Antipsychotics associated with rhabdomyolysis
Clinical and pharmacovigilance data have identified several antipsychotics linked to reports of rhabdomyolysis. It is important to note that case reports and adverse event databases, like the FDA Adverse Event Reporting System (FAERS), show associations but do not always confirm a causal link. The risk profile varies, with some atypical antipsychotics being more frequently reported than older, typical agents.
Atypical antipsychotics
- Quetiapine (Seroquel): A recent analysis of the FAERS database found that quetiapine was the most reported drug in rhabdomyolysis cases. The adverse effect can occur even at therapeutic doses and is often seen in the first month of treatment or following a dose adjustment.
- Olanzapine (Zyprexa): The same FAERS study noted that olanzapine had the highest positive signal values for rhabdomyolysis, indicating a strong association. Cases have been reported even at low doses and can be triggered by medication changes or other risk factors.
- Risperidone (Risperdal): This medication has also been reported in association with rhabdomyolysis, sometimes in conjunction with other interacting medications like statins. The risk may increase with higher doses or during drug interactions involving the CYP2D6 enzyme.
- Aripiprazole (Abilify): Case reports of aripiprazole-associated rhabdomyolysis exist, some in younger patients and even at low doses shortly after initiation.
- Clozapine (Clozaril): Case reports have linked clozapine to rhabdomyolysis, though the onset can sometimes be delayed compared to other agents.
- Ziprasidone (Geodon): Reports also exist for ziprasidone, though some cases involved overdose situations or multiple medications.
Typical antipsychotics
While less common due to their decreased overall usage compared to atypical agents, typical antipsychotics have also been implicated, primarily within the context of Neuroleptic Malignant Syndrome (NMS).
- Haloperidol (Haldol): Case reports of haloperidol-associated rhabdomyolysis often occur within the syndrome of NMS, which is characterized by fever, severe muscle rigidity, and altered mental status.
Understanding the mechanism of action
The exact mechanism by which antipsychotics cause rhabdomyolysis is not fully understood, but several theories point to their effects on dopamine and serotonin receptors.
- Dopaminergic blockade: Antagonism of dopamine D2 receptors is a key action of many antipsychotics. A theory suggests this blockade can lead to increased muscle tone and rigidity, potentially causing muscle damage. In severe cases, this is part of the presentation of NMS.
- Serotonergic blockade: Atypical antipsychotics like risperidone and quetiapine also have strong effects on serotonin 5-HT2A receptors. Blockade of these receptors may increase the permeability of the muscle cell membrane (sarcolemma), leading to an uncontrolled influx of calcium. This excess calcium can activate enzymes that break down muscle fibers.
- Other factors: Metabolic disturbances, sedation causing immobility, and direct toxic effects on muscle cells are also considered contributing factors.
Recognizing the signs and symptoms
Early detection is crucial to prevent serious complications like acute kidney injury. The classic triad of rhabdomyolysis symptoms includes muscle pain, weakness, and dark-colored urine. However, this triad is not always present. Other symptoms include:
- Generalized fatigue and malaise
- Abdominal pain
- Fever
- Nausea and vomiting
- Limb swelling
- Rapid heartbeat
Risk factors for antipsychotic-induced rhabdomyolysis
Several factors can increase a patient's risk of developing this adverse effect:
- High or rapidly escalating doses: Sudden dose increases, especially with potent agents, are a significant risk factor.
- Combination therapy: Taking multiple antipsychotics or other medications known to cause muscle toxicity (e.g., statins) can increase risk.
- Dehydration: Volume depletion increases myoglobin's nephrotoxic effects.
- Substance abuse: Illicit drugs can independently cause rhabdomyolysis or exacerbate the risk.
- Other underlying conditions: Pre-existing chronic kidney disease or intense physical exertion can increase susceptibility.
A comparison of risk among different antipsychotics
| Antipsychotic | Type | Reported Cases (FAERS, 2025) | Signal of Association (ROR)* | Typical Onset Time** |
|---|---|---|---|---|
| Quetiapine | Atypical | Most frequently reported | 3.81 | Early (Median ~31 days) |
| Olanzapine | Atypical | High frequency | Highest signal (4.02) | Early-mid (Median ~174 days) |
| Risperidone | Atypical | High frequency | 2.12 | Early (Median ~11 days) |
| Aripiprazole | Atypical | Moderate frequency | 2.00 | Early (Median ~35.5 days) |
| Clozapine | Atypical | Moderate frequency | 1.47 | Delayed (Median ~595 days) |
| Haloperidol | Typical | Less frequent (case reports) | Not specified | Variable (often tied to NMS) |
*ROR (Reporting Odds Ratio): Higher values suggest a stronger signal of association in the database. **Based on median time-to-onset in the FAERS study; individual onset times can vary greatly.
Management and treatment
Timely intervention is critical for managing antipsychotic-induced rhabdomyolysis and preventing life-threatening complications. The standard approach includes:
- Discontinue the offending agent: The first step is to stop the suspected antipsychotic immediately.
- Aggressive intravenous fluid resuscitation: To flush out myoglobin and other toxins from the kidneys, large volumes of isotonic fluids are administered. The goal is to achieve a urine output of 200-300 ml/hour.
- Monitor laboratory values: Closely track serum CK levels to monitor the trend of muscle breakdown, along with kidney function tests, electrolytes, and urine analysis.
- Treat complications: Any electrolyte imbalances (especially hyperkalemia) must be addressed. If acute renal failure develops, hemodialysis may be necessary.
- Consider NMS treatment: If the condition presents as part of NMS, medications like dantrolene or bromocriptine may be used to reduce muscle rigidity and hyperthermia.
Conclusion: The importance of vigilance
While a rare adverse event, antipsychotic-induced rhabdomyolysis is a serious condition that requires prompt recognition and management. All antipsychotics, both typical and atypical, carry some level of risk. Atypical agents such as quetiapine, olanzapine, and risperidone have been more frequently reported, but even low doses or short-term use can be sufficient to trigger it in susceptible individuals. Clinicians and patients should be aware of the risk factors and the importance of monitoring for symptoms like unexplained muscle pain, weakness, and dark urine, especially during dose adjustments or polypharmacy. Early identification and aggressive fluid therapy can lead to a positive outcome. It is essential to communicate any concerning symptoms with a healthcare provider immediately to ensure proper treatment. For more information on general rhabdomyolysis management, a resource like the StatPearls article is available from the NCBI Bookshelf.
