Can valproic acid (valproate) and quetiapine (ketiapine) increase the risk of rhabdomyolysis, particularly in patients with pre-existing muscle or kidney conditions?

Can Valproic Acid and Quetiapine Cause Rhabdomyolysis?

Yes, both valproic acid (valproate) and quetiapine can cause rhabdomyolysis, though the risk is relatively low and typically occurs in specific clinical contexts or when combined with other risk factors.

Quetiapine and Rhabdomyolysis Risk

Quetiapine is a documented cause of rhabdomyolysis, particularly when combined with other serotonergic agents or during periods of increased physical activity. 1, 2

• Quetiapine was identified among antipsychotics associated with rhabdomyolysis in children and adolescents, with cases occurring within 2 months of starting treatment or during dose adjustments 1
• A case report documented severe rhabdomyolysis induced by quetiapine combined with mirtazapine in a military soldier, attributed to 5-HT2A serotonergic receptor inhibition combined with muscle training 2
• The mechanism involves serotonergic receptor effects that, when combined with physical exertion, can trigger muscle breakdown 2

High-Risk Scenarios for Quetiapine

• Dose escalation or medication changes: Monitoring should be intensified during the first 2 months of treatment, especially when doses are increased or medications are switched 1
• Athletic or military populations: Individuals engaged in regular physical training face higher risk when quetiapine is combined with exercise 2
• Combination with other psychotropics: Concurrent use with other serotonergic agents (like mirtazapine) increases risk 2

Valproic Acid and Rhabdomyolysis Risk

The relationship between valproic acid and rhabdomyolysis is complex and context-dependent—it can trigger rhabdomyolysis in patients with underlying metabolic disorders but may actually protect against it in other circumstances.

When Valproic Acid Triggers Rhabdomyolysis

• In patients with carnitine palmitoyltransferase (CPT) type II deficiency: Valproic acid should be absolutely avoided in these patients, as it can trigger acute rhabdomyolysis with renal failure 3
• The mechanism involves valproic acid's effects on carnitine metabolism and mitochondrial fatty acid oxidation, which unmasks the underlying metabolic defect 3

Protective Effects of Valproic Acid

• Paradoxically, experimental evidence shows valproic acid (300 mg/kg) can attenuate glycerol-induced rhabdomyolysis and acute kidney injury in rats by reducing oxidative stress and inflammation 4
• This protective effect appears mediated through increased glutathione levels and reduced IL-1β expression 4

Clinical Monitoring and Warning Signs

Watch for these precursory symptoms that may develop before full rhabdomyolysis:

• Muscle pain, weakness, or soreness 1, 5
• Abdominal pain (often overlooked but commonly reported) 1
• Dark urine (indicating myoglobinuria) 1, 5
• General weakness or malaise 1

Laboratory Monitoring Strategy

• Check creatine kinase (CK) immediately if any muscle symptoms develop during treatment with either medication 1, 5
• Measure serum myoglobin for earlier detection, as it is more sensitive than CK 5
• Monitor renal function (creatinine, BUN) and electrolytes, particularly potassium 5
• Approximately 10% of acute renal failure cases are due to rhabdomyolysis 5

Patients at Highest Risk

Identify and monitor these high-risk patients more closely:

• Those with pre-existing metabolic muscle disorders (especially CPT II deficiency for valproic acid) 3
• Patients on multiple psychotropic medications 1
• Athletes or individuals engaged in intense physical training 2
• Patients with hypothyroidism, renal impairment, or cardiovascular disease 6
• Those taking concurrent medications that increase rhabdomyolysis risk (statins, fibrates) 6

Management When Rhabdomyolysis Occurs

Immediately discontinue the offending agent if rhabdomyolysis is confirmed 5

• Initiate aggressive intravenous hydration with isotonic saline 5
• Force diuresis with sodium bicarbonate to prevent myoglobin precipitation in renal tubules 5
• Correct electrolyte imbalances, particularly hyperkalemia and hypocalcemia 5
• Consider plasmapheresis for enhanced myoglobin elimination in severe cases 5
• Hemodialysis may be necessary if acute renal failure develops 5

Critical Pitfalls to Avoid

• Do not overlook seemingly minor symptoms like abdominal pain or mild muscle aches—these may be early warning signs 1
• Do not use valproic acid in patients with known or suspected CPT II deficiency—this combination can be catastrophic 3
• Do not ignore the timing of symptom onset—most cases occur within the first 2 months of treatment or after dose changes 1
• Do not fail to screen for underlying metabolic disorders in patients with recurrent episodes or family history of muscle problems 3

The prognosis for muscle recovery after rhabdomyolysis is generally excellent if diagnosed and treated early, but prevention through vigilant monitoring remains the best strategy 5.