Psychosomatics 46:565-568, November-December
doi: 10.1176/appi.psy.46.6.565
© 2005 Academy of Psychosomatic Medicine
Antidepressant and Statin Interactions: A Review and Case Report of Simvastatin and Nefazodone-Induced Rhabdomyolysis and Transaminitis
Niranjan S. Karnik, M.D., Ph.D., and
José R. Maldonado, M.D.
Received July 26, 2004; accepted Jan. 25, 2005. From the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine. Address correspondence and reprint requests to Dr. Karnik, Department of Psychiatry, 401 Quarry Rd., Stanford, CA 94305; nkarnik{at}stanford.edu (e-mail).
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INTRODUCTION
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The use of statins (HMG-CoA Inhibitors), which inhibit cholesterol biosynthesis, has increased in recent years. Similarly, there has been a dramatic rise in the use of antidepressant agents, particularly since the selective serotonin reuptake inhibitors (SSRIs) became available. Both sets of medications are considered reasonably safe when used by themselves. Nevertheless, the increased use of drug combinations may lead to a greater risk for significant drug-drug interactions. All antidepressant agents are metabolized to some extent by the cytochrome P450 system. Similarly, most statins are hepatically biotransformed by cytochrome P450 action.1 Knowledge of these hepatic pathways has become required for practitioners within internal medicine and psychiatry. Given that patients are likely to have multiple practitioners managing their medications, it is vital for both internists and psychiatrists to be familiar with potential drug interactions and be able to assess the risks when reviewing a patient’s existing medication strategies. In this article we present the case of a patient, successfully treated for years with nefazodone without complications or side effects, who experienced rhabdomyolysis and transaminitis after initiation of treatment with simvastatin.
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Case Presentation
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Ms. A was a 79-year-old Caucasian woman with a history of depression and multiple medical problems including chronic lymphocytic leukemia, atrial fibrillation, coronary artery disease, hypothyroidism, and hyperlipidemia. She came to a large university medical center emergency room complaining of having experienced bilateral arm and leg weakness over the preceding week. She reported an inability to ambulate in the 2 days preceding admission, which was a marked change from her baseline. Table 1 summarizes her initial laboratory results upon presentation to the emergency room.
The CBC differential showed a preponderance of lymphocytes in keeping with the patient’s diagnosis of chronic lymphocytic leukemia. Routine chemistries were within normal limits. Liver function tests show transaminitis and evidence of rhabdomyolysis consistent with this patient’s clinical presentation. Her urinalysis results showed pronounced hematuria and proteinuria without evidence of infection. Microscopic analysis showed evidence of granular casts and moderate amorphous crystals.
Further history obtained from the patient indicated that she had been diagnosed with major depressive disorder 10 years earlier. She reported having been initially treated with several antidepressant agents that were each unsuccessful. Finally, she was placed on a regimen of nefazodone, with subsequent full remission of her depressive symptoms. She had remained on the same dose of nefazodone (150 mg twice a day) for the last 8 years. Furthermore, she reported no significant side effects at this dose.
In addition, the patient was taking a beta-blocker, warfarin (for atrial fibrillation), thyroid replacement medication, a number of vitamins, stool softeners, and occasional use of zolpidem for sleep. The patient also indicated that she had initiated treatment with simvastatin, 20 mg/day, about 9 months earlier. She was kept at this dose until about 1 month before admission when her primary care physician increased her dose to 40 mg/day. This represented her only medication change in the last 12 months.
She was appropriately treated in the emergency department with intravenous fluids, bicarbonate, and mannitol and then transferred to the inpatient medical service for continued treatment and evaluation. Both simvastatin and nefazodone regimens were held. Over the next 3 days her creatine kinase dropped by greater than 60%, with a 30%–40% decrease in her transaminases. Both the transaminitis and rhabdomyolysis were believed to be secondary to the interaction of nefazodone and simvastatin, which caused a dramatic increase in serum simvastatin levels. Nefazodone treatment was restarted before discharge, and the patient was advised to consult with her primary care physician for alternative lipid-lowering strategies.
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Discussion
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The root cause of this interaction is believed to be due to the potent inhibition that nefazodone exerts on the cytochrome P450 isoenzyme 3A4. Rhabdomyolysis has been associated with the coadministration of some statins and CYP3A4 inhibitors such as cyclosporine, tacrolimus, and multiple other agents.2,3 Prior case reports of the nefazodone/simvastatin interaction centered on the addition of nefazodone to existing treatment with simvastatin.4–6 In this report the reverse situation occurred where the patient had been stable on a regimen of nefazodone for an extended period of time. It is interesting that the initial dose of simvastatin (20 mg/day) failed to produce toxic effects.
In reviewing the available literature on statins we find that adverse reactions involving skeletal muscle are not uncommon and have been found among all statins marketed in the United States and Canada.7 In fact, serious adverse reactions resulting in myopathy and rhabdomyolysis have been previously described that required discontinuation of the offending agent.2,4,8 The reported incidence of myotoxic reactions with the use of these agents has been reported to be between 1% and 7%, depending on the agent.1 Rhabdomyolysis has been described as an uncommon syndrome occurring in approximately 0.1% of patients receiving statin monotherapy.9 Nevertheless, the incidence of myopathy, rhabdomyolyisis, or other side effects appear to be dose dependent,10 and thus the risk increases when statins are used in combination with other drugs or substances that inhibit its metabolism. Similarly, it is clear that the variability of inhibition of P450 systems based in part on pharmacogenetics11 combined with the routine use of statins for general health maintenance place significant numbers of patients at risk, and neither psychiatrists nor internists are sufficiently familiar about medications used by their counterparts to anticipate these significant drug-drug interactions and side effects. In fact, the coadministration of simvastatin and nefazodone has already been reported to potentially result in a 20-fold increase in simvastatin and simvastatin acid.12
Most statins (simvastatin, lovastatin, cerivastatin, and atorvastatin) are metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme. An exception to this rule is fluvastatin, which is largely metabolized by CYP 2C9. Pravastatin is unusual among this class of drugs in that it has a significant degree (about 50%) of renal clearance13 and only acts in the P450 system in a limited way.8,14 In fact, pravastatin is a specific substrate of the type-2 organic anion transporting polypeptide transporter (OATP-2) in human liver cells and is excreted into bile in high concentrations via a primary active transport mechanism.15 Consideration of the pathways of antidepressant metabolism are essential when considering choice of statin; likewise for the reverse scenario when choosing antidepressant therapy in the face of existing statin use. In Table 2 and Table 3 we summarize the major hepatic induction pathways for the P450 system by drug and isoenzyme.
For antidepressants, the major metabolic pathways required for metabolism and elimination are CYP 2D6 and CYP 3A4. In fact, about 50% of clinically used drugs are hepatically metabolized via CYP 3A4.25 Together, CYP 2D6 and 3A4 comprise about 80% of all metabolic activity. The accuracy of information presented in Table 2 and Table 3 is limited because of the recent and rather small number of studies done to examine P450 systems and specific medications. The potent inhibition of certain isoenzymes is better understood because these are the pathways that have often resulted in drug-drug interactions. It is the weak inhibition that is less understood and for which there is some disagreement in the literature. Citalopram and its enantomer escitalopram, for example, are widely believed to have little drug-drug interactions despite some effect on the P450 system. Its safety is thought to result from virtually equal clearance by isoenzymes 2D6, 3A4, and 2C19.20 While this may promote its safety, it is conceivable that some other medication may be developed or currently exists with a similar isoenzyme profile, and such a combination could theoretically result in an interaction.
In this case given the patient’s excellent response to nefazodone without a history of any significant side effects for 8 years, and the uncertainty of equal therapeutic response or absence of side effects if switched to a different antidepressant agent, we recommended to resume treatment with nefazodone and to find an alternative to simvastatin. Given our discussion regarding metabolic considerations, acceptable alternatives would include fluvastatin (CYP 2C9), pravastatin (with significant renal clearance), and rosuvastatin (which is not extensively metabolized, undergoes little or no transformation by the different isoenzymes of cytochrome P450, and is mainly eliminated in the feces).
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Conclusions
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The expansion of the choices of antidepressants and statins available for clinicians provides good opportunities for therapeutic benefit. These benefits must be weighed against the risks of drug-drug interactions, especially in the face of patients who are receiving multiple pharmacological agents. Prudent choices with regard to medication cannot guarantee medication safety but they can certainly decrease the risk of adverse events. Knowledge of the cytochrome P450 system is essential when choosing both antidepressants and statins and even more important when combining these medications.
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J. A. Dykens, J. D. Jamieson, L. D. Marroquin, S. Nadanaciva, J. J. Xu, M. C. Dunn, A. R. Smith, and Y. Will
In Vitro Assessment of Mitochondrial Dysfunction and Cytotoxicity of Nefazodone, Trazodone, and Buspirone
Toxicol. Sci.,
June 1, 2008;
103(2):
335 - 345.
[Abstract]
[Full Text]
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INTRODUCTION
Case Presentation
