Evidence-Based Reviews

Drug-drug interactions: Avoid serious adverse events with mood stabilizers

Current Psychiatry. 2005 May;4(5):27-40

In clinical practice, prescribed drug combinations are often uncontrolled experiments, with unknown potential for toxic effects.

PDF Download

References

1. Langdorf MI, Fox JC, Marwah RS, et al. Physician versus computer knowledge of potential drug interactions in the emergency department. Acad Emerg Med 2000;7:1321-9.

2. Lazarou J, Pomeranz BH, Cory PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5.

3. Incalzi RA, Gemma A, Capparella O, et al. Predicting mortality and length of stay of geriatric patients in an acute care general hospital. J Gerontol 1992;47(2):M35-9.

4. Preskorn SH. Fatal drug-drug interaction as a differential consideration in apparent suicide. J Psychiatr Pract 2002;8(4):233-8.

5. Peterson JF, Bates D. Preventable medication errors: identifying and eliminating serious drug interactions. J Am Pharm Assoc (Wash) 2001;41(2):159-60.

6. Nichol MB, Stimmel GL, Lange SC. Factors predicting the use of multiple psychotropic medications. J Clin Psychiatry 1995;2:60-6.

7. Ananth J, Parameswaran S, Gunatilake S. Antipsychotic polypharmacy. Curr Pharm Des 2004;10(18):2231-8.

8. Medwatch Web site. Food and Drug Administration. Search for Drug-drug interactions. Available at: http://www.fda.gov/med-watch/index.html. Accessed March 31, 2005.

9. Rascati K. Drug utilization review of concomitant use of specific serotonin reuptake inhibitors or clomipramine and antianxiety/sleep medications. Clin Ther 1995;17:786-90.

10. Tanaka E, Hisawa S. Clinically significant pharmacokinetic drug interactions with psychoactive drugs: antidepressants and antipsychotics and the cytochrome P450 system. J Clin Pharm Ther 1999;24:7-16.

11. Bergendal L, Friberg A, Schaffrath A. Potential drug-drug interactions in 5,125 mostly elderly outpatients in Gothenburg, Sweden. Pharm World Sci 1995;17(5):152-7.

12. De Las Cuevas C, Sanz EJ. Polypharmacy in psychiatric practice in the Canary Islands. BMC Psychiatry 2004;4(1):18.-

13. Raschetti R, Morgutti M, Menniti Ippolito F, et al. Suspected adverse drug events requiring emergency department visits or hospital admissions. Eur J Clin Pharmacol 1999;54:959-63.

14. Bates DW, Spell N, Cullen DJ, et al. The costs of adverse drug events in hospitalized patients. JAMA 1997;277:307-11.

15. Frye MA, Ketter TA, Leverich GS, et al. The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study. J Clin Psychiatry 2000;1:9-15.

16. Werder SF, Preskorn SH. Managing polypharmacy: walking the fine line between help and harm. Current Psychiatry 2003;2(2):24-36.

17. Physicians’ Desk Reference (59th ed). Montvale, NJ: Thomson PDR; 2005.

18. Sandson NB. Exploring drug interaction in psychiatry. Psychiatric times 2004;May:42-8.

19. Todi SK, Hartmann RA. Pharmacologic principles. In: Civetta JM, Taylor RW, Kirby RR, (eds). Critical care (3rd ed). Philadelphia: Lippincott-Raven Publishers; 1997;485-8.

20. Shapiro LE, Shear NH. Drug interactions: Proteins, pumps, and P-450s. J Am Acad Dermatol 2002;47:467-84.

21. Keck PE, Jr, Dewan N, Nasrallah HA. Bipolar disorder: the clinician’s guide to pharmacotherapy for patients with co-occurring medical conditions. Current Psychiatry 2005;4(Feb)(suppl):1-51.

22. Sadock BJ, Sadock VA. Kaplan and Sadock’s pocket handbook of psychiatric drug treatment (3rd ed). Philadelphia: Lippincott Williams & Wilkins; 2001;144-5,178-83,256-7.

23. Shukla S, Godwin CD, Long LE, Miller MG. Lithium-carbamazepine neurotoxicity and risk factors. Am J Psychiatry 1984;141:1604-6.

24. Licht RW, Vestergaard P, Kessing LV, et al. Psychopharmacological treatment with lithium and antiepileptic drugs: suggested guidelines from the Danish Psychiatric Association and the Child and Adolescent Psychiatric Association in Denmark. Acta Psychiatr Scand Suppl 2003;(419):1-22.

25. Phelan KM, Mosholder AD, Lu S. Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry 2003;64:1328-34.

26. Ragheb M, Ban TA, Buchanan D, Frolich JC. Interaction of indomethacin and ibuprofen with lithium in manic patients under steady-state lithium level. J Clin Psychiatry 1980;11:397-8.

Drug-drug interactions (DDIs) can be viewed as physiologic combat wherein a “perpetrator” drug affects a “victim” drug’s pharmacokinetics or pharmacodynamics. Your challenge is to deter that interaction in patients taking two or more medications.

This article—first in a series—discusses polypharmacy risk factors that increase the likelihood of detrimental DDIs, then focuses on DDIs in patients taking mood stabilizers for bipolar disorder. We also offer practical tips to reduce DDI risk. Future articles will discuss DDI risks with antidepressants, antipsychotics, and anxiolytics.

To predict DDIs, you need to know psychotropics’ mechanism of action, metabolism, and effects on cytochrome P-450 (CYP) enzymes. Our discussion is not exhaustive because the data base is massive and new interactions continue to be discovered. Our aim is to equip you to anticipate and prevent DDIs when prescribing.

WHAT ARE ADVERSE DDIs?

An adverse event (AE) is any undesirable experience that occurs when a patient uses a medical product, whether or not the product caused the event. The FDA says an “undesirable experience” may be:

an unfavorable and unintended symptom or sign
an abnormal lab or radiographic finding
a disease that is temporarily associated with the medical product.

A temporal relationship is all that is required, although preexisting conditions and events clearly related to other causes are not usually considered adverse events.

An AE becomes “serious” (an SAE) when its duration, intensity, and/or frequency leads to death, a life-threatening condition, initial or prolonged hospitalization, disability, or congenital anomaly. Reporting is voluntary, but we strongly recommend that you report all SAEs to the FDA.

These definitions can help you confirm that a patient has experienced an SAE, but the task becomes more complicated when you try to attribute an SAE to a drug interaction. In the absence of an FDA definition, we assert that DDIs are responsible for SAEs when a perpetrator drug affects the pharmacokinetics or pharmacodynamics of a victim drug and exacerbates a known untoward event of the victim drug (Box 1).^1-5 Which drug is the perpetrator and which is the victim is not always clear, and sometimes a medication—such as carbamazepine—can be both at once.

Box 1

Drug-drug interactions: Taking a toll

More than 100,000 possible detrimental DDIs have been documented in medical literature and pharmaceutical company data. This number is likely to grow with increased scrutiny, as

DDIs cause morbidity, mortality, and increased health care costs. More than 106,000 Americans die each year from properly prescribed, correctly taken medications. Polypharmacy is associated with extended hospital stays, and using >6 drugs is an independent predictor of death. DDIs contribute to the cause of death in acute overdoses and can be responsible for false-positive suicide diagnoses.

In clinical practice, DDI-associated toxicity may be mistaken for a new disease process, or a disease may be incorrectly perceived as progressing when a medication is rendered ineffective.

Source: References 1-5

RISKS OF POLYPHARMACY

Individuals with psychiatric illnesses are at particular risk for DDIs (Box 2). Patients seen by psychiatrists, for example, are six times more likely than patients seen by primary care physicians to be taking multiple medications.⁶

Polypharmacy increases the risk of adverse events, nonadherence, medication errors, and drug interactions.⁷ FDA’s MedWatch Web site lists more than 630 DDI warnings.⁸ The more medications a patient is taking, the greater the risk for detrimental DDIs and cumulative toxicity,⁹ which often lead to DDI-induced AEs.¹⁰

A study of DDIs in 5,125 mostly older outpatients¹¹ found that:

1,594 (31%) had at least one interacting drug combination (average 1.6)
subjects with one or more DDIs were taking an average 8.1 drugs, compared with 5.2 drugs in those without DDIs—a significant difference
155 (3%) had interactions of “major clinical significance.”

‘Uncontrolled experiments.’ Drug combinations often are “uncontrolled experiments” with unknown potential for toxic effects.¹² Studies have linked polypharmacy and DDIs as well as DDIs and AEs:

Although drug interactions are responsible for only 3.8% of emergency department visits, patients with DDIs are usually admitted to the hospital.¹³
Preventable drug interactions cause approximately one-third of all AEs in hospitalized patients and account for one-half of all AE costs.¹⁴

DDI risk is increasing over time as the number of medications used to treat psychiatric patients has grown. For example, 3.3% of patients discharged between 1974 and 1979 from the National Institute of Mental Health Biological Psychiatry Branch were taking 3 or more medications, compared with more than 40% of patients discharged between 1990 and 1995—a 12-fold increase.¹⁵

Box 2

Psychiatric patients: High risk for DDIs

Symptom-based prescribing. Patients with psychiatric illness are often prescribed >1 medication to manage symptoms and signs, rather than a single medication targeting a specific psychiatric disorder.

Multiple prescribers. Patients with anxiety and depressive disorders may see multiple providers, which increases the risk for polypharmacy, drug-drug interactions, and adverse events.

Medical comorbidity. Persons with psychiatric illness are at increased risk for concomitant medical illness, and persons with medical illness are at increased risk for psychiatric illness.

Psychiatric comorbidity. Persons with one psychiatric illness are at increased risk for other psychiatric illnesses.

Source: Adapted from reference 6.