US Pharm. 2014;39(11):34-36.
ABSTRACT: Mental-health disorders, such as depression, are common and can have devastating effects on patients. Pharmacists may be significantly burdened by the management of adverse effects that result from the pharmacologic treatment of depression. Potential adverse effects include suicidal thoughts, sexual dysfunction, discontinuation syndrome, and serotonin syndrome. Pharmacists can play a crucial role in helping patients achieve optimal therapeutic outcomes while avoiding or minimizing the occurrence of these adverse effects. Patient education and appropriate monitoring are effective for achieving desired therapeutic outcomes and preventing potential adverse drug events.
Mental health is a significant issue affecting the U.S. population. In 2012, an estimated 43.7 million persons aged 18 years and older—18.6% of all U.S. adults—had a mental illness.1 According to National Comorbidity Study data, the lifetime prevalence of experiencing any mood disorder, including depression or bipolar disorder, exceeds 20%.2 Pharmacologic agents often are required in the treatment of mental-health disorders. However, these medications may cause troubling adverse effects. This article highlights key adverse drug events, including hallmark drug-drug interactions, that may be associated with psychotropic medications used to treat depression. Useful strategies for minimizing risks associated with these agents are also discussed.
Adverse drug events are an important factor influencing health outcomes of individuals treated with psychotropic medications. Nationally, adverse effects are associated with more than 770,000 injuries and deaths per year, costing millions of dollars annually per hospital.3 It is difficult to predict which specific characteristics increase the risk of adverse drug events. Patients who are prescribed psychotropic medications are at risk for polypharmacy, and the risk exceeds that for polypharmacy in elderly persons.4 Despite these challenges, up to 95% of adverse drug events are preventable.3 This article aims to increase awareness of some of the common concerns surrounding the use of antidepressant medications, thereby enabling pharmacists to play a vital role in reducing the risk of adverse drug events.
Antidepressants are the third most common prescription drug taken by Americans of all ages, and they rank second in persons aged 18 to 44 years.5 Therefore, it is critical that pharmacists practicing in any setting understand common concerns with antidepressant use.
Suicidality: One of the most alarming potential adverse effects associated with antidepressants is suicidality.6 In 2004, the FDA required all manufacturers to add a black box warning to the labels of all antidepressants to notify patients and caregivers about the risk of suicidal thinking or suicide attempts in children and adolescents. In 2007, this warning was expanded to include adults aged up to 24 years.
Patients or prescribers may be hesitant to initiate an antidepressant owing to the black box warning in these agents’ labeling. The FDA has suggested strategies to prevent the occurrence of suicidality, and healthcare providers should clearly and confidently communicate this information to patients and caregivers. To minimize the risk of suicidality, patients should be monitored for any changes in behavior, such as increased agitation, insomnia, worsening depression, anger, or violence. Pharmacists should familiarize themselves with the FDA’s antidepressant medication guide, which can help them explain the risks and benefits of antidepressant use.7 This guide can serve as a useful resource for patients and families. Patients should be informed that untreated depression carries a greater risk of suicide than antidepressant medication does, and that appropriate treatment is paramount. Careful monitoring during treatment is imperative, and more frequent provider visits during the early stage of treatment can help reassure wary patients.
QT Prolongation With Citalopram: A more recent warning from the FDA concerns abnormal heart rhythms with the use of high dosages of the selective serotonin reuptake inhibitor (SSRI) citalopram. The alert released by the FDA notes that patients taking more than 40 mg of citalopram per day may be at risk for dose-dependent QT-interval prolongation, which can lead to torsades de pointes, ventricular tachycardia, and sudden death.8 To minimize this risk, ECG and electrolyte monitoring may be prudent in certain patient populations. Citalopram should not be used in patients taking other QT-prolonging medications or in those with congenital long-QT syndrome, bradycardia, hypokalemia, or hypomagnesemia. The maximum recommended dosage of citalopram is 20 mg daily in patients who are poor CYP2C19 metabolizers, have hepatic impairment, are older than 60 years, or are taking concomitant CYP2C19 inhibitors. Patients should be instructed to contact a health professional immediately if they experience fainting, shortness of breath, dizziness, or irregular heartbeat.
The FDA alert specifies that citalopram dosages exceeding 40 mg daily have no added benefit and may increase the risk of QT prolongation.8 Although it is important for pharmacists to remember that this warning is controversial, a lack of response at dosages up to 40 mg indicates that it would be advisable to select another first-line antidepressant.9-12 Pharmacists should also keep in mind that some medications, including ethinyl estradiol–containing oral contraceptives, omeprazole, esomeprazole, fluvoxamine, and cimetidine, may increase exposure to citalopram through CYP2C19 inhibition.13 Pharmacists must also consider that the benefits of treatment with higher dosages of citalopram may outweigh potential risks in selected patients.
Sexual Dysfunction: Generally not life-threatening but troublesome nonetheless, sexual dysfunction is another potential adverse effect that patients taking antidepressants may experience. Sexual issues can present along the entire spectrum, from arousal and excitement to orgasm.14 In addition to having a negative impact on quality of life, this adverse effect is a frequent cause of nonadherence.15 Up to 80% of patients may experience sexual dysfunction related to antidepressant use, with one review citing the greatest risk existing among users of citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.16 However, the precise incidence of antidepressant-related sexual dysfunction is difficult to determine owing to the overlap of this symptom with a primary psychiatric disorder.15
Regardless of the root cause of the sexual dysfunction, management strategies have been used to control this adverse effect. First, pharmacists must become skilled at and comfortable with discussing this sensitive topic with patients.17 Patients should be encouraged to report the signs and symptoms of medication-induced sexual dysfunction to their healthcare provider. This is critical, since patients are four times more likely to report a concern if asked specifically about any sexual dysfunction, versus spontaneous reporting.18 Finally, the use of an antidepressant that has no sexual side effects, such as bupropion or mirtazapine, should be strongly considered.15
Discontinuation Syndrome: Another potential adverse effect that may be experienced with certain antidepressants is discontinuation syndrome. Patients who are taking antidepressants should not stop the medication abruptly, owing to the potential for this syndrome, particularly with certain SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs). Signs and symptoms of discontinuation syndrome include dizziness, headache, nausea, vomiting, diarrhea, movement disorders, insomnia, irritability, visual disturbance, lethargy, anorexia, tremor, electric-shock sensations, and lowered mood.19 These symptoms can be uncomfortable and distressing to the patient, but are not life-threatening. They are likely to occur 1 to 3 days after decreasing the dosage or discontinuing the medication, and generally resolve within 10 days. It is suggested that the patient taper the dosage slowly to avoid discontinuation syndrome.19,20 SSRIs and SNRIs with shorter half-lives, including paroxetine and venlafaxine, have a higher risk of discontinuation syndrome compared with SSRIs and SNRIs with longer half-lives.12,20,21
Serotonin Syndrome: Adverse effects caused by drug-drug interactions are another important consideration for pharmacists. One example is serotonin syndrome, a potentially life-threatening reaction caused by an increase in dosage of a serotonergic agent or by concurrent use of more than one drug with proserotonergic activity. Signs and symptoms of serotonin syndrome include mental-status changes (e.g., agitation, confusion, delirium), autonomic hyperactivity (e.g., hyperthermia, profuse sweating, tachycardia, flushing), and neuromuscular abnormalities (e.g., muscle rigidity, tremor, severe shivering).22 Patients may initially experience mild symptoms, such as akathisia, tremor, and altered mental status, which can progress to more severe symptoms, such as hyperthermia, clonus, muscular hypertonicity, and life-threatening toxicity.23
The coprescribing of antidepressants and triptans is often a red flag for potential serotonin syndrome. In 2006, the FDA released an alert regarding the potential for life-threatening serotonin syndrome with the concomitant use of triptans (e.g., sumatriptan, rizatriptan, zolmitriptan) and SSRIs or SNRIs.24 However, in 2010, the American Headache Society published a position paper citing conflicting and insufficient data to support this warning, and debates persist regarding whether the FDA is being overcautious.25 There have been no updates to the FDA alert since 2006, and no case series reporting serotonin syndrome have been published in peer-reviewed journals. Although the impact of combination treatment is likely negligible, patients should be instructed about the potential risk and advised to contact their healthcare provider immediately if they experience any signs and/or symptoms of serotonin syndrome.25 In clinical practice, triptans and SSRIs or SNRIs are frequently coprescribed; therefore, pharmacists can play an important role in educating patients about the signs and symptoms of serotonin syndrome when both agents are prescribed.25,26
Another potential risk for serotonin syndrome is the combination of serotonergic antidepressants and tramadol, especially with higher dosages. Tramadol, a partial mu-opioid agonist, is often used for moderate-to-severe pain, especially when other opioids that have a higher abuse rate are being avoided.23 There is documentation of serotonin syndrome with this combination, but the evidence is rare or limited.23 Owing to this potential interaction, it is recommended to avoid concurrent use of tramadol and SSRIs. Tramadol is metabolized by CYP2D6, and certain SSRIs are CYP2D6 inhibitors, including fluoxetine and paroxetine. Patients with genetic variations, including poor metabolizers of CYP2D6, may be at greater risk for serotonin syndrome.23 The combination of serotonergic agents and tramadol should be avoided, if possible. If it is unavoidable, careful monitoring, as well as patient education about the signs and symptoms of serotonin syndrome, should be conducted. In addition, these medications should be initiated at low dosages and titrated cautiously.22
Pharmacist’s Role in Identifying and Preventing Adverse Drug Events
Because of their consistent interactions with patients, pharmacists can play an essential role in ensuring the efficacy and safety of antidepressants. Pharmacists can educate patients about their medications and conditions, monitor for side effects, inquire about drug combinations, and determine appropriateness of dosing. Since antidepressant medications can have severe and potentially life-threatening adverse effects, it is important for pharmacists to provide patient education to ensure safe and appropriate use. Regular evaluations for depression and suicidal ideation can be useful for identifying patients who are at risk.27,28 A careful assessment of the efficacy of patients’ medication regimens is critical so that agents that are no longer needed may be discontinued. With a strong foundation of pharmacotherapeutic knowledge and evidence-based pharmacotherapy, pharmacists can protect patients from preventable drug-drug interactions and other adverse effects.
Mental health is a significant issue affecting patients’ quality of life. Although psychotropic medications are available to treat mental-health conditions such as depression, these agents carry a risk of adverse effects ranging from uncomfortable issues like sexual dysfunction to potentially fatal consequences like serotonin syndrome, suicidal ideation, and QT prolongation. Pharmacists can play an important role in preventing adverse drug events by providing patient education and monitoring patients for key drug interactions and other adverse events.
1. National Institute of Mental Health. Any mental illness (AMI) among adults. www.nimh.nih.gov/statistics/1ANYDIS_ADULT.shtml. Updated 2012. Accessed May 24, 2014.
2. Harvard Medical School. National comorbidity survey (NCS). Table 1. Lifetime prevalence of DSM-IV/WMH-CIDI disorder by sex and cohort. www.hcp.med.harvard.edu/ncs/ftpdir/NCS-R_Lifetime_Prevalence_Estimates.pdf. Updated 2005. Accessed May 25, 2014.
3. Agency for Healthcare Research and Quality. Reducing and preventing adverse drug events to decrease hospital costs: research in action. www.ahrq.gov/research/findings/factsheets/errors-safety/aderia/index.html. Updated 2001. Accessed June 2, 2014.
4. Preskorn SH, Flockhart D. 2006 guide to psychiatric drug interactions. Prim Psychiatry. 2006;13:35-64.
5. National Center for Health Statistics (NCHS). Health, United States, 2013: With Special Feature on Prescription Drugs. Hyattsville, MD: NCHS; 2014.
6. FDA. FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108905.htm. Accessed June 2, 2014.
7. FDA. Medication guide: antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions. www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/ucm100211.pdf. Accessed June 2, 2014.
8. FDA. FDA drug safety communication: revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. www.fda.gov/drugs/drugsafety/ucm297391.htm. Accessed June 3, 2014.
9. Howland RH. A critical evaluation of the cardiac toxicity of citalopram: part 1. J Psychosoc Nurs Ment Health Serv. 2011;49:13-16.
10. Zivin K, Pfeiffer PN, Bohnert AS, et al. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry. 2013;170:642-650.
11. Vieweg WV, Hasnain M, Howland RH, et al. Citalopram, QTc interval prolongation, and torsade de pointes. How should we apply the recent FDA ruling? Am J Med. 2012;125:859-868.
12. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd ed. Arlington, VA: APA; 2010:1.
13. FDA. Drug development and drug interactions: table of substrates, inhibitors and inducers. www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm. Accessed June 3, 2014.
14. Prabhakar D, Balon R. How do SSRIs cause sexual dysfunction? Understanding key mechanisms can help improve patient adherence, prognosis. Curr Psychiatry. 2010;9:30-34.
15. Clayton AH, Balon R. The impact of mental illness and psychotropic medications on sexual functioning: the evidence and management. J Sex Med. 2009;6:1200-1211.
16. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J Clin Psychopharmacol. 2009;29:259-266.
17. Stimmel GL, Gutierrez MA. Counseling patients about sexual issues. Pharmacotherapy. 2006;26:1608-1615.
18. Montejo-González AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997;23:176-194.
19. Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44:77-87.
20. How to switch antidepressants. Pharmacist’s Letter/Prescriber’s Letter. 2006;22:220605.
21. World Health Organization (WHO). WHO Expert Committee on Drug Dependence. 35th report. Geneva, Switzerland: WHO; 2003.
22. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:1112-1120.
23. Nelson EM, Philbrick AM. Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors. Ann Pharmacother. 2012;46:1712-1716.
24. FDA. Information for healthcare professionals: selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), 5-hydroxytryptamine receptor agonists (triptans). www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085845.htm. Accessed June 3, 2014.
25. Sclar DA, Robison LM, Castillo LV, et al. Concomitant use of triptan, and SSRI or SNRI after the US Food and Drug Administration alert on serotonin syndrome. Headache. 2012;52:198-203.
26. Rolan PE. Drug interactions with triptans: which are clinically significant? CNS Drugs. 2012;26:949-957.
27. Oberleitner LM, Tzilos GK, Zumberg KM, Grekin ER. Psychotropic drug use among college students: patterns of use, misuse, and medical monitoring. J Am Coll Health. 2011;59:658-661.
28. Schiff GD, Galanter WL, Duhig J, et al. Principles of conservative prescribing. Arch Intern Med. 2011;171:1433-1440.
To comment on this article, contact firstname.lastname@example.org.