To the Editors
A 27-year-old woman was admitted to Imam Hospital in Tehran, Iran, because of chief complaints of fever, night sweat, and arthralgias. In past medical and drug history, she had been receiving citalopram 20 mg daily for panic attacks since 2 years ago, and her disease was under control without any complication up to the recent hospital admission. After clinical evaluation and serological tests results, she was diagnosed with brucellosis infection and received doxycycline 100 mg twice daily and rifampin 600 mg once daily. Five days after starting the brucellosis treatment regimen, she developed gastrointestinal symptoms (dyspepsia, nausea, and abdominal pain), anxiety, agitation, and tachycardia. In routine review of the patient’s chart by the infectious diseases ward clinical pharmacists and based on the patient’s medical and drug history, recurrence of panic attack symptoms after citalopram, a rifampin drug interaction was proposed. Propranolol with a dose of 20 mg orally twice daily was started, and citalopram dose was gradually increased to 40 mg daily. The patient’s symptoms gradually improved, and propranolol doses were tapered down. On day 20 of hospitalization, the patient was stable and discharged with citalopram 40 mg daily and an antibrucellosis regimen (doxycycline and rifampin).
Only 2 cases of rifampin interaction with sertraline and citalopram were reported in the literature. Relapse of panic symptoms occurred 5 days after rifampin and doxycycline therapy, and symptoms of our patient were controlled by doubling dose of citalopram. Based on patient’s chart review, clinical characteristics, presentations, and outcome, recurrence of panic attacks after interaction between rifampin and citalopram is highly probable.
Drug interactions can affect the efficacy and safety of drug treatment. Drug interactions are the major causes of hospital admissions, treatment failures, and poor patient’s compliance with drug therapy regimens.1 Pharmacokinetic and pharmacodynamic mechanisms are 2 major types of drug-drug interactions.2 From pharmacokinetic drug interactions, induction or inhibition of the cytochrome P450 (CYP450) isoenzyme activity plays an important role in the occurrence of drug interactions. Rifampin is a strong CYP450 inducer that accelerates the metabolism of variety of CYP3A4 and CYP2C19 substrates and reduces serum concentrations of concomitant administered drugs.3 Citalopram is a selective serotonin reuptake inhibitor antidepressant that metabolized principally by CYP P450 enzyme subtypes 2C19 and 3A4.4 In this report, we have described a drug-drug interaction between rifampin and citalopram that led to recurrence of panic attacks in a patient with a diagnosis of brucellosis. We also have done a literature review to find similar cases by Medline search until June 2011. Drug interactions, SSRI, rifampin, and citalopram were selected index terms for our search.
After a complete workup during 5 days of her hospitalization, clinical presentations, positive history of unpasteurized dairy products consumption, and positive serum agglutination tests (Wright and combs Wright titer equal to 1/320), a diagnosis of brucellosis was made. The patient’s past medical history included episodic panic attacks (intense discomfort with symptoms of palpitation, sweating, shortness of breath, felling of chocking, nausea, chills, and hot flash) from 2 years ago before the recent hospital admission. She had been receiving citalopram 20 mg daily for panic attacks, and her disease was under control without any complication during the recent 2 year period. After the brucellosis diagnosis, doxycycline 100 mg twice daily and rifampin 600 mg daily were started. Five days later, the patient complained of being light-headed, tremor, exacerbation of sweating, nausea, vomiting, agitation, tachycardia, and fear of dying. Diagnostic evaluations, such as thyroid function tests, cardiology, and gastrointestinal workup, were performed. All were within normal limits. It was concluded that the patient’s recent symptoms may be related to doxycycline and rifampin therapy. The patient was educated about doxycycline and rifampin consumption, and omeprazole 20 mg orally daily and metoclopramide 10 mg as needed (up to 10 mg 3 times daily) were administered for control of GI problems. GI symptoms partially responded to this intervention, but other symptoms (sweating, tachycardia, anxiety agitation, and fear of dying) were progressive. In routine review of the patient chart by the infectious diseases ward’s clinical pharmacist and based on patient’s medical and drug history, recurrence of panic attack symptoms after citalopram, a rifampin drug interaction was proposed. In coordination with the patient’s responsible consultant, propranolol with a dose of 20 mg orally twice daily was started, and citalopram dose was gradually increased to 40 mg daily. Also, the patient’s metoclopramide and omeprazole were discontinued. After these modifications, the patient’s symptoms gradually improved, and propranolol doses were tapered down. On day 20 of hospitalization, the patient was stable and discharged with citalopram 40 mg daily and an antibrucellosis regimen (doxycycline 100 mg orally twice daily and rifampin 600 mg orally once daily).
Citalopram is a selective serotonin reuptake inhibitors antidepressant that metabolized principally by CYP P450 enzyme subtypes 2C19 and 3A4.4 Although it was reported that clinically important interactions with citalopram are unlikely to have happened since it undergoes metabolism by various enzyme systems and also has high drug tolerability,5 but available data showed that cimetidine and carbamazepine can significantly affect the metabolism of citalopram by inhibition and induction of P450 3A4 respectively. Clearance of citalopram was increased by concomitant administration of carbamazepine.6,7 Also carbamazepine augmentation therapy can decrease plasma concentrations of citalopram.7,8 Concomitant administration of cimetidine can lead to moderate increase in the serum levels of citalopram.6 Apart from limited interactions of citalopram that were reported, rifampin is a potent inducer of CYP450 enzyme system which resulted in different clinically significant drug interactions.3 Simultaneous administration of rifampin with neuroleptic drugs can cause therapeutic failure or recurrence of patient symptoms.3
Following literature review, only two cases of rifampin interaction with sertraline and citalopram were found. In case one, a patient with diagnosis of general anxiety disorder that had been stable with sertraline 200 mg orally daily complained anxiety symptoms following 7 days treatment with rifampin and cotrimoxazole for staphylococcal skin infection. In this patient sertraline serum concentration and its metabolite decreased up to 2–3 fold following rifampin therapy.9 In another case, rifampin-citalopram interaction was reported.10 In this case, a 55-year-old man with diagnosis of osteomyelitis experienced panic attacks after treatment of his osteomyelitis with rifampin. This patient had a history of uncontrolled panic attack that had been under treatment with bupropion, citalopram, and lorazepam before recent episodes. After a citalopram dose increase from 20 to 40 mg daily, the patient’s panic attack had been controlled, and the patient experienced nearly 1 attack per week. Five weeks after osteomyelitis’ antibiotic regimen change from intravenous vancomycin and clindamycin to oral rifampin and cotrimoxazole, the patient panic attacks were relapsed more frequently. Because patient’s attacks were not controlled with increase of citalopram and clonazepam doses and GI intolerability after citalopram to escitalopram change, the rifampin was discontinued. One week after stopping rifampin, the patient felt well, and her panic symptoms were under control with the previous regimen.
The rifampin and sertraline interaction was documented with blood sampling and measuring sertraline and its active metabolite serum concentrations. This interaction occurred 7 days after sertraline and rifampin concomitant therapy, and the patent’s anxiety symptoms resolved after sertraline dose increase. In the citalopram and rifampin interaction case, because the patient’s panic attacks were not under control before rifampin therapy, the time of interaction could not be determined. Also in this case, patient’s symptoms ameliorated only after rifampin discontinuation.
Drug probability interaction score11 was calculated to determine citalopram and rifampin drug interaction probability. Based on this scoring system (Table 1), the total score for our patient and reported interaction was 6, and it was categorized as a highly probable drug interaction.
In our case, relapse of panic symptoms occurred 5 days after rifampin and doxycycline therapy that is in accordance with an other documented report.9 Also, symptoms of our patient were controlled by doubling the dose of citalopram. Brucellosis with CNS involvement can produce psychiatric symptoms, but our patient had not complained of those symptoms at the time of admission. Also, rifampin can induce flulike symptoms and toxic psychosis. Flulike symptoms of rifampin are self-limiting, but rifampin-induced psychosis is not a self-limiting adverse effect.12 Although doxycycline was reported as a weak13 to moderate14 inhibitor of CYP3A4 enzyme system, rifampin is a potent inducer of CYP3A4 and CYP2C19 enzymes (that citalopram is a substrate for both of them). The outcome of doxycycline and rifampin interaction on citalopram metabolism seems to be induction of citalopram metabolism. Based on the patient’s chart review, clinical characteristics, presentations, and outcome, recurrence of panic attacks after interaction between rifampin and citalopram is highly probable.
Hossein Khalili, PharmD
Department of Clinical Pharmacy
Faculty of Pharmacy
Tehran University of Medical Sciences
Simin Dashti-Khavidaki, PharmD
Shahideh Amini, PharmD
Maryam Mousavi, PharmD
Department of Clinical Pharmacy
Faculty of Pharmacy
Tehran University of Medical Sciences
AUTHOR DISCLOSURE INFORMATION
The authors declare no conflicts of interest.
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