Decreased citalopram concentration caused by enzyme induction effect of rifampin: a case report

Abstract

Citalopram is a selective serotonin reuptake inhibitor used to treat depression and various anxiety disorders, which is mainly metabolized by the P450 (CYP) enzyme. Rifampin is a rifamycin with bactericidal activity against Mycobacterium tuberculosis. Rifampin significantly induces the P450 (CYP) enzyme system, which makes it susceptible to potential drug interactions with other medications. However, there have been few reports on the possible interaction between rifampin and citalopram. We report a 76-year-old patient who had been taking citalopram 20 mg daily for long-term treatment of depression. After 2 months of rifampin treatment for tuberculosis, the patient presented with intractable depressive symptoms, insomnia, and a profound sense of hopelessness. The trough plasma concentration of citalopram was monitored, which was 8.19 ng/mL, and failed to reach the guideline-recommended effective therapeutic range (50–110 ng/mL). Based on the therapeutic drug monitoring results of citalopram, the dosage of citalopram was adjusted to 40 mg daily, resulting in a significant improvement in depressive symptoms. This case provides further evidence of a clinically significant interaction that may occur between rifampin and citalopram.

Plain language summary

Decreased citalopram concentration caused by enzyme induction effect of rifampin

Citalopram is a selective serotonin reuptake inhibitor used to treat depression and various anxiety disorders, which is mainly metabolized by the P450 (CYP) enzyme. Rifampin is one of the first-line antituberculosis (anti-TB) drugs and a potent inducer of the P450 (CYP) enzyme system. However, there have been limited reports on the potential interaction between rifampin and citalopram. Moreover, there is a lack of studies investigating the usefulness of monitoring serum drug concentrations of citalopram to guide clinical dosing, especially in older patients. This is the first case in which citalopram serum concentrations have been observed to guide clinical administration.

The patient is a 76-year-old woman who has suffered from depression for over 17 years. Two years ago, she started taking citalopram tablets (20mg once daily, orally) and the condition was well controlled. However, due to lumbar tuberculosis, the depression recurred after taking anti-TB drugs including rifampin, ethambutol and pyrazinamide.

Clinical pharmacists considered the possibility of drug interaction between rifampin and citalopram, and used therapeutic drug monitoring (TDM) to make individualized dose adjustments. After 6 days of treatment with an individualized citalopram dose regimen, the symptoms of depression and insomnia were relieved. And after 2 weeks of continuous standardized medication after discharge, the patient’s emotional fluctuations, anxiety, and irritability were effectively controlled.

This case highlights the interaction between citalopram and rifampicin and the role of TDM in individualized therapy, which can provide a reference for clinicians to make individualized dose adjustments and improve the treatment effect.

Introduction

Depression is a common psychiatric disorder characterized by somatic symptoms, primarily encompassing, but not limited to, fatigue, pain, or sleep disturbance. Depression affects more than 300 million individuals worldwide, accounting for approximately 4.4% of the global population. ¹ Depression is prevalent among the elderly population, with a prevalence rate of depressive symptoms observed in individuals 75 years and over at 17.1%. ² The treatment of depression adopts a comprehensive approach, including pharmacotherapy, psychotherapy, and physical therapy. Pharmacotherapy is the primary modality. A diverse array of pharmacological interventions is available for the management of depression, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. ³ SSRIs are utilized due to their effectiveness and safety, not only in the treatment of depression but also for panic disorder and other anxiety disorders. Citalopram, a selective SSRI, is metabolized by the CYP450 enzyme system, primarily involving subtypes 2C19 and 3A4. ⁴ Compared to other SSRIs, citalopram exhibits a more potent inhibitory effect on 5-HT reuptake and demonstrates higher selectivity. ⁵

Rifampin is a first-line therapeutic agent for treating Mycobacterium tuberculosis infections and can also demonstrate efficacy against non-mycobacteria, Staphylococcus aureus, Neisseria meningitidis, and Haemophilus influenzae.^6,7 It is a potent inducer of the cytochrome P450 (CYP) oxidase system, strongly inducing CYP3A4 and CYP2C19 in the liver and intestines. As a result, it can expedite the metabolism of CYP3A4 and CYP2C19 substrates, thereby affecting drug therapeutic efficacy and safety.^8,9 The interaction of rifampin with other drugs, such as warfarin, digoxin, verapamil, nifedipine, simvastatin, midazolam, and human immunodeficiency virus-associated protease inhibitors, has been confirmed.^10,11

However, there have been few reports on the potential interaction between rifampin and citalopram. To our knowledge, only two cases of reduced citalopram efficacy associated with rifampin treatment have been documented.^12,13 Moreover, there is a lack of studies monitoring serum drug concentrations of citalopram to guide clinical dosing. Therefore, it is crucial to determine the interaction of citalopram with rifampicin and the role of therapeutic drug monitoring (TDM) in the individualized treatment of patients with depression and tuberculosis. Here, we presented a case study involving a patient with depression and tuberculosis who underwent TDM to guide the clinical dosing of citalopram.

Case study

A 76-year-old woman weighing 54 kg was admitted to our hospital from the outpatient department due to chronic lower back pain that had persisted for over a year. The patient presented with unexplained lower back pain a year ago and did not receive any targeted interventions. Six months earlier, the patient started experiencing recurrent episodes of low-grade fever. More than 2 months before presentation, she underwent a percutaneous endoscopic biopsy and drainage procedure targeting the lesion at the fifth lumbar and first sacral level under local anesthesia at an external hospital. The biopsy specimen tested positive for XPERT, and the next-generation sequencing analysis revealed a significant abundance of M. tuberculosis, confirming the diagnosis of lumbar tuberculosis. She received antituberculosis therapy, which included oral administration of rifampin (0.6 g/daily), ethambutol (1 g/daily), and pyrazinamide (0.5 g, three times a day). However, the patient experienced significant gastrointestinal adverse reactions, such as nausea, vomiting, and poor appetite after administration of the antituberculosis regimen.

Consequently, the administration of pyrazinamide was discontinued, and the tuberculosis treatment regimen was modified to rifampin (0.6 g/daily) and ethambutol (1 g/daily). After two months of antituberculosis treatment, the patient continued to experience persistent lower back pain. Magnetic resonance imaging (MRI) results revealed degenerative changes and potential tuberculosis involvement in the fifth lumbar and first sacral vertebrae. Therefore, she was admitted to our hospital.

The patient also had been experiencing depressive symptoms for over 17 years and initiated the administration of citalopram hydrobromide (20 mg, administered every morning at 10:30 a.m.) 2 years earlier. This treatment regimen effectively stabilized her condition. However, following admission, the patient reported experiencing depression and anxiety 1 week after initiating antituberculosis therapy, particularly in the afternoon. In addition, she exhibited nocturnal insomnia, which has recently become more pronounced. She could not alleviate her symptoms and expressed concerns regarding a potential relapse of depression. Due to persistent insomnia, the patient was administered zolpidem (10 mg at night) for sleep enhancement. However, despite strict adherence to the prescribed medication regimen, the patient reported no improvement in her insomnia symptoms and subsequently discontinued the zolpidem treatment on the second day.

On the third day, the clinical pharmacist observed that the patient presented depressive symptoms, including pronounced mood swings and insomnia, and considered it may be associated with a reduction in serum concentration of citalopram due to the potent inducing effect of rifampin. For further confirmation, the citalopram trough concentration was monitored at 10 a.m. on the third day (30 min before dosing). The clinical pharmacist recommended adjusting rifampin to rifapentine capsules (0.6 g twice weekly), which have been reported to have a weaker induction effect on the CYP450 enzyme. In addition, an amikacin injection of 0.5 g a day was selected as part of the antituberculosis treatment regimen due to its lack of interaction with citalopram. These recommendations were implemented.

On the fifth day, TDM results revealed a citalopram trough concentration of 8.19 ng/mL, which falls significantly below the effective therapeutic range (50–110 ng/mL). After consulting with a clinical pharmacist, it was recommended that the citalopram dosage be adjusted to 40 mg daily. Consequently, the clinician adopted the pharmacist’s recommendation.

On the ninth day, the patient exhibited significant improvements in sleep quality, accompanied by a reduction in irritability and anxiety. However, the patient reported a worsening of back pain and increased numbness on the soles of their feet following one week of taking rifapentine. Therefore, the medical advice was modified rifapentine to prescribe rifampin at 0.6 g daily.

On the tenth day, the patient opted for conservative treatment and requested an early discharge. Unfortunately, it was not feasible to ascertain whether the dosage adjustment of citalopram resulted in achieving therapeutic drug concentrations.

Two weeks post-discharge, a follow-up was conducted with the patient to assess the treatment of lower back pain and depression after hospital discharge. The patient reported a return to normal sleep, reasonable depression control, and relief of lower back pain and sole numbness after the combination of ethambutol (1 g/daily) and rifampicin (0.6 g/daily) antituberculosis therapy and citalopram (40 mg/daily) antidepressant therapy. The timeline of the treatment process is displayed in Table 1. The patient was informed that he should visit the hospital regularly for follow-up visits and monitoring of heart function. Moreover, the clinical pharmacist suggested that the dose of citalopram could be adjusted to 20 mg/daily after the patient had been cured of lumbar tuberculosis, and the patient should adjust the dose of citalopram according to the doctor’s recommendation.

Table 1.

The timeline of the overall treatment process.

Time	Patient symptoms	Accessory examination	Treatment
More than 2 months before admission	Underwent a percutaneous endoscopic biopsy and drainage procedure targeting the lesion at the fifth lumbar and first sacral level under local anesthesia at an external hospital	The biopsy specimen tested positive for XPERT, and NGS analysis revealed a significant abundance of Mycobacterium tuberculosis, confirming the diagnosis of lumbar tuberculosis	Antituberculosis therapy: rifampin (0.6 g, qd, po.) ethambutol (1.0 g, qd, po.) pyrazinamide (0.5 g, q8h, po.) Patient self-medication: citalopram (20 mg, qd, po.)
More than 2 months before admission (After lumbar tuberculosis was diagnosed and of 1 week anti-TB treatment)	After anti-TB treatment, the patient experienced significant gastrointestinal adverse reactions, such as nausea, vomiting, and poor appetite	—	Rifampin (0.6 g, qd, po.) ethambutol (1 g, qd, po.) citalopram (20 mg, qd, po.) Discontinue: pyrazinamide (0.5 g, tid, po.)
Hospitalization admission (on the first day)	Continued to experience persistent lower back pain, depression, and anxiety	MRI: Degenerative changes and potential tuberculosis involvement in the fifth lumbar and first sacral vertebrae	Rifampin (0.6 g, qd, po.) ethambutol (1 g, qd, po.) citalopram (20 mg, qd, po.) Adding: zolpidem (10 mg, qn, po.)
On the second day	Experiencing depression, anxiety and nocturnal insomnia did not relieve	—	Rifampin (0.6 g, qd, po) ethambutol (1 g, qd, po) citalopram (20 mg, qd, po) Discontinue: zolpidem (10 mg, qn, po)
On the third day	Insomnia	The citalopram trough concentration was monitored	Ethambutol (1 g, qd, po) citalopram (20 mg, qd, po) Adding: rifapentine (0.6 g, W2D, po) amikacin injection (0.5 g, qd, ivgtt.) Discontinue: rifampin (0.6 g, qd, po)
On the fifth day	Feeling irritable and insomnia	TDM: Ctrough of citalopram: 8.19 ng/mL (effective therapeutic range: 50–110 ng/mL)	Ethambutol (1 g, qd, po.) rifapentine (0.6 g, W2D, po.) citalopram (40 mg, qd, po.)
On the ninth day	Significant improvements in sleep quality reduced irritability and anxiety, but back pain and increased numbness	—	Ethambutol (1 g, qd, po.) citalopram (40 mg, qd, po.) Adding: rifampin (0.6 g, qd, po.) Discontinue: rifapentine (0.6 g, W2D, po.)
On the tenth day	Back pain relief, anxiety, and other symptoms are reduced	—	The patient was discharged. Continue anti-TB treatment regimen and antidepressant treatment, including: ethambutol (1 g, qd, po) rifampin (0.6 g, qd, po) citalopram (40 mg, qd, po)
2 weeks after discharge	The patient recovered from normal sleep; depression can be controlled, and low back pain and numbness of the soles have improved	—	Ethambutol (1 g, qd, po) rifampin (0.6 g, qd, po) citalopram (40 mg, qd, po)

C_trough, trough concentration; NGS, next-generation sequencing; po, peros; qd, one day at a time; TB, tuberculosis; TDM, therapeutic drug monitoring; W2D, twice a week; XPERT MTB, detection of Mycobacterium tuberculosis.

The reporting of this study conforms to the CARE statement (Supplemental Material). ¹⁴ All data are accurate, valid, and have obtained informed consent from the patient.

Discussion

Citalopram is a racemic compound consisting of S-(+) and R-(−) enantiomers. The pharmacologically active component of citalopram is its S-(+) enantiomer, which inhibits the reuptake of 5-hydroxytryptamine (5-HT), accounting for 24% to 49% of the total plasma concentration of citalopram.^4,5 On the other hand, the R-(−) enantiomer does not exhibit any discernible pharmacological activity. In vitro data demonstrate that citalopram exhibits weak inhibitory activity toward the CYP1A2, CYP2D6, and CYP2C19 isoenzymes. At the same time, it does not have any inhibitory effect on CYP3A4. ¹⁵ These findings suggest that citalopram has minimal to no impact on drugs metabolized by these isoenzymes in vivo. Notably, this inhibitory effect on hepatic enzymes is significantly lower than other SSRIs.

Consequently, when considering reducing potential drug interactions, citalopram is often favored as an SSRI of choice. ¹⁶ However, a report indicates that citalopram in combination with rifampin and doxycycline for the treatment of panic and tuberculosis, patients’ panic symptoms recurred on the fifth day, which was subsequently relieved by increasing the dose of citalopram (40 mg/day). ¹² This finding suggests a potential drug interaction between rifampin and citalopram; the strong induction of rifampicin on CYP3A4 may lead to decreased serum concentration of citalopram. However, few studies have investigated the magnitude of the effect of interaction between rifampin and citalopram, and no reports have been published regarding TDM-guided dose adjustment of citalopram.

The major metabolic enzymes involved in the metabolism of citalopram are CYP3A4 and 2C19.^4,17 It has been demonstrated that carbamazepine significantly affects the metabolism of citalopram by inducing P450 3A4, resulting in a decrease of 27% and 31% in serum concentrations of S-citalopram and R-citalopram, respectively. ¹⁸ In our study, a 76-year-old had been prescribed a daily dose of 20 mg citalopram for long-term management of depression, which controlled depressive symptoms. However, following the initiation of rifampin-based antituberculosis therapy for lumbar spine tuberculosis two months ago, the patient experienced poorly managed symptoms of depression, including mood fluctuations, irritability, and anxiety. After admission to the hospital, the patient’s serum trough concentration of citalopram was measured at 8.19 ng/mL, which falls significantly below the recommended adequate concentration level (effective therapeutic range: 50–110 ng/mL).^19,20 However, by adjusting the dosage of citalopram to 40 mg daily, effective control over the patient’s distressing depressive symptoms was achieved. This suggested that rifampicin and citalopram may have a potential interaction.

A temporal correlation was observed between rifampicin and depressive symptoms. The patient exhibited reasonable depression control before taking rifampin, whereas symptoms indicating poor control of depression, such as irritability and insomnia, emerged after initiating treatment with rifampin. Nassar et al. ²¹ found that the rifampin enzyme induction effect occurred 22 h after administration, peaked at approximately 28–30 h, and subsequently exhibited a rapid decline within 1–2 h to nearly baseline levels. It takes about 1 week after the initiation of treatment to achieve complete induction of rifampin’s metabolizing enzymes. ²² The plasma elimination half-life of citalopram is approximately 1.5 days, and a steady state is reached within 1 to 2 weeks following drug administration. ⁵ Therefore, it is evident that the induction time for complete activation of metabolizing enzymes in rifampin, which lasts approximately 1 week, coincides with the period when the patient reported symptoms of depression, moodiness, anxiety, and nocturnal insomnia following 1 week of rifampin antituberculosis treatment. Furthermore, after discharge, the patient took rifampin in combination with continuous use of 40 mg qd citalopram for more than half a month, at which time citalopram reached steady-state concentration, and the patient reported satisfactory control of depression at follow-up. Therefore, it can be inferred that the recurrence of depression in this patient was associated with the duration of rifampin administration.

The pharmacokinetic-pharmacodynamic interactions were clinically significant. Citalopram is a highly selective ligand for 5-serotonin (5-HT) transporters. Citalopram can prevent the reuptake of 5-HT by presynaptic neurons, is mainly metabolized to desethylcitalopram (DCT) through CYP3A4 and CYP2C19, and CYP2D6 catalyzes DCT to form dimethylcitalopram (DDCT), which are weak antagonists for 5-HT reuptake. ³ Rifampicin is a potent inducer of CYP3A4 and CYP2C19, resulting in a ⩾80% reduction in the area under the curve (AUC) of sensitive substrates within the metabolic pathway. ²¹ The results of serum trough concentration monitoring revealed a reduction of approximately 83.62%, with the value only reaching 16.38% of the lower limit of the normal range. The specific mechanism is illustrated in Figure 1. The patient’s clinical manifestations of poorly controlled depression, including marked mood swings and irritability, were consistent with the blood concentration monitoring results. Therefore, there may be an interaction between rifampicin and citalopram (Figure 1).

Figure 1.

The induction mechanism of rifampin on CYP3A4 enzyme and its effect on citalopram metabolism.

PXR, pregnane X receptor; RXR, retinoid X receptor; SERT, serotonin transporter.

Dose adjustment: Several studies indicated that using single and multiple doses of citalopram in individuals over 60 years results in a 23% to 30% increase in the AUC compared to younger subjects. ²³ Consequently, it is recommended to administer a lower dosage of 20 mg daily for elderly patients (>60 years). The long-term management of depression in our patient using citalopram 20 mg daily has demonstrated favorable outcomes. After co-administration with rifampin for 2 months, the serum trough concentration of citalopram was monitored to be 8.19 ng/mL. Consequently, the dosage of citalopram was adjusted from 20 mg daily to 40 mg daily. After maintaining this regimen continuously for 2 weeks, the patient experienced effective control over symptoms associated with depression.

In addition, possible arrhythmias associated with the use of citalopram should also be considered, especially in elderly patients (> 65 years). ²⁴ After tuberculosis has subsided, the dose of citalopram needs to be reduced. Some literature reports suggest that the enzyme induction effect of rifampicin will not disappear immediately after discontinuation of rifampicin, and its induction effect will generally disappear after 10–14 days of discontinuation. ²⁵ The time to adjust the dose of citalopram also needs attention.

Based on this analysis, rifampin has the potential to enhance citalopram metabolism by inducing cytochrome P450 (CYP) 3A4 and 2C19, which results in a reduction in its serum concentration. This pharmacokinetic interaction may lead to a decrease in the therapeutic efficacy of citalopram. However, it is noteworthy that neither rifampin nor citalopram instructions explicitly mention this drug-drug interaction. The instructions should recommend adding information about significant interactions between the two. This study aims to provide clinicians with valuable references and insights into the medication administration process, enhancing therapeutic effects and improving patients’ quality of life.

Limitations

First, the serum trough concentrations were not reassessed due to patient-related factors after adjusting the citalopram dosage. Second, analyzing data based on individual patients has limitations that make it difficult to generalize to the broader population. Moreover, some studies have identified significant inter-individual variability in serum concentrations of citalopram,^20,26 even when adjusting the dosage according to body weight. Third, due to environmental factors in the hospital, patients reported significant symptoms of depression, anxiety, and insomnia at home upon admission. However, the noisy nighttime environment during hospitalization cannot rule out the possibility that the hospital environment may lead to further depressive symptoms. Therefore, additional studies are needed to determine the causes affecting the pharmacokinetic variation of citalopram.

Conclusion

The induced effect of rifampicin on CYP3A4 may lead to the decrease of serum citalopram concentration in patients with depression and tuberculosis. For elderly patients requiring concurrent use of rifampin and citalopram, a dose increase (up to twice the daily previous maintenance dose) may be required. Individualized dose adjustment using TDM is essential to improve the efficacy of disease treatment.