Transfer of the Serotonin Modulator Vortioxetine into Human Milk: A Case Series

Introduction

The highest prevalence rate for major depression occurs in women of childbearing age. ¹ Up to 70% of pregnant women report symptoms of depression and ∼13% fulfill diagnostic criteria.^1,2 During the first postpartum year, the period prevalence of depression is 21.9%. ³ Major depressive disorder affects a woman's quality of life, and maternal depression adversely affects mother-child bonding and child socioemotional and psychomotor development. ² Untreated depression during the postpartum period can be a significant cause of mortality with suicide accounting for 20% of postpartum deaths, the second most common cause of mortality in postpartum women. ³ Pregnancy and postpartum depression are also associated with shorter breastfeeding duration, which may lead to suboptimal outcomes for mother and child. ⁴ The choice of antidepressant for women with major depression who are breastfeeding depends on prior treatment history and potential adverse effects for mother and nursing infant. ⁵ This approach is shared in presence of their partners after informative sessions, in which clinicians clearly specify the risks and benefits related to a psychopharmacological treatment and an untreated mental illness. ⁶

Vortioxetine (Trintellix) is an antidepressant that works through serotonin modulation, inhibiting the reuptake of serotonin and acting as an agonist at the 5-HT1A receptor and as an antagonist at the 5-HT3 receptor. ⁷ This medication is approved to treat major depressive disorder in adults and has fewer side effects compared to other antidepressants, including lack of weight gain, lack of changes in the QT interval, and low incidence of sexual dysfunction. ⁸ The relative lack of weight gain and sexual dysfunction may make vortioxetine a compelling choice for postpartum women. A typical dose is 5–20 mg once per day. There are no previous studies on the transfer of vortioxetine into human milk, although the manufacturer reports its presence in rodent milk. The pharmacokinetic profile of vortioxetine suggests that it is capable of transferring into human milk. The present study determined the drug concentration-time profile in the milk samples collected from three lactating mothers at steady state, two taking 10 mg and one taking 20 mg/day.

Case Presentation

Patient 1 is a 35-year-old woman weighing 63.6 kg who gave birth to a female infant after 40 weeks of gestation. She was diagnosed with depression and anxiety in 2005 and was prescribed the maximum dose of 20 mg vortioxetine once daily in March 2018 and continued throughout pregnancy. She donated her milk samples in September 2019, very well in steady state. At the time of the study, she was exclusively breastfeeding her 2-month-old infant. Her other medications included vitamins, aspirin 81 mg, and levothyroxine 50 mcg/day.

Patient 2 is a 28-year-old woman weighing 93 kg who gave birth to a female infant after 39 weeks of gestation. She had a history of depression and anxiety for 7 years of age and was prescribed vortioxetine in March 2018, initially 20 mg once daily but due to side effects, the dose was reduced to 10 mg once daily. She donated her milk samples in July 2019 when at steady state. During the study, she was exclusively breastfeeding her 6-month-old infant. She continued on this drug throughout pregnancy. Her other medications included magnesium glycinate 120 mg twice a day and vitamins.

Patient 3 is a 28-year-old woman weighing 50 kg who gave birth to a male infant after 37 weeks of gestation. She was diagnosed with depression at 15 years of age and was prescribed 10 mg of vortioxetine once daily in June 2015. She continued on this drug throughout pregnancy. She donated her milk samples in May 2018 at steady state concentration. At the time of the study, she was exclusively breastfeeding her 1-month-old infant. Her other medications included 2 mg of buprenorphine tablets, fish oil, and 5 mg of clonazepam. They were all asked to report if any changes were observed in their infants while taking this medication. All the participants donated milk samples at 0, 5, 7, 10, 12, and 24 hours following the dose for both the doses. To preserve the homogeneity of the samples, the women were advised to pump both the breasts completely, gently mix them together, and collect one to two ounces into a provided collection tube. The samples were frozen immediately in their freezer and mailed to our research facility overnight. The samples were stored at −80°C until analyzed.

Methods

Quantification of vortioxetine was determined using an Agilent 1260 Quadrupole mass spectrometer and a Phenomenex Biphenyl column, 100 × 4.6 mm, 5 μm. Isocratic elution was followed using water and acetonitrile with a flow rate of 0.5 mL/min. Single ion monitoring at m/z 299.3 for vortioxetine was determined. Milk samples were extracted using protein precipitation. Blank milk containing no drug concentration was spiked with appropriate concentrations of vortioxetine and internal standard for determining the calibration curve (range 3.1–100 ng/mL and r² = 0.99). The values for area under the curve were obtained using the GraphPad Prism software version 9.0.2. The absolute infant dose was calculated by multiplying the average concentration by 150 mL/[kg·day] (based on general assumption). The relative infant dose (RID) was calculated by dividing the infant dose by maternal dose times 100, to represent it as percent.

Results

In the two patients who were using 10 mg vortioxetine once daily, milk samples were collected at 0, 5, 7, 10, 12, and 24 hours after the dose. The average concentration (C_avg) of vortioxetine observed was 11.64 ng/mL. The maximum concentration was detected at 7 hours, and was calculated at 13.89 ng/mL. The levels gradually receded over time. The infant dose calculated was 0.0017 mg/kg/day and the RID was calculated at 1.1% of the maternal dose.

For the patient consuming 20 mg vortioxetine once daily, milk samples were collected at 0, 5, 7, 10, 12, and 24 hours. The C_avg determined in milk was 35.12 ng/mL, with the maximum level (C_max) detected at 5 hours as 52.32 ng/mL. The RID observed was 1.7%. In addition, mothers reported no unusual behavior in their infants. Figure 1 represents milk concentration-time profile of vortioxetine in human milk following the oral administration of 10 and 20 mg daily. Table 1 summarizes pharmacokinetic parameters for patients taking 10 mg once daily and for the patient taking 20 mg once daily. All the samples were processed and analyzed in triplicate and described as a mean of values. The RID values are well below the theoretical level of concern of 10%. ⁹

OPEN IN VIEWER

FIG. 1.

Milk concentration-time profile of vortioxetine following the oral administration of 10 mg taken once daily (n = 2) and 20 mg once daily (n = 1).

Discussion

This study establishes the presence of vortioxetine in milk samples collected from three lactating mothers, with a low and dose proportional transfer into milk. It is known that poor metabolizers have up to a twofold increase in exposure to vortioxetine. A genetic polymorphism in cytochrome P450 2D6 has been described in 4% of the population. ¹⁰ Even in a poor metabolizer, the RIDs might be doubled, but this would still be a low value. The low RIDs found in this study indicate that milk levels are likely to stay far below the standard 10% RID threshold for safety.

Several pharmacokinetic factors impact the transfer of a drug into breast milk, including maternal dose, plasma protein-binding, half-life, T_max, peak serum time, and volume of distribution. Vortioxetine has linear and dose proportional pharmacokinetics. The half-life is 66 hours, and steady-state plasma concentrations are reached in 2 weeks. ¹⁰ Vortioxetine is well absorbed orally and the time to maximal serum concentration is within 7–11 hours. Vortioxetine has a large volume of distribution, so the drug is mostly in peripheral compartments, outside of the plasma. Vortioxetine's minimal transfer into breast milk may be explained by its high plasma protein binding (98%). Drugs that circulate highly bound plasma proteins transfer poorly into breast milk.

Sertraline is one of the current first-line treatments for lactating patients starting an antidepressant. ¹¹ Most other selective serotonin reuptake inhibitors (SSRIs) are still considered compatible with breastfeeding, but have higher accumulation in breast milk. Serotonin-norepinephrine reuptake inhibitors appear to be safe for breastfeeding women based on lack of adverse events in infant observational studies, but infant exposure is greater than with most SSRIs. Sertraline and paroxetine all have similar but fortunately low RIDs. ¹² While there are few studies on the effects of serotonin reuptake inhibitors in breastfed infants, adverse effects are quite uncommon. One review described adverse events in 0.9% of paroxetine cases and in one case out of 279 for sertraline. ¹¹ The most common effects are irritability and lethargy. This study is limited by a small sample size and corresponding mother's plasma samples, which would have allowed us to calculate the milk:plasma (M:P) ratio. This value defines the extent of transfer of medication from mother's milk to her infant's plasma. Vortioxetine, with a RID of 1.1% and 1.7% at 10 and 20 mg daily, respectively, suggests a low risk to the infant. This report also adds preliminary information for breastfeeding women who are advised to take vortioxetine to treat depression.

Conclusions

This case series found the RID of vortioxetine to range from 1.1% to 1.7%. These findings likely suggest a minimal risk of infant toxicity. The RID for vortioxetine is comparable or lower than with sertraline and paroxetine, which are considered the current first-line treatments for depression in lactating patients. However, caution must be exercised until further studies are conducted reporting the bioavailability of vortioxetine in infants.