Interactions Between Non-Tamoxifen Endocrine Therapies and Antidepressants: A Narrative Mini-Review

Abstract

Non-tamoxifen endocrine therapies used in hormone receptor (HR)-positive breast cancer include aromatase inhibitors (letrozole, anastrozole, exemestane), selective estrogen receptor degraders (fulvestrant), and gonadotropin-releasing hormone (GnRH) analogs (leuprorelin, goserelin). Due to the high prevalence of depression in this patient population, antidepressant use is common. While CYP2D6-mediated interactions between tamoxifen and antidepressants are well established, interactions with other endocrine agents are less well defined and are primarily based on pharmacokinetic and indirect pharmacodynamic mechanisms. Aromatase inhibitors are metabolized via cytochrome P450 enzymes and have a theoretical interaction potential with certain SSRIs/SNRIs that act as strong CYP inhibitors. However, current clinical data are limited and heterogeneous, and the direction and magnitude of these interactions remain uncertain. Available evidence suggests that any changes in drug levels are generally modest; however, their impact on estrogen suppression has not been clearly established. Exemestane, due to its CYP3A4-dependent metabolism, may be susceptible to pharmacokinetically significant interactions with strong CYP3A4 inhibitors or inducers, and clinically relevant changes in drug exposure cannot be excluded, although direct outcome data remain limited. Fulvestrant, due to its wide therapeutic window and minimal enzyme inhibition, appears to have a low potential for clinically significant interactions with antidepressants. GnRH analogs do not undergo CYP-mediated metabolism and therefore CYP-mediated pharmacokinetic interactions are not expected. However, a shared mechanism across these therapies is estrogen suppression, which may influence serotonergic and other neurotransmitter systems in the central nervous system and may contribute to neuropsychiatric symptoms such as depression, anxiety, and sleep disturbances. These effects may, in turn, contribute to the need for antidepressant treatment. In clinical practice, agents such as escitalopram, sertraline, and venlafaxine are commonly preferred due to their lower interaction potential, whereas strong CYP inhibitors such as fluoxetine and paroxetine may be less preferred or may warrant caution. In conclusion, interactions between non-tamoxifen endocrine therapies and antidepressants appear to be of limited clinical significance; however, given the potential for estrogen-depletion–related neuropsychiatric effects, appropriate psychiatric management and a multidisciplinary approach remain important in-patient care.