Mental Illness 2019; volume 11:8115 Interactions between of cancer and cancer treatment-mediated antidepressants, sleep aids and structural and functional brain dysfunction, Correspondence: Robert G. Bota, Department which affects the hippocampus and decreas - of Psychiatry, University of California Irvine, selected breast cancer therapy es hippocampal neurogenesis. 1-4 As many 101 City Drive as 35% of cancer patients suffer from Orange, CA, USA. Jody Jacobson Wedret, 1 Thanh G. Tu, 2 depression and over 10% have major Tel.: +1.229.815.0219 - Fax: +1.714.456.2056. E-mail: [email protected] Doru Paul, 3 Camille Rousseau, 4 depressive disorder. 5,6 Similarly, insomnia 1 1 affects up to 50% of patients with cancer. 7 Augustin Bonta, Robert G. Bota Key words: depression, insomnia, cancer Therefore, pharmacological options are 1University of California Irvine, Orange, patients, drugs interaction. often employed to address insomnia and/or CA, USA; 2University of California San depression in this patient population. Contributions: the authors contributed equally. Francisco, San Francisco, CA, USA; With all disease states and especially 3 Cornell University, Ithaca, NY, USA; with cancer, close attention to drug-drug Conflict of interest: the authors declare no 4 University of Bordeaux, France interactions and the potential impact on the potential conflict of interest. efficacy of therapy is paramount. One area of particular interest due to the lack of well- Funding: none. Abstract done clinical trials is drug-drug interaction(s) between antidepressants and Received for publication: 18 March 2019. Depression and insomnia are very sig - cancer treatment. Without reliable clinical Accepted for publication: 18 March 2019. nificant pathologies in cancer patients as trials to vet the potential drug-drug This work is licensed under a Creative they contribute to the patient’s overall cure interactions, we are left with theoretical and quality of life. Moreover, untreated Commons Attribution-NonCommercial 4.0 evidence and educated deductive reasoning. International License (CC BY-NC 4.0). depression and ongoing insomnia are asso - With that said, the pharmacological ciated with decreased immune responses treatment of depression in patients with ©Copyright J.J. Wedret, et al., 2019 and lower survival rates. With all disease cancer presents unique challenges caused Licensee PAGEPress, Italy states and especially with cancer, close by drug-drug interactions between Mental Illness 2019; 11:8115 attention to drug-drug interactions and the antidepressants and cancer doi:10.4081/mi.2019.8115 potential impact on the efficacy of therapy pharmacotherapy, which may lower the is paramount. One area of particular interest effectiveness of cancer treatment. 1-4 Despite due to the lack of well-done clinical trials is the impact of depression in patients with level of active metabolites or decreased level drug-drug interaction(s) between cancer, studies looking at the efficacy of of active parent drugs. Secondly, considera - antidepressants and cancer treatment. antidepressant medications in this tion for the clinical significance of drug inter - Pharmacokinetics of a certain drug allows population are very few and of low quality. actions to inform our clinical decisions is a for prediction of certain drug interactions On the other hand, the pharmacological must. In regards to pharmacodynamics, based on chemical properties of the agents options available for treatment of insomnia changes in drug levels secondarily to involved. If the agents depend on their pose less of a challenge in terms of drug- cytochrome P450 inhibition or induction may metabolites for activity, active drug level drug interactions for patients currently on not be as clinically significant as hypotheti - will be decreased through this enzyme inhi - cancer pharmacotherapy. cally predicted depending on the therapeutic bition. In this paper, we looked at the indexes of the agents involved. cytochrome-P450 drug interactions between antidepressants and sleep aids with Methodology Selective Estrogen Receptor Modulators (SERM). Newer SERM metabolisms are We approached the topic of drug Selective Estrogen Receptor less influenced by interactions with interactions in setting of depression and/or Modulators (SERMs): tamoxifen, medications used to treat depression. insomnia and breast cancer from two raloxifene, toremifene different perspectives. First, the pharmacoki - However, tamoxifen metabolism could be Selective estrogen receptor modulators severely altered by several antidepressants. netics of a certain drug allows for prediction of certain drug interactions based on chemi - (SERMs), including tamoxifen, raloxifene This has direct consequences as patients on and toremifene, are drugs commonly used in tamoxifen and antidepressant can have cal properties of the agents involved. In gen - eral, inhibitors of cytochrome P450 breast cancer treatment. Particularly, tamox - double the risk of relapse to cancer in two ifen, a cost effective SERM that is commonly years. We discussed those interactions and enzyme(s) will reduce metabolism of enzyme substrates. If the agents depend on their used, is a prodrug that is metabolized through made recommendations for clinical use. metabolites for activity, active drug level will various cytochrome P450 enzymes, specifi - be decreased through this enzyme inhibition. cally CYP3A4, CYP3A5 and CYP2D6, to For instance, tamoxifen is a prodrug, a bio - give three active metabolites. 7 Therefore, logically inactive compound that requires drugs that inhibit these enzymes, especially Introduction CYP2D6 enzymatic activation to yield the CYP2D6, may decrease tamoxifen active Depression and insomnia are very sig - active metabolite, endoxifen. Therefore, metabolite level, potentially diminishing nificant pathologies in cancer patients as enzymatic inhibition of CYP2D6 will tamoxifen’s anti-cancer effect. Importantly, they contribute to the patient’s overall cure decrease metabolism of parent drug tamox - this drug-drug interaction through and quality of life. Moreover, untreated ifen and thus decrease level of active metabo - cytochrome P450 metabolic pathways may depression and ongoing insomnia are asso - lite endoxifen. On the other hand, inducers of increase the recurrence of cancer in patients ciated with decreased immune responses cytochrome P450 enzyme(s) will increase concomitantly taking tamoxifen and a and lower survival rates. Depression in can - metabolism and excretion of enzyme sub - CYP2D6 inhibitor. 8 cer patients is the phenotypic manifestation strates, which will result in either increased Conversely, SERMs that are not reliant [page 36 ] [Mental Illness 2019; 11:8115] Review on CYP2D6 for metabolism pose a less com - drug interaction are largely dependent on the cokinetic studies of various antidepressants plicated challenge in regards to drug-drug therapeutic indexes of drugs involved. and their potential impact on the metabolism interactions relative to tamoxifen. Raloxifene of SERMs, especially tamoxifen, the follow - undergoes glucuronidation while toremifene ing conclusions were drawn. As shown in utilizes CYP3A4 for its metabolism. Figure 1, paroxetine, fluoxetine and bupropion Therefore, the challenge in using raloxifene Pharmacological treatment for are amongst the strongest CYP2D6 inhibitors or toremifene concomitantly with CYP2D6 depression of the antidepressants. 1-6,8-17 Despite the con - inhibitors such as certain antidepressants is Pharmacological interventions for troversial evidence available regarding the unparalleled to tamoxifen. The differences in depression include several categories of med - clinical significance of these strong inhibitory metabolism and the pathways employed by ications, including selective serotonin reup - activity on tamoxifen’s anticancer effect, it is each medication partially explain the varia - take inhibitors (SSRI), serotonin norepineph - premature to dismiss these interactions given tions in drug-drug interactions between rine reuptakes inhibitors (SNRI), and tricyclic the lack of strong evidence proving unchanged SERMs and antidepressants. 9,10 Overall, the antidepressants (TCA). mortality rate with paroxetine, fluoxetine and clinical pharmacodynamic effects of each Upon review of clinical trials and pharma - bupropion. On the other hand, Trazodone, 11 Figure 1. Cytochrome-P450 Drug Interactions between Antidepressants and Selective Estrogen Receptor Modulators (serms). Classification of antidepressants’ cytochrome P450 inhibition based on available pharmacokinetic data. 1-6,8-17 Green ( ): No inhibi - tion; Yellow ( ): Mild inhibition; Orange ( ): Moderate inhibition; Red ( ): Strong inhibition. Recommendation based on clinical relevance of cytochrome P450 interactions. aConsider therapy modification: Evidence available to support clinically significant decrease in efficacy of selected breast cancer pharmacotherapy as measured by all-cause mortality and/or breast cancer recurrence. bMonitor ther - apy: Lack of evidence available or available evidence suggests clinically insignificant decrease in efficacy of selected breast cancer phar - macotherapy as measured by all-cause mortality and/or breast cancer recurrence. Cno action required: No known or exp⟷ected clinically significant int↓eraction. ↓↓ ↓↓↓ [Mental Illness 2019; 11:8115] [page 37 ] Review death. Harv Ment Health Lett 2010;26:6- 7. 9. Kim J, Peraire C, Sola J, et al. Drug inter - action potential of toremifene and N- desmethyltoremifene with