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Suicidal while receiving treatment for Deepti Chopra, MBBS, MPH, and Walter F. Baile, MD

Mrs. L, age 46, is undergoing treatment for . Three How would you weeks into a new regimen, she feels sad and irritable, and has handle this case? Answer the challenge thoughts of suicide. What could be causing these symptoms? questions at MDedge.com/ psychiatry and see how your colleagues responded

CASE Worsening mood symptoms What could be the reason for Mrs. L’s and suicidal ideation depressed mood? On a recent visit to the oncology clinic, where a) cancer she has been receiving treatment for breast b) tamoxifen and other cancer treatments cancer for 11 months, Mrs. L, age 46, reports c) a previously undiagnosed mood disorder the abrupt onset of sadness, irritability, dif- d) all of the above ficulty sleeping, and negative self-thoughts. Eleven months ago, Mrs. L was diagnosed with invasive lobular carcinoma of the right The authors’ observations breast that was classified as T2N0MX, repre- The prevalence of depression is higher in senting relatively early-stage disease. Shortly patients with cancer than in the general after her diagnosis, Mrs. L completed 4 cycles population.1 The etiology of depression is of neoadjuvant chemotherapy with doxoru- often multifactorial.2 In Mrs. L’s case, we bicin and cyclophosphamide, followed by hypothesized that the possible cause of her treatment with trastuzumab. Subsequently, depressive symptoms included concerns she underwent a right segmental mastec- about her self-image after mastectomy and tomy with bilateral mastopexy and radiation the adverse effects of chemotherapy and therapy. Recently, Mrs. L’s oncology team tamoxifen. prescribed tamoxifen, 20 mg/d, and trastu- Among these possible causes, zumab, 420 mg IV every 3 weeks; however, level is particularly important. Estrogen within 3 weeks after starting tamoxifen, affects the in numerous ways, includ- Mrs. L’s mood symptoms worsened to the ing by modulating different neurotransmit- point where she says she is considering sui- ters,3,4 regulating neuroplasticity, providing cide—with a plan to use her husband’s gun neuroprotection by preventing formation of to kill herself. oxidative free radicals and of beta amyloid, Mrs. L has no other pertinent medical his- Dr. Chopra is Assistant Professor, Department of Psychiatry, tory and no reported history of psychiatric University of Texas, MD Anderson Cancer Center, Houston, Texas. Dr. disease. Baile is Professor, Department of Psychiatry and Behavioral Science, University of Texas, MD Anderson Cancer Center, Houston, Texas. The primary oncology team discontinues Disclosures tamoxifen (after 5 weeks of treatment) and Dr. Baile is a consultant to Amgen Pharmaceuticals. Dr. Chopra refers Mrs. L to psychiatry for further mood reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of Current Psychiatry evaluation. competing products. Vol. 19, No. 2 47 Cases That Test Your Skills

and possibly avoiding inflammation. From she is constantly preoccupied with thoughts a behavioral standpoint, estrogen acts as about the adverse effects of hormone ther- an antidepressant while enhancing mem- apy, and specifically about the oncology ory and modulating maternal behavior.4 team’s suggestion of a retrial of tamoxifen. Therefore, decreased estrogen levels could Due to her constant worry, she has difficulty result in depression and other neuro­ relaxing; her Generalized Anxiety Disorder–7 psychiatric problems. This is illustrated item scale score is 12, indicating moder- in Mrs. L’s case, where tamoxifen admin- ate anxiety. She has a history of cigarette istered after breast cancer treatment coin- smoking but stopped after her breast cancer cided with the abrupt onset of depression diagnosis. She also reports gaining weight with suicidal ideation. since beginning cancer treatment (body Depression in patients receiving tamoxi- mass index: 28.0 kg/m2) and experiencing Clinical Point fen might be explained by the fact that . tamoxifen is a selective Mrs. L’s vital signs are normal. Results Tamoxifen diminishes blocker with dual properties. Specifically, of her laboratory workup reveal a thyroid- the growth-promoting while it has antagonistic action in breast stimulating hormone level of 1.40 µU/mL action of estrogen on tissue, diminishing the growth-promoting (reference range: 0.27 to 4.20 µU/mL); a breast cancer cells, but action of estrogen on breast cancer cells, it follicle-stimulating hormone (FSH) level also blocks estrogen’s additionally crosses the blood-brain barrier, of 78.4 mIU/mL (postmenopausal reference so it may block the neuroprotective action range: 25.8 to 134.8 mIU/mL); and an estra- neuroprotective of estrogen in the brain. diol level of <12.0 pg/mL (postmenopausal action in the brain range: <55 pg/mL).

EXAMINATION Improvement in depression but slightly anxious The authors’ observations During her psychiatric examination, Mrs. L Studies investigating the effects of tamoxi- is fairly well-groomed and cooperative. Her fen on mood have produced varying results speech is normal, thought process is orga- (Table,5-16 page 50). Some researchers have nized, and she has fair insight into her medi- found a significant relationship between cal situation, with fair judgment. She is alert, depression and tamoxifen in patients with attentive, and oriented to time, place, as well breast cancer. In a case-control study, 42 as person. She confirms that she has no prior postmenopausal women with breast cancer psychiatric history, including no prior suicide who received tamoxifen reported statisti- attempts. She lives with her husband, who cally significant elevated depression scores.5 has been supportive. Mrs. L has no children, Similarly, in a prospective trial that assessed and she continues to work. mood symptoms in 21 pre- and postmeno- Mrs. L reports that per her oncology team’s pausal women who developed estrogen instruction, she has not taken tamoxifen for deficiency during breast cancer treatment almost 1 week, and notes improvement in (including treatment with tamoxifen and her mood. She describes her mood as “fine chemotherapy), 38% of patients met the cri- Discuss this article at now,” but appears slightly anxious. She ada- teria for major depressive disorder (MDD) www.facebook.com/ mantly denies suicidal ideation since stop- in the first 6 months of treatment. Sixty-six MDedgePsychiatry ping tamoxifen; however, she confirms that percent of these patients were postmeno- prior to stopping tamoxifen, she experi- pausal, and 38% were premenopausal. enced low mood, suicidal thoughts, and Twenty-five percent of the premenopausal a decreased interest in activities. Mrs. L’s women who experienced MDD symp- Patient Health Questionnaire–9 score is 13, toms had been treated with tamoxifen and Current Psychiatry 48 February 2020 indicating moderate depression. She says chemotherapy.6 Cases That Test Your Skills

In a larger prospective trial (N = 257), A multicenter randomized, placebo- an oncologist assessed mood symptoms controlled trial (the National Surgical in 2 groups of patients with breast can- Adjuvant Breast and Bowel Project) cer: individuals who received tamoxifen, assessed the incidence of negative health and those who did not receive tamoxi- outcomes, including depression, in a sec- fen.7 They found that 15% of patients who ondary outcome analysis.16 These research- received tamoxifen experienced depres- ers did not find a statistically significant sion, compared with 3% of patients who association between tamoxifen and depres- did not receive tamoxifen; this difference sion. However, in this study, assessment was statistically significant.7 Overall, 31% of depression was based on self-report of the patients had “significant depres- using the Center of Epidemiologic Studies sion” and 27% discontinued tamoxifen Depression (CES-D) scale, which does not because of adverse effects.7 There have clinically categorize depression. Furthermore, Clinical Point been 2 case reports of tamoxifen use and these researchers strongly recommended severe depression in patients with no prior screening for mood disorders in routine Avoid the use of psychiatry history8,9 and 3 case reports of clinical practice. In this study, 3 women antidepressants with tamoxifen use and severe depression in completed suicide, 2 of whom were in the strong 2D6-inhibiting patients who had a psychiatric history.10-12 tamoxifen arm.16 properties in patients One study that examined 24 men with receiving tamoxifen breast cancer found that 62.5% of these Which antidepressant(s) might interfere with patients experienced adverse effects related the of tamoxifen? to tamoxifen, and 25% discontinued tamox- a) bupropion ifen because of its adverse effects.13 Among b) duloxetine the various adverse effects related to c) tamoxifen, mood alteration was reported in d) 20.8% of cases, and depressed feelings were e) all of the above reported in 16.6%.13 Despite this evidence, other studies have not found an association between tamoxi- The authors’ observations fen and depressed mood in patients with Tamoxifen is a that converts to the breast cancer. One group of researchers who active metabolite, , via cytochrome assessed various symptoms self-reported by P450 2D6 (CYP2D6) activity. Antidepressants postmenopausal women who were breast with strong 2D6-inhibiting properties, such cancer survivors found that the depression as fluoxetine, duloxetine, bupropion, and scores were not significant.14 A retrospective paroxetine, should be avoided in patients cohort study assessed the onset of depres- receiving tamoxifen because they interfere sion in patients with breast cancer with posi- with the formation of the active metabolite tive hormone receptor status (who received and could reduce the effectiveness of tamox- tamoxifen) vs negative hormone receptor ifen and its ability to reduce the risk of cancer status (who did not receive tamoxifen). recurrence.17 Antidepressants can help treat These researchers did not find a statisti- psychological distress, especially depres- cally significant hazard ratio for “new-onset sion, which is common in patients with can- depression.”15 Unfortunately, the criteria for cer, and vasomotor symptoms, which may “new-onset depression” used in this study impair quality of life and to long- was the diagnosis of depression or use of an term endocrine therapy. Because tamoxifen antidepressant given or ordered by a clini- can decrease cancer recurrence and associ- cian, which is not a sensitive assessment of ated mortality,18 adherence with treatment Current Psychiatry depressed mood.15 is crucial. Vol. 19, No. 2 49 continued Cases That Test Your Skills

Table Studies of tamoxifen and depression Study Design Measures of depression/ administered Outcomes Shariff et al5 Case-control study State-Trait Anxiety Inventory Depression scores were higher during tamoxifen therapy (1995) Postmenopausal women (N = 42) Institute for Personality and Ability Testing and statistically significant Assessed at baseline and 8 months Depression Scale after tamoxifen treatment State-Trait Anger Expression Inventory Functional Living Index–Cancer Millon Clinical Multiaxial Inventory II Duffy et al6 (1999) Prospective cohort study Structured Clinical Interview for the Diagnostic Thirty-eight percent of patients were diagnosed with Both pre- and postmenopausal Statistical Manual major depressive disorder in the first 6 months of women (N = 21) treatment Clinical Point Cathcart et al7 Prospective trial Serial evaluations of cancer status and mood Temporal association between depressed mood and Antidepressants with (1993) Both pre- and postmenopausal symptoms by an oncologist initiation of tamoxifen. Fifteen percent of patients in tamoxifen group developed depression strong 2D6-inhibiting women (N = 257) Lin and Case report Beck Depression Inventory After tamoxifen treatment, the patient developed properties could 8 Thompson Female, age 51, no history administered depression. Patient wanted to restart tamoxifen, so reduce tamoxifen’s (2001) of depression sertraline was initiated for prophylaxis. Depression ability to reduce improved and remained stable with antidepressant plus tamoxifen regimen the risk of cancer Pluss et al9 Case report No scales Cerebellar symptoms and depression improved after recurrence (1984) Female, age 69, no history Temporal association considered tamoxifen was discontinued of depression Bourque et al10 Case report DSM-IV-TR criteria Depressed mood with suicidal ideation with 2 trials of (2009) Female, age 34, with history No scales tamoxifen. Antidepressant added and maintained for third trial of tamoxifen of depression Venlafaxine administered De Berardis et al11 Case report Hamilton Depression Rating Scale Depression improved with agomelatine. Tamoxifen was (2014) Female, age 42, with history Snaith–Hamilton Pleasure Scale continued with antidepressant. No recurrence of breast cancer reported of adjustment disorder Agomelatine administered Ito et al12 Case report Hamilton Depression Rating Scale Depression improved after discontinuing tamoxifen. (2006) Female, age 63, with family history Milnacipran administered Antidepressant was maintained after stopping tamoxifen of depression Anelli et al13 Descriptive study Telephone interview during tamoxifen treatment. Mood alteration reported in 20.8% and (1994) Male patients with breast cancer To avoid confounding by other adjuvant treatments, depression noted in 16.6% of patients (N = 24) the interview was done 8 weeks after chemotherapy or radiation therapy. None of the patients were receiving any kind of chemotherapy at the time of the evaluation Love et al14 Randomized placebo- Self-report of various symptoms Study did not find statistical significance for depression (1991) controlled trial scores, but found statistical significance for anxiety Postmenopausal women (N = 140) symptoms Lee et al15 Retrospective cohort study No instrument used to measure depression Study did not find a statistically significant association (2007) Women with genetic mutation New diagnosis of depression or start of between tamoxifen and new-onset depression (N = 2,943) antidepressant treatment was used as a tool to assess depressed mood Day et al16 Multicenter randomized controlled Center of Epidemiological Studies–Depression Study did not find a statistically significant association (2001) trial (N = 11,064) between tamoxifen and depression; however, the authors recommended screening for and treatment of Current Psychiatry depression 50 February 2020 Cases That Test Your Skills

Table TREATMENT Starting an Studies of tamoxifen and depression antidepressant The psychiatry team initiates venlafaxine, Study Design Measures of depression/medication administered Outcomes 37.5 mg/d, to treat Mrs. L’s anxiety and help Shariff et al5 Case-control study State-Trait Anxiety Inventory Depression scores were higher during tamoxifen therapy prevent the recurrence of severe depression. (1995) Postmenopausal women (N = 42) Institute for Personality and Ability Testing and statistically significant They prescribe venlafaxine because they Depression Scale Assessed at baseline and 8 months anticipate that, based on Mrs. L’s age, the after tamoxifen treatment State-Trait Anger Expression Inventory oncology team might reconsider treatment Functional Living Index–Cancer with tamoxifen. Venlafaxine is preferred Millon Clinical Multiaxial Inventory II because it has a favorable pharmacodynamic 6 Duffy et al (1999) Prospective cohort study Structured Clinical Interview for the Diagnostic Thirty-eight percent of patients were diagnosed with profile and does not interfere with the metab- Statistical Manual major depressive disorder in the first 6 months of Both pre- and postmenopausal olism of tamoxifen, as is the case with many women (N = 21) treatment selective serotonin reuptake inhibitors.17 7 Clinical Point Cathcart et al Prospective trial Serial evaluations of cancer status and mood Temporal association between depressed mood and Although Mrs. L’s depression had abated (1993) symptoms by an oncologist initiation of tamoxifen. Fifteen percent of patients in Both pre- and postmenopausal once she stopped receiving tamoxifen, she Venlafaxine does women (N = 257) tamoxifen group developed depression continues to experience anxiety and tearful- not interfere with Lin and Case report Beck Depression Inventory After tamoxifen treatment, the patient developed ness, primarily due to fear of adverse effects Thompson8 depression. Patient wanted to restart tamoxifen, so the metabolism of Female, age 51, no history Sertraline administered of , and due to family as (2001) of depression sertraline was initiated for prophylaxis. Depression tamoxifen improved and remained stable with antidepressant plus well as work stressors. Therefore, venlafaxine tamoxifen regimen is gradually titrated up to 150 mg/d. Pluss et al9 Case report No scales Cerebellar symptoms and depression improved after The oncology team proposes a trial of (1984) Female, age 69, no history Temporal association considered tamoxifen was discontinued leuprolide, a -releasing hor- of depression mone that downregulates pituitary Bourque et al10 Case report DSM-IV-TR criteria Depressed mood with suicidal ideation with 2 trials of receptors, subsequently suppressing female (2009) Female, age 34, with history No scales tamoxifen. Antidepressant added and maintained for reproductive hormones, which in turn stops third trial of tamoxifen of depression Venlafaxine administered the from producing estrogen so De Berardis et al11 Case report Hamilton Depression Rating Scale Depression improved with agomelatine. Tamoxifen was there is a minimal amount of estrogen to (2014) Female, age 42, with history Snaith–Hamilton Pleasure Scale continued with antidepressant. No recurrence of breast promote the growth of estrogen–receptor- cancer reported of adjustment disorder Agomelatine administered positive breast cancer. Mrs. L declines this agent because she is concerned that she Ito et al12 Case report Hamilton Depression Rating Scale Depression improved after discontinuing tamoxifen. will gain weight. Instead, Mrs. L expresses (2006) Female, age 63, with family history Milnacipran administered Antidepressant was maintained after stopping tamoxifen of depression interest in undergoing an oophorectomy to reduce her estrogen level. In the meantime, Anelli et al13 Descriptive study Telephone interview during tamoxifen treatment. Mood alteration reported in 20.8% and based on her reproductive hormone levels (1994) Male patients with breast cancer To avoid confounding by other adjuvant treatments, depression noted in 16.6% of patients (N = 24) the interview was done 8 weeks after chemotherapy (FSH and levels) which are indica- or radiation therapy. None of the patients were tive of postmenopausal status, the oncol- receiving any kind of chemotherapy at the time of ogy team prescribes the the evaluation (AI) 25 mg/d. The AI helps to Love et al14 Randomized toxicity placebo- Self-report of various symptoms Study did not find statistical significance for depression decrease the amount of estrogen the body (1991) controlled trial scores, but found statistical significance for anxiety makes peripherally, which is the main source Postmenopausal women (N = 140) symptoms of estrogen in postmenopausal women. Lee et al15 Retrospective cohort study No instrument used to measure depression Study did not find a statistically significant association (2007) Women with genetic mutation New diagnosis of depression or start of between tamoxifen and new-onset depression (N = 2,943) antidepressant treatment was used as a tool to The authors’ observations assess depressed mood Day et al16 Multicenter randomized controlled Center of Epidemiological Studies–Depression Study did not find a statistically significant association Estrogen originates in the ovaries in pre- (2001) trial (N = 11,064) between tamoxifen and depression; however, the menopausal women; it is also produced authors recommended screening for and treatment of by peripheral conversion of to Current Psychiatry depression estrogen in adipose tissues and muscle in Vol. 19, No. 2 51 Cases That Test Your Skills

OUTCOME Related Resource After starting exemestane, and while still • Agarwala P. Tailoring depression treatment for women with receiving venlafaxine, Mrs. L no longer expe- breast cancer. Current Psychiatry. 2010;9(11):39-40,45-46,48-49. riences severe depressive symptoms. After Drug Brand Names 8 months, venlafaxine is discontinued. She Agomelatine • Valdoxan Leuprolide • Eligard, Lupron Bupropion • Wellbutrin, Zyban Milnacipran • Savella continues to deny depressive symptoms but Cyclophosphamide • Cytoxan Paroxetine • Paxil has intermittent anxiety, which she is able to Doxorubicin • Adriamycin Sertraline • Zoloft Duloxetine • Cymbalta Tamoxifen • Soltamox manage without psychiatric medication. She Exemestane • Aromasin Trastuzumab • Herceptin continues to remain adherent with ongoing Fluoxetine • Prozac Venlafaxine • Effexor exemestane treatment, with no evidence of disease progression or recurrence.

Clinical Point postmenopausal women.19 Aromatase The authors’ observations The results of studies inhibitors block the aromatase For patients with estrogen-positive breast assessing the adverse that converts to estrogen, which cancer, the decision to discontinue tamoxifen psychiatric effects of leads to estrogen deficiency in postmeno- because of unacceptable adverse effects is an aromatase inhibitors pausal women and possibly to neuropsy- important one because it may increase the 19 are mixed chiatric effects. risk of cancer recurrence. Psychiatrists have The results of studies assessing the an important role in supporting the patient adverse psychiatric effects of AIs are through this process, helping patients mixed. When the results of studies evaluat- understand alternatives, and working with ing tamoxifen are compared with those eval- the oncology team to formulate a plan that is uating AIs, overall patients who received AIs acceptable to everyone. had less severe or less frequent mood symp- References toms. One possible explanation could be 1. Zabora J, BrintzenhofeSzoc K, Curbow B, et al. The prevalence of psychological distress by cancer site. that AIs are relatively new compared with Psychooncology. 2001;10(1):19-28. tamoxifen. Second, AIs are more commonly 2. Thompson DS, Spanier CA, Vogel VG. The relationship between tamoxifen, estrogen, and depressive symptoms. used in postmenopausal women with breast Breast J. 1999;5(6):375-382. cancer, and these patients’ overall estro- 3. Halbreich U. Role of estrogen in postmenopausal depression. Neurology. 1997;48(5 suppl 7):S16-S19. gen level is significantly lower than that of 4. Schiller CE, Johnson SL, Abate AC, et al. Reproductive premenopausal women with breast cancer. regulation of mood and behavior. Compr Physiol. 2016;6(3):1135-1160. Therefore, the degree of hormone fluctua- 5. Shariff S, Cumming CE, Lees A, et al. Mood disorder in tion is less intense in postmenopausal breast women with early breast cancer taking tamoxifen, an estradiol . An expected or unexpected cancer survivors. effect? Ann N Y Acad Sci. 1995;761:365-368.

Bottom Line For patients with estrogen–positive breast cancer, anti-estrogen treatment can reduce the risk of cancer recurrence. However, it can cause adverse effects, including depression, that might impair quality of life and treatment adherence. For patients with severe depression, stopping estrogen blockers may be warranted. Initiating an antidepressant that does not interfere with the metabolism of tamoxifen may Current Psychiatry 52 February 2020 help treat depression and vasomotor symptoms. Cases That Test Your Skills

6. Duffy LS, Greenberg DB, Younger J, et al. Iatrogenic acute limiting symptoms in patients. Cancer. estrogen deficiency and psychiatric syndromes in breast 1994;74(1):74-77. cancer patients. Psychosomatics. 1999;40(4):304-308. 14. Love RR, Cameron L, Connell BL, et al. Symptoms 7. Cathcart CK, Jones SE, Pumroy CS, et al. Clinical recognition associated with tamoxifen treatment in postmenopausal and management of depression in node negative breast women. Arch Intern Med. 1991;151(9):1842-1847. cancer patients treated with tamoxifen. Breast Cancer Res 15. Lee KC, Ray GT, Hunkeler EM, et al. Tamoxifen treatment Treat. 1993;27(3):277-281. and new-onset depression in breast cancer patients. 8. Lin J, Thompson DS. Case report: tamoxifen-induced Psychosomatics. 2007;48(3):205-210. depression. Primary Care Update for Ob/Gyns. 2001;8(5): 16. Day R, Ganz PA, Costantino JP. Tamoxifen and depression: 207-208. more evidence from the National Surgical Adjuvant 9. Pluss JL, DiBella NJ. Reversible central nervous system Breast and Bowel Project’s Breast dysfunction due to tamoxifen in a patient with breast cancer. (P-1) Randomized Study. J Natl Cancer Inst. 2001;93(21): Ann Intern Med. 1984;101(5):652. 1615-1623. 10. Bourque F, Karama S, Looper K, et al. Acute tamoxifen- 17. Juurlink D. Revisiting the drug interaction between induced depression and its prevention with venlafaxine. tamoxifen and SSRI antidepressants. BMJ. 2016;354: Psychosomatics. 2009;50(2):162-165. i5309. 11. De Berardis D, Brucchi M, Serroni N, et al. Successful use of 18. Davies C, Godwin J, Gray R, et al. Relevance of breast agomelatine in the treatment of major depression in a woman cancer hormone receptors and other factors to the taking tamoxifen: a case report. Clin Neuropharmacol. 2014; efficacy of adjuvant tamoxifen: patient-level meta- 37(1):31-33. analysis of randomised trials. Lancet. 2011;378(9793): 12. Ito M, Baba H, Kawashima R, et al. A case of prolonged 771-784. depression with tamoxifen. Japan Med Assoc J. 2006;49(4): 19. Buijs C, de Vries EGE, Mourits MJE, et al. The influence 167-172. of endocrine treatments for breast cancer on health- 13. Anelli TF, Anelli A, Tran KN, et al. Tamoxifen related quality of life. Cancer Treat Rev. 2008;34(7): administration is associated with a high rate of treatment- 640-655.

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