A Case of Prolonged Depression with Tamoxifen

Case Report

JMAJ 49(4): 167–172, 2006

Masanobu Ito,*1 Hajime Baba,*1 Ritsuko Kawashima,*1 Heii Arai*1

Abstract Tamoxifen is known to trigger depressive symptoms as a result of its anti-estrogenic activity. We experienced a patient with a history of depression, who received tamoxifen (an estrogen partial agonist) as a postoperative therapy for breast cancer and developed an relapse of depressive symptoms after about 10 months of treatment. The symptoms aggravated to the state of psychotic depression. This case was poorly responsive to antidepressants and resistant to treatment, but the symptoms improved after interruption of tamoxifen. This observation suggests that tamoxifen may aggravate depression in severe and refractory conditions.

Key words Depression, Tamoxifen, Estrogen, Breast cancer

Introduction The Case

Depressive symptoms accompanying malignant Patient: Female, 63 years old. tumors have recently been studied extensively Genetic factors: Mother committed suicide. from the standpoint of liaison psychiatry. In Younger sister had depression. particular, several cases of depression have been Past history: Tuberculosis at the age of 42, hyper- reported in association with breast cancer, which tension at the age of 51, breast cancer surgery is a common disease in females.1,2 Although the at the age of 62. etiology is not clear, suspected causes include Personality before illness: Meticulous and worri- the lowering of self-esteem due to the alteration some. of appearance and the psychogenic reaction to Life history: The patient was born as the 3rd the disease and to surgical treatment, in addition daughter in a family of 5 children. After gradu- to the influence of hormonal changes.1 While ating from a local high school, she worked for anti-estrogens such as tamoxifen are often used an insurance company as a clerk. After marrying to prevent cancer recurrence, this treatment at the age of 23, she mothered 2 children while may increase the risk of depressive symptoms.1 working part-time. In this paper, we report our experience with a History of present illness: The patient first vis- patient who had a history of depression, received ited our department 19 years ago (44 years old) tamoxifen after surgery for breast cancer, presenting with depressive mood, insomnia, and then developed severe depression with appetite loss, anxiety, thirst, and palpitations. psychotic symptoms, which became prolonged. No abnormality was noted in blood counts, bio- To ensure anonymity, details of the patient’s chemistry, etc. Depression was suspected. The personal information have been modified as symptoms were relieved by treatment with anti- necessary. depressants for several months, and treatment

*1 Department of Psychiatry, Juntendo University School of Medicine, Tokyo Corespondence to: Masanobu Ito MD, Department of Psychiatry, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Tel: 81-3-5802-1071, Fax: 81-3-5802-1701, E-mail: [email protected]

JMAJ, April 2006 — Vol. 49, No. 4 167 Ito M, Baba H, Kawashima R, et al.

was terminated after about 1 year. Recurrence of pression, and treatment was started with a drip depression occurred several times thereafter, but infusion of clomipramine, an antidepressant. each episode was improved by medication. Because delirium was noted and drug-induced Two years ago, the patient received regular delirium due to clomipramine was suspected, the screening for breast cancer in the insurance sys- dose was reduced and then stopped. Thereafter, tem, and was found to have breast cancer of the the patient gradually came to show longer lucid left breast. Total mammectomy and axillary dis- intervals. section were performed in August (61 years old). In mid September, the patient mainly showed Histopathological study proved invasive ductal depressive symptoms, including depressive mood, carcinoma, n0, G2, ER(), PR(), pT0.8 cm. appetite loss, and malaise, while abnormal speech Administration of tamoxifen 20 mg was com- and behavior almost disappeared. Blood analysis menced shortly after surgery, and the progress became largely normal (GOT 20, GPT 21, CK of treatment was good. Her mental state before 31). The Hamilton Depression Rating Score was and after surgery was stable. 32. The brain MRI conducted after improvement About 1 year ago, in January (62 years old, of disturbance of consciousness demonstrated 5 months from the beginning of tamoxifen no abnormality relative to the condition before therapy), the patient voluntarily stopped taking admission (Fig. 2). EEG indicated improvement, psychotropic drugs because she felt her condi- showing a slight increase in the frequency of tion was good. Outpatient treatment at our de- alpha waves. partment was terminated, ending with the visit Three months later, the patient strongly com- in March. She continued to use tamoxifen and plained about insomnia. Blood analyses were hypotensive medication. stable, and the condition was considered to be an In May, the younger sister of the patient aggravation of depression. The Hamilton score was admitted to a hospital for the treatment of was 22, and the persistence of severe depression depression, and the patient took care of her without psychotic symptoms was inferred. Her sister. In June (10 months after the beginning of condition aggravated further when the patient tamoxifen therapy), the sister was discharged was temporarily released for regular monitoring from the hospital. The patient then gradually of breast cancer. In addition to guilt and suicidal started to complain depressive mood, loss of feeling, she started to have delusion of poverty. motivation, thirst, hypogeusia, lack of concent- No recurrence of breast cancer was noted, and ration, etc., and she revisited our department in tamoxifen was continued. early July. Blood counts, biochemistry, and head The condition did not improve for 4 months, CT (Fig. 1) revealed no clear abnormality, and and the complaints involving persecution and the relapse of depression was suspected. EEG self-accusation continued. The Hamilton score was irregular with few alpha waves, suggesting was 22. The antidepressant was switched to a strained state. The patient remained irregular milnacipran 100 mg, and the patient was kept in the use of drugs. In addition to the above- under careful observation. mentioned symptoms, she showed panic attacks, In January of this year, the patient started insomnia, appetite loss, and perplexity. Two weeks to smile occasionally when she was with her later, persecutory delusions developed, including family. However, she stayed mostly in bed during the belief that the police and ﬁre ﬁghters would the daytime. Her facial expression was stiff, and come to collect her debt. The patient was hospi- she expressed suicidal feelings. The Hamilton talized for the second time in August. score was 22, and no improvement of depression On admission, the patient was very agitated was seen. and perplexed. While her breast cancer had been Because tamoxifen had been suggested to monitored regularly on an outpatient basis, no be a cause of depression, we considered the recurrence had been noted. Because tamoxifen possibility that tamoxifen might affect for the had been continued, we continued administra- prolonged presence of depression. Following the tion after admission. Blood sampling at the time discussion with the surgeon, tamoxifen was of admission showed slight liver dysfunction stopped 5 months later. No other changes were (GTP 49 and GPT 61). CK was as high as 1099. made to the regimen, and the patient was kept The patient was considered to have severe de- under careful observation. Within about 2 weeks

168 JMAJ, April 2006 — Vol. 49, No. 4 A CASE OF PROLONGED DEPRESSION WITH TAMOXIFEN

Fig. 1 Head CT Fig. 2 Head MRI Slight brain atrophy predominantly in the region from the Slight atrophy in the temporal and parietal lobes and multiple frontal to the temporal lobe. No remarkable change as com- lacunar infarction are noted, but no organic changes that pared with the condition 5 years previously. may cause disturbance of consciousness were found.

after stopping tamoxifen, the patient started to GOT 49, GPT 61, ␥GTP 84, Na 140, K 3.2, talk more with nurses. Although she described Cl 103, CRP 1.25 that her condition was “not improving and not f-T3 2.67, f-T4 0.90, TSH 3.29, ACTH 25.2, good,” she stopped complaining about insomnia. cortisol 29.1 She started to smile during interviews with the • EEG physician. Her facial expression improved in July, last year: Irregular basic pattern with about one month, and the patient started to marked presence of beta waves. show active behavior, such as walking in the September, last year: Irregular basic pattern. ward. She became able to take a walk with her Appearance of 9–10 Hz alpha waves as com- husband, and to eat meals regularly. Although pared with the previous data. the patient’s self-evaluation remained poor, October, last year: Slow alpha rhythm. Im- evaluation by family members improved and proved appearance of 9–10 Hz alpha waves the Hamilton score dropped to 7. The condition as compared with the previous data. clearly improved (Fig. 3). The Treatment course is shown in Fig. 3. A different physician was later appointed to take charge of this patient. While aggravation Discussion was not seen, remission did not occur and the symptoms became prolonged. Although the main Tamoxifen is a partial agonist of estrogen, which drug was changed to amoxapine and maproti- is used as an adjuvant therapy for breast cancer line, no remarkable changes were observed. Ex- based on the fact that breast cancer cells often acerbation did not occur in the course of about have estrogen receptors and the cancer cells one year including several stays at home, and are activated by estrogen. Because the partial the patient was discharged from the hospital. No agonist binds to estrogen receptors in competi- recurrence of breast cancer has since been noted, tion with estrogen and its estrogenic effect is and no abnormality has been shown by monthly weaker than that of estrogen, it exerts an anti- blood tests. The brain MRI conducted in Octo- estrogenic effect (Fig. 4). In addition, tamoxifen ber of this year showed no remarkable changes has various effects such as promoting translation (Fig. 2). of denatured RNA, reducing cell proliferation, Laboratory test results: promoting apoptosis of malignant cells, reducing • Blood analyses on admission circulation of insulin-like growth factor-I, and WBC 5800, Hb 12.0, Plt 196,000, TP 5.6, increasing circulation of serum hormone binding

JMAJ, April 2006 — Vol. 49, No. 4 169 Ito M, Baba H, Kawashima R, et al.

Date Jan. Mar. May Jul. Oct. Nov. Dec. Jan.

Fluvoxamine 50 75 100 100 100 50 25

100 50 Milnacipran 30 60 40 30 20 Mianserin 10 tamoxifen 20

Loss of motivation Disturbance of consciousness Admission Hamilton Depression Rating Scale 50 Hamilton 40 30 Score 20 10 0 Aug. Oct. Dec. Feb.

Fig. 3 Treatment course

estrogen tamoxifen estrogen

cannot bind to receptor estrogen receptor

Estrogenic Weaker estrogenic effects effects

Fig. 4 Antagonism of estrogenic effects by tamoxifen Tamoxifen binds to the same receptor as estrogen but causes weaker effects

globulin (SHBG) (Fig. 5).1 These effects are con- during the menopause. While there is clinical sidered to derive from the action of tamoxifen evidence that estrogen may counter the develop- itself, in addition to its anti-estrogenic activity. ment of depression, this effect is considered to The possibility that tamoxifen as an anti-estrogen derive from the positive effect of estrogen on may promote development, severity, and prolon- serotonin and noradrenaline.4 Tamoxifen passes gation of depression has not been discussed through the blood-brain barrier (BBB) and in- much in Japan, but this possibility has been hibits these effects of estrogen. It has been pointed out by several authors2–6 based on the reported that depression in patients receiving facts that a decrease in estrogen may cause de- tamoxifen most frequently occurs within 12 pression and women often develop depression months from the beginning of treatment, in

170 JMAJ, April 2006 — Vol. 49, No. 4 A CASE OF PROLONGED DEPRESSION WITH TAMOXIFEN

Tamoxifen

Anti-estrogenic Increase in SHBG* Decrease in cell effect in circulation proliferation

Apoptosis of Promotion of transcription malignant cells of denatured RNA

Decreases in serotonin and noradrenaline

Depressive Antitumor effect symptoms

Fig. 5 Effects of tamoxifen *: Serum hormone binding globulin

particular during the period from 3 to 6 months, by hospitalization and home care of her younger and dose reduction or termination of tamoxifen sister. As reported by Ishige7 and Takao et al.,8 usually results in alleviation of symptoms within aggravation to psychotic depression may occur weeks. The depression related to tamoxifen does even 16 months after drug administration. There- not always coincide with climacteric symptoms, fore, the direct involvement of tamoxifen in the which are also major side effects of tamoxifen, pathogenesis of this case may not be ruled out. and patients with severe depression often lack Past episodes in this patient were characterized symptoms such as ﬂushing of the face.2 These by prompt response to antidepressants even clinical features also suggest the possibility that when there was severe perplexity. The present the development and prolongation of depression episode was unprecedentedly severe, involving related to tamoxifen may not be a result of psychotic symptoms during the acute phase. simple anti-estrogenic activity. The development Physical illness was excluded by blood counts, of depression probably results from the action biochemistry, thyroid hormone, brain CT, EEG, of tamoxifen itself, in addition to the action and other data, and depression improved after mediated by estrogen. The reported incidence the termination of tamoxifen. Because of these rate of depression ranges widely from 1 to 15%. facts, it is considered probable that tamoxifen Our search of the literature indicated only 1 may have affected the severity and prolongation paper (by Love3) that reported the low level of of this episode. 1%, and the other 3 studies provided incidence In this case, the dose of antidepressant was rates in the range from 12 to 16%. The depres- not changed during observation for one month sion in these patients usually improved after dose after termination of tamoxifen. While depression reduction or termination of tamoxifen in 2 to 4 improved gradually, the improvement was not weeks.2 sufﬁcient to stop administration of antidepres- The patient reported here is considered to be sant, and complete remission did not take place. a case of recurrent depressive disorder, in view As depression gradually exacerbated 2 months of her past history. Because recurrence of de- later, the dose of antidepressant had to be in- pression did not occur directly following the use creased again. In many previous reports, termi- of tamoxifen after breast cancer surgery, this nation of tamoxifen after development of depres- case is considered to be an endogenous episode sion led to improvement in a reversible manner. triggered by the psychological pressure caused However, it is not clear whether there are irre-

JMAJ, April 2006 — Vol. 49, No. 4 171 Ito M, Baba H, Kawashima R, et al.

versible factors. Ishige reported a case that re- and there has been no report suggesting the quired antidepressant therapy after termination involvement of tamoxifen in such alteration of of tamoxifen and continued to have symptoms. pharmacological effects. However, in view of We cannot rule out the possibility that the drug the timing, such involvement should also be con- was involved in the prolongation of depression sidered as a possibility. More detailed study after termination of tamoxifen in our case. is needed concerning the use of tamoxifen Our patient had previously been showing in patients with depression. Because it may be prompt response to tricyclic antidepressants involved in the severity and prolongation of without remarkable side effects. However, in this symptoms, we should be careful regarding the episode, she developed severe delirium during use of tamoxifen in patients with a history of the use of a tricyclic antidepressant. This could depression. be related to the changes in organic factors,

References

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