Pilot Evaluation of Selective Serotonin Reuptake Inhibitor Antidepressants in Hot Flash Patients Under Androgen-Deprivation Therapy for Prostate Cancer

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Pilot evaluation of selective serotonin reuptake inhibitor antidepressants in hot flash patients under androgen-deprivation therapy for prostate cancer

M Naoe, Y Ogawa, T Shichijo, K Fuji, T Fukagai and H Yoshida Department of Urology, Showa University, Tokyo, Japan

Purpose: Hot flash (HF) is a common side effect in prostate cancer patient undergoing androgen- deprivation therapy (ADT). In this study, we evaluated the efficacy of paroxetine (selective serotonin reuptake inhibitors (SSRIs)) for HF. Patients and methods: In total, 10 men with prostate cancer under ADH who were suffering with HF entered this study. Self-report questionnaire was used for the evaluation. Results: The average rating for HF frequency decreased (P ¼ 0.009) and HF severity decreased (P ¼ 0.0332) also, reported QOL score increased (P ¼ 0.0218). Conclusion: These preliminary data suggest that low dose (10 mg/day) of antidepressant paroxetine can be helpful in the treatment of HFs in patients under ADT for prostate cancer. Further controlled studies are needed to more fully evaluate the efficacy of the SSRIs. Prostate Cancer and Prostatic Diseases (2006) 9, 275–278. doi:10.1038/sj.pcan.4500891; published online 20 June 2006

Keywords: prostate cancer; hot flashes; paroxetine; serotonin uptake inhibitors

Introduction be a significant clinical problem in men undergoing ADT with gonadotropin releasing hormone analogs, oral Vasomotor symptoms, or hot flashes (HFs), are frequent antiandrogens and/or surgical bilateral orchiectomy side effects of hormonal ablation and can be distressing and some of prostate cancer patients have considered to the patient. In a retrospective study, Karling et al.1 discontinuing ADT. Several nonhormonal agents have reported that 68% of men had HFs during treatment with been reported to reduce HFs. These agents include medical or surgical castration, and that symptoms clonidine, vitamin E, and soy supplementation. How- generally did not subside with time on treatment, with ever, these agents are only moderately more effective 48% of men experiencing symptoms at 5 years and 40% than placebo. Thus, a well-tolerated nonhormonal treat- of men continuing to experience symptoms at 8 years. A ment for HFs would be of great value. Selective serotonin HF is a transient sensation of heat or without objective reuptake inhibitors (SSRIs) are commonly prescribed for signs of skin vasodilation and is often accompanied with the treatment of depression. Besides, it is known that varying degrees of sweating, flushing, palpitations, SSRI is effective for HFs of breast cancer patients.1 anxiety, irritability, and even panic.2 Vasomotor symp- Loptinzi suggested that 12.5–37.5 mg/day of paroxetine toms associated with cancer therapies represent an is effective for reducing HFs in men receiving ADT.3 In increasingly common problem for prostate cancer pa- their study, it was concluded that it seems reasonable to tients. Androgen-deprivation therapy (ADT) is indicated use 12.5 mg/day of paroxetine, with the option to in- for the treatment of metastatic prostate cancer and locally crease to 25.0 mg/day if needed. Based on the result, we advanced disease. With the increasing indications for the evaluated whether low dose (10 mg/day) of paroxetine use of ADT in the treatment of men with prostate cancer, (SSRIs) reduce the frequency and severity of HFs in side effects such as HFs, decreased libido, decreased patients who have undergone ADT for prostate cancer. sexual function, and fatigue of the therapy deserve greater attention. Long-time ADT sometimes cause vasomotor side effects. HFs have been reported to Patients and methods interfere with daily activities and sleep. Also, HFs may From July 2005 to November 2005, 10 patients entered the study. Patients included in this study were men with prostate cancer under ADT for prostate cancer (Table 1) Correspondence: Dr M Naoe, Department of Urology, Showa and were evaluated for drug efficacy. A subject was University, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, Japan. E-mail: [email protected] deemed ineligible for the study if the patient; (1) was Received 6 January 2006; revised 3 May 2006; accepted 10 May 2006; treated with paroxetine in the last 6 months; (2) had a published online 20 June 2006 hypersensitivity to paroxetine; (3) had multiple drug Pilot evaluation of SSRI antidepressants in HF patients M Naoe et al 276 Table 1 Patients characteristics (n ¼ 10) after the treatment for to evaluate the biochemical adverse effect of this drug. Additionally, potential side Characteristics Mean (range) effects were asked to the patients at fourth week. Age (years) 70.7 (60–82)

Prostate cancer stage Statistical analysis II 6 Three measures of HFs symptoms were used to assess III 1 IV 3 treatment effectiveness: frequency in a day, mean severity grade, QOL score of their lives. Frequency, Prostatectomy severity grade, and QOL score of their lives at baseline Yes 2 and during the treatment were expressed as percentage No 8 changes from the baseline. Changes of the frequency, severity score, and QOL scores between baseline and Androgen-deprivation therapy Castration 3 week 4 were analyzed using Paired t-test. Bicaltamide 3 Bicaltamide+goserelin acetate 2 Leuprorelin acetate 1 Bicaltatnide+leuprorelin acetate 1 Results

Duration of ADT (n ¼ 8, unknown ¼ 2) 8.8710.3 (Mo) A total of 10 patients participated in the study. All the patients were under ADT for prostate cancer (Stage Duration of HF symptom II ¼ 6, III ¼ 1, IV ¼ 3). The mean age for the sample was o2 M 4 70.7 years (range: 60–82 years). Further demographic and 2–3 M 1 medical information for the study participants are listed 4–9 M 2 X10 M 3 in Table 1. All patients attained a dose of paroxetin 10 mg taken in morning and none had any significant adverse Average frequency of HFs reactions that require discontinuation from the study. All o2 per day 1 patients were experiencing HFs at base line 2–3 day 2 (mean ¼ 3.50/day). Likewise, all patients were complain- 4–9 day 6 X10 per day 1 ing HFs rated ‘quite a bit’ or ‘extremely’ severe at base line (mean ¼ 3.80). Following the 4 weeks administration Abbreviations: ADT, androgen-deprivation therapy; HF, hot flash. of 10 mg/day of paroxetine, the average rating for HF frequency decreased significantly (mean ¼ 3.5/day to mean ¼ 2.0/day, P ¼ 0.009) (Figure 1a). Also, the average rating for HF severity decreased significantly allergies; (4) had any clinically significant uncontrolled (mean ¼ 4.6–2.0, P ¼ 0.0332) (Figure 1b). Similarly, re- or unstable medical disease; (5) had a myocardia ported QOL score improved significantly (mean ¼ 3.8 infarction in the last 6 months; and (6) had a history or ¼ 6.9, P ¼ 0.0218) (Figure 1c). (Change of each patients’ presence of any psychotic disorder. Also, patients were frequency, severity, and QOL scores are showed in not allowed to be receiving antineoplastic chemotherapy, Table 2.) Mean levels of HF frequency, severity and estrogens, progestational drugs, or chinese medicine QOL score before and 4 weeks after administration of except for ADT drugs. Additionally, to be included in 10 mg/day of paroxetine are listed in Table 3. Adverse this study, patients must have had a history of at least effects were minimal and included mostly dry mouth seven HFs per week, for a period of at least 1 month. All (5/10: 50%) and somnolence (4/10: 40%) (Table 4). Also, 10 patients were evaluable for safety and tolerability. The nonhematological toxicities (including: WBC, Hb, BUN patients’ characteristics are summarized in Table 1. creatinine, GOT, GPT) were observed after 4 weeks Following completion of the interview and blood administration of 10 mg/day of paroxetine (data not examination, subjects were given paroxetine, 10 mg shown). No patient discontinued paroxetine therapy due orally every morning. to adverse effect. Only one patient (1/10: 10%) discontinued the paroxetine after the study, because the patient was not satisfied with the efficacy of paroxetine. Treatment evaluation Self-report methods were used because the patients’ evaluation of symptoms was of principal importance Discussion and greatest clinical relevance.4 Data on HFs were obtained before the treatment and at first, second, third, HFs are a major clinical problem for many women as and fourth week during the treatment. The diary they enter menopause and also for men who have consisted of self-administered questionnaires on the undergone ADT for prostate cancer. ADT for managing number of hot flushes during a day, severity of HFs prostate cancer has become increasingly popular. The (severity grade; 1: not at all, 5: intermediate, 10: extremely treatment aims to deprive cancer cells of androgens; the severe) and rate their lives on a scale (from 1: worst leading methods are bilateral orchidectomy and the possible life to 10: best possible life) at each assessment administration of LH-RH analogs. After bilateral orchi- was incorporated. Pill count was performed to test for dectomy about half of patients have hot flushes and they compliance. Also, blood examinations (WBC, Hb, BUN tend to occur within a few months.5,6 With LH-RH creatinine, GOT, GPT) were performed before and 4 weeks analogs, the incidence of hot flushes is approximately

Prostate Cancer and Prostatic Diseases Pilot evaluation of SSRI antidepressants in HF patients M Naoe et al 277 a 12 Table 2 Changes of frequency, severity of HF and QOL score before and 4 weeks after paroxetine in 10 patients 10 Patient Frequency/day Severity score QOL score

8 No. 1 2-10-05-5 No. 2 5-35-34-5 No. 3 7-410-01-10 6 No. 4 3-13-01-5 No. 5 13-10 5-55-5 4 No. 6 7-65-55-5 No. 7 7-38-73-4 2 No. 8 5-05-05-10 No. 9 6-05-08-10 - - - 0 No. 10 1 000110 Number of Hot flashes per day Abbreviation: HF, hot flash. –2 Base line 1 2 3 4 week Table 3 Paired t-test comparisons before and 4 weeks after paroxetine (n ¼ 10) b 10 Pretreatment Post-treatment

8 Test Mean s.d. Mean s.d. P

Frequency of HF 3.500 2.593 2.000 2.708 0.009 6 Severity of HF 4.600 3.098 2.000 2.749 0.0332 QOL score 3.800 2.300 6.900 2.685 0.0218

4 Abbreviation: HF, hot flash.

2 Table 4 Paroxetine hydrochloride adverse event profile at week 4 (n ¼ 10) 0

Avg. Daily Severity of Hot flashes Daily Severity Avg. Adverse effect No. of patients

–2 Dry mouth 5 (50%) Base line 1 2 3 4 Somnolence 4 (40%) week Diarrhea 2 (20%) Constipation 2 (20%) c 11 Nausea 1 (10%) 10 Sexual dysfunction 0 9 8 7 6 must be addressed and treated effectively. Although HF is not a serious adverse effect, when it become severe and 5 frequent it can be very annoying to the patient, and 4 interfere patients quality of life, and some of prostate Avg. QOL Score Avg. 3 cancer patients have considered discontinuing ADT. 2 Therefore the available treatments should be considered 1 and treatment should be individualized and administered after balancing the benefits and risks. Although the 0 pathophysiology underlying HF induced by ADT is not Base line 1234 entirely clear, Beckman’s theory has been considered week predominant.9 With animal experiments, Beckman Figure 1 (a) Weekly summary of HF frequency in 10 patients showed that the intrahypothalamic administration of completing the study: average daily number of HF episodes. noradrenaline affects thermoregulation. The thermore- (b) Weekly summary of HF severity in 10 patients completing the gulatory center in the hypothalamus is anatomically study: average score of HF severity. (c) Weekly summary of QOL close to the GnRH (LH-RH) secreting neurones. These score in 10 patients completing the study: average QOL score. (At each week, the horizontal line indicates the median value for the 10 neurones are stimulated by noradrenaline to secrete LH- patients, the box indicates the range encompassing 50% of patients, RH. Increased hypothalamic noradrenaline therefore bars indicate the range of more extreme values.) stimulates LH-RH neurones and by proximity resets the thermoregulatory center (i.e. the ‘watering-can’ effect) to activate heat-losing mechanisms. These include 60–70%.7,8 However, consideration should be given to cutaneous vasodilatation and profuse perspiration. So, the fact that the actual number of patients experiencing treatment for restore the regulatory negative feedback HF could be much higher. Exposure to ADH and its side would reasonable. For the reason, oestrogens (DES) and effects is lengthy, and because it is palliative, side effects progesterones and androgens have been tried. However,

Prostate Cancer and Prostatic Diseases Pilot evaluation of SSRI antidepressants in HF patients M Naoe et al 278 the treatment aims to be deprive cancer cells of References androgens in prostate cancer thus androgen replacement therapy would therefore be contraindicated. Other 1 Karling P, Hammar M, Varenhorst E. Prevalence and duration of theory about the mechanism of HF is that thermoregu- hot flushes after surgical or medical castration in men with latory centers are regulated by neurotransmitters, in- prostatic carcinoma. JUrol1994; 152: 1170–1173. 10 2 Kronenberg F. Hot flashes: Phenomenology. Quality of life, and cluding norepinephrine, serotonin, and endorphins. search for treatment options. Exp Gerontol 1994; 29: 319–336. Changes in the levels of the neurotransmitters can cause 3 Loprinzi CL, Barton DL, Carpenter LA, Sloan JA, Novotny PJ, dysregulation of the thermoregulatory centers. The Guttman MT et al. Pilot evaluation of paroxetine for treating hot beneficial results observed in paroxetine trial are flashes in men. Mayo Clin Proc 2004; 79 (10): 1247–1251. consistent with the theory that SSRIs might be an 4 Swartzman LC, Edelberg R, Kemmann E. The menopausal hot effective therapy for HFs. Nonhormonal agents such as flush:symptom reports and concomitant physiological changes. J harval medicine, clonidine, vitamin E11 have also been Behav Med. 1990; 13: 15–30. reported to reduce HFs. However, prospective rando- 5 Charig CR, Rundle JS. Flushing. Long-term side effects of mized clinical trials have demonstrated that these agents orchidectomy in treatment of prostatic cancer. Urology 1989; 33: are only moderately more effective than placebo.12–14 175. 6 Frodin T, Alund G, Varenhorst E. Measurement of skin blood Thus, a well-tolerated nonhormonal agent for HF is flow and water evaporation as a means of objectively assessing needed. Newer antidepressants such as SSRIs and hot flushes after orchidectomy in patient with prostatic cancer. inhibitors of serotonin and norepinephrine reuptake, Prostate 1985; 7: 203–208. are promising nonhormonal treatments for HFs. Rando- 7 Sarosdy MF, Schellhammer PF, Soloway MS, Vogelzang NJ, mized placebo-controlled trials have shown that venla- Crawford ED, Presti J et al. Endocrine effect, efficacy and faxine,15 fluoxetine,16 and gabapentine17 are effective in tolerability of a 10.8 mg depot formulation of goserelin acetate control of HFs. A differential effect of the newer administered every 13 weeks to patients with advanced prostate antidepressants on HF is consistent with the known cancer. BJU Int 1999; 83: 801–806. differential effect of such drugs on depressive symptoms 8 Parmar H, Edwards L, Phillips RH, Allen L, Lightman SL. Orchidectomy versus long acting D-Trip-6-LHRH in advanced in individual patients. Also, toxicities differ among the 18 prostate cancer. Br J Urol 1987; 59: 248–254. newer antidepressants illustrating that these drugs 9 Beckman AL. Effect of intrahypothalamic norepinephrine on have varying effects. Within those antidepressants, it is thermoregulatory responses in the rat. Am J Physiol 1970; 218: reported that SSRI is relatively effective agent for 1596–1604. alleviating HFs.4,9 Also, Loprinzi et al.3 reported rela- 10 Shanafelt TD, Barton DL, Adjei AA, Loprinzi CL. Pathophysiology tively good results of a pilot evaluation of the 12.5 mg/ and treatment of hot flashes. Mayo Clin Proc 2002; 77: 1207–1218. day of paroxetine in prostate cancer patients on ADT. 11 Barton DL, Loprinzi CL, Quella SK, Sloan JA, Veeder MH, Egner Paroxetine is in a class of drugs called SSRIs, a class that JR et al. Prospective evaluation of vitamin E for hot flashes in also contains fluoxetine (Prozac) and sertraline (Zoloft). breast cancer survivors. J Clin Oncol 1998; 16: 495–500. Within those SSRIs, it is known that the incidence of 12 Lebherz TB, French L. Nonhormonal treatment of the menopausal syndrome. A double-blind evaluation of an autonomic nausea caused by side effect of paroxetin is relatively system stabilizer. Obstet Gynecol 1969; 33: 795–799. low. Thus, we choose paroxetine for this study. As it has 13 Goldberg RM, Loprinzi CL, O’Fallon JR, Veeder MH, Miser AW, reported that low dose (10–20 mg/day) of paroxetine is Mailliard JA et al. Transdermal clonidine for ameliorating effective and safe for HF patients with breast cancer tamoxifen-induced hot flashes. J Clin Oncol 1996; 14 (8): 2411. survivor,19 we propose that 10 mg/day is reasonable 14 Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini F, initial dosages. In this study, efficacy of low dose of DeAloysio D. The effect of dietary soy supplementation on hot paroxetine (10 mg/day) were observed at first week in flushes. Obstet Gynecol 1998; 91: 6–11. three patients (3/10: 30%), second week in three patients 15 Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, La Vasseur BI, (3/10: 30%), third week in two patients (2/10: 20%) and Barton DL et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial. Lancet fourth week in two patients (2/10 20%), so the progress 2000; 356: 2025–2026. of HF symptoms should be observed for at least 4 weeks 16 Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard and if symptoms do not improve within a month, the JA et al. Phase III evaluation of fluoxetine for treatment of hot dosage can be increased. However, it is important to flashes. J Clin Oncol 2002; 20: 1578–1583. keep in mind that this is a pilot trial, as opposed to a 17 Pandya KJ, Morrow GR, Roscoe JA, Zhao JA, Hickok JT, Pajon E placebo-controlled trial. In conclusion, the data from this et al. Gabapentin for hot flashes in 420 women with breast pilot study suggest that 10 mg/day of paroxetine is an cancer: a randomized double-blind placebo-controlled trial. effective treatment for HF patients who have undergone Lancet 2005; 3–9; 366 (9488): 818–824. ADT for prostate cancer. Further study on dosing, 18 Schatzberg AF, Nemeroff CB (eds), Textbook of Psychopharmacol- duration of treatment is needed to further define the ogy, 2nd edn, American Psychiatric Press: Washington, DC, 1998. 19 Stearns V, Isaac C, Rowland J, Crawford J, Ellis MJ, Kramer R role of SSRIs in the treatment of HFs. Also, the treatment et al. A pilot trial assessing the efficacy of peroxetine for HF should be individualized and administered after hydrochloride (Paxils) in controlling hot flashes in breast cancer balancing the benefits and risks. survivors. Ann Oncol 2000; 11: 17–22.

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