General Hospital Psychiatry 37 (2015) 373.e1–373.e2
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Case Report
Trazodone induced galactorrhea: a case report☆ Filiz Civil Arslan, M.D. ⁎, Emel Korkmaz Uysal, M.D., Evrim Ozkorumak, M.D., Ahmet Tiryaki, M.D. Department of Psychiatry, Karadeniz Technical University School of Medicine, Trabzon 61080, Turkey
a r t i c l e
i n f o
Article history: Received 8 December 2014 Revised 2 April 2015 Accepted 3 April 2015 Keywords: Galactorrhea Trazodone Citalopram Prolactin
a b s t r a c t Trazodone is a heterocyclic antidepressant that exerts its effect via the inhibition of selective serotonin reuptake and the antagonism of 5-HT2A and 5-HT2C receptors. Antidepressant-induced galactorrhea and increases in prolactin levels have rarely been reported. Trazodone can potentiate the serotonergic activity of citalopram. To our knowledge, no cases of galactorrhea associated with use of trazodone have been reported to date. This report describes a unique case of the development of galactorrhea following the addition of trazodone (100 mg/day, 2 weeks) to the treatment of a patient who was receiving citalopram (40 mg/day, 6 weeks) therapy for a diagnosis of depressive disorder, which improved upon the discontinuation of trazodone. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Case
Hyperprolactinemia refers to the elevation of the hormone prolactin (PRL) in the blood. Galactorrhea is the most common finding in hyperprolactinemia and refers to spontaneous milk flow from the ducts of both breasts [1]. Galactorrhea is often observed as a side effect of antipsychotic drugs in psychiatric patients, and an increasing number of case reports and small-scale studies show that it may also emerge with the use of antidepressant drugs [2–5]. Although the reason why antidepressants lead to hyperprolactinemia is unclear, two different mechanisms have been implicated. In the first, the activation of the serotonergic system causes hyperprolactinemia and galactorrhea by suppressing dopamine release; in the second mechanism, the serotonergic system causes an increase in PRL by directly stimulating postsynaptic serotonergic receptors in the hypothalamus [1–3]. Cases of galactorrhea and hyperprolactinemia related to several antidepressants, including tricyclic antidepressants, monoamine oxidase inhibitors, serotonin noradrenalin reuptake inhibitors and selective serotonin reuptake inhibitors, have been reported [3,6]. This report describes a case of galactorrhea that developed upon the addition of trazodone to the treatment regimen of a patient who was receiving citalopram therapy for a diagnosis of depressive disorder.
A 23-year-old single female university student presented to the psychiatric clinic with symptoms of pessimism, hopelessness, avolition, irritability, insomnia, forgetfulness and weight loss. Her Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scores were 40 and 20, respectively. Depressive disorder was suspected, and citalopram (20 mg/day) treatment was initiated. Hydroxyzine (25 mg/day) was added to the treatment protocol for its acute therapeutic effect on insomnia. No improvement in the symptoms or changes in the inventory scores was observed at a follow-up 1 month later. The citalopram was increased to 40 mg/day. The insomnia persisted, hydroxyzine was discontinued and trazodone (50 mg/day) was added to the treatment. The patient described an improvement in her depressive symptoms at a follow-up 1 month later and was assessed with a BDI score of 27 and a BAI score of 17. Because the insomnia persisted, the trazodone was increased to 100 mg/day. Two weeks later, the patient presented to the clinic and reported that milk had begun to be secreted from both breasts over the previous week to the extent that it marked her clothing, and she reported no previous history of this condition. The patient was using no drugs other than those prescribed by the psychiatry department and reported that her menstrual cycle was regular, that she had no active sex life and that she had recently engaged in no unusual physical activity. Laboratory tests, including PRL, liver and kidney function tests, and a beta subunit of human chorionic gonadotropin (B-HCG) analysis were performed. No additional pathology was identified, with the exception a PRL level of 43.61 ng/ml (normal range: 3.3–26 ng/ml). Magnetic resonance imaging (MRI) of the pituitary indicated normal results. Trazodone was tapered and discontinued, but the patient was maintained on citalopram at 40 mg/day. One month later,
☆ This case report was presented as a poster in 50th National Psychiatry Congress, Sungate Resort Hotel, Antalya, Turkey, November 12–16, 2014. ⁎ Corresponding author. Karadeniz Teknik Üniversitesi Tıp Fakültesi Psikiyatri AD, Kalkınma Mh, 61040 Trabzon, Turkey. Tel.: +90-4623775375; fax: +90-462337252270. E-mail address: fi[email protected] (F.C. Arslan). http://dx.doi.org/10.1016/j.genhosppsych.2015.04.002 0163-8343/© 2015 Elsevier Inc. All rights reserved.
373.e2
F.C. Arslan et al. / General Hospital Psychiatry 37 (2015) 373.e1–373.e2
the PRL level was 10.78 ng/ml, and the galactorrhea had resolved. Quetiapine (25 mg/day) was added to the insomnia treatment. The symptoms had improved significantly after 1 month, and the patient’s BDI and BAI inventory scores were 15 and 10, respectively. 3. Discussion PRL levels can be affected by various conditions, such as psychological stress and exercise, but they are normally below 20–25 ng/ml [7]. PRL levels in cases of drug-related galactorrhea are normal or below 100 ng/ml [7]. One study reported that women were more sensitive to increases in PRL levels when taking antidepressant drugs [8]. The facts that our patient was a woman who used no drugs other than antidepressants and had a PRL level of 43.61 ng/ml, that the results of her B-HCG, TSH and routine blood tests were within the normal limits and that there were no pathological findings on an MRI of the pituitary support the hypothesis that the galactorrhea in this case was associated with antidepressant drug use. The galactorrhea symptoms that appeared following the addition of trazodone to the treatment in our patient, who was already receiving citalopram at 40 mg/day, the improvements in the galactorrhea symptoms at the follow-ups after the trazodone had been discontinued while the use of citalopram alone continued and the decrease in the PRL levels to normal suggest that the trazodone triggered the galactorrhea. The effects of trazodone on PRL are unclear, although one study reported that trazodone increases the PRL levels, and another study reported that trazodone reduces them [9]. Citalopram has been reported to induce galactorrhea via its serotonergic activity, and trazodone and citalopram both increase serotonin levels in the blood and can cause serotonin syndrome. However, no cases of galactorrhea induced by trazodone or the combination of trazodone and citalopram have been reported to date. In this case, trazodone may have increased the PRL levels by further increasing the serotonergic effect of citalopram and may thus have led to galactorrhea. At hypnotic doses (25–150 mg), trazodone normally antagonizes the
serotonin 2A (5-HT2A) receptors and does not exhibit serotonergic activity, as indicated by the fact that trazodone does not inhibit the serotonin reuptake transporter (SERT) at low doses [10]. However, in our case, the inhibition of SERT by citalopram might have caused the serotonergic activity of trazodone and resulted in the synergistic effect tuberoinfundibular dopaminergic neuron inhibition. Additionally, trazodone may increase the dopamine levels by antagonizing 5-HT2A receptors in dopaminergic neurons and may thus decrease the PRL levels. Although these two mechanisms function in diametrically opposed manners, it is more likely that, in our case, the trazodone use led to hyperprolactinemia via hypothalamic postsynaptic receptor stimulation. It should be remembered that galactorrhea may appear as a rare side effect of trazodone. Accumulated data and further studies are needed to elucidate the mechanisms by which trazodone affects the hormone PRL. References [1] Belli H, Akbudak M, Ural C. Duloxetine-related galactorrhea and restless legs syndrome: a case report. Psychiatr Danub 2013;25:266–7. [2] Nebhinani N. Sertraline-induced galactorrhea: case report and review of cases reported with other SSRIs. Gen Hosp Psychiatry 2013;3:376.e3–5. [3] Özcan S, Tamam L, Soydan A. Seçici serotonin geri alım inhibitörleri ve galaktore: aynı olgu üzerinden sertralin ve sitalopramın karşılaştırması. Klin Psikiyatri 2012; 15:252–5. [4] Aggarwal A, Kumar R, Sharma RC, Sharma DD. Escitalopram induced galactorrhoea: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:557–8. [5] Shim SH, Lee YJ, Lee EC. A case of galactorrhea associated with escitalopram. Psychiatry Invest 2009;3:230–2. [6] Gülsün M, Evrensel A, Verim S. Galactorrhea during escitalopram treatment: a case report. Bull Clin Psychopharmacol 2006;16:39–41. [7] Korkmaz S, Kuloğlu M, Işık U, Sağlam S, Atmaca M. Duloksetin tedavisi sirasinda gelişen galaktore: olgu sunumu. Turk Psikiyatri Derg 2011;22:200–1. [8] Halbrech U, Knon BJ, Glmore JA, Kahn LS. Elevated prolactin levels in patients with schizophrenia: mechanism and related adverse effects. Psychoneuroendocrinology 2003;28(Suppl. 1):53–67. [9] Madhusoodanan S, Parida S, Jimenez C. Hyperprolactinemia associated with psychotropics-a review. Hum Psychopharmacol 2010;25:281–97. [10] Stahl SM. Stahl’s Essential Psychopharmacology. 4th edit. Cambridge: Cambridge University Press; 2013.
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Case Report
Trazodone induced galactorrhea: a case report☆ Filiz Civil Arslan, M.D. ⁎, Emel Korkmaz Uysal, M.D., Evrim Ozkorumak, M.D., Ahmet Tiryaki, M.D. Department of Psychiatry, Karadeniz Technical University School of Medicine, Trabzon 61080, Turkey
a r t i c l e
i n f o
Article history: Received 8 December 2014 Revised 2 April 2015 Accepted 3 April 2015 Keywords: Galactorrhea Trazodone Citalopram Prolactin
a b s t r a c t Trazodone is a heterocyclic antidepressant that exerts its effect via the inhibition of selective serotonin reuptake and the antagonism of 5-HT2A and 5-HT2C receptors. Antidepressant-induced galactorrhea and increases in prolactin levels have rarely been reported. Trazodone can potentiate the serotonergic activity of citalopram. To our knowledge, no cases of galactorrhea associated with use of trazodone have been reported to date. This report describes a unique case of the development of galactorrhea following the addition of trazodone (100 mg/day, 2 weeks) to the treatment of a patient who was receiving citalopram (40 mg/day, 6 weeks) therapy for a diagnosis of depressive disorder, which improved upon the discontinuation of trazodone. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Case
Hyperprolactinemia refers to the elevation of the hormone prolactin (PRL) in the blood. Galactorrhea is the most common finding in hyperprolactinemia and refers to spontaneous milk flow from the ducts of both breasts [1]. Galactorrhea is often observed as a side effect of antipsychotic drugs in psychiatric patients, and an increasing number of case reports and small-scale studies show that it may also emerge with the use of antidepressant drugs [2–5]. Although the reason why antidepressants lead to hyperprolactinemia is unclear, two different mechanisms have been implicated. In the first, the activation of the serotonergic system causes hyperprolactinemia and galactorrhea by suppressing dopamine release; in the second mechanism, the serotonergic system causes an increase in PRL by directly stimulating postsynaptic serotonergic receptors in the hypothalamus [1–3]. Cases of galactorrhea and hyperprolactinemia related to several antidepressants, including tricyclic antidepressants, monoamine oxidase inhibitors, serotonin noradrenalin reuptake inhibitors and selective serotonin reuptake inhibitors, have been reported [3,6]. This report describes a case of galactorrhea that developed upon the addition of trazodone to the treatment regimen of a patient who was receiving citalopram therapy for a diagnosis of depressive disorder.
A 23-year-old single female university student presented to the psychiatric clinic with symptoms of pessimism, hopelessness, avolition, irritability, insomnia, forgetfulness and weight loss. Her Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scores were 40 and 20, respectively. Depressive disorder was suspected, and citalopram (20 mg/day) treatment was initiated. Hydroxyzine (25 mg/day) was added to the treatment protocol for its acute therapeutic effect on insomnia. No improvement in the symptoms or changes in the inventory scores was observed at a follow-up 1 month later. The citalopram was increased to 40 mg/day. The insomnia persisted, hydroxyzine was discontinued and trazodone (50 mg/day) was added to the treatment. The patient described an improvement in her depressive symptoms at a follow-up 1 month later and was assessed with a BDI score of 27 and a BAI score of 17. Because the insomnia persisted, the trazodone was increased to 100 mg/day. Two weeks later, the patient presented to the clinic and reported that milk had begun to be secreted from both breasts over the previous week to the extent that it marked her clothing, and she reported no previous history of this condition. The patient was using no drugs other than those prescribed by the psychiatry department and reported that her menstrual cycle was regular, that she had no active sex life and that she had recently engaged in no unusual physical activity. Laboratory tests, including PRL, liver and kidney function tests, and a beta subunit of human chorionic gonadotropin (B-HCG) analysis were performed. No additional pathology was identified, with the exception a PRL level of 43.61 ng/ml (normal range: 3.3–26 ng/ml). Magnetic resonance imaging (MRI) of the pituitary indicated normal results. Trazodone was tapered and discontinued, but the patient was maintained on citalopram at 40 mg/day. One month later,
☆ This case report was presented as a poster in 50th National Psychiatry Congress, Sungate Resort Hotel, Antalya, Turkey, November 12–16, 2014. ⁎ Corresponding author. Karadeniz Teknik Üniversitesi Tıp Fakültesi Psikiyatri AD, Kalkınma Mh, 61040 Trabzon, Turkey. Tel.: +90-4623775375; fax: +90-462337252270. E-mail address: fi[email protected] (F.C. Arslan). http://dx.doi.org/10.1016/j.genhosppsych.2015.04.002 0163-8343/© 2015 Elsevier Inc. All rights reserved.
373.e2
F.C. Arslan et al. / General Hospital Psychiatry 37 (2015) 373.e1–373.e2
the PRL level was 10.78 ng/ml, and the galactorrhea had resolved. Quetiapine (25 mg/day) was added to the insomnia treatment. The symptoms had improved significantly after 1 month, and the patient’s BDI and BAI inventory scores were 15 and 10, respectively. 3. Discussion PRL levels can be affected by various conditions, such as psychological stress and exercise, but they are normally below 20–25 ng/ml [7]. PRL levels in cases of drug-related galactorrhea are normal or below 100 ng/ml [7]. One study reported that women were more sensitive to increases in PRL levels when taking antidepressant drugs [8]. The facts that our patient was a woman who used no drugs other than antidepressants and had a PRL level of 43.61 ng/ml, that the results of her B-HCG, TSH and routine blood tests were within the normal limits and that there were no pathological findings on an MRI of the pituitary support the hypothesis that the galactorrhea in this case was associated with antidepressant drug use. The galactorrhea symptoms that appeared following the addition of trazodone to the treatment in our patient, who was already receiving citalopram at 40 mg/day, the improvements in the galactorrhea symptoms at the follow-ups after the trazodone had been discontinued while the use of citalopram alone continued and the decrease in the PRL levels to normal suggest that the trazodone triggered the galactorrhea. The effects of trazodone on PRL are unclear, although one study reported that trazodone increases the PRL levels, and another study reported that trazodone reduces them [9]. Citalopram has been reported to induce galactorrhea via its serotonergic activity, and trazodone and citalopram both increase serotonin levels in the blood and can cause serotonin syndrome. However, no cases of galactorrhea induced by trazodone or the combination of trazodone and citalopram have been reported to date. In this case, trazodone may have increased the PRL levels by further increasing the serotonergic effect of citalopram and may thus have led to galactorrhea. At hypnotic doses (25–150 mg), trazodone normally antagonizes the
serotonin 2A (5-HT2A) receptors and does not exhibit serotonergic activity, as indicated by the fact that trazodone does not inhibit the serotonin reuptake transporter (SERT) at low doses [10]. However, in our case, the inhibition of SERT by citalopram might have caused the serotonergic activity of trazodone and resulted in the synergistic effect tuberoinfundibular dopaminergic neuron inhibition. Additionally, trazodone may increase the dopamine levels by antagonizing 5-HT2A receptors in dopaminergic neurons and may thus decrease the PRL levels. Although these two mechanisms function in diametrically opposed manners, it is more likely that, in our case, the trazodone use led to hyperprolactinemia via hypothalamic postsynaptic receptor stimulation. It should be remembered that galactorrhea may appear as a rare side effect of trazodone. Accumulated data and further studies are needed to elucidate the mechanisms by which trazodone affects the hormone PRL. References [1] Belli H, Akbudak M, Ural C. Duloxetine-related galactorrhea and restless legs syndrome: a case report. Psychiatr Danub 2013;25:266–7. [2] Nebhinani N. Sertraline-induced galactorrhea: case report and review of cases reported with other SSRIs. Gen Hosp Psychiatry 2013;3:376.e3–5. [3] Özcan S, Tamam L, Soydan A. Seçici serotonin geri alım inhibitörleri ve galaktore: aynı olgu üzerinden sertralin ve sitalopramın karşılaştırması. Klin Psikiyatri 2012; 15:252–5. [4] Aggarwal A, Kumar R, Sharma RC, Sharma DD. Escitalopram induced galactorrhoea: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:557–8. [5] Shim SH, Lee YJ, Lee EC. A case of galactorrhea associated with escitalopram. Psychiatry Invest 2009;3:230–2. [6] Gülsün M, Evrensel A, Verim S. Galactorrhea during escitalopram treatment: a case report. Bull Clin Psychopharmacol 2006;16:39–41. [7] Korkmaz S, Kuloğlu M, Işık U, Sağlam S, Atmaca M. Duloksetin tedavisi sirasinda gelişen galaktore: olgu sunumu. Turk Psikiyatri Derg 2011;22:200–1. [8] Halbrech U, Knon BJ, Glmore JA, Kahn LS. Elevated prolactin levels in patients with schizophrenia: mechanism and related adverse effects. Psychoneuroendocrinology 2003;28(Suppl. 1):53–67. [9] Madhusoodanan S, Parida S, Jimenez C. Hyperprolactinemia associated with psychotropics-a review. Hum Psychopharmacol 2010;25:281–97. [10] Stahl SM. Stahl’s Essential Psychopharmacology. 4th edit. Cambridge: Cambridge University Press; 2013.
