Journal of Clinical Psychopharmacology
&
Volume 35, Number 1, February 2015
11. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239Y245. 12. John AP, Koloth R. Severe serotonin toxicity and manic switch induced by combined use of tramadol and paroxetine. Aust N Z J Psychiatry. 2007;41:192Y193. 13. Gonzalez-Pinto A, Imaz H, De Heredia JL, et al. Mania and tramadol-fluoxetine combination. Am J Psychiatry. 2001; 158:964Y965. 14. Post RM, Altshuler LL, Leverich GS, et al. Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry. 2006;189:124Y131.
Bupropion-Associated Galactorrhea A Case Report To the Editors:
B
upropion is a second-generation antidepressant used in both depressive disorders and cessation of smoking; it increases extracellular concentration of dopamine and norepinephrine by blocking dopamine and norepinephrine reuptake. It increases noradrenaline and dopamine levels at prefrontal cortex by blocking noradrenaline and dopamine carriers; however, it has no effect on serotonergic transmission.1 Its sexual adverse effects rate is similar to placebo and lower than that of selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors.2 Bupropion has a chemical structure similar to certain psychostimulants, and its sedating effect is very low, and loss of weight is significant with bupropion.2,3 Nonproductive cough, nausea, constipation, headache, and insomnia are the most frequently reported adverse effects. Reducing epileptic threshold is among its disadvantages.4 Hyperprolactinemia is a clinical presentation that may be caused by medical conditions such as pituitary tumors leading to galactorrhea, amenorrhea and infertility, craniopharyngioma, metastatic tumors, and thyroid function disorders and also by various drugs including antipsychotics, metoclopramide, oral contraceptives, and thyroid hormone preparations.5,6 Hyperprolactinemia and galactorrhea are adverse effects mostly seen during treatment with antipsychotic agents and rarely with selective serotonin reuptake inhibitors. In the literature, there are reported hyperprolactinemia and galactorrhea cases associated with tricyclic antidepressant clomipramine; selective serotonin reuptake
inhibitors escitalopram, sertraline, fluoxetine, fluvoxamine, and paroxetine; and serotonin-norepinephrine reuptake inhibitors venlafaxine and duloxetine.6Y13 In a pharmacovigilance study by Trenque et al,14 hyperprolactinemia was reported in 187 of 11,863 patients using selective serotonin reuptake inhibitors, and many of these cases (71%) were middle-aged women. Hyperprolactinemia was mostly related to fluvoxamine, citalopram, fluoxetine, and paroxetine, and the risk was not increased by duloxetine, milnacipran, and sertraline. In the literature search, no case of galactorrhea related to bupropion was found. Here we present a case developing galactorrhea during usage of bupropion and improvement of this galactorrhea following discontinuation of bupropion treatment.
CASE REPORT The patient was a housewife, 34 years of age, celibate, and graduated from high school. She admitted to psychiatry outpatient clinic with complaints of demoralization, malaise, loss of interest, and increased sleep and appetite for 3 years. At her psychiatric examination, she was conscious, cooperative, and oriented. Depressive affection was observed, and depressive mood was identified. Sleep and appetite were increased. Anergy and anhedonia were present. No psychotic sign was detected. There were no suicidal attempts and thoughts. The patient did not have organic diseases that can lead to depression such as thyroid disease, connective tissue disease, cardiac drugs, or steroids. The patient was previously treated with sertraline 100 mg/d for 2 months 2 years ago; however, she did not benefit from it. No organic disorder, chronic drug usage, or history of surgery was detected. She was not using alcohol or narcotic. Her menstrual cycle was normal. She was not pregnant, and she did not use oral contraceptives. She was not sexually active. No family history of psychiatric diseases was present. Her diagnosis was major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Beck Depression Scale score was 35, and Beck Anxiety Scale score was 14. Treatment of bupropion 150 mg/d was initiated. The patient presented at the outpatient clinic within second week of treatment with complaint of galactorrhea. Examination including hemogram, fasting blood glucose, lipid profile, and thyroid function tests was normal. Blood prolactin level was 98 ng/mL. The patient had no such complaint in the past. Cranial magnetic resonance was obtained in order to eliminate organic origin, and it showed no space-occupying mass at pituitary gland. Gynecologic consultation was asked, and no
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editors
pathology was detected. Galactorrhea was considered to be adverse effect of bupropion treatment, and the treatment was discontinued. Galactorrhea disappeared 2 days after withdrawal of treatment, and PRL level was 3 ng/mL 1 week later. Fluoxetine 20 mg/d was initiated, and no galactorrhea was observed during 4 months of observation period. Beck Depression Scale score decreased to 15, and Beck Anxiety Scale score decreased to 5.
DISCUSSION In our case, hyperprolactinemia and galactorrhea were considered to be related to bupropion in that hyperprolactinemia and galactorrhea appeared immediately following initiation of bupropion, absence of any other drug usage and physical illness, cranial magnetic resonance with normal appearance, spontaneously resolving hyperprolactinemia following cessation of treatment, and lack of this complaint previously. The drug side effect scale developed by Naranjo and colleagues15 is a 10-item questionnaire. The relationship of a drug and corresponding side effect is certain with 9 points, probably with 5Y8 points, and possible with 1Y4 points. Based on this scale, the relationship between bupropion and galactorrhea was possible (score 5). Normal prolactin level is less than 20 to 25 mg/mL. Prolactin level is lower than 100 ng/mL in galactorrhea related to drug usage, as in our case.16 Women are suggested to be more prone to antidepressantrelated prolactin increase.14 According to our knowledge, our case is the first case of galactorrhea associated with bupropion. However, the mechanism is still not clear. Hyperprolactinemia and galactorrhea are adverse effects mostly seen during treatment with antipsychotic agents and rarely with selective serotonin reuptake inhibitors. Activation of serotonergic system leads to prolactin increase and galactorrhea by blocking dopamine, which has an inhibitory effect on prolactin at the tuberoinfundibular pathway. In addition, prolactin release is also increased by direct stimulation of hypothalamic postsynaptic serotonergic receptors.17 Rittenhouse and colleagues18 put forward that activation of the receptor subtypes HT2/5-HT1C can increase prolactin. Despite similar mechanisms and receptor profile, there are different effects of SSRIs on prolactin. In one study, one patient developed galactorrhea with sertraline 50 mg/day. In the same study, patients were treated with 20 mg/day doses of citalopram, and galactorrhea did not develop.19 In literature, typical antidepressant bupropion has been defined as neutral in respect of prolactin, even if it lowered prolactin level by increasing dopamine reuptake.20 Clinicians should exercise caution www.psychopharmacology.com
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
113
Journal of Clinical Psychopharmacology
Letters to the Editors
for galactorrhea during antidepressant treatment, and further investigations are warranted to clarify the mechanism and receptor effects of this adverse effect. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Birmay C ¸ am, MD Psychiatry Department Manisa Mental Health Hospital Manisa, Turkey [email protected]
AslN Aktu¨men Bilgin, MD Specialist psychiatrist Free psychiatrist Bursa, Turkey
REFERENCES 1. Stahl SM, Pradko JF, Haight BR, et al. A review of the neuropharmacology of bupropion a dual norepinephrine and dopamine reuptake inhibitor. Prim Care Companion J Clin Psychiatry. 2004;6:159Y166. 2. Jain AK, Kaplan RA, Gadde KM, et al. Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obes Res. 2002;10(10):1049Y1056. 3. Moreira R. The efficacy and tolerability of bupropion in the treatment of major depressive disorder. Clin Drug Investig. 2011;19(31 suppl 1):5Y17.
114
www.psychopharmacology.com
4. Dwoskin LP, Rauhut AS, King-Pospisil KA, et al. Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev. 2006;12(3Y4):178Y207. 5. Keinberg DL. Endocrinology of mammary development, lactation and galactorrhea. In: DeGroot LJ, Jameson JL, eds. Endokrinology. 4th ed. 2003:2470Y2472. 6. Girayalp ABO. Galactorrhea due to fluoxetine in a patient with depression and a pituitary adenoma: a case report. Bull Clin Psychopharmacol. 2009;19:159Y163.
&
Volume 35, Number 1, February 2015
13. Sternbach H. Venlafaxine induced galactorrhea. J Clin Psychopharmacol. 2003;23(1):109Y110. 14. Trenque T, Herlem E, Auriche P, et al. Serotonin reuptake inhibitors and hyperprolactinaemia: a case/non-case study in the French pharmacovigilance database. Drug Saf. 2011;34(12):1161Y1166. 15. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharacol Ther. 1981;30:239Y245.
7. Bronzo MR, Stahl SM. Galactorrhea induced by sertraline [letter]. Am J Psychiatry. 1993;150:1269Y1270.
16. Cooper DS, Gelenberg AJ, Wojcik JC, et al. The effect of amoxapine and imipramine on serum prolactin levels. Ann Intern Med. 1981;141:1023Y1025.
8. Korkmaz S, Kulo?lu M, Is¸Nk U, et al. Galactorrhea during duloxetine treatment: a case report. Turk J Psychiatry. 2011; 22(3):200Y201.
17. Egberts AC, Meyboom RH, de Koning FH, et al. Non puerperal lactation associated with antidepressant drug use. Br J Pharmacol. 1997;44:277Y281.
9. Anand VS. Clomipramine induced galactorrhoea and amenorrhoea. Br J Psychiatry. 1985;147:87Y88.
18. Rittenhouse PA, Levy AD, Li Q, et al. Neurons in the hypothalamic paraventricular nucleus mediate the serotonergic stimulation of prolactin secretion via 5-HT1C/2 receptors. Endocrinology. 1993;133:661Y667. ¨ zcan S, Tamam L, Soydan A. Selective 19. O serotonin reuptake inhibitors and galactorrhea: a comparison of sertraline and citalopram based on a case report. Klin Psikiyatr. 2012;15:252Y254.
10. Shim SH, Lee YJ, Lee EC. A case of galactorrhea associated with escitalopram. Psychiatry Investig. 2009;6:230Y232. 11. Spigset O, Mjorndal T. The effect of fluvoxamine on serum prolactin and serum sodium concentrations: relation to platelet 5-HT2A receptor status. J Clin Psychopharmacol. 1997;17:292Y297. 12. Morrison J, Remick RA, Leung M, et al. Galactorrhea induced by paroxetine. Can J Psychiatry. 2001;46(1):88Y89.
20. Meltzer HJ, Fang VS, Tricou BJ, et al. Effect of antidepressants on neuroendocrine axis in humans. Adv Biochem Psychopharmacol. 1982;32:303Y316.
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
&
Volume 35, Number 1, February 2015
11. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239Y245. 12. John AP, Koloth R. Severe serotonin toxicity and manic switch induced by combined use of tramadol and paroxetine. Aust N Z J Psychiatry. 2007;41:192Y193. 13. Gonzalez-Pinto A, Imaz H, De Heredia JL, et al. Mania and tramadol-fluoxetine combination. Am J Psychiatry. 2001; 158:964Y965. 14. Post RM, Altshuler LL, Leverich GS, et al. Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry. 2006;189:124Y131.
Bupropion-Associated Galactorrhea A Case Report To the Editors:
B
upropion is a second-generation antidepressant used in both depressive disorders and cessation of smoking; it increases extracellular concentration of dopamine and norepinephrine by blocking dopamine and norepinephrine reuptake. It increases noradrenaline and dopamine levels at prefrontal cortex by blocking noradrenaline and dopamine carriers; however, it has no effect on serotonergic transmission.1 Its sexual adverse effects rate is similar to placebo and lower than that of selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors.2 Bupropion has a chemical structure similar to certain psychostimulants, and its sedating effect is very low, and loss of weight is significant with bupropion.2,3 Nonproductive cough, nausea, constipation, headache, and insomnia are the most frequently reported adverse effects. Reducing epileptic threshold is among its disadvantages.4 Hyperprolactinemia is a clinical presentation that may be caused by medical conditions such as pituitary tumors leading to galactorrhea, amenorrhea and infertility, craniopharyngioma, metastatic tumors, and thyroid function disorders and also by various drugs including antipsychotics, metoclopramide, oral contraceptives, and thyroid hormone preparations.5,6 Hyperprolactinemia and galactorrhea are adverse effects mostly seen during treatment with antipsychotic agents and rarely with selective serotonin reuptake inhibitors. In the literature, there are reported hyperprolactinemia and galactorrhea cases associated with tricyclic antidepressant clomipramine; selective serotonin reuptake
inhibitors escitalopram, sertraline, fluoxetine, fluvoxamine, and paroxetine; and serotonin-norepinephrine reuptake inhibitors venlafaxine and duloxetine.6Y13 In a pharmacovigilance study by Trenque et al,14 hyperprolactinemia was reported in 187 of 11,863 patients using selective serotonin reuptake inhibitors, and many of these cases (71%) were middle-aged women. Hyperprolactinemia was mostly related to fluvoxamine, citalopram, fluoxetine, and paroxetine, and the risk was not increased by duloxetine, milnacipran, and sertraline. In the literature search, no case of galactorrhea related to bupropion was found. Here we present a case developing galactorrhea during usage of bupropion and improvement of this galactorrhea following discontinuation of bupropion treatment.
CASE REPORT The patient was a housewife, 34 years of age, celibate, and graduated from high school. She admitted to psychiatry outpatient clinic with complaints of demoralization, malaise, loss of interest, and increased sleep and appetite for 3 years. At her psychiatric examination, she was conscious, cooperative, and oriented. Depressive affection was observed, and depressive mood was identified. Sleep and appetite were increased. Anergy and anhedonia were present. No psychotic sign was detected. There were no suicidal attempts and thoughts. The patient did not have organic diseases that can lead to depression such as thyroid disease, connective tissue disease, cardiac drugs, or steroids. The patient was previously treated with sertraline 100 mg/d for 2 months 2 years ago; however, she did not benefit from it. No organic disorder, chronic drug usage, or history of surgery was detected. She was not using alcohol or narcotic. Her menstrual cycle was normal. She was not pregnant, and she did not use oral contraceptives. She was not sexually active. No family history of psychiatric diseases was present. Her diagnosis was major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Beck Depression Scale score was 35, and Beck Anxiety Scale score was 14. Treatment of bupropion 150 mg/d was initiated. The patient presented at the outpatient clinic within second week of treatment with complaint of galactorrhea. Examination including hemogram, fasting blood glucose, lipid profile, and thyroid function tests was normal. Blood prolactin level was 98 ng/mL. The patient had no such complaint in the past. Cranial magnetic resonance was obtained in order to eliminate organic origin, and it showed no space-occupying mass at pituitary gland. Gynecologic consultation was asked, and no
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editors
pathology was detected. Galactorrhea was considered to be adverse effect of bupropion treatment, and the treatment was discontinued. Galactorrhea disappeared 2 days after withdrawal of treatment, and PRL level was 3 ng/mL 1 week later. Fluoxetine 20 mg/d was initiated, and no galactorrhea was observed during 4 months of observation period. Beck Depression Scale score decreased to 15, and Beck Anxiety Scale score decreased to 5.
DISCUSSION In our case, hyperprolactinemia and galactorrhea were considered to be related to bupropion in that hyperprolactinemia and galactorrhea appeared immediately following initiation of bupropion, absence of any other drug usage and physical illness, cranial magnetic resonance with normal appearance, spontaneously resolving hyperprolactinemia following cessation of treatment, and lack of this complaint previously. The drug side effect scale developed by Naranjo and colleagues15 is a 10-item questionnaire. The relationship of a drug and corresponding side effect is certain with 9 points, probably with 5Y8 points, and possible with 1Y4 points. Based on this scale, the relationship between bupropion and galactorrhea was possible (score 5). Normal prolactin level is less than 20 to 25 mg/mL. Prolactin level is lower than 100 ng/mL in galactorrhea related to drug usage, as in our case.16 Women are suggested to be more prone to antidepressantrelated prolactin increase.14 According to our knowledge, our case is the first case of galactorrhea associated with bupropion. However, the mechanism is still not clear. Hyperprolactinemia and galactorrhea are adverse effects mostly seen during treatment with antipsychotic agents and rarely with selective serotonin reuptake inhibitors. Activation of serotonergic system leads to prolactin increase and galactorrhea by blocking dopamine, which has an inhibitory effect on prolactin at the tuberoinfundibular pathway. In addition, prolactin release is also increased by direct stimulation of hypothalamic postsynaptic serotonergic receptors.17 Rittenhouse and colleagues18 put forward that activation of the receptor subtypes HT2/5-HT1C can increase prolactin. Despite similar mechanisms and receptor profile, there are different effects of SSRIs on prolactin. In one study, one patient developed galactorrhea with sertraline 50 mg/day. In the same study, patients were treated with 20 mg/day doses of citalopram, and galactorrhea did not develop.19 In literature, typical antidepressant bupropion has been defined as neutral in respect of prolactin, even if it lowered prolactin level by increasing dopamine reuptake.20 Clinicians should exercise caution www.psychopharmacology.com
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
113
Journal of Clinical Psychopharmacology
Letters to the Editors
for galactorrhea during antidepressant treatment, and further investigations are warranted to clarify the mechanism and receptor effects of this adverse effect. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Birmay C ¸ am, MD Psychiatry Department Manisa Mental Health Hospital Manisa, Turkey [email protected]
AslN Aktu¨men Bilgin, MD Specialist psychiatrist Free psychiatrist Bursa, Turkey
REFERENCES 1. Stahl SM, Pradko JF, Haight BR, et al. A review of the neuropharmacology of bupropion a dual norepinephrine and dopamine reuptake inhibitor. Prim Care Companion J Clin Psychiatry. 2004;6:159Y166. 2. Jain AK, Kaplan RA, Gadde KM, et al. Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obes Res. 2002;10(10):1049Y1056. 3. Moreira R. The efficacy and tolerability of bupropion in the treatment of major depressive disorder. Clin Drug Investig. 2011;19(31 suppl 1):5Y17.
114
www.psychopharmacology.com
4. Dwoskin LP, Rauhut AS, King-Pospisil KA, et al. Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev. 2006;12(3Y4):178Y207. 5. Keinberg DL. Endocrinology of mammary development, lactation and galactorrhea. In: DeGroot LJ, Jameson JL, eds. Endokrinology. 4th ed. 2003:2470Y2472. 6. Girayalp ABO. Galactorrhea due to fluoxetine in a patient with depression and a pituitary adenoma: a case report. Bull Clin Psychopharmacol. 2009;19:159Y163.
&
Volume 35, Number 1, February 2015
13. Sternbach H. Venlafaxine induced galactorrhea. J Clin Psychopharmacol. 2003;23(1):109Y110. 14. Trenque T, Herlem E, Auriche P, et al. Serotonin reuptake inhibitors and hyperprolactinaemia: a case/non-case study in the French pharmacovigilance database. Drug Saf. 2011;34(12):1161Y1166. 15. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharacol Ther. 1981;30:239Y245.
7. Bronzo MR, Stahl SM. Galactorrhea induced by sertraline [letter]. Am J Psychiatry. 1993;150:1269Y1270.
16. Cooper DS, Gelenberg AJ, Wojcik JC, et al. The effect of amoxapine and imipramine on serum prolactin levels. Ann Intern Med. 1981;141:1023Y1025.
8. Korkmaz S, Kulo?lu M, Is¸Nk U, et al. Galactorrhea during duloxetine treatment: a case report. Turk J Psychiatry. 2011; 22(3):200Y201.
17. Egberts AC, Meyboom RH, de Koning FH, et al. Non puerperal lactation associated with antidepressant drug use. Br J Pharmacol. 1997;44:277Y281.
9. Anand VS. Clomipramine induced galactorrhoea and amenorrhoea. Br J Psychiatry. 1985;147:87Y88.
18. Rittenhouse PA, Levy AD, Li Q, et al. Neurons in the hypothalamic paraventricular nucleus mediate the serotonergic stimulation of prolactin secretion via 5-HT1C/2 receptors. Endocrinology. 1993;133:661Y667. ¨ zcan S, Tamam L, Soydan A. Selective 19. O serotonin reuptake inhibitors and galactorrhea: a comparison of sertraline and citalopram based on a case report. Klin Psikiyatr. 2012;15:252Y254.
10. Shim SH, Lee YJ, Lee EC. A case of galactorrhea associated with escitalopram. Psychiatry Investig. 2009;6:230Y232. 11. Spigset O, Mjorndal T. The effect of fluvoxamine on serum prolactin and serum sodium concentrations: relation to platelet 5-HT2A receptor status. J Clin Psychopharmacol. 1997;17:292Y297. 12. Morrison J, Remick RA, Leung M, et al. Galactorrhea induced by paroxetine. Can J Psychiatry. 2001;46(1):88Y89.
20. Meltzer HJ, Fang VS, Tricou BJ, et al. Effect of antidepressants on neuroendocrine axis in humans. Adv Biochem Psychopharmacol. 1982;32:303Y316.
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
