Selective serotonin reuptake inhibitor-induced galactorrhea with hyperprolactinemia.

Galactorrhea in nonpregnant woman of child-bearing age is related to various pathologies including the use of psychotropic. Although common with antipsychotics, galactorrhea with antidepressants was infrequent. Previously reported cases of galactorrhea were mostly with combined antidepressants and cases of galactorrhea with paroxetine and fluvoxamine were with normal serum prolactin level. We reported three cases of galactorrhea, one with single use of paroxetine and other two with fluvoxamine with elevated serum prolactin level in all three cases. Copyright:

INTRODUCTION

Galactorrhea is the spontaneous discharge of milk from the breast which is not associated with pregnancy, childbirth, or lactation. Although it is benign in most of the cases, serious underlying pathology and adverse drug conditions are also related to galactorrhea.[1] Various psychotropic, mostly antipsychotic drugs are known to block tuberoinfundibular dopaminergic (D2) pathway which ultimately leads to increased prolactin secretion from hypothalamus and causes galactorrhea[2]. Although the incidence of galactorrhea with antidepressants, mostly selective serotonin reuptake inhibitor (SSRI) was reported previously, they were very few in number and clear pharmacopathology cannot be postulated behind it.[34] We know reported cases of sertraline induced galactorrhea. There are reported cases of galactorrhea with the use of paroxetine and citalopram where prolactin level is normal, and there is also a single case report where fluvoxamine is directly associated with galactorrhea. Till now there is no clinical trial reported on SSRI- induced galactorrhea. Here, we are reporting three cases of galactorrhea, one with the use of paroxetine and other two cases were with the use of fluvoxamine. In all three cases, galactorrhea was associated with increased serum prolactin level which was normalized after discontinuation of medicines.

CASE REPORTS

Case-1

A 24 years old unmarried female had attended a psychiatric clinic in a town of West Bengal in 2020 with complaints of excessive worry, prominent tension, and feelings of apprehension in most of her day-to-day events and most of the day for the past 9 months. Whenever she was excessively worried, her mouth and throat were becoming dry, she started to tremble and can hear his heart beating very fast. With increasing symptoms, she was feeling dizzy, unsteady, faint, or light-headed. Her sleep was also decreased for the past 6 months. There was no history suggestive of depressed mood, delusion, hallucination, and repetitive unwanted thoughts. She was diagnosed to be suffering from generalized anxiety disorder according to the International classification of diseases (ICD-10). On the Hamilton Anxiety Rating Scale (HAM-A), she scored 36, which indicated severe anxiety. She was advised for routine blood tests, particularly was searched for thyroid profile and electrocardiogram. She was found to be euthyroid and having no abnormal electrocardiogram. She was prescribed tablet paroxetine at a dose of 12.5 mg at night for the first 6 days then at a dose of 25 mg. She was also given tablet clonazepam 0.5 mg at night to address her sleep disturbance. When she was followed up after 20 days, her anxiety symptoms were decreased in severity and she scored 18 on the HAM-A scale. Her sleep was also improved. However, she was distressed with a new symptom of white, sticky discharge from her breasts which was apparent for the past 4 days. Her menstruation was regular; she was not taking any other medication and was not pregnant. Drug-induced galactorrhea was suspected and she was advised for computed tomography (CT) scan brain, ultrasonography (USG) of lower abdomen, and serum prolactin level. There was no pituitary pathology, her ovaries had no cyst or tumorous pathology in respective investigations, but her serum prolactin level was high and it was 145.7 ng/ml. Dose of paroxetine was lowered to 12.5 mg/day after this blood report and was asked to return after 14 days with repeat serum prolactin level. Now her distressing symptom of galactorrhea had decreased but still with high serum prolactin level of 95.3 ng/ml. Hence, paroxetine is totally stopped and she was put only on clonazepam 0.5 mg at night. After 2 weeks, her symptom was vanished with a normal prolactin level of 19.5 ng/ml. She was changed to tablet escitalopram 10 mg at night which was increased to 15 mg after 21 days. She was followed up for next 3 months and was doing well without any symptoms of galactorrhea. Naranjo Adverse Drug Reaction Scale was applied with a score of 7 which indicated probable reaction.[9]

Case 2

A 36-year-old married homemaker, mother of two children, from rural West Bengal had attended a psychiatry clinic with complaints of recurrent intrusive unwanted thoughts of getting corona infection through touching any grocery items, fruits, and vegetables, bought from market. She admitted that her thoughts are irrational, but she cannot stop it and felt marked distressed and anxiety with her thoughts. She remained engaged in repeated washing those things for several hours, bought from market. Her family members repeatedly failed to make her understand, change her washing habits and she started to spend near about 2 h in washing and cleaning fruits and vegetables, although it cannot relieve her distress. She had no history suggestive of delusion, hallucination, and any other anxiety and somatoform disorder. She was diagnosed to be suffering from obsessive-compulsive disorder, mixed obsessional thoughts and acts (F42.2). On the Yale-brown obsessive-compulsive (Y-BOCS) scale, her score was 28, meaning “moderate-severe symptoms.” She was investigated for routine laboratory investigations including thyroid profile and was normal on every parameter except the presence of anemia, microcytic, and hypochromic with Hb% - 10.5 g %. She was given tablet fluvoxamine 50 mg for 6 days then dose was increased to 100 mg next week. Tablet clonazepam 0.5 mg was given to take on a need basis. She returned after 15 days with mild improvement in the Y-BOCS scale (Score-24), but she presented with a newly onset symptom of whitish, nonsmelling, and fluid discharge from her nipples. Her menstruation was regular; she had gone through ligation operation 6 years ago after her second baby and was not taking any other medication. Galactorrhea was suspected, fluvoxamine was stopped and she was advised for CT scan of the brain, USG of lower abdomen, and serum prolactin level. Her serum prolactin level was high (125 ng/ml), CT scan of the brain and USG of lower abdomen were nonsignificant. Her galactorrhea disappeared 10 days after stoppage of fluvoxamine and repeat serum prolactin level became normal at 5.5 ng/ml. On applying Naranjo Adverse Drug Reaction Scale, the score was 6, i.e., in probable range.[9] She was put on tablet clomipramine which was gradually increased to 150 mg over the next 4 weeks. She was followed up for 8 weeks, with improvement on the Y-BOCS scale (score-10) without reappearance of galactorrhea.

Case 3

A 22-year-old unmarried female of urban background came to psychiatric OPD with the complaints of repeated hand washing, taking 2–3 h for bathing, irritability, and decreased sleep for 5–6 months. Her mother admitted that she had all these symptoms for the past 3 years but recently increased in severity. Most of the time she thought that she will be contaminated with dirt and germ, for which she used to wash hands and feet repeatedly and engage herself in cleaning her room. She stopped going outside the home and prevented others to enter her room. She also forced her family members to go washroom directly if come from outside. On interview, she acknowledged that these thoughts were her own thoughts and irrational but she cannot stop. She became very much anxious until she compulsively cleaned herself. Mean squared error revealed that she had obsession of contamination. No significant past or family history was there. According to ICD-10, her diagnosis was obsessive-compulsive disorder, mixed obsessional thoughts and acts (F42.2). On the Y-BOCS, her score was 32, i.e., in severe range. Initially, she was treated by a psychiatrist with fluoxetine 40 mg for 2 weeks, but she could not tolerate and stopped the medicine 1 month back. Hence, the patient was started with tablet fluvoxamine 50 mg and tablet clonazepam 0.5 mg/day. The dose of fluvoxamine was increased gradually up to 150 mg/day within 14 days as she tolerated well. While came for follow-up after 1 month she complained of mild pain in the breast and whitish discharge from both the nipple. Her menstruation was regular, symptoms of OCD slightly reduced, and the Y-BOCS score was 23. Routine blood reports were normal. She was further advised blood for thyroid-stimulating hormone, luteinizing hormone/follicle-stimulating hormone, prolactin level, urine for pregnancy test, USG whole abdomen, and CT scan of the brain. All the reports were within the normal range except serum prolactin level which was 112 ng/ml. Hence, the dose of fluvoxamine was gradually tapered over 2 weeks and clomipramine was started with 25 mg/day and increased up to 150 mg/day over 1 month along with exposure and response prevention. The symptoms of pain and nipple discharge went off immediately after stopping fluvoxamine. Serum prolactin level, measured 1 month after starting clomipramine was 14.2 ng/ml. Her symptoms reduced slightly with the Y-BOCS score of 26. Dose of clomipramine increased up to 200 mg and followed up after 2 months. She was doing relatively well with the Y-BOCS score of 20. She had no galactorrhea at that time. The score of 6 in Naranjo's adverse drug reaction scale suggested probable causal relationship.[9]

DISCUSSION

There are previous case reports of galactorrhea with paroxetine.[46] However, serum prolactin level was normal in those reported cases. In our index case, galactorrhea and elevated serum prolactin level was seen with the use of paroxetine 25 mg/day. Interestingly, serum prolactin level reduced slightly when dose of paroxetine reduced to half and touches baseline after it has been stopped.

There are very few case reports with fluvoxamine-associated hyperprolactinemia. Among them, one was coprescribed with risperidone and fluvoxamine[101112] and another was euprolactinemic galactorrhea[13] and only one case report is there where fluvoxamine was directly associated with hyperprolactinemia.[8] In our 2nd and 3rd cases, we have seen galactorrhea along with markedly elevated serum prolactin level with the single use of fluvoxamine. Moreover, serum prolactin level normalized and galactorrhea disappeared after stopping the drug.

Lactation is always due to increased serum prolactin level and galactorrhea in the presence of hyperprolactinemia points toward tuberoinfundibular dopamine (D2) blockade, leading to decrease the release of prolactin-inhibiting factor, likely to be dopamine.[14] Hence, we can say that in our three cases, galactorrhea was due to elevated prolactin level, evident from laboratory findings. Particular mechanism for elevated prolactin level with paroxetine was not clear and probable mechanism points toward direct stimulation of postsynaptic serotonergic receptors in the hypothalamus and the serotonergic inhibition of dopamine, which is a prolactin inhibiting factor-a complex serotonin receptor (5HT) and dopamine receptor interaction.[456] It is hypothesized that high affinity of fluvoxamine toward sigma1 receptor can also modify striatal dopamine activity which may alter serum prolactin level.[13]

Other possible causes of galactorrhea such as thyroid dysregulation, pituitary adenoma, and chronic renal failure were excluded in our cases.[151617] There was no history of taking commonly used drugs such as domperidone, oral contraceptive pills by the cases which are also known to cause galactorrhea.[18] In all of our cases, the score of Naranjo adverse drug reaction scale was 7, 6, and 6, respectively, which support the probable causal relationship.

Galactorrhea is very much distressing in nonpregnant woman and such side effect with antidepressants is not usually expected. Patients are also reluctant to report this problem. It has been reported that chronic hyperprolactinemia causes sexual dysfunction, decrease in bone density, infertility, and increased chance of breast cancer.[1920]

Clinicians must have knowledge of galactorrhea associated with hyperprolactinemia while using paroxetine and fluvoxamine. Patients who are on SSRI, particularly paroxetine and fluvoxamine should be enquired about these symptoms during follow-up. We should act promptly in such condition. The detection of further cases will help us for future research to explore definite receptor level interactions.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.