Sociodemographic and illness-related data
Between 1993 and 2015, a total of 475,096 psychiatric inpatients were monitored within the AMSP program in 86 hospitals. During this time frame, 175,884 women (320,383 patients in total) were treated with APDs for the main indications of schizophrenia, schizotypal, and delusional disorders, as well as mood and organic disorders. Galactorrhea was assessed as a severe ADR during antipsychotic treatment in 170 cases. This corresponds to a rate of 0.97 cases in 1000 female inpatient admissions. No cases were assessed in males.
The occurrence of galactorrhea presented with highly significant differences among age groups (Table 1; p < 0.0001). Women between 16 and 40 years of age were most commonly affected, with 80% of all cases occurring within the reproductive age and an incidence of 2.57 in 1000 inpatients. The rate was highest in the youngest group between 16 and 30 years (3.18 in 1000 inpatients). A total of 31 cases were identified among patients between 41 to 55 years (18% of all cases, incidence 0.59 in 1000 inpatients), while patients aged 55 years and older reported only 3 cases (2% of all cases, incidence 0.04 in 1000 inpatients). Cases of galactorrhea occurred significantly more frequently (p < 0.0001) in patients treated with APDs diagnosed with schizophrenia, schizotypal, and delusional disorders (1.34 per 1000), organic mental disorders (1.27 per 1000), as well as mania (1.04 per 1000). Patients treated with APDs suffering from unipolar depression (0.62 per 1000) or neurosis and personality disorders (0.53 per 1000; see Table 1) were much less commonly affected.
Antipsychotic drugs associated with galactorrhea
Seventeen different APDs were attributed to 170 cases of galactorrhea. In 132 patients (77.4% of all galactorrhea cases), a single antipsychotic drug was held responsible for the ADR as the only probable cause (rated as grade 2). Only 20 of these cases (15.2%) occurred under monotherapy (three each under olanzapine and paliperidone, six under amisulpride, and eight under risperidone). In 76 cases (57.6%), another drug (between one and four substances per case) was imputed as possible contributor to galactorrhea (rated as grade 1). In 38 cases, combinations of several drugs were imputed as equal contributors to the galactorrhea (rating as grade 2). Most of cases imputing more than one drug were due to the combination of two antipsychotic drugs, however, the individual numbers are too small to identify a specific risk combination of APDs.
Table 2 as well as Figs. 1 and 2 show the rates of galactorrhea under treatment with different substances. Amisulpride showed the highest relative risk for inducing galactorrhea and was considered to have caused the ADR in 30 cases (0.48% of all patients exposed). Most cases occurred under treatment with risperidone which was imputed alone in 53 cases (0.19% of all patients exposed). Olanzapine was imputed alone as probable cause in 13 cases (0.05% of all patients exposed). Among subgroups of APDs, we found most cases of galactorrhea to arise under the treatment with second generation APDs which were consequently imputed alone in 119 cases or 0.11% of all patients exposed. In the class of first-generation APDs, most cases appeared under treatment with high potency APDs which were imputed alone in 17 cases or 0.04% of all patients exposed. Regarding the homogenous chemical subgroups of first-generation APDs, most cases of galactorrhea occurred under treatment with thioxanthenes (imputed alone in 7 cases or 0.04% of all patients exposed). Other drugs were imputed only as a possible additional contributor to galactorrhea (e.g. low potency APDs, selective serotonin reuptake inhibitors [SSRI], selective serotonin and noradrenaline reuptake inhibitors [SSRNI]), when the time course was unusual or because these drugs only rarely lead to galactorrhea. Of the 30 cases in which amisulpride was imputed alone as a probable cause, other APDs or antidepressant drugs were imputed as possible contributors in 12 cases. Monotherapy with amisulpride was observed in only 6 cases of galactorrhea. Of the 53 risperidone cases, where the substance was imputed alone as a probable cause, risperidone was prescribed as monotherapy in only 8 cases. In 22 cases, other APDs or antidepressant drugs were imputed as possible contributors. In 5 of the 13 olanzapine cases, SSRIs or venlafaxine were additionally prescribed; in 1 case, olanzapine was combined with valproate and in 3 cases, with other APDs that were imputed as only possible contributors due to the course of time (twice pipamperone and once perazine). Only 2 cases of olanzapine as monotherapy (20 mg/d in both cases) were observed. Benzodiazepines, a common comedication, were not applied more frequently in galactorrhea cases overall (29.4%) in comparison to all patients exposed to APDs (33.7%). There were not enough patients exposed to long-acting injectables (LAI) to perform a separate analysis. Flupentixol LAI was imputed alone in 2 cases, paliperidone and risperidone LAI in one case each. Zuclopenthixol LAI was imputed in combination therapy in one case, but was not imputed alone. Galactorrhea in relation to aripiprazole was not observed. Clozapine was imputed in combination therapy in 1 case, but never imputed alone. Due to the low prescription rates of paliperidone over the period of our survey, it was not considered for further analysis. Of the 1367 patients treated with paliperidone, 12 experienced clinically severe galactorrhea, in 10 cases, paliperidone was imputed alone as probable cause (1 case under application of the depot, 9 cases under oral medication).
Among 170 cases of galactorrhea, 3 cases were attributed to quetiapine alone as a probable cause. This finding is significant insofar that quetiapine has only rarely been associated with elevated prolactin levels and galactorrhea in the currently available literature. All 3 cases of quetiapine-associated galactorrhea affected patients suffering from mood disorders. In the first case of a 48-year-old woman with severe mania, galactorrhea started after 1 month of treatment with quetiapine 600 mg/d. The serum level of quetiapine was elevated (996 nmol/l, ref. 80–780 nmol/l). Zuclopenthixol 6–25 mg had been given in addition to quetiapine for 2 weeks, but discontinued the day before the galactorrhea started. Galactorrhea persisted for 3 weeks and disappeared 1 week after discontinuation of quetiapine. Therefore, zuclopenthixol was rated as only a possible contributor to the ADR. The medication was switched to risperidone 4 mg/d in monotherapy, under which galactorrhea did not re-appear despite further increases in prolactin levels. In the second case of a 30-year-old woman with a manic episode with psychotic symptoms, galactorrhea was present after 1 week of treatment with up to 800 mg quetiapine per day. In addition, the patient was treated with 1125 mg of lithium. Levomepromazine (given in a maximum dose of 100 mg per day for 4 weeks) had been discontinued the day prior to the occurrence of galactorrhea. As in the previous case, levomepromazine was rated as only a possible contributor to the ADR due to the time course. In this case, elevated prolactin levels could not be detected. Quetiapin was tapered over 16 days while continuing treatment with lithium, causing the symptoms to mitigate and finally dissolve completely. In the third case of a 64-year-old female patient suffering from a major depression with psychotic symptoms, galactorrhea presented under treatment with 400 mg quetiapine per day. Quetiapine was started 10 weeks before the occurrence of galactorrhea with 400 mg, then 200 mg. Afterwards, dose was again increased to 400 mg for 3 weeks, during which time treatment with venlafaxine extended release 75–150 mg was additionally started. Another possibly contributing factor in this case was the second and last intramuscular injection of risperidone depot 25 mg 6 weeks prior to the beginning of the ADR. The prolactin level was 103.3 ng/ml 1 day after galactorrhea had started (ref. < 15 ng/ml). Quetiapine was tapered and finally discontinued over the course of 2 weeks with galactorrhea stopping 9 days later under continuation of treatment with venlafaxine. Venlafaxine and risperidone were rated only as possibly contributing factors due to time course.
For the sake of completeness, we want to mention 5 cases of galactorrhea in our database that were not related to antipsychotic drugs. In one case, pregabalin (300 mg/day) was imputed as probably responsible in a combination therapy with carbamazepine, prothipendyl, and trazodone. Galactorrhea stopped after discontinuing pregabalin, while all other substances were continued and partly even increased. 2 cases were reported under monotherapy with antidepressant drugs (trimipramine and paroxetine), 1 case under a combination of trimipramine and paroxetine, and 1 case under the combination of imipramine and doxepin.
Table 3 gives information on median daily dosage of patients suffering from galactorrhea and all exposed patients. For most of the drugs, the daily dosages were higher among patients with galactorrhea compared to all patients exposed; exceptions were mainly amisulpride and zuclopenthixol.
The administered dosages in all exposed patients differed in relation to the diagnoses for the 3 drugs most often involved in galactorrhea: risperidone, amisulpride, and olanzapine.
Median daily dose of oral risperidone was 4 mg in patients with schizophrenia, 2 mg in patients with depression, 3 mg in patients with mania, and 1 mg in patients with organic mental disorders. The median daily dosages were identical in the group of galactorrhea cases except in patients with organic mental disorders (median daily dosage 3.5 mg). Among all 67 (52 imputed alone = i.a.) cases of risperidone-induced galactorrhea, the daily dosage was > 2 mg in 42 cases (34 i.a.), between 1.1 and 2 mg in 16 (10 i.a.) cases, and 1 mg or less in 9 (8 i.a.) cases. There were only 2 cases under risperidone depot (1 case imputed alone under 50 mg every 2 weeks) so the dosages mentioned above refer to the oral medication, that was imputed alone in 52 cases.
Patients suffering from schizophrenia were prescribed a median daily dosage of 600 mg amisulpride, while patients with depression were treated with 300 mg/d, and patients with mania as well as organic mental disorders were prescribed 400 mg/day. In cases of galactorrhea causally associated with amisulpride, the median daily dosage was 400 mg for all diagnoses except for patients suffering from schizophrenia, who were prescribed a median dosage of 500 mg per day. Among 29 of all cases in which amisulpride was imputed, galactorrhea occurred under a daily dosage of min. 200 mg (median 400 mg), in 5 cases the dosage was between 150 and 200 mg per day.
Among users of olanzapine, the median dosage per day was 15 mg in patients with schizophrenia and mania, 10 mg in patients with depression, and 7.5 mg in patients with organic mental disorders. The median daily dosage of olanzapine was higher among patients with galactorrhea than in the group of all patients exposed for the diagnoses schizophrenia (20 mg) and organic mental disorders (15 mg). The dosage in patients with depression was the same (10 mg), while olanzapine-induced galactorrhea was not recorded in patients with mania. Of the 13 cases in which olanzapine was imputed alone, 4 occurred under a daily dosage of 10 mg, 2 cases under 15 mg, 5 cases under 20 mg, and 1 case each under 30 resp. 40 mg.
Serum prolactin levels were documented in 123 (72.4%) of the 170 galactorrhea cases, the reference value was set to 15 ng/ml. The mean value was 110.75 ng/ml (median value 91.76 ng/ml; min. 6.80, max. 430.50 ng/ml). Cases in which multiple prolactin levels were given, the highest value was used for further analysis. In our sample, we found 5 cases (2.9%) of galactorrhea in spite of normal levels of prolactin. The drugs imputed were amisulpride (with a daily dosage of 300 mg), risperidone (3 mg/d), olanzapine (10 mg/d), haloperidol (10 mg/d), and quetiapine (800 mg/d) in 1 case each.
Countermeasures and course of the ADR
Discontinuation of the implicated drug(s) was performed in 145 (85.3%) of the 170 patients with galactorrhea. In 20 other patients (11.8%), dosage of the imputed drug was reduced, whereas no changes in medication were made in the remaining 5 patients (2.9%). Further consultation by an internal medicine specialist or gynecologist was provided in 20 cases (11.8%). In only 6 cases, drugs to counteract galactorrhea were used (3 times additional treatment with bromocriptine and one time each with cabergoline, metergoline, and calcium + magnesium). Galactorrhea disappeared in 127 cases (74.7% of all cases), mostly after discontinuation or dose reduction of the implicated drug. In 1 case, symptoms ceased with no changes in medication, while in another case, symptoms receded following the addition of bromocriptine. In 26 patients (15.3%), galactorrhea improved but was still present at the end of the observation period. In 14 patients, galactorrhea was unchanged at the end of observation whereas the further course was unknown in 3 patients. Further contributory risk factors in addition to those mentioned above (female gender, age, drug dosage) could not be identified.