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By what mechanism does Risperidone swell breast tissue?

By what mechanism does Risperidone swell breast tissue?


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There has been much talk of the anti-psychotic drug Rispeirdone causing un-natural breast tissue growth as well as galactorhea (milk production). Especially in young men and boys.

What is the mechanism of this drug that is causing this? Is it actually introducing some amount of female hormones into the male's body or is just causing increased production of them?


Risperidone prevents dopamine from acting on the pituitary gland by blocking dopamine type 2 receptors. One of dopamine's effects on the pituitary is to suppress prolactin production. In patients taking risperidone, prolactin production thus increases and prolactin levels in the body are higher than normal. In younger males, this can result in abnormal growth of breast tissue and even milk production.

See e.g. Melkersson, K. I. (2006). Prolactin elevation of the antipsychotic risperidone is predominantly related to its 9‐hydroxy metabolite. Human Psychopharmacology: Clinical and Experimental, 21(8), 529-532.


Selective estrogen receptor modulator

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), [1] [2] are a class of drugs that act on the estrogen receptor (ER). [3] A characteristic that distinguishes these substances from pure ER agonists and antagonists (that is, full agonists and silent antagonists) is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.


The Effects of Antipsychotics on Prolactin Levels and Women’s Menstruation

Introduction. Typical and atypical antipsychotic agent is currently used for treatment in the majority of patients with psychotic disorders. The aim of this review is to assess antipsychotic induced hyperprolactinaemia and the following menstrual dysfunction that affects fertility, quality of life, and therapeutic compliance of women. Method. For this purpose, Medline, PsychInfo, Cochrane library, and Scopus databases were accessed, with a focus on the publication dates between 1954 and 2012. Research of references was also performed and 78 studies were retrieved and used for the needs of this review. Results. A summary of several antipsychotics as well as frequency rates and data on hyperprolactinaemia and menstrual disorders for different agent is presented. Conclusion. Diverse prevalence rates of hyperprolactinaemia and menstrual abnormalities have been found about each medication among different studies. Menstruation plays an important role for women, thus, understanding, careful assessment, and management of hyperprolactinaemia could enhance their lives, especially when dealing with women that suffer from a psychotic disorder.

1. Introduction

Acute psychotic episodes as well as psychotic relapses are treated effectively with antipsychotic drugs. Most patients with confirmed diagnoses of psychiatric disorders need to undergo antipsychotic drug therapy throughout their whole lives [1, 2]. Typical antipsychotic medications and some of the novel antipsychotics frequently cause an elevation of plasma prolactin levels. Among the several side reactions related with hyperprolactinaemia, are menstrual disorders such as amenorrhea or oligomenorrhea which have not been adequately evaluated. Menstrual dysfunction can be an important source of distress for women, as it influences their libido and fertility [1] and, thus, interferes with their quality of life, a consequence that should be taken into account by clinicians when antipsychotic treatment for each woman is chosen.

This review aims to summarize the effects of antipsychotic agents on prolactin levels and menstruation and investigate the frequency of hyperprolactinaemia and menstrual abnormalities that affect female patients, depending on the selected antipsychotic therapy. It also indicates the need for further research on these adverse effects, the severity of which is not always reported in a clinically meaningful way to experts.

2. Background

2.1. How Do Antipsychotics Lead to Hyperprolactinaemia?

A great number of studies have investigated antipsychotic medication and its important effects on human endocrine function. In everyday practice, there are drugs that reduce hypothalamic dopamine secretion and pituitary activation and result in hyperprolactinaemia [3–8].

Conventional antipsychotic agents and some, but not all, of the marketed novel agents, elevate serum prolactin levels via inhibition of dopamine action at

receptors in the tuberoinfundibular system of hypothalamus, where prolactin secretion is regulated. Specifically, the neurotransmitter dopamine, which acts as the primary prolactin inhibiting factor, is provided to the pituitary gland by the dopaminergic neurons of the periventricular and arcuate nuclei of the medial basal hypothalamus, through the pituitary venus system [1, 9, 10]. Dopamine stimulates receptors located on the surface of the lactotroph pituitary cells and provokes a tonic suppression on prolactin secretion. On the other hand, serotonin stimulates prolactin release [5, 9, 11]. In addition, neuropeptides such as thyrotropin releasing hormone TRH, oxytocin, vasoactive intestinal polypeptide VIP, and peptide histidine-methionine, which are under the control of serotonin, promote prolactin (PRL) secretion.

Typical antipsychotic drugs block nonselective dopamine receptors in all the regions of the brain. Antipsychotic action that includes reduction of hallucinations, delusions, and other psychotic symptoms is a result of antagonism of dopamine receptors in the limbic system, a fact that raises plasma prolactin levels. By acting to the striatum, classical antipsychotics induce extrapyramidal side effects [5]. Second generation antipsychotics present a higher ratio of serotonin

/dopamine receptor binding affinity. Additionally, they have binding affinities for variable neurotransmitter systems, showing selectivity for the mesolimbic than the striatal dopamine system. These agents are called serotonin-dopamine antagonists SDAs, while first generation neuroleptics are potent antagonists with low affinity for

receptor and no significant serotonergic effects [12].

The primary therapeutic target of traditional antipsychotics was the decrease of symptom intensity and the prevention of psychotic recurrence. However, clinicians had to accept hyperprolactinaemia as an implication and a biological marker that came with the drug’s efficacy. Data changed in clinical practice after the introduction of novel antipsychotics, which represent an advance in the treatment of psychotic disorders and have a lower tendency to induce hyperprolactinaemia. It has been suggested that the antagonism of receptors mitigates the effects of receptors inhibition and diminishes extrapyramidal side effects [9].

2.2. Side Effects of Hyperprolactinaemia

The majority of clinical adverse effects of hyperprolactinaemia involves the reproductive system and is attributed to prolactin direct relation with several tissues as well as indirect suppression of pulsatile gonadotropin secretion, leading to gonadal dysfunction. Hyperprolactinaemia deregulates systems and processes affected by the pituitary and gonadal hormones (Figure 1).


2.3. How Do Antipsychotics Lead to Menstrual Disorders?

When antipsychotics produce hyperprolactinaemia, menstrual abnormalities like anovulation, irregular menses or amenorrhea occur [7–9]. Normally, hypothalamus secrets gonadotropin releasing-hormone—GnRH in a pulsatile manner, resulting in normal follicular growth and normal pituitary secretion of luteinizing hormone—LH and follicle-stimulating hormone—FSH. This action induces normal ovarian response and normal follicle growth and thus, normal menstruation and reproduction (Figure 2).


The great response of prolactin in women of a reproductive age, who are not nursing or pregnant, leads to the inhibition of the normal pulsatile secretion of gonadotropin-releasing hormone (GnRH) of the hypothalamus. These, not so frequent, pulses of GnRH result in regular menses, on the one hand, but impaired follicular growth on the other. Greater impairment of pulsatile GnRH secretion leads to an anovulatory stage with menses being too frequent, too heavy, or infrequent. Further restraining of pulsatile GnRH secretion provokes deficient secretion of LH and FSH, in amounts not adequate to induce a proper ovarian response. That provokes a hypoestrogenized amenorrheic cycle and side reactions of estrogen deficiency—comparable to what occurs during menopause or infertility [13, 14]. Hence, as hyperprolactinaemia is associated with estrogen suppression, the initial prolactin elevation is clinically identified by reproductively related symptoms, primarily in females [9].

2.4. Preexisting Menstrual Abnormalities in Women with Psychotic Disorders

Despite the fact that various studies described how antipsychotics lead to menstrual irregularities, sometimes it remained unclear whether menstrual dysfunction was the benign sequale of treatment or it was secondary to the disease. Prior to the introduction of antipsychotic medication, psychotic women were found to have abnormal menses. Amenorrhea is combined with infertility thus, psychotic illness was supposed to be an indirect, natural contraceptive for female patients [15–17].

Studies in women with schizophrenia proved that they exhibit greater infertility rates compared to healthy females. Some studies support that a high percentage of menstrual irregularity and estrogen deficiency cannot be fully explained by antipsychotic induced prolactin elevation [4]. Another article argued that lifetime psychiatric disorders are associated with the length and regularity of the menstrual cycle only in Caucasians and not in Africans [18]. Aston et al. (2010) supported that it could be stress that leads to hyperprolactinaemia [19]. According to this study, the increase of dopamine levels in psychotic patients could be a feedback mechanism, in order to regulate prolactin elevation, on the one hand, without keeping away the reproductive side reactions, on the other hand. However, there are a lot of studies that suggest that prolactin levels are normal in unmedicated schizophrenic patients [20].

3. Materials and Methods

3.1. Methods

In order to perform this review numerous studies related to the topic were sought and selected. Most articles were electronically found via databases and citations. Manual research of references was also conducted. The research was carried out using Medline, PsychInfo, Cochrane library, and Scopus and focusing on dates from 1954 to 2010. Studies of each database were extracted and examined. Access to electronic databases was conducted by using the following sequence: #1- menstru* OR reproduct* OR amenorrhea OR hyperprolactinaemia OR prolactin OR endocrin* OR fertility, #2- disorder* OR abnormalit*, #3- #1 AND #2, #4- antipsychotic* OR neuroleptic*, #5- psychot* OR psychos* OR schizophren*, #6- #4 AND #5, #7- #3 AND #6. Words with * are root terms (we use the beginning of the word so as more related words can be identified). Selection and examination of the studies were performed and 78 of them were reviewed for the needs of this paper.

3.2. Definitions

Prolactin—PRL is a single chain peptide hormone, structurally and evolutionarily homologe to growth hormone GH, as PRL gene on chromosome 6 has 40% similarity to the pituitary GH gene located on chromosome 17 [21]. It was identified as a separate hormone in the early 1970’s [2]. PRL receptor (PRL-R), is a transmembrane protein, that is not only located in the breast tissue and in the ovaries but also in peripheral tissues [22]. Pituitary prolactin release is pulsatory and follows a diurnal rhythm. Highest plasma concentration occurs during night sleep and declines during waking periods, reaching a nadir around noon. This circadian rhythm does not depend on sleep but on the circadian pacemaker in the suprachiasmatic nucleus of hypothalamus where prolactin secretion is regulated [9, 10, 14].

The normal levels of prolactin in serum are below 25 μg/L in women and below 20 μg/L in men. 1 μg/L is equivalent to 21,2 mU/L (WHO Standard 84/50).

Hyperprolactinaemia can be defined as an increase in circulating prolactin levels and represents the most common abnormality of pituitary hormones met in clinical practice. There are several reasons responsible for hyperprolactinaemia [10, 11] (Figure 1). Guidelines of Pituitary Society support that PRL values up to 100 μg/L (

2000 mU/L) may be due to psychotropic medications, estrogens, functional causes, or microprolactinomas, while macroadenomas are associated with levels over 250 μg/L (

Menstrual dysfunction was historically defined in association with bleeding patterns (menorrhagia, amenorrhea, oligomenorrhea, polymenorrhea), but now definitions based on ovarian function (anovulation, luteal deficiency) are also used. Another group of menstrual disorders is defined in terms of pain (dysmenorrhea) and onset of bleeding (premenstrual syndrome) [24]. Amenorrhea describes the complete absence of menses for six months. It may be physiological (prepubertal, pregnancy, or postmenopausal) or pathological (disorder at hypothalamic-pituitary-ovarian axis, at uterus or outflow tract) [25]. Oligomenorrhea refers to infrequent periods (cycle length > 35 days) opposite to very frequent periods of polymenorrhea (cycle length > 21 days) [26].

3.3. Antipsychotics That Will Be Used in This Review

The term neuroleptics, introduced by Delay in 1955, is not widely accepted. In this paper, we are going to focus on the traditional antipsychotic drugs haloperidol, chlorpromazine, and flupenthixol that along with some of the atypical antipsychotics like risperidone and amisulpride cause an elevation of prolactin levels and menstrual irregularities. Novel antipsychotic agents like clozapine, paliperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, and zotepine, which do not result in hyperprolactinaemia, are also under the scope of this review. However, the terms “prolactin-sparing” and “prolactin-elevating” that will be used in this review and also describe these drugs are believed to be incomplete, because they may lead clinicians to believe that agents like olanzapine and quetiapine can never induce significant hyperprolactinaemia [27, 28].

4. Results

A number of 78 articles were examined and included in our study. Endocrine disorders in women provoke several problems like galactorrhea and menstrual disturbances which are responsible for fertility problems [1, 4].

First, Polishuk and Kulcsar in 1956 [29] reported amenorrhea associated with the use of antipsychotic drugs and then several studies followed to support this belief [30, 31]. Although the exact mechanism still remained unknown, they related it with hyperprolactinaemia attributed to conventional antipsychotics. Ghadirian et al. supported the fact that classical antipsychotics frequently show higher incidence of amenorrhea when compared with placebo. Some researchers estimated the prevalence of menstrual disorders in psychotic females on prolactin raising antipsychotic therapy, around 15–50% [32]. Later, Peuskens et al. (1998) [2] reported that amenorrhea occurred in 22–50% of women treated with antipsychotics. In general, the prevalence of menstrual irregularities and amenorrhea is considered to be between 15% and 97% in women receiving therapy for a psychotic disorder [32, 33]. Scientists reported that amenorrhea develops at serum PRL levels above 60–100 ng/mL [34].

4.1. Typical Antipsychotics

Typical antipsychotics, acting as nonselective antagonists of prolactin receptors, are regarded as the most common medications related to hyperprolactinaemia. They lead to acute and persistent increase of prolactin levels [35]. According to multiple studies, the lowest rate of prevalence for typical agents was 33%–35% and the patients received mainly depot drugs. Intramuscular depot administration keeps prolactin levels high for six months after withdrawal of therapy [27, 36]. Hyperprolactinaemia was noticed in 57% of patients receiving typical antipsychotics, in the study by Wong and Seeman (2007) [37]. Montgomery et al. (2004) found prevalence rates for patients in treatment with traditional antipsychotics to be at 68% [28]. A treatment lasting 3–9 weeks, with mostly traditional antipsychotics, can elevate prolactin levels 10-fold above the baseline, and although chronic continuation of the therapy tends to normalize prolactin due to tolerance, it still remains at high levels [38].

The classical antipsychotic drug haloperidol has a high binding affinity for dopamine and sigma1 receptors but a reduced one for

receptors. In studies where rates of prevalence were higher, the dose of haloperidol was also higher [39]. The increase in prolactin levels occurs in a dose dependent manner [6, 28, 40]. Spitzer et al. (1998), using fifteen patients and their response of prolactin to haloperidol, showed a rapid increase during the first six to nine days between the levels of 30 mg and 50 mg [41]. This elevation was not influenced by dose and remained below 77 ng/mL during the study. Even low dosage of this agent can cause sustained prolactin elevation. Crawford et al. found hyperprolactinaemia at around 72% of the cases at two weeks and around 60% at six weeks of taking haloperidol [42].

Chlorpromazine leads to hyperprolactinaemia in the beginning of treatment, a few hours after the first intramuscular or oral intake and persists throughout the whole therapy project [43]. Flupenthixol has been reported as a half-atypical antipsychotic and elevates serum prolactin levels 2-3 fold in the first month, but these levels normalize in a few months’ period.

According to Ghadirian et al. (1982) [31], 91% of female patients treated with traditional agents reported a change in their menstruation. Another study conducted by Nonacs (2000) reported that 17% of women treated with conventional antipsychotics developed menstrual abnormalities [44]. Frequency of menstrual dysfunction was decreased after the introduction of prolactin sparing drugs, in women receiving antipsychotics.

4.2. Atypical Antipsychotics

Most atypical antipsychotic medications do not elevate serum prolactin levels, in contrast to risperidone which is the exception and leads to a significant increase of prolactin, to a level similar to older antipsychotics [3, 9].

Risperidone is a novel antipsychotic that shows a high affinity with ,

, , , , and receptors, and although it belongs to atypical agents, it has been found to exceed in hyperprolactinaemia compared to conventional antipsychotic drugs [45]. Risperidone has been found in a number of different datasets to raise prolactin in a more substantial and prolonged way than haloperidol does. A percentage of 72%–100% of the females treated with oral risperidone and 53%–67% treated with long-acting intramuscular injection developed hyperprolactinaemia [1, 14, 45]. Kinon et al. (2003) proved that the prevalence rate among women taking risperidone was 88% in contrast to 47% of those taking conventional drugs [6]. A study by Kleinberg et al. (1999) [45] revealed that risperidone was associated with higher mean values of prolactin than haloperidol. However, others found greater elevation in prolactin levels with typical antipsychotics [46].

Risperidone does not completely cross the blood-brain barrier and as a result, tights longer and heavier with receptors in the pituitary rather than the striatum. Prolactin levels rise directly some hours after receiving risperidone, reaching maximum levels after eight weeks and maintaining these high levels for a long period of time. A lot of studies demonstrated a correlation between dose of risperidone and prolactin levels, while others did not [47].

The prevalence of menstrual side effects such as amenorrhea in patients on risperidone is reported to be 1%–10% [48], while others support the incidence of abnormal menstrual manifestations to be about 8%–48% of women on risperidone [6]. Another study suggested that there is no significant correlation between plasma prolactin levels and clinical effects of risperidone. Specifically, they found menstrual disorders in only seven out of twenty-seven females under treatment with risperidone for six weeks which is not a high frequency of menstrual dysfunction, but only a tendency to menstrual irregularity symptoms. Women have been found to have greater elevation in plasma prolactin than men when treated with risperidone [7].

Clozapine was the first introduced atypical antipsychotic agent and it leads to a short-lived and slight increase of plasma prolactin which may remain undetected in routine laboratory controls [1, 3, 14]. Clozapine binds weakly to dopamine receptor and results in transient and low hyperprolactinaemia. This comes in accordance with researches that reported prevalence of hyperprolactinaemia with clozapine treatment from 0% to 5% [37, 49]. Clozapine can sometimes result in a great elevation of prolactin but this is transient and develops in the first few hours. This drug is supposed to reduce hyperprolactinaemia.

Feldman and Goldberg (2002) reported that there is no association between clozapine induced menstrual irregularities and weight gain [50]. Normal menses have returned to women that switched from typical antipsychotics to clozapine [51]. Further studies need to be conducted, related to clozapine and its effects on menstruation.

Paliperidone was introduced to Europe in 2007 and it is the active metabolite of risperidone. This 9-hydroxy-risperidone contributes predominantly to hyperprolactinaemia. There are only a few studies about paliperidone induced hyperprolactinaemia and its clinical relevance [52]. Skopek and Manoj (2010) found the elevation of prolactin to be above the normal limit, which resulted after the discontinuation of medication, in four female patients. Values of paliperidone were almost double of those reported for risperidone [53].

Olanzapine is an atypical medication that binds intermediately with receptor and more tightly with , at all doses. Olanzapine, which is widely used in Europe, America and Japan, produced transient and mild prolactin elevation compared to that caused by risperidone and haloperidol. In one study with olanzapine and placebo groups there were differences at 2 weeks of therapy but no significant difference was found with regard to the prevalence of hyperprolactinaemia at 6 weeks [42]. According to Kapur et al. (1998) [54], a dose of olanzapine above 30 mg/day induced hyperprolactinaemia equivalent to the one induced by risperidone due to binding with receptor occupancy, while other reports suggest that dopamine receptor occupancy of risperidone is lower than olanzapine.

The prevalence rate of hyperprolactinaemia in patients on olanzapine has been found to be 68% [49], 28% [37], 40% [29], and 24% [55]. Levels of prolactin have been found to be higher in patients treated with olanzapine and risperidone in comparison to clozapine. Kinon et al. (2006) proved that 90% of patients that were switched to olanzapine were found to have a 50% reduction in prolactin levels, while none of the patients that stayed on prestudy treatment experienced the same decrease [56].

Furthermore, olanzapine treatment improved reproductive comorbid symptoms. Specifically, two out of three women that switched to olanzapine therapy developed a resolution of menstrual disorders opposite to women with menstrual irregularities and prestudy therapy, who continued to have the problem. Additionally, Sawamura et al. conducted a study among Japanese psychotic patients and confirmed gender differences in olanzapine induced prolactin elevation [35]. Nonacs found that no woman on olanzapine experienced endocrine symptoms [44].

Quetiapine binds tightly with and has a lower binding affinity for receptors in anterior pituitary than most typical antipsychotics and risperidone, and elevates prolactin levels only occasionally. occupancy moves from 64%—two hours after dose—to 0%–27%, when twelve hours have passed. Prevalence rates associated with hyperprolactinaemia have been estimated in different studies. Bushe and Shaw report a rate of 0% [49], Wong and Seeman 14% [37], and Polishuk and Kulcsar 22% [29]. Concerning menstrual irregularities, many studies suggest that altering patients’ treatment from risperidone to quetiapine could help resume menstruation [57].

Aripiprazole is an atypical antipsychotic that is known to act pharmacologically as a partial agonist of and and a full antagonist of . This leads to low prolactin elevation compared to traditional drugs. Aripiprazole is associated with <5% rate of hyperprolactinaemia [58]. Aripiprazole has been found to provoke a normalization of prolactin levels and menstrual cycles in a woman previously treated with amisulpride and ziprasidone [59].

Benzamides are considered to belong to atypical agents but they were introduced during the 1960’s. Amisulpride is a substituted benzamide derivative that is not commercially approved in the USA. Although it causes few extrapyramidal symptoms, it provokes a potent prolactin elevating effect, similar to conventional antipsychotics and risperidone [3]. Hyperprolactinaemia occurs after acute and chronic treatment and even in low doses [60], as amisulpride seems to have higher occupancy in the pituitary than in the striatum, because it crosses hard the brain-barrier [61].

Amisulpride is regarded to be the antipsychotic with the maximal tendency to cause hyperprolactinaemia. Paparrigopoulos et al. (2007) found that the prevalence rate of hyperprolactinaemia was 100% and this was observed more in women than in men [62]. Amisulpride increases prolactin levels even in low doses, which means that decreased dose of amisulpride has little result on enhancing hyperprolactinaemia [63].

Amenorrhea develops in about 4% of women treated with amisulpride. Menstrual irregularities after usage of amisulpride were also reported in another study [64], but no frequency rate was estimated. Rajnish and Singh (2008) reported that symptoms ameliorate when switching to a prolactin-sparing drug, while there are still no adequately researched studies investigating the prevalence of menstrual abnormalities related to amisulpride [65].

Ziprasidone acts as an agonist of serotonin receptors, resulting in a transient and no-sustained elevation of prolactin. Goff et al. compared ziprasidone with haloperidol and found that ziprasidone was associated only with a transient increase in prolactin levels that returned to normal within the dosing interval [66]. One study tried to value ziprasidone adverse reactions and did not find menstrual abnormalities in contrast with risperidone side effects [67].

Zotepine is an atypical agent, considered to cause prolactin elevation in humans after acute or long-term therapy [68, 69]. It is uncertain whether there are any published studies that systematically investigate the prevalence of menstrual disorders (Table 1).

5. Discussion

Regular, periodical menstruation represents for women an aspect of normality, an indicator of female fertility, and a way to “clean” their bodies [70–72]. It also marks their femininity and health [25]. According to a research conducted in Brazil [70], menstruation was considered by many women to be a “necessary nuisance” determined by nature as an essential part of their reproductive life. Over the last decade, even more contemporary women from diverse cultural backgrounds use methods like contraceptives to suppress menstruation [26, 73, 74].

Nevertheless, menstruation plays an important role in women’s lives and any abnormalities interfere with their fertility and quality of life. Especially concerning psychotic women, menstrual disturbances can also influence their compliance to therapy. Therefore, clinicians should examine all aspects before prescribing any medication.

5.1. Assessment of a Patient with Hyperprolactinaemia and Menstrual Disorders

In order to asses a woman with hyperprolactinaemia, the clinician should first discover which treatment with antipsychotics resulted in it. Magnetic Resonance Imaging—MRI is the examination of choice so as to investigate the pathological structure in the hypothalamo-pituitary region. If there is any contraindication for MR imaging, then computed tomography scan with contrast, administered intravenously, is the best option [48]. Clinical screening for hyperprolactinaemia should include a carefully taken medical—drug and clinical—history, a physical examination, blood tests, renal, hepatic, and thyroid function tests, as well as testing of visual fields [10].

However, it is worth mentioning that this assessment is often limited to a few questions about clinical manifestations of hyperprolactinaemia and clinicians underestimate hyperprolactinaemia and its side reactions. Another complicating factor is macroprolactinaemia, where a molecular complex of an immunoglobulin G and prolactin is formed. Macroprolactin is biologically inactive as it is restricted to the vascular system but may lead to asymptomatic, falsely elevated prolactin levels [75].

In order to evaluate amenorrhea, a medical history should be carefully taken so as to know if any genital anomalies, thyroid disorders, weight gain, or loss have been observed. Physical examination should be conducted to check for anatomical causes, as well as urine tests to exclude pregnancy. Menstrual status and history is not always adequately documented. Sometimes, the disturbances in menstruation cannot be apparent in short studies. Women might feel stressed and not comfortable to reveal information about reproductive side effects and clinicians might not have the appropriate scales to find out more information [1]. However, they have to monitor for menstrual disturbances during medication therapy. Furthermore, it should be noted that the validity of self-report assessments of menstrual status in psychotic women is uncertain [17].

5.2. Management of Hyperprolactinaemia and Menstrual Disorders

Clinicians should be certain about the severity of symptoms and whether they contributed to hyperprolactinaemia or not. Current antipsychotic therapy can be switched to prolactin sparing agents like olanzapine [76], quetiapine, aripiprazole, or clozapine. If this is not feasible, then other treatments, such as estrogen substitution or dopamine agonists, can be used. With regard to dopamine agonists, attention needs to be paid. Although they reduce hyperprolactinaemia, they also cause aggravated acute psychotic episodes in women. Bromocriptine, cabergoline, quinagolide, and amantadine are some common dopamine agonists. Correcting prolactin levels improves symptoms like amenorrhea and other menstrual abnormalities.

Bromocriptine should be prescribed with attention as it resolves amenorrhea but has been found to cause gastrointestinal implications and hypotension [36]. Cabergoline has been found to reduce and normalize prolactin, improving menstrual side effects without deteriorating psychotic symptoms [48]. Some studies support the introduction of aripiprazole in a combination therapy with other antipsychotics for correction of hyperprolactinaemia, but further research is required [77].

5.3. Conclusion

Prevalence of hyperprolactinaemia and menstrual disturbances varies not only among antipsychotic agents but also among different researchers (Table 1). Major deviations are observed in prevalence rates of hyperprolactinaemia that occurs during treatment with olanzapine and quetiapine. Most novel antipsychotic agents cause minimal hyperprolactinaemic action or no hyperprolactinaemia at all, compared with classical neuroleptics and risperidone. The study of medication characteristics and interplays contributes to the understanding, assessment, and management of these situations.

Menstrual disturbances like amenorrhea usually recover after prolactin levels have been normalized. However, they can no longer be regarded as a necessary but rather a troublesome consequence of an effective antipsychotic remedy. More studies need to be conducted related to the usage of dopamine agonists and combination therapies for the treatment of prolactin elevation. Clinicians should take into account menstrual abnormalities when they cure women of reproductive age. New antipsychotic agents should be designed to lead to fewer side reactions and improve the lives of psychiatric patients.

6. Limitations of the Study

Antipsychotic induced hyperprolactinaemia is an interesting and important topic and many authors have worked on this. Thus, our review tried to summarize most of the data related to this topic, but may have failed to include all the sources available in the literature.

Conflict of Interests

The authors declare that there is no conflict of interests in connection with the preparation of this paper.

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Copyright

Copyright © 2013 S. I. Bargiota et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Risperidone 1 mg Tablets

Each film-coated tablet contains 49.88 mg lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1

White, oval film-coated tablets with breaking notch and debossed with 𔄙” on one side.

The tablet can be divided into equal doses.

Risperidone is indicated for the treatment of schizophrenia.

Risperidone is indicated for the treatment of moderate to severe manic episodes associated with bipolar disorders.

Risperidone is indicated for the short-term treatment (up to 6 weeks) of persistent aggression in patients with moderate to severe Alzheimer's dementia unresponsive to non-pharmacological approaches and when there is a risk of harm to self or others.

Risperidone is indicated for the short-term symptomatic treatment (up to 6 weeks) of persistent aggression in conduct disorder in children from the age of 5 years and adolescents with sub-average intellectual functioning or mental retardation diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other disruptive behaviours require pharmacologic treatment. Pharmacological treatment should be an integral part of a more comprehensive treatment programme, including psychosocial and educational intervention. It is recommended that risperidone be prescribed by a specialist in child neurology and child and adolescent psychiatry or physicians well familiar with the treatment of conduct disorder of children and adolescents.

Risperidone may be given once daily or twice daily. Patients should start with 2 mg/day risperidone. The dosage may be increased on the second day to 4 mg.

Subsequently, the dosage can be maintained unchanged, or further individualised, if needed. Most patients will benefit from daily doses between 4 and 6 mg. In some patients, a slower titration phase and a lower starting and maintenance dose may be appropriate.

Doses above 10 mg/day have not demonstrated superior efficacy to lower doses and may cause increased incidence of extrapyramidal symptoms. Safety of doses above 16 mg/day has not been evaluated and are therefore not recommended.

A starting dose of 0.5 mg* twice daily is recommended. This dosage can be individually adjusted with 0.5 mg* twice daily increments to 1 to 2 mg twice daily.

* for doses not achievable with Risperidone other risperidone presentations are available

Paediatric population

Risperidone is not recommended for use in children and adolescents below age 18 with schizophrenia due to a lack of data on efficacy.

Manic episodes in bipolar disorder

Risperidone should be administered on a once daily schedule, starting with 2 mg risperidone. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments of 1 mg per day. Risperidone can be administered in flexible doses over a range of 1 to 6 mg per day to optimize each patient's level of efficacy and tolerability. Daily doses over 6 mg risperidone have not been investigated in patients with manic episodes.

As with all symptomatic treatments, the continued use of Risperidone must be evaluated and justified on an ongoing basis.

A starting dose of 0.5 mg* twice daily is recommended. This dosage can be individually adjusted with 0.5 mg* twice daily increments to 1 to 2 mg twice daily. Since clinical experience in elderly is limited, caution should be exercised.

* for doses not achievable with Risperidone other risperidone presentations are available

Paediatric population

Risperidone is not recommended for use in children and adolescents below age 18 with bipolar mania due to a lack of data on efficacy.

Persistent aggression in patients with moderate to severe Alzheimer's dementia

A starting dose of 0.25 mg* twice daily is recommended. This dosage can be individually adjusted by increments of 0.25 mg* twice daily, not more frequently than every other day, if needed. The optimum dose is 0.5 mg* twice daily for most patients. Some patients, however, may benefit from doses up to 1 mg twice daily.

Risperidone should not be used more than 6 weeks in patients with persistent aggression in Alzheimer's dementia. During treatment, patients must be evaluated frequently and regularly, and the need for continuing treatment reassessed.

* for doses not achievable with Risperidone other risperidone presentations are available

Paediatric population: Children and adolescents from 5 to 18 years of age

For subjects 󖾦 kg, a starting dose of 0.5 mg* once daily is recommended. This dosage can be individually adjusted by increments of 0.5 mg* once daily not more frequently than every other day, if needed. The optimum dose is 1 mg once daily for most patients. Some patients, however, may benefit from 0.5 mg* once daily while others may require 1.5 mg* once daily. For subjects <50 kg, a starting dose of 0.25 mg* once daily is recommended. This dosage can be individually adjusted by increments of 0.25 mg* once daily not more frequently than every other day, if needed. The optimum dose is 0.5 mg* once daily for most patients. Some patients, however, may benefit from 0.25 mg* once daily while others may require 0.75 mg* once daily.

* for doses not achievable with Risperidone other risperidone presentations are available

As with all symptomatic treatments, the continued use of Risperidone must be evaluated and justified on an ongoing basis.

Risperidone is not recommended in children less than 5 years of age, as there is no experience in children less than 5 years of age with this disorder.

Renal and hepatic impairment

Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than in adults with normal renal function. Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone.

Irrespective of the indication, starting and consecutive dosing should be halved, and dose titration should be slower for patients with renal or hepatic impairment.

Risperidone should be used with caution in these groups of patients.

Risperidone is for oral use. Food does not affect the absorption of Risperidone.

Upon discontinuation, gradual withdrawal is advised. Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic medicines (see section 4.8). Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported.

Switching from other antipsychotics.

When medically appropriate, gradual discontinuation of the previous treatment while Risperidone therapy is initiated is recommended. Also, if medically appropriate, when switching patients from depot antipsychotics, initiate Risperidone therapy in place of the next scheduled injection. The need for continuing existing anti-Parkinson medicines should be re-evaluated periodically.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Elderly patients with dementia

Increased mortality in elderly people with dementia

In a meta-analysis of 17 controlled trials of atypical antipsychotics, including risperidone, elderly patients with dementia treated with atypical antipsychotics have an increased mortality compared to placebo. In placebo-controlled trials with oral risperidone in this population, the incidence of mortality was 4.0% for risperidone-treated patients compared to 3.1% for placebo-treated patients. The odds ratio (95% exact confidence interval) was 1.21 (0.7, 2.1). The mean age (range) of patients who died was 86 years (range 67-100).

Data from two large observational studies showed that elderly people with dementia who are treated with conventional antipsychotics are also at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Concomitant use with furosemide

In the risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3% mean age 89 years, range 75-97) when compared to patients treated with risperidone alone (3.1% mean age 84 years, range 70-96) or furosemide alone (4.1% mean age 80 years, range 67-90). The increase in mortality in patients treated with furosemide plus risperidone was observed in two of the four clinical trials. Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.

No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this combination or co-treatment with other potent diuretics should be considered prior to the decision to use.

There was no increased incidence of mortality among patients taking other diuretics as concomitant treatment with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.

Cerebrovascular Adverse Events (CVAE)

An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The pooled data from six placebo-controlled studies with risperidone in mainly elderly patients (>65 years of age) with dementia showed that CVAEs (serious and non-serious, combined) occurred in 3.3% (33/1009) of patients treated with risperidone and 1.2% (8/712) of patients treated with placebo. The odds ratio (95% exact confidence interval) was 2.96 (1.34, 7.50). The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Risperidone should be used with caution in patients with risk factors for stroke.

The risk of CVAEs was significantly higher in patients with mixed or vascular type of dementia when compared to Alzheimer's dementia. Therefore, patients with other types of dementias than Alzheimer's should not be treated with risperidone.

Physicians are advised to assess the risks and benefits of the use of risperidone in elderly patients with dementia, taking into account risk predictors for stroke in the individual patient. Patients/caregivers should be cautioned to immediately report signs and symptoms of potential CVAEs such as sudden weakness or numbness in the face, arms or legs, and speech or vision problems. All treatment options should be considered without delay, including discontinuation of risperidone.

Risperidone should only be used short term for persistent aggression in patients with moderate to severe Alzheimer's dementia to supplement non-pharmacological approaches which have had limited or no efficacy and when there is potential risk of harm to self or others.

Patients should be reassessed regularly, and the need for continuing treatment reassessed.

Due to the alpha-blocking activity of risperidone, (orthostatic) hypotension can occur, especially during the initial dose-titration period. Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment. Risperidone should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disease), and the dosage should be gradually titrated as recommended (see section 4.2). A dose reduction should be considered if hypotension occurs.

Leukopenia, neutropenia, and agranulocytosis

Events of leucopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including risperidone. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during post-marketing surveillance.

Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of risperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1 x 10 9 /L) should discontinue risperidone and have their WBC followed until recovery.

Tardive dyskinesia/extrapyramidal symptoms (TD/EPS)

Medicines with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical involuntary movements, predominantly of the tongue and/or face.

The onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics should be considered.

Caution is warranted in patients receiving both, psychostimulants (e.g. methylphenidate) and risperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medications. Gradual withdrawal of stimulant treatment is recommended (see section 4.5).

Neuroleptic malignant syndrome (NMS)

Neuroleptic Malignant Syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels has been reported to occur with antipsychotics. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. In this event, all antipsychotics, including risperidone, should be discontinued.

Parkinson's disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including risperidone, to patients with Parkinson's Disease or Dementia with Lewy Bodies (DLB). Parkinson's Disease may worsen with risperidone. Both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medicinal products these patients were excluded from clinical trials. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, diabetes mellitus and exacerbation of pre-existing diabetes have been reported during treatment with risperidone. In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Association with ketoacidosis has been reported very rarely, and rarely with diabetic coma. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any atypical antipsychotic, including risperidone, should be monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus should be monitored regularly for worsening of glucose control.

Significant weight gain has been reported with risperidone use. Weight should be monitored regularly.

Hyperprolactinaemia is a common side-effect of treatment with risperidone. Evaluation of the prolactin plasma level is recommended in patients with evidence of possible prolactin-related side-effects (e.g. gynaecomastia, menstrual disorders, anovulation, fertility disorder, decreased libido, erectile dysfunction, and galactorrhoea).

Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics has so far been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. Risperidone should be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible prolactin-dependent tumours.

QT prolongation has very rarely been reported postmarketing. As with other antipsychotics, caution should be exercised when risperidone is prescribed in patients with known cardiovascular disease, family history of QT prolongation, bradycardia, or electrolyte disturbances (hypokalaemia, hypomagnesaemia), as it may increase the risk of arrhythmogenic effects, and in concomitant use with medicines known to prolong the QT interval.

Risperidone should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Priapism may occur with risperidone treatment due to its alpha-adrenergic blocking effects.

Body temperature regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicines. Appropriate care is advised when prescribing Risperidone to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant treatment with anticholinergic activity, or being subject to dehydration.

An antiemetic effect was observed in preclinical studies with risperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain medicines or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumour.

Renal and hepatic impairment

Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than adults with normal renal function. Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone (see section 4.2).

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with risperidone and preventative measures undertaken.

Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, including risperidone (see section 4.8).

IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicines with alpha1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.

Before risperidone is prescribed to a child or adolescent with conduct disorder they should be fully assessed for physical and social causes of the aggressive behaviour such as pain or inappropriate environmental demands.

The sedative effect of risperidone should be closely monitored in this population because of possible consequences on learning ability. A change in the time of administration of risperidone could improve the impact of the sedation on attention faculties of children and adolescents.

Risperidone was associated with mean increases in body weight and body mass index (BMI). Baseline weight measurement prior to treatment and regular weight monitoring are recommended. Changes in height in the long-term open-label extension studies were within expected age-appropriate norms. The effect of long-term risperidone treatment on sexual maturation and height has not been adequately studied. Because of the potential effects of prolonged hyperprolactinaemia on growth and sexual maturation in children and adolescents, regular clinical evaluation of endocrinological status should be considered, including measurements of height, weight, sexual maturation, monitoring of menstrual functioning, and other potential prolactin-related effects.

Results from a small post-marketing observational study showed that risperidone-exposed subjects between the ages of 8-16 years were on average approximately 3.0 to 4.8 cm taller than those who received other atypical anti-psychotic medications. This study was not adequate to determine whether exposure to risperidone had any impact on final adult height, or whether the result was due to a direct effect of risperidone on bone growth, or the effect of the underlying disease itself on bone growth, or the result of better control of the underlying disease with resulting increase in linear growth.

During treatment with risperidone regular examination for extrapyramidal symptoms and other movement disorders should also be conducted.

For specific posology recommendations in children and adolescents see Section 4.2.

Lactose: The film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Medicinal products known to prolong the QT interval

As with other antipsychotics, caution is advised when prescribing risperidone with medicinal products known to prolong the QT interval such as antiarrhythmics (e.g., quinidine, dysopiramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (i.e., amitriptyline), tetracyclic antidepressants (i.e., maprotiline), some antihistamines, other antipsychotics, some antimalarials (i.e., quinine and mefloquine), and with medicines causing electrolyte imbalance (hypokalaemia, hypomagnesiaemia), bradycardia, or those which inhibit the hepatic metabolism of risperidone. This list is indicative and not exhaustive.

Centrally-acting medicinal products and alcohol

Risperidone should be used with caution in combination with other centrally-acting substances notably including alcohol, opiates, antihistamines and benzodiazepines due to the increased risk of sedation.

Levodopa and dopamine agonists

Risperidone may antagonise the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, particularly in end-stage Parkinson's disease, the lowest effective dose of each treatment should be prescribed.

Medicinal products with hypotensive effect

Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment.

Concomitant use of oral risperidone with paliperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive active antipsychotic fraction exposure.

The combined use of psychostimulants (e.g. methylphenidate) with risperidone can lead to extrapyramidal symptoms upon change of either or both treatments (see section 4.4).

Food does not affect the absorption of risperidone.

Risperidone is mainly metabolised through CYP2D6, and to a lesser extent through CYP3A4. Both risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that modify CYP2D6 activity, or substances strongly inhibiting or inducing CYP3A4 and/or P-gp activity, may influence the pharmacokinetics of the risperidone active antipsychotic fraction.

Strong CYP2D6 inhibitors

Co-administration of risperidone with a strong CYP2D6 inhibitor may increase the plasma concentrations of risperidone, but less so of the active antipsychotic fraction. Higher doses of a strong CYP2D6 inhibitor may elevate concentrations of the risperidone active antipsychotic fraction (e.g., paroxetine, see below). It is expected that other CYP 2D6 inhibitors, such as quinidine, may affect the plasma concentrations of risperidone in a similar way. When concomitant paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at higher doses, is initiated or discontinued, the physician should re-evaluate the dosing of risperidone.

CYP3A4 and/or P-gp inhibitors

Co-administration of risperidone with a strong CYP3A4 and/or P-gp inhibitor may substantially elevate plasma concentrations of the risperidone active antipsychotic fraction. When concomitant itraconazole or another strong CYP3A4 and/or P-gp inhibitor is initiated or discontinued, the physician should re-evaluate the dosing of risperidone.

CYP3A4 and/or P-gp inducers

Co-administration of risperidone with a strong CYP3A4 and/or P-gp inducer may decrease the plasma concentrations of the risperidone active antipsychotic fraction. When concomitant carbamazepine or another strong CYP3A4 and/or P-gp inducer is initiated or discontinued, the physician should re-evaluate the dosing of risperidone. CYP3A4 inducers exert their effect in a time-dependent manner, and may take at least 2 weeks to reach maximal effect after introduction. Conversely, on discontinuation, CYP3A4 induction may take at least 2 weeks to decline.

Highly protein-bound medicinal products

When risperidone is taken together with highly protein-bound medicinal products, there is no clinically relevant displacement of either medicinal product from the plasma proteins. When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism and the possible need to adjust dose.

Interaction studies have only been performed in adults. The relevance of the results from these studies in paediatric patients is unknown.

The combined use of psychostimulants (e.g., methylphenidate) with risperidone in children and adolescents did not alter the pharmacokinetics and efficacy of risperidone.

Examples of drugs that may potentially interact or that were shown not to interact with risperidone are listed below:

Effect of other medicinal products on the pharmacokinetics of risperidone

• Erythromycin, a moderate CYP3A4 inhibitor and P-gp inhibitor, does not change the pharmacokinetics of risperidone and the active antipsychotic fraction.

• Rifampicin, a strong CYP3A4 inducer and a P-gp inducer, decreased the plasma concentrations of the active antipsychotic fraction.

• Donepezil and galantamine, both CYP2D6 and CYP3A4 substrates, do not show a clinically relevant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction.

• Carbamazepine, a strong CYP3A4 inducer and a P-gp inducer, has been shown to decrease the plasma concentrations of the active antipsychotic fraction of risperidone. Similar effects may be observed with e.g. phenytoin and phenobarbital which also induce CYP 3A4 hepatic enzyme, as well as P-glycoprotein.

• Topiramate modestly reduced the bioavailability of risperidone, but not that of the active antipsychotic fraction. Therefore, this interaction is unlikely to be of clinical significance.

• Itraconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200 mg/day increased the plasma concentrations of the active antipsychotic fraction by about 70%, at risperidone doses of 2 to 8 mg/day.

• Ketoconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200 mg/day increased the plasma concentrations of risperidone and decreased the plasma concentrations of 9-hydroxyrisperidone.

• Phenothiazines may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.

• Protease inhibitors: No formal study data are available however, since ritonavir is a strong CYP3A4 inhibitor and a weak CYP2D6 inhibitor, ritonavir and ritonavir-boosted protease inhibitors potentially raise concentrations of the risperidone active antipsychotic fraction.

• Some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.

• Verapamil, a moderate inhibitor of CYP3A4 and an inhibitor of P-gp, increases the plasma concentration of risperidone and the active antipsychotic fraction.

Gastrointestinal medicinal products:

• H2-receptor antagonists: Cimetidine and ranitidine, both weak inhibitors of CYP2D6 and CYP3A4, increased the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction.

SSRIs and tricyclic antidepressants:

• Fluoxetine, a strong CYP2D6 inhibitor, increases the plasma concentration of risperidone, but less so of the active antipsychotic fraction.

• Paroxetine, a strong CYP2D6 inhibitor, increases the plasma concentrations of risperidone, but, at dosages up to 20 mg/day, less so of the active antipsychotic fraction. However, higher doses of paroxetine may elevate concentrations of the risperidone active antipsychotic fraction.

• Tricyclic antidepressants may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.

• Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at dosages up to 100 mg/day are not associated with clinically significant changes in concentrations of the risperidone active antipsychotic fraction. However, doses higher than 100 mg/day of sertraline or fluvoxamine may elevate concentrations of the risperidone active antipsychotic fraction.

Effect of risperidone on the pharmacokinetics of other medicinal products

• Risperidone does not show a clinically relevant effect on the pharmacokinetics of valproate or topiramate.

• Aripiprazole, a CYP2D6 and CYP3A4 substrate: Risperidone tablets or injections did not affect the pharmacokinetics of the sum of aripiprazole and its active metabolite, dehydroaripiprazole.

• Risperidone does not show a clinically relevant effect on the pharmacokinetics of digoxin.

• Risperidone does not show a clinically relevant effect on the pharmacokinetics of lithium.

Concomitant use of risperidone with furosemide

• See section 4.4 regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.

There are no adequate data from the use of risperidone in pregnant women. Risperidone was not teratogenic in animal studies but other types of reproductive toxicity were seen (see section 5.3). The potential risk for humans is unknown.

Neonates exposed to antipsychotics (including risperidone) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently newborns should be monitored carefully.

Risperidone should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.

In animal studies, risperidone and 9-hydroxy-risperidone are excreted in the milk. It has been demonstrated that risperidone and 9-hydroxy-risperidone are also excreted in human breast milk in small quantities. There are no data available on adverse reactions in breast-fed infants. Therefore, the advantage of breastfeeding should be weighed against the potential risks for the child.

As with other medicinal products that antagonize dopamine D2 receptors, risperidone elevates prolactin level. Hyperprolactinaemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.

There were no relevant effects observed in the non-clinical studies.

Risperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects (see section 4.8). Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.

The most frequently reported adverse drug reactions (ADRs) (incidence 󖽾%) are:

Parkinsonism, sedation/somnolence, headache, and insomnia.

The ADRs that appeared to be dose-related included parkinsonism and akathisia.

The following are all the ADRs that were reported in clinical trials and post-marketing experience with risperidone by frequency category estimated from clinical trials. The following terms and frequencies are applied: very common (𕟳/10), common (𕟳/100 to <1/10), uncommon (𕟳/1000 to <1/100), rare (𕟳/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse Drug Reactions (ADRs) by System Organ Class and Frequency

Infections and infestations

Pneumonia, Bronchitis, Upper respiratory tract infection, Sinusitis, Urinary tract infection, Ear infection, Influenza

Respiratory tract infection, Cystitis, Eye infection, Tonsillitis, Onychomycosis, Cellulitis, Localised infection, Viral infection, Acarodermatitis

Blood and lymphatic system disorders

Neutropenia, White blood cell count decreased, Thrombocytopenia, Anaemia, Haematocrit decreased, Eosinophil count increased

Immune system disorders

Inappropriate antidiuretic hormone secretion, Glucose urine present

Metabolism and nutrition disorders

Weight increased, Increased appetite, Decreased appetite

Diabetes mellitus b , Hyperglycaemia, Polydipsia, Weight decreased, Anorexia, Blood cholesterol increased

Water intoxication c ,Hypoglycaemia, Hyperinsulinaemia c, Blood triglycerides increased

Psychiatric disorders

Sleep disorder, Agitation, Depression, Anxiety

Mania, Confusional state, Libido decreased, Nervousness, Nightmare

Catatonia, Somnambulism, Sleep-related eating disorder, Blunted affect, Anorgasmia

Nervous system disorders

Sedation/Somnolence, Parkinsonism d , Headache

Akathisia d , Dystonia d , Dizziness, Dyskinesia d , Tremor,

Tardive dyskinesia, Cerebral ischaemia, Unresponsive to stimuli, Loss of consciousness, Depressed level of consciousness, Convulsion d , Syncope, Psychomotor hyperactivity, Balance disorder, Coordination abnormal, Dizziness postural, Disturbance in attention, Dysarthria, Dysgeusia, Hypoaesthesia, Paraesthesia,

Neuroleptic malignant syndrome, Cerebrovascular disorder, Diabetic coma, Head titubation

Vision blurred, Conjunctivitis

Photophobia, Dry eye, Lacrimation increased, Ocular hyperaemia

Glaucoma, Eye Movement disorder, Eye rolling, Eyelid margin crusting, Floppy iris syndrome (intraoperative) c

Ear and labyrinth disorders

Vertigo, Tinnitus, Ear pain

Atrial fibrillation, Atrioventricular block, Conduction disorder, Electrocardiogram QT prolonged, Bradycardia, Electrocardiogram abnormal, Palpitations

Hypotension, Orthostatic hypotension, Flushing

Pulmonary embolism, Venous thrombosis

Respiratory, thoracic and mediastinal disorders

Dyspnoea, Pharyngolaryngeal pain, Cough, Epistaxis, Nasal congestion

Pneumonia aspiration, Pulmonary congestion, Respiratory tract congestion, Rales, Wheezing, Dysphonia, Respiratory disorder

Sleep apnea syndrome, Hyperventilation

Gastrointestinal disorders

Abdominal pain, Abdominal discomfort, Vomiting, Nausea, Constipation, Diarrhoea, Dyspepsia, Dry mouth, Toothache

Faecal incontinence, Faecaloma, Gastroenteritis, Dysphagia, Flatulence

Pancreatitis, Intestinal obstruction, Swollen tongue, Cheilitis

Hepato-biliary disorders

Transaminases increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased

Skin and subcutaneous tissue disorders

Urticaria, Pruritus, Alopecia, Hyperkeratosis, Eczema, Dry skin, Skin discolouration, Acne, Seborrhoeic dermatitis, Skin disorder, Skin lesion,

Musculoskeletal and connective tissue disorders

Muscle Spasms, Musculoskeletal pain, Back pain, Arthralgia

Blood creatine phosphokinase increased, Posture abnormal, Joint stiffness, Joint swelling, Muscular weakness, Neck pain

Renal and urinary disorders

Pollakiuria, Urinary retention, Dysuria

Pregnancy, puerperium and neonatal conditions

Drug withdrawal syndrome neonatal c

Reproductive system and breast disorders

Erectile dysfunction, Ejaculation disorder, Amenorrhoea, Menstrual disorder d , Gynaecomastia, Galactorrhoea, Sexual dysfunction, Breast pain, Breast discomfort, Vaginal discharge

Priapism c , Menstruation delayed, Breast engorgement, Breast enlargement, Breast discharge

General disorders and administration site conditions

Oedema d , Pyrexia, Chest pain, Asthenia, Fatigue, Pain

Face oedema, Chills, Body temperature increased, Gait abnormal, Thirst, Chest discomfort, Malaise, Feeling abnormal, Discomfort

Hypothermia, Body temperature decreased, Peripheral coldness, Drug withdrawal syndrome, Induration c

Injury, poisoning and procedural complications

a Hyperprolactinaemia can in some cases lead to gynaecomastia, menstrual disturbances, amenorrhoea, anovulation, galactorrhea, fertility disorder, decreased libido, erectile dysfunction.

b In placebo-controlled trials diabetes mellitus was reported in 0.18% in risperidone-treated subjects compared to a rate of 0.11% in placebo group. Overall incidence from all clinical trials was 0.43% in all risperidone-treated subjects.

c Not observed in risperidone clinical studies but observed in post-marketing environment with risperidone.

d Extrapyramidal disorder may occur: Parkinsonism (salivary hypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, and glabellar reflex abnormal, parkinsonian rest tremor), akathisia ( akathisia, restlessness, hyperkinesia, and restless leg syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia. Dystonia includes dystonia, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus.. It should be noted that a broader spectrum of symptoms are included, that do not necessarily have an extrapyramidal origin. Insomnia includes: initial insomnia, middle insomnia Convulsion includes: Grand mal convulsion Menstrual disorder includes: Menstruation irregular, oligomenorrhoea Oedema includes: generalised oedema, oedema peripheral, pitting oedema.

Undesirable effects noted with paliperidone formulations

Paliperidone is the active metabolite of risperidone, therefore, the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another. In addition to the above adverse reactions, the following adverse reaction has been noted with the use of paliperidone products and can be expected to occur with risperidone.

Cardiac disorders: Postural orthostatic tachycardia syndrome

As with other antipsychotics, very rare cases of QT prolongation have been reported postmarketing with risperidone. Other class-related cardiac effects reported with antipsychotics which prolong QT interval include ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest and Torsades de Pointes.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic drugs (frequency unknown). ´

The proportions of risperidone and placebo-treated adult patients with schizophrenia meeting a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain for risperidone (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint was comparable in the risperidone (2.5%) and placebo (2.4%) groups, and was slightly higher in the active-control group (3.5%).

In a population of children and adolescents with conduct and other disruptive behaviour disorders, in long-term studies, weight increased by a mean of 7.3 kg after 12 months of treatment. The expected weight gain for normal children between 5-12 years of age is 3 to 5 kg per year. From 12-16 years of age, this magnitude of gaining 3 to 5 kg per year is maintained for girls, while boys gain approximately 5 kg per year.

Additional information on special populations

Adverse drug reactions that were reported with higher incidence in elderly patients with dementia or paediatric patients than in adult populations are described below:

Elderly patients with dementia

Transient ischaemic attack and cerebrovascular accident were ADRs reported in clinical trials with a frequency of 1.4% and 1.5%, respectively, in elderly patients with dementia. In addition, the following ADRs were reported with a frequency 𕟷% in elderly patients with dementia and with at least twice the frequency seen in other adult populations: urinary tract infection, peripheral oedema, lethargy, and cough.

Paediatric population

In general, type of adverse reactions in children is expected to be similar to those observed in adults.

The following ADRs were reported with a frequency 𕟷% in paediatric patients (5 to 17 years) and with at least twice the frequency seen in clinical trials in adults: somnolence/sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infection, nasal congestion, abdominal pain, dizziness, cough, pyrexia, tremor, diarrhoea, and enuresis. The effect of long-term risperidone treatment on sexual maturation and height has not been adequately studied (see section 4.4 subsection “Paediatric population”).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in Google play or Apple App store.

In general, reported signs and symptoms have been those resulting from an exaggeration of the known pharmacological effects of risperidone. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. In overdose, QT-prolongation and convulsions have been reported. Torsade de Pointes has been reported in association with combined overdose of risperidone and paroxetine.

In case of acute overdose, the possibility of multiple drug involvement should be considered.

Establish and maintain a clear airway and ensure adequate oxygenation and ventilation. Administration of activated charcoal together with a laxative should be considered only when drug intake was less than one hour before. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

There is no specific antidote to Risperidone. Therefore, appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, an anticholinergic medicinal product should be administered. Close medical supervision and monitoring should continue until the patient recovers.

Pharmacotherapeutic group: Other antipsychotics, ATC-code: N05AX08

Risperidone is a selective monoaminergic antagonist with unique properties. It has a high affinity for serotoninergic 5-HT2 and dopaminergic D2 receptors. Risperidone binds also to alpha1-adrenergic receptors, and, with lower affinity, to H1-histaminergic and alpha2 adrenergic receptors. Risperidone has no affinity for cholinergic receptors.

Although risperidone is a potent D2 antagonist, which is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy than classical antipsychotics. Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side effect liability and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.

Clinical efficacy and safety

The efficacy of risperidone in the short-term treatment of schizophrenia was established in four studies, 4- to 8-weeks in duration, which enrolled over 2500 patients who met DSM-IV criteria for schizophrenia. In a 6-week, placebo-controlled trial involving titration of risperidone in doses up to 10 mg/day administered twice daily, risperidone was superior to placebo on the Brief Psychiatric Rating Scale (BPRS) total score. In an 8- week, placebo-controlled trial involving four fixed doses of risperidone (2, 6, 10, and 16 mg/day, administered twice daily), all four risperidone groups were superior to placebo on the Positive and Negative Syndrome Scale (PANSS) total score. In an 8-week, dose comparison trial involving five fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day administered twice-daily), the 4, 8, and 16 mg/day risperidone dose groups were superior to the 1 mg risperidone dose group on PANSS total score. In a 4-week, placebo-controlled dose comparison trial involving two fixed doses of risperidone (4 and 8 mg/day administered once daily), both risperidone dose groups were superior to placebo on several PANSS measures, including total PANSS and a response measure (>20% reduction in PANSS total score). In a longer-term trial, adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medicinal product were randomised to risperidone 2 to 8 mg/day or to haloperidol for 1 to 2 years of observation for relapse. Patients receiving risperidone experienced a significantly longer time to relapse over this time period compared to those receiving haloperidol.

Manic episodes in bipolar disorder

The efficacy of risperidone monotherapy in the acute treatment of manic episodes associated with bipolar I disorder was demonstrated in three double-blind, placebo-controlled monotherapy studies in approximately 820 patients who had bipolar I disorder, based on DSM-IV criteria. In the three studies, risperidone 1 to 6 mg/day (starting dose 3 mg in two studies and 2 mg in one study) was shown to be significantly superior to placebo on the pre-specified primary endpoint, i.e., the change from baseline in total Young Mania Rating Scale (YMRS) score at Week 3. Secondary efficacy outcomes were generally consistent with the primary outcome. The percentage of patients with a decrease of ≥ 50% in total YMRS score from baseline to the 3-week endpoint was significantly higher for risperidone than for placebo. One of the three studies included a haloperidol arm and a 9-week double-blind maintenance phase. Efficacy was maintained throughout the 9-week maintenance treatment period. Change from baseline in total YMRS showed continued improvement and was comparable between risperidone and haloperidol at Week 12.

The efficacy of risperidone in addition to mood stabilisers in the treatment of acute mania was demonstrated in one of two 3-week double-blind studies in approximately 300 patients who met the DSM-IV criteria for bipolar I disorder. In one 3-week study, risperidone 1 to 6 mg/day starting at 2 mg/day in addition to lithium or valproate was superior to lithium or valproate alone on the pre-specified primary endpoint, i.e., the change from baseline in YMRS total score at Week 3. In a second 3-week study, risperidone 1 to 6 mg/day starting at 2 mg/day, combined with lithium, valproate, or carbamazepine was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this study was induction of risperidone and 9-hydroxy-risperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxy-risperidone. When the carbamazepine group was excluded in a post-hoc analysis, risperidone combined with lithium or valproate was superior to lithium or valproate alone in the reduction of YMRS total score.

Persistent aggression in dementia

The efficacy of risperidone in the treatment of Behavioural and Psychological Symptoms of Dementia (BPSD), which includes behavioural disturbances, such as aggressiveness, agitation, psychosis, activity, and affective disturbances was demonstrated in three double-blind, placebo-controlled studies in 1150 elderly patients with moderate to severe dementia. One study included fixed risperidone doses of 0.5, 1, and 2 mg/day. Two flexible-dose studies included risperidone dose groups in the range of 0.5 to 4 mg/day and 0.5 to 2 mg/day, respectively. Risperidone showed statistically significant and clinically important effectiveness in treating aggression and less consistently in treating agitation and psychosis in elderly dementia patients (as measured by the Behavioural Pathology in Alzheimer's Disease Rating Scale [BEHAVE-AD] and the Cohen-Mansfield Agitation Inventory [CMAI]). The treatment effect of risperidone was independent of Mini-Mental State Examination (MMSE) score (and consequently of the severity of dementia) of sedative properties of risperidone of the presence or absence of psychosis and of the type of dementia, Alzheimer's, vascular, or mixed. (See also section 4.4)

The efficacy of risperidone in the short-term treatment of disruptive behaviours was demonstrated in two double-blind placebo-controlled studies in approximately 240 patients 5 to 12 years of age with a DSM-IV diagnosis of disruptive behaviour disorders (DBD) and borderline intellectual functioning or mild or moderate mental retardation/learning disorder. In the two studies, risperidone 0.02 to 0.06 mg/kg/day was significantly superior to placebo on the pre-specified primary endpoint, i.e., the change from baseline in the Conduct Problem subscale of the Nisonger-Child Behaviour Rating Form (N-CBRF) at Week 6.

Risperidone is metabolised to 9-hydroxy-risperidone, which has a similar pharmacological activity to risperidone (see Biotransformation and elimination).

Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) compared with a solution. The absorption is not affected by food and thus risperidone can be given with or without meals. Steady-state of risperidone is reached within 1 day in most patients. Steady-state of 9-hydroxy-risperidone is reached within 4-5 days of dosing.

Risperidone is rapidly distributed. The volume of distribution is 1-2 l/kg. In plasma, risperidone is bound to albumin and alpha1-acid glycoprotein. The plasma protein binding of risperidone is 90%, that of 9-hydroxyrisperidone is 77%.

Biotransformation and elimination

Risperidone is metabolised by CYP 2D6 to 9-hydroxy-risperidone, which has a similar pharmacological activity as risperidone. Risperidone plus 9-hydroxy-risperidone form the active antipsychotic fraction. CYP 2D6 is subject to genetic polymorphism. Extensive CYP 2D6 metabolisers convert risperidone rapidly into 9-hydroxy-risperidone, whereas poor CYP 2D6 metabolisers convert it much more slowly. Although extensive metabolisers have lower risperidone and higher 9-hydroxy-risperidone concentrations than poor metabolisers, the pharmacokinetics of risperidone and 9-hydroxy-risperidone combined (i.e., the active antipsychotic fraction), after single and multiple doses, are similar in extensive and poor metabolisers of CYP 2D6.

Another metabolic pathway of risperidone is N-dealkylation. In vitro studies in human liver microsomes showed that risperidone at clinically relevant concentration does not substantially inhibit the metabolism of medicines metabolised by cytochrome P450 isozymes, including CYP 1A2, CYP 2A6, CYP 2C8/9/10, CYP 2D6, CYP 2E1, CYP 3A4, and CYP 3A5. One week after administration, 70% of the dose is excreted in the urine and 14% in the faeces. In urine, risperidone plus 9-hydroxy-risperidone represent 35-45% of the dose. The remainder is inactive metabolites. After oral administration to psychotic patients, risperidone is eliminated with a half-life of about 3 hours. The elimination half-life of 9-hydroxy-risperidone and of the active antipsychotic fraction is 24 hours.

Linearity/non-linearity

Risperidone plasma concentrations are dose-proportional within the therapeutic dose-range.

Elderly, hepatic and renal impairment

A single-dose PK study with oral risperidone showed on average a 43% higher active antipsychotic fraction plasma concentration, a 38% longer half-life and a reduced clearance of the active antipsychotic fraction by 30% in the elderly In adults with moderate renal disease the clearance of the active moiety was

48% of the clearance in young healthy adults. In adults with severe renal disease the clearance of the active moiety was

31% of the clearance in young healthy adults. The half-life of the active moiety was 16.7 h in young adults, 24.9 h in adults with moderate renal disease (or

1.5 times as long as in young adults), and 28.8 h in those with severe renal disease (or

1.7 times as long as in young adults). Risperidone plasma concentrations were normal in patients with liver insufficiency, but the mean free fraction of risperidone in plasma was increased by 37.1%. The oral clearance and the elimination half-life of risperidone and of the active moiety in adults with moderate and severe liver impairment were not significantly different from those parameters in young healthy adults.

Paediatric population

The pharmacokinetics of risperidone, 9-hydroxy-risperidone and the active antipsychotic fraction in children are similar to those in adults.

Other special populations: Gender, race and smoking habits

A population pharmacokinetic analysis revealed no apparent effect of gender, race or smoking habits on the pharmacokinetics of risperidone or the active antipsychotic fraction.

In (sub)chronic toxicity studies, in which dosing was started in sexually immature rats and dogs, dose-dependent effects were present in male and female genital tract and mammary gland. These effects were related to the increased serum prolactin levels, resulting from the dopamine D2-receptor blocking activity of risperidone. In addition, tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Risperidone was not teratogenic in rat and rabbit. In rat reproduction studies with risperidone, adverse effects were seen on mating behaviour of the parents, and on the birth weight and survival of the offspring. In rats, intrauterine exposure to risperidone was associated with cognitive deficits in adulthood. Other dopamine antagonists, when administered to pregnant animals, have caused negative effects on learning and motor development in the offspring.

In a toxicity study in juvenile rats, increased pup mortality and a delay in physical development was observed. In a 40-week study with juvenile dogs, sexual maturation was delayed. Based on AUC, long bone growth was not affected in dogs at 3.6-times the maximum human exposure in adolescents (1.5 mg/day) while effects on long bones and sexual maturation were observed at 15 times the maximum human exposure in adolescents.

Risperidone was not genotoxic in a battery of tests. In oral carcinogenicity studies of risperidone in rats and mice, increases in pituitary gland adenomas (mouse), endocrine pancreas adenomas (rat), and mammary gland adenomas (both species) were seen. These tumours can be related to prolonged dopamine D2 antagonism and hyperprolactinaemia. The relevance of these tumour findings in rodents in terms of human risk is unknown. In vitro and in vivo, animal models show that at high doses risperidone may cause QT interval prolongation, which has been associated with a theoretically increased risk of torsade de pointes in patients.


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Gross Anatomic Changes

Tanner described the most well-accepted macroscopic stages of development in the breast at puberty ( Fig. 2 ). 35 These gross anatomic changes begin with stage 1, the preadolescent phase with only elevation of the papilla. At this point, there is no additional development of the stroma or parenchyma beyond what has occurred in infancy. Breast development is generally the first secondary sexual characteristic to develop, preceding pubic hair development by about 6 months. 19 , 36 Although the pubertal surge of estrogen is the immediate stimulus to mammary development, the action of estrogen depends upon the presence of pituitary growth hormone and the ability of growth hormone to stimulate production of insulin-like growth factor-1 (IGF-I) in the mammary gland. 37 The age range in which this can occur is 8½ to 13½ years. No breast development by 14 years of age in girls should prompt further investigation. 20

Tanner stages of breast development. (Reprinted with permission from Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 196944:291�. Copyright BMJ Publishing).

Tanner stage 2 involves formation of the breast bud with elevation of the nipple as well as a small mound of breast tissue along with enlargement of the diameter of the areola. 35 The average age of girls at this stage is 11 years in a British cohort and has been shown to occur 6 months earlier in the United States. 38 , 39 There is recent literature pointing toward an earlier age at onset of breast development in girls in the United States (average age 9.8 vs. 10.8 years over approximately a decade). 38 , 40 The normal range of thelarche is from 8½ to 13 years. 35

Significant variations in breast development occur in individuals at the same age based on level of pubertal maturation, ethnicity, 36 and hormonal concentrations. Clinically, Tanner stage 2 of breast development correlates with the entity of thelarche. Tanner stage 3, attained at an average age of 12.5 years, is characterized by further enlargement of the breast and areola. No separation of the contours is noted at this time. 35 , 36 Between Tanner stages 2 and 3, discrepancy in size between the breasts of a pubertal girl is commonly seen and tends to become less noticeable by Tanner stage 4 and 5. 20 If marked breast asymmetry is persistent, reconstructive surgery may be a consideration, generally when Tanner 5 breast maturity is reached. 19 , 20 , 35 Marked discrepancy between breast size in puberty, particularly if persistent, is presumed to be due to poor mammary bud development in the smaller breast. 20

During Tanner stage 4, at the average age of 13 to 14 years, there is enlargement of the nipple and areola, leading to the formation of a secondary mound on the breast. Menarche tends to occur between Tanner stage 3 and Tanner stage 4. 38 Some girls may progress from Tanner stage 3 to 5 without a transitory stage 4. 20

Tanner stage 5 is characterized by the recession of the areola on to the breast with resulting loss of the separation of contours. This stage is attained by an average age of 15 years. 35

The average time spent between Tanner stages 2 and 5 is 4 to 4½ years. 13 , 36 , 38 There are inherent variations in this estimate and the duration of time spent progressing through Tanner stages of breast development can range from 1.5 to 6 years. Also, the breast bud stage can persist from 6 months to 2 years before advancing to Tanner stage 3. 35

After or during these stages of development, breast shrinkage may occur if there is weight loss due to decrease in adipose tissue. 19 , 20 This is particularly relevant in the pubertal girl when eating disorders such as anorexia nervosa are most commonly encountered. The loss of fatty tissue gives a wrinkled appearance to the skin of the breast, leading Capraro and Dewhurst to coin the term “instant senility” to describe this phenomenon in adolescents. 41 Unilateral or bilateral pathologic enlargement of the breast at puberty is termed juvenile hypertrophy, and it is histologically similar to gynecomastia in males and distinct from lactational hypertrophy. 19

Significant development of the nipple also occurs during puberty. 42 The most marked increase in size and diameter of the nipple is seen between Tanner stages 3 and 5, particularly soon after menarche. 43 The average increase in diameter between Tanner stages 1 to 5 is 5 to 6 mm. 43 It is difficult to form measurable criteria of nipple diameter at each Tanner stage due to extensive variations found in increments of nipple size based on hormonal status, race, nutrition, and genetics. 44

Cellular Changes

Underlying the extensive tissue remodeling that occurs at puberty is a mammary cell hierarchy composed of multipotent stem and lineage-restricted progenitor cells. 45 , 46 , 47 , 48 At the cellular level, both stromal and parenchymal changes are occurring during pubertal development, 13 but increase in fibrous and fatty tissue of the stroma precedes further ductal changes. Following a period of stromal changes, ductal elongation and dichotomous branching occurs, with both these events being under the influence of estrogen. 13 , 49

During puberty, the epithelium forms into a branching, bilayered ductal structure, consisting of an outer basal myoepithelial layer of cells and an inner luminal cell layer that can be divided further into ductal luminal cells, lining the inside of the ducts, and alveolar luminal cells, which secrete milk during lactation ( Fig. 3 ). 5 More alveoli are laid during each menstrual cycle, but the degree of alveolar expansion is only significant once pregnancy occurs. 34 , 49

Pubertal breast development. (A) Carmine-stained whole-mount preparation of the advancing edge (arrow) of the parenchyma from a 13-year-old girl. (B) Hematoxylin- and eosin-stained developing breast of 13-year-old girl showing solid end bud-like structures (denoted teb) and lateral buds (arrows). (C) Coronal section of breast of 15-year-old girl. (D) Higher power view of panel C, arrows indicate ducts and unfilled arrowheads indicate duct termini. (E) Histology section of the peripheral region of parenchyma seen in (C). teb denotes terminal end bud. (F) Carmine-stained whole mount preparation of breast from 18-year-old nulliparous woman. A segmental duct divides into two subsegmental ducts (ss), which then lead to the terminal duct lobular units (tdlu). (G) Electron micrograph of a normal adult subsegmental duct. The bilayered histology with paler luminal cells (l), darker basal (myoepithelial) cells (m) is evident. An intraepithelial lymphocyte (arrow) is also seen. (H) Electron micrograph of a terminal duct lobular unit showing two basal clear cells. These have microfilaments in the basal part of the cell (large arrows) and desmosome attachments with the luminal cells (small arrows). (Reprinted with permission from Howard BA, Gusterson BA. Human breast development. J Mammary Gland Biol Neoplasia 20005(2):119�. 2000 Copyright Springer).

Ductal elongation and complex branching originates at the site of the terminal end bud, specifically at the site of the mammary stem cells in the cap cell layer of the terminal end bud. 13 , 28 , 47 , 48 The primary ducts that reach the nipple form a complex of subsidiary ducts. The primary ducts branch into segmental and subsegmental ducts. 5 , 13 , 34 The subsegmental ducts lead to terminal duct formation, which further subdivides to form several terminal ductules or acini. 13 , 38 A collection of acini arising from one terminal duct along with the surrounding intralobular stroma is termed a terminal duct lobular unit (TDLU), which is the functional unit of the breast. 13

As ductal elongation continues, the remainder of the space in the breast is taken up by adipose tissue, along with a mixture of blood vessels, immune cells, and fibroblasts. 50 Estrogen and progesterone are thought to be responsible for ductal elongation and side branching, respectively. 51

As for lobular development, four types of lobules, from 1 to 4, are well recognized in the human female breast. 13 Lobule type 1 consists of a short terminal duct ending in a cluster of secretory cells called alveoli. Lobule types 2, 3, and 4 consist of a terminal duct branching into several ductules and an increasing number of alveoli. 13 Lobule type 4 is attained in adult women having gone through pregnancy and lactation. 52 , 53 The adult nulliparous breast is complete in ductal and stromal maturation by 18 to 20 years of age and the lobules it contains are mainly type 1. The mammary glands remain in this mature, but inactive state until pregnancy, which brings about the next major change in the hormonal environment. 2


Conclusions

In conclusion, this mouse model study demonstrates that hyperprolactinemia-inducing antipsychotics activate JAK-STAT5 signaling to lower the apoptosis anticancer barrier in preexisting precancerous early lesions and to incite their progression to cancer. To our knowledge, this is the first study that decisively links antipsychotic use to increased breast cancer risk while also providing a mechanistic insight. Our work also suggests short-term or intermittent ruxolitinib treatment as a potentially effective and more acceptable approach for preventing breast cancer risk in women on these antipsychotics.


USE IN SPECIFIC POPULATIONS

Pregnancy

The teratogenic potential of oral risperidone was studied in three embryofetal development studies in Sprague-Dawley and Wistar rats (0.63&ndash10 mg/kg or 0.4 to 6 times the oral maximum recommended human dose [MRHD] on a mg/m 2 basis) and in one embryofetal development study in New Zealand rabbits (0.31&ndash5 mg/kg or 0.4 to 6 times the oral MRHD on a mg/m 2 basis). The incidence of malformations was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the oral MRHD on a mg/m 2 basis. In three reproductive studies in rats (two peri/post-natal development studies and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16&ndash5 mg/kg or 0.1 to 3 times the oral MRHD on a mg/m 2 basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.

There was no no-effect dose for increased rat pup mortality. In one peri/post-natal development study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the oral MRHD on a mg/m 2 basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Days 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the oral MRHD on a mg/m 2 basis.

No studies were conducted with Risperdal Consta ® .

Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero . The causal relationship to oral RISPERDAL ® therapy is unknown.

Neonates exposed to antipsychotic drugs (including RISPERDAL ® ) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Risperdal Consta ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The effect of Risperdal Consta ® on labor and delivery in humans is unknown.

Nursing Mothers

Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women should not breast-feed during treatment with Risperdal Consta ® and for at least 12 weeks after the last injection.

Pediatric Use

Risperdal Consta ® has not been studied in children younger than 18 years old. However, juvenile animal toxicology studies have been conducted with oral risperidone.

Juvenile dogs were treated for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen, with a no-effect dose of 0.31 mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus paliperidone about half those observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest testable dose (1.25 mg/kg/day). This dose produced plasma levels (AUC) of risperidone plus paliperidone which were about two thirds of those observed in humans at the MRHD.

The long-term effects of risperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.

Geriatric Use

In an open-label study, 57 clinically stable, elderly patients (&ge 65 years old) with schizophrenia or schizoaffective disorder received Risperdal Consta ® every 2 weeks for up to 12 months. In general, no differences in the tolerability of Risperdal Consta ® were observed between otherwise healthy elderly and nonelderly patients. Therefore, dosing recommendations for otherwise healthy elderly patients are the same as for nonelderly patients. Because elderly patients exhibit a greater tendency to orthostatic hypotension than nonelderly patients, elderly patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). In addition, monitoring of orthostatic vital signs should be considered in elderly patients for whom orthostatic hypotension is of concern [see Warnings and Precautions (5.7)] .

Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis

In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus oral risperidone when compared to patients treated with oral risperidone alone or with oral placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. An increase of mortality in elderly patients with dementia-related psychosis was seen with the use of oral risperidone regardless of concomitant use with furosemide. Risperdal Consta ® is not approved for the treatment of patients with dementia-related psychosis. [see Boxed Warning and Warnings and Precautions (5.1)]


Contents

Gynecomastia is the abnormal non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogen and androgen. [4] [5] Gynecomastia is different from "pseudogynecomastia", [5] [6] which is defined as an excess of skin and adipose tissue in the male breasts without the development of true breast glandular tissue [19] [20] pseudogynecomastia is commonly present in men with obesity. [13] [14]

In gynecomastia there is typically enlargement of one or both breasts, symmetrically or asymmetrically, in a man. Soft, compressible, and mobile breast tissue is felt under the nipple and its surrounding skin in contrast to softer fatty tissue. [9] [21] Dimpling of the skin and nipple retraction are not typical features of gynecomastia. [9] Milky discharge from the nipple is not a typical finding, but may be seen in a gynecomastic individual with a prolactin secreting tumor. [7] An increase in the diameter of the areola and asymmetry of the chest are other possible signs of gynecomastia. [22]

Men with gynecomastia may appear anxious or stressed due to concerns about its appearance and the possibility of having breast cancer. [23] [24]

Gynecomastia is thought to be caused by an altered ratio of estrogens to androgens mediated by an increase in estrogen production, a decrease in androgen production, or a combination of these two factors. [7] Estrogen acts as a growth hormone to increase the size of male breast tissue. [7] [23] The cause of gynecomastia is unknown in around 25% of cases. [21] [24] Drugs are estimated to cause 10–25% of cases of gynecomastia. [25]

Linalool, which contains lavender, is found in the fragrance of cosmetic products and shampoos such as Pantene Pro-V. [26] Lavender and tea tree oil have been linked to gynecomastia and act as a endocrine disruptor with certain males. [27]

Certain health problems in men such as liver disease, kidney failure, or low testosterone can cause breast growth in men. Drugs and liver disease are the most common cause in adults. [28] Other medications known to cause gynecomastia include methadone aldosterone antagonists (spironolactone and eplerenone) HIV medication cancer chemotherapy hormone treatment for prostate cancer heartburn and ulcer medications calcium channel blockers antifungal medications such as ketoconazole antibiotics such as metronidazole tricyclic antidepressants such as amitriptyline and herbals such as lavender, tea tree oil, and dong quai. [4] The insecticide phenothrin possesses antiandrogen activity and has been associated with gynecomastia. [29] [30]

Physiologic Edit

Both male and female newborns may show breast development at birth or in the first weeks of life. [31] During pregnancy, the placenta converts the androgenic hormones dehydroepiandrosterone (DHEA) and DHEA sulfate to the estrogenic hormones estrone and estradiol, respectively after these estrogens are produced by the placenta, they are transferred into the baby's circulation, thereby leading to temporary gynecomastia in the baby. [23] [32] In some infants neonatal milk (also known as "witch's milk") can leak from the nipples. [21] The temporary gynecomastia seen in newborn babies usually resolves after two or three weeks. [23]

Gynecomastia in adolescents usually starts between the ages of 10 and 12 and commonly goes away after 18 months. [23]

Declining testosterone levels and an increase in the level of subcutaneous fatty tissue seen as part of the normal aging process can lead to gynecomastia in older men. This is also known as senile gynecomastia. [23] Increased fatty tissue in these men leads to increased conversion of androgenic hormones such as testosterone to estrogens. [23]

When the human body is deprived of adequate nutrition, testosterone levels drop, while the adrenal glands continue to produce estrogens, thereby causing a hormonal imbalance. [23] Gynecomastia can also occur once normal nutrition is restarted (this is known as refeeding gynecomastia). [23]

Non-physiologic Edit

Medicines Edit

About 10–25% of cases are estimated to result from the use of medications, known as nonphysiologic gynecomastia. [17] [24] Medications known to cause gynecomastia include cimetidine, ketoconazole, gonadotropin-releasing hormone analogues, human growth hormone, human chorionic gonadotropin, 5α-reductase inhibitors such as finasteride and dutasteride, certain estrogens used for prostate cancer, and antiandrogens such as bicalutamide, flutamide, and spironolactone. [7] [17] [36] [37]

Medications that are probably associated with gynecomastia include calcium channel blockers such as verapamil, amlodipine, and nifedipine risperidone, olanzapine, anabolic steroids, [17] [38] alcohol, opioids, efavirenz, alkylating agents, and omeprazole. [17] [29] Certain components of personal skin care products such as lavender essential oil [39] or tea tree oil and certain dietary supplements such as dong quai and Tribulus terrestris have been associated with gynecomastia. [24]

Chronic disease Edit

People with kidney failure are often malnourished, which may contribute to gynecomastia development. Dialysis may attenuate malnutrition of kidney failure. Additionally, many kidney failure patients experience a hormonal imbalance due to the suppression of testosterone production and testicular damage from high levels of urea also known as uremia-associated hypogonadism. [24] [40]

In individuals with liver failure or cirrhosis, the liver's ability to properly metabolize hormones such as estrogen may be impaired. Additionally, those with alcoholic liver disease are further put at risk for development of gynecomastia ethanol may directly disrupt the synthesis of testosterone and the presence of phytoestrogens in alcoholic drinks may also contribute to a higher estrogen to testosterone ratio. [24] Conditions that can cause malabsorption such as cystic fibrosis or ulcerative colitis may also produce gynecomastia. [24]

A small proportion of male gynecomastia cases may be seen with rare inherited disorders such as spinal and bulbar muscular atrophy and the very rare aromatase excess syndrome. [41] [42]

Tumors Edit

Testicular tumors such as Leydig cell tumors or Sertoli cell tumors [43] (such as in Peutz–Jeghers syndrome) [10] or hCG-secreting choriocarcinoma [29] may result in gynecomastia. Other tumors such as adrenal tumors, pituitary gland tumors (such as a prolactinoma), or lung cancer, can produce hormones that alter the male–female hormone balance and cause gynecomastia. [21]

Individuals with prostate cancer who are treated with androgen deprivation therapy may experience gynecomastia. [44]

The causes of common gynecomastia remain uncertain, but are thought to result from an imbalance between the actions of estrogen and androgens at the breast tissue. [8] [17] Breast prominence can result from enlargement of glandular breast tissue, chest adipose tissue (fat) and skin, and is typically a combination. [29] As in females, estrogen stimulates the growth of breast tissue in males. [7] In addition to directly stimulating male breast tissue growth, estrogens indirectly decrease secretion of testosterone by suppressing luteinizing hormone secretion, resulting in decreased testicular secretion of testosterone. [7] Furthermore, estrogens can increase blood levels of the protein sex hormone-binding globulin (SHBG), which binds free testosterone (the active form) leading to decreased action of testosterone in male breast tissue. [7]

Primary hypogonadism (indicating an intrinsic problem with the testes in males) leads to decreased testosterone synthesis and increased conversion of testosterone to estradiol potentially leading to a gynecomastic appearance. [23] Klinefelter syndrome is a notable example of a disorder that causes hypogonadism and gynecomastia, and has a higher risk of breast cancer in males (20–50 times higher than males without the disorder). [45] Central hypogonadism (indicating a problem with the brain) leads to decreased production and release of luteinizing hormone (LH, a stimulatory signal for endogenous steroid hormone synthesis) which leads to decreased production of testosterone and estradiol in the testes. [23]

Individuals who have cirrhosis or chronic liver disease may develop gynecomastia for several reasons. Cirrhotics tend to have increased secretion of the androgenic hormone androstenedione from the adrenal glands, increased conversion of this hormone into various types of estrogen, [7] and increased levels of SHBG, which leads to decreased blood levels of free testosterone. [23] Around 10–40% of individuals with Graves' disease (a common form of hyperthyroidism) experience gynecomastia. [23] Increased conversion of testosterone to estrogen by increased aromatase activity, [7] increased levels of SHBG and increased production of testosterone and estradiol by the testes due to elevated levels of LH cause the gynecomastia. Proper treatment of the hyperthyroidism can lead to the resolution of the gynecomastia. [23]

Medications are known to cause gynecomastia through several different mechanisms. These mechanisms include increasing estrogen levels, mimicking estrogen, decreasing levels of testosterone or other androgens, blocking androgen receptors, increasing prolactin levels, or through unidentified means. [23] High levels of prolactin in the blood (which may occur as a result of certain tumors or as a side effect of certain medications) has been associated with gynecomastia. [23] A high level of prolactin in the blood can inhibit the release of gonadotropin-releasing hormone and therefore cause central hypogonadism. [7] [23] Receptors for prolactin and other hormones including insulin-like growth factor 1, insulin-like growth factor 2, luteinizing hormone, progesterone, and human chorionic gonadotropin have been found in male breast tissue, but the impact of these various hormones on gynecomastia development is not well understood. [7]

To diagnose gynecomastia, a thorough history and physical examination are obtained by a physician. Important aspects of the physical examination include evaluation of the male breast tissue with palpation to evaluate for breast cancer and pseudogynecomastia (male breast tissue enlargement solely due to excess fatty tissue), evaluation of penile size and development, evaluation of testicular development and an assessment for masses that raise suspicion for testicular cancer, and proper development of secondary sex characteristics such as the amount and distribution of pubic and underarm hair. [7] Gynecomastia usually presents with bilateral involvement of the breast tissue but may occur unilaterally as well. [24]

A review of the medications or illegal substances an individual takes may reveal the cause of gynecomastia. [24] Recommended laboratory investigations to find the underlying cause of gynecomastia include tests for aspartate transaminase and alanine transaminase to rule out liver disease, serum creatinine to determine if kidney damage is present, and thyroid-stimulating hormone levels to evaluate for hyperthyroidism. If these initial laboratory tests fail to uncover the cause of gynecomastia, then additional tests to evaluate for an underlying hormonal balance due to hypogonadism or a testicular tumor should be checked including total and free levels of testosterone, luteinizing hormone, follicle stimulating hormone, estradiol, serum beta human chorionic gonadotropin (β-hCG), and prolactin. [24]

High levels of prolactin are uncommon in people with gynecomastia. [24] If β-hCG levels are abnormally high, then ultrasound of the testicles should be performed to check for signs of a hormone-secreting testicular tumor. [24] Markers of testicular, adrenal, or other tumors such as urinary 17-ketosteroid or serum dehydroepiandrosterone may also be checked if there is evidence of hormonal imbalance on physical examination. If this evaluation does not reveal the cause of gynecomastia, then it is considered to be idiopathic gynecomastia (of unclear cause). [24]

Differential diagnosis Edit

Other causes of male breast enlargement such as mastitis, [24] [46] breast cancer, pseudogynecomastia, lipoma, sebaceous cyst, dermoid cyst, hematoma, metastasis, ductal ectasia, fat necrosis, or a hamartoma are typically excluded before making the diagnosis. [24] Another condition that may be confused with gynecomastia is enlargement of the pectoralis muscles. [ citation needed ]

Imaging Edit

Mammography is the method of choice for radiologic examination of male breast tissue in the diagnosis of gynecomastia when breast cancer is suspected on physical examination. [7] [9] However, since breast cancer is a rare cause of breast tissue enlargement in men, mammography is rarely needed. [7] If mammography is performed and does not reveal findings suggestive of breast cancer, further imaging is not typically necessary. [9] If a tumor of the adrenal glands or the testes is thought to be responsible for the gynecomastia, ultrasound examination of these structures may be performed. [7]

Histology Edit

Early histological features expected to be seen on examination of gynecomastic tissue attained by fine-needle aspiration biopsy include the following: proliferation and lengthening of the ducts, an increase in connective tissue, an increase in inflammation, and swelling surrounding the ducts, and an increase in fibroblasts in the connective tissue. [23] Chronic gynecomastia may show different histological features such as increased connective tissue fibrosis, an increase in the number of ducts, less inflammation than in the acute stage of gynecomastia, increased subareolar fat, and hyalinization of the stroma. [22] [23] When surgery is performed, the gland is routinely sent to the lab to confirm the presence of gynecomastia and to check for tumors under a microscope. The utility of pathologic examination of breast tissue removed from male adolescent gynecomastia patients has recently been questioned due to the rarity of breast cancer in this population. [47]

Classification Edit

The spectrum of gynecomastia severity has been categorized into a grading system: [48]

  • Grade I: Minor enlargement, no skin excess
  • Grade II: Moderate enlargement, no skin excess
  • Grade III: Moderate enlargement, skin excess
  • Grade IV: Marked enlargement, skin excess

Mild cases of gynecomastia in adolescence may be treated with advice on lifestyle habits such as proper diet and exercise with reassurance. In more severe cases, medical treatment may be offered including medication or surgical intervention. [23]

Medication Edit

Gynecomastia can respond well to medical treatment although it is usually only effective when done within the first two years after the start of male breast enlargement. [7] Selective estrogen receptor modulators (SERMs) such as tamoxifen, raloxifene, and clomifene may be beneficial in the treatment of gynecomastia but are not approved by the Food and Drug Administration for use in gynecomastia. [7] [17] [49] Clomifene seems to be less effective than tamoxifen or raloxifene. [49] Tamoxifen may be used to treat gynecomastia in adults and of the medical treatments used, tamoxifen is the most effective. [50] [51] Recent studies have shown that treatment with tamoxifen may represent a safe and effective mode of treatment in cases of cosmetically disturbing or painful gynecomastia. [17] [52] Aromatase inhibitors (AIs) such as anastrozole have been used off-label for cases of gynecomastia occurring during puberty but are less effective than SERMs. [16] [49]

A few cases of gynecomastia caused by the rare disorders aromatase excess syndrome and Peutz–Jeghers syndrome have responded to treatment with AIs such as anastrozole. [16] Androgens/anabolic steroids may be effective for gynecomastia. [49] Testosterone itself may not be suitable to treat gynecomastia as it can be aromatized into estradiol, but nonaromatizable androgens like topical androstanolone (dihydrotestosterone) can be useful. [49]

Surgery Edit

If chronic gynecomastia does not respond to medical treatment surgical removal of glandular breast tissue is usually required. [17] The American Board of Cosmetic Surgery reports surgery is the "most effective known treatment for gynecomastia." [53] Surgical approaches to the treatment of gynecomastia include subcutaneous mastectomy, liposuction-assisted mastectomy, laser-assisted liposuction, and laser-lipolysis without liposuction. Complications of mastectomy may include hematoma, surgical wound infection, breast asymmetry, changes in sensation in the breast, necrosis of the areola or nipple, seroma, noticeable or painful scars, and contour deformities. [48] In 2019, 24,123 male patients underwent surgical treatment for gynecomastia in the US, accounting for a 19% increase since 2000. Thirty-five percent of those patients were between the ages of 20 and 29, and 60% were younger than age 29 at the time of the operation. At an average surgeon's fee of $4,123, gynecomastia surgery was also the 11th most costly male cosmetic surgery of 2019. [54]

Others Edit

Radiation therapy and tamoxifen have been shown to help prevent gynecomastia and breast pain from developing in prostate cancer patients who will be receiving androgen deprivation therapy. The efficacy of these treatments is limited once gynecomastia has occurred and are therefore most effective when used prophylactically. [55]

In the United States, many insurance companies deny coverage for surgery for gynecomastia treatment or male breast reduction on the basis that it is a cosmetic procedure. [56] [57] [58] [59]

Gynecomastia is not physically harmful, but in some cases it may be an indicator of other more serious underlying conditions, such as testicular cancer. [7] The glandular tissue typically grows under the influence of hormonal stimulation and is often tender or painful. Furthermore, gynecomastia frequently presents social and psychological difficulties such as low self-esteem or shame for the sufferer. [47] [48] Weight loss can alter the condition in cases triggered by obesity, but losing weight will not reduce the glandular component and patients cannot target areas for weight loss. Massive weight loss can result in sagging chest tissue known as chest ptosis. [ citation needed ]

Gynecomastia is the most common benign disorder of the male breast tissue and affects 35 percent of men, being most prevalent between the ages of 50 and 69. [5] [9]

New cases of gynecomastia are common in three age populations: newborns, adolescents, and men older than 50 years old. [48] Newborn gynecomastia occurs in about 60–90 percent of male babies and most cases resolve on their own. [23] [24] During adolescence, around 50 to 70 percent of males are estimated to exhibit signs of gynecomastia. [7] Gynecomastia in older men is estimated to be present in 24–65 percent of men between the ages of fifty and eighty. Estimates on asymptomatic gynecomastia is about up to 70% in men aged 50 to 69 years. [23] [60]

The prevalence of gynecomastia in men may have increased in recent years, but the epidemiology of the disorder is not fully understood. [29] The use of anabolic steroids and exposure to chemicals that mimic estrogen in cosmetic products, organochlorine pesticides, and industrial chemicals have been suggested as possible factors driving this increase. [29] [59] According to the American Society of Plastic Surgeons, breast reduction surgeries to correct gynecomastia are becoming increasingly common. In 2006, there were 14,000 procedures of this type performed in the United States alone. [59]

Gynecomastia can result in psychological distress for those with the condition. Common slang or derogatory terms for gynecomastia include man tits, man boobs or moobs. [61] Support groups exist to help improve the self-esteem of affected people. [62]

In 2019, a 12-person Philadelphia jury awarded $8 billion in punitive damages to plaintiffs tied to the use of Risperidone. Risperidone is an atypical antipsychotic that was originally approved to treat psychosis, but its use in children, including those with autism, ADHD, and schizophrenic diagnoses, has grown over the last two decades. [63]

In Murray v. Janssen Pharmaceuticals, Murray was a Risperidone user who was prescribed the medication at age 9 and developed male breasts. A jury decided in Murray's favor in November 2015 and awarded him $1.75 million. The $1.75 million jury verdict represented damages for "disfigurement and mental anguish," though it was later reduced to $680,000. [64] In the second portion of the bifurcated trial, the plaintiffs sought to prove that the companies knew and deliberately disregarded evidence that Risperidone could lead to gynecomastia in young males, and nonetheless promoted the medication off-label and released the medication into the open market for prescription and use by patients without disclosing the side effects. [64] The jury found for the plaintiffs in the second portion of the trial and awarded $8 billion in punitive damages. The amount was later reduced to $6.8 million by Judge Kenneth Powell Jr. [65]

The term comes from the Greek γυνή gyné (stem gynaik-) meaning "female" and μαστός mastós meaning "breast". [3]


Patient Counseling Information

Physicians are advised to discuss the following issues with patients for whom they prescribe Risperidone and their caregivers:

Orthostatic Hypotension

Advise patients and caregivers about the risk of orthostatic hypotension, especially during the period of initial dose titration [see Warnings and Precautions (5.7)].

Interference with Cognitive and Motor Performance

Inform patients and caregivers that Risperidone has the potential to impair judgment, thinking, or motor skills. Advise caution about operating hazardous machinery, including automobiles, until patients are reasonably certain that Risperidone therapy does not affect them adversely [see Warnings and Precautions (5.9)] .

Pregnancy

Advise patients and caregivers to notify their physician if the patient becomes pregnant or intends to become pregnant during therapy [see Use in Specific Populations (8.1)] .

Nursing

Inform patients and caregivers that Risperidone and its active metabolite are present in human breast milk there is a potential for serious adverse reactions from Risperidone in nursing infants. Advise patients that the decision whether to discontinue nursing or to discontinue the Risperidone should take into account the importance of the drug to the patient [see Use in Specific Populations (8.3)] .

Concomitant Medication

Advise patients and caregivers to inform their physicians if the patient is taking, or plans to take, any prescription or over-the-counter drugs, because there is a potential for interactions [see Drug Interactions (7)] .

Alcohol

Advise patients to avoid alcohol while taking Risperidone [see Drug Interactions (7.2)] .

Metabolic Changes

Inform patients and caregivers that treatment with Risperidone can be associated with hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain [see Warnings and Precautions (5.5)] .

Tardive Dyskinesia

Inform patients and caregivers about the risk of tardive dyskinesia [see Warnings and Precautions (5.4)] .


Watch the video: Risperdal Male Breast Growth Side Effects Explained (November 2022).