**6. How common is hyperprolactinaemia in an antipsychotic-treated cohort?**

#### **6.1 Overview**

438 Health Management – Different Approaches and Solutions

population. Many of their study reports suggest prolactin levels to be linked to the risk of breast cancer development both in pre- and postmenopausal women (Tworoger and Hankinson, 2006; Tworoger et al, 2007). An example of these data found prolactin levels in the upper quartile of normal to be associated with an increased risk compared to the lower quartile of normal (OR 1.34, 95% CI 1.02-1.76) (Tworoger et al, 2007). Any definitive link,

A large retrospective cohort study of 52,819 females receiving antipsychotics and 55,289 control women reported a 16% increased risk of breast cancer (Wang et al, 2002) with a dose response relationship suggesting a greater risk of breast cancer with increased doses of antipsychotic. Regardless of relationship with prolactin, identical breast cancer screening should be encouraged in all schizophrenia subjects as in the general population. Screening rates for schizophrenia patients are very low compared with the general population for an illness that is very common (lifetime prevalence 1 in 9 and rising) and often curable (Bushe

Hyperprolactinaemia has also been linked to pituitary adenomas and adenocarcinomas and putatively to prostate cancer (Harvey et al, 2008). The US Food and Drug Administration Adverse Event Reporting System pharmacovigilance database study strongly linked risperidone (adjusted reporting ratio 18.7) with the highest frequency of pituitary adenomas compared with haloperidol (5.6), ziprasidone (3.0) and olanzapine (2.3) (Szarfman et al, 2006). A recent case series is suggestive that amisulpride may also be associated with the development of prolactinomas mediated via hyperprolactinaemia (Akkaya et al, 2009). The multiple actions of prolactin and relative lack of research into hyperprolactinaemia suggest that additional potential long-term effects may be discovered potentially in glands such as the thyroid. Recent data suggest there may be an association with autoimmune thyroiditis and in 75 schizophrenia patients, the prevalence of hyperprolactinaemia was

however, has yet to be established in schizophrenia and bipolar disorder.

higher in patients with thyroid autoantibodies (p=0.045) (Poyraz et al, 2008).

**5. Relationship between serum prolactin concentration and adverse events**  This is a complex question that remains totally unanswered for the potential longer term sequelae but can be partially addressed for short-term adverse events. There would seem to be two potential associations. Firstly, a chronic prolactin elevation that reaches a cumulative threshold over a longer term and secondly, a peak prolactin level that requires a trigger threshold to initiate pathology. Levels <1000 mIU/L are associated with decreased libido and infertility, 1000-1600 mIU/L with oligomenorrhoea, and >2000 mIU/L with amenorrhea and hypogonadism (Peveler et al, 2008). Hypogonadism is the main driver for bone mineral density loss and fractures although the possibility exists that prolactin may have a direct osteoclastic effect. Data on longer term prolactin levels tend not to report the associated changes in sex hormones making interpretation complex. The topic has, however, been reviewed (Bushe et al, 2008) and in cross-sectional prevalence studies that report bone mineral density loss in association with typicals or risperidone over 8-21 years, the mean cohort values ranged 908-3024 mIU/L (Bushe et al, 2010). These levels are common and are reached quickly in patients treated with risperidone and amisulpride (Bushe and Shaw 2007; Bushe et al, 2008). A small case series of patients receiving paliperidone reported hyperprolactinaemia within 3 weeks with levels ranging from 1500-3996 mIU/L (Skopek et al, 2010). Prolactin levels related to breast cancer in schizophrenia and bipolar disorder are unknown, however data are supportive of levels

et al, 2010).

There are few cohorts where prolactin levels have been obtained in a complete cohort and rates of hyperprolactinaemia will be dependent on many factors including medication choice, gender, age and length of follow up. Data derived from epidemiological databases is also confounded by selection bias. Without knowing how many subjects were tested there is little way to put perspective around these data (Montgomery et al, 2004). A true perspective requires a complete cohort to be tested. Many other confounders will remain, however, including gender, smoking status, adherence to treatment, age and time on treatment.

Olanzapine, for example, may give a transient elevation of prolactin that reduces over the first months in some patients but during chronic administration prolactin elevation may remain (Bushe et al, 2008). Naturalistic data may thus be informative as prolactin monitoring is not routine and prevalence rates in complete populations screened will reflect previous under-diagnosis. Two recent naturalistic analyses in which asymptomatic schizophrenia populations have been screened for prolactin report similar prevalence of hyperprolactinaemia: 38% and 39% in UK (n=194) and Norway (n=106), respectively (Bushe and Shaw 2007; Johnsen et al, 2008). The UK study measured prolactin in the total population of a catchment area in Halifax receiving antipsychotics for schizophrenia or bipolar disorder. The population was clinically asymptomatic prior to the study. Hyperprolactinaemia was more common in females than males (52 vs. 26%), consistent with most other data (Bushe et al, 2008), and significantly elevated levels (>1000 mIU/L) were measured in 21% of subjects. For 13% of females and 19% of males, prolactin levels were above the normal limit but below 1001 mIU/L. Categorical rates of hyperprolactinaemia in trials range from 33 to 69% and confirm that no antipsychotic is prolactin neutral (Bushe et al, 2008). Most studies report both a higher prevalence and severity of hyperprolactinaemia in females as was the case in the Halifax study which found 13% of females had levels >2000 mIU/L compared with 2% of males (Bushe and Shaw, 2007).

#### **6.2 Rates of hyperprolactinaemia with individual antipsychotics**

The ideal studies to evaluate prolactin would be a long-term, first episode study where the confounding factor of previous antipsychotic usage would not need addressing and which included multiple treatment arms and a longer term randomised study in chronic schizophrenia. There are few such studies with the exception of EUFEST (Kahn et al, 2008) and CATIE (Lieberman et al, 2005). EUFEST was a 1-year, first episode study and CATIE, an 18-month study with multiple treatment arms. Both these studies concluded that hyperprolactinaemia was common though EUFEST failed to find a direct link between prolactin and sexual dysfunction.

Prolactin and Schizophrenia, an Evolving Relationship 441

concluded that although risperidone was associated with higher rates of hyperprolactinaemia compared with 10 mg haloperidol, no comparative differences emerged with 20mg haloperidol (Kleinberg et al, 1999). Doses of haloperidol currently used are more reflective of studies such as EUFEST, in which the maximum permitted dose was

Our own naturalistic series concluded that hyperprolactinaemia with oral risperidone was indeed almost 100% in females and between 63-100% in males (Bushe et al, 2008). Similar levels of hyperprolactinaemia are measured with amisulpride though data in large cohorts is lacking other than from EUFEST (Bushe et al, 2008). Depot formulations of risperidone may have a lower prevalence of hyperprolactinaemia relating to dose (53-67%) (Bushe et al, 2008; Bushe and Shaw, 2007). Paliperidone is the major metabolite of risperidone (9 hydroxyl-risperidone) and prolactin values are either similar or greater than those of

Aripiprazole is associated with the lowest rates of hyperprolactinaemia with prevalence rates of 3-5% in RCTs that increase to incidence rates of 17% in naturalistic studies (Bushe et al, 2010) .Recent data have evaluated aripiprazole as a prolactin-lowering agent when combined with haloperidol or risperidone with some success. Although studies report rapid reductions in prolactin levels after commencing aripiprazole (Shim et al, 2007), this may partially relate to removal of a previously used prolactin-elevating drug. Aripiprazole, however, in a placebo controlled trial when added to high-dose haloperidol (20-25 mg/day) in a cohort of schizophrenia patients resulted in normalisation of prolactin in 85% of subjects by 8 weeks contrasting with 3.6% of the placebo group (p<0.001) (Shim et al, 2007). Further research is indicated into the dosage of aripiprazole

For the remaining antipsychotics, hyperprolactinaemia is sometimes reported though significantly less often than for risperidone and amisulpride. Our review of the data found that for quetiapine reported rates range from 0-29% and for olanzapine from 6-40% (Bushe et al, 2008) although most studies report rates at the lower end of the spectrum. In a recent 6 month study of schizophrenia, patients randomised to quetiapine or olanzapine, 33% had hyperprolactinaemia at baseline which normalised in almost all patients as early as 14 days (Bushe et al, 2009). There were no significant differences between the drugs in changes in

The depot formulation of olanzapine has recently been trialled in a complex, non-inferiority study compared with oral olanzapine. The quality of the data and trial design has meant that aspects such as dose response with variables such as prolactin have been investigated (Hill et al, 2011). Significant dose-related changes in prolactin were measured over the 24 week study, however it should be noted that a small mean increase in prolactin was measured only in the cohort receiving 600 mg/month (oral equivalent estimated as 20 mg/day). In this 600 mg/month cohort, 7/21 of female subjects (33%) moved from a normal into a high range level (Table 1). This emphasises the importance of analysing prolactin data not only as mean changes in a cohort but also the categorical changes to provide data that are meaningful in terms of patient outcomes (Bushe et al, 2008). This concept is also well demonstrated in the 555 schizophrenia patient study, Schizophrenia Trial of Aripiprazole ( STAR), in which subjects were randomised to either aripiprazole or standard of care treatment (Hanssens et al, 2008; Kerwin et al,2007). There was a mean decrease of 34.2 mg/dl in the aripiprazole-treated cohort, however using a categorical analysis,

4 mg.

risperidone (Berwaerts et al, 2010).

that may give maximal benefit.

hyperprolactinaemia was reported in 16.8% of subjects.

prolactin.

The totality of the data is convincing that there is no such entity as a "prolactin-sparing" antipsychotic, however, data are sometimes complex to interpret. There are numerous confounding factors but broadly psychotropic polypharmacy, the choice and the dose of medication are relevant factors as are often the lack of reported data on previous antipsychotic treatment. Adherence is also important as many typicals are now administered by long-acting depot formulations whereas rates of non-adherence to all forms of antipsychotic are high. When these factors are compounded with other confounders (gender, age and smoking), definitive statements regarding prolactin become less precise though some conclusions can be made with reasonable certainty.

Much of the reported data tend to come from relatively short-term clinical trials, often done for drug registration purposes, or cross-sectional prevalence data. Neither data set has properly established the long-term trajectory of hyperprolactinaemia and there are no data to support the concept of regression back to baseline.

There are, however, a number of disparate data on comparable rates of hyperprolactinaemia amongst antipsychotics and the largest data sets reporting prolactin include a 6-week paliperidone study in 628 schizophrenia patients (Kane et al, 2007) and a 1-year risperidone and haloperidol in first episode psychosis study in 555 patients (Schooler et al, 2005). Cohort sizes range from <50 to 2725 (Bushe et al, 2010). There is also surprisingly little dissonance amongst the data sets despite many of the confounders already discussed. .

In summary, for individual antipsychotics the prevalence of hyperprolactinaemia is highest in risperidone, paliperidone and amisulpride-treated patients and approaches 100% in female patients (72-100%) being significantly higher than in patients treated with conventional antipsychotics (33% in a UK cohort on depot antipsychotics) (Bushe et al, 2008; Bushe and Shaw 2007). The recently licensed paliperidone, which is 9-hydroxyl-risperidone, the active metabolite of risperidone, has similar prolactin elevation to risperidone (Berwaerts et al, 2010).

Clinicians have been aware for many years that risperidone is associated with hyperprolactinaemia, however there has been less clarity regarding whether hyperprolactinaemia with risperidone is more prevalent than with conventional antipsychotics. A key study was a long-term, randomised clinical trial (RCT) in first-episode psychosis with subjects randomised to risperidone or haloperidol and a median treatmentlength of 206 days (Schooler et al, 2005). This study reported significantly higher rates of hyperprolactinaemia (74% vs. 50%) and mean prolactin levels in the risperidone cohort than the haloperidol cohort. CATIE also reported significantly greater prolactin elevation with risperidone than perphenazine (Lieberman et al, 2005) though only mean changes in individual drug cohorts were reported, not categorical numbers of patients with hyperprolactinaemia.

Although conventional antipsychotics were for a long time regarded as almost uniformly being associated with hyperprolactinaemia, the data are not supportive of this conclusion and recent data on conventional antipsychotics suggest significantly lower prevalence rates of 33-35% in a depot-treated population (Bushe and Shaw, 2007). In part, this may relate to dosing issues. For example, Asian populations using higher doses of haloperidol (15-16mg) than typically used in Europe, have prevalence rates of hyperprolactinaemia (60-66%) approaching those of risperidone and amisulpride (Bushe et al, 2010). Supportive of this dosing issue is the excellent study from Kleinberg in approximately 2000 patients which

The totality of the data is convincing that there is no such entity as a "prolactin-sparing" antipsychotic, however, data are sometimes complex to interpret. There are numerous confounding factors but broadly psychotropic polypharmacy, the choice and the dose of medication are relevant factors as are often the lack of reported data on previous antipsychotic treatment. Adherence is also important as many typicals are now administered by long-acting depot formulations whereas rates of non-adherence to all forms of antipsychotic are high. When these factors are compounded with other confounders (gender, age and smoking), definitive statements regarding prolactin become less precise

Much of the reported data tend to come from relatively short-term clinical trials, often done for drug registration purposes, or cross-sectional prevalence data. Neither data set has properly established the long-term trajectory of hyperprolactinaemia and there are no data

There are, however, a number of disparate data on comparable rates of hyperprolactinaemia amongst antipsychotics and the largest data sets reporting prolactin include a 6-week paliperidone study in 628 schizophrenia patients (Kane et al, 2007) and a 1-year risperidone and haloperidol in first episode psychosis study in 555 patients (Schooler et al, 2005). Cohort sizes range from <50 to 2725 (Bushe et al, 2010). There is also surprisingly little dissonance

In summary, for individual antipsychotics the prevalence of hyperprolactinaemia is highest in risperidone, paliperidone and amisulpride-treated patients and approaches 100% in female patients (72-100%) being significantly higher than in patients treated with conventional antipsychotics (33% in a UK cohort on depot antipsychotics) (Bushe et al, 2008; Bushe and Shaw 2007). The recently licensed paliperidone, which is 9-hydroxyl-risperidone, the active metabolite of risperidone, has similar prolactin elevation to risperidone

Clinicians have been aware for many years that risperidone is associated with hyperprolactinaemia, however there has been less clarity regarding whether hyperprolactinaemia with risperidone is more prevalent than with conventional antipsychotics. A key study was a long-term, randomised clinical trial (RCT) in first-episode psychosis with subjects randomised to risperidone or haloperidol and a median treatmentlength of 206 days (Schooler et al, 2005). This study reported significantly higher rates of hyperprolactinaemia (74% vs. 50%) and mean prolactin levels in the risperidone cohort than the haloperidol cohort. CATIE also reported significantly greater prolactin elevation with risperidone than perphenazine (Lieberman et al, 2005) though only mean changes in individual drug cohorts were reported, not categorical numbers of patients with

Although conventional antipsychotics were for a long time regarded as almost uniformly being associated with hyperprolactinaemia, the data are not supportive of this conclusion and recent data on conventional antipsychotics suggest significantly lower prevalence rates of 33-35% in a depot-treated population (Bushe and Shaw, 2007). In part, this may relate to dosing issues. For example, Asian populations using higher doses of haloperidol (15-16mg) than typically used in Europe, have prevalence rates of hyperprolactinaemia (60-66%) approaching those of risperidone and amisulpride (Bushe et al, 2010). Supportive of this dosing issue is the excellent study from Kleinberg in approximately 2000 patients which

though some conclusions can be made with reasonable certainty.

amongst the data sets despite many of the confounders already discussed. .

to support the concept of regression back to baseline.

(Berwaerts et al, 2010).

hyperprolactinaemia.

concluded that although risperidone was associated with higher rates of hyperprolactinaemia compared with 10 mg haloperidol, no comparative differences emerged with 20mg haloperidol (Kleinberg et al, 1999). Doses of haloperidol currently used are more reflective of studies such as EUFEST, in which the maximum permitted dose was 4 mg.

Our own naturalistic series concluded that hyperprolactinaemia with oral risperidone was indeed almost 100% in females and between 63-100% in males (Bushe et al, 2008). Similar levels of hyperprolactinaemia are measured with amisulpride though data in large cohorts is lacking other than from EUFEST (Bushe et al, 2008). Depot formulations of risperidone may have a lower prevalence of hyperprolactinaemia relating to dose (53-67%) (Bushe et al, 2008; Bushe and Shaw, 2007). Paliperidone is the major metabolite of risperidone (9 hydroxyl-risperidone) and prolactin values are either similar or greater than those of risperidone (Berwaerts et al, 2010).

Aripiprazole is associated with the lowest rates of hyperprolactinaemia with prevalence rates of 3-5% in RCTs that increase to incidence rates of 17% in naturalistic studies (Bushe et al, 2010) .Recent data have evaluated aripiprazole as a prolactin-lowering agent when combined with haloperidol or risperidone with some success. Although studies report rapid reductions in prolactin levels after commencing aripiprazole (Shim et al, 2007), this may partially relate to removal of a previously used prolactin-elevating drug. Aripiprazole, however, in a placebo controlled trial when added to high-dose haloperidol (20-25 mg/day) in a cohort of schizophrenia patients resulted in normalisation of prolactin in 85% of subjects by 8 weeks contrasting with 3.6% of the placebo group (p<0.001) (Shim et al, 2007). Further research is indicated into the dosage of aripiprazole that may give maximal benefit.

For the remaining antipsychotics, hyperprolactinaemia is sometimes reported though significantly less often than for risperidone and amisulpride. Our review of the data found that for quetiapine reported rates range from 0-29% and for olanzapine from 6-40% (Bushe et al, 2008) although most studies report rates at the lower end of the spectrum. In a recent 6 month study of schizophrenia, patients randomised to quetiapine or olanzapine, 33% had hyperprolactinaemia at baseline which normalised in almost all patients as early as 14 days (Bushe et al, 2009). There were no significant differences between the drugs in changes in prolactin.

The depot formulation of olanzapine has recently been trialled in a complex, non-inferiority study compared with oral olanzapine. The quality of the data and trial design has meant that aspects such as dose response with variables such as prolactin have been investigated (Hill et al, 2011). Significant dose-related changes in prolactin were measured over the 24 week study, however it should be noted that a small mean increase in prolactin was measured only in the cohort receiving 600 mg/month (oral equivalent estimated as 20 mg/day). In this 600 mg/month cohort, 7/21 of female subjects (33%) moved from a normal into a high range level (Table 1). This emphasises the importance of analysing prolactin data not only as mean changes in a cohort but also the categorical changes to provide data that are meaningful in terms of patient outcomes (Bushe et al, 2008). This concept is also well demonstrated in the 555 schizophrenia patient study, Schizophrenia Trial of Aripiprazole ( STAR), in which subjects were randomised to either aripiprazole or standard of care treatment (Hanssens et al, 2008; Kerwin et al,2007). There was a mean decrease of 34.2 mg/dl in the aripiprazole-treated cohort, however using a categorical analysis, hyperprolactinaemia was reported in 16.8% of subjects.

Prolactin and Schizophrenia, an Evolving Relationship 443

periods has not been clinically recommended due to risk of worsening of the mental state although in theory this could be considered a diagnostic tool for patients taking oral

The management of treatment-emergent hyperprolactinaemia is complex and many of the issues have been considered by the 2008 prolactin guidelines who referenced previous recommendations (Serri et al, 2003). However, newer data have since emerged allowing novel potential management strategies to be considered (Peveler et al, 2008). Levels <1000 mIU/L can simply be monitored but in the presence of symptoms that suggest sex hormone deficiency, it is suggested that such levels should not be allowed to continue long-term due to the potential risk of bone mineral density loss (Peveler et al, 2008). Persistent levels >1000 mIU/L need consideration for medication change or dose reduction, if appropriate. The consensus group concluded that the use of dopamine agonists should be considered only in exceptional circumstances due to the risk of worsening the psychosis (Peveler et al, 2008). This view however is challenged by the Maudsley guidelines (Taylor et al, 2009) which advocate use of dopamine agonists if patients need to remain on the specific prolactinelevating antipsychotic. They make an interesting observation that although the three agents cited (amantadine, cabergoline and bromocriptine ) have the potential to worsen psychosis, that this has not been shown in clinical trials. Although there are many reviews relating to prolactin in the context of severe mental illness, there are currently few, if any, systematic reviews and meta-analyses. A recent systematic review that incorporated a meta-analysis compared the effects of bromocriptine and cabergoline in treating hyperprolactinaemia due to idiopathic causes and prolactinomas (Dos Santos Nunes et al, 2011). They concluded that cabergoline was significantly superior to bromocriptine in normalising both prolactin levels and resuming normal ovulatory cycles. Thus, cabergoline may potentially be the dopamine

What is currently emerging in an early research phase is the use of specific polypharmacy designed to reduce prolactin levels whilst maintaining treatment on the original antipsychotic. There is little doubt that aripiprazole may have the lowest potential for prolactin elevation, although as we have already stated, in the STAR study 17% of patients did have hyperprolactinaemia (Kerwin et al, 2007 ;Hanssens et al, 2008) although in RCTs, the prevalence rates of 3% seem consistent (Bushe et al, 2008). The combination of adding aripiprazole to risperidone results in significant reductions in plasma concentrations of prolactin of between 35-63%, with maximal benefit measured with aripiprazole doses around 6 mg (Yasui-Furukori, 2010) and possibly doses as low as 3 mg. In 2009, the Maudsley guidelines stated their view that in the presence of symptomatic hyperprolactinaemia options included changing antipsychotics or adding aripiprazole to the existing treatment. As a strategy it is clear that there may be benefit to some patients, however aripiprazole as a partial dopamine agonist has been shown to be associated with worsening of psychosis in some patients. The complete risk-benefit equation for use of aripiprazole in this manner will require further clinical trials. Other salient issues to consider include the reality that schizophrenia the illness, and its associated symptomatology, is the cause of some of the more overt sexual dysfunction (Malik et al, 2011). Reducing prolactin may not always lead to clinical improvement. The correlation between prolactin and sexual dysfunction however is thus complex. In a case series

**8. The management of treatment-emergent hyperprolactinaemia** 

preparations (Peveler et al, 2008).

agonist of choice should this be mandated.


Table 1. Prolactin changes over 24 weeks with depot olanzapine at various dosages in a randomised controlled trial (Hill et al, 2011)
