**7. What are the current views of EU guidelines on all aspects of prolactin?**

Only one set of guidelines, published in 2008, is devoted to prolactin and it provides both advice and the data and rationale behind the consensus group's conclusions (Peveler et al, 2008). Prior to this many guidelines did not give specific recommendations (Citrome et al, 2008). In general terms, other guidelines and relevant Summaries of Product Characteristics do not provide a specific monitoring schedule and tend to advocate prolactin monitoring only when symptoms are detected.

In 2006, guidelines on bipolar disorder from the National Institute of Clinical Excellence recommended limited pre-treatment monitoring of prolactin levels for risperidone with further monitoring should symptoms develop. The only other guideline to recommend pretreatment monitoring are the Maudsley guidelines (Taylor et al, 2009). These guidelines recommend baseline prolactin monitoring, followed up at 6 and 12 months. Furthermore, the guidelines advise switching medications if hyperprolactinaemia is symptomatic or, alternatively, adding aripiprazole. The guidelines also concur broadly that hyperprolactinaemia is associated with both short- and longer term adverse events that include bone mineral density loss and a possible increase in the risk of breast cancer. The 2005 recommendations from the World Federation Society of Biological Psychiatry (WFSBP) curiously conclude that whereas prolactin elevation was frequent with amisulpride and typicals (>10%), it was measured only "sometimes" (<10%) with risperidone (Falkai et al, 2006). Current data now seems to have clarified these frequencies rather differently (Bushe et al, 2010; Bushe et al, 2008). The 2008 UK prolactin guidelines recommend prolactin monitoring in all patients pre-treatment regardless of medication and after 3 months of treatment with a stable dose, in addition to further monitoring when there are relevant clinical symptoms (Peveler et al, 2008). With a normal prolactin level there is no further need for monitoring in the absence of clinical symptoms. Significant dose change should also lead to consideration of further monitoring. These UK guidelines give a clear strategy for investigating the aetiology of hyperprolactinaemia in patients receiving antipsychotics and warn against concluding too easily that antipsychotics are responsible. A differential diagnosis must be considered but must always include a pregnancy test in females and thyroid function tests. Prolactin levels can be elevated to levels in excess of >2000 mIU/L in patients taking antipsychotics, however in any patient with prolactin elevation greater than 3000 mIU/L, a prolactinoma should be considered and referral to an endocrinologist is warranted. In the Halifax cohort we measured prolactin levels >2000 mIU/L in 13% of all antipsychotic-treated females and 2% of males. Antipsychotic cessation even for short

Table 1. Prolactin changes over 24 weeks with depot olanzapine at various dosages in a

**7. What are the current views of EU guidelines on all aspects of prolactin?** 

Only one set of guidelines, published in 2008, is devoted to prolactin and it provides both advice and the data and rationale behind the consensus group's conclusions (Peveler et al, 2008). Prior to this many guidelines did not give specific recommendations (Citrome et al, 2008). In general terms, other guidelines and relevant Summaries of Product Characteristics do not provide a specific monitoring schedule and tend to advocate prolactin monitoring

In 2006, guidelines on bipolar disorder from the National Institute of Clinical Excellence recommended limited pre-treatment monitoring of prolactin levels for risperidone with further monitoring should symptoms develop. The only other guideline to recommend pretreatment monitoring are the Maudsley guidelines (Taylor et al, 2009). These guidelines recommend baseline prolactin monitoring, followed up at 6 and 12 months. Furthermore, the guidelines advise switching medications if hyperprolactinaemia is symptomatic or, alternatively, adding aripiprazole. The guidelines also concur broadly that hyperprolactinaemia is associated with both short- and longer term adverse events that include bone mineral density loss and a possible increase in the risk of breast cancer. The 2005 recommendations from the World Federation Society of Biological Psychiatry (WFSBP) curiously conclude that whereas prolactin elevation was frequent with amisulpride and typicals (>10%), it was measured only "sometimes" (<10%) with risperidone (Falkai et al, 2006). Current data now seems to have clarified these frequencies rather differently (Bushe et al, 2010; Bushe et al, 2008). The 2008 UK prolactin guidelines recommend prolactin monitoring in all patients pre-treatment regardless of medication and after 3 months of treatment with a stable dose, in addition to further monitoring when there are relevant clinical symptoms (Peveler et al, 2008). With a normal prolactin level there is no further need for monitoring in the absence of clinical symptoms. Significant dose change should also lead to consideration of further monitoring. These UK guidelines give a clear strategy for investigating the aetiology of hyperprolactinaemia in patients receiving antipsychotics and warn against concluding too easily that antipsychotics are responsible. A differential diagnosis must be considered but must always include a pregnancy test in females and thyroid function tests. Prolactin levels can be elevated to levels in excess of >2000 mIU/L in patients taking antipsychotics, however in any patient with prolactin elevation greater than 3000 mIU/L, a prolactinoma should be considered and referral to an endocrinologist is warranted. In the Halifax cohort we measured prolactin levels >2000 mIU/L in 13% of all antipsychotic-treated females and 2% of males. Antipsychotic cessation even for short

405 mg/month (N=318)


600 mg/month (N=141)

300 mg/month (N=140)

Mean change (micrograms/l) (SD)

randomised controlled trial (Hill et al, 2011)

only when symptoms are detected.

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 preparations (Peveler et al, 2008).

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

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 agonist of choice should this be mandated.

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

Prolactin and Schizophrenia, an Evolving Relationship 445

without clinical symptoms, as stated by the authors. Studies suggest that children are more sensitive to the prolactin elevating adverse effects of antipsychotics and care is needed to keep these to a minimum (Correll, 2011). The second high risk group would include those

1. **What are the longer term trajectories of prolactin levels for patients with elevated prolactin?** Research has firmly established that hyperprolactinaemia emerges within days as a consequence of treatment and, as we have shown in a large RCT, equally rapidly reverts to normal with removal of the prolactin-elevating antipsychotic (Bushe et al, 2009). What is less well established is the trajectory of prolactin levels over a longer term period. Do they remain at the same level? Short-term RCTs are unlikely to address this issue and current data that follow patients for 1 year have only reported baseline and endpoint data, not the trajectory of the prolactin response (Schooler et al, 2005). In the absence of a proven mechanism for how and why antipsychotics elevate

2. **What are the longer term outcomes for patients with elevated prolactin?** Over the last 10 years patients receiving biologics to treat rheumatoid arthritis have been entered into voluntary, long-term databases that have addressed, albeit in a naturalistic manner, incidence of potentially associated adverse events (cancers, reactivation of tuberculosis (TB), serious infections). There is a need to formally determine the longer term harm of untreated hyperprolactinaemia in psychiatry. The last decade has better defined potential longer term sequelae of hyperprolactinaemia and these clearly cannot be measured within formal RCTs. In 2011, the clear options involve using either large epidemiological databases, prospectively and retrospectively or creating prospective collections of clinical data such as through usage of registers. The challenge exists in creating appropriate databases that allow long-term follow up of both prolactin levels and clinical outcomes. Certainly the data on bone fractures (Howard et al, 2007; Abel et al, 2008) has shown us the potential. The World Health Organization (WHO) initiated a number of databases to measure cancer rates in schizophrenia in the 1970s (Bushe and Hodgson, 2010) and have the knowledge and ability to conduct similar projects

3. **What is and how can we measure the true risk-benefit of switching antipsychotic treatments**? There is absolute agreement that usage of drugs such as dopamine agonists have significant potential to worsen schizophrenia illness (Peveler et al, 2008). This creates a dichotomy where the clinician can reduce the dose or change the antipsychotic, or do nothing. There is no single pragmatic endpoint that captures this risk. A relatively short-term RCT (1 year or less) looking at formal changes in rating scales, remission levels or relapse rates may be helpful. At a minimum, it may tell us the psychiatric outcome of switching patients from prolactin-elevating antipsychotics compared to maintaining the status quo. It is difficult to see any individual institution or pharmaceutical company undertaking such a complex and expensive study, and the only viable option would be for larger bodies, such as the European Medicines Agency, National Institute of Mental Health or potentially WHO to undertake this

with a relevant strong family history of breast cancer or osteoporosis.

**10. Further research. What are the unanswered questions?** 

prolactin differentially (Bushe et al, 2010), one can only speculate.

worldwide relating to outcomes of hyperprolactinaemia.

work.

although all subjects had reduction in prolactin levels, only around half reported improved sexual function (Chen 2011). The reality of the situation is that individual patients will require individual solutions. A physician considering changing an antipsychotic in a stable patient must carefully balance the risks and benefits of continued treatment.

There will be patients who are clearly at high risk of prolactin-related adverse events for whom usage of potentially prolactin-elevating antipsychotics needs to be carefully considered,eg, patients with a history of breast cancer or osteoporosis. The other angle to management is to ensure high screening rates for patients at high risk of treatment-emegent osteoporosis and provision of relevant treatment to potentially reduce fracture incidence (Graham et al, 2011).
