**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 as low as 500 mIU/L being associated with an increased risk of breast cancer in the general population over the medium term (Tworoger and Hankinson 2006, Tworoger et al, 2007). However, it is critical to understand that whereas there is a strong link between prolactin and breast cancer in the general population, there are no data to address this topic in schizophrenia and bipolar disorder. In addition, breast cancer has very many aetiological factors that include social demographics, education, obesity and family history and the role of prolactin is simply not known.
