Hyperprolactinemia and risperidone use in autism

The findings reported by Yaowaluck Hongkaew and colleagues [1] (open-access) on prolactin levels being "positively and significantly associated with risperidone dose" in cases of children and adolescents diagnosed with an autism spectrum disorder (ASD) is the point of discussion today.

Prolactin by the way, is the hormone most commonly associated with stimulating breast development and milk production in women. To quote from the US National Institute of Health (NIH) entry on prolactin: "There is no known normal function for prolactin in men." Risperidone is a neuroleptic (antipsychotic) which has quite a few clinical indications including for the management of irritability in (some) autism [2]. Indeed, risperidone is one of the few (only?) drugs to be specifically approved for pediatric autism and dealing with irritability.

It's been known for a while that risperidone use is associated with elevations in prolactin levels [3]. More recently, the research base has expanded to suggest that various factors might impact on the elevations in prolactin correlated with risperidone use [4] including "sex, pubertal stage, psychiatric disease, and associated autoimmune disorders."

So, then to the Hongkaew study which is open-access but...

• Data on 147 children and young adults diagnosed with an autism spectrum disorder (ASD) were included for study. "All participants receiving a risperidone-based regimen for at least 4 weeks were enrolled in this study." Researchers also made sure that (a) medication was taken before the donation of a blood sample, and (b) participants were not taking other medications "that could potentially affect risperidone metabolism and prolactin elevation." This did not however exclude all other medicines.
• Said blood draws was analysed for serum prolactin concentration using a chemiluminescence immunoassay system.
• Results: "mean risperidone dose of the subjects was 1 mg/day or 0.03 mg/kg/day" and "mean duration of therapy was 46.06 months". Sixty-six participants (44%) presented with hyperprolactinemia - elevated levels of serum prolactin - most of whom were male. 
• Dosage of risperidone also seemed to have an effect on prolactin results: "The median prolactin level at the high dose was significantly higher than at the recommended dose and low dose" based on categorisations of dose higher or lower than the FDA recommended amount taking into account body weight.
• Duration of treatment, age, weight and other variables did not show any statistical correlation with prolactin levels.
• The authors conclude: "This information will be helpful to clinicians by providing significantly important clinical information to properly inform therapeutic practice and prevent sexual dysfunction consequently in autistic children treated with risperidone."

I don't mean to come down too hard on risperidone with this post but this is not the first time that prolactin levels have been reported as elevated when it comes to autism [5] following the use of this pharmaceutic. Aside from the aesthetic changes potentially associated with higher prolactin levels and in particular, their potential effects on males (the subject of litigation), there is some suggestion in the literature that elevations in prolactin over the longer term might elevate risk of certain other issues [6] albeit correlation not necessarily being the same as causation and reiterating the duration of treatment measured by Hongkaew et al. As an aside, I'm going to be coming to the paper by Stubbs and colleagues [7] in the near future in light of other work on the potential effects of elevated prolactin.

Insofar as the use of risperidone for managing irritability in cases of autism, I've talked before about it's usefulness in this area and how certain adjuvant therapies might also help (see here). Accepting that irritability under the heading of 'challenging behaviours' is a mighty complicated issue (see here) and potentially tied into many different factors, there remains a place for risperidone under certain circumstances (assuming good medicines management accompanies such use). 

Still, the collected literature on prolactin and risperidone use with autism in mind adds a cautionary note to this medicine and other relations allied to other important side-effects such as weight gain. Use and monitor with care is perhaps the important message from the Hongkaew and other data...

Music: the quite controversial Disarm from the Smashing Pumpkins.

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[1] Hongkaew Y. et al. Hyperprolactinemia in Thai children and adolescents with autism spectrum disorder treated with risperidone. Neuropsychiatr Dis Treat. 2015 Jan 22;11:191-6.

[2] Dinnissen M. et al. Clinical and pharmacokinetic evaluation of risperidone for the management of autism spectrum disorder. Expert Opin Drug Metab Toxicol. 2015 Jan;11(1):111-24.

[3] Aboraya A. et al. Hyperprolactinemia associated with risperidone: a case report and review of literature. Psychiatry (Edgmont). 2004 Nov;1(3):29-31.

[4] Margari L. et al. Prolactin variations during risperidone therapy in a sample of drug-naive children and adolescents. Int Clin Psychopharmacol. 2015 Mar;30(2):103-8.

[5] Anderson GM. et al. Effects of short- and long-term risperidone treatment on prolactin levels in children with autism. Biol Psychiatry. 2007 Feb 15;61(4):545-50.

[6] Tworoger SS. et al. A 20-year prospective study of plasma prolactin as a risk marker of breast cancer development. Cancer Res. 2013 Aug 1;73(15):4810-9.

[7] Stubbs B. et al. Schizophrenia and the risk of fractures: a systematic review and comparative meta-analysis. Gen Hosp Psychiatry. 2015 Jan 15. pii: S0163-8343(15)00005-5.

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Hongkaew Y, Ngamsamut N, Puangpetch A, Vanwong N, Srisawasdi P, Chamnanphon M, Chamkrachchangpada B, Tan-Kam T, Limsila P, & Sukasem C (2015). Hyperprolactinemia in Thai children and adolescents with autism spectrum disorder treated with risperidone. Neuropsychiatric disease and treatment, 11, 191-6 PMID: 25653528