Risk of breast cancer in women with schizophrenia: meta-analysed

"In this meta-analysis of 12 cohort studies that included 125 760 women and in which conventional methods of meta-analysis had been used, schizophrenia in women was associated with an increased breast cancer incidence compared with the general population."

That was a primary findings reported by Chuanjun Zhuo & Patrick Triplett [1] following their survey of the peer-reviewed research literature on the topic of breast cancer risk and schizophrenia up to August 2017. The authors caution however that their review of this topic might not be the last word on it - "it is possible that a future study will show a decreased breast cancer risk in women with schizophrenia compared with the general population" - given "substantial between-study variance" among the research literature they examined. Another very good example of how the currency of science is probability and big sweeping generalisations may not necessarily stand the test of time.

"The status of physical health in patients with schizophrenia has become an important topic in health care management research" introduced the the Zhuo/Triplett paper, and with it, important recognition that diagnoses like schizophrenia can lead to an over-emphasis on the psychiatric often to the detriment of the somatic (see here). This, allied to other findings that have suggested that risk of premature mortality from various somatic complaints / diagnoses / issues is potentially heightened in relation to schizophrenia (see here).

Authors located studies fulfilling their study entry criteria, including "schizophrenia identified as exposure at baseline" and "documented incidence of breast cancer on follow-up" and applied their statistical analyses to results. Importantly: "Studies reporting breast cancer–related mortality rather than incidence were also excluded because the mortality outcome may be affected by many factors other than breast cancer incidence, such as comorbidities and treatments." Most of the included studies/data were found to be methodologically sound based on scores on the Newcastle-Ottawa Scale.

Alongside their finding that women with schizophrenia seemed to be at an elevated risk of breast cancer, authors also suggested that "intensive prevention and treatment against breast cancer are warranted for women with schizophrenia." So yes, this means discussing about potentially modifiable risk factors for breast cancer such as alcohol use and obesity (obesity, at the time of writing, being something of a focus for one large cancer charity here in Blighty). But this also means looking at how schizophrenia and its management might also place someone at elevated risk of something like breast cancer as a result of it sometimes being a "hormone-dependent cancer" and, as the authors note, "a significant positive association between plasma prolactin levels and the risk of breast cancer, has been observed." Minus any scaremongering, prolactin elevations have been noted following the use of certain antipsychotic medicines typically indicated for schizophrenia [2] and other conditions (see here). Any additional risk needs to be managed, and managed well.

I don't think anyone should be unduly alarmed by the Zhuo/Triplett results, but rather more mindful of the fact that a psychiatric diagnosis does not disqualify someone from other risks of more somatic conditions / complaints. The key, yet again, is screening and keeping an open mind...

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[1] Zhou C. & Triplett PT. Association of Schizophrenia With the Risk of Breast Cancer Incidence: A Meta-analysis. JAMA Psychiatry. 2018. March 7.

[2] Wu Chou AI. et al. Female schizophrenia patients and risk of breast cancer: A population-based cohort study. Schizophr Res. 2017 Oct;188:165-171.

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Psychopharmacologic intervention for adults with autism: systematically reviewed

"The results indicate that only two medications, fluoxetine and risperidone, can be considered as promising evidence-based practices for adults with ASD [autism spectrum disorder]."

So said Lauren Taylor [1] and her (systematic) review of what might work, pharmaceutically speaking, when it comes to managing "behavioural disturbance in adults with ASD." Including over 40 studies examining psychopharmacology in adults diagnosed with ASD, Taylor concluded that many medicines/formulations did not cut the scientific mustard in this area. Further: "The subsequent establishment of clinical guidelines for medication use in this population is essential."

My first thoughts when I came across the Taylor paper was the guidance provided here in Blighty with regards to medication and autism (see here). To quote from the NICE document as it currently stands: "Do not use antipsychotic medication for the management of core symptoms of autism in adults. Do not use antidepressant medication for the routine management of core symptoms of autism in adults." One might argue that the review detailed by Taylor does not just focus on 'core symptoms' but rather a wider recognition of "psychiatric and behavioural disorder in adults with autism" in light of what is known about comorbidity (see here for example). Based on this assumption, there are indeed various levels of evidence to suggest that for some at least, time-sensitive trials of psychopharmacology might be useful where autism is mentioned.

But just before the floodgates are opened to widespread use of preparations such as fluoxetine and risperidone 'for autism', a word or two of caution. First and foremost are a few questions that everyone should be asking when confronted with so-called challenging behaviours (behavioural disturbances?) when it comes to autism: 'Is the behaviour something new?' and 'What might the triggers be?' I say this because I've covered this topic before, and sometimes one needs to turn detective before reaching for the medicines cabinet (see here). Second, the advantages of such medicines use has to be always balanced against potential side-effects from medication. Not to come down to hard on something like risperidone for example, there is a volume of research suggesting a possible link between this medicine use and elevated prolactin levels for example (see here). Monitoring is key. Finally, the idea that there is increased recognition of 'psychiatric comorbidity' being potentially over-represented alongside a diagnosis of autism is an important one for preferential screening (see here). When emphasizing the possibility of a heightened risk of schizophrenia or psychotic disorder when it comes to the autism spectrum (see here), one might look to the wider literature for clues about how one might mitigate such risk (see here and see here for example). I say that last point with the knowledge that within the massive heterogeneity that is autism, not every person is going to transition to schizophrenia or other psychotic disorder and not every experience of this phenomenon when it does happen, will be the same.

And like buses, yet more on the issue of psychopharmacological intervention for autism [2]. Conclusion: "Overall, randomized, placebo-controlled studies of medications for the treatment of ASD are scarce."

Indeed.

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[1] Taylor LJ. Psychopharmacologic intervention for adults with autism spectrum disorder: A systematic literature review. Research in Autism Spectrum Disorders. 2016; 25: 58-75.

[2] Accordino RE. et al. Psychopharmacological Interventions in Autism Spectrum Disorder. Expert Opin Pharmacother. 2016 Feb 18.

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Taylor, L. (2016). Psychopharmacologic intervention for adults with autism spectrum disorder: A systematic literature review Research in Autism Spectrum Disorders, 25, 58-75 DOI: 10.1016/j.rasd.2016.01.011

Schizophrenia and the risk of fractures

The systematic review and meta-analysis published by Brendon Stubbs and colleagues [1] provides some food for thought for healthcare providers and others looking at the wider implications following a diagnosis of schizophrenia. "People with schizophrenia are at significantly increased risk of fractures" was the conclusion reached based on the collected analysis of tens of thousands of people diagnosed with schizophrenia compared with nearly 4 million controls.

My immediate thought (and tweet) when I read this paper was whether this heightened risk of fracture may be connected to some of the various research done on the sunshine vitamin/hormone that is vitamin D and schizophrenia (see here) given the link between vitamin D and bone health. Acknowledging that correlation is not the same as causation and the requirement for some clarity on exactly how vitamin D might link into the presentation of schizophrenia, there is quite a body of evidence to suggest that a diagnosis of schizophrenia is in no way protective against vitamin D insufficiency or deficiency. Mmm, now where have I heard that before? Indeed, with reference to what other label have I read about bone health and vitamin D potentially being 'correlated'?

I might also add that in view of some evidence on the possible connection between vitamin D levels and dental caries for example, combined with the idea that certain dental conditions may be more likely in cases of schizophrenia [2], one might see something of a strengthening of the relationship between vitamin D status and schizophrenia?

But then there was this: "narrative review consistently highlighted that antipsychotic medication was an important risk factor for fractures." Very interesting. Indeed, after a short Twitter conversation with Brendon (@BrendonStubbs) about this, there was some mention of the idea that hyperprolactinemia might be something to consider (see a recent post) as a function of the link between certain antipsychotics and elevated levels of prolactin [3]. A quick scan of the research literature does indeed reveal that issues with bone mineral density (a potential feature increasing the risk of fracture) may well be present in cases of hyperprolactinemia in patients with schizophrenia [4]. Some interesting details to be sure.

Whatever the ways and means that might lead a person diagnosed with schizophrenia to show an increased risk of fracture, the paper from Stubbs et al offers a pretty clear message: "there is a need to develop preventative strategies to improve bone health and reduce fracture risk involving the wider multidisciplinary team and incorporating falls-prevention strategies." Save that is, any further health inequality being thrust on the label of schizophrenia.

So: Leftfield and Open Up to close.

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[1] 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.

[2] Tani H. et al. Dental conditions in inpatients with schizophrenia: a large-scale multi-site survey. BMC Oral Health. 2012 Aug 18;12:32.

[3] Haddad PM. & Wieck A. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs. 2004;64(20):2291-314.

[4] Kinon BJ. et al. Bone loss associated with hyperprolactinemia in patients with schizophrenia. Clin Schizophr Relat Psychoses. 2013 Oct;7(3):115-23.

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Stubbs B, Gaughran F, Mitchell AJ, De Hert M, Farmer R, Soundy A, Rosenbaum S, & Vancampfort D (2015). Schizophrenia and the risk of fractures: a systematic review and comparative meta-analysis. General hospital psychiatry PMID: 25666994

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