The positive effects of 12 weeks of probiotics and vitamin D in chronic schizophrenia?

The findings reported by Amir Ghaderi and colleagues [1] (open-access) provide the blogging fodder today, and the results of a study looking at a "novel combination of vitamin D and probiotic on metabolic and clinical symptoms in chronic schizophrenia." Said probiotic formulation contained "Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum (each 2 × 109)" and was delivered over a period of 12 weeks alongside a vitamin D supplement - "50,000 IU vitamin D3 every 2 weeks" - utilising a "randomized, double-blind, placebo-controlled trial" design. We are also told that the trial protocol was "retrospectively registered."

The Ghaderi study wasn't solely focused on what their combined intervention might do for the 'clinical symptoms' of schizophrenia despite this being a prominent part of the results obtained. They also wanted to examine things like "biomarkers of oxidative stress and cardiometabolic risk in chronic schizophrenia." This was done via the measurement of marker compounds pertinent to establishing total antioxidant capacity, total glutathione levels and high-sensitivity C-reactive protein (hs-CRP) among other things.

Results: first things first, vitamin D supplementation raised vitamin D levels in those who received the vitamin D + probiotic supplement. Not exactly an unexpected result I grant you, but important from the point of view that any subsequent findings *could* be linked to those increasing vitamin D levels. Further: "Vitamin D and probiotic co-supplementation was associated with a significant improvement in the general... and total PANSS scores." PANSS stands for the Positive and Negative Syndrome Scale and has some important uses in the context of schizophrenia, and the presentation of positive and negative symptoms. That all being said, the authors also mention how their supplementation combination did not seemingly affect scores on another measure included in the study - the Brief Psychiatric Rating Scale (BPRS) - which kinda demonstrates that vitamin D + probiotics is not a panacea for every aspect of schizophrenia.

Researchers also report on how their combined supplement also *correlated* with a some changes in those oxidative stress and cardiometabolic risk measures included for study in line with other study results (see here). There's quite a bit of data so I won't provide details. Suffice to say that some of them might be 'positively' important to those health inequalities that seem to follow a diagnosis of schizophrenia (see here).

What else? Well, I can't seem to find too much in the way of side-effects details in the Ghaderi paper so I'm assuming that it wasn't a significant issue. The fact that participants in the study were "being hospitalized during the intervention" means that they were, I assume, being monitored with greater assiduity than for example if they were in the community, including looking for potential side-effects.

And with that, and the requirement for further study (see here and see here), I say no more...

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[1] Ghaderi A. et al. Clinical and metabolic response to vitamin D plus probiotic in schizophrenia patients. BMC Psychiatry. 2019; 19:77.

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"people on the autism spectrum have a high prevalence of physical and mental health conditions in midlife and old age"

Should anyone really be that surprised by the findings reported by Lauren Bishop-Fitzpatrick & Eric Rubenstein [1] talking about "a high prevalence of physical and mental health conditions in midlife and old age" when it comes to autism?

Well, yes and no. No, because things like 'psychiatric symptoms and disorders' have already been talked about with regards to older age adults with autism [2] (see here also), alongside various other 'medical comorbidity' being noted in this group (see here). But also yes, because the scale of the physical and mental health conditions identified by Bishop-Fitzpatrick & Rubenstein is quite literally jaw-dropping: "immune conditions (70.6%), cardiovascular disease (49.0%) and its risk factors (46.2%), sleep disorders (85.3%), gastrointestinal disorders (49.7%), neurologic conditions (55.9%), and psychiatric disorders (72.0%) were highly prevalent in our full sample." Said full sample consisted of "de-identified Medicaid claims data for 143 adults with a recorded autism spectrum disorder diagnosis aged 40–88 years."

Researchers also mention how 44% of their sample had an intellectual (learning) disability. This kinda accords with various other data on this topic (see here). Other observations mentioned by the authors also complement existing (peer-reviewed scientific) knowledge that: (a) intellectual (learning) disability seems to bring about an increased risk of epilepsy appearing alongside autism (see here), and (b) depression and anxiety prevalence seems to be particularly elevated in those with autism without any accompanying learning disability (see here) (assuming that depression and/or anxiety are actually being screened for in those with autism + learning disability).

What do the collected data imply? Well, screening is important. Screen and screen and screen and screen. Screen for lots of things, and if something turns up, treat / manage it. If your average Jane or Joe turned up at their Doctors office with a sleep disorder or the symptoms of cardiovascular disease, medical professionals would do something about it. If the Doctor also knew that Jane / Joe might, for example, be more likely than usual to be in receipt of certain classes of medicines that potentially elevates such risks further, they'd be even more keen to screen and intervene. So it should be the same if Joe or Jane is diagnosed with autism or an autism spectrum disorder (ASD).

I'd also suggest that such data should really be leading to a lot more questioning about why? Why do people on the autism spectrum seem to be at particularly high risk of 'immune conditions' or 'digestive disorders'? Are there potential genetic links between autism and such conditions as per the notion that 'autism genes aren't necessarily just genes for autism' (see here) or that such genes might also affect other biological systems as well as the grey-pink matter floating around the skull (see here for example)? Are there other intricate connections between such classes of conditions as per the idea that sleep problems seem to follow gut problems for some (see here)? Why? Pain, discomfort, something else? And don't even get me started on the whole 'immune system - autism' connection (see here for example) which has been known about for many, many, many years. Known about but brushed under the carpet by some.

And whilst talking about the research tag-team that is Bishop-Fitzpatrick & Rubenstein, I once again would direct you to another important paper of theirs [3] about how we need to be very careful about using the word 'comorbidity' when referring to the various mental and physical issues that are over-represented around autism. As we've seen from other research (see here and see here), the core features of autism may very well predispose to a lot more than just autism and, in that respect, this might go way beyond just comorbidity...

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[1] Bishop-Fitzpatrick L. & Rubenstein E. The physical and mental health of middle aged and older adults on the autism spectrum and the impact of intellectual disability. Research in Autism Spectrum Disorders. 2019. Jan 29.

[2] Lugo-Marín J. et al. Prevalence of psychiatric disorders in adults with autism spectrum disorder: A systematic review and meta-analysis. Research in Autism Spectrum Disorders. 2019; 59: 22-33.

[3] Rubenstein E. & Bishop-Fitzpatrick L. A matter of time: The necessity of temporal language in research on health conditions that present with autism spectrum disorder. Autism Res. 2019 Jan;12(1):20-25.

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Mortality patterns in older adults with learning disability

"Older adults with ID [intellectual disability] in Sweden carry a higher mortality risk compared with the general population, mainly attributable to respiratory, nervous and circulatory diseases."

So said the findings reported by Nawi Ng and colleagues [1] (open-access) looking at the records of some 15,000 individuals diagnosed with an intellectual (learning) disability compared with a similar number of control participants with respect to "patterns and risk of mortality." Researchers observed "a 4-fold higher mortality rate and a shorter median survival time among older adults with ID compared with the general older adult population." Such findings add to a growing body of research literature (see here and see here) suggesting that behavioural, cognitive and/or psychiatric diagnoses seem to be accompanied by some significant health inequalities too.

I could go into the details about the Ng study and the various ins-and-outs of how they arrived at their conclusions but to be honest, I'm just not minded to. I say that on the basis that the figures speak for themselves: "the mortality rate among individuals with ID was three times higher than in the control population" and: "Individuals with DS [Down's syndrome] had an 11-fold higher mortality risk than the control population." Sombre reading, perhaps partially reflecting how modern-day society treats some of its most vulnerable citizens.

The ultimate question should be: is there anything that can be done to improve this situation for those with a learning disability? Yes, is the answer; taking into account how a diagnosis of ID for example, means that some might be "more prone to cardiovascular disease risk factors, morbidity and mortality than the general population." The authors add that: "Cardiovascular disease health promotion and prevention programmes should be tailored for individuals with ID, to prevent or delay cardiovascular diseases and premature mortality in this vulnerable group." Corresponding action in relation to deaths resulting from epilepsy for example, should also (and always) be a priority.

"How a society treats its most vulnerable is always the measure of its humanity" is a phrase attributed to many speakers. On the basis of the research from Ng and other study results, society is seemingly failing many of those diagnosed with a learning disability as it is other vulnerable sections of society (see here).

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[1] Ng N. et al. Mortality patterns and risk among older men and women with intellectual disability: a Swedish national retrospective cohort study. BMC Geriatrics. 2017; 17: 269.

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Vitamin D deficiency and psychosis

In amongst my various ramblings about how vitamin D - the sunshine vitamin/hormone - might show more than a few connections to conditions/labels outside of just the English disease (see here), I've covered some science on a possible connection with psychosis (see here) and schizophrenia (see here). There are still gaps in terms of the hows and whys of vitamin D insufficiency and deficiency when it comes to this area of psychiatry, but I believe there is enough science in this area to initially warrant screening of vitamin D levels as and when a diagnosis is received. This similarly extends to other labels too (see here and see here).

The paper by Lally and colleagues [1] (open-access) puts a little more scientific flesh on the bones about how vitamin D insufficiency/deficiency might manifest in cases of psychosis, with a particular focus on "increased cardiovascular disease risk factors and in particular metabolic syndrome [MetS]."

With thanks to Brendon Stubbs (one of the authors of the paper) for bringing the findings to my attention, researchers set about looking at "the prevalence of vitamin D deficiency in a cohort of community patients with established psychotic illnesses" (N=324). Given my earlier mention of the 'English disease', the cohort were indeed all living in England and drawn from a larger study initiative. Vitamin D levels were assayed via a chemiluminescence immunoassay based on the examination of serum samples. Various other measures were also included for study around the issue of cardiovascular risk factors including body mass index (BMI), waist circumference, blood pressure, serum cholesterol levels and glucose levels. High sensitivity serum C-reactive protein (HS-CRP) was also included.

Results: "Almost half of the sample (48.8 %, n = 158) were deficient in vitamin D while only 13.9 % (n = 45) had sufficient vitamin D." Ethnicity seemed to play a role in those determinations of deficiency/sufficiency with vitamin D levels generally lower in those who were black African or black Caribbean. Likewise the season of testing showed an effect. When it came to determining whether there was an association between vitamin D status and mental state, researchers reported nothing significant based on the use of the Positive And Negative Syndrome Scale (PANSS) and related measures.

But... there might be quite a bit more to look at when taking into account those cardiovascular disease risk factors and vitamin D levels as the authors reported various significant correlations. So: "those with the highest levels of vitamin D have a lower prevalence of MetS (20.5 %), compared to those in the lowest (39.1 %), second (48.3 %) and third quartile (43.1 %) of vitamin D." Indeed, just about every measure of cardiovascular risk showed an association with measured serum vitamin D levels when controlling for "age, gender, ethnicity and season of 25-OHD blood sampling." The authors also add that: "Those engaging in low intensity physical activity over the week prior to sampling... had significantly lower 25-OHD levels... than those who engaged in moderate or high intensity physical activity."

Teasing apart what might actually be doing what is a difficult task in such studies where various outcome measures might be implicated. The authors do speculate on how for example, their finding of "raised CRP and vitamin D deficiency in established psychosis" might tie into other research on inflammation or inflammatory processes with both variables in mind (see here and see here). Indeed, this might also tie in with calls for further integration of immunopsychiatry with psychotic disorders in mind [2]. But there remains more to do, including the intriguing question: "would the supplementation of vitamin D in psychosis prevent and/or ameliorate cardiovascular and metabolic risk?"

I do have some small points to make about the study that might also require attention in follow-up work, not least the idea that immunoassay for determining functional vitamin D levels might not be the most accurate method [3]. Indeed, the authors make this point in their conclusions. One might also hope that comparisons with other patient groups might offer some further information about how specific the findings are to just psychosis or other psychiatric groupings. If found in a more general sense, the idea that vitamin D is related to variables affecting cardiovascular risk in such groups could make lots and lots of waves.

For now however, this research extends the ideas that: (a) preferential screening for vitamin D might be indicated for this group/label, and (b) the focus on psychiatric presentation should not be made at the expense of somatic presentation. Parity of esteem and all that; or rather just making sure that health inequality does not follow from receipt of a psychiatric label...

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[1] Lally J. et al. Clinical correlates of vitamin D deficiency in established psychosis. BMC Psychiatry. 2016; 16: 76.

[2] Leboyer M. et al. Is it time for immunopsychiatry in psychotic disorders? Psychopharmacology (Berl). 2016 Mar 18.

[3] Yang Y. et al. High-throughput measurement of 25-hydroxyvitamin D by LC-MS/MS with separation of the C3-epimer interference for pediatric populations. Clin Chim Acta. 2016 Feb 15;454:102-6.

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Lally, J., Gardner-Sood, P., Firdosi, M., Iyegbe, C., Stubbs, B., Greenwood, K., Murray, R., Smith, S., Howes, O., & Gaughran, F. (2016). Clinical correlates of vitamin D deficiency in established psychosis BMC Psychiatry, 16 (1) DOI: 10.1186/s12888-016-0780-2