Get ready to amend your dopamine hypothesis and stop trying to wrap your neurons around the role of glutamate in the brain.  The rising star of the neurobiological schizophrenia literature is…. Vitamin D.  Yes, really.

The more sceptical amongst you (including me) may feel that finding a vitamin deficiency in psychosis patients is perhaps not surprising, and certainly not the most pressing health concern for this patient group.  It is widely accepted by the medical professions and charities, and highlighted by initiatives such as the Royal College of Psychiatry’s HeAL (Healthy Active Lives) statement (previously blogged about on Mental Elf), that chronic mental illness and continued treatment with antipsychotic medication impacts heavily upon your physical health.  Patients with schizophrenia, according to the Schizophrenia Commission’s recent report (PDF), die on average 15-20 years younger than the general population and are twice as likely to die from heart disease.  The report also suggests that people with severe mental illness ‘have poorer diets, take less exercise and smoke more than the general population’ (pg 37).

So why does such a seemingly niche physical concern – a deficiency of a particular vitamin – matter?

Well, in their comprehensive review of the role of vitamin D in brain development and function, Eyles et al (2013) propose a role for vitamin D in the development of schizophrenia.  They highlight the importance of vitamin D in brain development: particularly in relation to the cell-cycle of neurons – especially cell death and cell differentiation – and the relationships between abnormalities in these processes and further abnormalities in dopamine metabolism in the brain.  Since dopamine is widely considered central to neurobiological differences in psychosis, this is a notable relationship.  Apart from a study by McGrath et al (2010), which found a relationship between neonatal levels of vitamin D precursors in the blood and risk of schizophrenia, much of the work investigating the effects of pre- and peri-natal vitamin D deficiency on the developing brain has been done using rat models.  Eyles et al propose that these models are useful for investigating the developmental neurobiology of schizophrenia, since they replicate many neurobiological and behavioural aspects of schizophrenia – therefore emphasising the parallels or even equivalence between a vitamin D deficient (rodent) brain and a psychosis-like (rodent) brain.

But what do we know about vitamin D in adult humans?  All these associations and behaviours in rats are all very well and good, but what is the state of the evidence for vitamin D’s association with psychosis in us?

These questions are exactly what Murri et al (in press, Schizophrenia Research) asked in their “mini meta-analysis” of research addressing vitamin D and psychosis.

Methods

Murri et al carried out a PubMed search for relevant studies in order to address whether:

• Psychosis patients have lower vitamin D levels than healthy controls (and how much lower)?
• Lower-than-average vitamin D levels are specific to psychosis?
• Vitamin D levels are associated with the severity of psychotic symptoms?
• Giving vitamin D would improve psychotic symptoms?

To answer these questions, Murri et al performed separate meta-analyses comparing patients with psychosis against healthy controls and comparing patients with psychosis against patients with other psychiatric diagnoses.

Only 7 studies were found that fit criteria for the meta-analysis.  (Hence the description of the meta-analysis as “mini”, I presume…!)

Results

The results were as follows:

• Patients with psychosis did have significantly lower vitamin D levels than healthy controls (6 studies analysed).
  • The large effect size for this result reduced (to medium) after excluding outliers (5 studies analysed).
  • All studies demonstrated mean levels of vitamin D ‘in the range of insufficiency’ for their psychosis group.
  • Another study not included in the meta-analysis found no difference between the vitamin D levels in patients with psychosis and healthy controls.
• There was a non-significant finding that patients with psychosis have lower vitamin D levels than patients with major depression (3 studies analysed).
• 2 studies examined the relationship between severity of vitamin D deficiency and severity of psychotic symptoms: 1 found no correlations; 1 found correlations between low vitamin D and high disorientation, psychomotor activity, low physical energy and somatic complaints.
• No studies were found examining the effect of vitamin D supplements on psychotic symptoms.
• Low vitamin D levels were associated with: seasonality, ethnicity (darker skin pigmentation), poor diet and low levels of objectively-measured sun exposure.  Vitamin D levels did not correlate with self-reported sun exposure or time spent in hospital.
  • None of the above factors fully explained the differences in vitamin D levels between patients and controls.

Conclusions

Murri et al’s meta-analysis was seriously hampered by the very small number of relevant studies available and their ‘significant heterogeneity’ – notably, there was not a single study available that tested whether giving a vitamin D supplement to patients with psychosis improved their symptoms.

Those of you with keen eyes will notice that Murri et al only used one research database.  This is unusual for a meta-analysis, and the decision to use only PubMed and not search several different databases for relevant studies isn’t explained in the paper.  This is another serious limitation of the study.

Unsurprisingly, the main conclusion that I take away from this paper is that research on vitamin D deficiency in psychosis is at a very preliminary stage.  Murri et al have identified a need for more research in this area – particularly that addressing the potential use of vitamin D supplements therapeutically and the specificity of vitamin D deficiency to psychosis over other diagnoses.

It also seems that more accurate measures or definitions of the factors affecting vitamin D levels (for example, exposure to sunlight – which is considered to be vital by the Vitamin D Council) are required in order to understand why factors expected to correlate with vitamin D levels (i.e. self-reported sun exposure) did not appear to do so.

Importantly for the understanding of the role in vitamin D in the development of psychosis, Murri et al state that:

At present, the few available evidence does not support a clear pathophysiological role of [vitamin D] in adult psychosis: its levels did not correlate with specific symptoms of psychosis and were not significantly different from those found in major depression, making [vitamin D] deficiency a more probable consequence than a cause of psychosis.

So, as a spectator of the field, it’s ok to be sceptical for now: where research is available, it is limited and conflicting.

But what we really need is more involvement: more research and more people pushing the development of this knowledge-base further.  Eyles et al and other authors have outlined a feasible and persuasive argument for the role of vitamin D in the development of psychosis and Murri et al have found something going on but have been held back by the lack of research…

Watch this space!

Links

Belvederi Murri M, Respino M, Masotti M, Innamorati M, Mondelli V, Pariante C, Amore M. Vitamin D and psychosis: Mini meta-analysis. Schizophr Res. 2013 Jul 29. pii: S0920-9964(13)00361-7. doi: 10.1016/j.schres.2013.07.017. [Epub ahead of print] [PubMed abstract]

Healthy Active Lives (HeAL): Tackling premature death in young people with psychosis. André Tomlin, Mental Elf, 19 June 2013.

The abandoned illness: a report from the Schizophrenia Commission (PDF). The Schizophrenia Commission 2012, Rethink Mental Illness.

Eyles, D.W, Thomas, T.H.J., & McGrath, J.J. (2013).  ‘Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease.’ Frontiers in Neuroendocrinology.  [Abstract]

McGrath JJ, Eyles DW, Pedersen CB, et al. Neonatal Vitamin D Status and Risk of Schizophrenia: A Population-Based Case-Control Study. Arch Gen Psychiatry.2010;67(9):889-894. doi:10.1001/archgenpsychiatry.2010.110.

The Vitamin D Council website. Last accessed 6 Sep 2013.