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Papers: Vitamin D supplementation may reduce many long term severe consequences of taking antipsychotics

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lxjuice

I hope this is relevant and useful for anyone who is either worried about or has started to suffer from the long term complications of antipsychotics, and is on this site for that reason.

 

Papers/references:

[1] A potential role for adjunctive vitamin D therapy in the management of weight gain and metabolic side effects of second-generation antipsychotics., Benjamin U. Nwosu, Bruce Meltzer, Louise Maranda, Carol Ciccarelli, Daniel Reynolds, Laura Curtis, Jean King, Jean A. Frazier, and Mary M. Lee, Pediatr Endocrinol Metab. 2011;24(9-10):619-26, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094142/

Abstract
Second-generation antipsychotic (SGA) medications introduced about 20 years ago are increasingly used to treat psychiatric illnesses in children and adolescents. There has been a five-fold increase in the use of these medications in U.S. children and adolescents in the past decade. However, there has also been a parallel rise in the incidence of side effects associated with these medications, such as obesity, dyslipidemia, insulin resistance, and diabetes mellitus. Despite the severity of these complications and their financial impact on the national healthcare budget, there is neither a clear understanding of the mechanisms contributing to these side effects nor the best ways to address them. Studies that examined lifestyle modification and pharmaceutical agents have yielded mixed results. Therefore, clinical studies using agents, such as vitamin D, which are inexpensive, readily available, with low side effects profile, and have mechanisms to counteract the metabolic side effects of SGA agents, are warranted. Vitamin D is a prohormone with skeletal and extraskeletal properties that could potentially reduce the severity of these metabolic side effects. Its role as an adjunctive therapy for the management of metabolic side effects of SGA agents has not been adequately studied. Effective strategies to curb these side effects will improve the overall health of youths with psychiatric illnesses who receive SGAs. Herein we present a pilot study on the use of vitamin D in patients on treatment with SGAs.

 

[2] Vitamin D deficiency exacerbates atypical antipsychotic-induced metabolic side effects in rats: Involvement of the INSIG/SREBP pathway, Dang R, Jiang P, Cai H, Li H, Guo R, Wu Y, Zhang L, Zhu W, He X, Liu Y, Xu P., Eur Neuropsychopharmacol. 2015 Aug;25(8):1239-47. doi: 10.1016/j.euroneuro.2015.04.028. Epub 2015 May 9., https://www.ncbi.nlm.nih.gov/pubmed/26003080

Abstract
Metabolic syndrome is a major concern in psychotic patients receiving atypical antipsychotics. Recent evidence suggests that sterol regulatory element-binding proteins (SREBPs) and insulin-induced genes (INSIGs) are implicated in the antipsychotic-induced metabolic side-effects. Vitamin D (VD) deficiency, a highly prevalent phenomenon among patients with psychosis, might also predispose individuals to metabolic syndrome Considering that VD has modulating effects on the INSIG/SREBP pathway, it is possible that VD may have a role in the antipsychotic-induced metabolic disturbances involving its effects on the INSIG/SREBP system. Thus, the present study aimed to evaluate the effects of VD deficiency and VD supplementation on antipsychotic-induced metabolic changes in rats. After 4-week administration, clozapine (10mg/kg/d) and risperidone (1mg/kg/d) both caused glucose intolerance and insulin resistance in VD deficient rats, but not in rats with sufficient VD status. Antipsychotic treatments, especially clozapine, elevated serum lipid levels, which were most apparent in VD deficient rats, but alleviated in VD-supplemented rats. Additionally, antipsychotic treatments down-regulated INSIGs and up-regulated SREBPs expression in VD deficient rats, and these effects were attenuated when VD status was more sufficient. Collectively, this study disclose the novel findings that antipsychotic-induced metabolic disturbances is exacerbated by VD deficiency and can be alleviated by VD supplementation, providing new evidence for the promising role of VD in prevention and treatment of metabolic disorders caused by antipsychotic medications. Furthermore, our data also suggest the involvement of INSIG/SREBP pathway in the antipsychotic-induced hyperlipidemia and beneficial effects of VD on lipid profile.

 

[3] Prevention of antipsychotic-induced hyperglycaemia by vitamin D : a data mining prediction followed by experimental exploration of the molecular mechanism, Takuya Nagashima, Hisashi Shirakawa, Takayuki Nakagawa, and Shuji Kanekoa, Sci Rep. 2016 May 20;6:26375. doi: 10.1038/srep26375., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873813/

Abstract
Atypical antipsychotics are associated with an increased risk of hyperglycaemia, thus limiting their clinical use. This study focused on finding the molecular mechanism underlying antipsychotic-induced hyperglycaemia. First, we searched for drug combinations in the FDA Adverse Event Reporting System (FAERS) database wherein a coexisting drug reduced the hyperglycaemia risk of atypical antipsychotics, and found that a combination with vitamin D analogues significantly decreased the occurrence of quetiapine–induced adverse events relating diabetes mellitus in FAERS. Experimental validation using mice revealed that quetiapine acutely caused insulin resistance, which was mitigated by dietary supplementation with cholecalciferol. Further database analysis of the relevant signalling pathway and gene expression predicted quetiapine-induced downregulation of Pik3r1, a critical gene acting downstream of insulin receptor. Focusing on the phosphatidylinositol 3-kinase (PI3K) signalling pathway, we found that the reduced expression of Pik3r1 mRNA was reversed by cholecalciferol supplementation in skeletal muscle, and that insulin-stimulated glucose uptake into C2C12 myotube was inhibited in the presence of quetiapine, which was reversed by concomitant calcitriol in a PI3K-dependent manner. Taken together, these results suggest that vitamin D coadministration prevents antipsychotic-induced hyperglycaemia and insulin resistance by upregulation of PI3K function.

 

My piece:

 

The mechanism by which several antipsychotics share several severe long term consequences such as metabolic syndrome has been a total mystery up until some years ago. We didn't even know if it was one mechanism. Even now very few people even psychiatrists seem to be aware of the discovered link. If you are blood tested either at the start of treatment or intermittently, they will test lots of symptomatic markers, but no causative ones and certainly not vitamin D.

 

The papers speak for themselves, especially [3]. Maintaining good vitamin D levels will prevent diabetes and metabolic syndrome. It's a shame that while this paper received a fair amount of press, the medical profession didn't pay much attention and clinical practice is unaffected.

I posted [1] to highlight how far back vitamin D was considered, yet it's still not common practice to check it. I posted [2] to show how there was seemingly little follow-up and the researchers in [3] found vitamin D by themselves. How is there so little consistency in research sometimes!

 

Now why didn't I just post a press release for [3] on the media forum? Well here is some conjecture but it is still mostly based on what we know than guesswork. Vitamin D depletion causes many problems beyond metabolic syndrome. If you take the side effects list of quetiapine from wikipedia it's not just hyperglycaemia and hyperlipidemia that overlap with vitamin D depletion. High cholesterol, liver enzymes, lethargy (and other psychiatric side effects), all the inflamed organs (hepatitis etc), all the low immune system markers (neutropenia etc), cardiomyopathy - just off the top of my head, are all linked to varying degrees but usually strongly, to vitamin D deficiency. It is also no coincidence that these effects are rare which would correlate to the long amount of time it takes to both deplete vitamin D plus start suffering consequences from that. These consequences are shared amongst many antipsychotics. They are also amongst the most severe and long term consequences of taking them so it should be a lot of comfort that you are at least reasonably protected if your vitamin D levels are good.

 

So my advice to anyone coming off APs due to worry of long term side effects is that the best thing to do is to stick to whatever is best for your situation regarding your taper but get tested for vitamin D and supplement it. I would suggest getting tested to be on the safe side because we don't know much from a clinical perspective - how much APs deplete vitamin D, whether it varies depending on the person, and whether all of these variables put together allows for the usual 400-5000 IU/day people take to be good for everyone.

Even if you are already suffering from long term sides that can be linked to vitamin D, if they are not too far progressed you may be able to reverse or at least halt them by restoring vitamin D. If this is you I would definitely talk to your doctor about it as it's nothing to do with your taper and not even directly due to your AP, if you are worried about them telling you to taper differently based on this.

If vitamin D causes a hypersensitivity reaction to you due to withdrawal syndrome it is definitely a good idea to get tested because you may be taking too much and can find you can get away with less. Now I can take 5000 IU (but I don't) but when I did after stopping sertraline I couldn't. It overactivated me for several hours.

I imagine many doctors will be receptive to giving you a blood test for vitamin D once you show them the link between it and antipsychotic use. Particularly if you have started to or are suffering from these complications. If not there are usually at home tests you can order online for not too much money - prick your finger for a blood sample and post it back.

 

None of this applies to movement disorders. I don't know much about them but I do know vit D is not implicated in tardive dyskinesia.

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Altostrata

Interesting, lxjuice, thank you.

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