Vitamin D and Other Immune Regulating Therapies for Schizophrenia

Brain tonic!

Within the last year the understanding of schizophrenia has advanced considerably. Most notably, the origins of the disease have been traced to an overactive expression of the C4 (complement component 4) immune system protein, which is responsible for tagging neurons for “pruning” (destruction) in the adolescent and young adult brain. This “overdrive brain pruning” leads to the devastating symptoms of schizophrenia (delusions, hallucinations, difficulties in planning and life management, paranoia and social isolation). Earlier research, in 2014, linked ultra-high-risk individuals (in terms of developing schizophrenia) to overactive microglial activity. (Microglia are the macrophage immune system cells of the central nervous system, destroying “plaques, damaged or unnecessary neurons and synapses, and infectious agents.“)

A number of different genes in the short arm of chromosome 6, all associated with the immune system, influence expression of the C4 protein. This has made finding “the schizophrenia gene” very difficult (because there isn’t a single one), and only recent advances in gene sequencing and computational statistical analysis have provided a glimpse of understanding in terms of how and why schizophrenia develops.

Which genes, exactly, are involved? In 2014 a group of researches claimed to have isolated eight specific subtypes of schizophrenia, based on different gene “networks.” In other words, not a single schizophrenia gene, but interactions of various alleles leading to the schizophrenic phenotype. Other psychiatric geneticists have criticized the methods and findings, saying “not so fast.” Obviously there is plenty of work still to be done.

It does seem likely that multiple genes are involved, that there are both genetic and environmental factors, and that the disease can manifest in different ways (without or without severe paranoia, with or without mood symptoms, etc.).

What interests me at this point are the following questions:

1. If schizophrenia is an immune disease, can therapies that modulate/regulate the immune system halt the progression of symptoms?
2. If the expression of the C4 protein is regulated to within a normal range, to what extent can the adult schizophrenic brain heal itself? And to what extent would this correspond with a reduction of schizophrenic symptoms and a reduced reliance on psychiatric medication?
3. What potential therapies (nutritional, social, circadian, etc.) could potentially influence the expression of the C4 protein and normalize immune function in those people genetically vulnerable to the development of schizophrenia?

My Own Direct Experience

I have a close family member who has experienced schizoaffective (basically schizophrenia and manic-depression) symptoms for more than twenty years. His symptoms started in late high school and have continued throughout his adult life, controlled to some extent by medication regimes (including, at various times, high-dose lithium, Depakote, Prozac, Latuda, Cogentin, Navane, and Clozaril — not all at the same time and not all prescribed by the same psychiatrist).

For the vast majority of that time this family member has been “mid-functioning” — living independently, holding down a job, and engaging socially with family members, but no career, lasting friendships, or long-term romantic relationships. Those have been the good times. The bad times have involved hospitalizations (voluntary), one extended period of homelessness, extremely strained family relationships, and worse. Mental illness sucks.

At times I have tried to suggest nutritional interventions that might improve health and potentially, gradually reduce reliance on psychiatric medications (all of which have dangerous side effects). Sometimes I’ve given good advice (fish oil to improve mood), other times not so good (I recommended nicotinamide for social anxiety, but this resulted in severe sugar cravings — possibly because of the way this vitamin interacts with insulin). So my credibility with this person is just so-so. As we all know, getting any family member to make any lifestyle adjustment is pretty much impossible. Often the best you can do is lead by example, and be willing to answer questions if asked.

Note that I’ve never taken any kind of Tom Cruise “psychiatry is evil” position — I’m all for better living through chemistry, and chemicals are chemicals. Some drugs are dangerous (depending on the dose), and so are some nutritional supplements. Some are effective, some just make your pee expensive.

But I am deeply interested in adjunct nutritional therapies for mental illness, for the following reasons:

1. Even if they don’t work to improve mental illness symptoms, they might have other positive effects (on weight, immune function, blood pressure, etc.).
2. They’re inexpensive (at least compared to most psychiatric medications).
3. Moderate dietary adjustments and nutritional supplements are unlikely to do much harm, as long as they aren’t presented as a cold-turkey alternative to currently prescribed medications.

Vitamin D and Schizophrenia

My first thought when I learned about the link between immune function and schizophrenia was “I wonder if vitamin D is involved?” My own experience of cessation of asthma symptoms after a dietary change and vitamin D supplementation was only a single data point, but I’d read dozens of anecdotes on Mark Sisson’s site and others of people who had reversed autoimmune conditions with lifestyle changes (better diet, vitamin D, sun exposure, etc.).

It didn’t take long to find this article, an overview of research looking at the association between vitamin D levels and schizophrenia symptoms. Multiple studies point to a strong inverse relationship. There have yet to be clinical trials experimenting directly with therapeutic vitamin D supplementation, but for individuals with below-normal vitamin D levels and symptoms of psychosis, it seems like a reasonable adjunct therapy at the very least.

Here’s a meta-analysis of vitamin D and schizophrenia. The authors state “We found a strong association between vitamin D deficiency and schizophrenia.”

“We found a strong association between vitamin D deficiency and schizophrenia.” –Valipour G¹, Saneei P, Esmaillzadeh A.

Here’s a detailed review of vitamin D/schizophrenia research.

In addition to increasing calcium absorption and strengthening bones, vitamin D functions as a sort of master immune system regulator. Vitamin D regulates the function of hundreds of immune system genes, and low vitamin D levels are associated with autoimmune disorders. It makes sense that getting vitamin D to optimal levels might reduce schizophrenic symptoms, especially in the early onset of the disease.

Can the Adult Schizophrenic Brain Heal?

Much of the vitamin D research looks at vitamin D levels and the development of schizophrenia. Keeping vitamin D levels in a good range during adolescence and early adulthood may be a good way of reducing the risk for those that are genetically vulnerable to the disease.

But what about adults who have experience schizophrenic symptoms for decades? Is it too late for them? Most of these individuals will have reduced cortical thickness, basically brain damage, from the progression of the disease.

Recent neuroimaging studies show that the adult schizophrenic brain is constantly trying to heal itself, and that during the long progression of schizophrenia there are both losses and gains in cortical thickness. It’s not all downhill. Possibly the right combination of therapies (drug, nutritional, social, etc.) could modulate C4 expression to the point where growth phases overtake shrinkage phases.

Depakote (valproate)

Depakote (generic name valproate) is an interesting drug, and it’s the one psychiatric drug I might even consider taking experimentally. Often prescribed an an alternative to high-dose lithium (which, unlike micro-dose lithium, can cause flattening of mood and has serious associate health risks), I’ve heard Depakote nicknamed “Dope-a-kote.” At high doses, grogginess and drowsiness are common side effects.

Despite its serious potential side effects, Depakote is a drug that has potential brain healing qualities. For injured brains, valproic acid (one form of valproate) increases white matter repair and neurogenesis. If I experienced a brain injury, even a serious concussion, I would consider asking for a low-dose valproate prescription as part of my recovery protocol.

The most fascinating aspect of valproate? One study found that valproate reawakened the ability to learn perfect pitch in adult men, an ability that can usually only be acquired in certain period of childhood.

But Depakote is not some miracle brain healing drug. In studies of epileptic patients, valproate use was associated with reduced cortical thickness and brain volume. But valproate is associated with increased brain plasticity, and this may have therapeutic implications for treating long-term schizophrenia. Unfortunately it’s also a toxic drug with many nasty side effects.

Marijuana and Schizophrenia

There’s an association between early marijuana use and the onset of mental illness. But is this causation or correlation? Or even possibly self-medication?

THC modifies structure and function of the adolescent brain in numerous ways, including synaptic pruning. This article suggests that heavy marijuana use in adolescence may interfere with brain pruning mechanisms, resulting in increased cortical thickness, particularly in the left hippocampus, resulting in poorer verbal memory and attention span.

So, schizophrenia is a result of out-of-control brain pruning during adolescence and early adulthood, and marijuana reduces brain pruning during adolescence? Obviously it’s more complex than this, and even if schizophrenia and marijuana use do affect the adolescent brain in semi-opposing ways, it sounds a little like trying to get your kid clean while spraying them with a hose while they run around fully clothed. Inefficient, and likely to end in tears.

So to be clear, I am not recommending the use of marijuana to treat mental illness symptoms. Marijuana use can worsen schizophrenia symptoms in some people, and sometimes even causes acute psychosis in non-schizophrenic individuals. But I do wonder if some “wake ‘n bakers” are self-medicating, trading off some motivation and memory in order to stave off delusional thinking and hallucinations.

Early Intervention, Social Support and Immune Function

This long article by Jonathan Cohn describes the successes of early intervention in schizophrenia, a treatment philosophy that centers on early diagnosis, very low dose medication (patients are much more sensitive to psychiatric medications if they have never taken them before), non-permanent medication regimes, and abundant social support. I wish that my family member had access to this kind of treatment program when he first began experiencing symptoms.

Low-dose medication combined with talk therapy during the first two years of treatment is effective, according to an NIH-funded study. This seems to be the trend in treating young people experiencing schizophrenic symptoms, and I think it’s a good one.

But there’s a lessons here for people with long-term schizophrenia too. Schizophrenia is essentially an immune-system disease, and social interactions, lifestyle, and even having a sense of meaning and purpose influence immune system function. The immune system basically has two general modes:

1. Threat mode: optimized to fight bacteria and infections and associated with “fight or flight” reactions, the immune system produces inflammatory compounds to kill pathogens. Effective, but when the immune system is in this mode all time it can lead to chronic inflammation, heart disease, cancer, and reduced longevity.
2. Peace mode: optimized to fight viruses (which we’re exposed to more when we’re around a lot of people).

“You have a forward-looking immune system,” Fredrickson told me, “If you have a long track record of adversity, it prepares you for bacterial infections. For our ancestors, loneliness and adversity were associated with bacterial infections from wounds with predators and fights with conspecifics.” On the other hand, if you are doing well and having a lot of healthy social connections, your immune system shifts forward to prepare you for viruses, which you’re more likely to contract if you’re interacting with a lot of people.

I suspect one reason early intervention is so effective at treating schizophrenia is the emphasis on social support. Is the “threat mode” of the immune system associated with increased expression of C4/microglial activity and overactive brain pruning? According to this paper, “microglial activation elicits a broad range of pro-inflammatory cytokines and chemokines that are involved in the recruitment and subsequent activation of peripheral immune cells infiltrating the infected CNS.” Just a lead, not an answer, but there does seem to be some relationship between social support and immune activity, and this extends to immune activity in the brain.

An Adjunct Nutritional Protocol?

I want to make it clear that I think the early intervention approach (very conservative medication combined with talk therapy and social support) is probably the best treatment plan for young people experiencing the first symptoms of schizophrenia. I’ve also written in detail about what my pipe dream of an ideal intake process would look like. Policy makers, that’s my two bits.

I’m not in favor of any kind of “all natural, drugs are bad” approach to mental illness. In paleolithic times, people with mental illness were probably socially ostracized and then died of starvation or exposure. I’m in favor of what works, what’s humane and compassionate and honors both personal choice and public safety (California’s 5150 rule is a good guideline, threading that needle pretty well).

With that in mind, what kind of nutritional protocol would I recommend, in additional to early intervention therapies? Basically the exact same thing I recommend in my Asthma Protocol post:

1. Supplemental vitamin D3 to get blood levels into the “high normal” range. 5000IU a day will probably be enough for most people, but absorption can vary based on fructose and alcohol intake. Combining vitamin D with some form of chelated magnesium (glycinate, malate, etc.) is a good idea to balance increased calcium absorption and prevent constipation which sometimes results from higher doses. The best time to take vitamin D is probably in the morning, with food/fat.
2. Omega-3 supplementation, either from fatty fish (sardines, wild salmon) and/or fish oil. Generally good for brain function and mood support, I’ve written extensively about the benefits of moderate-dose omega-3 intake here.
3. A “more paleolithic” diet, not necessarily strict paleo but making whatever dietary modifications are necessary to reduce intestinal permeability (“leaky gut”) which tends to correspond with autoimmune disorders. This might mean reducing or eliminating wheat, other grains containing gluten, cow dairy, refined sugar, and/or alcohol.

Once again, not a “natural cure for schizophrenia,” but rather dietary changes that might help (and probably won’t harm), and may reduce reliance on medication, especially if implemented early in the course of the disease.

If you’re suffering from schizophrenic symptoms, or have a family member or friend who is, my heart goes out to you. It’s a rough disease. Hang in there, and don’t give up hope, and don’t let it ruin your life.

Psychiatrists, geneticists, and other scientists who are working on this problem, thank you and please keep going! After a decades-long dry spell, some progress is finally being made.