Stem Cell Research Provides New Approach to Study Bipolar Disorder

 

Researchers have detected mitochondrial abnormalities, and differences in neuronal firing, in young neurons from patients with bipolar disorder by using induced pluripotent stem-cell (iPSC) technology. These stem cells are created from patient’s skin cells (fibroblasts) or from patient’s white blood cells (lymphocytes). It is possible to take skin cells or white blood cells and reverse engineer them back to the state where they have the ability to grow into different types of cells (basically back to the very early embryo state when the original template cells are just beginning to turn into different types of cells.)  Then these stem cells can be grown in the lab and encouraged to become neurons. By imaging these created neurons from people with and without bipolar disorder, researchers have seen a difference in neuron firing between people who respond to lithium treatment vs those who don’t respond to treatment. This hyperexcitability activity of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment.

Mitochondria are structures found within all cell types, and they are the organelles that help provide energy for the cells, along with other important functions. Mitochondria contain their own DNA separate from the cell’s nuclear DNA. Mitochondria DNA is mainly inherited from the egg, therefore the maternal side of the family. In one study, in about 80% of the bipolar patients, hippocampal mitochondria were smaller than even the smallest of the control subjects’ mitochondria. The hippocampus is the elongated ridges on the floor of each lateral ventricle of the brain, thought to be the center of emotion, memory, and the autonomic nervous system. Differences in expression of the genes in the mitochondria were also found between subjects and controls. Is it possible then that a greater predisposition to bipolar disorder could be influenced by the maternal family side?

Brain research is complicated because tissue is difficult and dangerous to extract, and studying brain tissue after death doesn’t give us a good picture of cause and effect across the lifetime. In post-morteum brain tissue, abnormalities could be due to a number of different environmental exposures (such as drug treatment) or trauma such as concussions that are difficult to control in living subjects. A model that does not use living subjects is difficult to create.

However,  researchers have been able to use stem cell from patients to create tissue in the lab for study.  They can take stem cells and “engineer” them to create many different types of tissues; in this study they use patients’s stem cells to create neurons. The hyperexcitability of the neurons is one early indicator of bipolar disorder, and this model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

Here is a link to the study in Nature:

https://www.ncbi.nlm.nih.gov/pubmed/28242870

And a link to one of the earlier studies:

https://www.nature.com/nature/journal/v527/n7576/full/nature15526.html

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C4 and Schizophrenia

When I hear “C4” I immediately think of the television series “Lost” and explosive material. C4 is also the shortened name of Complement component 4- one of a group of proteins that work together to make the immune system.  The C4 gene that codes for this protein is on Chromosome 6, and everyone has different variations in this gene, referred to alleles. Researchers from the Broad Institute, Harvard Medical School and Boston Children’s Hospital, recently published a study with a hypothesis that a key cause of schizophrenia involves different alleles of this gene. The researchers noted that people who had schizophrenia were more likely to have a certain variation that promotes neural “pruning.”

Pruning is part of normal brain development during childhood, and especially during adolescence. Pruning is the process where synapses in the brain are eliminated. It is believed that the purpose of synaptic pruning is to remove unnecessary neuronal structures from the brain; as the human brain develops, the need to understand more complex structures becomes much more pertinent, and simpler associations formed at childhood are thought to be replaced by complex structures.

It may be that different alleles cause different amounts of pruning. Perhaps less pruning, which could lead to too much information being retained, could be a risk factor for mental health.  This could be one of the factors contributing to schizophrenia- there are likely many genetic and environmental factors. More knowledge of these mechanisms may be helpful in creating or refining treatment.

Here is the link to the study’s abstract:

http://www.nature.com/nature/journal/v530/n7589/full/nature16549.html#access

Business Insider’s Discussion of Direct-to-Consumer Genetic Testing (with some quotes from yours truly)

I was interviewed for Business Insider Magazine regarding Kailos direct to consumer genetic tests. I think Lydia did a nice job discussing the benefits and limitations of at home genetic testing.genes

Here’s her article:

I shipped my spit to a genetics company to have it tested, 23andMe style — here’s what I found out

That information can be used for everything from finding out where your family came from to figuring out if you’re predisposed to certain diseases.

Companies like AncestryDNA and23andMe have been partnering with drug companies to try and figure out what role genetics plays in getting sick, and how it can help us get better faster.

But how much can the average consumer learn from his or her genes?

I decided to try out some tests from Kailos Genetics, a genetic-testing company based in Huntsville, Alabama, to find out. All of the tests Kailos offers are designed to help determine how you might respond to certain medications. These include antidepressants, contraceptives, breast-cancer medication, pain-management treatments, blood thinners, and stomach-acid reducers. You can also opt for an all-inclusive test that includes all of these genetic markers.

About me: I’m a 22-year-old woman who is, apart from some seasonal allergies, healthy. I ordered the contraceptives and antidepressant tests that Kailos offers, since those would be the types of medications I’d be most likely to use at this point in my life. I also have a family history of blood-clot problems, which in some cases can be worsened by oral contraceptives.

Here’s how it went down:

Sending my spit to Kailos

A week after ordering the two tests, I got a big purple envelope in the mail:

praxis envelope cropLydia Ramsey/Business Insider

The kit came with instructions, a letter explaining the test, two swabs, a collection bag, and an envelope:

kailos kitLydia Ramsey/Business Insider

I opened up the first swab and started collecting samples of my cheek tissue on the left side of my mouth. To get a good sample, I had to scrape the side of my cheek up and down with the swab for about 30 seconds.

IMG_4990Lydia Ramsey/Business Insider

After repeating the process with the other swab, I put both of them back in the collection bag, packed them all up in the return envelope, and shipped it off to Kailos for testing:

IMG_4992Lydia Ramsey/Business Insider

The results

Once Kailos’ diagnostic lab got my envelope, my sample went through an enrichment process to separate the genetic material — my DNA — from the rest of the stuff on the cotton swab so they can have a better look. Then, the lab technicians looked at my DNA and used a computer to home in on the genetic regions that are relevant to the specific test they were running.

Next, they turned the results over to Kailos’ in-house physicians to interpret the results. These doctors are what allow Kailos to sidestep the problem of needing a middleman — who’d most likely be my primary-care doctor — to discuss my results with me.

Instead of talking to a doctor, my results were posted online to my account on Kailos’ website, which I’d created to order the test.

Thumbs-up for medication No. 1

Screen Shot 2015 10 01 at 4.37.12 PMLydia Ramsey/Business Insider

For the first part of my results, which looked at whether I should avoid certain contraceptives, I saw two big “thumbs-up” symbols.

This meant that the test, which looked at two genes related to how my blood clots, found they were functioning normally — there was no reason they could see that I shouldn’t take the medication.

Those genes were my Factor 2 and Factor 5 genes. Research has found that people with a specific mutation, or tweak, on either of these genes can be at risk of dangerous blood clots, which can stop the blood from flowing from your heart to other parts of your body.

All of this is important for someone considering using contraceptives, since the kind that are taken orally (aka many traditional birth-control pills) can be linked with an increased risk of blood clots in some people; the hormone estrogen in the pills increases certain proteins in the blood that help it stick together and clot.

Thumbs-up for medication No. 1 … sort of

Screen Shot 2015 10 08 at 4.44.21 PMLydia Ramsey/Business Insider

The next part of my test results focused on whether I had genetic tweaks that could make it a bad idea for me to take antidepressants. The test looked at potential indications against taking three of the most popular types: tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs).

Genetics can give us clues about how good our body is at absorbing certain oral antidepressant medications. The CYP2D6 and CYP2C19 genes, for example, make proteins in the liver that break down a hefty proportion of prescription drugs, including antidepressants.

The good news? I should be good to go with all three types: I don’t have any mutations that would cause my body to absorb the drugs poorly.

But while my results suggested my body could handle any of these medications — should a psychiatrist or mental-health professional prescribe them to me, of course — experts say the results aren’t so clear.

Carmela Thompson, a genetic counselor with Genetic Discovery SF, told Business Insider that although she thinks genetic tests are great for figuring out if a person has a hereditary condition like Huntington’s disease, she wouldn’t recommend using them as the sole way to determine the best solution to treating psychiatric conditions.

At least not yet.

“As far as psychiatric conditions go, we’re not there yet and we may never be there,” said Thompson. That’s because the conditions often have multiple factors in addition to genes at play, like environmental factors, so what’s influenced by genetics isn’t quite as clear.

Why Kailos didn’t run into the same problem as 23andMe

Genetic testing companies, like 23andMe, have run into trouble with the FDA for not getting its approval before making their genetic-health tests, which are pretty similar to the ones Kailos offers, available.

But Kailos is already government regulated. As a Clinical Laboratory Improvement Amendments-regulated industry, Kailos’ lab facilities are regularly inspected by the Centers for Medicare and Medicaid Services, which is in charge of ensuring they’re up to par.

Also, having a physician analyze the tests on Kailos’ end is a key way to steer clear of the roadblocks other genetic-testing companies face. Instead of providing uninterpreted information directly to a consumer, that information is going through a trained professional who can make sure it’s interpreted accurately. Troy Moore, Kailos’ chief scientific officer, told Business Insider the reason they opted for more specific tests for certain medications came from their background as a clinical lab.

The verdict

While it was easy to submit my samples and see my results, I didn’t find the test incredibly helpful. I’m grateful to see my results were positive, but part of me was hoping to learn something more nuanced about how my genetics interacted with medicine, like if a certain type of contraceptive would have less negative side effects or would work better for me than another, or if I shouldn’t take contraceptives at all.

Along with the thumbs-up/thumbs-down rankings, Kailos also provides all the raw information for the genes each test looked at, which could help a doctor dive deeper into what the test means for me.

I could have asked a doctor to go over my results with me typically the tests Kailos provides are coordinated with a physician, but when I saw the thumbs-up signs, I didn’t think going over my results with a doctor was necessary.

Which brings up a potential concern when it comes to consumer tests overall: What if, after receiving his or her results, a patient who was on medication chose to use them to start making changes to when and how he or she takes it?

This was a concern Thompson brought up when I told her I hadn’t contacted my doctor about my results. Because parts of genetic tests can get really complex, it’s helpful to have people with at least a physician-level knowledge of genetics around to interpret what it all means, she said.

“It’s just a tool,” Thompson added.

Microbiome and Major Depression (i.e. Bacteria and Mood)

probiotics

Embryos develop from a small ball of cells to a flat sheet of cells. This sheet rolls up into a tube. One end of the tube becomes the brain, the other end becomes the digestive tract.

There is communication along this brain-gut axis via nerves, hormones and the immune system (via the blood). And I’m probably not the only person who asked out loud for my stomach to stop growling, so there’s a cognitive connection too :).

There is some evidence that our intestinal micro biota, the bacteria that we harbor that aids in digestion, actually communicates with our brain via the immune system. Scientists are also investigating the hypothesis that modification of microbial ecology, for example by supplements containing microbial species (probiotics), may be used therapeutically to modify stress responses and symptoms of anxiety and depression.

A recent study from the Netherlands reported the first evidence that the intake of probiotics may help reduce negative thoughts associated with sad mood and suggest that probiotics supplementation warrants further research as a potential preventive strategy for depression.

The study was small, 40 people total for cases and controls, but it certainly works as a pilot study for more research.

The study was published with open access- you can read it here:

http://www.sciencedirect.com/science/article/pii/S0889159115000884

This also adds to the evidence that chocolate is good for us! Also, probiotics do not have to be taken as supplements. Besides chocolate, probiotics are found in fermented foods such as kim chi, and in yogurt.

http://www.webmd.com/digestive-disorders/features/what-are-probiotics

Is Clinical Depression an Allergic Reaction?

Mast_cells

Interesting concept that researchers have been studying for some time: Is clinical depression an allergic reaction?

A study in 2008 showed that during manic episodes, pro-inflammatory cytokines, IL-2, IL-4 and IL-6, were increased in comparison with healthy subjects. Patients in depressive episode showed only increased IL-6 levels. There were no significant differences in cytokine levels between patients in remission and healthy subjects, except for IL-4.1

A double- blind study in 2006 in German of 40 patients with a diagnosis of clinical showed more improvement in the half who took anti-inflammatory drugs for a certain time, vs those that didn’t. All patients showed some improvement, perhaps from placebo effect, but those treated with anti-inflammatories did better.2

In 1999 a study of 6836 people in the U.S., subjects with a history of any allergy were more likely to report low-back pain, to be diagnosed with major depression, and much more likely to have both major depression and low-back pain.3

Perhaps depression is a response to the world around us, on a micro level- such as dust, or a macro level- such as stress from daily living. Inflammation, the common allergic reaction, is seen in patients with bipolar disorder and depression.

Even as far back as 1930, it was thought there was some hereditary element to allergies.

 

asthma allergy

Who know, in the future, people prone to a depressed allergic reaction may carry some kind of inhaler, like those for asthma. Or anti-inflammatory drugs may become the new “anti-depressant”.

1Elisa Brietzke, Laura Stertz, Brisa Simões Fernandes, Marcia Kauer-Sant’Anna, Marcello Mascarenhas, Andréia Escosteguy Vargas, José Artur Chies, Flávio Kapczinskicorrespondenceemail (2008). Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. Journal of Affective Disorders, 116, 3, 214–217.

2N Müller, M J Schwarz, S Dehning, A Douhe, A Cerovecki, B Goldstein-Müller, I Spellmann, G Hetzel, K Maino, N Kleindienst, H-J Möller, V Arolt and M Riedel.(2006).  The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Molecular Psychiatry (2006) 11, 680–684

3Eric L. Hurwitz and Hal Morgenstern (1999).  Cross-Sectional Associations of Asthma, Hay Fever, and Other Allergies with Major Depression and Low-Back Pain among Adults Aged 20–39 Years in the United States. Am. J. Epidemiol. (1999) 150 (10): 1107-1116

Robin Williams and the tipping point.

 

dead-poets-society-04

According to CNN, Robin Williams took his life today. He was 63 years old.

Williams should be remembered for creative talent in comedy and acting, and as Larry King also mentioned, he should be remembered as a “genuine caring guy.”

 

Williams appeared to “have it all” in so many ways- marriage, family, money, a career in the competitive world of show business, unbridled talent.

 

He had a diagnosis of bipolar disorder and had dealt with addiction to alcohol and cocaine. He publicly addressed his disease and his decision to go to rehab. Even with all the resources possible at his disposal, he still got to a place that was so dark he could not find his way back.

 

My hope is that he will someday be remembered as the guy who tipped the scales on the stigma of mental illness. Maybe  Robin Williams’ death can become the tipping point for change.

The point where we accepted that mental illness is a disease that needs to be acknowledged without stigma.

 

The point where we realized that we need to help all people with their depression, mania or psychosis.

 

The point where we realized that money spent on mental health is a great investment in our community.

 

The point where we realized that it might make sense to offer voluntary screening programs to determine who is at risk for mental illness, and be able to offer intervention for those that need it and want it.

 

The point where we can say

 

“O Captain! my Captain! our fearful trip is done,

 

The ship has weather’d every rack, the prize we sought is won”

 

 

 

 

 

 

Do People With Mental Illness Age Faster Than People Who Are Unaffected?

Last week I attended a talk by Dr. Owen Wolkowitz, psychiatrist and professor at UCSF Langley Porter Institute.  His answer to this question is “yes.”  He refers to mental illness as “disorders of the whole body.”

There is data that people with mental illness die, on an average, 25 years earlier than people in the general population.  30-40% of people with mental illness die of suicide or accidents, but the remaining 60% die of natural causes earlier than the general population.

There are some obvious reasons as to why:

1)      Poor lifestyle – smoking , drinking, illicit drug use, bad nutrition

2)      Poor access to healthcare, poor medication compliance, homelessness

3)      Medication side effects such as obesity, increased lipids

Less obvious are some of the behind the scenes factors, such as inflammation due to stress.

It is also possible that mental illness actually changes our DNA, in particular our telomeres. Telomeres are the pieces of DNA at the ends of the chromosomes. Each time a cell divides, it duplicates its chromosomes, and a little bit of the end of the chromosome is lost. At some point, too much information is lost, and instead of dividing, the cell dies. This is the aging process in a nutshell. We can’t have cells that live forever (that’s what happens in cancer, the mechanism gets screwed up and the cell keeps dividing forever.)  Telomerase, the enzyme that adds the telomeres to the end of the chromosome, can be measured in the blood, and can be used as a marker for aging.

telemore-image2

Studies have been done on telomeres of people with mental illness. Studies of people with depression show telomere shortening. Adults with early life trauma have shorter telomeres, demonstrating perhaps a “scar in the brain.”  There’s evidence that people with schizophrenia who take anti-psychotic meds have longer telomeres than people with schizophrenia who aren’t taking any medication- demonstrating a potential benefit of medication. It’s possible that anti-psychotics can have an effect by reducing inflammation and oxidative stress.

The good news is that telomeres can lengthen. Factors known to extend telomere length to a healthy level include exercise, dietary restraint, multivitamins, folate, Omega 3’s, stress management, statins, estrogen and social support. So while good nutrition, good sleep, exercise and avoidance of illicit drugs are good plans for everyone, they are especially important for people with mental illness, or people at risk for mental illness.

Link to article on telemore shortening:

http://www.sciencedirect.com/science/article/pii/S0006322306001363