Monday, February 25, 2013

Accu-sane?

This is you in high school...

Hayley Chilton

Imagine you’re in high school again in the peak of puberty. You can hardly concentrate in class with that cute boy sitting in front of you.  You unconsciously spend most of the class period dreaming about how you should just introduce yourself as his next girlfriend because, let’s face it, you two would be perfect together! Well, that is if the unsightly blemishes on your cheeks disappear before he has time to notice them.

No amount of over the counter creams or medications can remedy the war zone that is your face. Not even Windex, as promised in My Big Fat Greek Wedding. You have a form of grade III acne vulgaris, also known as severe nodular acne. This type of acne can be very painful and doesn’t often respond well to medications and treatments, which can make living with it very difficult because without treatment, the condition will progress into grade IV acne vulgaris, also known as cystic acne. Both types III and IV are types of inflammatory acne.

So what are the physiological differences between inflammatory and non-inflammatory acne? To put it simply non-inflammatory acne is the result of dead cells and/or oil build-up that clog hair follicles. This type of acne is painless and usually characterized by whether or not the follicle is open (blackhead) or closed (whitehead). 
Normal hair follicle

Blackhead
Whitehead
 
Meanwhile, inflammatory acne is the result of a hormone imbalance, characterized by an elevated production of male hormones (androgens) and a decreased production of female hormones (estrogens). The increase in androgen production results in the escalation of sebum production, an oil produced by the sebaceous glands under the skin near a hair follicle. Androgen production is responsible for the elevated levels of sebum and dead skin cells shed from the follicle. These cells clog the follicle and form a plug under which sebum begins to accumulate. This inadvertently creates an ideal environment for the proliferation and survival of bacteria, which leads to the painful inflammatory lesions/pustules characteristic of individuals with this condition. Your body’s immune system will naturally respond, sending cells to fight the infection; however, this is rarely enough to “cure” nodular acne.

Nodular Acne
  Now imagine someone told you that you could eliminate this problem forever by taking a regimented dosage of oral medication over the course of several months. Don’t worry there’s only a few potential side effects which could include: nausea, muscle aches and pains, vomiting, fever, changes in hearing and vision, weight loss, liver damage, colon damage (this could be anything from the development of ulcers on your colon, to rectal bleeding, bloody diarrhea, inflammation of the lining of your colon, or the development of an autoimmune disorder in which your own body breaks down the healthy tissue in your digestive tract), miscarriages/birth defects if you become pregnant while on the drug, and depression/suicidal thoughts. Would you take it? After reading this list probably not. What if I told you the drug I just described was Accutane – a drug the millions of Americans opted to take over the last few decades.
Before and after Accutane treatment
 
So what is Accutane? Accutane is an acne medication created by Roche Pharmaceuticals. It is derivative of Vitamin A, more specifically, isotretinoin or (13cis)-retinoic acid. Therefore, Accutane is the brand name for a specific type of synthetic retinoid. Accutane was originally marketed as a chemotherapy drug, when doctors noted a marked improvement in the condition of patients’ skin. While the exact mechanism is unknown, Accutane works by reducing oil production in the sebaceous glands underneath your skin. Basically, the drug aims to trigger stem cells to differentiate into into new cells in your skin that produce less oil.

So, if Accutane is a derivative of Vitamin A, does that mean it can already be naturally found in your body? Well, not exactly…Accutane is a synthetic retinoid engineered by Roche Pharmaceuticals. However, other retinoids can be found naturally in your tissues and blood stream and can also be absorbed through the digestion of foods containing Vitamin A. Normally retinoids play roles in growth, vision, and in development – whether it’s the development of a new baby, or the development of new neurons and new neuronal connections in your brain. As with most chemical signals, in order for the presence of Accutane to elicit a functional response, the right machinery in your body needs to be present.

So let’s take a step back and make an analogy. The brain serves as the hard-drive for your body, from which several insulated wires (symbolic of your neurons) extend to different regions of your body. These wires are responsible for relaying information from the hard-drive (your brain) to different outputs (your extremities or organs). Breaking it down even further – the hard-drive can be separated into different regions in order to speed up the efficiency for which it processes information, just like your brain is divided into regions dedicated to thought, motor control, eyesight, and so forth. Given what we just outlined wouldn’t it make sense that regions of the hard-drive with more complex circuits and wire connections would be able to process more complex signals? What if I also told you that every time the hard-drive was programmed to do something new it made a new wire circuit? Well the same is true for your brain. The process of making these new neurons (wires) and new neuron connections (new circuits formed) is called neurogenesis. There is a specific region of the brain that we will be focusing on today called your hippocampus.


The hippocampus is the region of the brain associated with learning and spatial memory. So, why would scientists want to look at this part of the brain when looking at whether or not Accutane is responsible for suicidal ideology and depression? Well, the development of new neurons and new neuronal connections in this region of the brain is extremely important in order for your brain to form new memories and process information. Several studies have found that the hippocampus contains several binding proteins that bind Accutane and regulate how your body metabolizes it.
 
But, how does this relate to suicidal ideology and depression?! A study by J. Crandall demonstrated that when mice underwent long-term elevated exposure to Accutane there was a decrease in the number of these new neuron connections made. This in turn, made it harder for mice to learn! Now how on earth were they able to test that? Well, mice were initially placed in a radial arm maze and allowed to familiarize themselves/explore the maze for a given amount of time.

Mice were then trained to find a food reward in each of the given arms of the maze. Some mice were given a clinical dose of Accutane, the dose prescribed to Accutane patients, prior to experimentation. The mice that weren’t given Accutane were better able to navigate around the maze and had fewer errors when navigating than the group of mice that did receive Accutane. Therefore, results indicate a large decrease in the rate of spatial learning ability after Accutance treatment. Given that several studies have found a relationship between spatial learning ability and neurogenesis, it can be proposed that exposure to Accutane could lead to a reduction in the formation of new neurons and new neuronal connections.

Accutane usage has also been correlated with the onset of suicidal thoughts, anger and depression in several patients. While it has been proposed that a decrease in neurogenesis can be accompanied by depression, another study by K.C. O’Reilly showed that chronically administering Accutane to mice could also contribute to this behavior. Mice were again given a clinical dose of Accutane and their levels of mobility were assessed. Those that were given Accutane showed decreased levels of mobility, a behavior characteristic to an individual with depression. I’m sure anyone who has experienced depression or knows someone who has depression can relate to this concept – being depressed literally makes you want to do nothing. Accutane could thus have an influence on dopamine levels. So, how does dopamine relate to depression?

Well, dopamine is a hormone released in your brain that is associated with your brain’s “reward” system. “Rewards” increase the level of dopamine release in your brain, which leads to positive, happy, and or satisfactory feelings. Highly addictive drugs are often responsible for eliciting this response, which is why people have a hard time quitting addictive habits…because it literally feels so good! Therefore, while the direct mechanism is unknown, scientists have hypothesized that Accutane could be involved in inhibiting dopamine release. Another supportive study by Y. Sakai also perpetuates the notion that if Accutane results in a decrease in the amount of neurons formed/retained in mice, through the disruption of the normal retinoid-signaling pathway, Accutane usage may somehow be linked to depression in humans.

In 2009, Accutane was recalled from the market due to several lawsuits filed against it, with respect to birth defects, suicide, and inflammatory bowel disease. While there are several generic isotretinoin drugs available, the side effects that they cause should be taken into heavy consideration before you decide whether or not you’re willing to compromise other bodily functions for clear skin. Here we merely touched on how Accutane affects the brain, but as mentioned, there are several other ways that this drug attacks more than just acne in your body.

NOTE: In the experiments scientists used 13-ci-retinoic acid, not the brand name Accutane. However, for the sake of simplicity and conceptual understanding it was referred to as Accutane throughout this blog.

Works Cited

Cocco, S., G. Diaz, R. Stancampiano, M. Carta, R. Curreli, L. Sarais, and F. Fadda. 2002. Vitamin A deficiency produces spatial learning and memory impairment in rats. Neuroscience 115(2):475-82.

Crandall, J., Y. Sakai, J. Zhang, O. Koul, Y. Mineur, W.E. Crusio, and P. McCaffery. 2004. 13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice. PNAS 101(14): 5111-5116.

“Nodular Acne: What is nodular acne and how to treat it.” Acne Hubs: A Comprehensive Guide to the Treatment and Prevention of Acne. N.p., n.d. Web. 23 Feb. 2013.
http://acnehubs.com/types-of-acne/nodular-acne-treatment/

O’Reilly, K.C., J. Shumake, F. Gonzales-Lima, M.A. Lane, and S.J. Bailey. 2006. Chronic administration of 13-cis-retinoic acid increases depression-related behavior in mice. Neuropsychopharmacology 31: 1919-1927.

Sakai, Y., J.E. Crandall, J. Brodsky, and P. McCaffrey. 2004. 13-cis-retinoic acid (Accutane) suppresses hippocampal cell survival in mice.  Annual N.Y. Academy of Sciences 1021: 436-440.

“What is Accutane? Its uses and interactions.” Drug Watch. N.p., n.d. Web 23, Feb. 2013.
http://www.drugwatch.com/accutane

 




3 comments:

  1. Very interesting Hayley! I had no idea that the side-effects of this acne treatment were that extensive! It's amazing that with all those side-effects a drug like Accutane could even make it to the market to begin with! Just shows that where there are customers willing to pay, pharmaceutical companies will find a way!

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  2. Great topic Hayley! I'm curious as to why Accutane was recalled in 2009 but none of the other drugs were. If these side effects are such a concern, why is this drug still on the market? I can't imagine that if the FDA had sufficient evidence, they wouldn't hesitate to ban isotretinoin across the board. Food for thought!

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