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Darwinian Test To Detect Antidepressant Drug Toxicity

Pharmaceutical companies spend exorbitant sums of money developing new drugs. Getting a drug through clinical trials and proving that it works can take millions, or in other cases, billions of dollars. When a drug does get approval, the pharmaceutical company typically makes back significantly more money than they spent on development for the drug. This is why individuals who work for top pharmaceutical companies are highly compensated.

Unfortunately, many drugs end up getting approval for the FDA to treat a specific condition, but are found to be unsafe years after their approval. Although this isn’t a good look for the FDA, it is an especially bad look for the developing drug company. In this case, there are typically many lawsuits filed against the company in attempt to get patients financial compensation for damages that they’ve incurred.

This causes existing prescriptions to get withdrawn from the market for safety concerns. We’ve seen it happen in the past with many medications, some of which were antidepressants. It is important to be aware that although drugs may initially seem safe for human consumption, there is often hidden toxicity associated with certain drugs that clinical trials are unable to detect.

University of Utah: Detecting Antidepressant and Drug Toxicity

Researchers from the University of Utah are attempting to make it easier to detect toxicity and adverse side effects before they actually damage patients. In other words, the goal of these researchers is to identify any potential dangers when drugs are still in clinical trials. This will allow patients to be better informed, especially if the patient is a pregnant mother taking a drug that could cause birth defects.

Their goal isn’t only to help pregnant mothers protect their unborn children, rather it is to protect the general public from potential toxicity resulting from pharmaceutical drugs. If you want proof that certain antidepressants have been associated with toxicity in the past, look no further than Paxil. This drug was originally considered “safe,” but years later was found to cause birth defects when taken by pregnant women. (Read: “Are antidepressants safe while pregnant?”).

Fittingly enough, the team of researchers from the University of Utah chose to test their protocol on the drug Paxil. These researchers published their study in “Neurotoxicology and Teratology” and were able to detect adverse properties at human levels of dosing. Previously, toxic effects could only be detected at doses significantly greater those recommended for human administration.

Darwinian Test: “Survival of the Fittest” Mice (Study)

A major component to the testing conducted by researchers is using a “survival of the fittest” concept. They are using wild mice, as opposed to tame laboratory created strains. They make the mice compete for shelter, food, etc. just like they would in the wild. The mice then race for a particular positioning in a large pen that is divided into six specific “zones” with fencing. This fencing separates the mice from their neighbors, but they can climb it if they want to infiltrate the territory of other mice.

Four of the divided “zones” are considered to be top-notch with available nesting and direct access to food and water. The test the researchers run is based on what’s called “organismal performance” (OPA). Researchers noticed that the male mice were extremely competitive with one another over various territories. If certain males aren’t able to win a territory, the female mice don’t end up choosing them as mates.

Research published a year ago revealed that the amount of sugar consumed by the average person is likely toxic. Mice who ate diets of 25% more sugar were noticeably different: females died at double the frequency of those without the sugar increase and males were less likely to find partners for mating and claim favorable territory.

Testing the antidepressant Paxil

Researchers conducted a study involving the antidepressant drug Paxil. They did this by giving mice food that was strategically infused with Paxil to 20 different pairs of mice. They continued feeding them over the course of several weeks with doses at approximately 1.8 the amount that are given to humans. The offspring of the 20 mice pairs also ate the Paxil infused food until they were of age to mate.

The researchers then took the offspring of the mice who ate the Paxil infused-food and placed them into the pen that is divided into “zones.” They simultaneously released a group of mice as a “control group” that was never exposed to Paxil. The groups of mice were comprised of 8 males and 14-16 females, making for similar density of population to those in natural environments. Researchers had created five populations and continued them for six months.

Results: The results from their study were pretty interesting. The male mice that had been exposed to Paxil were significantly less likely to control territory; approximately 50% less likely. The Paxil-exposed group of mice also had unfavorable bodyweights and higher mortality rates than the control group. Male mice exposed to Paxil produced 44% less offspring. Females exposed to the Paxil experienced not major weight or mortality differences, but they yielded 50% less offspring than non-Paxil females.

Note: It should be mentioned that there is even newer unpublished data of Paxil vs. Placebo for the treatment of depression that questions the drugs efficacy.  The unpublished studies reveal that the drug may not work as was originally portrayed by manufacturers and marketers.

Detecting Antidepressant Toxicity and Adverse Effects

The testing used for mice may be able to help account for possible toxic effects in humans. In this particular study, researchers were able to note that Paxil caused problems associated with ability to generate offspring. Researchers speculate that if this study had been conducted sooner, it may have tipped them off to the possibility of birth defects when Paxil is used among humans.

A leader of the study was quoted as saying, “It’s unknown how Paxil causes birth defects and why Paxil has a stronger correlation with birth defects than other SSRIs.” They believe that the drugs alter functioning within the endocrine system to produce adverse effects. Prior research has established that Paxil reduces levels of various hormones involved in female rat reproductive processes.

Among male rats, doses lowered levels of testosterone, reduced sperm count, and reduced the quality. As a side note, it should be mentioned that many believe antidepressants lower testosterone, particularly the SSRIs. The new research coming from these researchers may be capable of shedding further light on this often overlooked possibility.

The goal of these researchers is to expand their studies to involving more than just antidepressant drugs. They want to determine toxicity of various agricultural chemicals, industrial pollutants, and other possible toxic chemicals that may be found in certain environments. The fact is that we currently lack a sufficient toxicity assessment protocol for research.

A researcher stated, “that’s why these things slip through the cracks and we often don’t discover harmful effects until 10 or 20 years of epidemiology studies using the public as experimental guinea pigs.” He is completely correct, but my question would be how does he know his method with mice is more accurate? Just because he found some interesting evidence in a Paxil study doesn’t necessarily indicate a superior testing method.

Benefits of Detecting Antidepressant / Drug Toxicity

These researchers do highlight the importance of thoroughly evaluating toxicity with superior methods. The only problem is that problems found in mice may not be problems for humans and vice versa. However, it does seem that this group of researchers is on the right track in coming up with a superior method. There are several key benefits associated with detecting toxicity of antidepressants.

  • Adverse effects: It is important to be aware of any potential adverse effects prior to them actually occurring in human trials. The new studies may be better able to identify dosages that are considered safe as well as dosages that are more likely to cause adverse effects and/or toxicity.
  • Protection: It is important to understand whether a drug is toxic and/or whether it could be toxic to a developing fetus in various stages of pregnancy. The new method of understanding drug toxicity may be able to protect people as well as developing fetuses. Many mothers took the drug Paxil and it lead to birth defects among their children. This research may be able to prevent such problems from occurring.
  • Savings: Assuming they’ve come up with an improved way to identify toxic effects from various drugs, this could save pharmaceutical companies significant time and finances. There’s nothing worse than investing a lot of money into a particular drug and then having the drug discontinued due to adverse effects. Pharmaceuticals could then focus only on the substances that pass preclinical screenings.
  • Side effects: It is important to adequately understand the side effect profile of a particular medication. Under the assumption that these researchers have a superior method for detecting toxic and adverse effects, they may also be able to identify some side effects.
  • Toxicity: If a drug is toxic, it would be helpful to be aware of this fact at the earliest possible stages. We now know that many drugs are not properly evaluated for potential toxicity and can be detrimental to human health even when used in clinical trial stages. The new research may be able to identify toxicity before a drug is even used in clinical trials.

The study’s lead author (Shannon M. Gaukler) was quoted as saying, “We are doing it exactly the way we need to determine if it presents a risk of harm to a developing fetus.” If toxicity concerns could be ruled out in early phases of drug development and trials, pharmaceuticals would be able to tweak their formulations and/or better determine which drugs are suited for human administration.

The unfortunate reality is that many drugs end up getting “approved” but are later discontinued from the market due to toxicity concerns decades after the fact. The new method of detecting problems has potential to save pharmaceutical companies a significant amount of money.

Final thoughts on Darwinian Test for Toxicity

It would be interesting if they tested other SSRIs to determine how they affect mice in this same territory with divided “zones.” Would any SSRI cause the mice to produce less offspring and hold less territory? Although we already know the drug Paxil is problematic in both mice and humans, what if they would’ve found another drug to cause the exact same rates of mortality and decline in offspring?

Then they really wouldn’t have much ground to stand on for their hypothesis that this method is superior to others in predicting toxicity and adverse effects. Their research isn’t able to identify specific causal relationships that hold true for both mice and humans. However, due to the fact that all of their study information isn’t available, they may in fact have established a superior method.

It is hoped that these researchers have come up with a solid way to prevent dangerous drugs from hitting the market for consumption. Sure everyone gets excited to try a new drug, but they aren’t too excited when they find out years after they take it that it’s linked to development of some unwanted ailment or increased mortality.

Source: http://unews.utah.edu/news_releases/darwinian-test-uncovers-an-antidepressants-hidden-toxicity/

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