Zoloft study on primates - brain structure

[Vonnegutjunky]

http://www.neuroscientistnews.com/research-news/common-antidepressant-may-change-brain-differently-depressed-and-non-depressed-people

[Futurerecovery]

A very important study!

 

Long term sertraline effects on neural structures in depressed and nondepressed adult female nonhuman primates.

http://www.ncbi.nlm.nih.gov/pubmed/26116816

[oskcajga]

I downloaded the full article and found it somewhat uninspiring, to be honest.  The whole thing is based on data that depressed people have different brain volumes in certain regions than non depressed people.  I'm not sure what can be really concluded about shifts in brain volume like this, but here's some of the segnments of the study I found to be pertinent:

 

They used the following treatment:  "Following training, either 20 mg/kg sertraline HCl
(Zoloft®) in vehicle, or vehicle alone (placebo) was administered
orally daily at about 08:00 am for 18 months." 

 

20mg/kg seems like a HUGE HUGE dose.  For reference, that would be 1800mg of zoloft for a 200lb human.  Am I reading this correctly?????

 

Aside from that....interesting point:

 

They measured volumes of brains using MRI scans, here's an example of a section of the discussion:

 

They didn't find that setriline decreased depression in monkeys:

"Due to the small reported effect sizes of SSRIs for depression, this study could not be powered to detect a decrease in depressive behavior."

 

There were a number of brain regions that changed in volume, and some others that did not change in volume:

"Most importantly, the effects of sertraline treatment were different in depressed versus nondepressed individuals. In nondepressed
monkeys, sertraline reduced right HC volume, mostly the right anterior HC which was reduced by 21%. In depressed monkeys sertraline increased left ACC volume. However, in nondepressed monkeys, sertraline reduced left BA24 volumes. This resulted in nondepressed monkeys having smaller BA24 volumes than depressed monkeys in the sertraline treated group."

 

 

Here's another relatively interesting finding:

"These observations are made even more intriguing in light ofsertraline effects on the cardiovascular system in depressed and
nondepressed individuals in this same study. We measured the extent of atherosclerosis, a principal cause of myocardial infarction, in the coronary arteries of these NHPs. Coronary artery atherosclerosis was more extensive in depressed than nondepressed monkeys, and more extensive in those treated with sertraline than placebo. These effects were additive; thus coronary artery atherosclerosis was most extensive in sertraline-treated depressed animals."

 

One thing I was not clear about what the baseline amount of brain volumes that change. The study apparently controls for a number of factors that can influence brain volume, such as housing condition, diet etc.  But I can't help but wonder if the findings in this study are less so a result of depression/setriline, and moreso just an underlying baseline shift in brain volumes that is unrelated to the treatment or depression.

 

If I was reviewing this article for publication I would certainly ask the authors why they used such a whooping dose - if I am reading that correctly, then does it really surprising anyone that there are volumetric changes in the brain with such a huge dose?  that's something like 10 fold higher than normal doses in humans at 20mg/kg as they used in the study.

[Futurerecovery]

and moreso just an underlying baseline shift in brain volumes that is unrelated to the treatment or depression.

There was a placebo group.

[Meimeiquest]

Apart from the ridiculous dosage, I was wondering why the monkeys were depressed.

[oskcajga]

 

and moreso just an underlying baseline shift in brain volumes that is unrelated to the treatment or depression.

There was a placebo group.

 

 

Yes, good point.  

 

1.  The whole idea of diagnosing primates as "depressed" is suspicious to me.  It's hard enough to diagnose humans.

 

Doesn't it seem ludicrous to label a group of monkeys as "depressed"?

 

2.  Here's another flaw of the present study:  the same monkeys were not tested before zolft and then compared during zoloft.  Any scientist will tell you that morphological features differ among individuals, and the best way to avoid confounding factors in these cases are pairwise comparisons.  They did not do this - most likely because it's challenging, and requires a lot of dedication and a bit of luck.  But comparing morphological features among individuals rather than within the SAME individuals before and after treatment is a weaker experimental design requiring more complicated statistics.

 

3.  And what about AFTER zoloft?  Here's another massive problem:  these monkeys are going to be used in future studies.  I know this - no investigator is going to be foolish enough to sacrifice monkeys - they cost a tremendous amount of money.   So all these future studies are going to be affected by the fact that these monkeyes have a history of exposure to a powerful neurotoxin:  Zoloft - at HUGE doses. 

 

So not only are antidepressants hurting people, they're now influencing future studies that are probably going to be published and no one will ever realize that these same monkeys had a treatment of antidepressants, possibly affecting ALL future studies carried out on them.

 

What if these monkeys have protracted withdrawal when they go into future studies?

 

 

/sighs

[Futurerecovery]

You mean that they didn't compare the same depressive monkeys as the pre-treatment depressive monkeys? Where did you read that?

Nonetheless this study shows that SSRIs can have a completely different result among individuals concerning brain structure.

 

Someone should ask them whether the decrease/increase of volume was reversible.

[oskcajga]

From methods:  "The monkeys lived in these stable social groups for 18 months, during which depressive behavior was recorded. At the end of the
18 months, the monkeys were assigned by social group to either placebo (n ¼ 20) or sertraline (n ¼ 21) treatment balanced on body weight (BW), body mass index (BMI) and the rate of depressive behavior during the pretreatment period using stratified randomization (Table 1)."

[oskcajga]

You mean that they didn't compare the same depressive monkeys as the pre-treatment depressive monkeys? Where did you read that?

Nonetheless this study shows that SSRIs can have a completely different result among individuals concerning brain structure.

 

Someone should ask them whether the decrease/increase of volume was reversible.

 

It's not really apparent if a decrease in volume has any functional consequences - according to the research that they cite, monkeys/humans naturally experiences alterations in brain region volumes when they become depressed. 

[Futurerecovery]

I don't know whether I understand what you mean. Do you mean that when one assigns for example 20 depressive monkeys to two groups (A,placebo ) that the 10 depressive monkeys in group A could have (independently from the medication) a natural and different alteration of a brain region than the 10 depressive monkeys in the placebo group? But that's not very likely.

 

Or do you mean that at the end of the treatment they identified once again which monkeys are depressive?

[oskcajga]

I don't know whether I understand what you mean. Do you mean that when one assigns for example 20 depressive monkeys to two groups (A,B ) that the 10 depressive monkeys in group A could have (independently from the medication) a natural and different alteration of a brain region than the 10 depressive monkeys in group B?

 

Or do you mean that at the end of the treatment they identified once again which monkeys are depressive?

 

What I mean is that the most correct way to carry out the study is to have all of the monkeys be their own placebos, and therefore there's a total of say 20 monkeys.  Each monkey is tested once before any treatment for brain volume, then administered a dose of zoloft, and measured again during the treatment.  Ideally, if these researchers were interested in the real effects of these drugs, they would then measure again AFTER the dose of zoloft was out of the animals system for a while - but apparently they chose the easy way out and did not carry out those latter tests (my guess is that it was cheaper not to).

 

This is called a pairwise comparison - and it's the preferable method in science for comparing any morphological change (sometimes this is not possible, because the morphological change being investigated is something that requires the sacrifice of the animal).  I'm honestly not sure why they didn't do pariwise comparisons, there's really no reason that I can see why they couldn't have done it based on the methods that I read - therefore it's a weakness to the study.

 

Anyways, with a maximum sample size of 10, and these weak comparisons (non pairwise) the results from this study are rather weak in my opinion, and the results therefore would require future studies in order to verify whether or not there is something really going on here or not.

 

Overall, it seems like they wasted a lot of money on a study that could have easily been done with a better experimental design and made it a MUCH more concrete piece of evidence - but what we have here instead is not more than a possible pattern that requires future testing with larger sample sizes and better experimental design.

[Futurerecovery]

Do I understand correctly, they didn't measure the volume before the treatment? Then the abstract is very misleading.