antipsychotics/neuroleptics reduce brain size

[Guardian]

According to this paper:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3476840/

people who got diagnosed with schizophrenia and given neuroleptics  were found to have lower brain volume after a longer period of the onset MRI scan.

As a control it was tested on animals with similar results.

Quote from a conclusion:

"During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices in 1991 through 2009. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes. Greater intensity of antipsychotic treatment was associated with indicators of generalized and specific brain tissue reduction after controlling for effects of the other 3 predictors. More antipsychotic treatment was associated with smaller gray matter volumes. Progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment. Illness severity had relatively modest correlations with tissue volume reduction, and alcohol/illicit drug misuse had no significant associations when effects of the other variables were adjusted."

 

Edit:

Another paper might be solidating the findings on even 8 weeks of exposure to anti-psychotics/neuroleptics.

https://www.sciencedirect.com/science/article/abs/pii/S0006322310011716

"Chronic (8 weeks) exposure to both haloperidol and olanzapine resulted in significant decreases in whole-brain volume (6% to 8%) compared with vehicle-treated control subjects, driven mainly by a decrease in frontal cerebral cortex volume (8% to 12%). "

 

nihms405144.pdf

Edited September 23, 2021 by Guardian

[Michael569]

37 minutes ago, Guardian said:

"During longitudinal follow-up

The longitudinal study being an observational study within a single geographical region does not have enough strength or statistical power to suggest a correlation or causation relationship. The best they can do is hypotheses generation. You will notice that the study does not say A causes B. They are aware that more research needs to be done. 

While I agree that this is a disturbing finding I wouldn't straight away assume that everyone who takes these drugs end up with cortex atrophy. 211 patients isn't that huge of a study. There is just too many confounders and potential biases in here (recruitment, choice of treatment etc) here that could influence it. For example patients with schisophrenia are often more likely to smoke and we know smoking is a risk factor for neurodegeneration. These patients are more likely to have a junk food diet, sleep deprivation and recreational drug abuse. 

So the question is, is it really the drug or an overall behaviour? 211 people longitudinal study won't be able to catch that relationship. You need a prospective cohort of 50,000+ (hundred even) across different populations to determine a statistically strong relationship.

Obviously drugs are never an ideal long term treatment but sometimes this is what prevents the patient from killing themselves or becoming deluded and instable. In the long-terms they are probably not the best line of treatment though but they keep the patient sane so that the problems can be worked on for example by working through some shadow work, nutrition therapy, herbs, mindfulness etc. But without those drugs, the patients wouldn't be able to ground themselves.  Or at least not in the short term 

[undeather]

15 minutes ago, Michael569 said:

The longitudinal study being an observational study within a single geographical region does not have enough strength or statistical power to suggest a correlation or causation relationship. The best they can do is hypotheses generation. You will notice that the study does not say A causes B. They are aware that more research needs to be done. 

While I agree that this is a disturbing finding I wouldn't straight away assume that everyone who takes these drugs end up with cortex atrophy. 211 patients isn't that huge of a study. There is just too many confounders and potential biases in here (recruitment, choice of treatment etc) here that could influence it. For example patients with schisophrenia are often more likely to smoke and we know smoking is a risk factor for neurodegeneration. These patients are more likely to have a junk food diet, sleep deprivation and recreational drug abuse. 

So the question is, is it really the drug or an overall behaviour? 211 people longitudinal study won't be able to catch that relationship. You need a prospective cohort of 50,000+ (hundred even) across different populations to determine a statistically strong relationship.

Obviously drugs are never an ideal long term treatment but sometimes this is what prevents the patient from killing themselves or becoming deluded and instable. In the long-terms they are probably not the best line of treatment though but they keep the patient sane so that the problems can be worked on for example by working through some shadow work, nutrition therapy, herbs, mindfulness etc. But without those drugs, the patients wouldn't be able to ground themselves.  Or at least not in the short term 

well put.

[Guardian]

21 minutes ago, Michael569 said:

The longitudinal study being an observational study within a single geographical region does not have enough strength or statistical power to suggest a correlation or causation relationship. The best they can do is hypotheses generation. You will notice that the study does not say A causes B. They are aware that more research needs to be done. 

While I agree that this is a disturbing finding I wouldn't straight away assume that everyone who takes these drugs end up with cortex atrophy. 211 patients isn't that huge of a study. There is just too many confounders and potential biases in here (recruitment, choice of treatment etc) here that could influence it. For example patients with schisophrenia are often more likely to smoke and we know smoking is a risk factor for neurodegeneration. These patients are more likely to have a junk food diet, sleep deprivation and recreational drug abuse. 

So the question is, is it really the drug or an overall behaviour? 211 people longitudinal study won't be able to catch that relationship. You need a prospective cohort of 50,000+ (hundred even)  people across different countries to determine a statistically strong relationship.

Obviously drugs are never an ideal long term treatment but sometimes this is what prevents the patient from killing themselves or becoming deluded and instable. In the long-terms they are probably not the best line of treatment though but they keep the patient sane so that the problems can be worked on for example by working through some shadow work, nutrition therapy, herbs, mindfulness etc. But without those drugs the patients wouldn't be able to ground themselves.  

There are a couple things that could stand not in favor of this.

- Neglecting the possible effects of long term drug exposure on the psyche.

- On onset, people could have had normal range brain size

- Animal control group

- People that were given least-neuroleptics treatment had lower abnormalities:

"...The least-treatment group showed increased total cerebral WM over time in contrast to WM volume reductions among patients in the most-treatment group (mean regression slopes, 1.30 vs −0.64, respectively)..."

Edited September 23, 2021 by Guardian

[Michael569]

8 minutes ago, Guardian said:

Neglecting the possible effects of long term drug exposure on the psyche.

yes, agreed this is a general issue with pharmacology, especially polypharmacy. Lack of long-term holistic solutions and leaving people on meds for decades. Absolutely agree that this is a huge huge problem 

9 minutes ago, Guardian said:

On onset, people could have had normal range brain size

Brains of people with long terms mental health may often undergo some atrophy of the executive regions such as prefrontal cortex or cingulate cortex and hypertrophy of regions such as amygdala which creates a vicious cycle and makes it harder to treat. But I'm not sure to what degree this is relevant in terms of wider population and "normal brain" size/weight. Might just be academic speculation rather than a crucial point. 

12 minutes ago, Guardian said:

Animal control group

Animal research does have a huge value in early stages when lack of human data is available or it would be unethical to conduct human studies but once the research availability grows, animal trials start losing their value. 

14 minutes ago, Guardian said:

People that were given least-neuroleptics treatment had lower abnormalities: "...The least-treatment group showed increased total cerebral WM over time in contrast to WM volume reductions among patients in the most-treatment group (mean regression slopes, 1.30 vs −0.64, respectively)..."

Not disputing the results. They are indeed scary findings. But they are aware of the limitations. When you conduct observational study, there is just way too much that can interfere with your results as much as we'd love to see a direct association, it cannot be drawn as simply despite those results. 

"Our results must be interpreted in the context of additional limitations. Identifying an association does not necessarily indicate a causal relationship. Furthermore, observational studies involving long durations such as ours inevitably preclude use of the “gold standard”: a random-assignment controlled trial. The current study could have been strengthened by having control groups, eg, schizophrenia patients assigned to deferred or no antipsychotic treatment or healthy volunteers treated with antipsychotics for comparable periods. However, ethical standards in human subject research prohibit such comparison groups. The small number of schizophrenia patients in our sample who received no antipsychotic treatment did not allow for meaningful statistical analyses. "

[undeather]

1 hour ago, Guardian said:

There are a couple things that could stand not in favor of this.

- Neglecting the possible effects of long term drug exposure on the psyche.

- On onset, people could have had normal range brain size

- Animal control group

- People that were given least-neuroleptics treatment had lower abnormalities:

"...The least-treatment group showed increased total cerebral WM over time in contrast to WM volume reductions among patients in the most-treatment group (mean regression slopes, 1.30 vs −0.64, respectively)..."

Here is a triple-blind, placebo-controlled, randomised trial published in one of the most prestigious journals dealing with neuromedical papers: https://www.nature.com/articles/s41386-021-00980-0

This recruitment protocol is insanely well-considered, the study design is beyond gold standard and the statisticial evaluiaton/follow-up is decent as well. This far outweighs any longitudinal data, which is highly prone to bias.

"We found evidence of regionally heterogeneous effects associated with both illness and medication, with the most robust effect being an illness-related decline of pallidal GMV in the placebo group coupled with an antipsychotic-related increase in the medicated group. Consistent with a therapeutic benefit of the antipsychotic-induced increase in pallidal GMV, a greater volumetric change in this area was associated with a greater reduction in symptomology within the first 3 months of illness. Evidence for medication-related white matter decline was identified in the cerebellum. These results suggest that both psychotic illness and medication exposure exert distinct and spatially distributed effects on GMV, and converge with prior work in suggesting that the therapeutic efficacy of antipsychotic medications is primarily mediated through their effects on the basal ganglia"

 

Edited September 23, 2021 by undeather

[flowboy]

Drugs are not a perfect long-term solution. Who knew

[Guardian]

https://www.nature.com/articles/s41386-021-00980-0

On the above study that was mentioned here:

 

- A time span of 3 months seems insufficient to find long term overall brain volume changes on lower doses of anti-psychotics

"...Longer-term follow-up would be required to determine the extent to which further volume-loss emerges with additional antipsychotic exposure..."

 

- False conclusion of anti-psychotics being neuroprotective

The right conclusion is:

Within the time span of 3 months there was an effect on the grey matter of the right pallidum. Which seems typical because people on anti-psychotics execute a lot of involuntary movement. That explains the increase in grey matter of the pallidum.

 

The study also mentions to have found neuroleptics related white mater decline in the cerebellum.

s41386-021-00980-0.pdf

Edited September 23, 2021 by Guardian

[undeather]

2 hours ago, Guardian said:

 

Following Issues :

- It describes a change in the basal ganglia region, specifically the right pallidum.

- As some brain regions get repressed by the drugs, others might become overdeveloped temporarily.

- The time span was 3 months, Insufficient to determine overall brain volume changes

"...Longer-term follow-up would be required to determine the extent to which further volume-loss emerges with additional antipsychotic exposure..."

Their conclusion of neuroleptics being neuroprotective looks unreasonable.

The right conclusion is within the time span of 3 months there was an effect on the gray matter of the right pallidum which is typical because people on anti-psychotics execute a lot of involuntary movement. That explains the increase in grey matter of the pallidum.

The medication related white mater decline in the cerebellum is worrisome.

 

- It describes a change in the basal ganglia because...thats where most of the change occured.....and thats the potential mechanism of action. 

- "As some brain regions get repressed by the drugs, others might become overdeveloped temporarily." - Brain region changes happen all the time. It doesnt necessarily mean that its "good" or "bad". Medidation demonstrably does this and we love the benefits.
https://www.nature.com/articles/s41598-019-47470-4

- The time span was 3 months with a FOLLOW up at 12 months.

The medication related white mater decline in the cerebellum is worrisome.
-> True, but again - this could be a correlation. 

Dont get me wrong, psychopharmacology is in my opinion the least successful drug intervention field of modern medicine. Those drugs are sometimes a live safer but they may come with disasterous consequences in other cases. Even though I think that is the truth, I have to admit that I dont know what the fuck I am talking about when it comes to psychiatry/neurology. I am a trained physician but the brain is far beyond my current understanding. You should admit that too. Drawing rigid conclusions out of some hand picked studies is just not right. There are people who spent a lifetime trying to undertand a small part of this organ or how drugs interact with it. We have to show some humility right there... thats all! It doesnt mean you are wrong though by the way. You could be right all the way - But you dont know and neither do I! Nor do I have the time to find out! 

Edited September 23, 2021 by undeather