A New Randomized Control Trial Finds That Estradiol Improves The Symptoms Of Schizophrenia In Women

agnostic

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I was really surprised that they could demonstrate a significant benefit of this treatment even in a relatively large sample. Any idea how this could happen?

Importance Several lines of evidence suggest that estradiol influences the course of schizophrenia, and a previous randomized controlled trial demonstrated that transdermal estradiol improved symptoms in female patients of childbearing age. However, many initial positive findings in schizophrenia research are not later replicated.

Objective To independently replicate the results of the effect of estradiol on schizophrenia in women of childbearing age.

Design, Setting, and Participants An 8-week randomized, placebo-controlled trial performed in the Republic of Moldova between December 4, 2015, and July 29, 2016, among 200 premenopausal women aged 19 to 46 years with schizophrenia or schizoaffective disorder as defined by the DSM-5.

Intervention Patients were randomized to receive a 200-μg estradiol patch or placebo patch changed twice a week added to their antipsychotic treatment.

Main Outcomes and Measures The primary outcome was the positive subscale of the Positive and Negative Syndrome Scale (PANSS; lower scores indicated fewer symptoms and higher scores indicated more symptoms), analyzed with mixed models for repeated measures on an intention-to-treat basis.

Results A total of 100 women (median age, 38 years; interquartile range, 34-42 years) were randomized to receive an estradiol patch and 100 women (median age, 38 years; interquartile range, 31-41 years) were randomized to receive a placebo patch; the median age at baseline for the entire group of 200 women was 38.0 years (range, 19.5-46.0 years). At baseline, the mean positive PANSS score was 19.6 for both groups combined; at week 8, the mean positive PANSS score was 14.4 in the placebo group and 13.4 in the estradiol group. Compared with placebo, participants receiving add-on estradiol patches had statistically significant improvements in the primary outcome measure, PANSS positive subscale points (–0.94; 95% CI, –1.64 to –0.24; P = .008; effect size = 0.38). Post hoc heterogeneity analyses found that this effect occurred almost entirely in 100 participants older than 38.0 years (46 in placebo group vs 54 in estradiol group; difference, –1.98 points on the PANSS positive subscale; 95% CI, –2.94 to –1.02; P < .001). Younger participants did not benefit from estradiol (difference, 0.08 points on the PANSS positive subscale; 95% CI, –0.91 to 1.07; P = .87). Breast tenderness was more common in the estradiol group (n = 15) than in the placebo group (n = 1) as was weight gain (14 in estradiol group vs 1 in placebo group).

Conclusions and Relevance The results independently replicate the finding that transdermal estradiol is an effective add-on treatment for women of childbearing age with schizophrenia and extend it, finding improvements in negative symptoms and finding that the effect could be specific to those older than 38 years. The results should be viewed in the context of the differences in the natural course of schizophrenia between females and males.
Importance Several lines of evidence suggest that estradiol influences the course of schizophrenia, and a previous randomized controlled trial demonstrated that transdermal estradiol improved symptoms in female patients of childbearing age. However, many initial positive findings in schizophrenia research are not later replicated.
 
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It’s a very small study with a very small effect.

They claim it’s statistically significant but it doesn’t look like it really is.
 

lampofred

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What parameters were they measuring? Estradiol is a brain excitant, so if they were looking at "negative" symptoms like flat affect, it could have had a seemingly positive effect there.
 

agnostic

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It’s a very small study with a very small effect.

They claim it’s statistically significant but it doesn’t look like it really is.

I wouldn't call a study with sample of 200 participants a very small study, quite the opposite. If it was a very small study, it probably would not have been published in one of the most prestigious journals of psychiatry. Also, they reported an effect size of Cohen's d of 0.38, which is closer to a medium effect size than a small effect size (0.2 is considered a small effect size and 0.5 a medium effect size).
 

agnostic

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What parameters were they measuring? Estradiol is a brain excitant, so if they were looking at "negative" symptoms like flat affect, it could have had a seemingly positive effect there.
They used the PANSS and found that estradiol improved both positive and negative psychotic symptoms.
 
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I wouldn't call a study with sample of 200 participants a very small study, quite the opposite. If it was a very small study, it probably would not have been published in one of the most prestigious journals of psychiatry. Also, they reported an effect size of Cohen's d of 0.38, which is closer to a medium effect size than a small effect size (0.2 is considered a small effect size and 0.5 a medium effect size).

100 in each group is a very small study and I think insignificant. The effect was quite small. This is a meaningless effect, too low powered to mean anything.

At baseline, the mean positive PANSS score was 19.6 for both groups combined; at week 8, the mean positive PANSS score was 14.4 in the placebo group and 13.4 in the estradiol group. Compared with placebo, participants receiving add-on estradiol patches had statistically significant improvements in the primary outcome measure, PANSS positive subscale points (–0.94; 95% CI, –1.64 to –0.24; P = .008; effect size = 0.38). Post hoc heterogeneity analyses found that this effect occurred almost entirely in 100 participants older than 38.0 years (46 in placebo group vs 54 in estradiol group; difference, –1.98 points on the PANSS positive subscale; 95% CI, –2.94 to –1.02; P < .001).
 
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You would have to look at how they did this study. My contention is that people could tell they were getting estradiol. You would be surprised how many such small studies are methodologically flawed on purpose.
 
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and I do think that in the short term, estrogen may help women who are schizophrenic. There is some other evidence that it does. I doubt it is helpful in the longer run.
 

agnostic

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100 in each group is a very small study and I think insignificant. The effect was quite small. This is a meaningless effect, too low powered to mean anything.

I agree that it is not enough to approve it as a new treatment, but if you look at other randomized controlled trials in psychiatry, you will find that they have rarely more participants than that. The fact that a small-to-medium effect size became statistically significant indicates that the study was not underpowered.

I find it a bit hypocritical to dismiss the results as insignificant when at the same time much weaker evidence (e.g. animal research, small human trials) is not questionned on this forum as long as it is in line with Peat's view. No offense, I'm just playing the devils advocate here. I'm also not saying that I believe now that estradiol is beneficial in schizophrenia. I just think that there must be better explanations.
 
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I agree that it is not enough to approve it as a new treatment, but if you look at other randomized controlled trials in psychiatry, you will find that they have rarely more participants than that. The fact that a small-to-medium effect size became statistically significant indicates that the study was not underpowered.

I find it a bit hypocritical to dismiss the results as insignificant when at the same time much weaker evidence (e.g. animal research, small human trials) is not questionned on this forum as long as it is in line with Peat's view. No offense, I'm just playing the devils advocate here. I'm also not saying that I believe now that estradiol is beneficial in schizophrenia. I just think that there must be better explanations.

yes you have raised some good points. I think it probably is beneficial for awhile. There are other studies with similar findings and as you say, a study with 200 people in this field is considered a larger study.
 

SOMO

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The fault in this study relies on using a (likely) vague or incorrect model.

If there is even 1 fault with PANNS, there will be many faults with the study.
 

Goobz

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I highly doubt there is anything wrong with this research. Estradiol seems to help the other diseases which seem to share an etiology with schizophrenia - namely parkinsons and Lewy body diseases. One of the most effective agents they’ve found for dissolving alpha synuclein in Lewy bodies is estriol. There is a case of a man with PD who improved on nothing but transdermal estradiol.

This also makes a lot of sense epidemiologically when you consider these diseases affect many more men than women.
 

tankasnowgod

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I find it a bit hypocritical to dismiss the results as insignificant when at the same time much weaker evidence (e.g. animal research, small human trials) is not questionned on this forum as long as it is in line with Peat's view.

The PANSS scale is a subjective test that is done by a 45-50 minute interview. Since the positive scale goes from 7 to 49, a one point difference between the two groups comes out to about a 2.4% difference between the two groups, on what is a very subjective scale. A lot of of animal and human trials that are discussed on this forum at least have objective results.
 

schultz

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The results appear to be mainly due to the fact that a lot of the participants were recent inpatients and thus hospitalized for the duration of the study. The placebo group had almost close to the same results as the estrogen group. Possibly this is due to consistent food intake, being around people at the hospital, or just the feeling of being "looked after", or even consistent antipsychotic medication. Some of the participants might not have been consistent with their medication until they were being monitored. I'm not sure what antipsychotic was being prescribed generally. None-the-less there was a greater improvement in the estradiol group. I don't know much about the PANSS test except that it is a doctor/patient interview type of assessment. It doesn't seem outside the realm of possibilities that the estradiol group had a "brain excitant" effect, as mentioned by @lampofred . This type of effect would be beneficial for a patient going through an oral assessment IMO.

Consider this quote from Ray...

"The amphetamine-like action of estrogen, which undoubtedly contributes to the general level of stress and excitotoxic abuse of nerve cells, is probably the only
"useful" facet of estrogen treatment, but a little cocaine might achieve the same effect with no more harm, possibly less. The toxicity of catecholamines has been
known for over 30 years, and conversion to catechol-estrogens which increase the activity of brain catecholamines."


So in the short-term (8 weeks), it seems as though estradiol does indeed help a person modestly with the PANSS test compared to a placebo (though they are both effective apparently), but in the long-term I would think the risks and damage would be more apparent than they are in an 8 week trial. In just the 8 weeks of the study, several women in the estradiol group already had weight gain and breast pain.

From the study...

"More women in the estradiol group reported breast discomfort (15 vs 1 in placebo group) and weight gain (14 vs 1 in placebo group)"


EtradiolPlacebo.jpg
 
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