@lowmegatron: “If serotonin is so bad then w...

“If serotonin is so bad then why do SSRIs help my depression and anxiety?" The effectiveness of SSRIs is debatable, but if and when they do help, it may be due to a reaction against serotonin/SSRI in the brain, increasing protective neurosteroids. 🧵

Brexanolone is a drug treatment for postpartum depression. It is an IV of allopregnanolone, a brain hormone (neurosteroid). It costs 30-40,000 dollars.

Allopregnanolone activates GABA-A receptors, which can explain some of its antianxiety and antidepressant effects. It has a similar effect to benzodiazepines without the addictive, zombifying properties. (Though tapering off high doses may be required.)

Some SSRIs, like Prozac, increase brain allopregnanolone. Any anti-anxiety/antidepressant effects of Prozac seem to be due to increasing allopregnanolone rather than serotonin (5-HT).

It’s not just female hormone mood disorders that are improved by allopregnanolone. Low levels are linked to depression, anxiety disorders, premenstrual dysphoric disorder, schizophrenia, and impulsive aggression.

The increase in brain allopregnanolone in response to SSRIs may be a protective reaction to the drug or the elevation in serotonin. Some research shows an initial increase in serotonin (during the homicidal period) followed by decreased serotonin...

Social isolation (SI) causes depressive and anxious behaviors in rodents. Brain allopregnanolone drops in parallel. Allopregnanolone reverses the signs of anxiety/depression.

Brexanolone works, it has reduced suffering, probably saved lives, but it is just IV allopregnanolone, sold for tens of thousands of dollars. The administration method seems to be designed for extortionate profit.

400 mg of oral pregnenolone increased blood allopregnanolone in humans. Pregnenolone is cheap and over-the-counter in many places.

"In animal models, serum neurosteroid levels appear to be closely related to hippocampal levels." PMID: 23348009

The allo-boosting pregnenolone supplement reduced the activation of brain regions associated with negative emotions.

"These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion."

Combining pregnenolone with the anti-serotonin, anti-cortisol substance L-theanine reduces symptoms, even in schizophrenia.

"Pregnenolone with L-theanine augmentation may offer a new therapeutic strategy for treatment of negative and anxiety symptoms in schizophrenia."

Bioidentical progesterone is another cheap OTC hormone that has an antidepressant and antianxiety effect partly mediated by increasing allopregnanolone.
[Beware non-bio-identical progesterone.]

Progesterone and allopregnanolone reduce learned helplessness, an animal behavioral condition analogous to human "affective disorders" like depression. Learned helplessness is characterized by increased brain serotonin.

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There is more going on with these drugs than their effects on serotonin and allopregnanolone, but this explains why they may have some beneficial effects. I am very skeptical about their alleged benefits and the idea that boosting serotonin is beneficial.

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