Antipsychotics, 5α-reductase inhibitors, SSRI’s, SNRI’s and TCA’s do all mess with neurosteroids!

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quagmire
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Antipsychotics, 5α-reductase inhibitors, SSRI’s, SNRI’s and TCA’s do all mess with neurosteroids!

Unread post by quagmire »

Antipsychotics, 5α-reductase inhibitors, SSRI’s, SNRI’s and TCA’s do all mess with neurosteroids!

Use of antipsychotics, 5α-reductase inhibitors, SSRI’s, SNRI’s and tetracyclic antidepressants (TCA’s) can all lead to sexual dysfunction. All can lead to the same sexual dysfunction symptoms as PSSD. There may be a possibility that there are different ways these drugs cause sexual dysfunction, but these drugs share some similarities.

Selective serotonin reuptake inhibitors (SSRIs) are a widely used class of drug. Post-SSRI sexual dysfunction (PSSD) is a condition in which patients continue to have sexual side effects after discontinuation of SSRI use. The prevalence of persistent sexual side effects after discontinuing SSRIs is unknown.
SSRI and SNRI antidepressants are well known to cause adverse sexual effects. This was first established in healthy volunteer phase 1 trials in the 1980s. Current product labeling warns of disturbances to sexual functioning, but these warnings are insufficient.
The common assumption that sexual functioning typically returns to pre-drug baseline after the use of an SSRI or SNRI has no clear basis. While clinical experience points to some recovery of function in many people, there is no robust evidence that anyone who takes an SSRI or SNRI actually recovers 100% of their original genital sensation, sexual response and capacity to experience sexual pleasure.

If we look at antipsychotics Risperidone was associated with the most frequent overall sexual impairment (96%) compared to olanzapine (90%) and quetiapine (88%), although it was not statistically significant. It has been reported an overall sexual dysfunction of 89% due to risperidone. Up to 93% of risperidone-treated patients reported an overall impairment of sexual functioning in yet another study. Even in the case of olanzapine and quetiapine, a frequency of overall sexual impairment has been observed.

The post-Finasteride syndrome (PFS) has been claimed to occur in men who have taken oral finasteride to treat hair loss or benign prostatic hyperplasia. While the incidence of persistent sexual, mental, and physical side effects despite quitting finasteride is unknown, and the condition is not recognized by the scientific community, individuals who suffer from PFS do present with very distinctive and homogenous symptoms.


Neurosteroids

Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors.
Some major known biological functions of neurosteroids include modulation of neural plasticity, learning and memory processes, behavior,and seizure susceptibility, as well as responses to stress, anxiety, and depression. Neurosteroids also appear to play an important role in various sexually-dimorphic behaviors and emotional responses.
Olanzapine increases brain allopregnanolone levels sufficiently to modulate neuronal activity by allosterically regulating GABAA receptors.

Clozapine and olanzapine increase the GABAergic neuroactive steroid allopregnanolone, and it has been hypothesized that NS induction may contribute to the therapeutic actions of these agents.

Mirtazapine affects neuroactive steroid composition similarly as do SSRIs. The inhibition of the oxidative pathway catalyzed by the microsomal 3alpha-HSD is compatible with an enhanced formation of 3alpha-reduced neuroactive steroids. However, the changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of this antidepressant rather than clinical improvement in general.
Contrarily, 3α-HSD is induced to varying extents by certain selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, fluvoxamine, sertraline, and paroxetine, as well as by certain other antidepressants like venlafaxine and mirtazapine, and these antidepressants have been found to increase inhibitory neurosteroid levels.

Finasteride inhibits 5α-reductase and thus preventing DHT production, finasteride reduces androgen signaling in tissues like the prostate gland and the scalp.
Neurosteroids like 3α-androstanediol (derived from DHT) and allopregnanolone (derived from progesterone) activate the GABAA receptor in the brain; because finasteride prevents the formation of neurosteroids, it functions as a neurosteroidogenesis inhibitor and may contribute to a reduction of GABAA activity. Reduction of GABAA receptor activation by these neurosteroids has been implicated in depression, anxiety, and sexual dysfunction.

There are indications that the SSRIs fluoxetine, sertraline, and paroxetine decrease the Km of the conversion of 5α-dihydroprogesterone to allopregnanolone by human 3α-HSD type III 10- to 30-fold. Only sertraline inhibited the reverse oxidative reaction. SSRIs also affected conversions of androgens to 3α- and 3α, 17β-reduced or -oxidized androgens mediated by 3α-HSD type IIBrain. The region-specific expression of 3α-HSD type IIBrain and 3α-HSD type III mRNAs suggest that SSRIs will affect neurosteroid production in a region-specific manner.
Specific drugs could manipulate the synthesis of both excitatory and inhibitory neurosteroids. For example, the biosynthesis of inhibitory acting neurosteroids can be inhibited by 5α-reductase inhibitors such as finasteride or by inhibitors of 3α-HSD such as medroxyprogesterone acetate. Inhibition of inhibitory neurosteroids with finasteride or medroxyprogesterone acetate (Figure 1., MPA) has been associated with depression, anxiety, irritability, and sexual dysfunction. These behavioral alternations are well known side effects of 5α-reductase inhibitors or MPA.

Also, specific drugs could activate steroidogenic enzymes. The term “selective steroidogenic brain stimulants” (SSBSs) has been proposed for drugs that activate steroidogenesis and potentiate the effects of endogenously synthesized neurosteroids. Good examples of SSBSs are fluoxetine and norfluoxetine. Fluoxetine is a well-known antidepressant drug that belongs to a class of selective serotonin reuptake inhibitors (SSRIs), and norfluoxetine is an active metabolite of fluoxetine. Fluoxetine, norfluoxetine, several other SSRI (paroxetine, sertraline), and other non-SSRI antidepressant drugs (venlafaxine, mirtazapine) are potent inducers of the 3α-HSD enzyme. These drugs have been found to increase levels of inhibitory neurosteroid allopregnenalone and to potentiate its behavioral effects. The TSPO activators, a new group of investigational drugs that have the potential to treat important neurological and psychiatric diseases also increase brain levels of inhibitory neurosteroids and potentiate their behavioral action.


σ1 receptors

SSRI’s, Mirtazapine and Quetiapine all binds to the sigma-receptor σ1
Although originally proposed as a subtype of opioid receptors, the sigma receptor is now confirmed to be a non-opioid receptor that binds diverse classes of psychotropic drugs. Sigma receptors are subdivided into two subtypes, sigma-1 and sigma-2. The sigma-1 receptor is a 25-kDa protein possessing one putative transmembrane domain and an endoplasmic reticulum retention signal. Sigma-1 receptors are highly expressed in deeper laminae of the cortex, olfactory bulb, nuclei of mesencephalon, hypothalamus, and Purkinje cells in the brain. Sigma-1 receptors are predominantly localized at the endoplasmic reticulum of both neurons and oligodendrocytes. From behavioral studies, sigma-1 receptors were shown to be involved in higher-ordered brain functions including memory and drug dependence. The actions mediated by sigma-1 receptors at the cellular level can be considered either as acute or chronic. The acute actions include the modulation of ion channels (i.e., K+ channel, NMDA receptors, IP3 receptors) and the sigma-1 receptor translocation. Chronic actions of sigma-1 receptors are basically considered to be the result of an up- or down regulation of the sigma-1 receptor itself. For example, the upregulation of sigma-1 receptors per se, even without exogenous ligands, promotes cellular differentiation and reconstitution of lipid microdomains (lipid rafts) in cultured cells. These findings together suggest that sigma-1 receptors might possess a constitutive biological activity, and that sigma-1 receptor ligands might merely work as modulators of the innate activity of this protein. Recent in vitro and in vitro studies strongly point to the possibility that sigma-1 receptors participate in membrane remodeling and cellular differentiation in the nervous system.

There is been addressed a possible role of sigma receptors in mediating neurosteroid action and the regulation of inhibitory and excitatory ion channels by neurosteroids has implications for the role of these molecules in learning and memory, nociception, and excitotoxicity.
“The order of potency for drugs at the sigma-1 receptor chaperone was as follows: fluvoxamine>sertraline>fluoxetine>escitalopram>citalopram>paroxetine>duoxetine. Venlafaxine, milnacipran, and mirtazapine showed very weak affinity for this chaperone.”
Interestingly, the interaction of fluvoxamine, a selective serotonin reuptake inhibitor [SSRI], and the σRs may account for its potential amelioration of psychotic depression, where increased glutamate release occurs through activation of serotonin [5-HT3] mediated by σ1Rs, and in patients with schizophrenia. These findings are supported by research on a depressive phenotype in σ1R knockout mice. In contrast, the SSRI sertraline worsens the symptoms. Not all SSRIs induce their antidepressant activity via the σ1R, e.g. paroxetine.

Several psychoactive drugs show high to moderate affinity for σ1 receptors, including the antipsychotic haloperidol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in addition, the anticonvulsant drug phenytoin allosterically modulates σ1 receptors. Quetiapine activates σ1/2 receptors. Certain neurosteroids are known to interact with σ1receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in intracellular Ca2+ signaling.
Although the precise mechanism of the biological response of σRs is still uncertain, it is accepted that σR can modulate a number of neurotransmitter systems, including neurosteroids, glutamatergic, noradrenergic and dopaminergic ones thought to be especially important functional modulators of Glutamat activity at this site.

Sources:
https://en.wikipedia.org/wiki/Neurosteroid
https://www.ncbi.nlm.nih.gov/pubmed/15100702
https://www.ncbi.nlm.nih.gov/pubmed/28778697
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004927/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802373/
http://www.ijtrichology.com/article.asp ... st=Rezende
https://www.mdedge.com/psychiatry/artic ... ysfunction
https://www.ncbi.nlm.nih.gov/pubmed/16962649
https://www.semanticscholar.org/paper/I ... cf7b5eb6cc
https://en.wikipedia.org/wiki/Neuroster ... _inhibitor
https://en.wikipedia.org/wiki/Finasteride#Pharmacology
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC23979/
http://eom.hdeo.eu/wp-content/uploads/2 ... rdetic.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268997/
https://www.researchgate.net/publicatio ... _Limelight
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906365/

https://www.ncbi.nlm.nih.gov/m/pubmed/2 ... H6dWUJ_hMk
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701284/
https://www.lktlabs.com/product/quetiapine-fumarate/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906365/
quagmire
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Re: Antipsychotics, 5α-reductase inhibitors, SSRI’s, SNRI’s and TCA’s do all mess with neurosteroids

Unread post by quagmire »

As mentioned in the post above, SSRI's and also other antidepressants modulate brain steroids that has important roles in sexual function.

Various antidepressants, including the SSRIs fluoxetine, fluvoxamine, sertraline, and paroxetine, the SNRI venlafaxine, and mirtazapine, have been found to activate certain 3α-HSD enzymes, resulting in a selective facilitation of 5α-dihydroprogesterone conversion into allopregnanolone. This action has been implicated in their effectiveness in affective disorders, and has resulted in them being described as selective brain steroidogenic stimulants.

The human androgen receptor (AR) is a ligand activated nuclear transcription factor and mediates the induction of genes involved in the development of the male phenotype and male secondary sex characteristics, as well as the normal and abnormal growth of the prostate. We have identified the pair of hydroxysteroid dehydrogenases (HSDs) that regulate ligand access to the AR in human prostate. We find that type 3 3α-HSD (aldo-keto reductase (AKR)1C2) catalyzes the NADPH dependent reduction of the potent androgen 5α-dihydrotestosterone (5α-DHT) to yield the inactive androgen 3α-androstanediol (3α-diol). We also find that RoDH like 3α-HSD (RL-HSD) catalyzes the NAD+ dependent oxidation of 3α-diol to yield 5α-DHT. Together these enzymes are involved in the pre-receptor regulation of androgen action. Inhibition of AKR1C2 would be desirable in cases of androgen insufficiency.

The steroid products of the 5α-Rs pathways undergo further metabolism by the 3α-hydroxy-steroid dehydrogenase (3α-HSD) to produce a host of active neurosteroids with important physiological function, in many tissues including the central nervous system (CNS)

Sources:

https://en.wikipedia.org/wiki/3%CE%B1-H ... ydrogenase
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2225387/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064044/
Jazzmatazz
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Re: Antipsychotics, 5α-reductase inhibitors, SSRI’s, SNRI’s and TCA’s do all mess with neurosteroids

Unread post by Jazzmatazz »

Any more information about this @quagmire? Any ideas how the imbalances in those neurosteroids could be fixed? Could using exogenous anabolic androgenic steroids fix it?
iull1k
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Re: Antipsychotics, 5α-reductase inhibitors, SSRI’s, SNRI’s and TCA’s do all mess with neurosteroids

Unread post by iull1k »

Yeah you are right, but that's not new.
http://www.pssdforum.com/viewtopic.php? ... 4297#p4288

This theory is seriously considered by propeciaforum admins.
DrugsAreBad
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Re: Antipsychotics, 5α-reductase inhibitors, SSRI’s, SNRI’s and TCA’s do all mess with neurosteroids!

Unread post by DrugsAreBad »

Sounds very interesting. Question is: what do you do about it.
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