July 10, 2020
Post-SSRI sexual dysfunction (PSSD) is a protracted syndrome that begins after quitting antidepressants and remains for months or even years on end. Symptoms are numerous and can be life-disabling.
Antidepressants can trigger PSSD from just a few pills in the unlucky few, depending on genetic vulnerability. Symptoms can be fully present or partially present, depending on which pathways are affected:
Different theories have been proposed to explain the pathophysiology of PSSD: R
Sexual behavior is impaired by many 5-HT agonists and agents that increase 5-HT. R
Serotonin (5-HT) is primarily inhibitory, although stimulation of 5- HT2C receptors increases erections and inhibits ejaculation, whereas stimulation of 5-HT1A receptors has the opposite effects like facilitation of ejaculation and, in some circumstances, inhibition of erection. R
Stimulation of other 5-HT2 receptors hypothetically mediates several of the side effects of the SSRIs sexual dysfunction. R
Excessive release of serotonin (which has a mixed but essentially inhibitory role on sexual functions) by the serotonergic neurons (concentrated in the raphe nuclei of the midbrain) causes "desensitization" of 5-HT1A autoreceptors (that act as sentinels that regulate the release of a substance according on how much there is already in circulation). R
The "down-regulation" of the 5-HT1A autoreceptors is instead caused by chronic and excessive activation by its natural "agonist" (serotonin) that is made available in abnormal quantities by the use of SSRIs. R
It is therefore natural to think to the autoreceptors as something that is "damaged" by excessive competition and that can be cured using an antagonist that lead the person to be again "sensitive." R
For example, when rodents were administered an SSRI medication, they noted a sustained desensitisation of 5-HT1A receptors after removal of the drug. R
In another study, a 5-HT1A antagonist was shown to reverse and prevent sexual dysfunction in rodents that were being administered with fluoxetine. R
However, PSSD sufferers through online support forums have tried and reported on the effects of all combinations of medicines acting on serotonin and dopamine systems, and medicines known to enhance functionality (ie sildenafil), are without benefit. R
It is also hypothesized that SSRI treatment induces disturbances of Transient Receptor Potential (TRP) ion channels of mechano-, thermo- and chemosensitive nerve endings and receptors resulting in the penile anesthesia in PSSD. R
The raphe-to-spinal projections are serotonergic with receptors subtypes 5HT1A, 5HT1B, 5HT2A and 5HT2C (formerly known as 5HT1C) present .
5HT2C receptor: Pro-erectile. Directly opposes the anti-erectile effect of 5HT1A receptor, but might be following an inverted U-shaped curve  . Chronic activation might by anti-sexual though inhibition of melanocortin MC4 receptors by 5HT2C and 5HT2A agonism .
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