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How a single dose of antidepressants can trigger post-SSRI sexual dysfunction (PSSD): a hypothesis

Updated: Mar 31, 2021

Many patients report having protracted post-SSRI sexual dysfunction (PSSD) that keeps getting worse just after a single or a few doses of antidepressants. Here I theorize about how that can happen.

In posttraumatic stress disorder (PTSD), a single traumatic event triggers a life-long disorder. Not everyone develops PTSD, it all comes down to pre-existing vulnerability factors.

Not everyone develops PSSD as well. It comes down to vulnerability factors - and I did find a clear pattern. Many of PSSD sufferers used to have a severe anxiety disorder, let that be panic disorder, GAD, or social anxiety disorder. Also they used to be hypersexual with a hearty libido and used to be overly-emotional.

These traits are suggestive of an overly-responsive HPA axis. High reactivity in circuits underlying stress response and emotional learning, includes prefrontal cortex circuits, the orbitofrontal cortex, and amygdala. Hyperactivity of emotional circuits also play a role in increasing risk for PTSD [1].

5HTTPLR allele:

Mice exposed to 5-HTT inhibitors exhibit increased anxiety-like behaviors in adulthood and mimicked stress-response phenotypes of mice lacking the 5-HTT gene. These data suggest that loss of 5-HTT function during development may be an important factor in the role of 5HTTPLR in risk for stress disorders.

The low expression variant of 5HTTPLR allele show greater risk for development of stress disorders, including PTSD, but only after exposure to high levels of stress.[2]


Carriers of the Met allele have been shown to exhibit increased brain activation in the frontal cortex, amygdala and hippocampus in response to emotional or painful stimuli. The COMT Met allele has also been associated with poorer fear extinction than Val carriers in healthy controls, as well as reduced response to exposure therapy in a small sample of panic disorder patients. Thus, one might speculate that Met carriers may have altered or “increased” function of neural circuits underlying emotion processing and memory, which could act as a vulnerability for PTSD symptoms via impaired fear extinction processes.

This gene allele is also closely linked to panic and anxiety disorder. It contributes to HPA-axis over-reactivity.[2]

FKBP5 rs1360780 T allele:

The FKBP5 gene product regulates glucocorticoid receptor (GR) sensitivity and hypothalamic-pituitary-adrenal axis functioning and has been associated with many stress-related psychiatric disorders. Genetic variants of FKBP5 may be associated with risk for stress-related psychiatric disorders via differential effects on hippocampal structure and function.

FKBP5 polymorphism causes the negative feedback inhibition of cortisol to be dysregulated. So, the HPA axis can no longer manage to suppress cortisol level efficiently when it's high. This gene is also involved with panic disorder and other anxiety disorders, which are common disorders that we used to suffer from [3].

You might be asking why am I comparing PSSD to PTSD?

The main driving factor for developing the chronic neurobiological changes in the brain circuits leading to protracted PTSD is HPA axis over-reactivity, and in particular cortisol hypersecretion. It only takes one event, and one sharp increase in cortisol secretion, to trigger this life-long condition. It has been found recently that by blocking cortisol secretion altogether, people never develop PTSD.

A single dose of SSRIs can significantly elevate cortisol, and if a person has a genetic vulnerability (or two), this can lead to permanent changes in brain circuits, albeit different than changes that happen in PTSD.

In PTSD, intense emotional distress determine the changes that happen. In PSSD, there isn't an emotional trigger, but the solidification still occur, producing different potentiation and inhibition of the emotional and stress response circuits.

How does this "solidification" happen? The glutamatergic system!

Glutamate is the main mediator for synaptic plasticity, controlling both long-term potentiation (LTP) and long-term depression (LTD). What this means is that, glutamate can "potentiate" certain brain circuits permanently and semi-permanently (LTP), and can also "suppress" other circuits also permanently and semi-permanently (LTD).

Glucocorticoids (such as cortisol) rapidly induce glutamate release in the hippocampus and prefrontal cortex, leading to LTP. Cortisol, via cross-talk with the endocannabinoid (eCB) system, can rapidly stimulate endocannabinoid production in the brain, whereupon eCBs bind to the CB1 and TRPV1 receptors and inhibit neurotransmitter release, leading to long-term depression (LTD) [4].

It has been argued that the effect of antidepressants on glutamate release in the PFC could be involved in the long-term anxiolytic and antidepressant action of these drugs, because they are able to dampen glutamate release in response to acute stress. This happens after chronic SSRI intake, as they dampen the HPA axis, but a single acute dose of SSRI actually increases glucocorticoid secretion, mimicking stress, and releasing glutamate, inducing LTP and LTD that can happen over-rapidly in the genetically susceptible and inducing PSSD.

Glutamate's control of synaptic plasticity is a function of AMPA, NMDA, and mGluR receptors. Since NMDA and AMPA modulation doesn't confer benefit for PSSD, I think there's a primary mGluR dysregulation, as evident by how psychedelics have permanently cured a few people.

Psychedelics work via activation of 5HT2A receptors. 5HT2A receptors form a heterocomplex with mGluR2 receptors. So, activation of 5HT2A receptors inhibits mGluR2 activity. There are 5HT2A agonists that doesn't affect mGluR2, dubbed "non-psychedelic" 5HT2A agonists. Examples of which, are serotonin itself (5-HT) and Lisuride.

mGluR2 is an autoreceptor for glutamate. When it is inhibited by 5HT2A agonism, glutamate release is disinhibited, causing activation of all mGluR receptors. When this happens, rapid alteration of synaptic activity occurs, which can produce long-term antidepressant and anxiolytic effect.

This can also induce a permanent condition called hallucinogen persisting perception disorder (HPPD). It can happen after a single dose of psychedelics (or never at all, depending on risk genes).

This is a strong evidence that altering glutamate release in the genetically susceptible can induce a permanent condition after a single dose (HPPD, PSSD), or single event (PTSD).


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