Why is PSSD so damn persistent and treatment-resistant: more insight into the glutamatergic system

It's very common that patients experience a mere window of complete relief from post-SSRI sexual dysfunction symptoms, while trying one drug or another, just for that relief to depart and never return. Despite the hope it gives that the brain is still capable of experiencing pre-PSSD normality, it also adds frustration yearning for a state of permanent relief. More insight into the glutamatergic system could be the key to the persistent and treatment-resistant nature of PSSD.

Sufferers often feel trapped and frustrated

Neuroplasticity:

The glutamatergic system is closely involved in neuroplasticity and the process of long-term potentiation (LTP) and long-term depression (LTD) and can maintain certain pathological neurochemical states and circuit remodeling, most notable in addiction [1].

There is a clear association between post-SSRI sexual dysfunction and the glutamatergic system as I've previously mentioned in the 'how serotonin modulates the glutamatergic system' article, but it doesn't explain why only a small number of people who have taken antidepressants end up developing PSSD.

I recently learned that single nucleotide polymorphisms (SNPs) in genes that code for glutamate receptors, most notably GRIA1 (AMPA1), GRIA3 (AMPA3), and GRIK2 (kainate2) are associated with sexual dysfunction in patients treated with the SSRI Citalopram [2]. The polymorphism in GRIA1 (rs1994862), in particular, was associated with loss of libido [3].

Certain SSRIs interfere with the glutamatergic signalling in a more direct manner unrelated to their serotonergic effects. For instance, Sertraline was reported to inhibit Kv1.5, Kir4.1, Na+, and Ca2+ channels [4][5][6][7][8][9], with Fluoxetine and Fluvoxamine sharing its Kir4.1 inhibition.

In another study, Sertraline also reduces glutamate uptake in human platelets [10]. This is important as platelets are viewed as peripheral markers of cerebral glutamatergic dysfunction as the impairment of glutamate transport in platelets in a variety of neurodegenerative diseases often reflects glutamatergic alterations in the CNS [11][12][13]

All these channels modulate glutamate uptake and function of glutamate transport. Glutamate uptake is essential to maintaining glutamate clearance and inhibition of Kir4.1 would disrupt astroglial control of said clearance, causing increased glutamate in the synaptic cleft, increasing glutamate neurotransmission [14]. Suffice to say, the additive total or synergistic effect through inhibition of these channels can potentially alter glutamate-driven neuroplasticity.

To further complicate matters, chronic SSRI stimulation of 5-HT2B receptors change multiple gene expressions and metabolism of glutamate, glucose and glycogen [15]. Keep in mind that glycogen is a precursor for glutamate, as such glycogen is crucial for long-term potentiation [16].

(You can view a list of these genes here: PMC4335176/table/T1)

Why only a small percentage of people end up suffering from PSSD?

Just a though, but since antidepressants excessively modulate the glutamatergic system, both directly and indirectly, leading to downstream modulation of neuroplasticity and circuit remodeling processes, then maybe certain genetic vulnerabilities or methylation affecting glutamate receptors or transporters genes could predispose the brain to having permanently altered excitatory tone upon antidepressant withdrawal.

More rat studies involving PSSD genetics are certainly needed to pinpoint the causes. For now, we can only hypothesize. Thanks for reading.