1. An epigenetic basis for PSSD:
2. 5-HT1A: How SSRIs work
3. 5-HT1A Heteroreceptors
4. What is CaMKII?
5. Epigenetic Repression of CaMKII
6. Article Summary
7. The Surprising Effects Of Tianeptine
8. Mu-opioid And the Link To 5-HT1A
9. Lithium & Epigenetics
10. References

An epigenetic basis for PSSD:

It seems trivial to most people that medications, including over the counter medications, can cause unwanted side effects in some people. It’s also taken for granted that to remediate any unintended side effects, all that’s needed is to simply discontinue the perpetrating medication. But what if the side effects don’t resolve themselves. What if instead they continue for years or even indefinitely. This is situation not as readily acknowledged by the average person, or even within the medical community, and yet it’s the reality for a great many people treated with certain medications including SSRIs.

For some people this class of antidepressants are well tolerated and effective, however others suffer a spectrum of lasting changes to their physical health and mental wellbeing. Whilst there’s some degree of individual variation, the most typical symptoms are a complete loss of sexual interest and a general state of anhedonia. Perhaps just as troubling as the symptoms themselves is that apparent inability by doctors to explain why these side effects can persist long after the drug has fully metabolised out of the body. It’s only been in recent years with the advent of epigenetics that a plausible explanation has presented itself.

Epigenetics is the field of genetics that explains how gene expression can be altered without changing the underlying genetic code directly. Epigenetic mechanisms can essentially switch genes on and off in a lasting manner, and thereby influence an organism’s traits and behaviour. Two twins sharing the same genes can experience vastly different health outcomes based on their exposure to epigenetic agents. SSRIs are one such type of agent, that are now understood to have lasting impacts on gene expression, which might elucidate the lasting nature of PSSD. You can read my attempt to simplify the science of epigenetic in this article.

In this post I’ll delve into a crucial piece of evidence for SSRI induced epigenetic changes and do my best to convey the science in a way that’s accessible to the layman. The evidence presented in this post reveals specifically how SSRI’s can negatively impact sexual behaviour long after discontinuation.

5-HT1A: How SSRIs work

Neurotransmitters, such as Serotonin, are like chemical messengers that are released from presynaptic neurons across a synapse to a postsynaptic neuron, where it can affect mood and cognition. Once these neurotransmitter have crossed over the synapse they bind to certain receptor sites on the postsynaptic neuron. After this signal has been transmitted to the post synaptic neuron, the neurotransmitter is taken back to the presynaptic neuron via protein called SERT, also known as the serotonin transporter.

This process of reabsorption allows the neurotransmitter to be recycled or broken down. SSRIs inhibit the action of SERT, the serotonin transporter, in order to enhance the effect of Serotonin on the postsynaptic neuron. It’s through this means that SSRIs aim to improve mood and resolve symptoms of depression. [22]

A crucial component in considering how Serotonin will impact mood and cognition is the variety of different serotonin receptors distributed in different neurons throughout the brain. A blanket approach of simply increasing Serotonin throughout the brain doesn’t consider the fact that serotonin can have very different effects on neurons depending on what type of serotonin receptor they expressed. The primary target receptor is 5-HT1A, which is the first receptor type to be sequenced as well as being among the most abundant. [23] I’ve discussed the somewhat complicated behaviour of this serotonin receptor at length in other articles, so I’ll only offer a brief overview here.

“Creative Commons, Sagittal Graphic, Servier / Modified from original image with added graphics to indicate 5-HT1A Circuitry”

The 5-HT1A receptor is present on neurons in dorsal raphe nuclei, which is a small structure on the brain stem in the centre of the brain. Much like the central position of this structure in the brain, the Dorsal Raphe Nuclei is central to the release of serotonin throughout the rest of the brain, which serotonergic neurons projecting out from the brain stem in the cortex and limbic system. [24]

The 5-HT1A receptor can be further subdivided into two subtypes, the autoreceptor and the heteroreceptor. The autoreceptors are present on the neurons in the Dorsal Raphe Nuclei, and serotonin binding to these autoreceptors triggers a negative feedback response that limits further serotonin release out to the heteroreceptors.

The heteroreceptors are present in the limbic system, the area of the brain responsible for learning and emotion, and the cortex. When serotonin binds to 5-HT1A heteroreceptors the postsynaptic serotonin neurons, such as in the hippocampus, are inhibited. [25] This can have the effect of shifting the balance of neurotransmission to favour dopamine release in Cortical areas. [26]

In fact, the inhibition of serotonin transmission triggered by binding to the 5-HT1A heteroreceptor is believed to be key to how serotonin positively impacts mood. Some medications, such as Flibanserin, can selectively bind to this receptor and acutely increase dopamine transmission. By facilitating dopamine transmission Flibanserin can improve mood and even sexual desire. [29]

The goal of SSRIs would be to disable the inhibitory effect of the 5-HT1A autoreceptor so more serotonin can reach those postsynaptic heteroreceptor sites. Whilst there’s evidence to suggest that this is precisely what SSRI treatment does, the long-term effects are now in question. [27] At the beginning of treatment the autoreceptor undergoes a process of desensitisation due to the prolonged activation of the receptor by inhibiting the serotonin transporter. [28]

These autoreceptors in the Dorsal Raphe Nuclei are said to become internalised, as the receptor is removed from the cells surface and brought back into the cell. In theory this achieves the desired goal, and more serotonin can be released to the heteroreceptors. Newer research has revealed that after prolonged SSRI treatment, the heteroreceptor also undergoes the same process of internalisation – and so their beneficial impact on mood also becomes muted. The unintended consequences of long-term treatment, and the eventual desensitisation of the target serotonin receptor is a pattern observed across other serotonin receptor subtypes.

5-HT1A Heteroreceptors

The post-synaptic heteroreceptor sites are distributed in the limbic and cortical regions. The limbic system is responsible for regulating emotion, learning and sexual behaviour. Like the presynaptic autoreceptor, binding at the 5-HT1A heteroreceptor triggers hyperpolarisation of that neuron. Understanding how the 5-HT1A works is made vastly more complicated by the fact that it is present on two type of neuron with opposing effects: interneurons and pyramidal neurons.

Interneurons are GABAergic, meaning they release the inhibitory neurotransmitter GABA. Conversely, pyramidal neurons release excitatory neurotransmitters such as glutamate and dopamine. These neurons are particularly abundant in the cerebral cortex, making them crucial for motivation and executive functioning. The excitatory pyramidal neurons are counteracted by the GABAergic interneurons that feed into them.

Selectively binding to the interneurons reduces their firing rate and prevents them from inhibiting the pyramidal neurons and resulting in elevated dopamine transmission in the prefrontal cortex. This is why medications that more selectively bind to the interneuron heteroreceptors such as Buspirone can improve cognition in certain circumstances, by increasing cortical activation. Furthermore, dopamine transmission is needed more generally to mediate feelings of reward, including sexual reward, which is why heighten libido is a reported side effect of these medications.

What is CaMKII?

Although 5-HT1A receptors are G-protein-coupled receptors that undergo desensitisation or sensitisation in response to various stimuli, SSRIs may impact these receptors through a more enduring mechanism. As previously explained, serotonin reduces neuronal activity in the prefrontal cortex by binding to 5-HT1A receptors on pyramidal neurons. It is important to differentiate between 5-HT1A heteroreceptors located on interneurons and those on pyramidal neurons. When serotonin binds to interneurons, it enhances cortical activity, whereas binding to pyramidal neurons suppresses it.

This suppression occurs because 5-HT1A receptor activation reduces glutamatergic activity in the prefrontal cortex by inhibiting the activity of a key protein called CaMKII (Calcium/Calmodulin-dependent Protein Kinase II). CaMKII is activated by calcium and plays an essential role in various synaptic processes, including those related to memory, cognition, and reward. It is particularly critical in pyramidal neurons within the prefrontal cortex, where its suppression by serotonin leads to a reduction in AMPA receptor-mediated currents. [1]

Mice that lack 5-HT1A on excitatory pyramidal neurons are found to experience heightened anxiety and stress, due to an increase in CaMKII activity. [2] Conversely, mice that lack CaMKII are shown to have decreased attention, memory, and cognition – as predicted by lower cortical activity. [3][4]

Given that CaMKII is closely associated with glutamatergic activity, it is unsurprising that it plays a key role in the brain’s reward systems. The nucleus accumbens, often referred to as the brain’s primary reward center, is heavily involved in the effects of addictive substances, such as cocaine. In fact, CaMKII-expressing neurons have been implicated in the development of behaviors linked to excessive stimulation of the reward system, including hypersexuality. [5] CaMKII neurons have even been implicated in explaining the excessive hypersexuality caused by these stimulants. [6]

Epigenetic Repression of CaMKII

CaMKII has long been of interest in neuroscience due to its unique property of “self-perpetuation.” Once activated by calcium, CaMKII can translocate to NMDA receptor sites and remain there even after the initial calcium signal has dissipated. This phenomenon is sometimes referred to as “molecular memory” because it allows CaMKII to maintain its active state independently of the original trigger. [7] The lasting complex formed between NMDA receptors and activated CaMKII is believed to play a key role in long-term potentiation (LTP), a process critical for memory formation. [8]

Any medication that influences CaMKII could potentially have lasting effects on neural plasticity and memory. One such medication is the SSRI fluoxetine (commonly known as Prozac). Fluoxetine has been shown to repress CaMKII expression in the nucleus accumbens through epigenetic modifications. Specifically, chronic fluoxetine treatment reduces H3 acetylation at the CaMKII gene promoter, preventing the binding of the transcription factor FosB.

Epigenetics is the field of genetics that explains how gene expression can be altered without changing the underlying genetic code directly. Epigenetic mechanisms can essentially switch genes on and off in a lasting manner, and thereby influence an organism’s traits and behaviour. Two twins sharing the same genes can experience vastly different health outcomes based on their exposure to epigenetic agents. You can read more details on epigenetic processes in this article.

The researchers who identified this repression of CaMKII considered this finding ‘paradoxical’, as such a change would dampen the reward system. Crucially the researchers found the same changes in H3 Histone acetylation at the CaMKII promoter in postmortems of depressed patients taking antidepressants at time of death. [9]

Acetyl groups (Ac) on histone tails maintain an open chromatin structure (Euchromatin). Chromatin is a complex of DNA and protein that makes the DNA more compact, helping to regulate gene expression. When Chromatin is tightly bundled it’s less accessible to transcriptional machinery less gene transcription takes place.

modified from original byAnnabelle L. Rodd, Katherine Ververis, and Tom C. Karagiannis, CC BY-SA 4.0, via Wikimedia Commons

The authors of the study were ultimately unable to explain why an antidepressant would induce epigenetic changes that are otherwise linked to depression – but they hypothesise that it might be a compensating for an increase synaptic plasticity through alternative pathways. In fact, Histone Deacetylase Inhibitors (HDACis) are known to have an antidepressant effect when administered directly into the Nucleus Accumbens, by enhancing gene expression – an effect opposite to that of Fluoxetine on the CaMKII promotor in the Nucleus Accumbens. [10]

Article Summary

• SSRIs and Long-Term Side Effects: While it’s well-known that medications can cause side effects, it’s less acknowledged that these side effects may persist long after discontinuation, especially with certain drugs like SSRIs (Selective Serotonin Reuptake Inhibitors). SSRIs can cause some patients to experience long-lasting changes in health, such as sexual dysfunction and anhedonia (lack of pleasure).
• Epigenetics and Persistent Effects: SSRIs are now thought to cause lasting side effects through epigenetic changes, which alter gene expression without changing the DNA code. This explains why side effects like Post-SSRI Sexual Dysfunction (PSSD) might persist even after the drug is metabolized out of the body.
• Role of 5-HT1A Receptors: These receptors, particularly in the brain’s Raphe Nuclei, regulate serotonin release. Over time, SSRIs desensitize these receptors, which alters serotonin circuitry in the brain, impacting mood, cognition, and libido.
• Complex Effects on Neurons: The behaviour of the 5-HT1A receptor is complex and so desensitisation can have different effects depending on what time of neuron its expressed on (inhibitory interneurons vs. excitatory pyramidal neurons). Inhibiting the interneurons can enhance cortical activity, while pyramidal neuron suppression can impair cognition and reward response, including sexual reward.
• Role of CaMKII Protein: SSRIs suppress the activity of CaMKII, a protein involved in cognitive functions and the brain’s reward system. This suppression could be linked to reduced sexual function and motivation. Studies on SSRIs like fluoxetine show they repress CaMKII expression through epigenetic mechanisms (like reduced H3 acetylation). This paradoxical effect might dampen the brain’s reward system, contributing to side effects like low libido.

The Surprising Effects Of Tianeptine

Given that FosB is reward sensitising, the inability for FosB to bind to the promotor of CaMKII in the Nucleus Accumbens would in theory hamper the reward system. We can contrast the effect of Fluoxetine on CaMKII with other substances known to enhance FosB. Tianeptine is an atypical older tricyclic antidepressant, that has been mostly abandoned as it was found to potentially cause liver damage, although this has been disputed. Unlike Fluoxetine, Tianeptine can enhance glutamate expression through CaMKII activation. This exerts an antidepressant effect, preventing neuronal loss and dendritic atrophy. [11]

Related Articles

5-HT1A: Libido, Cognition and Anhedonia

How SSRIs Affect Hypothalamus and Hormones