Post-SSRI Syndrome

Post-SSRI Syndrome/PSSD is a condition characterized by persistent and often debilitating symptoms that continue or emerge after the discontinuation of sertonergic medications such as serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Whilst these medications are prescribed to treat mental health conditions such as depression or anxiety- for a certain subset of the population in particular, they can perversely cause a worsening of symptoms. [10]

Concerningly for those that have experienced a adverse response to this class of medication, there’s additionally the risk of these adverse symptoms persisting long after treatment has ended. This dramatic difference in patient outcome most likely has to do with individual genetics – a factor this isn’t often considered by health care professionals when prescribing these medicines. For example, the 5-HT1A serotonin receptor (arguably one of primary targets of SSRI treatment) is crucial for cognition and hormonal regulation via the hypothalamus, and its expression is subject to a high degree of variability based on individual polymorphisms (read more).

Single-nucleotide polymorphisms (called SNPs for short) are simple ‘letter’ swaps in the DNA code that can result in dramatically different health outcomes. In one study of 200 men treated with SSRIs, one of these simple ‘letter swaps’ was found to be responsible in a 3-fold increase in the risk of developing sexual side effects. [11] This is one of the polymorphisms we can check for with our Custom Genetic Reporting service (read more). Sexual side effects stemming from use of SSRIs are are particularly troubling given their especially enduring nature as a condition referred to as ‘PSSD’.

What is PSSD?

Post-SSRI Sexual Dysfunction (PSSD) refers to a condition where an individual appears to experience persistent sexual dysfunction following treatment with anti-depressants, particularly of the class called Selective Serotonin Reuptake Inhibitors (SSRIs). The symptoms of this condition include genital anaesthesia (or numb genitals), decreased desire for sexual activity and weak or even pleasureless orgasms. [1]

The condition doesn’t only pertain to use of SSRIs but can also include use of related medications such as Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs). Whilst the condition is still subject to some scrutiny by medical establishments, there is an increasing recognition of its risk with 2019 committee by the European Medicines Agency recognising this discontinuation syndrome for Fluoxetine. [2]

Sexual dysfunction can occur both during treatment with these medications, and also following cessation of treatment. It’s characterised by its lasting nature, with symptoms persisting for years following drug withdrawal. As of yet it’s unknown how prevalent the condition may be, however an analysis of patients treated with the SSRIs Paroxetine, Sertaline and Fluoxetine found that 60% of males and 57% of Females experience emergent sexual dysfunction after 8 weeks of treatment. [3] A larger analysis of over 1000 patients estimated the rate of sexual dysfunction as being as high as 70%! [4]

What are SSRIs?

SSRI is short for selective serotonin reuptake inhibitor, and this precisely what this class of medication aims to do, inhibit the reuptake of serotonin. The goal of SSRIs is to boost the activity of serotonin in the brain. The primary aim of SSRIs is to increase serotonin activity in the brain. Serotonin, a neurotransmitter, has long been associated with the regulation of mood and feelings of happiness, making it a key target for drugs treating depression. The serotonin hypothesis of depression stems from early studies on patients suffering from major depressive disorder that found significantly lower levels of blood platelet serotonin. [5] Depressed patients have also been found to have lower levels of the precursor to serotonin called L-tryptophan. [6][7]

Neurotransmitters, such as Serotonin, are like chemical messengers that are released from presynaptic neurons across a synapse to a postsynaptic neuron. Once serotonin has sent its signal across to the post-synaptic neuron it is 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, so that it remains at the postsynaptic neuron for longer, prolonging its signal.

What is the cause of PSSD?

Whilst there’s no agreed upon mechanism of action to explain the cause and enduring nature of some of the side effects of SSRI treatment, there are several theories that I present on this website that are backed by the latest scientific literature. These three mechanisms may each play a role together to varying degrees in different individuals suffering from Post-SSRI Syndrome, or one mechanism may take primacy. Without a thorough understanding of an individuals genetic risk factors it’s reasonable to consider each of the following:

1. The 5-HT1A Receptor

The 5-HT1A receptor is one of the most widely distributed type of serotonin receptor is crucial not only for the intended action of SSRIs, but also for the broad range of unintended effects too. The 5-HT1A receptor exists in two forms with distinct brain distributions: presynaptic autoreceptors and postsynaptic heteroreceptors. The autoreceptors are located in the brainstem, specifically in the Raphe Nuclei, a central region from which serotonergic neurons project throughout the brain. The 5-HT1A autoreceptors in the Raphe Nuclei are primary targets in SSRI treatment, as they regulate serotonin release into the brain via a negative feedback mechanism. [8]

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

The therapeutic aim of SSRI treatment is to desensitize these 5-HT1A autoreceptors, diminishing their negative feedback effect. This desensitisation allows more serotonin to be released to target heteroreceptors in the prefrontal cortex and limbic system, where serotonin binding is associated with beneficial changes in cognition and mood.

However, more recent research has revealed that SSRI treatment is fundamentally undermined by that fact that eventually the heteroreceptor also undegoes this same process of desensitisation and internalisation. As explained over previous articles, this results in a number secondary effects, such as reduced brain metabolism in the prefrontal cortex.

The 5-HT1A receptors are G-protein-coupled receptors (GPCRs), making them particularly susceptible to changes in sensitivity and expression levels. With prolonged activation, 5-HT1A receptors undergo internalisation, a process in which they are removed from the cell surface, preventing further activation. These adaptations can be long-lasting and may play a central role in explaining the persistence of post-SSRI sexual dysfunction (PSSD). In an animal study, just two weeks of fluoxetine treatment led to significant desensitisation of 5-HT1A receptors in the hypothalamus. This caused pronounced alterations in hormonal release that persisted for 60 days after the treatment had ended, long after the fluoxetine had cleared from the body. (read more)

Given the critical role of 5-HT1A receptors in brain regions related to cognition and mood, such as the prefrontal cortex and limbic system, enduring desensitisation may help explain many of the non-sexual symptoms of PSSD, including changes in cognition and mood. The 5-HT1A receptor is also significant in understanding how some individuals are more prone to negative outcomes in response to SSRI treatment, since it is regulated by a number of single nucleotide polymorphisms. These variations in the DNA sequence could perhaps predispose some individuals to developing PSSD. (read more)

2. Epigenetic modifications.

Epigenetics is the field of genetics that explains how gene expression can be altered without changing the underlying genetic code directly. One example of a particularly enduring form of epigenetic modification is DNA methylation. Methylation at the promoter of gene reduces its expression by making it less accessible to transcriptional machinery. When the promoter of gene is hypermethylated, it is essentialled ‘switched off‘.

Chromatin Immunoprecipitation sequencing has confirmed that Fluoxetine treatment can result in epigenetic modifications that left researchers puzzled. Chronic exposure to Fluoxetine reduced the expression of an enzyme called CaMKII (calmodulin-dependent protein kinase II) in the Nucleus Accumbens. The Nucleus Accumbens is a small structure in the centre of the brain that key for mediating feelings of reward and motivation. CaMKII is an enzyme that regulates the level of Calcium in a cell and is conducive to glutamate and dopamine signalling as well as memory formation. These are neurotransmitters that are involved in feelings of excitement and reward.

Animal studies where CaMKII is ‘knocked-out’ left the animal with reduced cognition and memory formation. It’s therefore curious that an anti-depressant with the purported goal of treating depression would make such an alteration to the epigenome. The researchers even suggested this effect as being ‘paradoxical’, as the effect would be to dampen the reward circuitry in the brain. Interestingly CaMKII also appears to be fundamental to 5-HT1A signalling, and so this finding is possibility corroborated by the mechanism I’ve outlined in previous articles (read more).

3. Disruption of the ‘Gut-Brain’ Axis

The term PSSD can often appear limiting, as there are many individuals suffering from health complaints following SSRI treatment that are not primarily related to sexual function. The primary of these peripheral effects are those relating to Gut-Health. The gut is itself highly interconnected with the brain through the Gut-Brain axis. In fact, the gut is sometimes referred to as ‘The Second Brain’, being also highly regulated by neurotransmitters such as Serotonin and Dopamine. As much as 50% of the body’s dopamine is synthesised in the gut. [9]

Suganya, Kanmani, and Byung-Soo Koo, CC BY 4.0 https://creativecommons.org/licenses/by/4.0, via Wikimedia Commons

Studies have found that SSRIs exert an antimicrobial effect, which can be devastating for the delicately maintained ecosystem of microbiomes that live in the gut. These diverse strains of bacteria serve to synthesise vital neuroactive metabolites such as Tryptophan Indoles and Short Chain Fatty Acids, and so disrupting this process can wreak havoc on neurological health.

SSRIs have been found to decrease the diversity and abundance of key strains of bacteria involved in maintaining gut health. This effect is so pronounced that SSRI induced intestinal damage that some researchers suggest it could contribute to the 40% of relapse rate following treatment! For a full break down of this effect, you can read the article here.