The Mechanisms of Post-SSRI Sexual Dysfunction (PSSD)

in steemit •  3 years ago  (edited)

I wrote a few days ago about myself and my personal introduction to steemit. In brief: I'm a 20 year old neuroscience major who has sexual dysfunction from taking SSRI antidepressant Lexapro for 4 days 2 years ago. That should strike you as weird. It is, and it's not documented in the scientific community. We do have a large community of people, but few doctors know of our condition. That's why I've set out to bring PSSD to the medical community.

I don't blame you if you don't believe a word I've said so far. But it's all true, and I've outlined (the beginnings of) my theory of what has gone wrong, and cited the peer-reviewed literature that led me to these conclusions.

The Mechanisms of Post-SSRI Sexual Dysfunction (PSSD)

Abstract:

SSRI antidepressants are among the most widely prescribed prescription medications in the United States. They are most commonly prescribed for Major Depressive Disorder (MDD), Panic Disorder, and Anxiety. SSRIs are widely deemed to be the safest and most effective chemical treatments for these prevalent disorders. While SSRIs have a much lower side effect profile than most traditional antidepressants, they still have many side effects that drive patients to end treatment prematurely. In a vast majority of cases, these side effects recede within days or weeks of the end of treatment. For a few very unlucky people, they persist for months or years after the last pill. This has been largely undocumented in medical literature. Recently there have been a few studies that back up what the people with these lasting side effects already know: Things that go wrong while on SSRIs don’t always go away.

A Proposed Method of Action:

In the Raphe Nuclei (RN), the 5HT1A receptor acts as a presynaptic somatodendritic autoreceptor. At the ends of its projections in the in the hippocampus, frontal cortex, and hypothalamus, it functions a presysnaptic autoreceptor and a postsynaptic heteroreceptor (Sotelo et al., 1990; Burnet et al., 1995; Riad et al., 2000). When more Serotonin (5-HT) is found in the synapses in the RN, binding of autoreceptors inhibits for the release of 5-HT in the projections of RN neurons (Koek et al., 1998; Gobbi et al., 2001). In this manner, 5-HT1A autoreceptors work as an effective regulator of 5-HT levels in the brain (Bang et al., 2012). Decreased 5-HT transmission has long been associated with MDD (Van Praag et al. 1970) and it is thought that the RN is where SSRI antidepressants exhibit their therapeutic effects. It then comes as little surprise that the 5-HT1A has been heavily implicated in effective clinical treatment of depression and anxiety. SSRIs are believed to block 5-HT reuptake by binding to SERT (5-HTT) and reducing its reuptake abilities (Murphy et al., 2004). If this was the only result, increased somatodendritic and terminal autoreceptor binding would inhibit release of 5-HT into the synapse: Resulting in no increased 5-HT levels. Through a process that is still unknown, serotonin transmission is eventually enhanced by “desensitization” of both the somatodendritic and terminal autoreceptors (Chaput et al., 1985), allowing synaptic 5-HT to accumulate in the synapse. This accounts for the characteristic 4-8 week delay between treatment origins and therapeutic relief (Gartside et al., 1995; Blier, 2010; Richardson-Jones et al., 2010). 5-HT and 5-HT1A agonist binding on the presynaptic autoreceptor inhibits 5-HT activity by hyperpolarizing the neuronal membrane (Penington and Fox, 1994). Presynaptic 5-HT1A receptors are preferentially desensitized by chronic SSRI treatment while postsynaptic receptors are not (Pineyro and Blier, 1999). This preferential presynaptic desensitization is also seen after chronic administration of 5-HT1A agonists (Blier and de Montigny, 1994). 5-HT1B/1D autoreceptor agonists have shown less inhibitory action in cells treated chronically with low dose Fluvoxamine (Blier and de Montigny, 1983).
This model explains the widespread negative sexual and emotional changes that many people with PSSD report. Increased synaptic levels of Serotonin at RN projections would lead to more post-synaptic 5-HT receptor binding. Activation of post-synaptic 5-HT receptors inhibits the release of dopamine (DA) (Montgomery et al., 1991). Synaptic DA levels have been shown to have their activity and firing rate reduced after the administration of Escitalopram (a common SSRI antidepressant) for as little as two days (Dremencov et al., 2009). This suggests that there are several 5-HT receptors and autoreceptors that play a role in PSSD. With each SSRI likely affecting specific receptors differently. Dr. Dremencov observed that administration of a 5-HT2C antagonist completely reversed this DA inhibition in the VTA (Fig. 1). It is well known that Dopamine plays a critical role in pleasure and reward: Especially in the sexual response. A decrease in DA activity and firing rate could explain many of the symptoms associated with PSSD. Further, DA D2 binding has been shown to inhibit the secretion of Prolactin by the pituitory gland (Ben-Jonathan et al., 2001). Increased Prolactin levels are shown to negatively impact male sexual drive and ability, and play a role in the refractory period (Haake et al., 2003) (This can be seen as Hyperprolactinemia in some patients on D2 antagonists for the treatment of Schizophrenia). Because of these downstream implications of desensitization of the 5-HT1A Autoreceptor, it is very common to see sexual dysfunction in SSRI patients. However, this dysfunction is relieved in nearly all cases after the cessation of medication. Why then, do we see thousands of antidotal reports of sexual dysfunction after treatment has ceased? Even in the absence of residual mental illness? Male mice who had mothers on SSRIs showed a permanent decrease in sexual drive (Gouvêa et al., 2008) Recently there have been new studies that are reiterating what people suffering from PSSD already know (Sheetrit et al., 2015) (Farnsworth et al., 2009) (Stinson, 2009) (Waldinger et al., 2015) (Leiblum et al., 2008) (Bolton et al., 2006) (Csoka et al., 2006), sexual side effects can remain after treatment.

Discussion:

Due to the stigma of sexual dysfunction, and doubt from physicians that persisant sexual dysfunction from SSRIs is possible, many PSSD sufferers remain silent (Stinson, 2013). Even more patients may have dysfunction that is mild or that they attribute to other factors such as aging. The emotional, social, and sexual implications of PSSD are widspread, and often lead to patients feeling alientated from their peers and loved ones (Stinson, 2013). There are several antecdoctal reports of spontaneous recovery but they are quite rare in the PSSD world. Many with PSSD therefore fear that their dysfunction is permanent. The terror of this realization adds to preexisting depressive, obsessive, or anxious behavior. Further research should focus on the methods of 5-HT autoreceptor downregulation in the DRN, and the downstream neural and hormonal effects of DRN disinhibition.

References:

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Ben-Sheetrit, Joseph, et al. "Post-SSRI Sexual Dysfunction: Clinical Characterization and Preliminary Assessment of Contributory Factors and Dose-Response Relationship." Journal of clinical psychopharmacology 35.3 (2015): 273-278.

Blier P et al. “Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study.” Am J Psychiatry. 2010 Mar;167(3):281-8. Epub 2009 Dec 15.

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Richardson-Jones JW et al. “5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants.” Neuron. 2010 Jan 14;65(1):40-52.2009.12.003.

Stinson, Rebecca Diane. "The impact of persistent sexual side effects of selective serotonin reuptake inhibitors after discontinuing treatment: a qualitative study." PhD (Doctor of Philosophy) thesis, University of Iowa, 2013.

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Waldinger, Marcel D., et al. "Penile anesthesia in post SSRI sexual dysfunction (PSSD) responds to low-power laser irradiation: a case study and hypothesis about the role of transient receptor potential

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