Study finds changes in rats’ brain signaling after discontinuation of paroxetine, an SSRI

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Disclosure: The editor of this site has contributed funds to support research of the Melcangi lab.

A research group at the University of Milan has been investigating adverse effects of finasteride and selective serotonin reuptake inhibitors (SSRIs) which persist in some patients long after they have stopped taking these drugs. Drs. Roberto Cosimo Melcangi, Silvia Giatti and colleagues have explored whether these symptoms could be explained by disruptions to the neuroendocrine system, which helps govern emotion, behavior, thought and sexual function.1

The neuroendocrine system includes a cascade of reactions referred to as neurosteroidogenesis:

From Giatti et al, 20162. Neuroactive steroids are converted by neurosteroidogenic enzymes, represented by arrows.

This post highlights key findings of their most recent study, published in summer 2021, which investigated the effects of the SSRI paroxetine (brand name: Paxil) on neurosteroidogenesis in rats while they were taking the drug and after discontinuing it.3 Understanding the effect of an SSRI on neurosteroidogenesis in rats could reveal why some human patients experience severe, persistent symptoms after stopping SSRI drugs.

Study design

The study measured neurosteroidogenesis in rats at two time points: while they were receiving paroxetine, and 30 days after paroxetine was discontinued.

The investigators took two types of measurements: levels of neuroactive steroids, and the gene expression of enzymes that produce neuroactive steroids. Gene expression refers to transcription of a gene sequence into a protein by RNA. If gene expression is altered, enzymes are not produced correctly or in the right amounts, potentially disrupting neurosteroidogenesis. Such disruptions may have consequences on behavior, emotion, thought and sexual function.

The investigators measured neuroactive steroid levels in fluids and several brain areas:

  1. plasma: the fluid component of blood
  2. cerebrospinal fluid (CSF): fluid circulating in the central nervous system
  3. hippocampus: brain area involved in long-term memory
  4. hypothalamus: midbrain structure involved in emotion, pleasure and desire
  5. cerebral cortex: outer layers of the brain involved in higher-level brain functions
  6. cerebellum: ‘little brain’ behind the brain stem which coordinates movement and regulates balance.

Rats treated with paroxetine were compared to a control group which received injections of a neutral solution.

Results

Neuroactive steroid levels. 30 days after stopping treatment, the paroxetine group showed different levels of neuroactive steroids from controls. Most differences were in the hypothalamus, while one was in cerebral cortex. Statistically significant differences are outlined in yellow, with neuroactive steroid names in the far-left column:

From Giatti et al.3

In the Discussion, the authors point out that some of the altered neuroactive steroids modulate the activity of NMDA, AMPA and GABA-A receptors as well as androgen receptor. (NMDA, AMPA and GABA-A are involved in learning and memory, excitatory transmission, and inhibition, respectively.) Altered levels of neuroactive steroids could thus have broader consequences for neural signaling.

Expression of neurosteroidogenic enzymes. Differences were also found in the expression of neurosteroidogenic enzymes 30 days after stopping paroxetine. (These enzymes are represented by arrows in the above diagram of neurosteroidogenesis.) The tables below show differences in enzyme expression in hippocampus, hypothalamus and cerebral cortex. Bars with one or two asterisks indicate a statistically significant difference between groups:

Gene expression of neurosteroidogenic enzymes 30 days after stopping treatment.

Discussion

This study found that even 30 days after stopping paroxetine, the treatment group had significant differences in neuroactive steroids and related enzymes in brain areas which regulate emotion, behavior and sexuality. The study thus contributes original evidence as to why people might have lasting changes after stopping an SSRI drug such as paroxetine.

The authors concluded the paper with a hypothesis: that symptoms of post-SSRI sexual dysfunction might result from altered levels of neuroactive steroids disturbing cross-talk between the neurotransmitters serotonin and dopamine, which are involved in the control of male sexual behavior.

This post summarizes the paper Effects of paroxetine treatment and its withdrawal on neurosteroidogenesis. See also an earlier paper on the effects of finasteride on neurosteroidogenesis in rats: Effects of subchronic finasteride treatment and withdrawal on neuroactive steroid levels and their receptors in the male rat brain.

References

  1. Giatti S, Diviccaro S, Panzica G, Melcangi RC. Post-finasteride syndrome and post-SSRI sexual dysfunction: two sides of the same coin? Endocrine. 2018;61(2):180-193. doi: 10.1007/s12020-018-1593-5. PMID: 29675596.
  2. Giatti S, Foglio B, Romano S, et al. Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain. Neuroendocrinology. 2016;103(6):746-757. doi: 10.1159/000442982. PMID: 26646518.
  3. Giatti S, Diviccaro S, Cioffi L, Falvo E, Caruso D, Melcangi RC. Effects of paroxetine treatment and its withdrawal on neurosteroidogenesis. Psychoneuroendocrinology. 2021 Jul 21;132:105364. doi: 10.1016/j.psyneuen.2021.105364. PMID: 34325207.

Figures used with permission of the journals in which the articles appeared.