07/21/2025
SSRI Withdrawal Is Mitochondrial Dysfunction
Installment seven in our series on understanding the truth about SSRIs.
In analyzing the biochemical data of clients over the last year I have worked on two cases involving catastrophic failures of energy metabolism that occurred in the wake of SSRI withdrawal. In both cases, switching SSRIs from one to another also seemed to play a role in precipitating energetic dysfunction.
Here we will examine the concept that both SSRI withdrawal and SSRI switching can cause mitochondrial dysfunction.
This is the seventh installment in our series on the truth about serotonin and SSRIs and builds on the information in the last installment, SSRIs Are Mitochondrial Drugs.
This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.
The first individual had no issues being on Paxil long-term nor going off Paxil for the first time, but when he went on Paxil a second time he developed tachycardia and muscle cramps and spasms during sleep. Switching to Lexapro made these worse. Withdrawing from Lexapro then added to these problems a whole list of new problems: sexual dysfunction, peripheral neuropathy, shortness of breath, anxiety, muscle cramping, numbness, and excessive urination.
The second individual developed sexual dysfunction on Zoloft and chronic fatigue in the wake of Zoloft withdrawal in his 20s. At its worst point, he spent a year not being able to stand in the shower and a month needing to be bathed by another person and needing a portable bedside toilet.
Despite these problems onsetting during the withdrawal from Zoloft, Prozac immediately caused extreme spaciness and a low dose of Celexa caused restlessness. He is not confident that Zoloft would not have caused the same problems at that time because he felt hypersensitive to everything. However, the hypothesis that switching SSRIs did indeed worsen his situation should be considered, because SSRIs have different impacts on mitochondrial function.
Both people received individualized protocols based not on generalized information about SSRI withdrawal, but based on mitochondrial testing, whole genome sequencing, and comprehensive biochemical data.
The second just received his protocol so has no results to report yet.
The first received his protocol in November of last year. Despite “having gone to see dozens of specialists who could not tell me what was going on,” six weeks into his protocol he reported “the first time I felt normal in over two years.”
At the six-month mark, he wrote “six months later, I have regained quality of life and am able to do everything I used to be able to.”
After 8.5 months, he wrote “I've still been pretty amazed how effective your protocol has been. On the whole I feel like a whole different person from a year ago. It's wild. I've also gained close to 15 pounds in lean muscle mass since January. Making gains in the gym daily and I think I can end the year with another 10 pounds of mass. Been crushing it at work and also traveling and feel comfortable in my body for the first time in 2-3 years. Excited to see what continued progress I can make!”
The Mitome results of the two individuals were very different. Importantly, neither of them had Mitome tested in the immediate wake of SSRI withdrawal, so in each case the results reflect the combination of genetics, nutritional status, and prior experience, including the catastrophic effects of SSRIs and being off them for several years. The first showed a pattern associated with deficient methylation expected to suppress the hypoxia response, while the second showed a pattern associated with the impact of an excessive hypoxia response.
Whole genome sequencing suggested the first individual’s results were caused by a heterozygous defect in SLC25A26, which prevents methyl groups from being transported into the mitochondria, while the second individual’s results were caused by a heterozygous gain-of-function polymorphism in a receptor for TNF-alpha that creates a chronically increased inflammatory tone, which primes cells to easily activate a hypoxia response that suppresses mitochondrial respiration.
The second case is rather straightforward to explain: the hypoxia response is antagonized by sertraline (Zoloft) but exacerbated by fluoxetine (Prozac) and citalopram (Celexa). Thus, while the second individual remains deeply uncertain whether these different SSRIs had genuinely different impacts on him at the time they were tried, the response is consistent with the experimental evidence suggesting these different SSRIs have disparate impacts on the hypoxia response.
The first case is less straightforward to explain because paroxetine (Paxil) appeared to be harmless upon first use and withdrawal but the negative reaction to the second use implies that yo-yoing on paroxetine can be particularly harmful. This yo-yoing effect could be seen as a disorganized response to the conflicting positive and negative effects of paroxetine on mitochondrial function:
Paroxetine has the least activation of the sigma-1 receptor out of any SSRI, which suggests its ability to increase extracellular serotonin will lead to a high ratio of mitochondrial biogenesis to mitophagy, and this is consistent with rodent studies showing it increases markers of mitochondrial density.
While the hypoxia response usually opposes mitochondrial biogenesis, the unnatural level of extracellular serotonin achieved with SSRIs will activate both processes. Paroxetine’s lack of sigma-1 activation makes it deplete brain serotonin instead of increasing brain serotonin like the SSRIs that are powerful sigma-1 activators, which means it will increase the anti-respiration aspects of the hypoxia response without supporting the pro-respiration aspects mediated by intracellular serotonin and melatonin.
This individual was probably hyper-tolerant of the hypoxia response promotion due to his idiosyncratic mitochondrial pattern expected to suppress that response. So, the initial experience of paroxetine may have been simply balancing out the hypoxia response in his particular case, while its promotion of mitochondrial biogenesis may have been quite useful.
However, withdrawing from paroxetine could have caused a rebound decrease in mitochondrial density that created a greater vulnerability to the toxic actions of paroxetine that became evident upon reusing the drug. This could include the imbalanced hypoxia response, direct inhibition of mitochondrial serotonin receptors, and direct inhibition of respiratory chain complexes. While he may have initially tolerated the imbalanced hypoxia response, this tolerance could have been lost as a result of the rebound decrease in mitochondrial biogenesis.
Lexapro (escitalopram) shares with paroxetine (Paxil) the increase in extracellular serotonin and the promotion of respiration-impairing aspects of the hypoxia response. However, it is a ten times more powerful sigma-1 activator. It is nowhere near as powerful as fluovaxamine or sertraline, but it is much more powerful than paroxetine. This would be expected to balance mitochondrial biogenesis with mitophagy and to balance the hypoxia response with the preservation of respiration caused by intracellular serotonin and melatonin. However, it is also the most mitochondrially toxic of the SSRIs when compared head-to-head using isolated mitochondria. It is especially toxic toward complex IV compared to other SSRIs, and his complex IV was already hurt by his impairment in methyl group transport.
If the paroxetine yo-yoing effect was indeed caused by a rebound drop in mitochondrial density, then escitalopram’s stimulation of mitophagy via the sigma-1 receptor may have aggravated this with a further drop in mitochondrial density.
One thing we have to understand here is that, while the regulation of mitochondrial biogenesis is ordinarily stimulated by an energetic deficit, which signals a need for more mitochondria, the actual process of building new mitochondria is incredibly energy-intensive. It is anabolic. It cannot occur without energy no matter what the regulation says should be happening.
Given all that, this is the likely sequence of events:
The yo-yoing of paroxetine caused a rebound drop in mitochondrial density after the first withdrawal that flipped the response to a second use in favor of vulnerability to its mitochondrial toxicity.
This then caused energetic dysfunction that prevented the second use of paroxetine from rebuilding the lost mitochondria.
This then allowed the relative balance favoring of mitophagy by escitalopram to worsen this.
The lower mitochondrial content of tissues primed them to respond poorly to the higher mitochondrial toxicity of escitalopram.
The astounding benefits he obtained from his protocol were NOT based on trying to fix the catastrophic destruction induced by SSRI use, withdrawal, and switching, but rather on a coherent theory of his biochemical idiosyncrasies at the time I worked on his case informed by insights into which were genetic in nature based on the analysis of his whole genome sequencing. The lion’s share of the benefits were deducible from Mitome alone, though whole genome sequencing and nutritional/biochemical analysis enhanced the interpretation.
How much of this is generalizable across SSRI withdrawal? Let’s take a look at the literature.
In This Article:
* SSRI Discontinuation Syndrome
* Post-SSRI Sexual Dysfunction
* Prozac Withdrawal Causes Mitochondrial Dysfunction in Mice
* Near Infrared Light Reverses Ge***al Anesthesia
* Mitochondrial Dysfunction Tanks Testosterone
* Mitochondrial Dysfunction Causes Neurological Dysfunction
* How Common Is Mitochondrial Dysfunction as a Mediator of SSRI Discontinuation Syndrome and PSSD?
Click here to read the full article:
https://chrismasterjohnphd.substack.com/p/ssri-withdrawal-is-mitochondrial
