As another year ends and a new year begins, I want to wish you the happiest new year ever!
Today, we will answer this question:
"Is the serotonin hypothesis behind the use of Selective Serotonin Reuptake Inhibitors (SSRIs) for the treatment of depression valid or evidence-based?"
In addition, we will ask/answer these questions:
Do SSRIs cause withdrawal symptoms?
What are the potential molecular causes behind difficulties with tapering?
What has been helpful for psychotropic medication taper?
Without further ado, let's move on with a review of the cumulative research evidence behind psychiatry's current standard of care for depression.
Is the Serotonin Hypothesis Valid?
On SSRI dependency and withdrawal
In Nature (July 2022), an article entitled, The Serotonin Theory of Depression: a Systematic Umbrella Review of the Evidence (1), Moncrieff et. al. summarizes her extensive research on the serotonin theory of depression as follows:
This review suggests that the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis for depression.
This is consistent with research on many biological markers (2). We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.
In addition, this article states:
One study in this review found that antidepressant use was associated with a reduction of plasma serotonin (3), and it is possible that the evidence for reductions in SERT density and 5-HT1A receptors in some of the included imaging study reviews may reflect compensatory adaptations to serotonin-lowering effects of prior antidepressant use.
Authors of one meta-analysis also highlighted evidence of 5-HIAA levels [primary metabolite of serotonin] being reduced after long-term antidepressant treatment (4).
These findings suggest that in the long term, antidepressants might produce compensatory changes (5) that are opposite to their acute effects (6,7).
Lowered serotonin availability has also been demonstrated in animal studies following prolonged antidepressant administration (8).
Further research is required to clarify the effects of different drugs on neurochemical systems, including the serotonin system, especially during and after long-term use, as well as the physical and psychological consequences of such effects.
After years of research on the use of SSRIs that increase serotonin for the treatment of depression, it appears that the serotonin theory of depression is unjustified. Therefore, the use of SSRIs for the treatment of depression is not evidence-based.
With prolonged use, SSRIs harm the serotonin system and deplete this neurotransmitter, making it more difficult to taper from SSRIs. Increasingly, initial benefits from SSRIs fade away and are replaced by physical dependency due to a state of depletion (like other addictive drugs).
We now know that 95% of the serotonin system is produced in the gastrointestinal tract, so it follows that SSRIs' primary impact is in the digestive tract. Understanding this, we can infer that SSRIs will also harm the digestive system.
Once prescribed these medications, what happens to the patient? Since there is no formal psychiatric training or consensus for psychotropic medication withdrawal, many patients are told by their psychiatrists that they will need to stay on their medications for the rest of their lives.
If the current conventional approach remains unchanged, the negative consequences of prolonged SSRI exposure will eventually undermine the mental and physical health of millions of psychiatric patients all over the world.
Pharmaceutical companies like to minimize the harsh realities of psychotropic medication withdrawal by calling the often intense, crippling tapering process "discontinuation syndrome" to differentiate it from the "withdrawal syndrome" caused by other drugs.
However, in an article called Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review (9), Fava et. al., concludes:
Withdrawal "symptoms may be easily misidentified as signs of impending relapse. Clinicians need to add SSRIs to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with benzodiazepines, barbiturates, and other psychotropic drugs.
The term 'discontinuation syndrome' that is currently used minimizes the potential vulnerabilities induced by SSRIs and should be replaced by 'withdrawal syndrome.'
The "potential vulnerabilities" include the increased risk of suicide or homicide, loss of employment, marriage, or social connection, as well as the mental and physical incapacitation that can often result from mishandling psychotropic medication withdrawal.
In the New York Times article, Many People Taking Antidepressants Discover They Cannot Quit (10), Benedict Carey and Robert Gebeloff write about the challenges and suffering associated with antidepressant withdrawal.
In another article called, Depression: why drugs and electricity are not the answer (11), Read and Moncrieff make a case opposing the use of drugs and ECT for the treatment of depression altogether.
Over the past 20 years, I have been aware of these realities and focused on finding natural, effective solutions for healing mental illness and psychotropic medication withdrawal.
During this time, advances in functional and energy medicine brought clinical solutions to integrative practitioners that empower patients to heal from dependency and debility.
My integrative approach culminated last year in my ability to help a patient smoothly and successfully withdraw from six psychiatric medications over a year, using an integrative functional and energy medicine approach. She has been stable since March 2020.
Before using this integrative approach, she had five inpatient hospitalizations, two residential treatments, numerous psychotherapy sessions, and a suicide attempt. She was taking two antidepressants, a mood stabilizer, a benzodiazepine, an antipsychotic, and a beta-blocker.
After she began her holistic treatment, she improved, got off her medications, and remained well.
Both the process and content for healing mental illness and resolving psychiatric medication withdrawal were summarized in a case report called Successful Withdrawal from Six Psychiatric Medications Using Criteria-Based Energy Testing: Case Report and submitted to the 12th international ACEP Research Symposium happening on June 2023 in Baltimore, Maryland.
The report provides a summary of both the process and content involved in successful psychotropic medication withdrawal. I hope that you'll be able to join me at the ACEP conference in June!
For 2023, I will continue to share my evolving understanding of holistic, psychiatric healing from mental illness and medication withdrawal.
In the meantime, I hope you will explore the 210 other articles written in the past and available on my website to help you and your loved ones find a path to true freedom.
All the best,
Alice W. Lee, MD
References:
Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., & Horowitz, M. A. (2022). The serotonin theory of depression: A Systematic Umbrella Review of the evidence. Molecular Psychiatry. https://doi.org/10.1038/s41380-022-01661-0
Kennis, M., Gerritsen, L., van Dalen, M., Williams, A., Cuijpers, P., & Bockting, C. (2019). Prospective biomarkers of major depressive disorder: A systematic review and meta-analysis. Molecular Psychiatry, 25(2), 321–338. https://doi.org/10.1038/s41380-019-0585-z
Huang, T., Balasubramanian, R., Yao, Y., Clish, C. B., Shadyab, A. H., Liu, B., Tworoger, S. S., Rexrode, K. M., Manson, J. A. E., Kubzansky, L. D., & Hankinson, S. E. (2020). Associations of depression status with plasma levels of candidate lipid and amino acid metabolites: A meta-analysis of individual data from three independent samples of US postmenopausal women. Molecular Psychiatry, 26(7), 3315–3327. https://doi.org/10.1038/s41380-020-00870-9
Pech, J., Forman, J., Kessing, L. V., & Knorr, U. (2018). Poor evidence for putative abnormalities in cerebrospinal fluid neurotransmitters in patients with depression versus healthy non-psychiatric individuals: A systematic review and meta-analyses of 23 studies. Journal of Affective Disorders, 240, 6–16. https://doi.org/10.1016/j.jad.2018.07.031
Fava, G. A. (2020). May antidepressant drugs worsen the conditions they are supposed to treat? the clinical foundations of the oppositional model of tolerance. Therapeutic Advances in Psychopharmacology, 10, 204512532097032. https://doi.org/10.1177/2045125320970325
Kitaichi, Y., Inoue, T., Nakagawa, S., Boku, S., Kakuta, A., Izumi, T., & Koyama, T. (2010). Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats. European Journal of Pharmacology, 647(1-3), 90–96. https://doi.org/10.1016/j.ejphar.2010.08.026
Gartside, S. E., Umbers, V., Hajós, M., & Sharp, T. (1995). Interaction between a selective 5-HT1A receptor antagonist and an SSRI in vivo: Effects on 5-HT cell firing and extracellular 5-HT. British Journal of Pharmacology, 115(6), 1064–1070. https://doi.org/10.1111/j.1476-5381.1995.tb15919.x
Bosker, F. J., Tanke, M. A. C., Jongsma, M. E., Cremers, T. I. F. H., Jagtman, E., Pietersen, C. Y., van der Hart, M. G. C., Gladkevich, A. V., Kema, I. P., & Westerink, B. H. C. (2010). Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: Role of serotonin synthesis. Neurochemistry International, 57(8), 948–957. https://doi.org/10.1016/j.neuint.2010.10.001
Fava, G. A., Gatti, A., Belaise, C., Guidi, J., & Offidani, E. (2015). Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: A systematic review. Psychotherapy and Psychosomatics, 84(2), 72–81. https://doi.org/10.1159/000370338
Carey, B., & Gebeloff, R. (2018, April 7). Many people taking antidepressants discover they cannot quit. The New York Times. Retrieved December 21, 2022, from https://www.nytimes.com/2018/04/07/health/antidepressants-withdrawal-prozac-cymbalta.html
Read, J., & Moncrieff, J. (2022). Depression: Why drugs and electricity are not the answer. Psychological Medicine, 52(8), 1401–1410. https://doi.org/10.1017/s0033291721005031