Introduction- Much Ado About Bashing Serotonin’s Link to Depression…

Recently, a hot debate on the efficacy of antidepressants and the accuracy of the serotonin hypothesis of depression was once again stirred up. With the release of the results from a new analysis of a review of studies, the media’s headlines proclaimed that the whole concept was “debunked.” (source, source, source, source, source, source)

What does this mean for those with depression, people taking medications, mental health disorders, and psychiatry in general?

In this post and video, I’ll take a look at the study, what it does report and what got missed, and what its implications are for mental health.

Read on to enlighten yourself on why one pill, along one pathway, will never solve any brain health disorder.

The Sad State of Mental Health in America

Approximately 21% of adults reported experiencing a mental illness in 2019-2020. This is equivalent to over 50 million Americans. Depression is among the most common psychiatric diagnosis, affecting about 5% of adults, and a major cause of disability worldwide. Sadly, almost one-third (28.2%) of those suffering with these disorders were unable to receive the treatment they needed. (source, source, source, source)

Concerningly, our youth is also struggling. Over 1 in 10 young adults have depression so debilitating that it impairs their ability to function at school, work, with family, or their social life.

As a result of the recent world events and rising numbers of people with mental health symptoms, a national mental health crisis was declared.

Although more accessibility to treatments and resources is a noble interventional goal by our government, it only addresses half of the equation. More access is a great idea, but not if the treatment is ineffective and incomplete.

The Crash of the One Pill for a Mental Ill Mentality

According to an article in Neuroscience News, our current treatment for depression that hones in on serotonin has not been validated:

Despite the lack of direct evidence for disrupted serotonin signaling in the depressed brain, medications used to treat depression overwhelmingly target the serotonin signaling system to increase extracellular serotonin, also known as 5-hydroxytryptamine (5-HT).

Only about half of patients respond to antidepressants, and fewer than 30% experience total remission. A better understanding of 5-HT dynamics in depression could help guide more effective therapies.

Furthermore, many reviews have brought to light how biases and pharmaceutical funding could have skewed results in trials for antidepressants being any better than a placebo. One of the latest, from 2019, appears in BMJ Open.

This publication was a reanalysis of a previous systematic review with meta-analyses. It included 522 trials (116 477 participants) and clinical study reports for 19 of these trials. 21 different antidepressants were assessed across studies. The conclusion stated:

The evidence does not support definitive conclusions regarding the benefits of antidepressants for depression in adults. It is unclear whether antidepressants are more efficacious than placebo.

The (Recent) Study That Further “Debunked” the Serotonin Hypothesis

Recently, antidepressants and the whole serotonin and biochemical imbalance theory of depression was once again questioned, and this time more widely publicized. This was the result of a review of findings reporting no relationship between depression and serotonin levels, serotonin receptor function, and genetic variations in a serotonin gene.

Specifically, the research was based on a review of studies that reviewed studies, an umbrella review. The authors analyzed 17 studies: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study (using SERT, a serotonin transporter receptor variant), and 1 other umbrella review.

They assessed if any of the following were true in relationship to people with depression:

• Levels of serotonin and its metabolite 5-HIAA found in body fluids
• Serotonin receptor levels
• Levels of the SERT gene
• Tryptophan depletion (which lowers available serotonin)
• An interaction between the SERT gene and stress

The abstract conclusion reads:

The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.

Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

As you can imagine, the media had quite a field day with this study sparking controversy and debate among experts. (source, source, source, source, source, source)

What Wasn’t Reported About the Serotonin “Myth” Study

As noted above, one of the major issues with the much ado around the latest study on serotonin and depression is that it wasn’t new information. Although many media headlines portrayed the findings to be novel, big news, it really wasn’t for most psychiatrists. (source, source, source, source, source, source)

Many clinicians in the mental health field have been aware of the many lines of evidence that exist that demonstrate that depression is not a simple theory with one cause. These include animal studies, neuroimaging studies, twin and adoption studies, and inflammation research.

What was also not highlighted in the media from the study was that:

• There was some evidence that antidepressants did have an impact on depression, though the mechanism was not linked to serotonin.
• The effects of stressful life events, and their frequency, increased the risk of depression.
• There were some slight methodical flaws such as including large studies that did not employ conventional systematic review methods and one large genetic study which wasn’t an analysis.
• There is no biological marker for depression, only criteria.

This last factor deserves a whole separate section.

The Problems with the Tools to Diagnose Depression: Diagnoses Based on Symptoms, Not Dis-ease

With no biochemical marker to define mental health disorders, the Diagnostic Statistic Manual of Mental Disorders (DSM), based on symptom clusters, has been utilized by psychiatry. In 2013, with the release of the fifth edition (DSM-5), it was noted to have major problems such that the National Institute of Mental Health (NIMH) recommended to not use DSM diagnoses for biological research. This makes all studies using DSM criteria for addressing the biology of depression moot. (source, source, source)

Another issue with the tools to specifically diagnose depression is that the clinical scales used in studies are not objectively similar. As reported on Science News:

Fried looked at 52 depression symptoms across seven different scales for depression, including Hamilton’s scale. On average, each symptom appeared in three of the seven scales. A whopping 40 percent of the symptoms appeared in only one scale, Fried reported in 2017 in the Journal of Affective Disorders.

The only specific symptom common to all seven scales? “Sad mood.”

Therefore, we are not only not treating depression correctly, we also have issues of diagnosing the actual condition!

Psychology Today summarized the issue as follows:

So again this review is only documenting what is already known in general: Most DSM diagnoses, like MDD [major depression disorder], do not correlate with any biological measure, like serotonin.

Since SRIs improved depressive symptoms somewhat in clinical trials (though much less than people believe), it was assumed that depression had a basis in “low” serotonin.

This would be like saying that since aspirin is a prostaglandin inhibitor, and it reduces fever, then fever is a prostaglandin disorder. In fact, prostaglandin effects is just one way to reduce fever, and it is only a last step to reducing fever.

The real way to reduce fever is to stop the cause of fever earlier in the process, as with antibiotics for the bacteria that cause infections that produce fever.

The Many Factors of Mental Health

Brain health is multifactorial and complex. This is one reason why one can’t medicate depression away through manipulation of a single biochemical, such as serotonin.

For instance, I previously reviewed just some of the brain health factors to consider for any brain dysfunction:

• Inflammation and oxidative stress (e.g., several studies have shown IL-6, a cytokine marker of inflammation, to be elevated in depression)
• Nutrition and assimilation
• Dietary triggers and deficiencies (including cerebral folate deficiency)
• Mitochondrial dysfunction and imbalances
• Hormonal imbalances (Estrogen levels influence serotonin and progesterone impacts the calming neurotransmitter, GABA.)
• Stress & cortisol levels
• The microbiome (The microbiome communicates through the vagal nerve to the brain via microbiota metabolites. This impacts mood and nervous system tone.)
• Environmental toxicants (Heavy metals are associated with cognitive issues.)
• Blood sugar levels
• Stealth infections
• Childhood adversity
• Emotional tone and spirituality
• History of brain trauma or brain impact
• Genetic variations impacting neurotransmitter efficacy (such as SNPs, single nucleotide polymorphisms, related to MTHFR, DRD2, DRD4, COMT, CBS, and serotonin transporters (5HTT))
• Hyper or hypo-activity in a brain region
• Environmental stressors and technology overload
• Social support
• Mindset and beliefs
• Sleep
• Movement
• …and more!
  

Summary: Why You’re Mental Health Can’t Be Treated with One Pill

It’s become more obvious that one pathway can’t explain depression. Furthermore, depression is often defined as a cluster of symptoms, it’s not a disease that can be biologically or accurately measured. (Though brain function can be assessed.)

This means we must explore all the brain health factors and take an integrative approach to any mental health imbalance. In fact, balancing brain health factors should be considered as the foundation for anyone struggling with a mood or psychiatric issue. Clinicians should also be considering the literature and looking for newer associative patterns that affect their particular client or patient.

It is not a simple or short process. It takes some effort for both the practitioner and client. However, it’s the only way I ethically feel I can support my client’s brain health.

We must fully address the health of the organ that is causing the symptoms, not just trying to suppress the (non-agreed upon) symptoms with a pill.

Do you agree??

If so, please comment and share this information so others may become more informed and mental health treatment can be elevated.

In a follow up post, I’ll be addressing the various factors that can impact mental health and depression from an integrative perspective, including serotonin. The plot thickens! Stay tuned.

Naturopathic Medicine and Holistic Resources for Hormonal, Mood, and Digestive Support

• Free resources and more education on essential oils and mind-body wellness are available to you here.
• An Integrative Mental Health and Stress Resource Guide.
• Tools for coping with isolation and separation.

Stay Connected! Sign-up for my weekly newsletter.

Stay tuned for an upcoming opportunity that can support you in holistic mind-body-heart-soul healing. (Join my newsletter to learn more.)

Many blessings.

References

https://pubmed.ncbi.nlm.nih.gov/35854107/

https://www.psychologytoday.com/us/blog/mood-swings/202210/has-the-serotonin-hypothesis-been-debunked

https://www.psychologytoday.com/us/blog/side-effects/202207/decisive-blow-the-serotonin-hypothesis-depression

https://www.medscape.com/viewarticle/977753

https://www.ucl.ac.uk/news/2022/jul/analysis-depression-probably-not-caused-chemical-imbalance-brain-new-study

https://www.sciencenews.org/article/chemical-imbalance-explain-depression

https://www.mhanational.org/issues/state-mental-health-america

https://www.cdc.gov/nchs/fastats/depression.htm

https://www.whitehouse.gov/briefing-room/statements-releases/2022/03/01/fact-sheet-president-biden-to-announce-strategy-to-address-our-national-mental-health-crisis-as-part-of-unity-agenda-in-his-first-state-of-the-union/

https://www.nimh.nih.gov/health/statistics/major-depression

https://www.medicalnewstoday.com/articles/325767#Why-the-doubt?

https://bmjopen.bmj.com/content/9/6/e024886.full

https://pubmed.ncbi.nlm.nih.gov/34550588/

https://pubmed.ncbi.nlm.nih.gov/15087484/

https://www.psychologytoday.com/us/blog/abcs-child-psychiatry/202207/depression-and-serotonin-what-the-new-review-actually-says

https://www.psychiatrictimes.com/view/nimh-vs-dsm-5-no-one-wins-patients-lose

https://www.psychologytoday.com/us/blog/saving-normal/201305/nimh-vs-dsm-5

https://www.sciencedirect.com/science/article/abs/pii/S016503271631312X?via%3Dihub

http://www.ncbi.nlm.nih.gov/pubmed/24468642

http://www.hindawi.com/journals/omcl/2015/898393/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139933/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248201/

http://www.ncbi.nlm.nih.gov/pubmed/22579150

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640606/

https://medium.com/feed-your-brain/how-to-calm-your-overanxious-mind-6c9a8b0aa7f4

http://ndnr.com/anxietydepressionmental-health/toxicity-and-depression/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2740752/

http://www.sciencedaily.com/releases/2015/01/150120142817.htm

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2536546/

http://www.ncbi.nlm.nih.gov/pubmed/23775054

http://www.ncbi.nlm.nih.gov/pubmed/18628678

http://www.ncbi.nlm.nih.gov/pubmed/9603615

http://www.ncbi.nlm.nih.gov/pubmed/18628678

http://www.amenclinics.com/the-science/spect-gallery/attention-deficit-disorder-addadhd/

https://www.saratoga.com/healing-health-wellness/2018/02/social-relationships-heart-toxic-isolation/