Beyond Serotonin

We often assume mood disturbances are due to serotonin issues. But what if it’s not a serotonin issue? The fact that the vast majority (about 70%) of individuals who take SSRIs don't find significant relief would indicate there's more to the story than serotonin. Furthermore, amongst those that benefit from these meds, roughly half relapse back into depression within a year's time…even if they remain on the medication. This is telling.

Serotonin imbalances are just one piece of a larger puzzle. Symptoms often result from a combination of neurotransmitters including dopamine, norepinephrine, GABA, glutamate, and histamine-not one or two in isolation. Symptoms may arise from imbalances in all of them, a unique combination, or even none at all. Understanding the root causes requires investigating the broader context of metabolism, inflammation, hormone regulation, gut health, and environmental stressors. This line of inquiry highlights a central theme in functional medicine: asking “why” rather than “what” when striving to understand symptoms and provide support.

This question encourages us to move beyond a purely reductionist perspective and consider the interconnectedness of the biological, psychological, and social dimensions of health in order to determine the root causes of mental health challenges. It invites us to explore not only neurotransmitters but also the broader picture of an individual's existence–including their life, mind, societal context, health history, and the body’s functioning holistically.

The Role of Serotonin in Mental Health

To take a quick step back, it does make sense to assume serotonin may be part of the picture, some of the time, and for some people. What’s clear is that its influence isn’t uniform in all people, all the time. Serotonin is most commonly associated with the monoamine hypothesis of depression, which suggests that imbalances in serotonin, dopamine, and norepinephrine contribute to mood disorders (Cowen & Browning, 2015). We know these neurotransmitters play an important role because of a range of findings, including the mechanism of action of antidepressant medications, animal models of depressive-like behavior, and associations between neurotransmitter levels and mood symptoms. Going “Beyond Serotonin” doesn’t mean “forget” serotonin. It just means remember the bigger picture and overall balance.

Neurotransmitter balance supports feelings of well-being, safety, and contentment. Some symptoms of imbalance include:

● Serotonin deficiency: low mood, anxiety, obsessive thoughts, sleep disturbances

● Serotonin excess: agitation, confusion, or serotonin syndrome in extreme cases

● Dopamine deficiency: fatigue, anhedonia, lack of motivation

● Dopamine excess: psychosis, impulsivity, paranoia

● Norepinephrine deficiency: low energy, brain fog, poor concentration

● Norepinephrine excess: anxiety, hypervigilance, panic

Common medications like SSRIs, SNRIs, and dopaminergic agents target these systems, often in combination for treatment-resistant cases. Polypharmacy is common, with up to 40% of adults on antidepressants also taking another psychiatric medication without strong evidence for combined use (Bennett et al., 2020). Long-term use is the norm, yet many do not achieve remission after initial trials (Trivedi et al., 2006).

The Scope of Mental Health Challenges

Globally, mental health conditions are widespread. Nearly 1 billion people were living with a mental disorder in 2019, and nearly half of the global population is likely to experience at least one mental disorder by age 75 (WHO, 2019; Charlson et al., 2023). Despite the rise in prescriptions, many individuals do not find lasting relief. This underscores the need to look beyond serotonin alone.

Beyond the Brain: The Body’s Role

About 90–95% of the body’s serotonin is produced in the gastrointestinal tract, primarily by enterochromaffin cells using tryptophan as a precursor (Yano et al., 2015). Metabolic conditions frequently co-occur with mental health disorders, and mitochondrial dysfunction may link these comorbidities, affecting energy metabolism and cellular signaling (Picard et al., 2018). Peripheral neurotransmitters can influence mitochondrial function, further connecting metabolic and mental health.

Additional contributing factors include inflammation, hormonal imbalances, gut dysbiosis, trauma, psychosocial stress, environmental influences, the gamut of lifestyle practices, and foundational perceptions or beliefs.

Heterogeneity and Comorbidity

Mental health conditions are highly heterogeneous. Depression, for example, manifests differently across individuals in terms of symptoms, severity, and duration. Comorbidities such as anxiety, PTSD, ADHD, and metabolic disorders are common, demonstrating the interconnected nature of physical and mental health (Fried et al., 2015).

These variations highlight why one-size-fits-all approaches are often ineffective. Personalized, integrative care targeting root causes is essential. Symptoms are often the result of underlying imbalances, much like plants failing to grow due to poor soil or insufficient sunlight rather than a problem with the seeds themselves.

Functional Assessments

Investigating mood imbalances requires a systematic approach. First, serotonin needs to be reverentially dethroned as the king of mental health. Remember, it’s obviously important and has a role, but focusing on it alone or in isolation hasn’t proven effective for the majority. To balance serotonin, or any neurotransmitter, biomarker or health metric for that matter, balance the whole body, mind, and lifestyle.

● Nutritional factors: inadequate protein intake or deficiencies in iron, B6, folate, cobalamin

● Digestive factors: low stomach acid, pancreatic insufficiency, impaired enzyme activity

● Metabolic factors: blood sugar dysregulation, insulin resistance, oxidative stress

● Immune and inflammatory factors: systemic inflammation, neuroinflammation

● Detoxification issues: liver dysfunction, heavy metal accumulation

● Lifestyle factors: chronic stress, sleep disturbances, sedentary behavior

● Genetic factors: mutations such as MTHFR affecting methylation and nutrient activation

Functional health addresses these contributors through personalized lab testing, lifestyle analysis, and targeted interventions, often using Diet, Rest, Exercise, Stress reduction, and Supplements.

Integrating Serotonin Support

Serotonin-focused interventions should be integrated with broader health strategies and tailored  to the individual while adhering to evidence-based principles. This may include dietary optimization, GI restoration, hormone balancing, stress reduction, meditation, cofactors, omega-3 fatty acids, adaptogens, and amino acid supplementation such as 5-HTP when indicated. Addressing root causes while supporting neurotransmitter function creates a comprehensive approach to mental health restoration.

Cultivating Hope and Healing

A functional approach provides clarity, explaining why symptoms occur in the first place and identifying actionable strategies for improvement. The path to health and happiness is multi-dimensional but achievable. Empowering individuals to move beyond symptom management to holistic well-being and no longer viewing symptoms, signals, body, mind, and life in isolation is a good start.

If you would like support integrating a personalized approach to mental health through functional medicine, please book a complimentary consultation at seedtofruit.health

References

Bennett, H. S., et al. (2020). Polypharmacy in U.S. adults on antidepressants. JAMA Network Open, 3(9), e2017270.

Charlson, F., et al. (2023). Global epidemiology of mental disorders. The Lancet Psychiatry, 10(1), 20-35.

Cowen, P. J., & Browning, M. (2015). What has serotonin to do with depression? World Psychiatry, 14(2), 158–160.

Fried, E. I., et al. (2015). Heterogeneity and comorbidity in depression. World Psychiatry, 14(3), 299–301.

Mojtabai, R., & Olfson, M. (2017). National trends in long-term antidepressant use. JAMA, 317(7), 720–732.

Picard, M., et al. (2018). Mitochondrial dysfunction and psychiatric comorbidities. Biological Psychiatry, 83(6), 491–500.

Trivedi, M. H., et al. (2006). STAR*D trial: Outcomes with citalopram for depression. American Journal of Psychiatry, 163(1), 28–40.

World Health Organization. (2019). Mental health: Strengthening our response. Retrieved from https://www.who.int/news-room/fact-sheets/detail/mental-health-strengthening-our-response

Yano, J. M., et al. (2015). Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 161(2), 264–276.