Revisiting the serotonin theory of depression

October 2023

Commentary — A critical analysis of the Campfire Session at the 36th ECNP Congress 2023

Explore the latest insights from the #ECNP2023 Campfire Session CA21 'Serotonin and Depression - where do we stand?' through the eyes of Dogukan Koc, an early career researcher from the SEROTONIN and BEYOND EU project and PhD candidate at the department of child and adolescent psychiatry/psychology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.

The 36th ECNP Congress 2023 featured a session that explored the longstanding question of whether serotonin, a neurotransmitter traditionally linked to modulating mood, cognition, reward, learning, memory, and numerous physiological processes, acts as a causal factor in depression. The Campfire Session, guided by British psychiatrist, Professor Philip J. Cowen, provided attendees with an insightful exploration of extensive research and discussions spanning several decades on this crucial topic. The session gathered over 50 international researchers, clinicians, and experts in the fields of psychiatry and neuroscience to discuss on the nuanced relationship between serotonin and depression.

Rethinking the serotonin theory
At the heart of this campfire session, a recent review by Moncrieff et al (2022) that challenged the serotonin theory of depression was discussed (1). Led by Professor Cowen and his colleagues, this session disagreed that there's no solid proof linking serotonin to depression (2,3). Throughout the session, Professor Cowen aimed to shed light on the review's shortcomings, including its methodological issues and the oversimplification of serotonin's role in depression.

The session emphasized the nuances related to the methodological aspects of the review. The critique pointed out significant flaws, including the arbitrary setting of criteria for grading the quality of evidence, leading to questions about the reliability of the review's conclusions. These observations emphasized the significance of following established protocols and criteria in psychiatric research to guarantee robust and reliable results.

The Campfire Session also highlighted the importance of tryptophan depletion studies, which are a crucial part of the serotonin theory. The critique underscored that these studies, which investigate the effects of lowered serotonin levels, were not given sufficient consideration in the original review. In particular, the exclusion of data demonstrating a distinct effect of tryptophan depletion in patients with major depressive disorder who were not using antidepressants has raised substantial concerns. This exclusion reminds us of the necessity of including all relevant data to fully understand serotonin's role in depression. In essence, the omission of such data in the review leaves us with an incomplete picture of serotonin's function in depression.

Another key topic of debate revolved around the interpretation of molecular imaging data related to serotonin receptors. The analysis challenged the review's oversimplification of findings in this area, highlighting the intricate nature of serotonin receptor pharmacology. These discussions underscored the complexity inherent in the field, where multiple factors can influence receptor binding. This complexity encompasses aspects such as the specific receptor subtypes, regional variations in the brain, and the potential impact of external factors. It entails a need for researchers to consider these multifaceted elements, ensuring that interpretations are not overly simplistic and reflect the nuanced reality of serotonin receptor functioning.

Implications for clinical practice
Professor Cowen briefly summarized the discussion by stating that impaired brain serotonin activity does not play a necessary or sufficient role in causing depression. However, in individuals who are prone to depression due to their history of previous episodes of illness, low levels of serotonin may play a role in the development of relapse (4). This nuanced perspective emphasizes that the connection between serotonin and depression may be more complex than previously believed, especially in individuals with a history of depression.

The way forward
The session at the 36th ECNP Congress 2023 provided us with a comprehensive insight into the serotonin theory of depression. It highlighted critical areas that demand our attention as we navigate the dynamic landscape of psychiatric research. To chart a clearer path forward, several key points need to be addressed:

  1. Methodological rigor: Ensuring that research in the field adheres to established protocols and criteria, promoting robust and reliable results.
  2. Comprehensive data inclusion: Emphasizing the need to include all relevant data in future studies to achieve a holistic understanding of serotonin's role in depression.
  3. Complexities of serotonin receptors: Acknowledging the intricate nature of serotonin receptor pharmacology, which involves various receptor subtypes, regional variations in the brain, and external factors.
  4. Clinical implications: Understanding that the role of serotonin in depression is more complex than previously believed and may vary in individuals with a history of depression.

These key points represent the way forward in our exploration of the serotonin theory of depression. They call for a focused, systematic approach to research, encouraging collaboration and in-depth examination among psychiatrists, neuroscientists, and researchers worldwide.

In addition to the lively debates and critical analyses of the serotonin theory, it is important to acknowledge the pioneering efforts of the "Serotonin and Beyond" consortium project (5), which aligns seamlessly with the themes explored during the 36th ECNP Congress 2023. This project goes beyond conventional research by providing interdisciplinary training, utilizing brain organoids, translational rodent models, unique human databases, and cutting-edge techniques. It aims to uncover how serotonin-mediated developmental processes influence the risk of psychiatric disorders. As we dig deeper into the mysteries of the serotonin theory, the "Serotonin and Beyond" project reminds us of all the unexplored knowledge waiting for us.

Disclaimer
Dr Koc was funded by the Marie Skłodowska-Curie Actions Innovative Training Network (MSCA-ITN) programme (Serotonin and BEYOND, Grant agreement No: 953327). The author report no pharmaceutical industry funding.

Reference
1. Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA (2022): The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 1–14.
2. Jauhar S, Cowen PJ, Browning M (2023): Fifty years on: Serotonin and depression. J Psychopharmacol 37: 237–241.
3. Jauhar S, Arnone D, Baldwin DS, Bloomfield M, Browning M, Cleare AJ, et al. (2023): A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression. Mol Psychiatry 1–4.
4. Smith KA, Fairburn CG, Cowen PJ (1997): Relapse of depression after rapid depletion of tryptophan. The Lancet 349: 915–919.
5. About our study - Serotonin and BEYOND (2021, February 16): Retrieved October 20, 2023, from this website page.