The serotonin theory of depression: a post-mortem analysis
5 January 2024
This piece was written in collaboration with Aryan Arora and originally published in Vol XI Issue 1 of the RUMS Review Magazine. The full issue is available here.
Major depressive disorder, commonly referred to as depression, lies in the unfortunate realm of conditions which are simultaneously widespread, debilitating, stigmatised, and poorly understood. It is one of psychiatry’s paradigm-defining maladies; being the most common mental illness, it affects more than 264 million people globally and is the second leading cause of chronic disability worldwide. Its enigmatic nature has occupied minds both medical and artistic for millennia, from Hippocrates’ “humoral melancholia” to the “anomie” of the Romantics. Contemporary understandings emphasise a triad of symptoms: low mood, anhedonia (inability to feel pleasure in normally pleasurable activities), and fatigue.
In contending with this enigmatic condition, few theories have sparked as much debate and introspection as the serotonin hypothesis of depression. This enduring view, which posits a causative association between brain serotonin levels and depression, has recently come under intense scrutiny, compelling a reevaluation of not only the theory itself, but also the broader psychiatric paradigms it influenced.
The origins of the serotonin hypothesis are deeply rooted in the monoamine hypothesis, a theory which emerged in the 1950s and 1960s. This hypothesis was born from a confluence of serendipitous pharmacological discoveries and the burgeoning field of neurochemistry. Initially, researchers observed that drugs which depleted monoamine neurotransmitters, such as norepinephrine and serotonin, often induced depressive symptoms, while drugs that increased their levels seemed to have mood-elevating effects. This led to the conjecture that depression could be the result of a deficiency in monoamine neurotransmitters.
As research progressed, the focus sharpened on serotonin due to its widespread influence in the brain and its role in mood regulation. The discovery that reserpine, a medication that depleted serotonin levels, could induce a depression-like state in some patients, further cemented the link between serotonin and mood disorders. Over time, this generalised monoamine hypothesis evolved into a more specific serotonin hypothesis, leading to the development of selective serotonin reuptake inhibitors (SSRIs). These drugs, designed to specifically target serotonin reuptake, were seen as a vindication of the serotonin-centric view of depression, marking a significant shift in psychiatric tre atment paradigms. This discovery was more than just a scientific observation— it was a narrative that resonated deeply with both the medical community and the public. It offered a simple, tangible explanation for an otherwise elusive and complex condition.
As this theory began to be canonised into the default explanatory toolkit of psychiatrists, prescription of SSRIs became synonymous with the management of depression and associated affective disturbances. Beyond pharmacology, the serotonin hypothesis became a cornerstone of the biopsychosocial model in psychiatry. It conveniently folded biological factors in with psychological and environmental ones, painting a multifaceted picture of mental illness and softening the reductionist intensity of this biochemical narrative.
We are, however, seeing a critical counter-narrative take shape and challenge this established perspective. Although these scientific and philosophical discontentments with the status quo are not new in psychiatry, the recent Nature umbrella review by Moncrieff et al. conducted at UCL has brought them into sharp relief. Their analysis suggested that the relationship between serotonin and depression was far more complex and less direct than previously believed. It included 17 studies comprising systematic reviews, meta-analyses, and large dataset analyses, and found no consistent evidence supporting the association between serotonin and depression, nor did it support the hypothesis that depression is caused by lowered serotonin activity or concentrations. The review also highlighted that some evidence suggested long-term antidepressant use might reduce serotonin concentration.This revelation sparked a series of debates and discussions within the psychiatric community, revealing deeper issues within psychiatric epistemology.
Historically, clinicians have brought the biopsychosocial model into clinical practice via a “perspectivism” which allows them to maintain a pluralistic understanding of the psyche without collapsing into an overly reductive and single-minded school of thought. This ideally serves as a dynamic synthesis of the many schools of therapeutic thought, which privileges the utility of these narratives in situ over fervent adherence to a particular method. What this review perhaps reveals is that this perspectivism unintentionally functions as a conversational stopping point— instead of allowing the resolution of biological, psychological, and social factors into a coherent model, it holds them in an unstable superposition of “perspectives’’, never allowing them to make contact with reality. Despite its appealingly holistic approach, it suffers from a lack of clarity in integrating its diverse components: the biological explanations are given tacit priority over the socio-psychological conditions, often purely as a result of medicated treatment being more expedient and less costly than more multifaceted psychotherapeutic and community-based approaches.
Though it was intended to generate a richer understanding of the patient experience and avoid propagating false certainty, this raises concerns about the potential dilution of empirical standards in psychiatric research. The practice of psychiatry has always involved an intricate dance between the empirical and the subjective, but the separation of the ‘clinical art’ from scientific practice raises essential questions about how we reconcile the broader paradigm of evidence based medicine with the need for deeply individualised care that honours the subjectivity of psychiatric disorders.
The saga of the serotonin theory of depression is emblematic of the broader challenges faced by psychiatry as a field. It is a confluence of multitudes held in delicate equilibrium: the necessity for empirical rigour in the laboratory must always be counterbalanced by a profound appreciation for subjectivity in the clinic. Biopsychosocial perspectivism is more necessary than ever to navigate the radically widening field of possibilities in mental health treatment, but it mustn’t enjoy a lack of empirical restraint or give in to facile explanations of endlessly complex mental phenomena. It is in threading this conceptual needle that we may stitch together a richer and more complete tapestry of the maladies of the mind.