- Serotonin is a neurotransmitter associated with mood regulation and has been linked to depression.
- The serotonin-deficiency hypothesis has been the basis for understanding depression but has faced criticism.
- Some studies suggest a reduction in serotonin release capacity among depressed individuals.
- The psychedelic experience, mediated by serotonergic agonists, shows promise in treating depression.
Depression is a common mental health condition that continues to challenge researchers and clinicians in the quest for effective treatments. Serotonin, a neurotransmitter often associated with mood regulation, has long attracted significant attention. The relationship between serotonin and depression has been oversimplified at times, but recent recognition of serotonergic agonists—agents that stimulate the serotonin receptor—as potential treatments has brought renewed interest in the problem.
Serotonin's reputation as the "feel-good" neurotransmitter
Serotonin is a neurotransmitter involved in the modulation of many key biological functions studied in animals, such as sleep, appetite, cognition, and mood regulation. Its function in regulating animal behavior has been summarized as promoting behavioral inhibition, or the preference of passive over active responding.
More recently, this idea has been modified to emphasize patience or persistence to carry out an action that is itself costly or unrewarding but helps lead to delayed benefit. This work helps us to appreciate that equivalent functions in humans—concentrating on getting a complex task completed, for example—are likely to be associated with subtle issues around motivation and reward for which mood may be an important emergent consequence.
The recognition that the first drugs to treat depression influenced the activity of monoamine neurotransmitters, such as serotonin and noradrenaline, led to the simplistic hypothesis that the symptoms of depression are caused by insufficient levels of monoamines within the brain. Fifty years on, the serotonin-deficiency hypothesis still forms the basis of many people’s understanding of depression. While not completely wrong, it is too broad a brush to be completely right, and it has invited criticism.
The basis for a serotonin-deficiency hypothesis
The development of the serotonin-deficiency hypothesis was a very early result of the seminal studies of monoamine neurotransmission in the 1950s. Alec Coppen, an early clinical proponent, referenced a study that observed decreased serotonin levels in the post-mortem brains of depressed individuals who died by suicide, as compared to nondepressed individuals who died of natural causes.
Coppen was also arguably the first person to base a novel pharmacological strategy on the serotonin-deficiency hypothesis when he added tryptophan to a monoamine oxidase inhibitor to augment antidepressant treatment. Tryptophan is an essential amino acid and the precursor of serotonin. Actual depletion of tryptophan was also shown to induce depressive symptoms both in patients being treated for depression and in drug-free patients in remission. This is still the best evidence in humans for a direct link between serotonin and mood disorder.
The development of selective serotonin reuptake inhibitors (SSRIs) for the treatment of anxiety and depression was partly informed by the serotonin-deficiency hypothesis. Drugs like SSRIs can increase serotonin availability quite specifically yet work through indirect pathways, just as we can treat heart failure by using drugs that target the kidney. Nevertheless, it was very tempting to communicate about SSRIs as if they were correcting an actual deficiency by increasing serotonin availability in the brain through the inhibition of the serotonin reuptake site or transporter. This could not be directly tested because the brain in humans is largely inaccessible to chemical measurements, especially at very low concentrations.
With advancements in imaging techniques, we are now better able to measure serotonin release in live human participants. A recent study used a serotonin 5-HT2A receptor agonist radio-labeled to investigate serotonin release capacity in the frontal cortex of individuals with depression. The findings suggested a significant reduction in serotonin release capacity among patients with depression compared with a healthy control group. If confirmed, this research supports the findings of the tryptophan-depletion studies, suggesting that serotonin release is impaired in individuals with depression.
The limitations and controversies surrounding serotonin as the sole culprit in depression.
So, is serotonin deficiency a cause of depression? Does this explain the treatment effects of SSRIs? This simple formulation has attracted criticism of various kinds. Some authors deny that any drug can treat depression, despite large-scale meta-analyses of the relevant clinical trials suggesting that they consistently do. The denial is usually framed as criticism of clinical trials that use placebo, because patients may be unblinded or the modest differences between drug and placebo may not be clinical;ly relevant.
The mechanism has never been as clear cut as, for example, how insulin deficiency results in diabetes, which can then be treated with insulin. Instead, it links to the profoundly interesting problem of how we should think of mood as an emergent property of the brain.
Recently questions have been raised about the credibility of any of the evidence for a contribution of the serotonergic system to depression. A recent review, which brought together a range of different kinds of experimental studies (under a single umbrella, so to speak) contradicted the interpretation of the relevant tryptophan-depletion and imaging studies by their original authors. It also stated that more recent studies showed “no effect of tryptophan depletion on mood”, although earlier studies clearly had.
Jaugar et al (2023) have offered a rebuttal to both the methodology and the conclusions of the critique—there are holes in the umbrella. It seems likely that serotonin deficiency is associated with depression and its treatment, but we have a long way to go in understanding the relationship properly. There is no more reason for nihilism than there is for oversimplification.
Have we been missing the impact of the psychedelic experience for the serotonin deficiency hypothesis?
In the 1970s, clinical research on the serotonergic agonists that produce psychedelic experience was shut down. It resulted in a collective failure to remember the potent effects of serotonergic agonists in treating psychiatric disorders, including depression. SSRIs improve symptoms in only around half of people with depression. Even if patients do find SSRIs to be beneficial for their symptoms, a high number experience significant adverse effects, and there are high discontinuation rates. Patients who have experienced difficulty with first-line drugs are an urgent unmet need.
There is a growing body of evidence from clinical trials and experimental studies showing that serotonin agonists, which induce a psychedelic experience through 5-HT2A receptor binding, have significant mood-elevating effects. Trials of the agents have also demonstrated rapid and enduring effects on the symptoms of patients with depressed mood and are particularly promising for those patients that do not find SSRIs to be beneficial. Such promising effects correlate with positive rather than negative imaginal experiences under the influence of the most commonly studied drug, psilocybin. We can say with some confidence that these effects again directly implicate serotonin in the treatment of depressed patients.
Serotonergic brain pathways play a significant role in mood regulation. Some kind of serotonin deficiency may be implicated in the development and maintenance of depression. Treatment with SSRIs suggest that increased serotonin availability may be an effective treatment for many patients, but not all. There is substantial unmet clinical need. The psychedelic experience is mediated by agonists at serotonin receptors and may illustrate both the complexity of serotonin’s contribution to the human mind and its direct effects on affective experience. The potential for enhanced clinical outcomes in patients given psychedelic serotonergic agonists is a source of great interest and optimism.
Guy Goodwin, DPhil, FMedSci is Chief Medical Officer at COMPASS Pathways. He completed his medical degree and DPhil in physiology at the University of Oxford and, following training in psychiatry, worked as Clinical Scientist at the MRC Brain Metabolism Unit in Edinburgh for 10 years. He moved back to Oxford as head of the department of psychiatry and subsequently as a senior research fellow. His work has always included care of outpatients along with a primary commitment to research. He is a Fellow of the American College of Neuropsychopharmacology, and has previously held the position of President of the British Association for Psychopharmacology, President of the European College of Neuropsychopharmacology (ECNP), and Senior Investigator on the faculty of UK National Institute for Health Research (NIHR).