Myth: Serotonin deficiency as a cause of depression?

What is known about the cause of the disease?

Today, it is assumed that the disease arises from an interaction of several factors (so-called multifactorial pathogenesis). According to this, there are both neurobiological influences that promote the occurrence of this psychological condition, as well as environmental triggers, especially on the psychosocial side.

On the neurobiological side, genetic factors in particular are associated with an increased susceptibility to the depressive illness. On this basis, a change on the stress hormone axis causes an imbalance of neurotransmitters in certain brain areas, which then bring about the depressive state. Therapeutically, attempts are made to treat these neurobiological factors by administering drugs (psychotropic drugs, especially antidepressants).

On the psychosocial side, early traumatic experiences in particular have been identified as susceptibility factors for a later depressive illness on the basis of the existing genetically determined vulnerability. Triggers that can lead to a depressive state are, for example, experiences of loss or chronic overload in the social spheres of reference (family, friends, professional environment, etc.). Therapeutic intervention is provided by psychotherapy, especially talk therapy.

It should be noted that the psychosocial and neurobiological sides are by no means opposites, but rather complement each other. Because of this, it would be wrong to claim that a depressive illness has only biological or only psychosocial causes. Therapeutic approaches have to consider both sides, which is the reason for today's common depression therapy with both pharmacological and psychotherapeutic treatment.

The serotonin hypothesis - the current state of knowledge

It has long been assumed, since the 1960s, that an imbalance in the serotonin balance leads to depressive disorders. This hypothesis led to the development of various drugs, most notably the so-called "selective serotonin reuptake inhibitors" (SSRIs for short) in the 1990s. These drugs were thought to increase a rise in serotonin in the synaptic cleft. The hypothesis that a simple lack of serotonin would lead to depressive disorders was soon outdated, as it soon became apparent that this simple explanatory approach fell short. As brain research progressed, a system of complicated interactions in brain metabolism emerged, the functional principle of which could not be precisely interpreted. Although the connection has been increasingly questioned in recent times, the persistent rumor that depressive disorders are associated with serotonin metabolism persists to this day. The hypothesis is still held and supported in major psychiatric textbooks.

New study massively shakes the serotonin myth

Assumptions and initial considerations of the new study

A study conducted by British psychiatrist and researcher Joanna Moncrieff and her team, published in July 2022 in the renowned journal Nature, shakes the hypothesis that a depressive illness is associated with imbalances in serotonin balance, however they occur, to its foundations.

The team around Moncrieff took up assumptions according to which a certain positive effect of SSRIs on the clinical picture is not due to their actual mode of action, but to an increased placebo effect or the property of SSRIs to generally limit or blunt emotions. Despite the high impact of the serotonin theory especially on the treatment of depressive disorders, there has been a lack of a comprehensive review summarizing the main findings on the theory.

Accordingly, the aim of this study was to conduct a systematic review of all the established evidence related to the serotonin hypothesis.

Research Design / Methodology

Due to the large number of research findings to be considered, a so-called "umbrella review" was conducted. This form of review provides an overview of systematic reviews and meta-studies already available in the respective research field. Due to the large amount of data processed and considered, these "umbrella reviews" represent one of the highest possible levels of evidence synthesis.

First, a review was conducted of such research reports that supported the serotonin hypothesis, from which six key questions were derived, such as whether depressed sufferers had lower serotonin levels compared with the nondemented normal population or whether depressed sufferers were shown to have significant alterations in receptors compared with the normal population.

The inclusion criteria for the research reviewed were selected to provide the best available evidence from the respective research field. Animal studies and those studies that dealt exclusively with depression resulting from physical illness, such as after a stroke, were excluded. No restrictions were placed on the language or year of publication of the respective study. From the research areas in which there had been no systematic review or meta-study within the last 10 years, the 10 most recent studies in the same field were included in the Umbrella Review.

Results

The Umbrella Review found no evidence of an association between altered serotonin activity and the occurrence of symptoms of depression. Although there was some evidence linking the disorder to a general inactivity of serotonin, the results of these studies were subject to large uncertainties, mainly as a result of small samples and possible confounding of results by prior antidepressant use. Also of low certainty were previous studies associating the disorder with tryptophan deficiency, whose power is also limited by inadequate study designs.

A comprehensive review of the major research contributions on the topic shows that there is no convincing evidence to support the hypothesis in which depression is associated with lower serotonin concentration or activity or caused by any association whatsoever.

Also, an extended hypothesis that adds external stress to the serotonin hypothesis cannot be confirmed as a result of the Umbrella Review. Instead, the results of some studies suggesting a weak link between the disease and serotonin balance or tryptophan deficiency are associated with the effects of prior use of antidepressants. However, this assumption could not be sufficiently substantiated due to a lack of consistent evidence throughout.

Interpretation of the results

The theory that a chemical imbalance in brain metabolism leads to depressive disorders can be considered extremely shaken by this "Umbrella Review". In particular, it calls into question the previously common approach of drug therapy using SSRIs. The results of the study even indicate that long-term use of these drugs can lead to a decrease in serotonin levels, which could mean that an increase in serotonin concentration in the blood is compensated for by the antidepressants and that the drugs thus have exactly the opposite effect to that which was actually intended. In contrast, the "Umbrella Review" shows that it is primarily stressful and traumatic life events that have a major impact on the risk of becoming depressed.

The research findings are of great importance for two reasons in particular: Firstly, the current treatment approach using SSRIs is called into question and may even be associated with long-term negative effects on the clinical picture. Secondly, there are implications for the self-image of sufferers and their often fatalistic attitude toward the illness. The long-held assumption that depression is due to a disorder of brain metabolism has deprived many sufferers of the prospect of improving their condition, especially without taking medication on a long-term basis. Recent research now shows that rather than imbalances in brain metabolism, traumatic life events are associated with depressive illness. Further research will have to show which treatment approaches can most effectively alleviate symptoms of this serious condition. After the long misguided path concerning treatment with SSRIs, the study, with its indications of primarily psychosocial causes, could set new impulses in the field of psychotherapy or talk therapy.

Nevertheless, patients should never stop taking antidepressants without consulting their therapists.

Conclusion

For a long time, depression has been associated with brain metabolic dysfunction. Medications, especially SSRIs, are still considered the "gold standard" for treatment. This "Umbrella Review" shakes the serotonin hypothesis to its foundations and even provides evidence that SSRI use leads to adverse long-term effects on the clinical picture. Instead, there are indications that treatment concepts should focus more on dealing with external events from the psychosocial sphere.