Novel findings in the biology of depression: Is now the time to update the 60-year-old serotonin theory?

     Serotonin is a hormone produced by nerve cells from tryptophan, an amino acid which enters our body through our diet. Foods such as nuts, cheese and red meat are rich in tryptophan and hence, consumption of these products correlates with higher serotonin levels. Serotonin systemically affects our body, from motor functions to emotions. Serotonin in the brain is thought to regulate mood, anger, memory, sleep, appetite and relieve pain. Prior studies explored how dysregulation of the serotonergic system in utero and early in life may impact brain development and predispose to psychopathology such as depressive disorders. This research pinpointed the importance of genetic make-up and environmental stimuli in shaping the development and responses from the serotonergic system.

Image Credit: Image by Jennifer Marque from Pixabay

     Before the discovery of biogenic amines, such as noradrenaline and serotonin, as neurotransmitters in the brain in the 1940s, depression was thought of as an illness of the soul. These findings provided an impetus for subsequent research and importantly, depression gained clinical recognition. Nowadays, depression is known as the major depressive disorder (MDD) and affects 20% of women and 15% of men worldwide, who experience at least one depressive episode in their lifetime. MDD implies two or more weeks of diminished interest and depressed mood, followed by a decrease in appetite, insomnia, reduced concentration and prevailing thoughts of guilt and suicide. In 2017, according to the Lancet, depressive disorders were amongst the leading causes of years lived with disability (YLD) counts for both sexes combined. 

     The major theory of the role of serotonin in depression, “the serotonin theory”, dates from the 1960s. This theory states that decreased activity of synaptic serotonin drives the pathophysiology of depression. In this case larger numbers of serotonin transporter proteins would be expected to be expressed as they normally pump serotonin away from the cerebral neuron synapses.

     Generally, positron emission tomography (PET) scans, which produce elaborate 3-dimensional images of areas of interest inside the body, including the brain, are used for monitoring levels of serotonin transporters in MDD. However, due to low resolution of this imaging system with regard to observing small structures in the target area of the brain (median raphe) and variations in the results from individual studies, it was challenging to reach a firm conclusion. Importantly, there is a shortage of studies continuously examining serotonin transporter availability in depression over the duration of the disease, with symptoms alleviating in response to clinical interventions (pharmacological and non-pharmacological interventions).

Image Credit: Image by Gordon Johnson from Pixabay

     Researchers from the Department of Clinical Neuroscience of Karolinska Institutet in Sweden produced a comprehensive study by monitoring changes in the availability of serotonin transporters over the course of patient recovery from a depressed state. They examined changes in the behaviour of serotonin transporters in 17 patients with MDD, using internet-based cognitive behavioral therapy (ICBT), which was found to be as effective in treating illnesses with psychiatric comorbidities as pharmacological treatments. ICBT and regular data collection via molecular imaging studies allowed the investigation of the longitudinal course of serotonin transporter availability in MDD. Surprisingly, the findings of this study contradicted “the serotonin theory”, revealing that serotonin has a direct causal role in the pathophysiology of MDD since the number of cerebral serotonin transporters had increased when symptoms had been mitigated. As dysfunction of serotonin transporters in patients with depression reflected a temporary state, it was suggested that the serotonergic system might be part of the brain’s protection mechanism against depression.

     Antidepressants which are currently on the market block serotonin transporters, acting to preserve sufficient serotonin levels within the cerebral neuron synapses and hence preventing development of depression. The problem lies in delayed action and limited efficiency of modern antidepressants. Research into the interconnection between serotonin and depression could provide crucial information for the development of new improved drug therapies against depression. Further studies are being designed testing the dynamics of the serotonergic system as part of the brain’s defence mechanism against depression since the fundamental study possesses some limitations, hindering the veracity of the ground-breaking conclusions. For instance, this study involved only 17 participants with depression and the data from the control group was obtained only once. Furthermore, since between 76% and 85% of people in low- and middle-income countries do not receive any treatment for their condition, according to the WHO, global availability of treatments against depression is yet to be ensured.

     Overall, recent findings from a clinical study suggested that the brain can manipulate the number of functional serotonin transporters, thus combating depression. Thorough investigation of the brain’s protective response against depression could act as a platform for producing novel targeted therapies with potential to fully cure the major depressive disorder.

Written by Milena Flankova and edited by Shona Richardson

Milena is a 2nd year BSc Biological sciences student and you can find her on linkedin

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